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DISORDERS INCLUDED ON INHERIGEN PLUS PANEL

Congenital adrenal hyperplasia due to 17-alpha-hydroxylase/17,20-lyase deficiency is an autosomal recessive disorder which results in impaired production of cortisone and sex hormones. This results in hypertension and low serum potassium. Untreated, females do not develop breasts and pubic hair, and do not begin to menstruate at puberty. Males have incomplete sexual development at birth and may appear to be female or of uncertain gender. Untreated, affected males develop breast enlargement (gynecomastia) at puberty. Treatment is possible by providing the hormones that the body would normally produce. This rare disorder is more common in Mennonites and in parts of Brazil.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, commonly known as HMG-CoA lyase deficiency, is a rare inborn error that affects ketogenesis and leucine catabolism. Symptoms usually appear in the first year of life and include metabolic acidosis with hypoketotic hypoglycemia, hyperammonemia, abnormal liver function tests, vomiting and hypotonia. Other signs are hepatomegaly, macrocephaly, and less frequently microcephaly, seizures, acute pancreatitis, dilated cardiomyopathy and arrhythmia. Abnormal cerebral white matter foci on MRI has also been reported. Without treatment, rapid progression to coma and death or permanent neurological damage may occur. With treatment, many patients do well; however recurrent metabolic decompensation continues to occur especially with prolonged fasting or intercurrent illness. This disorder is fatal in approximately 20% of cases with the symptoms becoming milder after childhood.
6-Pyruvoyl-tetrahydropterin synthetase (PTPS) deficiency is an autosomal recessive neurological disorder that usually presents with elevated phenylalanine on newborn screening. In addition to elevated phenylalanine levels, levels of several neurotransmitters are reduced, which, when untreated, results in neurologic abnormalities that are typically severe, but can sometimes be milder and of later onset. Treatment consists of controlling the phenylalanine level and providing neurotransmitter replacement. The condition is more commonly identified in individuals of Chinese ancestry, but is present in other ethnic groups where consanguinity is common.
Abetalipoproteinemia is an autosomal recessive disorder that presents in neonates and infants with intestinal malabsortion, leading to neurologic abnormalities and retinitis pigmentosa which are, in part, related to deficiency of fat soluble vitamins. Red cells have a distinctive burr shape. Treatment consists of limiting dietary fat and supplementation with vitamin E. Abetalipoproteinemia is more common in the Ashkenazi Jewish population, but has also been described in many other populations as well.
Achromatopsia is a rare congenital autosomal recessive disorder. This disorder is characterized by a complete inability to discriminate colors, a low visual acuity, nystagmus, and photodysphoria (extreme photophobia) under daylight conditions. Examination of these patients by ophthalmoscope reveals a mild foveal hypoplasia, while ERG recordings and psychophysical tests reveal absent photopic responses and intact scotopic responses (Kohl et al., 2005, Kolh et al., 2000, Sundin et al., 2000, Wiszniewski et al., 2007). Mutations in the CNGA3, CNGB3, and the GNAT2 genea, have been shown to cause achromatopsia.
ADA deficiency is associated with an autosomal recessive form of severe combined immune deficiency (SCID) in which B, T, and NK cells are deficient. Bacterial, viral and fungal infections are common and often life-threatening, but there is a wide range of severity and age of onset. Diminished red cell adenosine deaminase activity is diagnostic, correlating with deoxyadenosine toxicity in lymphocytes. Enzyme replacement, bone marrow/stem cell transplantation, and gene therapy have been used successfully for treatment
ADA deficiency is associated with an autosomal recessive form of severe combined immune deficiency (SCID) in which B, T, and NK cells are deficient. Bacterial, viral and fungal infections are common and often life-threatening, but there is a wide range of severity and age of onset. Diminished red cell adenosine deaminase activity is diagnostic, correlating with deoxyadenosine toxicity in lymphocytes. Enzyme replacement, bone marrow/stem cell transplantation, and gene therapy have been used successfully for treatment
Agenesis of the corpus callosum with peripheral neuropathy, also referred to as Andermann syndrome, is an autosomal recessive disorder affecting the nerves and characterized by absent reflexes, progressive wasting of muscle tissues, low muscle tone, and weakness. There is absence or malformation of a structure in the brain called the corpus callosum, and this is identified by various brain imaging techniques. Affected children develop the ability to walk around age three, and usually lose that ability in adolescence. Mild to severe intellectual disability is common, and psychotic episodes may occur during adolescence. Individuals with this condition often have distinctive facial features, scoliosis, tight Achilles’ tendons, and seizures. Death generally occurs in the second through fourth decades of life. There is no specific treatment for this condition. Agenesis of the corpus callosum with peripheral neuropathy is most commonly reported in individuals with French-Canadian ancestry, more specifically individuals from the Saguenay-Lac-Saint-Jean and Charlevoix regions of Northeastern Quebec.
Alport syndrome affects the ears, eyes, and kidneys. Alport syndrome causes progressive sensorineural hearing loss. Ocular changes in Alport syndrome include anterior lenticonus, maculopathy, posterior polymorphous dystrophy, and recurrent erosion of the cornea. Renal disease associated with Alport syndrome is progressive.
Antley-Bixler syndrome is an autosomal recessive disorder characterized by severe skeletal malformations, including a very misshapen skull and joint contractures.
Argininosuccinic aciduria (ASA) is a disorder of the urea cycle. Patients may present at any age, but onset is typically in the neonatal period or late infancy. The neonatal presentation is characterized with a normal delivery followed by lethargy, vomiting, poor feeding, hypothermia, hyperventilation, decreased consciousness and coma, while later-onset patients usually present with less severe symptoms including vomiting, failure to thrive, irritability, behavioral problems or psychomotor retardation. Trichorrhexis nodosa may occur, but usually in severe cases.
Arthrogryposis, mental retardation, and seizures is associated with contractures of the fingers and other joints. Affected individuals have autism spectrum disorders with delayed speech development. Seizures typically develop in early to mid-childhood.
Aspartylglucosaminuria, also known as AGU, is an autosomal recessive disease that usually presents in childhood with developmental delay/clumsiness/aggressiveness, mild coarsening of facial features, and umbilical and inguinal hernias. Gradual loss of mental skills is evident from adolescence on, and by middle age affected persons are typically moderately mentally retarded. There is no specific treatment for this condition. AGU is far more common among individuals of Finnish ancestry than any other known ethnic group.
Ataxia neuropathy spectrum (ANS) is an autosomal recessive disease previously known by several different names, including Alpers syndrome, mitochondrial recessive ataxia syndrome, and sensory ataxia neuropathy dysarthria and ophthalmoplegia. There is wide variation in the symptoms, age of onset, and severity. Manifestations of ANS include progressive neurologic deterioration with seizures, abnormal gait, eye muscle problems, impaired speech, liver disease, and nerve damage. ANS may be more frequent among individuals of Scandinavian ancestry.
Ataxia with vitamin E deficiency is an autosomal recessive neurological disorder caused by the lack of ability to absorb vitamin E from the diet. During childhood, difficulties with coordination, clumsiness of the hands, loss of deep tendon reflexes, muscle weakness, and hand tremors become evident. Abnormal gait will also develop if left untreated. AVED is treated with life-long dietary supplementation with high doses of Vitamin E. AVED is a rare condition, although the disease is more frequently reported in individuals of North African and Italian ancestries.
Ataxia-telangiectasia is an autosomal recessive progressive neurologic disorder which also causes frequent infections due to an immune deficiency and is associated with an increased risk for developing cancer. Between one and four years of age, affected individuals begin to exhibit an abnormal gait and body instability (ataxia), which become more severe as the disease progresses. Most children are confined to a wheelchair by ten years of age. Other neurological symptoms include slurred speech, poor visual tracking, and involuntary body movements. Intelligence is usually normal, but mild learning disabilities may be present. Another characteristic finding is collections of small blood vessels on the whites of the eyes (telangiectasias). There is no specific treatment, other than heightened surveillance for cancer and avoidance of excessive X-rays. Ataxia-telangiectasia has been reported in many different world populations.
APECED is diagnosed in patients who have 2 of the triad of adrenal insufficiency (Addison disease), hypoparathyroidism, and chronic mucocutaneous candidiasis. Some allelic variants, in particular the IranianJewish polyglandular syndrome, are recognized with only parathyroid involvement. Polyendocrinopathy can include IDDM, hypergonadotropic hypogonadism, and autoimmune thyroid disease. Other autoimmune manifestations can include hepatitis, malabsorption, alopecia, vitiligo, and pernicious anemia. Typically candidiasis appears in early childhood, followed by hypoparathyroidism and then Addison disease, but presentation and severity can vary.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an autosomal recessive disorder that results in early childhood onset of abnormalities of walking and speech articulation. Children with this condition never walk normally, and most eventually become wheelchair bound as adults. Intellectual abilities are not impaired. There is no specific treatment for this slowly progressive neurological condition. ARSACS is most frequently found in the Charlevoix-Sanguenay region of northeastern Quebec population; however, it has been described in individuals from several other regions of the world as well.
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mild to moderate mental retardation, pigmentation of the retina with progressive deterioration of vision, obesity, and extra digits on the hands and/or feet. Treatment is symptomatic. There is no particular ethnic preponderance.
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mild to moderate mental retardation, pigmentation of the retina with progressive deterioration of vision, obesity, and extra digits on the hands and/or feet. Treatment is symptomatic. There is no particular ethnic preponderance.
Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mild to moderate mental retardation, pigmentation of the retina with progressive deterioration of vision, obesity, and extra digits on the hands and/or feet. Treatment is symptomatic. There is no particular ethnic preponderance.
Bardet-Biedl syndrome is a multisystem disorder resulting in progressive vision loss, obesity, polydactyly, cognitive impairment, genitourinary malformations, and renal abnormalities. Affected individuals may also have facial differences, eye and cardiovascular abnormalities, and hepatic disease.
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder due to defective platelet function. Nose bleeds and heavy periods are typical feature of this condition. Platelets appear abnormally large and may be moderately reduced in number. While the condition varies in severity, it is often mild, and treatment is symptomatic. Types A1 and C are both found worldwide.
Bernard-Soulier syndrome is an autosomal recessive bleeding disorder due to defective platelet function. Nose bleeds and heavy periods are typical feature of this condition. Platelets appear abnormally large and may be moderately reduced in number. While the condition varies in severity, it is often mild, and treatment is symptomatic. Types A1 and C are both found worldwide.
Beta-thalassemia is an autosomal recessive disorder that results in severe anemia of childhood onset. Treatment consists of administering blood transfusions every few weeks and use of chelating agents to remove from the body excess iron that results from the transfusions. In the United States, the condition is most commonly found in individuals of Mediterranean descent, but it is also present in persons from the Middle East, Africa, Central Asia, the Indian subcontinent, and the Far East.
Bilateral frontoparietal polymicrogyria (BFPP) is an autosomal recessive disorder. The name refers to the typical appearance of the brain on MRI examination. Disease characteristics include cognitive and motor delay, abnormal gait, seizures, and abnormal eye movements. There is no treatment. BFPP has been described in a variety of ethnicities.
Bloom Syndrome is an autosomal recessive disorder characterized by growth deficiency, both before and after birth, feeding difficulties in infancy, a characteristic facial rash on exposure to the sun, and recurrent respiratory and ear infections. Affected individuals have increased susceptibilities to various types of cancer (a leading cause of early death in this disorder), diabetes, and lung disease. Intelligence is usually normal. There is no specific treatment. Bloom syndrome is rare, but more common in the Ashkenazi Jewish population.
Canavan disease (CD) is a neurodegenerative leukodystrophy that typically presents as a neonatal/infantile (severe) form with onset of symptoms at 2-4 months that include poor head control, macrocephaly, truncal hypotonia, and developmental delay. Severe CD is associated with delayed motor skills and the inability for these children to sit, stand, walk or talk. Many severe patients also have optic atrophy. Over time, spasticity develops and sleep disturbance, seizures and feeding difficulties may be present. Spongy degeneration of the white matter is present, with swollen astrocytes and elongated mitochondria. The life expectancy of patients with the severe form is variable with survival reported from months to past the teen years. A much more rare mild/juvenile form of CD also exists that is characterized by mild developmental delay that may go unrecognized. CD occurs in all ethnic groups, but it is most common in the Ashkenazi Jewish population where the carrier rate has been estimated at 1 in 40 to 1 in 82.
Carnitine palmitoyltransferase deficiency Type 2 (CPT II deficiency) is an autosomal recessive disorder caused by defective cellular metabolism of fat. Signs of this disorder may first become apparent in newborns, children, or adults. In all cases, muscle disease is present; liver disease, heart disease, and severe hypoglycemia occur in affected newborns and children. Infants and children rarely survive, but some affected adults (who typically have exercise-induced muscle pain and weakness) lead nearly normal lives. Treatment, which is only partially effective, consists of a high carbohydrate diet, administration of carnitine, and avoidance of fasting. CPT II deficiency has been described among various world populations.
Carnitine palmitoyltransferase IA (CPT1A) deficiency is a very rare disorder of long-chain fatty acid oxidation that typically presents in childhood after a period of fasting or metabolic stress with a Reye-like illness: hypoketotic hypoglycemia, hepatomegaly, sudden onset of liver failure, seizures and in some instances coma. Between such episodes, individuals appear developmentally normal unless past episodes have resulted in neurological damage. Involvement of cardiac and skeletal muscle is typically not present; however, several cases with slight cardiomegaly or bradycardia have been described. At this time, a single individual homozygous for the P479L mutation presented as an adult with recurrent episodes of activity-induced muscle pain with elevated serum creatine kinase. Acute fatty liver of pregnancy (AFLP) or maternal HELLP syndrome (hypertension, elevated liver enzymes, low platelets) may occur in a pregnant woman carrying a fetus with CPT1A deficiency.
Carpenter syndrome, also referred to as acrocephalopolysyndactyly type II, is an autosomal recessive disorder characterized by premature closure of the cranial sutures of the skull. This results in a relatively flat skull and face. In addition, individuals with this condition nearly always have short fingers, fusion between some of the fingers, and extra fingers. Congenital heart defects occur in 30-50% of cases, and various other birth defects may also occur. There is no specific treatment for this condition; however, most individuals have surgery to correct the abnormal skull shape. The condition does not seem to be more common in any particular ethnic groups.
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder characterized by persistent diarrhea in infancy, childhood cataracts, xanthomas (lipid-filled subcutaneous lumps overlying tendons) in early adulthood, and progressive neurological dysfunction in adulthood. Long-term treatment with chenodeoxycholic acid improves many of the neurologic findings. This condition has been reported in various ethnicities.
Charcot-Marie-Tooth disease Type 4D is an autosomal recessive disorder characterized by slowly progressive muscle weakness, usually beginning in the legs in the first decade of life. Loss of sensation in the extremities eventually occurs, and sensorineural deafness usually develops in the third decade. There is no specific treatment. This particular type of Charcot-Marie-Tooth disease is found most commonly in the Roma (Gypsy) population living in, or having ancestors from Bulgaria.
Choroideremia is an X-linked disorder characterized by progressive loss of vision due to changes in the retina. Males are more frequently, and more severely, affected than women. In most cases for males, the first symptom is reduced night vision, which is usually discovered by early adolescence. Ultimately, most men lose peripheral vision, but central vision is preserved until age 50-70. Cataracts are present in about 1/3 of men. Women who are carriers for choroideremia typically have no visual symptoms, but retinal changes can often be observed by careful eye examination. Currently there is no cure for choroideremia, but is possible that symptoms can be ameliorated by appropriate dietary intake of fresh fruit, leafy green vegetables, and supplements of antioxidants and omega-3 fatty acids. Choroideremia is found in various ethnic groups, but is especially common among individuals of northern Finnish descent.
The two phenotypes of citrin deficiency are citrullinemia type II (CTLN2) and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). CTLN2 typically presents in adulthood with recurring neuropsychiatric symptoms associated with episodic hyperammonemia, including disorientation, irritability, delusions, delirium, seizures, and coma that can lead to death from brain edema. Onset is sudden usually between the ages of 20-50 and often prompted by medication, alcohol or surgery. The symptoms of NICCD are milder and present in children under one year of age as transient intrahepatic cholestasis, hypoproteinemia, growth retardation, hypoglycemia, fatty liver, mild liver dysfunction, and/or high levels of plasma alpha-fetoprotein. A few NICCD patients have a severe form of the disorder with liver damage associated with tyrosinemia and require liver transplantation. Most NICCD patients’ symptoms disappear by one year of age; however, some NICCD patients later develop CTLN2 with neuropsychiatric symptoms several decades later. Patients with both CTLN2 and NICCD tend to have a preference for protein-rich and lipid-rich foods and avoid sugar-rich and carbohydrate-rich foods. Some individuals with NICCD later develop severe CTLN2. The male to female ratio in CTLN2 is 2.4 to 1, while the ratio in NICCD is roughly equal. Citrin deficiency was once thought to be restricted to Japan where the carrier rate is 1 in 65. However, affected individuals in other countries have now been identified. The carrier rate is also high in the East Asian population: China (1 in 65), Taiwan (1 in 48) and Korea (1 in 112).
Coenzyme Q10 deficiency, primary, 7 is characterized by neonatal abnormalities in brain functioning, respiratory distress, deterioration of neurons in the cerebellum, cardiomyopathy (enlarged heart muscle), low muscle tone, neonatal seizures and lactic acidosis. Most patients present in the neonatal period with neonatal epilepsy, heart failure secondary to cardiomyopathy, or a combination of both.
Cohen syndrome (CS) represents a complex developmental disorder. Commonly observed features include: microcephaly, mental retardation, childhood hypotonia, motor clumsiness and non-progressive psychomotor retardation, joint hyperextensibility, ophthalmologic findings such as progressive myopia, retinochoroidal dystrophy, and pigmentary retinopathy, truncal obesity with slender hands and feet, and intermittent neutropenia. The facial gestalt, which becomes more distinct with age, is characterized by a low anterior hairline, thick hair, eyebrows, and eyelashes, high-arched or wave-shaped eyelids, prominent, beak-shaped nose, low nasal bridge, short, upturned philtrum, and open-mouthed appearance. Cohen syndrome is especially common in the Finnish population due to a founder mutation. While the phenotype is relatively homogenous in Finnish patients, the clinical spectrum is much wider in non-Finnish patients.
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder characterized by isolated thrombocytopenia and megakaryocytopenia in infancy with no associated physical abnormalities. However, the disorder can evolve into aplastic anemia and leukemia later in life. This MPL test is intended for diagnosis of congenital amegakaryocytic thrombocytopenia. It also can be used for certain inherited forms of thrombocytosis. It is not suitable for patients with myeloproliferative disease or other acquired adult disorders.
Congenital disorder of glycosylation, types Ia and Ib, are autosomal recessive disorders that manifest as developmental delay, which is usually identified in infancy, low muscle tone, failure to thrive, and a variety of non-specific findings. Type Ib consists primarily of hypoglycemia, vomiting, and loss of protein through the intestines. Treatment of individuals having type Ib with oral mannose improves the hypoglycemia and gastrointestinal symptoms. Otherwise, treatment is largely symptomatic. There is no particular ethnic preponderance for either type Ia or Ib.
Congenital disorder of glycosylation, types Ia and Ib, are autosomal recessive disorders that manifests as developmental delay, which is usually identified in infancy, low muscle tone, failure to thrive, and a variety of non-specific findings. Type Ib consists primarily of hypoglycemia, vomiting, and loss of protein through the intestines. Treatment of individuals having type Ib with oral mannose improves the hypoglycemia and gastrointestinal symptoms. Otherwise, treatment is largely symptomatic. There is no particular ethnic preponderance for either type Ia or Ib.
Congenital myasthenic syndrome CHRNE-associated is an autosomal recessive (occasionally an autosomal dominant) disorder characterized by weakness of the skeletal muscles which worsens with physical exertion. The disease is highly variable; however, onset in the neonatal period is marked by feeding difficulties, poor suck and cry, choking spells, drooping eyelids, generalized weakness, joint contractures, and respiratory insufficiency. Treatment with acetylcholinesterase inhibitors is often effective. This disorder has been described more frequently among individuals with North African or European Roma (Gypsy) ancestry.
Congenital myasthenic syndrome RAPSN-associated, is an autosomal recessive disorder characterized by weakness of the skeletal muscles which becomes worse with physical activity. Severity and clinical characteristics can be highly variable; although symptoms typically develop in neonates or in early childhood, onset in adolescence or adulthood is possible. Treatment with acetylcholinesterase inhibitors prevents episodes of respiratory insufficiency. Congenital myasthenic syndrome RAPSN-associated has been described among individuals from different world populations.
CRB1-associated retinal dystrophy is an autosomal recessive disorder resulting in serious, progressive visual impairment. The condition may be diagnosed clinically as retinitis pigmentosa or Leber congenital amaurosis, and manifestations of this condition are somewhat variable. The first symptom is usually reduced night vision in childhood, followed by tunnel vision, and ultimately leading to total loss of vision in adulthood. Abnormal pigment of the retina is often present. CRB1-associated retinal dystrophy does not appear to be markedly more frequent in any one particular ethnic group.
Crigler-Najjar syndrome is an autosomal recessive disorder in which bilirubin cannot be properly metabolized. The resulting accumulation of unconjugated bilirubin causes severe jaundice that by adolescence results in a particular type of brain damage known as kernicterus. There is limited available treatment to reduce the level of bilirubin prior to onset of neurologic symptoms. There is no particular ethnic preponderance.
Cystic fibrosis is one of the most common autosomal recessive diseases, affecting about one in 3,300 people in the United States. CF causes the body to produce thick mucus leading to pneumonia, diarrhea, poor growth and infertility. CF does not affect intelligence levels. While severely affected individuals die in childhood, the average life span is around thirty years and may improve as scientists search for better treatments. The condition is common in both Ashkenazi and Caucasian populations, but can also be found in other ethnicities.
Cystinosis is an autosomal recessive disease characterized by the accumulation of the amino acid cystine in the body. The most severe form, which begins in infancy, is called nephropathic cystinosis. If left untreated, it can lead to kidney failure by 10 years of age. Cystine crystals accumulate in the eye, leading to sensitivity to light in early childhood. Intermediate cystinosis includes many of the same features, but symptoms usually begin in adolescence. Non-nephrotic, or ocular cystinosis, is the least severe form of the disease, primarily characterized by sensitivity to light. Kidney disease (renal tubular Fanconi syndrome) is treated in the normal manner, and cysteamine eye drops can relieve the light sensitivity. Cystinosis has been diagnosed in a variety of populations, but it is more common among individuals of French-Canadian ancestry.
Autosomal Recessive Deafness 1A results in non-syndromic, profound, prelingual sensorineural deafness. It is also associated with vertigo.
Developmental Delay, Microcephaly, and Hypomyelination is characterized by global developmental delay, progressive postnatal microcephaly, and brain abnormalities. As a result of the developmental delay, speech is absent or minimal and walking is sometimes achieved. Affected individuals frequently also experience seizures.
Dihydrolipoamide dehydrogenase deficiency (DLD), also known as maple syrup urine disease type 3, is an autosomal recessive metabolic disorder in which protein cannot be properly metabolized. This causes accumulation of toxic byproducts. Symptoms include recurrent vomiting, episodes of abdominal pain and changes in consciousness, an enlarged liver, and neurological complications. The symptoms, severity, and age of onset vary considerably. Most cases in the United States are identified by newborn screening. Treatment, which must be continued life-long, may include a special protein-reduced diet, and in some cases large amount of certain vitamins. Liver transplantation has been tried for severe cases. This condition is described more frequently among individuals of Ashkenazi Jewish ancestry.
Dihyropyrimidine dehydrogenase deficiency (DPD), also known as hereditary thymine-uraciluria, is an autosomal recessive disorder with highly variable onset and severity. Some individuals with this condition have no clinical symptoms. When present, symptoms in infants usually include seizures, small head size, motor developmental delays, intellectual disability, eye defects, and behavioral manifestations.
Autosomal recessive dyskeratosis congenita 5 is classically associated with a triad of symptoms: underdeveloped nails, lacy pigmentation of the neck and/or upper chest, and white patches of the oral mucosa. Individuals are also at increased risk for progressive bone marrow failure, certain cancers, and pulmonary fibrosis. Varying degrees of developmental delay are present in some affected individuals.
Ehlers-Danlos syndrome, type VIIC results in tearing of the skin (dermatosparaxis) and joint and skin laxity. Other symptoms of Ehlers-Danlos syndrome, type VIIC include umbilical hernia, bruising easily, and characteristic facial features.
Ethylmalonic encephalopathy (EE) is a rare metabolic disorder characterized by psychomotor regression and generalized hypotonia, which progresses into spastic tetraparesis, dystonia and global neurological failure. MRI shows necrotic lesions in the basal ganglia and brainstem. The encephalopathy is typically accompanied by petechia and orthostatic acrocyanosis. Chronic diarrhea is also common. Most patients with EE have been from the Mediterranean basin or Arabic peninsula.
Factor XI deficiency is an autosomal recessive disorder. Deficiency of clotting factor XI causes a mild bleeding disorder. Typically, individuals are diagnosed in late childhood or early adulthood following dental work, surgery, or trauma that results in excessive bleeding. The severity of factor XI deficiency varies significantly between individuals. Except in extreme cases, life expectancy is not affected. Some carriers of factor XI deficiency may have bleeding symptoms, but these are typically less severe than in affected individuals. Factor XI deficiency is nearly always, but not exclusively, found in Ashkenazi Jewish individuals.
Familial dysautonomia is an autosomal recessive disorder with manifestations apparent at birth which are characterized by weakness, insensitivity to pain and temperature differences, fluctuating blood pressure, and feeding difficulties. Children with familial dysautonomia are frequently hospitalized, have a shortened life span, and are at risk for sudden death. Treatment is supportive and has resulted in lengthening of life spans of affected individuals. Familial dysautonomia almost exclusively affects individuals of Ashkenazi Jewish descent.
Familial hypercholesterolemia, LDLR-associated is an autosomal recessive disorder characterized by greatly increased blood cholesterol levels in children and young adults. This results in premature hardening of the arteries (atherosclerosis). Heart disease and strokes in the first two decades of life are common. Also present in many affected individuals are abnormal fat deposits underneath the skin near tendons (xanthomas), which are sometimes evident at birth. Unlike most recessive diseases, carriers of familial hypercholesterolemia have significant disease manifestations. These consist of elevated blood cholesterol (but not to the degree of affected children), xanthomas developing in adulthood, and premature coronary artery disease (often by age 40). Treatment consists of aggressive lowering of blood cholesterol; heart transplants have been tried in severely affected children. This condition has been described in various world populations, and may be more frequent among individuals of Ashkenazi Jewish descent, from the Saguenay-Lac-Saint-Jean region of Quebec Province, and in the Afrikaans-speaking community of South Africa.
Familial hypercholesterolemia LDLRAP1-associated is an autosomal recessive disorder characterized by severe hypercholesterolemia. Symptoms include premature atherosclerosis, and visible lipid/cholesterol deposits (xanthomas) around tendons. Treatment is primarily directed towards cardiovascular manifestations and lowering blood cholesterol. This particular form of familial hypercholesterolemia is most often seen in persons from Sardinia, but individuals of various other ethnicities have been affected.
Familial hyperinsulinism is an autosomal recessive disorder that presents shortly after birth, with severe episodes of low blood sugar (hypoglycemia) and failure to thrive. Infants often weigh over ten pounds at birth. Repeated episodes of hypoglycemia can lead to seizures, brain damage, and in severe cases, coma and death. Symptoms may be milder and of later onset in some individuals and families. Treatment consists of early recognition of, and careful attention to preventing, hypoglycemia. Familial hyperinsulinism is more common in the Ashkenazi Jewish and Finnish populations, but occurs in persons of many other ethnic backgrounds.
Familial Mediterranean fever (FMF) is an autosomal recessive disorder caused by mutations in the MEFV gene. It typically presents in childhood or adolescence with periodic attacks of acute fever and localized inflammation lasting from one to three days. Intervals between attacks vary from days to months, and onset may be precipitated by physical or emotional stress. Abdominal symptoms, pleural involvement, arthralgias and arthritis are common. Leukocytosis, accelerated ESR, and progressive amyloidosis also affect many patients. Erysipeloid erythema, when present, usually involves the lower extremities. Most patients are responsive to colchicine treatment.
Familial neurohypophyseal diabetes insipidus is an autosomal recessive disorder in which the kidneys cannot properly conserve water. This results in excessive urination and drinking, and the possibility of dehydration if water consumption is not adequate. Symptoms in infancy include failure to thrive, vomiting, and irritability. Treatment consists of providing sufficient oral intake of water to counteract the increased volume of urine, and administering a medication called desmopressin is also an option. One form of this disease occurs in Palestinians, but the condition has been reported in a variety of other ethnicities.
Fanconi anemia Type C is an autosomal recessive disorder manifest by physical anomalies (short stature, thumb and/or forearm malformations), an increased risk of leukemia and other cancers, and bone marrow failure. Bone marrow failure usually becomes apparent in the first 10 years of life, and most individuals do not live past 30 years old. Androgens and other factors that stimulate the bone marrow are used to improve blood counts. Fanconi anemia type C is more common in certain ethnicities, especially in the Ashkenazi Jewish population.
Fanconi anemia Type G is an autosomal recessive disorder manifest by physical anomalies (short stature, thumb and/or forearm malformations), an increased risk of leukemia and other cancers, and bone marrow failure. Bone marrow failure usually becomes apparent in the first 10 years of life. Androgens and other factors that stimulate the bone marrow are used to improve blood counts. Stem cell transplantation can be curative. This type of Fanconi anemia does not appear to be particularly frequent in any one ethnic group.
Fragile X syndrome is inherited in an X-Linked manner because the fragile X gene (FMR1) is on the X chromosome. Fragile X is the most common cause of inherited intellectual disability affecting approximately 1 in 3,600 males and 1 in 4,000-6,000 females. It can occur in any ethnic group and symptoms are usually more severe in males than females. Intellectual disability may range from learning disabilities to severe mental retardation and autism. Behavioral traits may include hyperactivity, poor eye contact, and speech disturbances. Physical characteristics may include enlarged ears and long face with a prominent chin. Approximately 1/260 women are carriers for fragile X syndrome
Hereditary fructose intolerance is characterized by an inability to digest a sugar called fructose. With ingestion of the sugars fructose, sucrose, or sorbitol, individuals with hereditary fructose intolerance may experience nausea, bloating, abdominal pain, diarrhea, vomiting, and low blood sugar. In some cases, seizures and coma can occur. Continued exposure to these sugars can lead to permanent damage to the liver and kidneys. If detected and treated before organ damage occurs, quality of life and life expectancy in affected individuals can be normal. Management involves restriction of certain sugars in the diet, vitamin supplementation, and medical treatment of symptoms such as seizures or organ failure.
Classical galactosemia is the most common disorder of galactose metabolism. Symptoms appear in the neonatal period after ingestion of galactose and include vomiting, diarrhea, failure to thrive, lethargy, hypotonia, jaundice, hepatomegaly, septicemia, cataracts and bleeding tendencies. If a galactose-restricted diet is initiated rapidly, the neonatal symptoms resolve and the complications of liver failure, sepsis, neonatal death and mental retardation can be prevented. Despite adequate galactose restriction from an early age children with galactosemia are at risk for ataxia, verbal apraxia, delayed speech and developmental delay. Females with galactosemia are at risk for premature ovarian failure.
Gaucher disease is an autosomal recessive disorder, symptoms of which include bone disease, enlarged liver and spleen, anemia, and lung disease. Gaucher disease is subdivided into types 1, 2 and 3, based on clinical symptoms. Manifestations of Gaucher disease type 1 are variable and do not affect the brain or nervous system. Many adults with Gaucher disease type 1 are asymptomatic, while other have symptoms ranging from mild spleen enlargement and/or bone disease to more severe childhood manifestations. Individuals with types 2 and 3 have progressive neurologic deterioration. Treatment consists of enzyme replacement by intravenous infusion, or oral medication. Bone marrow transplantation has also been used in some situations for types 2 and 3 and may halt, but not reverse, brain damage. Gaucher Disease, particularly type 1, is more common in individuals of Ashkenazi Jewish descent, but Gaucher disease occurs in a variety of ethnicities.
Glutaric acidemia Type 1 (GA I) is an autosomal recessive disorder of aminoacid metabolism. Affected infants often have a large head and enlarged liver. Neurologic abnormalities, developing during or just after an otherwise minor viral illness, may include rigidity, spasms, jerking movements, low muscle tone, and seizures. GA I can be identified by newborn screening, and some of the neurologic and metabolic symptoms can be treated by diet. GA I has been described among various populations; however, in certain ethnic groups, including the Old Order Amish, the condition is considerably more common.
Glutaric acidemia Type IIA, also known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of amino acid and fat metabolism. Prenatally, affected fetuses may have polycystic kidneys. GA IIA typically becomes apparent in neonates, who have rapid breathing, convulsions, an enlarged liver, elevated ammonia, sweaty-sock like odor, and facial abnormalities. Newborn screening effectively identifies babies with GA IIA. A late-onset form is characterized by recurrent vomiting, hypoglycemia, muscle weakness, and liver enlargement. Treatment is by special diet and, in some cases, by large amounts of particular vitamins. GA IIA does not appear to have a particular ethnic preponderance.
Glutaric acidemia Type IIC, also known as multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of amino acid and fat metabolism. Prenatally, affected fetuses may have polycystic kidneys. GA IIC typically becomes apparent in neonates, who have rapid breathing, convulsions, an enlarged liver, elevated ammonia, sweaty-sock like odor, and facial abnormalities. Newborn screening effectively identifies babies with GA IIC. A late-onset form is characterized by recurrent vomiting, hypoglycemia, muscle weakness, and liver enlargement. Treatment is by special diet and, in some cases, by large amounts of particular vitamins. GA IIC does not appear to have a particular ethnic preponderance.
Glycogen storage disease Type 1A is an autosomal recessive disorder in which glycogen, a form of glucose that is stored in muscle and liver, cannot be released. Since glycogen is used to provide energy in the form of glucose for normal muscle and liver function, low blood sugar (hypoglycemia) and ketosis develop on fasting. Affected neonates and infants often come to medical attention because of very low blood glucose and an enlarged liver. Seizures may occur from low glucose. Adherance to a specific diet and avoidance of fasting is an effective treatment. This condition is more common in the Ashkenazi Jewish population, but also found in Caucasian, Hispanic and certain Asian populations.
Glycogen storage disease, Type IB is an autosomal recessive disorder in which glycogen, the storage form of the blood sugar, glucose, cannot be properly metabolized. This results in enlargement of the liver and severe hypoglycemia on fasting. Also, white blood cell function is impaired with this type of glycogen storage disease, and this results in recurrent bacterial infections. Treatment with frequent feeding to reduce hypoglycemia is very helpful. Long term survival of treated individuals is the rule, but osteoporosis, gout, renal disease, pulmonary hypertension, and hepatic adenomas with potential for malignant transformation are potential long-term complications. This disorder is seen in many ethnic groups, but glycogen storage disease type Ib is predominantly found in persons of Ashkenazi Jewish ancestry.
Glycogen storage disease Type II, or Pompe disease, is an autosomal recessive disease caused by the accumulation of a form of glucose called glycogen. The excess glycogen prevents muscles, including the heart muscle, from working properly. The disease is characterized by muscle weakness, enlargement of the tongue, feeding problems, enlargement of the heart, and enlargement of the liver in early infancy. If untreated, death usually occurs within 1 year of life. Later-onset, milder cases may become apparent later in infancy, and there are even later-onset forms of the disease which mainly affect skeletal muscle. Treatment consists of replacement of the defective enzyme, alpha-glucosidase, by intravenous infusion. The condition is more common in those with African American ancestry, but present in many other populations.
Glycogen storage disease Type III (GSDIII) is an autosomal recessive disorder in which glycogen (the storage form of the blood sugar, glucose) cannot be properly mobilized. This condition is characterized by enlargement of the liver and heart due to stored glycogen. Adults with GSDIII often have muscle weakness due to glycogen accumulation. Lack of ability to metabolize glycogen causes hypoglycemia to develop on fasting. Most of the most serious manifestations of this condition can be prevented by frequent feeding and avoidance of fasting. A high protein diet is also beneficial. GSDIII is found in many ethnic groups, but is more common in the North African Jewish population.
Glycogen storage disease Type V (GSDV), also known as McArdle disease, is an autosomal recessive disorder characterized by exercise-induced muscle aches and painful cramping of skeletal muscles, as well as rapid muscle fatigue. The condition typically becomes apparent in the second to third decade of life. In some cases, muscle breakdown from overexercise results in pink urine (myoglobinuria), and this can cause kidney failure. Although there is no specific treatment for GSDV, lifestyle changes with regards to exercise can alleviate many symptoms of the condition. GSDV does not seem to be especially frequent in any one ethnic group.
GRACILE syndrome is an autosomal recessive disorder named for its key features, Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis, and Early death. Prenatally, the primary finding is intrauterine growth retardation. Almost all affected infants experience failure to thrive and die as neonates or in early infancy. GRACILE syndrome has only been found in the Finnish population, but it may be underdiagnosed and exist in other populations.
Hermansky-Pudlak syndrome 3 is an autosomal recessive disorder characterized by very light skin and eye color (albinism), impaired vision, involuntary jerky eye movements, and a tendency towards excessive bleeding. Lung disease and colitis may occur in some adults. There is no specific treatment for the features of this disease. Hermansky-Pudlak syndrome has been described among individuals from a variety of different ancestries, but more frequently among Puerto Rican individuals and, to a lesser extent, among the Ashkenazi Jewish population.
Holocarboxylase synthetase deficiency, also known as multiple carboxylase deficiency, is an autosomal recessive disorder that presents in infancy with a combination of excess acid in the blood (ketolactic acidosis), breathing problems, difficulty feeding, seizures, a skin rash, and lethargy. Early diagnosis (which can be made by newborn screening) and prompt treatment with biotin, before irreversible neurologic damage occurs, prevents disease complications. Holocarboxylase synthetase deficiency has been described among different ethnicities, and occurs with a higher frequency in the population of the Faroe Islands, in the North Atlantic Ocean.
Homocystinuria caused by cystathionine β-synthase deficiency is an autosomal recessive disease caused by impaired metabolism of several amino acids, resulting in elevations of the amino acids homocysteine and methionine. Untreated individuals, who are often tall and slender, typically have mental retardation, dislocated lenses of the eye, and a tendency to form blood clots. Newborn screening programs often include this condition, since early treatment with a special diet prevents development of most or all disease manifestations. Some affected children respond to large doses of vitamin B6 and need minimal dietary changes. The condition is more common in Qatar, Norway, and to a lesser extent, Germany and Ireland.
Homocystinuria, cobalamin E (cbIE) type, is an autosomal recessive disorder, most often identified in the first few months of life, and characterized by vomiting, developmental delay, anemia, and feeding difficulty. Low muscle tone, seizures, vision abnormalities, and brain atrophy are also commonly present. For most cases, no effective specific treatment exists. Thus far, the condition has mainly been found in European populations.
Mucopolysaccharidosis Type I (MPS I) is an autosomal recessive disease in which a chemical known as a mucopolysaccharide builds up within cells. MPS I is a progressive disease which affects the face, skeleton, eyes, heart, respiratory tract, and brain. The most severe form of MPS I is known as Hurler syndrome. Faces of Hurler patients are often referred to as coarse or thickened, there is progressive intellectual deterioration beginning in late infancy, and children usually die by 10 years of age from heart and/or lung problems caused by accumulated mucopolysaccharide. Progressive deformities of the skeleton, joint limitations, and clouding of the corneas (the clear portion of the eye) are major features of MPS I. A mild form of MPS I is called Scheie syndrome and primarily manifests with stiff joints, corneal clouding, and aortic valve leakage by early adulthood. There is also an intermediate form of the disease, called Hurler-Scheie syndrome. Specific treatment using a synthetic version of the enzyme missing in MPS I patients improves skeletal, joint, and ocular problems, but does not prevent intellectual deterioration. MPS I has been described in individuals from many ethnic backgrounds.
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome, is an autosomal recessive disorder characterized by failure to thrive, developmental delay, and episodes of unexplained vomiting and changes in consciousness associated with elevated blood ammonia. Low muscle tone and seizures may also occur. HHH syndrome has a variable age of onset and severity of symptoms. Treatment with a low protein diet and prevention of fasting is helpful, but cannot reverse preexisting neurologic damage. Additional medications are available for individuals whose symptoms are not controlled by diet alone. HHH syndrome is seen more frequently in the French-Canadian population.
Hypophosphatasia is an autosomal recessive disease characterized by osteoporosis and weak teeth due to lack of an essential enzyme known as alkaline phosphatase. The severity of hypophosphatasia varies from a condition found in stillborns with no calcium in the bones, to an adult-onset disorder in which the primary manifestations are fractures from weak leg bones and/or premature loss of teeth. Treatment is largely symptomatic. The condition is more common in the Mennonite community, but the disease occurs in individuals in North America, Europe, and Japan. It is uncommon in most parts of Africa.
Inclusion body myopathy 2 (IBM2), also known as distal myopathy with rimmed vacuoles, is an autosomal recessive disorder characterized by slowly progressive distal muscle weakness that becomes apparent in the late teens to early adult years. Individuals are usually wheelchair bound within 20 years after initial manifestations. Nonaka myopathy is clinically similar and due to defects in the same gene as IBM2. There is no specific treatment for either condition. IBM2 has been reported mainly in Iranian Jews, but has been found in Middle Eastern Jews as well as other ethnic groups. IBM2 does not appear to be more common in European (Ashkenazi) Jews. Nonaka myopathy has been more frequently reported in Japanese individuals.
Joubert syndrome 2 is an autosomal recessive disorder which is characterized by a distinctive brain malformation visible on MRI examination, low muscle tone, an abnormal breathing pattern, and developmental delay. Additional features may include abnormal eye movements, abnormal gait (ataxia), mental retardation, vision problems, extra fingers and/or toes, and kidney disease. The clinical findings and severity are highly variable. There is no specific treatment. Joubert Syndrome 2 may be more common among individuals with Ashkenazi Jewish descent, but the condition has also been reported in persons of other ethnic backgrounds.
Junctional epidermolysis bullosa (JEB) LAMA3 Type is an autosomal recessive disease characterized by extremely fragile skin and mucous membranes, causing the skin to blister and scar with minimal trauma. There are two types of JEB–a classic form, known as Herlitz, and the milder non-Herlitz type. Herlitz presents at birth and is characterized in infants by severe blistering, leaving the infant vulnerable to life-threatening infections; most children die by one year of age. In addition, fusion of the fingers and toes (syndactyly), nail and dental abnormalities, hair loss, and congenital malformation of the urinary tract are also seen. Non-Herlitz type exhibits many of the same features, though the symptoms are typically less severe. Treatment is symptomatic and supportive. While LAMA3-associated JEB is more common in individuals of Pakistani descent, the disease occurs in individuals of other ethnicities.
Junctional epidermolysis bullosa (JEB) LAMB3 Type is an autosomal recessive disease characterized by extremely fragile skin and mucous membranes, causing the skin to blister and scar with minimal trauma. There are two types of JEB–a classic form, known as Herlitz, and the milder non-Herlitz type. Herlitz presents at birth and is characterized in infants by severe blistering, leaving the infant vulnerable to life-threatening infections; most children die by one year of age. In addition, fusion of the fingers and toes (syndactyly), nail and dental abnormalities, hair loss, and congenital malformation of the urinary tract are also seen. Non-Herlitz type exhibits many of the same features, though the symptoms are typically less severe. Treatment is symptomatic and supportive. LAMB3-associated JEB is seen in persons of various ethnicities, including persons of European, Hispanic, and African-American descent.
Junctional epidermolysis bullosa (JEB) LAMC2 Type is an autosomal recessive disease characterized by extremely fragile skin and mucous membranes, causing the skin to blister and scar with minimal trauma. There are two types of JEB–a classic form, known as Herlitz, and the milder non-Herlitz type. Herlitz presents at birth and is characterized in infants by severe blistering, leaving the infant vulnerable to life-threatening infections; most children die by one year of age. In addition, fusion of the fingers and toes (syndactyly), nail and dental abnormalities, hair loss, and congenital malformation of the urinary tract are also seen. Non-Herlitz type exhibits many of the same features, though the symptoms are typically less severe. Treatment is symptomatic and supportive. LAMC2-associated JEB appears to be more frequent in persons of Italian ancestry, and is seen in various other populations.
Krabbe disease, also known as globoid cell leukodystrophy and galactosylceramide lipidosis, is an autosomal recessive disorder that results in progressive neurologic deterioration. Krabbe disease usually presents in early infancy with irritability, development regression, seizures, and loss of hearing and vision. Children diagnosed in infancy seldom live past the age of 2 years. There are also late infantile, juvenile, and adult-onset forms of the disease. Bone marrow transplantation has been used in infants identified by newborn screening and appears to halt much of the neurologic deterioration expected in untreated individuals; however, long term outcome following bone marrow transplantation is uncertain at this time. Krabbe disease is found in a variety of different ethnicities, but has not been reported in Ashkenazi Jews.
Kuskokwim disease is characterized by contractures, a chronic loss of joint movement. Affected individuals also frequently have webbing of the knees or elbows. They have fragile bones and are at increased risk of fractures. Other skeletal differences, such as curvature of the spine, are commonly seen in individuals with Kuskokwim disease. Short stature is also common. Management of Kuskokwim disease includes treatment with medications for calcium differences, casting for fractures, and physical therapy.
Lamellar ichthyosis, Type I is an autosomal recessive disorder in which newborns are born encased in a shiny, taut membrane called a collodian membrane. After a few days or weeks, the membrane dries and peels off; afterwards, brown, plate-like scales cover the body. After the collodion membrane has been shed, the clinical presentation and severity may greatly vary between individuals. The severity of Lamelar ichthyosis, type I ranges from severe to mild or almost complete resolution of the skin disorder. Affected individuals with severe involvement can have everted eyelids (ectropion) and lips (eclabium), scarring alopecia involving the scalp and eyebrows, and palmar and palantar hyperkeratosis. Lamellar ichthyosis type I is somewhat more frequent in the Norwegian population; however, the disease has been described in many other populations as well.
Leber congenital amaurosis (CEP290 Type) is an autosomal recessive disorder which causes significant impairment of vision that is usually identified by one year of age. A distinctive sign of this condition is that children with this disorder tend to poke, press, or rub their eyes. Kidney disease, leading to kidney failure, and/or intellectual disability may also be a component of the CEP290 type of Leber congenital amaurosis. There is no specific treatment for this condition. Although various forms of Leber congenital amaurosis are common causes of inherited blindness, the CEP290 type is described more frequently in individuals with Northern European ancestry.
Leber congenital amaurosis RDH12 Type is an autosomal recessive disorder which causes significant impairment of vision that is usually identified in the first few years of life. The specific vision problem is a severe retinal dystrophy which affects both rods and cones. This usually leads to legal blindness by late adolescence or early adulthood. There is no specific treatment. Too few cases have been reported to determine whether the disorder is more common in a particular ethnic group or groups.
Leigh syndrome French-Canadian Type (LSFC) is an autosomal recessive progressive neurodegenerative disorder. Clinical features in this form of Leigh syndrome include developmental delay, low muscle tone, lack of coordination, and abnormal facial features. There are episodic changes in consciousness (metabolic crises), and affected children typically die before 2 years of age. There is no effective treatment. LSFC primarily affects individuals with French-Canadian ancestry, particularly those from the Saguenay-Lac-Saint-Jean region of Quebec.
Leukoencephalopathy (or childhood ataxia with central nervous sytem hypoyelination) with vanishing white matter is an autosomal recessive disorder characterized by distinctive findings on brain MRI. Clinical features include an abnormal gait, spasticity, impaired vision, and progressive neurologic deterioration. The disorder has variable onset and severity. There is no specific treatment, and the disorder does not appear to be more common in a specific ethnic group or groups.
Limb-girdle muscular dystrophy (LGMD) Type 2A is an autosomal recessive disorder caused by mutations in the CAPN3 gene that result in progressive muscle weakness and atrophy. Onset can occur from two to forty years of age, and muscles around the shoulder and pelvis are most affected. Additional findings include the tendency to walk on tiptoes, difficulty in running, a waddling gait, and curvature of the spine. In most cases there is relative sparing of facial muscles and the heart. There is no specific management or treatment for LGMD. The disorder has been observed in various world populations; however, this type of LGMD may be more common in individuals with Russian, Turkish, Bulgarian, Basque, Amish, Croatian, and Northeastern Italian ancestry.
Limb-girdle muscular dystrophy (LGMD) Type 2C is an autosomal recessive disorder caused by mutations in the SGCG gene that result in progressive muscle weakness and atrophy. The disease course can be variable, even within the same family. Onset can occur from two to forty years of age, and muscles around the shoulder and pelvis are most affected. Additional findings include the tendency to walk on tiptoes, difficulty in running, a waddling gait, and curvature of the spine. In most cases there is relative sparing of facial muscles and the heart. There is no specific management or treatment for LGMD. This condition has been observed in various world populations; however, this type of LGMD may be more common in individuals of Roma (Gypsy) and North African descent.
Limb-girdle muscular dystrophy (LGMD) Type 2D is an autosomal recessive disorder caused by mutations in the SGCA gene that result in progressive muscle weakness and atrophy. The disease course can be variable, even within the same family. Onset can occur from two to forty years of age, and muscles around the shoulder and pelvis are most affected. Additional findings include the tendency to walk on tiptoes, difficulty in running, a waddling gait, and curvature of the spine. In most cases there is relative sparing of facial muscles and the heart. There is no specific management or treatment for LGMD. This condition has been observed in various world populations, but may be found more commonly in individuals of European and Brazilian descent.
Limb-girdle muscular dystrophy (LGMD) Type 2E is an autosomal recessive disorder caused by mutations in the SGCB gene that result in progressive muscle weakness and atrophy. The disease course can be variable, even within the same family. Onset can occur from two to forty years of age, and muscles around the shoulder and pelvis are most affected. Additional findings include the tendency to walk on tiptoes, difficulty in running, a waddling gait, and curvature of the spine. In most cases there is relative sparing of facial muscles and the heart. There is no specific management or treatment for LGMD. This condition has been observed in various world populations; mutations in the SGCB gene have been described more frequently in Amish individuals located in Indiana.
Lipoprotein lipase deficiency is an autosomal recessive disorder that results in greatly increased levels of triglycerides in the blood. Symptoms, which usually begin in childhood, include failure to thrive, episodic abdominal pain, pancreatitis, yellowish deposits of lipids on the skin (xanthomas), and an enlarged liver and spleen. Dietary management to limit fat intake usually is effective treatment. Lipoprotein lipase deficiency is seen in various populations, but is more prevalent in individuals with French-Canadian ancestry.
Long-chain 3-hydroxyacyl-Coenzyme A dehydrogenase (LCHAD) deficiency is an autosomal recessive metabolic disorder which is due to an inability to properly metabolize certain fats. Typically, infants present with low blood sugar, an enlarged liver, and cardiac problems following a brief period of illness or prolonged fasting. This is often accompanied by changes of consciousness or coma, and may result in sudden death. In addition, mothers carrying fetuses affected with LCHAD deficiency may develop vomiting, high blood pressure, serious liver problems, and low platelets (HELLP syndrome) during pregnancy. Dietary management and avoidance of prolonged fasting for affected infants may alleviate some symptoms of LCHAD deficiency. This condition has been reported more frequently in individuals of Northern European descent.
Lysinuric protein intolerance is an autosomal recessive disorder usually presenting in infancy with non-specific symptoms, which include recurrent vomiting and diarrhea, low muscle tone, failure to thrive, and an enlarged liver and spleen. Infants often have changes in consciousness after a protein-rich meal and will develop an aversion to protein-rich foods. Osteoporosis, fractures, and kidney disease often occur in older children and adults. Mental development is expected to be normal unless neurological damage occurs due to prolonged coma during an episode. Treatment, which is only partially effective, includes protein restriction, avoidance of prolonged fasting, and use of medications to reduce blood ammonia levels. Lysinuric protein intolerance is most frequently seen in individuals of Finnish descent, and it be more frequent in persons of Japanese and Italian ancestry.
Maple syrup urine disease (MSUD) type 1B is an autosomal recessive disorder of amino acid metabolism which usually presents at, or several days after, birth with irritability, lethargy, poor feeding, breathing irregularly, and decreased level of consciousness. Urine and ear wax have a smell reminiscent of maple syrup or burnt sugar. If the condition (which can be detected by newborn screening, but usually not before severe symptoms develop) is not discovered in time, serious problems, including irreversible neurologic damage or death, may result. Milder, later-onset forms also exist, but are uncommon. Treatment, which can dramatically improve prognosis, consists of strict dietary management and avoidance of prolonged fasting. MSUD type 1B is more frequent in individuals of Ashkenazi Jewish ancestry.
Maple syrup urine disease (MSUD) type 1A is an autosomal recessive disorder of amino acid metabolism which usually presents at, or several days after, birth with irritability, lethargy, poor feeding, breathing irregularly, and decreased level of consciousness. Urine and ear wax have a smell reminiscent of maple syrup or burnt sugar. If the condition (which can be detected by newborn screening, but usually not before severe symptoms develop) is not discovered in time, serious problems, including irreversible neurologic damage or death, may result. Milder, later-onset forms also exist, but are uncommon. Treatment, which can dramatically improve prognosis, consists of strict dietary management and avoidance of prolonged fasting. MSUD type 1A is more frequent in individuals with Old Order Mennonite ancestry and in persons of Portuguese-Roma (Gypsy).
Meckel-Gruber syndrome Type 1 is an autosomal recessive disorder characterized by severe brain defects, enlarged cystic kidneys, and extra fingers or toes. Many affected pregnancies result in fetal demise, and infants who survive to term rarely live for more than a few weeks. Meckel-Gruber syndrome type 1 has been described in individuals of various European and Caucasian ethnicities and is particularly frequent in persons of Finnish ancestry.
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an autosomal recessive disorder of fat metabolism with onset usually between 3 and 24 months of age, although some individuals present later. MCAD deficiency is characterized by episodes of hypoglycemia (without ketosis), lethargy, seizures, and changes in consciousness. These are triggered by common illnesses, particularly when there is prolonged fasting. MCAD, when unrecognized, can cause sudden death. Early identification (i.e., with newborn screening), dietary management, avoidance of fasting, and supplementation with carnitine dramatically improve the prognosis for affected individuals. MCAD deficiency has been reported in various European and Caucasian ethnicities, as well as in other world populations.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder that presents with an enlarged head size early in childhood, mild delay in walking, and seizures. MLC is a slowly progressive disorder, with a life expectancy that ranges from the first to the fourth decades of life. Findings on an MRI examination of the brain are diagnostic. Mental retardation occurs late and is typically mild. Treatment is generally symptomatic and supportive. MLC has been described more frequently among individuals with Libyan Jewish, Turkish, Japanese, and East Indian ancestors, but is present in other populations as well.
Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder characterized by progressive, and eventually complete, loss of motor and intellectual functioning. Age of onset varies from infancy to adulthood, and early onset of symptoms generally is associated with more severe disease and more rapid progression. There is no specific treatment, but bone marrow transplantation prior to occurrence of symptoms has been proposed. MLD has been described among individuals from a variety of different ethnicities and occurs at a higher frequency in certain populations, including individuals of Habbanite (southern Arabian/Yemeni) Jewish descent and Israeli Arabs.
Methylmalonic aciduria and homocystinuria, cblC Type, is a defect in B12 metabolism. Patients may present with severe early onset disease that includes megaloblastic and macrocytic anemia and failure to thrive, microcephaly, lethargy and feeding difficulties. Neurologic symptoms may include hypotonia, seizures, developmental delay, ataxia and optic atrophy. Late onset cases may present with neurologic symptoms such as anorexia, irritability, fatigue, myelopathy or dementia. Other complications are mental retardation, microcephaly, retinal degeneration, pigmentary retinopathy, microangiopathy and skin lesions.
Methylmalonic aciduria, MMAA-associated, is an autosomal recessive disease caused by the body’s inability to break down certain amino acids from proteins found in food. Feeding problems, vomiting, failure to thrive, low muscle tone, and delayed development are usually identified in infancy. Recurrent episodes of lethargy following high protein intake or during childhood illnesses is common prior to diagnosis. These episodes are associated with excess acid in the blood (metabolic acidosis), elevated blood ammonia, and changes in consciousness. Most affected individuals can be effectively treated with large doses of vitamin B12, avoidance of fasting, and a diet that is not overly high in protein. This form of methylmalonic aciduria been described among individuals from a variety of different world populations.
Methylmalonic aciduria (MMA), MUT-associated is an autosomal recessive disease characterized by the body’s inability to break down certain amino acids from proteins found in food. Individuals experience episodes of acute illness that include increased acid in the blood (metabolic acidosis), vomiting, lethargy, low muscle tone, enlargement of the liver, seizures, and respiratory distress. Onset of symptoms ranges from the neonatal period and infancy to, less frequently, early childhood. Without early identification (which is possible by newborn screening) and treatment, this form of MMA is life-threatening. Treatment with a special, highly protein restricted, diet and avoidance of fasting may improve the quality of life and life expectancy. MUT-associated MMA has been described among individuals from a variety of different world population.
Mitochondrial complex I deficiency presents with Leigh syndrome, a progressive neurological disorder resulting in progressive deterioration of intellectual and motor function and early death, in some affected individuals. The symptoms of Mitochondria Complex 1 Deficiency varies significantly among affected individuals. Other associated features may include: intrauterine growth restriction, adrenal insufficiency, and brain abnormalities.
Mucolipidosis IV (MLIV) is a progressive neurological lysosomal storage disease that usually is evident during the first year of life, and presents with mental retardation, corneal opacities, and delayed developmental milestones. Ocular findings also include retinal degeneration, myopia, strabismus, and photophobia. Neurological symptoms include hypotonia and pyramidal tract signs. There are cytoplasmic inclusions (“storage bodies”) in almost every cell type of the patients. Most affected individuals reach a maximal developmental age of 12-15 months. Mucolipidosis IV is due to mutations in the MCOLN1 gene and more than 80% of reported patients are of Ashkenazi Jewish descent. Two common mutations (IVS3-2 A>G and a 6,450bp deletion) account for 95% of cases in the Ashkenazi Jewish population. MLIV is rare in the general population.
Multiple sulfatase deficiency is characterized by progressive deterioration of neurological function, including intellectual disability, skeletal abnormalities, enlarged organs, and ichthyosis. Age of onset varies but is typically within the first two years of life.
Navajo neurohepatopathy (NNH), also known as mitochondrial DNA depletion syndrome 6, is an autosomal recessive disorder characterized by liver disease, recurrent metabolic acidosis, failure to thrive, and neurologic signs which include lack of appropriate pain sensation, weakness, and loss of motor coordination. Symptoms can present in infancy, childhood, or adulthood, and differently, even in individuals within the same family. Death usually occurs in the first decade, often before one year of life, from liver failure. Treatment for NNH is mainly symptomatic. Some patients have benefited from liver transplantation. NNH has been reported solely in the Navajo population.
Nemaline myopathy 2 is an autosomal recessive neuromuscular disorder characterized by muscle weakness, especially in the face, neck and limbs, low muscle tone, and depressed or absent tendon reflexes. The disease usually presents in infancy, and there is a characteristic finding (nemaline bodies) found on muscle biopsy. Treatment is supportive. Nemaline myopathy 2 is the most common genetic form of nemaline myopathy in the Ashkenazi Jewish population, although it has also been described in other ethnicities.
Congenital Finnish nephrosis is an autosomal recessive disorder in which the kidneys leak protein into the urine. During a pregnancy with an affected fetus, there is greatly elevated alpha-fetoprotein in maternal blood and amniotic fluid, as well as an enlarged placenta. Babies are typically born prematurely and have evidence of low serum protein at birth. Kidney function deteriorates over the next several years to end-stage disease. The only known cure is kidney transplantation. This condition is found more frequently in individuals with Finnish ancestry, and has been reported in members of an Old Order Mennonite community in Pennsylvania.
CLN3-associated Neuronal Ceroid Lipofuscinosis is a disorder characterized by progressive vision failure beginning around 5 to 10 years of age. Patients may also develop seizures, loss of control of bodily movements, tight or stiff muscles, and cognitive decline, including progressive dementia. Some patients may also experience depression and anxiety. For most patients, life expectancy ranges from the teens to the late thirties. Currently, treatment for patients with this disorder is symptom management and palliative care.
Neuronal ceroid lipofuscinosis, CLN5-associated, is an autosomal recessive disorder which results in progressive neurologic deterioration. Individuals with this condition show accumulation of a characteristic abnormal material within the cells of the brain and other tissues. Typically symptoms become apparent between four and seven years of age with clumsiness, followed by progressive visual failure, deterioration of mental and motor skills, and seizures. Children are blind by eight years of age and lose the ability to walk at ten. The disease follows a progressively declining course, and life expectancy ranges from ages 13 to age 35 years. Currently, there is no effective treatment. This condition is seen in various world populations; however, it is more commonly found in individuals with Finnish ancestry.
Neuronal ceroid lipofuscinosis, CLN6-associated, is an autosomal recessive disorder which results in progressive neurologic deterioration. Individuals with this condition show accumulation of a characteristic abnormal material within the cells of the brain and other tissues. Typically symptoms become apparent between two and four years of age, usually beginning with vision loss, followed by seizures, loss of intellectual abilities, and muscle weakness. Life expectancy ranges from six through thirty years. Currently there is no curative treatment Neuronal ceroid lipofuscinosis CLN6-associated has been observed in various world populations; however, it is more commonly identified in individuals of Costa Rican, Pakistani, or Portuguese ancestry.
Neuronal ceroid lipofuscinosis, CLN8-associated, also known as Northern epilepsy or progressive epilepsy with mental retardation, is an autosomal recessive disorder that results in progressive neurologic deterioration. Between the ages of five and ten years affected children develop seizures (initially once or twice a week, but they become less frequent after puberty). Slow decline in motor and mental skills is observed in late childhood, leading to mental retardation in early to mid adulthood. Individuals with this condition show accumulation of a characteristic abnormal material within the cells of the brain and other tissues. There is no specific treatment for this condition. Neuronal ceroid lipofuscinosis, CLN8-associated has been observed in various world populations, but is considerably more frequent in individuals with Finnish ancestry.
Neuronal ceroid lipofuscinosis, PPT1-associated is an autosomal recessive disorder which results in progressive neurologic deterioration. Individuals with this condition show accumulation of a characteristic abnormal material within the cells of the brain and other tissues. Typically symptoms become apparent between six and 24 months, usually beginning with cognitive and motor decline, decreased vision, and seizures. Life expectancy is usually less than fourteen years. In some families, manifestations begin later in childhood or in adulthood There is no curative treatment. Neuronal ceroid lipofuscinosis, PPT1-associated is more commonly found in individuals with Finnish ancestry, although it has been observed in North America and other areas of the world.
Neuronal ceroid lipofuscinosis, TPP1-associated is an autosomal recessive disorder which results in progressive neurologic deterioration. Individuals with this condition show accumulation of a characteristic abnormal material within the cells of the brain and other tissues. Typically symptoms, including vision loss, seizures, cognitive decline, and problems walking, become apparent at two to three years of age. Death usually occurs at ten to fifteen years. A form with onset later in childhood is present in some families, as are rare families with onset in late adolescence or early adulthood. There is no curative treatment. Neuronal ceroid lipofuscinosis, TPP1-associated has been observed in various world populations, but is found more frequently in persons from Newfoundland.
Niemann-Pick disease is an autosomal recessive disorder in which a substance known as sphingomyelin progressively accumulates within cells of the body due to lack of an enzyme that metabolizes that chemical. Type A presents in infancy with progressive enlargement of the liver and spleen, followed by feeding difficulties and poor growth. Cognitive and muscle development start declining by one year of life, and children with this condition rarely live past three years of age. A typical finding is a cherry-red spot on the retina. Type B is also characterized by progressive enlargement of the liver and spleen, but neurologic problems rarely occur. Lung problems can be significant for adults with type B disease. There is no specific treatment for either type. Type A is more prevalent in the Ashkenazi Jewish population, while Type B is more prevalent in north Africa and Saudi Arabia. Both are found in a variety of other populations.
Niemann-Pick Disease Type C (NPC) is a rare lipid storage disorder that is characterized by accumulation of LDL-derived cholesterol in lysosomes. This abnormality leads to progressive neurological deterioration, visceral symptoms and premature death. Neurologic abnormalities gradually develop, including ataxia, spasticity, seizures, dysarthria and dysphagia. Other features presenting later in life may include dystonia and vertical supranuclear gaze palsy, dementia and psychiatric manifestations. Hepatomegaly and/or splenomegaly may or may not be present. The age and severity of onset can vary widely. The biochemical diagnosis can be made on cultured skin fibroblasts by evaluating LDL-derived cholesterol esterification and/or with filipin staining showing intracellular accumulation of cholesterol. Two genes are associated with NPC. Mutations in the NPC1 and NPC2 genes result in similar clinical and biochemical phenotypes but can be distinguished by complementation group. NPC1 represents the major complementation group and is due to mutations in the NPC1 gene whereas NPC2 is caused by mutations in the NPC2/HE1 gene. Mutations in NPC1 are responsible for approximately 95% of Niemann-Pick Type C cases, while approximately 4-5% of patients have mutations in the NPC2/HE1 gene.
Nijmegen breakage syndrome is an autosomal recessive disorder which results in growth retardation, mental retardation, frequent infections, and tendency to develop cancer. Affected babies are generally underweight, with a small head circumference that is noted either at, or shortly after, birth. Children with this condition are generally shorter than expected for their age, and certain facial features are characteristic of this disease. Typically, cognitive development is normal in the first year, and then, over time, there is decline in intellectual ability. Individuals with Nijmegen breakage syndrome have frequent respiratory infections and an increased risk for certain cancers in childhood, particularly lymphoma. Females with this condition often have infertility due to early menopause. There is no specific treatment for this condition. Nijmegen breakage syndrome has most frequently been found in individuals with Eastern European/Slavic ancestry.
Oculocutaneous albinism (OCA1) is an autosomal recessive disorder characterized by a lack of melanin in skin, hair, and eyes. In addition to sun sensitivity due to very lightly pigmented skin, individuals with albinism have reduced visual acuity and typically also have a jerky involuntary motion of their eyes (nystagmus). Two categories of OCA are recognized: OCA1A presents at birth with white hair, white skin, and translucent irises that appear pink; In OCA1B, the skin is initially white but may darken and develop freckles, hair may be light yellow, and the eyes blue or hazel. Visual acuity is reduced in OCA1B, but is better than in OCA1A. There is no specific treatment for either category. Both forms of OCA1 are found in a variety of ethnic groups.
Oculocutaneous albinism, Type 4 (OCA4) is an autosomal recessive disorder which is characterized by reduced skin and hair pigmentation and vision problems. Symptoms generally are recognized within the first year of life and include underpigmentation of the skin, hair, and eyes, as well as a jerky motion of the eyes (nystagmus) and crossing of the eyes (strabismus). Hair color can be white or light yellow and may darken with time. Visual acuity, as well as the ability to see in three dimensions, is reduced, but is stable after early childhood. OCA4 is most commonly found in Japanese individuals.
A broad spectrum of clinical features has been found in ectodermal dysplasia patients who have compound heterozygous or homozygous mutations in WNT10A, with the most consistent clinical feature being severe oligodontia of permanent teeth. Both generalized hypohidrosis and hyperhidrosis have been reported. Excessive or reduced sweating involving palms and soles can occur. Skin is usually dry, while nails may be normal in shape and texture, or thinned, flat, convex, slow growing, or even absent at birth but develop later in childhood. Palmoplantar findings range from normal skin to severe hyperkeratosis. Scalp, body, and facial hair may be sparse. Photophobia has been described in a few patients. Patients with OODD have, in addition to oligodontia and abnormal teeth, dystrophic nails, erythematous lesions of face, and palmoplantar hyperkeratosis with hyperhidrosis. Hair may or may not be involved. SSPS is characterized by hidrocystomas (eyelid cysts) in association with other findings of ectodermal dysplasia. Heterozygotes frequently manifest mild symptoms.
Autosomal recessive osteopetrosis I is characterized by macrocephaly, progressive deafness and blindness, and enlargement of the liver and spleen resulting from abnormal bone formation. Affected individuals may also experience anemia due to bone marrow failure.
Pendred syndrome is autosomal recessive disorder characterized by congenital nerve deafness, which is usually present at birth and is nearly always identified by newborn hearing screening. Most individuals with this condition have a typical inner ear malformation known as bilateral dilation of the vestibular aqueduct, and this may also occur along with another malformation known as cochlear hypoplasia. Typically, an enlarged thyroid gland (goiter) develops later in childhood or in adulthood. There is variability in severity between and within families. There is no specific treatment. Pendred syndrome has most frequently been described in individuals of European ancestry, and has been reported in persons of various other ethnicities.
Affected individuals with peroxisome biogenesis disorder 5A typically present in the newborn period with failure to thrive due to hypotonia (low muscle tone), seizures, characteristic facial features, liver dysfunction, and bone abnormalities. Death usually occurs in the first year of life.
Phenylketonuria (PKU) is a well-characterized, treatable, biochemical disorder which results in dietary intolerance to the essential amino acid phenylalanine. It is the most common inborn error of amino acid metabolism in the Caucasian population with an average incidence of 1 in 10,000. Classic PKU is caused by complete or near-complete deficiency of phenylalanine hydroxylase activity secondary to mutations in the PAH gene. The primary route for phenylalanine metabolism is hydroxylation of phenylalanine to tyrosine catalyzed by phenylalanine hydroxylase; consequently a deficiency of this enzyme leads to an elevation of the plasma phenylalanine (phe) concentration (~ 1000 μmol/L). Without dietary restriction of phenylalanine, children with classic PKU will develop severe and irreversible mental retardation. Other clinical features evident in untreated children can include microcephaly, epilepsy, behavioral problems, eczema, hypopigmentation, decreased myelin formation and musty urine odor. Patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4) deficiency will not be expected to have disease causing mutations in PAH. BH4 deficiency is due to defects in the enzymes involved in the synthesis or regeneration of tetrahydrobiopterin (BH4), a cofactor for phenylalanine hydroxylase enzyme. BH4 deficient hyperphenylalaninemia is a genetically heterogeneous group of disorders caused by mutations in genes (GCH1, PTS, QDPR, PCBD) of the BH4 pathway.
Phosphoglycerate dehydrogenase deficiency is a metabolic disorder that is associated with growth retardation, microcephaly, hypogonadism, and hypertonia. Affected individuals develop intellectual disabilities and seizures.
Autosomal recessive polycystic kidney disease (ARPKD) is a severe autosomal recessive disease that typically begins during fetal development and primarily affects the kidney and liver. On ultrasound during pregnancy, the kidneys are enlarged, have multiple small cysts, and function poorly. Amniotic fluid is decreased, and the fetal lungs do not develop properly. In some cases, kidney and/or liver damage does not develop until later in childhood. About 1/3 of affected individuals die within the first year of life. However, treatment of the kidney disease in those who survive the first year results in survival to adolescence in about 2/3 of cases. ARPKD is most commonly reported in Caucasian individuals.
Primary ciliary dyskinesia, DNAH5-associated is an autosomal recessive disorder that affects the nasal sinuses, respiratory tract, and middle ear due to abnormalities of the cilia found in these regions. The disease presents at birth with respiratory distress, poor feeding and failure to thrive. In some affected individuals, chest and abdominal organ placement is reversed, which can result in complications. Chronic respiratory infections, nasal congestion, and persistent cough occur through adulthood. Males often are infertile, while fertility in females is variable. Primary ciliary dyskinesia, DNAH5-associated has been described most frequently in individuals of various European and Caucasian ethnicities.
Primary ciliary dyskinesia, DNAI1-associated is an autosomal recessive disorder that affects the nasal sinuses, respiratory tract, and middle ear due to abnormalities of the cilia found in these regions. The disease presents at birth with respiratory distress, poor feeding and failure to thrive. In some affected individuals, chest and abdominal organ placement is reversed, which can result in complications. Chronic respiratory infections, nasal congestion, and persistent cough occur through adulthood. Males are often infertile, while fertility in females is variable. Primary ciliary dyskinesia, DNAI1-associated has been described most frequently in individuals of various European and Caucasian ethnicities.
Glaucoma affects 67 million people worldwide, and represents a heterogeneous group of neurodegenerative disease characterized by optic disc cupping and visual field loss. Untreated, glaucoma is a leading cause of irreversible blindness caused by damage to the optic nerve. The three major types of glaucoma include primary open-angle glaucoma (POAG), primary congenital glaucoma (PCG) and primary acute closed angle glaucoma (PACG). A genetically heterogeneous group of developmental disorders known as anterior segment dysgenesis (ASD) have been reported to be associated with increased intraocular pressure (IOP) and glaucoma. Primary Congenital Glaucoma (PCG) is a form of glaucoma commonly referred to as infantile or congenital glaucoma. The incidence of PCG varies geographically from 1/10,000 in Western countries to 1/2500 in the Middle East. It is the most common form of glaucoma in infants, with more than 80% of cases observed within the first year of life. It typically manifests at birth or within the first year of life, but may manifest as late as three years of age. Characteristic clinical features of PCG include tearing, photophobia, corneal edema and buphthalmos resulting from elevated intraocular pressure, which can rapidly lead to axonal loss and permanent loss of vision in untreated individuals.
Primary hyperoxaluria Type 1 is an autosomal recessive disorder is characterized by kidney stones, calcium deposits in the kidney, and excretion in urine of large amounts of a chemical known as oxalic acid. Age of onset and severity are highly variable. Infants may fail to thrive and have anemia, excess acid in the blood, and urinary tract infections. Older individuals with milder forms of this condition most often have kidney stones as the first symptoms. Kidney failure is the most significant long term consequence of primary hyperoxaluria. Some affected individuals respond to large doses of vitamin B6, but for most part there is no specific treatment. Primary hyperoxaluria type 1 has been described in persons from many different ethnic backgrounds.
Primary hyperoxaluria Type 2 is an autosomal recessive disorder caused by excessive excretion of a chemical known as oxalic acid in the urine. Kidney stones and deposition of calcium in the kidneys are the first signs of this disorder and usually occur in childhood. About half of all individuals with this condition develop kidney failure by early adulthood. There is no specific treatment. Primary hyperoxaluria type 2 has been described mainly in Caucasian individuals with European ancestry.
Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive skeletal disorder that presents early in childhood, most often between the ages of three and eight years with joint stiffness first affecting the hips. Symptoms also include morning stiffness, decreased mobility of the neck, and swelling in the finger joints. While these symptoms are suggestive of rheumatoid arthritis, tests for rheumatoid arthritis are negative. Most affected adults are under five feet tall and have muscular weakness, difficulty walking, an abnormal gait, and are easily fatigued. There is no specific treatment for this condition. PPD has been reported more frequently in Middle Eastern/Arabic populations.
Prolidase deficiency is an autosomal recessive disorder with highly variable manifestations, both within and between families. Slowly healing, recurrent skin ulcers on the hands and feet are characteristic and become apparent between 19 months and late adolescence. Fifty to 75% of affected individuals are mentally retarded, half have recurrent upper respiratory tract infections, and about a third have an enlarged spleen. Affected, but asymptomatic, adults have also been reported. Early death may occur following a respiratory infection. No specific treatment is available for this condition. Prolidase deficiency has been described in many ethnic groups, but is more commonly found among the Druze of the Middle East.
Propionic acidemia, PCCA-associated is an autosomal recessive disorder of amino acid metabolism that presents shortly after birth or in the first months of life with poor feeding, vomiting, and lethargy. Vomiting and changes in consciousness typically occur in episodes, during which affected infants usually have elevated low blood sugar (hypoglycemia), excess acid in the blood, elevated ammonia in the blood, and a reduced number of white blood cells. The disorder can be identified by newborn screening, and usually results in early death if unrecognized and untreated. Prognosis is improved with dietary management and managing triggers such as fever, infections, and fasting; however, not all patients achieve normal growth and development, even with optimal treatment. This condition is found in various ethnicities and regions of the world.
Propionic acidemia, PCCB-associated is an autosomal recessive disorder with symptoms that usually present within the first few days of life and include poor feeding, vomiting, lethargy, low muscle tone, along with biochemical findings that are characteristic of the disorder. These symptoms may proceed to more serious medical problems such as heart abnormalities, seizures, developmental delay, coma and in some cases death. Dietary management with protein restrictions, and metabolic management can improve prognosis, however even with prompt treatment, children with this condition may still experience health problems, including intellectual disability. PCCB-associated Propionic Acidemia has been reported among a variety of world populations, although it is reported more frequently in individuals of Japanese descent.
Pseudoxanthoma elasticum is an autosomal recessive disorder affecting the skin, eyes, and blood vessels. Symptoms vary both between and within families; however, typical manifestations include skin and eye findings that become apparent in childhood or in young adults. Yellowish pimples, which eventually grow together into larger plaques, are usually the first cutaneous manifestations, followed by progressively lax skin that has the appearance of premature aging. There is a characteristic appearance to the retina (angioid streaks), and progressive visual loss leading to legal blindness, but usually not to total loss of vision, may occur. Less commonly, blood vessels are affected, leading to early heart attacks, pain when walking, or occasionally internal bleeding. Life expectancy for most affected individuals is normal. There is no specific treatment for this condition. Pseudoxanthoma elasticum is found in many populations, and is more frequent in Afrikaaners of South Africa.
Pycnodysostosis is an autosomal recessive disorder characterized by moderately short limbs and stature, a large and abnormally shaped head, a small nose, a receding chin, and increased density and fragility of the bones. Missing teeth or delayed eruption of primary and/or adult teeth is common. The soft spot (anterior fontanelle) on the top of the head, which usually closes in infancy, can remain open life long in this condition. Life span is generally normal. There is no specific treatment for this condition. Pycnodysostosis has been described in a number of different populations.
Pyridoxine-dependent epilepsy is an autosomal recessive disorder characterized by seizures, which usually begin soon after birth, and are resistant to standard treatment with anti-seizure medications. However, when large doses of pyridoxine (vitamin B6) are administered, the seizures vanish, and do not require anti-seizure medications as long as the pyridoxine is continued. Individuals with this disorder often have intellectual disability, but early treatment with pyridoxine may minimize this. Pyroxidine-dependent epilepsy has been most frequently reported in various European Caucasian ethnicities, but is probably present in other populations as well.
Retinal dystrophy, RLBP1-associated is an autosomal recessive disorder resulting in progressive loss of vision. In general, the retina eventually develops a distinctive appearance, with white dots spread out over the entire retina (retinitis punctata albescens). Night blindness is usually the first manifestation of this condition and can be present in early childhood. Loss of peripheral, central, and color vision occur later. Individuals from Newfoundland with this condition generally become symptomatic in the first decade of life, with rapid progression leading to legal blindness by the second to fourth decades and later to further decrease in visual acuity. Affected individuals from the Bothnia region of northern Sweden generally have severe night blindness in early childhood and macular degeneration starting in late childhood or the early teens. There is no specific treatment for this condition. Retinal dystrophy, RLBP1-associated is considerably more prevalent among individuals from Northern Sweden and the Canadian province of Newfoundland, but is seen in other ethnic groups as well.
Retinitis pigmentosa, EYS-associated (RP-EYS) is an autosomal recessive disorder causing progressive visual loss and accompanied by abnormal pigment in the retina. Symptoms of RY-EYS typically begin at an early age with night blindness, followed by progressive constriction of the peripheral visual field and, eventually, loss of central vision. There is no specific treatment for this condition. RP-EYS may be the most frequent genetic form of retinitis pigmentosa in Israel, and is more frequent in individuals with Moroccan Jewish, and possibly Spanish, ancestry
Retinitis pigmentosa is characterized by the deterioration on light detecting retinal cells, which results in a loss of night and peripheral vision. Vision loss associated with retinitis pigmentosa 59 is progressive.
Rhizometic chondrodysplasia punctata Type 1 is an autosomal recessive disorder characterized by shortening of the forearms and thigh bones and dot-like (punctate) calcium deposits in the cartilage at the ends of bones. Additional symptoms include seizures, cataracts, profound growth retardation, severe intellectual disability, and painful joint contractures. The majority of affected children do not survive past the first decade of life. There is no effective treatment. Rhizomelic chondrodysplasia punctata type 1 has been described in many different populations.
Salla disease, also known as Finnish type sialuria, is an autosomal recessive disorder which results in progressive neuromuscular deterioration. Affected infants appear healthy and normal at birth, but by one year of age exhibit low muscle tone and muscular incoordination. Over time, further slow progression results in intellectual disability, spasticity, an abnormal gait (ataxia), seizures, and coarsening of the facial features. A small proportion of individuals with Salla disease have later onset and less severe symptoms. Individuals with Salla disease usually live into adulthood, although lifespan tends to be shortened. There is no specific treatment for this condition. Salla disease is almost exclusively seen in individuals of Finnish descent, less frequently, in those of Swedish descent, and rarely in other ethnic groups.
Sandhoff disease is an autosomal recessive progressive neurodegenerative disorder. The condition typically begins with weakness at six months of age, an abnormal startle response to sounds, an enlarged head, vision loss with a cherry-red spot on the retina, and seizures. There is relentless, progressive loss of motor skills and mental functioning, leading to a complete vegetative state in early childhood. Juvenile and adult onset forms are rarer and present with muscle weakness, learning disabilities, slow cognitive decline, and dementia. No specific treatment for this condition exists. Sandhoff disease has been observed worldwide in many different populations; however, there are an increased number of cases seen in the Maronite population of Cyprus.
Sanfilippo syndrome, Type A, also known as mucopolysaccharidosis IIIA, is an autosomal recessive disorder caused by accumulation of a chemical known as a mucopolysaccharide within cells due to absence of an enzyme necessary to metabolize that substance. Affected individuals have progressive deterioration of cognitive function, accompanied by hyperactivity, seizures, aggressive behavior, sleep disturbances, and loss of hearing and vision. The first signs are usually serious behavior and sleep problems, which begin around two years of age. Thickened skin, abundant coarse hair, and mild changes in bones and joints become more noticeable with age. Death usually occurs in the second or third decade of life. Treatment is symptomatic. Sanfilippo syndrome, type A has been described in a variety of world populations.
Sanfilippo syndrome, Type B, also known as mucopolysaccharidosis IIIA, is an autosomal recessive disorder caused by accumulation of a chemical known as a mucopolysaccharide within cells due to absence of an enzyme necessary to metabolize that substance. Affected individuals have progressive deterioration of cognitive function, accompanied by hyperactivity, seizures, aggressive behavior, sleep disturbances, and loss of hearing and vision. The first signs are usually serious behavior and sleep problems, which begin around two years of age. Thickened skin, abundant coarse hair, and mild changes in bones and joints become more noticeable with age. Death usually occurs in the second or third decade of life. Treatment is symptomatic. Sanfilippo syndrome, type B has been described in a variety of world populations.
Sanfilippo syndrome, Type C, also known as mucopolysaccharidosis IIIA, is an autosomal recessive disorder caused by accumulation of a chemical known as a mucopolysaccharide within cells due to absence of an enzyme necessary to metabolize that substance. Affected individuals have progressive deterioration of cognitive function, accompanied by hyperactivity, seizures, aggressive behavior, sleep disturbances, and loss of hearing and vision. The first signs are usually serious behavior and sleep problems, which begin around two years of age. Thickened skin, abundant coarse hair, and mild changes in bones and joints become more noticeable with age. Death usually occurs in the second or third decade of life. Treatment is symptomatic. Sanfilippo syndrome, type C has been described in a variety of world populations.
Segawa syndrome, also known as dopa-responsive dystonia, is an autosomal recessive disease that presents typically by the end of the first year with drooping eyelids, inexpressive facial features, tremors, low muscle tone, abnormal posturing, and twisting or repetitive movements in the limbs. Some affected indivuals manifest more severe symptoms of Parkinson disease in infancy. Treatment with levodopa or other medications dramatically improves motor function in the majority of mildly affected individuals. Segawa syndrome has been described in various populations.
Severe combined immunodeficiency, Athabaskan-type (SCIDA) is an autosomal recessive immune deficiency. Both B cells and T cells are absent from the blood, and the amount of gamma globulin in blood is reduced in affected individuals. Children with this form of SCID typically develop oral thrush, diarrhea, or other recurrent and persistent infections in early infancy. Failure to thrive is frequent, and early death occurs if patients are untreated. Treatment is mainly symptomatic; bone marrow transplantation has been successful in some cases. This form of SCID is predominantly seen in Athabaskan-speaking Navajo and Apache native Americans.
Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency also known as 2-methylbutyryl-CoA dehydrogenase deficiency is a rare disorder of isoleucine metabolism. The clinical spectrum of this disorder has not been clearly defined as few patients with SBCAD deficiency have been described. Very few symptomatic patients have been reported. Several symptomatic patients presented with acute crisis in the newborn period including lethargy, poor feeding, apnea, hypothermia, hypoglycemia, EEG and MRI abnormalities, convulsions, lactic acidosis, respiratory distress, seizures, sepsis, disseminated intravascular coagulation and cerebral hemorrhage. Another group of symptomatic patients presented after the neonatal period with symptoms that include hypotonia, motor delay, strabismus, apnea, infantile spasms, developmental delay, attention deficit hyperactivity disorder, recurrent vomiting and failure to thrive. A mother of one of the affected patients was also diagnosed with SBCAD deficiency but is healthy. Most patients have been diagnosed following positive newborn screening result for C5 elevation or were identified after the diagnosis of SBCAD in a sibling. These individuals have remained healthy, most with little or no treatment.
Sialidosis Type 2 is an autosomal recessive disorder with symptoms usually appearing in early childhood that include gradual coarsening of facial features, enlarged liver and spleen, enlarged heart, abnormal development of bone and cartilage (dysostosis multiplex), abnormal muscle movements (myoclonus), mental retardation, and a cherry-red spot in the retina. In its severest form, it can present prenatally with abnormal ultrasound findings (hydrops fetalis), and babies are typically stillborn or die soon after birth. The milder infantile and juvenile forms of the condition appear during the first year of life and later in childhood, respectively. There is currently no effective treatment. Sialidosis type II has been described in various ethnicities.
Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by dry and scaly skin (ichthyosis), mental retardation, and spasticity of the legs. Ichthyosis, often accompanied by redness (erythema) is typically present at birth or in the first few months of life. Mental retardation ranges from mild to profound and does not appear until childhood. An abnormal appearance of the retina is often present. There is no specific treatment. SLS has most frequently been reported in individuals of Swedish descent; however, it has been described in other world populations as well.
Smith-Lemli-Opitz Syndrome (SLOS) is a severe developmental disorder. The clinical spectrum is wide and includes both pre- and post-natal growth retardation, mild to severe mental retardation, multiple congenital malformations (both major and minor), and characteristic facies. Frequent additionally observed findings include: microcephaly, micrognathia, cleft palate, cardiac defects, abnormal external genitalia, post-axial polydactyly, and 2-3 toe syndactyly. Infants are often hypotonic with poor suck, and have failure to thrive. Older children commonly have behavioral concerns including autism, hyperactivity, aggression, and self-injurious behavior. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and low levels of serum cholesterol. In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme 3b-hydroxysterol D7-reductase (sterol delta-7-reductase), which is encoded by the gene DHCR7. DHCR7 is also required to reduce 7-dehydrodesmosterol to desmosterol. Mutations in the DHCR7 gene underlie SLOS.
Spinal muscular atrophy is an auto-recessive neuromuscular disorder that affects the control of muscle movement. The disease is usually diagnosed early in life and is the leading cause of death in infants and toddlers due to genetic disease. It is characterized by a loss of motor neurons in the spinal cord and brainstem. This leads to weakness and atrophy of muscles used for activities such as crawling, walking, sitting up, and controlling head movement. In severe cases, the muscles used for breathing and swallowing are affected. Spinal muscular atrophy is divided into subtypes based on the severity of the disease and the age when symptoms appear. The disease affects individuals of all races and appears in 1 in 6,000 to 1 in 10,000 births.
Stargardt disease, Type 1 is an autosomal recessive disease that is the most common form of childhood onset macular degeneration. Symptoms typically manifest in the first or second decade of life, and initially include blurred or hazy vision, followed by decreased central vision. Although visual acuity is ultimately severely reduced, peripheral vision is retained. There is no specific treatment for this condition. Stargardt disease, type 1 has been reported in a variety of different world populations.
Stuve-Wiedemann syndrome, also known as Schwartz-Jampel Syndrome type 2, is an autosomal recessive disorder characterized by shortening and congenital bowing of the long bones, facial abnormalities, and finger and joint contractures. In addition to the skeletal abnormalities, affected babies have respiratory problems, feeding difficulties, and episodes of high fever. Death in infancy is common, although survival into childhood has been reported. Stuve-Wiedemann syndrome has been described more frequently in individuals from Oman and the United Arab Emirates.
Tay-Sachs disease (TSD) is a lysosomal storage disorder with symptoms ranging from an acute infantile form (classic TSD) to subacute juvenile and adult onset forms with later onset and slower disease progression. Infants with classic TSD generally appear normal at birth. At 3-6 months of age motor weakness, myoclonic jerks and an exaggerated startle reaction are usually the presenting features followed by developmental retardation and regression, paralysis, dementia and blindness with death by the second or third year of life. A cherry-red macula is a typical fundoscopic finding and, histologic examination reveals the lysosomal accumulation of GM2 gangliosides represented as distended, ballooned neurons in the central nervous system. The juvenile and adult forms have more variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, motor neuron disease, and in some individuals with the adult onset form, a bipolar form of psychosis. The juvenile and adult onset forms differ from each other primarily by the impact of the disease on intelligence, which is minimal through much of the course of the adult form. The carrier frequency in Ashkenazi Jews is approximately 1 in 30, while the carrier in Sephardic Jews and non-Jews is approximately 1 in 250 to 1 in 300. Other groups that are relatively genetically isolated have also been found to have carrier frequencies similar to or higher than that observed in Ashkenazi Jews including French Canadians from eastern Quebec, Cajuns from Louisiana and the Old Order Amish in Pennsylvania.
The Triple-A (Allgrove) syndrome is characterized by the triad of familial adrenoinsufficiency due to corticotropin (ACTH) resistance, achalasia (swallowing difficulties), and alacrima (deficient secretion of tears). The disorder usually manifests within the first decade of life with alacrima and/or achalasia, followed by glucocorticoid deficiency. Life-threatening complications include hypoglycemic episodes and severe feeding difficulties. Affected individuals typically have several additional clinical concerns, such as progressive peripheral and/or autonomic neuropathy, punctate palmoplantar keratoderma (patches of callused skin on palms and soles), dry mouth, angular cheilitis and fissured tongue, mild mental retardation, osteoporosis and, rarely, short stature. The pattern and severity of neurologic and autonomic dysfunction in Triple-A syndrome is quite variable, including hyperreflexia, impaired visual evoked potentials, optic nerve atrophy, anisocoria (unequal pupil size), abnormal sweating, postural (orthostatic) hypotension with compensatory tachycardia, muscle weakness, ataxia, parkinsonism, and motor peripheral neuropathy. Hence the clinical diagnosis of Triple-A syndrome may be difficult. Because autonomic neuropathy and amyotrophy (muscle wasting) appear to be integral features of this disorder, the name “4A syndrome” has been considered.
Tyrosinemia Type I, also known as hepatorenal tyrosinemia, is an autosomal recessive disorder of amino acid metabolism which results in severe liver and kidney disease. Many affected babies are identified by newborn screening. Affected children who are not detected by newborn screening often present prior to six months of age with acute liver failure, and may also have a characteristic boiled cabbage odor. Others may present between six months and one year with milder liver disease, low blood sugar, enlargement of the liver and spleen, and kidney disease. Some affected children show later onset of liver disease, kidney disease, growth failure, and rickets. All affected individuals, if untreated, have a high risk of developing liver cancer at a young age or dying suddenly. Management of tyrosinemia type I employs a special diet and treatment with a medication known as NTBC (nitisinone/Orfadin); liver transplantation is rarely necessary with current methods of treatment. Tyrosinemia type I occurs in various ethnic groups, but is more common in Finland and other parts of Scandinavia, and is considerably more common in the Canadian province of Quebec (particularly in the the Saguenay-Lac-Saint-Jean region).
Usher syndrome Type 1B is an autosomal recessive disorder characterized by profound congenital bilateral deafness, progressive vision abnormalities, and balance problems due to inner ear (vestibular) abnormalities. Aside from hearing loss, which is normally identified by newborn hearing screening, the earliest manifestation in affected children is difficulty walking and clumsiness related to the balance problems. Typically prior to puberty, affected children develop night blindness, which eventually progresses to loss of peripheral vision (tunnel vision) and to decreased acuity. A characteristic eye finding is abnormal pigmentation of the retina (retinitis pigmentosa). Early treatment of the hearing loss with cochlear implants permits development of speech. There is currently no treatment for the balance or vision problems. This condition occurs in a variety of ethnic groups.
Usher syndrome Type 1C is an autosomal recessive disorder characterized by profound congenital bilateral deafness, progressive vision abnormalities, and balance problems due to inner ear (vestibular) abnormalities. Aside from hearing loss, which is normally identified by newborn hearing screening, the earliest manifestation in affected children is difficulty walking and clumsiness related to the balance problems. Typically prior to puberty, affected children develop night blindness, which eventually progresses to loss of peripheral vision (tunnel vision) and to decreased acuity. A characteristic eye finding is abnormal pigmentation of the retina (retinitis pigmentosa). Early treatment of the hearing loss with cochlear implants permits development of speech. There is currently no treatment for the balance or vision problems. This condition occurs in a variety of ethnic groups, but is more frequent in persons of French-Canadian/Acadian (Cajun) ancestry.
Usher syndrome Type 1D is an autosomal recessive disorder characterized by profound congenital bilateral deafness, progressive vision abnormalities, and balance problems due to inner ear (vestibular) abnormalities. Aside from hearing loss, which is normally identified by newborn hearing screening, the earliest manifestation in affected children is difficulty walking and clumsiness related to the balance problems. Typically prior to puberty, affected children develop night blindness, which eventually progresses to loss of peripheral vision (tunnel vision) and to decreased acuity. A characteristic eye finding is abnormal pigmentation of the retina (retinitis pigmentosa). Early treatment of the hearing loss with cochlear implants permits development of speech. There is currently no treatment for the balance or vision problems. This condition occurs in a variety of ethnic groups.
Usher syndrome Type 1F is an autosomal recessive disorder characterized by profound congenital bilateral deafness, progressive vision abnormalities, and balance problems due to inner ear (vestibular) abnormalities. Aside from hearing loss, which is normally identified by newborn hearing screening, the earliest manifestation in affected children is difficulty walking and clumsiness related to the balance problems. Typically prior to puberty, affected children develop night blindness, which eventually progresses to loss of peripheral vision (tunnel vision) and to decreased acuity. A characteristic eye finding is abnormal pigmentation of the retina (retinitis pigmentosa). Early treatment of the hearing loss with cochlear implants permits development of speech. There is currently no treatment for the balance or vision problems. Usher syndrome type 1F is more common among individuals of Ashkenazi Jewish descent, but is also present in other populations.
Usher syndrome Type IIA is an autosomal recessive disorder characterized by congenital hearing loss which is mild to moderate in the low frequencies and profound in the higher frequencies. The degree of hearing loss tends to be variable, even among members of the same family. Night blindness, loss of peripheral vision (tunnel vision), and a characteristic finding of abnormal pigment of the retina (retinitis pigmentosa) develop in adolescence. Usher Syndrome type 2A has been described in a variety of ethnicities.
Usher syndrome Type 3 is an autosomal recessive disorder characterized by progressive hearing loss occurring after a child develops language skills, and eye findings consisting of abnormal retinal pigmentation (retinitis pigmentosa), night blindness, and tunnel vision. Both hearing and vision are initially normal. The vision problems typically become apparent after adolescence. Some, but not all individuals with this condition have balance issues due to inner ear (vestibular) abnormalities. Usher syndrome type 3 is more commonly found in Ashkenazi Jewish and Finnish individuals, but it also occurs in other ethnic groups.
Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) is an autosomal recessive, rare disorder of fatty acid oxidation. Presentation is variable, and has been classified into three forms: a severe neonatal form with high mortality and hypertrophic cardiomyopathy, hepatomegaly and hypotonia, a milder childhood form with hypoketotic hypoglycemia, hepatomegaly and hypotonia, and an adult-onset form with isolated skeletal muscle involvement, leading to muscle pain, rhabdomyolysis or myoglobinuria.
Vitamin D-dependent rickets Type 1 syndrome is an autosomal recessive condition caused by the inability of the body to make the active form of vitamin D. Symptoms are those of vitamin D deficiency and include seizures from low blood calcium, failure to thrive in infancy, muscle weakness, bone pain, bone deformity, and characteristic bone abnormalities (rickets) seen on X-rays. Symptoms usually occur prior to two years of age, and diagnosis is often delayed due to the non-specific nature of the early manifestations. Lifelong treatment with large doses of vitamin D and supplemental calcium is nearly always effective. Vitamin D-dependent rickets type 1 is more common among individuals of French-Canadian ancestry.
Walker-Warburg syndrome (WWS) associated with the FKTN gene is an autosomal recessive disorder characterized by muscular weakness present at birth, along with severe brain and eye abnormalities. The surface of the brain is abnormally smooth (lissencephaly), the cerebellum and brainstem are underdeveloped, and most infants have water on the brain (hydrocephalus). Congenital cataracts and retina malformations are usually also present. Severe developmental delay ensues, and most affected children die in early childhood. Although WWS has been described in a variety of ethnic populations, WWS associated with the FKTN gene is more commonly found among individuals of Ashkenazi Jewish and Japanese ancestry.
Werner syndrome is an autosomal recessive disorder characterized by premature aging and by early onset of diseases associated with old age. Physical development is usually normal until the teenage years, and lack of a normal growth spurt (often noted only in retrospect) is usually the first symptom. Gray hair and hair loss develops around age 20, followed by accelerated aging of the skin, cataracts, and diabetes in the following decades. The most common causes of death, which typically occurs by the fifth decade of life, are cancer and heart disease. Werner syndrome is more frequent in Japanese individuals and individuals from Sardinia; however, it has been described in many different populations.
Wilson disease is an autosomal recessive disorder of copper metabolism that presents as early as three years of age with liver, neurologic, and/or psychiatric problems. Liver disease may include hepatitis-like symptoms, including fatigue and abdominal pain, and liver failure may also occur. Neurological problems include tremors, poor coordination, loss of fine-motor control, and abnormal twisting muscle movements. Adults often present with psychiatric manifestations such as depression, neurotic behavior, and, occasionally, intellectual deterioration. A reduced copper diet and treatment with medications that remove excess copper from the body (chelating agents) can reduce or eliminate many of the health problems associated with this condition. Wilson disease has been described in many ethnicities.
X-Linked juvenile retinoschisis is an X-linked disorder usually presenting between five and ten years of age with decreased visual acuity. Acuity is typically 20/60 to 20/120 on initial presentation and generally stabilizes by adolescence, although progressive vision deterioration often occurs later in life. Retinal detachment is a rare complication. There is no specific treatment for this condition. For this and other X-linked conditions, males are considerably more frequently affected with X-linked juvenile retinoschisis than females. Although X-linked juvenile retinoschisis has been reported in various populations, the condition is most frequently found in individuals of European Caucasian descent.
X-Linked Severe Combined Immunodeficiency (XSCID) is a severe combined immunodeficiency disorder that typically has a lymphocyte profile of T−, B+, NK−, with a prevalence of about 1 in 50,000 to 1 in 100,000 live births. XSCID usually manifests in affected males between three and six months of age. The clinical presentation during the first year of life almost universally includes failure to thrive, oral/diaper candidiasis, recurrent infections, absent tonsils and lymph nodes, persistent infections and infections with opportunistic organisms. Other features that may be noted are disseminating infections, recurrent bacterial meningitis and transplacental transfer of maternal lymphocytes to the infant, resulting is graft-vs-host disease with erythematous skin rashes, hepatomegaly and lymphadenopathy. Atypical XSCID occurs in a small subset of patients whose IL2RG gene produces a small amount of protein with residual activity. These individuals have an atypical presentation that is T+B+NK−. These patients may display immune disregulation and autoimmunity presenting with rashes, splenomegaly, gastrointestinal malabsorption, other autoimmune conditions, and short stature.
Zellweger spectrum disorder, PEX1-associated is an autosomal recessive condition with variable manifestations, but categorized as: Zellweger syndrome, the most severe form; neonatal adrenoleukodystrophy, an intermediate form; and infantile Refsum disease, the least severe form. Zellweger syndrome manifests at or shortly after birth and is characterized by low muscle tone, feeding difficulty, seizures, characteristic abnormal facial features, severe developmental delay, and an enlarged, abnormally functioning liver. Death typically occurs within the first year of life. Neonatal adrenoleukodystrophy and infantile Refsum disease are more slowly progressing disorders that typically become evident in late infancy or early childhood with low muscle tone, deafness, vision problems with distinctive changes on the retina, liver dysfunction causing a bleeding tendency, and developmental delay. Survival into childhood is common in neonatal adrenoleukodystrophy, and individuals with infantile Refsum disease may survive into adulthood. There is no curative treatment. Zellweger spectrum disorders have been described in a variety of ethnic backgrounds.