List of monogenic conditions screened by VERAgene
| Condition | Impact | Summary | Symptoms |
| 3 Methylcrotonyl CoA Carboxylase Deficiency 1 | severe | 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC deficiency) is an inherited condition in which the body is unable to breakdown the amino acid, leucine (a building block of protein). Some children with 3-MCC deficiency will begin developing signs and symptoms during infancy or early childhood; however, more recent studies suggest that many affected babies identified through newborn screening will never experience symptoms of the condition. 3-MCC deficiency may be associated with episodes of “metabolic crisis” in which affected people experience poor appetite, lack of energy, irritability, weakness, nausea and/or vomiting. If metabolic crises are untreated, the condition can lead to developmental delay, seizures, coma, and even death. 3-MCC-1 deficiency is caused by changes (mutations) in MCCC1 gene. Treatment may include a low-leucine diet and appropriate supplements. | Acute hepatic steatosis, Generalized hypotonia, Failure to thrive, Ketonuria, Coma, Hyperreflexia, Phenotypic variability, Hypoglycemia, Episodic metabolic acidosis, Intellectual disability, Heterogeneous, Acute hyperammonemia, Lethargy, Vomiting, Opisthotonus, Seizures, Global developmental delay, Feeding difficulties in infancy. |
| 3 Methylcrotonyl CoA Carboxylase Deficiency 2 | severe | 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC deficiency) is an inherited condition in which the body is unable to breakdown the amino acid, leucine (a building block of protein). Some children with 3-MCC deficiency will begin developing signs and symptoms during infancy or early childhood; however, more recent studies suggest that many affected babies identified through newborn screening will never experience symptoms of the condition. 3-MCC deficiency may be associated with episodes of “metabolic crisis” in which affected people experience poor appetite, lack of energy, irritability, weakness, nausea and/or vomiting. If metabolic crises are untreated, the condition can lead to developmental delay, seizures, coma, and even death. 3-MCC-2 deficiency is caused by changes (mutations) in MCCC2 gene. Treatment may include a low-leucine diet and appropriate supplements. | Generalized hypotonia, Seborrheic dermatitis, Feeding difficulties, Failure to thrive, Coma, Hyperreflexia, Hyperglycinuria, Phenotypic variability, Intellectual disability, Heterogeneous, Metabolic acidosis, Acute hyperammonemia, Alopecia, Organic aciduria, Lethargy, Vomiting, Ketoacidosis, Opisthotonus, Skeletal muscle atrophy, Propionyl-CoA carboxylase deficiency, Seizures, Global developmental delay. |
| Abetalipoproteinemia | severe (moderate) | Abetalipoproteinemia is a condition characterized by the inability to fully absorb dietary fats, cholesterol and fat-soluble vitamins. Signs and symptoms appear in the first few months of life and can include failure to thrive; diarrhea; acanthocytosis; and stool abnormalities. Other features develop later in childhood and often impair the function of the nervous system, potentially causing slower intellectual development; poor muscle coordination; progressive ataxia; and an eye disorder called retinitis pigmentosa. Most of the symptoms are due to defects in the absorption and transport of vitamin E. Abetalipoproteinemia is caused by mutations in the MTTP gene. Early diagnosis, high-dose vitamin E therapy, and medium-chain fatty acid supplements may slow the progression of the nervous system abnormalities. Long-term outlook is reasonably good for most affected people who are diagnosed early. If left untreated, the condition can result in early death. | Retinopathy, CNS demyelination, Abetalipoproteinemia, Peripheral demyelination, Pigmentary retinal degeneration, Fat malabsorption, Ataxia, Acanthocytosis. |
| Arthrogryposis Mental Retardation Seizures | severe | Autism spectrum disorder-epilepsy-arthrogryposis syndrome is a form of congenital disorders of N-linked glycosylation characterized by distal arthrogryposis (mild flexion contractures of the fingers, deviation of the distal phalanges, swan-neck deformity), retromicrognathia, general muscle hypotonia, delayed psychomotor development, autism spectrum disorder (speech delay, abnormal use of speech, difficulties in initiating, understanding and maintaining social interaction, limited non-verbal communication and repetitive behavior), seizures, microcephaly and mild to moderate intellectual disability that becomes apparent with age. The disease is caused by mutations in the gene SLC35A3. | Abnormality of the skeletal system, arthrogryposis multiplex congenita, hip dislocation, microretrognathia, hammertoe, knee dislocation, camptodactyly of finger, scoliosis, hip dysplasia, microcephaly, abnormality of the nervous system, intellectual disability, seizures, autistic behavior, global developmental delay, abnormality of limbs, abnormality of the musculature, generalized hypotonia, abnormality of connective tissue, abnormality of head or neck. |
| Autosomal recessive polycystic kidney disease | severe | Autosomal recessive polycystic kidney disease (ARPKD) is a genetic condition that is characterized by the growth of cysts in the kidneys (which lead to kidney failure) and liver and problems in other organs, such as the blood vessels in the brain and heart. The severity varies from person to person. The signs of ARPKD frequently begin before birth, so it is often called “infantile PKD” but some people do not develop symptoms until later in childhood or even adulthood. Children born with ARPKD often, but not always, develop kidney failure before reaching adulthood; babies with the worst cases die hours or days after birth due to respiratory difficulties or respiratory failure. Liver scarring occurs in all patients. The condition is caused by mutations in the PKHD1 gene. Some symptoms of the condition may be controlled by medicines, antibiotics, healthy diet, and growth hormones. | Esophageal varix, Renal insufficiency, Portal hypertension, Renal cyst, Periportal fibrosis, Dehydration, Hepatic cysts, Pancreatic cysts, Potter facies, Enlarged kidney, Splenomegaly, Neonatal death, Oligohydramnios, Polycystic kidney dysplasia, Tubulointerstitial fibrosis, Pulmonary hypoplasia, Absence of renal corticomedullary differentiation, Hepatomegaly. |
| Bardet Biedl syndrome 12 | severe (blindness) | Bardet-Biedl syndrome (BBS) is an inherited condition that affects many parts of the body. People with this syndrome have progressive visual impairment due to cone-rod dystrophy; extra fingers or toes (polydactyly); truncal obesity; decreased function of the male gonads (hypogonadism); kidney abnormalities; and learning difficulties. Mutations in at least 14 genes are known to cause Bardet-Biedl syndrome. Bardet Biedl syndrome 12 is caused by mutations in the BBS12 gene. Treatment depends on the symptoms present in each person. | Rod-cone dystrophy, Cognitive impairment, Obesity, Abnormality of the kidney, Hypogonadism, Polydactyly. |
| Beta thalassemia | very severe | Beta-thalassemia is a blood disorder that reduces the body’s production of hemoglobin. Low levels of hemoglobin lead to a shortage of mature red blood cells and a lack of oxygen in the body. Affected people have anemia, which can cause paleness, weakness, fatigue, and more serious complications. Severe beta-thalassemia is called “thalassemia major” or “Cooley’s anemia.” Thalassemia intermedia is a less severe form. Beta-thalassemia is caused by mutations in the HBB gene. People who have only one HBB gene mutation may have no symptoms or develop mild symptoms, and are said to have thalassemia minor. Treatment depends on the severity in each person and may include transfusions, folic acid supplementation, iron chelation, and/or bone marrow transplantation (the only definitive cure). | Reduced beta/alpha synthesis ratio, Hypochromic microcytic anemia, abnormal haemoglobin. |
| Butyrylcholinesterase deficiency | moderate (anaesthetic usage) | Pseudocholinesterase deficiency is a condition that causes increased sensitivity to certain muscle relaxant drugs used during general anesthesia (choline esters). These drugs relax the muscles used for movement, including those used for breathing. Normally, the muscles are able to move again a few minutes after the drugs are given. People with pseudocholinesterase deficiency may not be able to move or breathe on their own for a few hours after these drugs are given. They therefore may need mechanical ventilation until the drugs are cleared from the body. People with this condition may also have increased sensitivity to other types of drugs as well as to some agricultural pesticides. Pseudocholinesterase deficiency can be inherited (genetic) or acquired. When it is inherited, it is caused by mutations in the BCHE gene. Acquired pseudocholinesterase deficiency may have various causes such as chronic infection, kidney or liver disease, malnutrition, major burns, cancer, or various medications. | Apnea, abnormality of metabolism/homeostasis |
| Canavan disease | severe | Canavan disease is an inherited disorder that causes progressive damage to nerve cells in the brain. This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies disrupt the growth or maintenance of the myelin sheath, which is the fatty covering that insulates nerve fibers. Canavan disease is caused by mutations in the ASPA gene. While it occurs in people of all ethnic backgrounds, it is most common in people of Ashkenazi (eastern and central European) Jewish heritage, and among Saudi Arabians. | CNS demyelination, Brain atrophy, Blindness, Nystagmus, Optic atrophy, Aplasia/Hypoplasia involving the central nervous system, Macrocephaly, Developmental regression, Hearing impairment, Delayed closure of the anterior fontanelle, Opisthotonus, Muscular hypotonia, Generalized seizures |
| Choreacanthocytosis | moderate | Choreacanthocytosis is one of a group of conditions called the neuroacanthocytoses that involve neurological problems and abnormal red blood cells. The condition is characterized by involuntary jerking movements (chorea), abnormal star-shaped red blood cells (acanthocytosis), and involuntary tensing of various muscles (dystonia), such as those in the limbs, face, mouth, tongue, and throat. Choreacanthocytosis is caused by mutations in the VPS13A gene. There are currently no treatments to prevent or slow the progression of choreacanthocytosis; treatment is symptomatic and supportive. | Limb muscle weakness, Self-mutilation of tongue and lips due to involuntary movements, Anxiety, Acanthocytosis, Aggressive behavior, Dementia, Drooling, Tics, Sensory neuropathy, Dystonia, Elevated serum creatine phosphokinase, Progressive, Mood changes, Seizures, Caudate atrophy, Dysarthria, Progressive choreoathetosis, Psychosis, Disinhibition, Pes cavus, Dysphagia, Hyporeflexia, Personality changes, Orofacial dyskinesia, Parkinsonism, Skeletal muscle atrophy, Areflexia |
| Crigler Najjar syndrome, Type I | Crigler Najjar syndrome, type 1 is an inherited disorder in which bilirubin, a substance made by the liver, cannot be broken down. This condition occurs when the enzyme that normally converts bilirubin into a form that can easily be removed from the body does not work correctly. Without this enzyme, bilirubin can build up in the body and lead to jaundice and damage to the brain, muscles, and nerves. Crigler Najjar syndrome, type 1 is caused by mutations in the UGT1A1 gene. Treatment relies on regular phototherapy throughout life. Blood transfusions and calcium compounds have also been used. Liver transplantation may be considered in some individuals. | Jaundice, Kernicterus, Unconjugated hyperbilirubinemia, Encephalopathy | |
| Cystic fibrosis | very severe | Cystic fibrosis (CF) is a genetic disorder that causes mucus to build up and clog some of the organs in the body, particularly in the lungs and pancreas. Symptoms may include very salty-tasting skin persistent coughing frequent lung infections including pneumonia or bronchitis, wheezing or shortness of breath, poor growth, weight loss, frequent greasy, bulky stools or difficulty with bowel movements, and, in males, infertility. Over time, mucus build up and infections can lead to permanent lung damage, including the formation of scar tissue (fibrosis) and cysts in the lungs. CF is caused by mutations in the CFTR gene. Treatment depends on the symptoms, and usually includes respiratory therapies, inhaled medicines, pancreatic enzyme supplement, nutritional supplements, and others. Newer medication such as CFTR modulators have been approved for use in United States. Ongoing research is focused on finding the cure for the disease. | Hypercalciuria, Male infertility, Elevated sweat chloride, Failure to thrive, Cor pulmonale, Dehydration, Exocrine pancreatic insufficiency, Biliary cirrhosis, Chronic lung disease, Recurrent bronchopulmonary infections, Rectal prolapse, Meconium ileus, Asthma, Bronchiectasis, Recurrent pneumonia |
| Factor V Leiden thrombophilia | moderate | Factor V Leiden thrombophilia is a genetic disorder that makes it more likely for you to develop a blood clot sometime during your life. Still, it is estimated that 95% of people with factor V Leiden never develop a clot. When a clot does form, the clot most often occurs in your leg (deep venous thrombosis or DVT) or lungs (pulmonary embolism or PE). Factor V Leiden is the name of a specific gene mutation in the F5 gene. This gene plays a role in how your body forms blood clots after an injury. People can inherit one or two copies of the factor V Leiden gene mutation. | Blood clots (deep venous thrombosis or DVT and pulmonary embolism or PE) resulting in leg pain, tenderness, swelling, increased warmth or redness in one leg, cough, chest pain, shortness of breath or rapid heartbeat or breathing. |
| Factor XI deficiency | severe | Factor XI deficiency is a bleeding disorder that interferes with the body’s clotting process. As a result, people affected by this condition may have difficulty stopping the flow of blood following dental extractions, trauma or surgery. Women with factor XI deficiency may also experience heavy menstrual periods or heavy postpartum bleeding. Within affected people and their families, highly variable bleeding patterns occur, and bleeding risk cannot be predicted by the level of factor XI (a clotting factor) in the blood. Although the condition can affect people of all heritages, it is most common in people of Ashkenazi Jewish descent. Most cases of factor XI deficiency are inherited and caused by changes (mutations) in the F11 gene. Treatment is often only recommended during periods of high bleeding risk (i.e. surgery) and may include fresh frozen plasma and/or antifibrinolytics (medications that improve blood clotting). Factor XI concentrates may be available for factor replacement in some countries. | Prolonged partial thromboplastin time, reduced factor XII activity, prolonged whole-blood clotting time. |
| Familial dysautonomia | moderate | Familial dysautonomia, also called hereditary sensory and autonomic neuropathy type III, is a genetic disorder that affects the development and survival of certain nerve cells. The disorder disturbs cells in the autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. Familial dysautonomia is caused by mutations in the IKBKAP gene. | Aseptic necrosis, Renal insufficiency, Corneal opacity, Hypohidrosis, Hypertension, Optic atrophy, Hyponatremia, Alacrima, Myopia, Recurrent respiratory infections, Abnormality of the pleura, EMG abnormality, Growth delay, Abnormality of the peritoneum, Orthostatic hypotension, Malignant hyperthermia, Ataxia, Seizures, Gastroesophageal reflux, Muscular hypotonia, Impaired pain sensation, Corneal erosion, Behavioral abnormality, Abnormal pupil morphology, Tachycardia, Recurrent fractures, Hyperhidrosis, Gait disturbance, Heterochromia iridis, Hyporeflexia, Osteolysis, Glomerulopathy, Acrocyanosis, Scoliosis, Feeding difficulties in infancy. |
| Familial Mediterranean fever | moderate | Familial Mediterranean fever (FMF) is an inherited condition characterized by episodes of painful inflammation of the abdominal lining (peritonitis); the lining surrounding the lungs (pleurisy); and the joints (arthralgia and occasionally arthritis). These episodes are often accompanied by fever, and sometimes, a characteristic ankle rash. The first episode usually occurs during childhood or the teenage years. In some cases, the first episode occurs much later in life. Between episodes, people often do not have any symptoms. FMF is caused by mutations in the MEFV gene. Treatment for FMF aims to control symptoms and often involves the use of a medication called colchicine. Without treatment, FMF can lead to kidney failure due to a build-up of certain protein deposits (amyloidosis). | Renal insufficiency, Renal amyloidosis, Arthralgia, Arthritis, Leukocytosis, Pericarditis, Episodic fever, Splenomegaly, Nephrotic syndrome, Meningitis, Abdominal pain, Pleuritis, Peritonitis, Elevated erythrocyte sedimentation rate, Hepatomegaly. |
| Fanconi anemia (FANCG-related) | severe | Fanconi anemia is an inherited condition that affects the bone marrow, resulting in decreased production of all types of blood cells. People with this condition have lower-than-normal numbers of white blood cells, red blood cells, and platelets (cells that help the blood clot). Not enough white blood cells can lead to infections; a lack of red blood cells may result in anemia; and a decreased amount of platelets may lead to excess bleeding. Fanconi anemia, complementation group G can be caused by mutations in the FANCG. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for the blood problems. | Multiple cafe-au-lait spots, Abnormality of the thumb, Anemia, Neutropenia, Microphthalmia, Leukemia, Myelodysplasia, Growth delay, Thrombocytopenia, Microcephaly, Abnormality of chromosome stability. |
| Glycine encephalopathy (GLDC-related) | very severe | Glycine encephalopathy is an inherited metabolic disease characterized by abnormally high levels of an amino acid called glycine. Glycine is a chemical messenger that transmits signals in the brain. According to the symptoms the disease onset, glycine encephalopathy may be divided in:
GLDC glycine encephalopathy is caused by changes (mutations) in the GLDC genes which result in a deficiency of the enzyme that break-up the glycine. Diagnosis is based in the symptoms, the high glycine levels and the enzyme deficiency, as well as genetic testing. Treatment may include sodium benzoate to reduce the levels of glycine, N-methyl D-aspartate (NMDA) receptor site antagonists, anti-seizure drugs and ketogenic diet. About half of the babies with the classic form, die within a few weeks of life and the survivors may have motor delay, very small head, seizures and stiffness. In the transient form symptoms may improve with time. |
Generalized hypotonia, Aggressive behavior, Irritability, Myoclonus, Hyperreflexia, Hyperglycinuria, Hyperactivity, Death in infancy, Restlessness, Intellectual disability, Lethargy, Encephalopathy, Recurrent singultus, Impulsivity, Hyperglycinemia, Seizures, Agenesis of corpus callosum. |
| Glycogen storage disease type 3 | severe | Glycogen storage disease type 3 (GSDIII) is an inherited disorder caused by the build-up of glycogen in the body’s cells. This build-up impairs the function of certain organs and tissues, especially the liver and muscles. Symptoms typically begin in infancy and may include hypoglycemia, hyperlipidemia (excess of fats in the blood), and elevated blood levels of liver enzymes; later symptoms may include hepatomegaly, chronic liver disease (cirrhosis) and liver failure later in life. Some individuals have short stature and noncancerous (benign) tumours called adenomas in the liver. GSDIII is cause by mutations in the AGL gene. Treatment typically includes a high-protein diet with cornstarch supplementation to maintain a normal level of glucose in the blood. GSDIII is divided into types IIIA, IIIB, IIIC, and IIID; types IIIA and IIIC mainly affect the liver and muscles, and GSD types IIIB and IIID typically affect only the liver. | Deeply set eye, Depressed nasal bridge, Midface retrusion, Ventricular hypertrophy, Thin upper lip vermilion, Cardiomyopathy, Elevated hepatic transaminases, Broad nasal tip, Muscle weakness, Hypoglycemia, Elevated serum creatine phosphokinase, Malar flattening, Short stature, Hepatomegaly, Hepatic fibrosis, Hyperlipidemia, Myopathy, Distal amyotrophy. |
| Glycogen storage disease type 7 | severe | Glycogen storage disease type 7 (GSD7) is an inherited condition in which the body is unable to break down glycogen (a complex sugar) in the muscle cells. Because glycogen is an important source of energy, this can interfere with the normal functioning of muscle cells. The severity of the condition and the associated signs and symptoms vary, but may include muscle weakness and stiffness; painful muscle cramps; nausea and vomiting; and/or myoglobinuria (the presence of myoglobin in the urine) following moderate to strenuous exercise. Symptoms typically resolve with rest. GSD7 is most commonly diagnosed during childhood; however, some affected people may rarely develop symptoms during infancy or later in adulthood. Those who develop the condition during infancy may experience additional symptoms such as hypotonia (poor muscle tone), cardiomyopathy and breathing difficulties that often lead to a shortened lifespan (less than 1 year). This condition is caused by changes (mutations) in the PFKM gene. There is no specific treatment for GSD7; however, affected people are generally advised to avoid vigorous exercise and high-carbohydrate meals. | Cholelithiasis, Exercise-induced myoglobinuria, Reduced erythrocyte 2,3-diphosphoglycerate concentration, Reticulocytosis, Hemolytic anemia, Variable expressivity, Muscle weakness, Exercise intolerance, Increased muscle glycogen content, Jaundice, Gout, Exercise-induced muscle cramps, Increased total bilirubin. |
| GRACILE Syndrome | GRACILE syndrome is an inherited metabolic disease. GRACILE stands for growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death. Infants are very small at birth and quickly develop life-threatening complications. During the first days of life, infants will develop a buildup of lactic acid in the bloodstream (lactic acidosis) and amino acids in the urine (aminoaciduria). They will also have problems with the flow of bile from the liver (cholestasis) and too much iron in their blood. Affected individuals aren’t typically born with unique physical features. Although alkali therapy is used as treatment, about half of affected infants do not survive past the first days of life. Those that do survive this period generally do not live past 4 months despite receiving treatment. GRACILE syndrome is caused by a mutation in the BCS1L gene. The BCS1L gene provides instructions needed by the mitochondria in cells to help produce energy. | Increased serum ferritin, Neonatal hypotonia, Chronic lactic acidosis, Intrauterine growth retardation, Aminoaciduria, Increased serum pyruvate, Increased serum iron, Cholestasis. | |
| Inclusion body myopathy type 2 | moderate | Inclusion body myopathy 2, also known as hereditary inclusion body myopathy (HIBM), GNE-related myopathy, distal myopathy with rimmed vacuoles, and Nonaka myopathy, is an inherited condition that primarily affects the skeletal muscles (the muscles that the body uses to move). This disorder is characterized by muscle weakness that appears in late adolescence or early adulthood and worsens over time. Early symptoms typically develop in the 20s and 30s and may include difficulty running or walking, tripping, weakness in the index finger, and frequent loss of balance. Inclusion body myopathy 2 is caused by mutations in the GNE gene. Treatment is focused on managing individual symptoms. | Rimmed vacuoles, Adult onset, EMG: myopathic abnormalities, Proximal muscle weakness, Gait disturbance, Elevated serum creatine phosphokinase, Limb-girdle muscle atrophy, Limb-girdle muscle weakness, Deposits immunoreactive to beta-amyloid protein, Distal amyotrophy. |
| Isovaleric acidemia | severe | Isovaleric acidemia (IVA) is a type of organic acid disorder in which affected individuals have problems breaking down an amino acid called leucine from the food they eat. Signs and symptoms may range from very mild to life-threatening. In severe cases, symptoms begin within a few days of birth and include poor feeding, vomiting, seizures, and lack of energy (lethargy); these may progress to more serious medical problems including seizures, coma, and possibly death. In other cases, signs and symptoms appear during childhood and may come and go over time. A characteristic sign of IVA is a distinctive odor of sweaty feet during acute illness. Other features may include failure to thrive or delayed development. IVA is caused by mutations in the IVD gene. Treatment involves moderate restriction of proteins in the diet and oral administration of glycine and L-carnitine which helps to rid the body of excess isovaleric acid. | Cerebellar hemorrhage, Dehydration, Coma, Hyperglycinuria, Bone marrow hypocellularity, Pancytopenia, Metabolic acidosis, Leukopenia, Lethargy, Thrombocytopenia, Vomiting, Ketoacidosis, Seizures, Global developmental delay. |
| Joubert syndrome Type 2 | severe | Joubert syndrome is a disorder of brain development that may affect many parts of the body. It is characterized by the absence or underdevelopment of the cerebellar vermis (a part of the brain that controls balance and coordination) and a malformed brain stem (connection between the brain and spinal cord). Together, these cause the characteristic appearance of a molar tooth sign on MRI. Signs and symptoms can vary but commonly include weak muscle tone (hypotonia); abnormal breathing patterns; abnormal eye movements; ataxia; distinctive facial features; and intellectual disability. Various other abnormalities may also be present. Joubert syndrome type 2 is caused by mutations in the TMEM216 gene. Treatment is supportive and depends on the symptoms in each person. | Encephalocele, Generalized hypotonia, Elongated superior cerebellar peduncle, Nystagmus, Failure to thrive, Renal cyst, Brainstem dysplasia, Visual impairment, Optic nerve coloboma, Thickened superior cerebellar peduncle, Phenotypic variability, Dolichocephaly, Esotropia, Microphthalmia, Low-set ears, Chorioretinal coloboma, Frontal bossing, Hypoplasia of the brainstem, Enlarged fossa interpeduncularis, Ataxia, Abnormality of the corpus callosum, Impaired smooth pursuit, Dysgenesis of the cerebellar vermis, Hypoplastic male external genitalia, Nephronophthisis, Depressed nasal bridge, Abnormal renal physiology, High palate, Molar tooth sign on MRI, Hypertelorism, Oculomotor apraxia, Hydrocephalus, Retinal dystrophy, Intellectual disability, Heterogeneous, Episodic tachypnea, Abnormality of the foot, Agenesis of cerebellar vermis, Macrocephaly, Central apnea, Postaxial hand polydactyly, Neonatal breathing dysregulation, Abnormality of saccadic eye movements, Global developmental delay. |
| Junctional epidermolysis bullosa: Herlitz type | severe | Junctional epidermolysis bullosa (JEB) is a type of Epidermolysis Bullosa, a group of genetic conditions that cause the skin to be very fragile and to blister easily. JEB is separated into two categories: the Herlitz type and the Non-Herlitz type. The Herlitz type of JEB is very severe, and individuals with this condition often do not survive infancy. The Non-Herlitz type includes several subtypes that cause mild to severe blistering of the skin present at birth or shortly thereafter. The Herlitz type of JEB is caused by mutations in the LAMC2 gene. There is no cure for JEB. Treatment is focused on management of blistering and prevention of secondary infections. | Hypoplasia of dental enamel, Nail dystrophy, Failure to thrive, Death in infancy, Congenital onset, Milia, Congenital localized absence of skin, Atrophic scars, Carious teeth, Pyloric stenosis, Nail dysplasia, Junctional split. |
| Leber congenital amaurosis (LCA5-related) | severe | Leber congenital amaurosis (LCA) is an eye disorder that primarily affects the retina. People with this condition typically have severe visual impairment beginning in infancy. Other features include photophobia, involuntary movements of the eyes (nystagmus), and extreme farsightedness. The pupils also do not react normally to light. Additionally, the cornea may be cone-shaped and abnormally thin (keratoconus). Franceschetti’s oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of poking, pressing, and rubbing the eyes with a knuckle or finger. Different subtypes have been described and can be distinguished by the genes in which the mutations are found as well as by their patterns of vision loss and related eye abnormalities. LCA5 is caused by mutations in the LCA5 gene. Treatment includes correction farsightedness and use of low-vision aids when possible. | Visual impairment, Hypermetropia, Undetectable electroretinogram, Nystagmus. |
| Leydig cell hypoplasia (Luteinizing Hormone Resistance) | moderate | Leydig cell hypoplasia (LCH) is a condition in males that affects sexual development. It is characterized by underdevelopment of the Leydig cells, which are cells in the testes that secrete male sex hormones (androgens) and are important for male sexual development. Individuals with LCH have a typical male genetic make-up (46, XY), but due to lowered levels of androgens, may have a range of genital (reproductive organ) differences. Individuals with LCH may have a small penis (micropenis), the opening of the urethra may be located on the underside of the penis (hypospadias), or the scrotum may be divided into two halves (bifid scrotum). Given these differences in development, the external genitalia may not appear clearly male or female (ambiguous genitalia). Some individuals with LCH can have female external genitalia and small testes that have not descended and are located in the pelvis, abdomen, or groin. This may be referred to as type 1, whereas less severe cases might be called type 2. LCH is caused by mutations in the LHCGR gene. Although there is no specific treatment or cure for LCH, there may be ways to manage the symptoms. A team of doctors or specialists is often needed to figure out the treatment options for each person. | Hyoplasia of the Leydig cells, Abnormal vas deferens morphology, Hypergonadotropic hypogonadism, Increased circulating gonadotropin level, Secondary amenorrhea, Primary amenorrhea, Male hypogonadism, Male pseudohermaphroditism, Decreased serum testosterone level, Cryptorchidism, Primary gonadal insufficiency, Breast aplasia, Hypospadias, Delayed skeletal maturation, Female hypogonadism, Testicular gonadoblastoma, Aplasia of the uterus, Absence of secondary sex characteristics, Ambiguous genitalia, Micropenis. |
| Limb girdle muscular dystrophy type 2E | severe | Limb-girdle muscular dystrophy is a group of disorders which affect the voluntary muscles around the hips and shoulders. The conditions are progressive, leading to a loss of muscle strength and bulk over a number of years. Onset may occur in childhood, adolescence, young adulthood, or even later. Males and females are affected in equal numbers. Limb girdle muscular dystrophy 2E is caused by mutations in the SGCB gene. While there are no treatments which directly reverse the muscle weakness associated with this condition, supportive treatment can decrease the complications. | Scapular winging, Calf muscle pseudohypertrophy, Proximal amyotrophy, Dilated cardiomyopathy, Shoulder girdle muscle atrophy, Pelvic girdle muscle atrophy, Elevated serum creatine phosphokinase, Juvenile onset, Limb-girdle muscle weakness, Muscular dystrophy. |
| Lipoprotein lipase deficiency | severe | Lipoprotein lipase deficiency is a rare genetic disorder is which a person lacks the enzyme lipoprotein lipase, a protein needed to break down fat molecules. Deficiency of this enzyme prevents affected individuals from properly digesting certain fats. This results in the accumulation of fatty droplets called chylomicrons in the blood and an increase in the blood concentration of triglycerides. Symptoms include episodes of abdominal pain, recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), and the development of skin lesions known as erruptive xanthomas. Familial lipoprotein lipase deficiency is caused by changes (mutations) in the LPL gene. Treatment aims to control symptoms and blood triglyceride levels with a very low-fat diet. Treatment for individual symptoms (i.e. pancreatitis) involves following established treatment guidelines. | Increased circulating chylomicron levels, Lactescent serum, Jaundice, Pancreatitis, Splenomegaly, Nausea, Eruptive xanthomas, Lipemia retinalis, Hepatosplenomegaly, Vomiting, Episodic abdominal pain, Hypercholesterolemia |
| Lipoamide Dehydrogenase Deficiency (Maple syrup urine disease type 3) | severe | Dihydrolipoamide Dehydrogenase (DLD) Deficiency is a very rare condition that can vary in age of onset, symptoms and severity. The condition may be characterized by early-onset lactic acidosis and delayed development (most commonly); later-onset neurological dysfunction; or adult-onset isolated liver disease. Signs and symptoms may include lactic acidosis shortly after birth; hypotonia and lethargy in infancy; feeding difficulties; seizures; and various other health issues. Liver problems can range from hepatomegaly to life-threatening liver failure. Symptoms often occur in episodes that may be triggered by illness or other stresses on the body. Many affected infants do not survive the first few years of life; those who survive through early childhood often have growth delay and intellectual disability. Some with onset later in childhood may have neurological dysfunction with normal cognitive development. DLD deficiency is caused by mutations in the DLD gene. | Generalized hypotonia, Feeding difficulties, Variable expressivity, Hypertrophic cardiomyopathy, Elevated hepatic transaminases, Hypoglycemia, Lactic acidosis, Metabolic acidosis, Dystonia, Lethargy, Encephalopathy, Decreased liver function, Ataxia, Seizures, Microcephaly, Hepatomegaly, Global developmental delay. |
| Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency | moderate | LCHAD deficiency, or long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, is a mitochondrial condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms typically appear during infancy or early childhood and can include feeding difficulties, lack of energy, low blood sugar (hypoglycemia), weak muscle tone (hypotonia), liver problems, and abnormalities in the retina. Later in childhood, people with this condition may experience muscle pain, breakdown of muscle tissue, and peripheral neuropathy. Individuals with LCHAD deficiency are also at risk for serious heart problems, breathing difficulties, coma, and sudden death. This condition is caused by mutations in the HADHA gene. Treatment includes diet and low-dose carnitine supplements, as well as avoiding fasting. | Cardiomyopathy, Sudden death, Decreased activity of 3-hydroxyacyl-CoA dehydrogenase, Hypoglycemia, Pigmentary retinopathy, Hepatomegaly, Muscular hypotonia. |
| Maple syrup urine disease type 1B | severe | Maple syrup urine disease (MSUD) is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. Beginning in early infancy, this condition is characterized by poor feeding, vomiting, lack of energy (lethargy), seizures, and developmental delay. The urine of affected infants has a distinctive sweet odour, much like burned caramel, that gives the condition its name. Maple syrup urine disease can be life-threatening if untreated. MSUD1B is caused by mutations in the BCKDHB gene. | Generalized hypotonia, Cerebral edema, Hallucinations, Growth abnormality, Ketosis, Coma, Hypoglycemia, Lactic acidosis, Intellectual disability, Pancreatitis, Lethargy, Hypertonia, Vomiting, Ataxia, Seizures, Elevated plasma branched chain amino acids, Feeding difficulties in infancy. |
| Methylmalonic acidemia (MMAA-related) | very severe | Methylmalonic acidemia is an inherited condition in which the body is unable to process certain proteins and fats properly. Signs and symptoms usually appear in early infancy and vary from mild to life-threatening. Affected infants can experience vomiting, dehydration, weak muscle tone (hypotonia), developmental delay, lethargy, hepatomegaly, and failure to thrive. Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and pancreatitis. Without treatment, this condition can lead to coma and death in some cases. Mutations in the MMAA gene cause MMAA-related methylmalonic acidemia. Methylmalonic acidemia is treated with a low-protein, high-calorie diet, certain medications, antibiotics and, in some cases, organ transplantation. | Generalized hypotonia, Failure to thrive, Ketonuria, Methylmalonic aciduria, Coma, Neutropenia, Tremor, Pancytopenia, Lethargy, Thrombocytopenia, Decreased methylmalonyl-CoA mutase activity, Seizures, Hepatomegaly, Infantile onset, Dehydration, Anemia, Methylmalonic acidemia, Ketosis, Hyperammonemia, Metabolic acidosis, Vomiting, Hyperglycinemia, Decreased adenosylcobalamin, Global developmental delay, Respiratory distress, Feeding difficulties in infancy. |
| Multiple sulfatase deficiency | very severe | Multiple sulfatase deficiency is a lysosomal storage disorder that mainly affects the brain, skin, and skeleton. The signs and symptoms of this condition vary widely, prompting researchers to divide it into three types: neonatal, late-infantile, and juvenile. The neonatal type is the most severe form, with symptoms developing soon after birth. The late-infantile type is the most common form and usually presents as progressive loss of mental abilities and movement after a period of normal development. The juvenile type is rare, with a slow regression of psychomotor development in mid to late childhood. Life expectancy is shortened in all types. Multiple sulfatase deficiency is caused by mutations in the SUMF1 gene. It is inherited in an autosomal recessive pattern. There is no cure for multiple sulfatase deficiency. Treatment includes physical therapy and supportive services. | Coarse facial features, Flat face, Corneal opacity, Peripheral demyelination, Dysostosis multiplex, Neonatal hypotonia, Increased CSF protein, Retinal degeneration, Anteverted nares, Spasticity, Ichthyosis, Hearing impairment, Large forehead, Ataxia, Short stature, Periorbital edema, Cerebellar atrophy, Hepatomegaly, Broad thumb, Hypoplastic vertebral bodies, CNS demyelination, Rapid neurologic deterioration, Broad hallux, Prominent forehead, Abnormality of the periventricular white matter, Ventriculomegaly, Hydrocephalus, Intellectual disability, Splenomegaly, Cerebral atrophy, Mucopolysacchariduria, Global developmental delay, Lower limb hyperreflexia |
| Navajo neurohepatopathy (MPV17-related hepatocerebral mitochondrial DNA depletion syndrome) | severe | MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is an inherited disorder that can cause liver disease and neurological problems. The signs and symptoms of this condition begin in infancy. Many affected infants have a buildup of a chemical called lactic acid in the body (lactic acidosis) and low blood sugar (hypoglycemia). Within the first weeks of life, infants develop liver disease that quickly progresses to liver failure. The liver is frequently enlarged (hepatomegaly) and liver cells often have a reduced ability to release a digestive fluid called bile (cholestasis). Rarely, affected children develop liver cancer. After the onset of liver disease, many affected infants develop neurological problems, which can include developmental delay, weak muscle tone (hypotonia), and reduced sensation in the limbs (peripheral neuropathy). Individuals with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome typically survive only into infancy or early childhood.MPV17-related hepatocerebral mitochondrial DNA depletion syndrome is most frequently seen in the Navajo population of the southwestern United States. In this population, the condition is known as Navajo neurohepatopathy. People with Navajo neurohepatopathy tend to have a longer life expectancy than those with MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. In addition to the signs and symptoms described above, people with Navajo neurohepatopathy may have problems with sensing pain that can lead to painless bone fractures and self-mutilation of the fingers or toes. Individuals with Navajo neurohepatopathy may lack feeling in the clear front covering of the eye (corneal anesthesia), which can lead to open sores and scarring on the cornea, resulting in impaired vision. The cause of these additional features is unknown. | Generalized hypotonia, Osteomyelitis leading to amputation due to slow healing fractures, Reye syndrome-like episodes, Nystagmus, Failure to thrive, Phenotypic variability, Microvesicular hepatic steatosis, Dystonia, Progressive, Ataxia, Cirrhosis, Short stature, Painless fractures due to injury, Hepatomegaly, Distal muscle weakness, Infantile onset, Decreased number of peripheral myelinated nerve fibers, Increased susceptibility to fractures, Abnormality of the immune system, Acral ulceration and osteomyelitis leading to autoamputation of digits, Elevated hepatic transaminases, Hypoglycemia, Lactic acidosis, Macrovesicular hepatic steatosis, Recurrent corneal erosions, Hyporeflexia, Abnormality of the foot, Vomiting, Prolonged neonatal jaundice, Diarrhea, Sensorimotor neuropathy, Areflexia, Pain insensitivity, Acute hepatic failure, Global developmental delay |
| Neuronal ceroid lipofuscinosis (MFSD8-related) | very severe | Neuronal ceroid lipofuscinosis 7 (CLN7-NCL) is a rare condition that affects the nervous system. Signs and symptoms of the condition generally develop in early childhood (average age 5 years) and may include loss of muscle coordination (ataxia), seizures that do not respond to medications, muscle twitches (myoclonus), visual impairment, and developmental regression (the loss of previously acquired skills). CLN7-NCL is caused by changes (mutations) in the MFSD8 gene. Treatment options are limited to therapies that can help relieve some of the symptoms. | Sleep disturbance, Neurodegeneration, Blindness, Optic atrophy, Retinopathy, Rapidly progressive, Cerebral atrophy, Juvenile onset, Visual loss, Mental deterioration, Generalized myoclonic seizures, Delayed speech and language development, Pigmentary retinopathy, Ataxia, Cerebellar atrophy, EEG abnormality, Global developmental delay. |
| Nijmegen breakage syndrome | severe | Nijmegen breakage syndrome (NBS) is a rare genetic disease presenting at birth with microcephaly, dysmorphic facial features, becoming more noticeable with age, growth delay, and later-onset complications such as malignancies and infections. Clinical manifestations are not pathognomonic and may vary in severity. By age 20, over 40% of patients develop a malignant disease. NBS is caused by mutations in the NBN gene (8q21-q24) which lead to partially functional truncated fragments of nibrin, the gene product involved in repairing DNA double strand breaks. NBS is caused by mutations in the NBN gene. There is no specific therapy for NBS. Due to the specific defect underlying immune deficiency and sensitivity to IR radiation, patients require multidisciplinary management and long term follow-up (malignancy, immunodeficiency, growth, hypergonadotropic hypogonadism in females). | Malar prominence, Glioma, Neurodegeneration, Premature ovarian insufficiency, Hydronephrosis, Sinusitis, Macrotia, Intrauterine growth retardation, Cleft upper lip, Micrognathia, Mastoiditis, Dysgammaglobulinemia, Lymphoma, Medulloblastoma, Otitis media, Thrombocytopenia, Anal stenosis, Short stature, Anal atresia, Sloping forehead, Upslanted palpebral fissure, Autoimmune hemolytic anemia, B lymphocytopenia, Recurrent bronchitis, Rhabdomyosarcoma, Cafe-au-lait spot, Hyperactivity, Intellectual disability, Progressive vitiligo, Recurrent infection of the gastrointestinal tract, Decrease in T cell count, Choanal atresia, Diarrhea, Bronchiectasis, Long nose, Recurrent pneumonia, Recurrent urinary tract infections, Cleft palate, Microcephaly. |
| Ornithine translocase deficiency (Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome) | severe | Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, also known as Ornithine translocase deficiency, is a disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or chronic liver dysfunction. Age of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. The neonatal presentation usually begins a few days after birth. Onset of symptoms (ranging from mild to severe) in the majority of patients occurs in infancy, childhood and adulthood. An aversion to protein-rich foods before diagnosis is often reported. HHH is caused by mutations in the SLC25A15 gene. Treatment involves the adherence to a low protein diet along with citrulline or arginine supplementation. In resistant cases, sodium benzoate and phenylbutyrate may be necessary for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, intercurrent infections) and when taking certain medications (i.e. corticosteroids) as they can trigger an episode of hyperammonemia. Hyperammonemic coma is treated in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy implemented, catabolism reversed (with glucose and lipid infusions) and special care taken to reduce the risk of neurological damage. | Morphological abnormality of the pyramidal tract, Abnormal pyramidal signs, Hypopigmentation of the fundus, Generalized hypotonia, Hyperornithinemia, Failure to thrive, Acute hepatitis, Coma, Phenotypic variability, Acute encephalopathy, Clonus, Lethargy, Decreased nerve conduction velocity, Generalized myoclonic seizures, Decreased liver function, Hepatomegaly, Cerebral cortical atrophy, Poor coordination, Specific learning disability, Chorioretinal atrophy, Hyperammonemia, Intellectual disability, Protein avoidance, Spastic paraparesis, Impaired vibratory sensation, Episodic vomiting, Global developmental delay. |
| Peroxisome biogenesis disorders Zellweger syndrome spectrum (PEX1-related) | severe | Zellweger syndrome (ZS) is the most severe variant seen in the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS), characterized by neuronal migration defects in the brain, dysmorphic craniofacial features, profound hypotonia, neonatal seizures, and liver dysfunction. Onset is in the neonatal period, reflecting both organ malformations that occurred in utero and progressive disease due to ongoing peroxisome dysfunction. Conditions in the Zellweger spectrum are caused by mutations in any of at least 12 genes. PEX1-related ZS is caused by mutations in the PEX1 gene. There is no cure for ZS. Standard epileptic drugs are used for seizure control. Hepatic coagulopathy can be treated with vitamin K supplementation while cholestasis may require the provision of all fat soluble vitamins. A gastrostomy tube may be needed to allow for adequate calorie intake. Foods rich in phytanic acids (i.e. cow’s milk) should be restricted. Supplementation of mature bile acids, cholic and chenodeoxycholic acid may help improve liver disease in infants with severe hepatopathy. As ZS patients cannot biosynthesize DHA, it can also be provided. | Generalized hypotonia, Opacification of the corneal stroma, Cataract, Nystagmus, High, narrow palate, Sensorineural hearing impairment, Hydronephrosis, Epicanthus, Hypospadias, Aminoaciduria, Brachyturricephaly, Seizures, Epiphyseal stippling, Widely patent fontanelles and sutures, Albuminuria, Redundant neck skin, Heterogeneous, Breech presentation, Renal cortical microcysts, Hyporeflexia, Flat occiput, Macrocephaly, Delayed skeletal maturation, Protruding tongue, Heterotopia, Intellectual disability, severe, Clitoral hypertrophy, Abnormality of the helix, Flat face, Failure to thrive, Ventricular septal defect, Cubitus valgus, Optic disc pallor, High forehead, Cryptorchidism, Micrognathia, Glaucoma, Anteverted nares, Polymicrogyria, Aplasia/Hypoplasia of the corpus callosum, Intellectual disability, progressive, Elevated long chain fatty acids, Pigmentary retinopathy, Bell-shaped thorax, Pulmonary hypoplasia, Upslanted palpebral fissure, Hepatomegaly, Rocker bottom foot, Hypertelorism, Single transverse palmar crease, Adrenal hypoplasia, Macroglossia, Intrahepatic biliary dysgenesis, Patent ductus arteriosus, Subependymal cysts, Posteriorly rotated ears, Abnormal electroretinogram, Round face, Metatarsus adductus, Prolonged neonatal jaundice, Talipes equinovarus, Malar flattening, Areflexia, Brushfield spots, Hypoplastic olfactory lobes, Ulnar deviation of the hand |
| Peroxisome biogenesis disorders Zellweger syndrome spectrum (PEX2-related) | severe | Zellweger syndrome (ZS) is the most severe variant seen in the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS), characterized by neuronal migration defects in the brain, dysmorphic craniofacial features, profound hypotonia, neonatal seizures, and liver dysfunction. Onset is in the neonatal period, reflecting both organ malformations that occurred in utero and progressive disease due to ongoing peroxisome dysfunction. Conditions in the Zellweger spectrum are caused by mutations in any of at least 12 genes. PEX2-related ZS is caused by mutations in the PEX2 gene. There is no cure for ZS. Standard epileptic drugs are used for seizure control. Hepatic coagulopathy can be treated with vitamin K supplementation while cholestasis may require the provision of all fat soluble vitamins. A gastrostomy tube may be needed to allow for adequate calorie intake. Foods rich in phytanic acids (i.e. cow’s milk) should be restricted. Supplementation of mature bile acids, cholic and chenodeoxycholic acid may help improve liver disease in infants with severe hepatopathy. As ZS patients cannot biosynthesize DHA, it can also be provided. | Generalized hypotonia, Opacification of the corneal stroma, Cataract, Nystagmus, High, narrow palate, Sensorineural hearing impairment, Hydronephrosis, Epicanthus, Hypospadias, Aminoaciduria, Brachyturricephaly, Seizures, Epiphyseal stippling, Widely patent fontanelles and sutures, Albuminuria, Redundant neck skin, Heterogeneous, Breech presentation, Renal cortical microcysts, Hyporeflexia, Flat occiput, Macrocephaly, Delayed skeletal maturation, Protruding tongue, Heterotopia, Intellectual disability, severe, Clitoral hypertrophy, Abnormality of the helix, Flat face, Failure to thrive, Ventricular septal defect, Cubitus valgus, Optic disc pallor, High forehead, Cryptorchidism, Micrognathia, Glaucoma, Anteverted nares, Polymicrogyria, Aplasia/Hypoplasia of the corpus callosum, Intellectual disability, progressive, Elevated long chain fatty acids, Pigmentary retinopathy, Bell-shaped thorax, Pulmonary hypoplasia, Upslanted palpebral fissure, Hepatomegaly, Rocker bottom foot, Hypertelorism, Single transverse palmar crease, Adrenal hypoplasia, Macroglossia, Intrahepatic biliary dysgenesis, Patent ductus arteriosus, Subependymal cysts, Posteriorly rotated ears, Abnormal electroretinogram, Round face, Metatarsus adductus, Prolonged neonatal jaundice, Talipes equinovarus, Malar flattening, Areflexia, Brushfield spots, Hypoplastic olfactory lobes, Ulnar deviation of the hand |
| Phenylketonurea | very severe | Phenylketonuria (PKU) is an inherited disorder that increases the levels of phenylalanine in the blood. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. If PKU is not treated, phenylalanine can build up to harmful levels in the body. The signs and symptoms of PKU vary from mild to severe. The most severe form of this disorder is known as classic PKU. Without treatment, these children develop permanent intellectual disability. Light skin and hair, seizures, delayed development, behavioral problems, and psychiatric disorders are also common. Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia, have a smaller risk of brain damage. Babies born to mothers with PKU and women who no longer follow a low-phenylalanine diet have a risk of intellectual disability because they are exposed to very high levels of phenylalanine before birth. PKU is caused by changes (mutations) in the PAH gene. The best treatment for PKU is a diet of low-protein foods. | Attention deficit hyperactivity disorder, Generalized hypopigmentation, Anxiety, Cataract, Depressivity, Dry skin, Aggressive behavior, Self-mutilation, Hyperphenylalaninemia, Obsessive-compulsive behavior, Eczema, Phenylpyruvic acidemia, Maternal hyperphenylalaninemia, Fair hair, Seizures, Psychosis, Blue irides, Irritability, Hyperreflexia, Cerebral calcification, Intellectual disability, Scleroderma, Reduced phenylalanine hydroxylase activity, Microcephaly. |
| Pontocerebellar hypoplasia type 2E | very severe | Pontocerebellar hypoplasia type 2 (PCH2) is a rare condition that affects the development of the brain. Signs and symptoms vary but may include microcephaly, developmental delay with lack of voluntary motor development, intellectual disability and movement disorders (i.e. chorea, dystonia, and spasticity). Affected people may also experience dysphagia (difficulty swallowing), impaired vision, seizures and an inability to communicate. Children with this condition often pass away prior to age 10 years, although survival beyond age 20 years has been reported. PCH2E is caused by changes (mutations) in the VPS53 gene and is inherited in an autosomal recessive manner. Treatment is supportive and based on the signs and symptoms present in each person. | Osteoporosis, Irritability, Neonatal hypotonia, Intellectual disability, Cerebral atrophy, Spastic tetraplegia, Progressive, Progressive microcephaly, Hypoplasia of the corpus callosum, Opisthotonus, Intellectual disability, profound, Short stature, Seizures, Cerebellar atrophy, Flexion contracture, Scoliosis, Microcephaly, Infantile onset, Global developmental delay. |
| Pycnodysostosis | severe | Pycnodysostosis is a genetic lysosomal disease characterized by short stature, increased density of the bones (osteosclerosis/osteopetrosis), and brittle bones. Other features may include underdevelopment of the tips of the fingers with absent or small nails, an abnormal collarbone (clavicle), distinctive facial features including a large head with a small face and chin, underdeveloped facial bones, a high forehead, and dental abnormalities. Pycnodysostosis is caused by mutations in the gene that codes the enzyme cathepsin K (CTSK) on chromosome 1q21. The diagnosis of pycnodysostosis is based on physical features and X-ray findings. Molecular genetic testing is available. Treatment should address the symptoms found in each patient and may include orthopedic monitoring, treatment of fractures, appropriate dental care, and craniofacial surgery. | Osteolytic defects of the distal phalanges of the hand, Increased bone mineral density, Ridged nail, Prominent nose, Hypodontia, Prominent occiput, Abnormality of pelvic girdle bone morphology, Absent frontal sinuses, Spondylolysis, Micrognathia, Abnormality of the thorax, Frontal bossing, Wormian bones, Brachydactyly, Spondylolisthesis, Delayed eruption of permanent teeth, Narrow palate, Short stature, Persistence of primary teeth, Scoliosis, Carious teeth, Persistent open anterior fontanelle, Delayed eruption of primary teeth. |
| Pyruvate dehydrogenase deficiency (PDHB-related) | severe | Pyruvate dehydrogenase deficiency is metabolic disorder associated with abnormal function of the mitochondria in cells, thus depriving the body of energy. Progressive neurological symptoms usually start in infancy but may be evident at birth, or in later childhood; these symptoms may include developmental delay, intermittent ataxia, poor muscle tone (hypotonia), abnormal eye movements, or seizures. Severe lethargy, poor feeding, and tachypnea (rapid breathing) commonly occur, especially during times of illness, stress, or high carbohydrate intake. Childhood-onset forms of the condition are often associated with intermittent periods of illness but normal neurological development. Prognosis is difficult to predict due to the many causes of the condition, but in most cases of neonatal and infantile onset, prognosis is described as poor. Mutations in the PDHB gene are a very rare cause of pyruvate dehydrogenase deficiency. In addition to directly treating acidosis and providing alternative energy for the body, treatment typically includes dietary supplementation with thiamine, carnitine, and lipoic acids, although not all individuals respond to this therapy. | Generalized hypotonia, Lactic acidosis. |
| Retinal Dystrophy: RLBP1-related (Bothnia retinal dystrophy) | severe (blindness) | Bothnia retinal dystrophy is a rare form of retinal dystrophy, seen mostly in Northern Sweden, presenting in early childhood with night blindness and progressive maculopathy with a decrease in visual acuity, eventually leading to blindness by adulthood. Retinal degeneration, without obvious bone spicule formation, accompanied by affected visual fields and the typical presence of retinitis punctata albescens (see this term) in the posterior pole are also noted. The condition is caused by mutations in the RLBP1 gene. No treatments are currently available for the disease. | Abnormal electroretinogram, Retinal dystrophy, Nyctalopia, Macular degeneration. |
| Retinitis pigmentosa (DHDDS-related) | severe (blindness) | Retinitis pigmentosa (RP) is a group of inherited eye diseases that affect the light-sensitive part of the eye (retina). RP causes cells in the retina to die, causing progressive vision loss. The first sign of RP usually is night blindness. As the condition progresses, affected individuals develop tunnel vision (loss of peripheral vision), and eventually loss of central vision. RP may be caused by mutations in any of at least 50 genes. Inheritance can be autosomal dominant, autosomal recessive, or X-linked. DHDDS-related RP is caused by mutations in the DHDDS gene. Treatment options to slow the progression of vision loss include light avoidance, use of low-vision aids, and vitamin A supplementation. Researchers are working to develop new treatment options for the future such as gene therapy, stem cell transplantation and prosthetic implants. | Rod-cone dystrophy, Cystoid macular edema. |
| Sanfilippo syndrome type D (Mucopolysaccharidosis IIID) | severe | Mucopolysaccharidosis type IIID (MPS IIID) is a genetic disorder that makes the body unable to break down large sugar molecules called glycosaminoglycans (GAGs, formerly called mucopolysaccharides). Specifically, people with this condition are unable to break down a GAG called heparan sulfate. Affected individuals can have severe neurological symptoms, including progressive dementia, aggressive behavior, hyperactivity, seizures, deafness, loss of vision, and an inability to sleep for more than a few hours at a time. MPS IIID is caused by the missing or deficient enzyme N-acetylglucosamine 6-sulfatase due to mutations in the GNS gene. There is no specific treatment for this condition. Most people with MPS IIID live into their teenage years, and some live longer. | Sleep disturbance, Coarse facial features, Thickened ribs, Dysostosis multiplex, Coarse hair, Drooling, Synophrys, Low-set ears, Frontal bossing, Recurrent upper respiratory tract infections, Anteverted nares, Progressive, Hearing impairment, Cellular metachromasia, Seizures, Flexion contracture, Hepatomegaly, Asymmetric septal hypertrophy, Dysarthria, Depressed nasal bridge, Prominent forehead, Growth abnormality, Ovoid thoracolumbar vertebrae, Hyperactivity, Hirsutism, Intellectual disability, Splenomegaly, Joint stiffness, Dysphagia, Wide mouth, Heparan sulfate excretion in urine, Thick lower lip vermilion, Thick eyebrow, Absent speech, Diarrhea, Short neck. |
| Sickle-cell disease | very severe | Sickle-cell disease (SCD) is an inherited condition that affects haemoglobin, the protein in red blood cells that carries oxygen to different parts of the body. Affected people have a different change (mutation) in each copy of their HBB gene: one that causes red blood cells to form a “sickle” or crescent shape and a second that is associated with beta thalassemia, a blood disorder that reduces the production of haemoglobin. Depending on the beta thalassemia mutation, people may have no normal haemoglobin (called beta zero thalassemia) or a reduced amount of normal haemoglobin (called beta plus thalassemia). The presence of sickle-shaped red blood cells, which often breakdown prematurely and can get stuck in blood vessels, combined with the reduction or absence of mature red blood cells leads to the many signs and symptoms of SCD. Features, which may include anaemia (low levels of red blood cells), repeated infections, and frequent episodes of pain, generally develop in early childhood and vary in severity depending on the amount of normal haemoglobin made. Treatment is supportive and depends on the signs and symptoms present in each person. | Cholelithiasis, Increased red cell sickling tendency, Renal insufficiency, Hypoxemia, Priapism, Recurrent bacterial infections, Hemolytic anemia, Leukocytosis, Retinopathy, Jaundice, Splenomegaly, Cardiomegaly, Abdominal pain, Stroke, Hepatomegaly, Hematuria. |
| Sjögren-Larsson syndrome | severe | Sjögren-Larsson syndrome (SLS) is an inborn error of lipid metabolism, characterized by congenital ichthyosis (dry, scaly skin), intellectual disability, and spasticity (stiffness and involuntary muscle spasms). The syndrome is caused by mutations in the gene called FADH (fatty aldehyde dehydrogenase). Treatment is symptomatic. | Photophobia, Hypoplasia of dental enamel, CNS demyelination, Intellectual disability, Thoracic kyphosis, Opacification of the corneal epithelium, Spasticity, Ichthyosis, Short stature, Seizures, Macular degeneration. |
| Tay-Sachs disease | very severe | Tay-Sachs disease is a rare inherited disorder that causes progressive destruction of nerve cells in the brain and spinal cord. Tay-Sachs is caused by the absence of a vital enzyme called hexosaminidase-A (HexA). Without HexA, a fatty substance, or lipid, called GM2 ganglioside accumulates abnormally in cells, especially in the nerve cells of the brain. This ongoing accumulation causes progressive damage to the cells. | Generalized hypotonia, Blindness, Dementia, Aspiration, Apathy, Cherry red spot of the macula, Exaggerated startle response, Poor head control, Seizures, Psychomotor deterioration, Infantile onset, Muscular hypotonia, GM2-ganglioside accumulation. |
| Usher syndrome type 1F | moderate (hearing loss) | Usher syndrome is a genetic disorder characterized by sensorineural hearing loss or deafness and progressive vision loss due to retinitis pigmentosa. Sensorineural hearing means it is caused by abnormalities of the inner ear. Retinitis pigmentosa is an eye disease that affects the layer of light-sensitive tissue at the back of the eye (the retina). Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. Night vision loss begins first, followed by blind spots that develop in the side (peripheral) vision, that can enlarge and merge to produce tunnel vision (loss of all peripheral vision). In some cases, vision is further impaired by clouding of the lens of the eye (cataracts). Three major types of Usher syndrome have been described – types I, II, and III. The different types are distinguished by their severity and the age when signs and symptoms appear. Usher syndrome type 1F is due to mutations in the PCDH15 gene. Treatment for the hearing loss may include hearing aids or surgery for a cochlear implant. | Motor delay, Rod-cone dystrophy, Congenital sensorineural hearing impairment.
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