480
(47.0%)

thrombophilia due to protein C deficiency, autosomal dominant

Abnormality of the eye Deep venous thrombosis Pulmonary embolism Warfarin-induced skin necrosis

Autosomal dominant inheritance

480
(47.0%)

hereditary hemorrhagic telangiectasia type 4

Cerebral hemorrhage Cyanosis Lip telangiectasia

Autosomal dominant inheritance Heterogeneous

483
(46.9%)

MGAT2-CDG

Abnormal isoelectric focusing of serum transferrin Long eyelashes Midfrontal capillary hemangioma Reduced factor XI activity

Autosomal recessive inheritance

MGAT2-CDG is a form of congenital disorders of N-linked glycosylation characterized by facial dysmorphism (large, posteriorly rotated ears with prominent antihelices, convex nasal ridge, open mouth, large and crowded teeth), stereotypic hand movements, seizures, and varying degrees of developmental delay. A bleeding tendency is also observed and this results from diminished platelet aggregation. The disease is caused by loss-of-function mutations in the gene MGAT2 (14q21).

484
(46.9%)

retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Micronodular cirrhosis Proteinuria Retinal hemorrhage Telangiectasia

Autosomal dominant inheritance

Retinal vasculopathy and cerebral leukodystrophy (RVCL) is an inherited group of small vessel diseases comprised of cerebroretinal vasculopathy (CRV), hereditary vascular retinopathy (HRV) and hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS); all exhibiting progressive visual impairment as well as variable cerebral dysfunction.

484
(46.9%)

classic homocystinuria

Cutis marmorata Hepatic steatosis Homocystinuria Thromboembolism

Autosomal recessive inheritance

Classical homocystinuria due to cystathionine beta-synthase (CbS) deficiency is characterized by the multiple involvement of the eye, skeleton, central nervous system, and vascular system.

486
(46.8%)

hydroxyacyl glutathione hydrolase deficiency

Elliptocytosis Glyoxalase deficiency

Autosomal dominant inheritance

486
(46.8%)

familial hypobetalipoproteinemia 1

Acanthocytosis Decreased LDL cholesterol concentration Rod-cone dystrophy

Autosomal recessive inheritance

Any hypobetalipoproteinemia in which the cause of the disease is a mutation in the APOB gene.

488
(46.5%)

combined immunodeficiency due to GINS1 deficiency

Dry skin Lymphadenopathy Microcephaly Neutropenia

Autosomal recessive inheritance

489
(46.4%)

glycine N-methyltransferase deficiency

Hepatomegaly Hypermethioninemia

Autosomal recessive inheritance

Glycine N-methyltransferase deficiency (GNMT deficiency) is a very rare condition characterized by persistent and isolated excess levels of methionine in the blood (hypermethioninemia). The only clinical abnormalities are mild increase of the liver size (hepatomegaly) and chronic elevation of the transaminase levels in the blood without liver disease. Methionine may also be increased in urine. However, because elevated levels of methionine in the blood itself is a risk factor for development of neurological signs and symptoms, people with GNMT deficiency can have neurological problems when methionine levelsare greater than 800μmol/L. GNMT deficiency is caused by mutations in the GNMT gene. Inheritance is autosomal recessive. Treatment is not needed in most cases.

489
(46.4%)

long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Hepatomegaly Hypoglycemia Pigmentary retinopathy

Autosomal recessive inheritance

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a mitochondrial disorder of long chain fatty acid oxidation characterized in most patients by onset in infancy/ early childhood with hypoketotic hypoglycemia, metabolic acidosis, liver disease, hypotonia and frequently cardiac involvement with arrhythmias and/or cardiomyopathy.

489
(46.4%)

CIDEC-related familial partial lipodystrophy

Acanthosis nigricans Hepatic steatosis Hepatomegaly Hypertriglyceridemia

Autosomal recessive inheritance

489
(46.4%)

hyperzincemia with functional zinc depletion

Hepatomegaly Increased serum zinc Osteoporosis

Autosomal dominant inheritance

489
(46.4%)

glycogen storage disease IXa

Hepatomegaly Hypoglycemia Motor delay

X-linked recessive inheritance

Any glycogen storage disease in which the cause of the disease is a mutation in the PHKA2 gene.

489
(46.4%)

combined oxidative phosphorylation defect type 9

Global developmental delay Hepatomegaly Increased serum lactate

Autosomal recessive inheritance

Combined oxidative phosphorylation defect type 9 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by initially normal growth and development followed by the infantile-onset of failure to thrive, psychomotor delay, poor feeding, dyspnea, severe hypertrophic cardiomyopathy and hepatomegaly. Laboratory studies report increased plasma lactate and alanine, abnormal liver enzymes and decreased activity of mitochondrial respiratory chain complexes I, III, IV, and V.

489
(46.4%)

glycogen storage disease VI

Failure to thrive in infancy Hepatomegaly Hypoglycemia

Autosomal recessive inheritance

Liver phosphorylase deficiency, or glycogen storage disease type 6b (Hers' disease, GSD 6b) is a benign and rare form of glycogen storage disease.

489
(46.4%)

Amish lethal microcephaly

Hepatomegaly Lactic acidosis Progressive microcephaly

Autosomal recessive inheritance

Amish lethal microcephaly is a very rare syndrome characterized by extreme microcephaly and early death, within the first year.

489
(46.4%)

Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

Hepatomegaly Proteinuria

Autosomal dominant inheritance

Any Fanconi syndrome in which the cause of the disease is a mutation in the HNF4A gene.

489
(46.4%)

carnitine palmitoyl transferase II deficiency, severe infantile form

Hepatomegaly Hypoketotic hypoglycemia Macrovesicular hepatic steatosis Seizure

Autosomal recessive inheritance

The severe infantile form of carnitine palmitoyltransferase II (CPT II) deficiency, an inherited disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the early-onset form of the disease.

489
(46.4%)

fructose-1,6-bisphosphatase deficiency

Hepatomegaly Irritability Metabolic acidosis

Autosomal recessive inheritance

Fructose-1,6-biphosphatase (FBP) deficiency is a disorder of fructose metabolism characterized by recurrent episodes of fasting hypoglycemia with lactic acidosis, that may be life-threatening in neonates and infants.

489
(46.4%)

retinitis pigmentosa 59

Cryptorchidism Cystoid macular edema Hepatomegaly

Autosomal recessive inheritance

Any retinitis pigmentosa in which the cause of the disease is a mutation in the DHDDS gene.

489
(46.4%)

hereditary sclerosing poikiloderma with tendon and pulmonary involvement

Cataract Elevated serum creatine kinase Hepatomegaly

Autosomal dominant inheritance

Hereditary fibrosing poikiloderma-tendon contractures-myopathy-pulmonary fibrosis syndrome is a rare, genetic, hereditary poikiloderma syndrome characterized by early-onset poikiloderma (mainly on the face), hypotrichosis, hypohidrosis, muscle and tendon contractures with varus foot deformity, progressive proximal and distal muscle weakness in all extremities, and progressive pulmonary fibrosis. Mild lymphedema of the extremities, growth retardation, liver impairment, exocrine pancreatic insufficiency and hematologic abnormalities are additional variable features.

489
(46.4%)

medium chain acyl-CoA dehydrogenase deficiency

Hepatic steatosis Hepatomegaly Metabolic acidosis Seizure

Autosomal recessive inheritance

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inborn error of mitochondrial fatty acid oxidation characterized by a rapidly progressive metabolic crisis, often presenting as hypoketotic hypoglycemia, lethargy, vomiting, seizures and coma, which can be fatal in the absence of emergency medical intervention.

489
(46.4%)

mitochondrial complex 1 deficiency, nuclear type 3

Hepatomegaly Metabolic acidosis Seizure

Autosomal recessive inheritance

489
(46.4%)

Leber congenital amaurosis 1

Hepatomegaly Hyperthreoninuria Sensorineural hearing impairment

Autosomal recessive inheritance

Any Leber congenital amaurosis in which the cause of the disease is a mutation in the GUCY2D gene.

489
(46.4%)

pyruvate carboxylase deficiency disease

Hepatomegaly Hypoglycemia Intellectual disability

Autosomal recessive inheritance

Pyruvate carboxylase (PC) deficiency is a rare neurometabolic disorder characterized by metabolic acidosis, failure to thrive, developmental delay, and recurrent seizures at an early age in severely affected patients.

489
(46.4%)

mitochondrial complex 1 deficiency, nuclear type 11

Hepatomegaly Macrovesicular hepatic steatosis Metabolic acidosis Retinopathy

Autosomal recessive inheritance

489
(46.4%)

polyglucosan body myopathy 1 with or without immunodeficiency

Elevated serum creatine kinase Hepatomegaly Ptosis

Autosomal recessive inheritance

489
(46.4%)

pyruvate dehydrogenase E3 deficiency

Hepatomegaly Metabolic acidosis Microcephaly

Autosomal recessive inheritance

Pyruvate dehydrogenase E3 deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD) characterized by either early-onset lactic acidosis and delayed development, later-onset neurological dysfunction or liver disease.

489
(46.4%)

D,L-2-hydroxyglutaric aciduria

Hepatomegaly L-2-hydroxyglutaric aciduria Microcephaly

Autosomal recessive inheritance

D,L-2-hydroxyglutaric aciduria is a rare inborn error of metabolism characterized by severe neonatal epileptic encephalopathy, episodes of apnea and respiratory distress, severe global developmental delay or absent psychomotor development, severe muscular hypotonia or absent voluntary movements, feeding difficulties and failure to thrive, absence of visual contact, abnormal brain morphology (including cerebral atrophy, ventriculomegaly and hypoplasia or dysplasia of the corpus callosum), mild dysmorphic features (frontal bossing, hypertelorism, downslanting palpebral fissures, flat nasal bridge), elevated CSF and plasma lactate and urinary Krebs cycle metabolites.

489
(46.4%)

very long chain acyl-CoA dehydrogenase deficiency

Hepatic steatosis Hepatomegaly Hypotonia Nonketotic hypoglycemia

Autosomal recessive inheritance

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid oxidation with a variable presentation including: cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis.

489
(46.4%)

glycogen storage disease due to glycogen branching enzyme deficiency

Cirrhosis Edema Hepatosplenomegaly

Autosomal recessive inheritance

Glycogen branching enzyme (GBE) deficiency (Andersen's disease or amylopectinosis), or glycogen storage disease type 4 (GSD4), is a rare and severe form of glycogen storage disease which accounts for approximately 3% of all the glycogen storage diseases.

489
(46.4%)

trichohepatoenteric syndrome 2

Cirrhosis Decreased serum iron Hepatomegaly Hypertelorism

Autosomal recessive inheritance

Any tricho-hepato-enteric syndrome in which the cause of the disease is a mutation in the SKIV2L gene.

489
(46.4%)

mitochondrial complex V (ATP synthase) deficiency, nuclear type 1

Cryptorchidism Hepatomegaly Hyperammonemia

Autosomal recessive inheritance

Any mitochondrial proton-transporting ATP synthase complex deficiency in which the cause of the disease is a mutation in the ATPAF2 gene.

489
(46.4%)

combined oxidative phosphorylation defect type 4

Hepatomegaly Metabolic acidosis Microcephaly

Autosomal recessive inheritance

Combined oxidative phosphorylation defect type 4 is a rare mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by a neonatal onset of severe metabolic acidosis and respiratory distress, persistent lactic acidosis with episodes of metabolic crises, developmental regression, microcephaly, abnormal gaze fixation and pursuit, axial hypotonia with limb spasticity and reduced spontaneous movements. Neuroimaging studies reveal polymicrogyria, white matter abnormalities and multiple cystic brain lesions, including basal ganglia, and cerebral atrophy. Decreased activity of complex I and IV have been determined in muscle biopsy.

489
(46.4%)

glycogen storage disease III

Hepatic fibrosis Hepatomegaly Hypoglycemia Thin upper lip vermilion

Autosomal recessive inheritance

Glycogen debranching enzyme (GDE) deficiency, or glycogen storage disease type 3 (GSD 3), is a form of glycogen storage disease characterized by severe muscle weakness and hepatopathy.

489
(46.4%)

peroxisome biogenesis disorder 1B

Cirrhosis Hepatomegaly Hyperoxaluria Renal cyst

Autosomal recessive inheritance

489
(46.4%)

mitochondrial pyruvate carrier deficiency

Hepatomegaly Hypoglycemia Thin upper lip vermilion

Autosomal recessive inheritance

An autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation.

489
(46.4%)

glutaryl-CoA dehydrogenase deficiency

Hepatomegaly Macrocephaly Metabolic acidosis

Autosomal recessive inheritance

Glutaryl-CoA dehydrogenase (GCDH) deficiency (GDD) is an autosomal recessive neurometabolic disorder clinically characterized by encephalopathic crises resulting in striatal injury and a severe dystonic dyskinetic movement disorder.

489
(46.4%)

combined oxidative phosphorylation deficiency 33

Hepatomegaly Metabolic acidosis Nephrotic syndrome

Autosomal recessive inheritance

489
(46.4%)

severe neurodegenerative syndrome with lipodystrophy

Delayed speech and language development Hepatomegaly Hypertriglyceridemia

Autosomal recessive inheritance

489
(46.4%)

T-B+ severe combined immunodeficiency due to gamma chain deficiency

Agammaglobulinemia Hepatomegaly Hypoplasia of the thymus

X-linked recessive inheritance

Severe combined immunodeficiency (SCID) due to gamma chain deficiency, also called SCID-X1, is a form of SCID characterized by severe and recurrent infections, associated with diarrhea and failure to thrive.

489
(46.4%)

carnitine palmitoyl transferase 1A deficiency

Hepatic steatosis Hepatomegaly Renal tubular acidosis Seizure

Autosomal recessive inheritance

Carnitine palmitoyltransferase 1A (CPT-1A) deficiency is an inborn error of metabolism that affects mitochondrial oxidation of long chain fatty acids (LCFA) in the liver and kidneys, and is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure.

489
(46.4%)

citrullinemia type I

Cirrhosis Hepatomegaly Irritability Respiratory alkalosis

Autosomal recessive inheritance

Citrullinemia type I is a rare autosomal recessive urea cycle defect characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting in the neonatal form (Acute neonatal citrullinemia type I) and by variable hyperammonemia in the later-onset form (adult-onset citrullinemia type I).

489
(46.4%)

carnitine-acylcarnitine translocase deficiency

Hepatomegaly Hypoglycemia Irritability

Autosomal recessive inheritance

Carnitine-acylcarnitine translocase (CACT) deficiency is a life-threatening, inherited disorder of fatty acid oxidation which usually presents in the neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and/or arrhythmia, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.

489
(46.4%)

Sandhoff disease

Abnormal glycosphingolipid metabolism Hepatosplenomegaly Urinary incontinence

Autosomal recessive inheritance

Sandhoff disease is a lysosomal storage disorder from the GM2 gangliosidosis family and is characterised by central nervous system degeneration.

489
(46.4%)

proximal tubulopathy-diabetes mellitus-cerebellar ataxia syndrome

Diabetes mellitus Hepatomegaly Polyuria

Mitochondrial inheritance

Proximal tubulopathy-diabetes mellitus-cerebellar ataxia syndrome is characterised by onset of proximal tubulopathy in the first year of life, followed by progressive development during childhood of skin anomalies (erythrocyanosis and abnormal pigmentation), blindness, osteoporosis, cerebellar ataxia, mitochondrial myopathy, deafness and diabetes mellitus.

489
(46.4%)

systemic primary carnitine deficiency disease

Hepatic steatosis Hepatomegaly Hypoglycemia Hypotonia

Autosomal recessive inheritance

Systemic primary carnitine deficiency (SPCD) is a potentially lethal disorder of fatty acid oxidation characterized classically by early childhood onset cardiomyopathy often with weakness and hypotonia, failure to thrive and recurrent hypoglycemic hypoketotic seizures and/or coma.

489
(46.4%)

mitochondrial myopathy with reversible cytochrome C oxidase deficiency

Hepatomegaly Increased serum lactate Macroglossia

Mitochondrial inheritance

489
(46.4%)

MOGS-CDG

Abnormality of metabolism/homeostasis Hepatomegaly High palate

Autosomal recessive inheritance

MOGS-CDG is a form of congenital disorders of N-linked glycosylation characterized by generalized hypotonia, craniofacial dysmorphism (prominent occiput, short palpebral fissures, long eyelashes, broad nose, high arched palate , retrognathia), hypoplastic genitalia, seizures, feeding difficulties, hypoventilation, severe hypogammaglobulinemia with generalized edema, and increased resistance to particular viral infections (particularly to enveloped viruses). The disease is caused by loss-of-function mutations in the gene MOGS (2p13.1).

489
(46.4%)

peroxisome biogenesis disorder 4B

Hepatomegaly Recurrent fever Ureterocele

Autosomal dominant inheritance Autosomal recessive inheritance

489
(46.4%)

argininosuccinic aciduria

Hepatic fibrosis Hepatomegaly Irritability Respiratory alkalosis

Autosomal recessive inheritance

Argininosuccinic aciduria (ASA) is a disorder of urea cycle metabolism most commonly characterized by either a severe, neonatal-onset form that manifests with hyperammonemia accompanied with vomiting, hypothermia, lethargy and poor feeding in the first few days of life, or late-onset forms (any age outside the newborn period) that manifest with stress or infection-induced episodic hyperammonemia or, in some, behavioral abnormalities and/or learning disabilities. Patients often manifest liver dysfunction.

489
(46.4%)

multiple mitochondrial dysfunctions syndrome 2

Hepatomegaly Lactic acidosis Visual impairment

Autosomal recessive inheritance

Any fatal multiple mitochondrial dysfunctions syndrome in which the cause of the disease is a mutation in the BOLA3 gene.

489
(46.4%)

neutral lipid storage myopathy

Diabetes mellitus Hepatic steatosis Hepatomegaly Sensorineural hearing impairment

Autosomal recessive inheritance

489
(46.4%)

ornithine translocase deficiency

Chorioretinal atrophy Hepatomegaly Hyperammonemia

Autosomal recessive inheritance

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (triple H syndrome) 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.

489
(46.4%)

Beckwith-Wiedemann syndrome

Cryptorchidism Hepatomegaly Neonatal hypoglycemia

Autosomal dominant inheritance

Beckwith-Wiedemann syndrome (BWS) is a genetic disorder characterized by overgrowth, tumor predisposition and congenital malformations.

489
(46.4%)

fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Hepatomegaly Increased serum lactate Visual impairment

Autosomal recessive inheritance

Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.

489
(46.4%)

combined oxidative phosphorylation defect type 11

Hepatic steatosis Hepatomegaly Renal insufficiency Renal tubular acidosis

Autosomal recessive inheritance

Any combined oxidative phosphorylation deficiency in which the cause of the disease is a mutation in the RMND1 gene.

489
(46.4%)

Wolcott-Rallison syndrome

Hepatomegaly Insulin-resistant diabetes mellitus Renal insufficiency

Autosomal recessive inheritance

Wolcott-Rallison syndrome (WRS) is a very rare genetic disease, characterized by permanent neonatal diabetes mellitus (PNDM) with multiple epiphyseal dysplasia and other clinical manifestations, including recurrent episodes of acute liver failure.

489
(46.4%)

mucopolysaccharidosis type 4A

Hepatomegaly Inguinal hernia Keratan sulfate excretion in urine

Autosomal recessive inheritance

A rare autosomal recessive lysosomal storage disease caused by deficiency of the enzyme galactosamine-6-sulfatase. It is characterized by skeletal and central nervous system deficits.

489
(46.4%)

mucopolysaccharidosis type 4B

Decreased beta-galactosidase activity Hepatomegaly Inguinal hernia

Autosomal recessive inheritance

A rare autosomal recessive lysosomal storage disease caused by deficiency of the enzyme beta galactosidase. It is characterized by skeletal dysplasia and short stature.