Amino Acid and Organic Acid Metabolism Disorders: Inherited Disorders of Metabolism: Merck Manual Professional

Disorders of Amino Acid and Organic Acid Metabolism
Disease (OMIM Number)	Defective Proteins or Enzymes	Defective Gene or Genes (Chromosomal Location)	Comments
Disorders of phenylalanine and tyrosine metabolism
Phenylketonuria (PKU), with classic and mild forms (261600)	Phenylalanine hydroxylase	PAH (12q24.1)*	Biochemical profile: Elevated plasma phenylalanine Clinical features: Intellectual disability, behavioral problems Treatment: Dietary phenylalanine restriction, tyrosine supplementation
Dihydropteridine reductase deficiency (261630)	Dihydropteridine reductase	QDPR (4p15.31)*	Biochemical profile: Elevated plasma phenylalanine, high urine biopterin, low plasma biopterin Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia Treatment: Dietary phenylalanine restriction, tyrosine supplementation, folinic acid, neurotransmitter replacement
Pterin-4α-carbinolamine dehydratase deficiency (264070)	Pterin-4α-carbinolamine dehydratase	PCBD (10q22)*	Biochemical profile: Elevated plasma phenylalanine, high urine neopterin and primapterin, low plasma biopterin Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia Treatment: Dietary phenylalanine restriction, tyrosine supplementation, neurotransmitter replacement
Biopterin synthesis deficiency	GTP-cyclohydrolase (233910)	GCH1 (14q22)*	Biochemical profile: Elevated plasma phenylalanine, low urine biopterin, low (GCH) or high (PTS and SPR) urine neopterin Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia Treatment: Tetrahydrobiopterin and neurotransmitter supplementation
	6-Pyruvoyl-tetrahydropterin synthase (261640)	PTS (11q22-q23)*
	Sepiapterin reductase (182125)	SPR (2p14-p12)*
Tyrosinemia type I (hepatorenal; 276700)	Fumarylacetoacetate hydrolase	FAH (15q23-q25)*	Biochemical profile: Elevated plasma tyrosine, elevated plasma and urinary succinylacetone Clinical features: Cirrhosis, acute liver failure, peripheral neuropathy, Fanconi syndrome Treatment: Dietary phenylalanine, tyrosine, and methionine restriction; 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC); liver transplantation
Tyrosinemia type II (oculocutaneous; 276600)	Tyrosine aminotransferase	TAT (16q22.1-q22.3)*	Biochemical profile: Elevated plasma tyrosine and phenylalanine Clinical features: Intellectual disability, palmoplantar hyperkeratitis, corneal ulcers Treatment: Dietary phenylalanine and tyrosine restriction
Tyrosinemia type III (276710)	4-Hydroxyphenylpyruvate dioxygenase	HPD (12q24-qter)*	Biochemical profile: Elevated plasma tyrosine, elevated urinary 4-hydroxyphenyl derivatives Clinical features: Developmental delay, seizures, ataxia Treatment: Dietary phenylalanine and tyrosine restriction, ascorbate supplementation
Transient tyrosinemia	4-Hydroxyphenylpyruvate dioxygenase	Not genetic	Biochemical profile: Elevated plasma phenylalanine and tyrosine Clinical features: Usually occurring in premature infants; mostly asymptomatic Occasionally poor feeding and lethargy Treatment: Tyrosine restriction and ascorbate supplementation for symptomatic patients only
Hawkinsinuria (140350)	4-Hydroxyphenylpyruvate dioxygenase complex	HPD (12q24-qter)*	Biochemical profile: Mild hypertyrosinemia, elevated urinary hawkinsin Clinical features: Failure to thrive, ketotic metabolic acidosis Treatment: Dietary phenylalanine and tyrosine restriction, ascorbate supplementation
Alkaptonuria (203500)	Homogentisate oxidase	HGD (3q21-q23)*	Biochemical profile: Elevated urine homogentisic acid Clinical features: Dark urine, ochronosis, arthritis Treatment: None; ascorbate supplementation to reduce pigmentation
Oculocutaneous albinism type I (A and B; 203100)	Tyrosinase	TYR (11q21)*	Biochemical profile: No abnormality in plasma and urine amino acids, absent (IA) or decreased (IB) tyrosinase Clinical features: Absent (IA) or decreased (IB) pigment in skin, hair, iris, and retina; nystagmus; blindness; skin cancer Treatment: Protection of skin and eyes from actinic radiation
Disorders of branched-chain amino acid (valine, leucine, isoleucine) metabolism
Maple syrup urine disease, or branched-chain ketoaciduria (248600)	Branched-chain α-ketoacid dehydrogenase complex (BCKD)		Biochemical profile: Elevated plasma valine, leucine, isoleucine, and alloisoleucine Clinical features (molecular forms do not correlate with clinical forms except that a high percentage of type II mutations are associated with thiamin responsiveness): In classic form, hypertonia, seizures, coma, death In intermediate form, intellectual disability, neurologic symptoms, full-blown picture developing with stress In intermittent form, symptoms only with stress (eg, fever, infection) In thiamin-responsive form, features similar to mild intermediate form In E3 subunit deficient form, features similar to intermediate form but accompanied by severe lactic acidosis because E3 is needed for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase Acute treatment: Peritoneal dialysis, hemodialysis, or both; aggressive nutrition management, including high-dose glucose, insulin, and special hyperalimentation Chronic treatment: Dietary branched-chain amino acid restriction, thiamin supplementation as needed
Type IA	BCKD E1α component	BCKDHA (19q13)*
Type IB	BCKD E1β component	BCKDHB (6p22-p21)*
Type II	BCKD E2 component	DBT (1p31)*
Type III	BCKD E3 component	DLD (7q31-q32)*
Propionic acidemia (606054)	Propionyl-CoA carboxylase		Biochemical profile: Elevated plasma glycine, urine methylcitrate, 3-hydroxypropionate, propionylglycine, and tiglylglycine Clinical features: Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth delay, intellectual disability, physical disability Treatment: During acute episodes, high-dose glucose and aggressive fluid resuscitation For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis For long-term management, controlled intake of threonine, valine, isoleucine, and methionine; carnitine supplementation; biotin for responsive patients (see also Multiple carboxylase deficiency and Biotinidase deficiency, below)
Type I	α-Subunit	PCCA (13q32)*
Type II	β-Subunit	PCCB (3q21-q22)*
Multiple carboxylase deficiency (253270)	Holocarboxylase synthetase	HLCS (21q22.1)*	Biochemical profile: Same as for propionic acidemia but also elevated lactate and 3-methylcrotonate Clinical features: Skin rash, alopecia, seizures, hypotonia, developmental delay, ketoacidosis, defective T- and B-cell immunity, hearing loss Treatment: Biotin 5–10 mg/day
Biotinidase deficiency (253260)	Biotinidase	BTD (3p25)*	Similar to multiple carboxylase deficiency
Methylmalonic acidemia (mut defects; 251000)	Methylmalonyl-CoA mutase Mut0 (no enzyme activity) Mut- (some residual enzyme activity)	MUT (6p21)*	Biochemical profile: Elevated plasma glycine; increased urine methylmalonate, 3-hydroxypropionate, methylcitrate, and tiglylglycine Clinical features: Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth delay, intellectual disability, and physical disability Treatment: During acute episodes, high-dose glucose and aggressive fluid resuscitation For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis For long-term management, controlled intake of threonine, valine, isoleucine, and methionine; carnitine supplementation; vitamin B₁₂ for patients with mut- type
Methylmalonic acidemia (cblA; 251100)	Mitochondrial cobalamin translocase	MMAA (4q31.1-q31.2)*	Biochemical profile: Similar to methylmalonic acidemia due to mutase deficiency Clinical features: Similar to methylmalonic acidemia due to mutase deficiency Treatment: Responsive to high-dose hydroxycobalamin
Methylmalonic acidemia (cblB; 251110)	ATP:cob(1)alamin adenosyl transferase	MMMB (12q24)*	Biochemical profile: Similar to methylmalonic acidemia due to mutase deficiency Clinical features: Similar to methylmalonic acidemia due to mutase deficiency Treatment: Responsive to high-dose hydroxycobalamin
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (cblC; 277400)	Methylmalonyl-CoA mutase and methylene tetrahydrofolate:homocysteine methyltransferase	Genetically heterogeneous	Biochemical profile: Similar to methylmalonic acidemia cblA and cblB but also homocystinemia, homocystinuria, low methionine, and high cystathionine; normal serum cobalamin Clinical features: Similar to cblA and cblB but also megaloblastic anemia Treatment: Protein restriction, high-dose hydroxycobalamin
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (cblD; 277410)	Not determined	Genetically heterogeneous	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (cblF; 277380)	Defective lysosomal release of cobalamin	Genetically heterogeneous	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (intrinsic factor deficiency; 261000)	Intrinsic factor	GIF (11q13)*	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (Imerslund-Graesbeck syndrome; 261100)	Cubilin (intrinsic factor receptor)	CUBN (10p12.1)*	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (transcobalamin II deficiency; 275350)	Transcobalamin II	TC2 (22q11.2)*	Similar to methylmalonic acidemia cblC
Methylmalonic semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia (603178)	Methylmalonic semialdehyde dehydrogenase (see also disorders of β- and γ-amino acids, below)	ALDH6A1 (14q24.1)	Biochemical profile: Moderate urine methylmalonate Clinical features: Developmental delay, seizures Treatment: No effective treatment
Methylmalonic acidemia-homocystinuria (cblH; 606169)	Not determined	Genetically heterogeneous	Similar to methylmalonic acidemia cblA
Isovaleric acidemia (243500)	Isovaleryl-CoA dehydrogenase	IVD(15q14-q15)*	Biochemical profile: Isovaleryl glycine, 3-hydroxyisovalerate Clinical features: Characteristic sweaty feet odor, vomiting, lethargy, acidosis, intellectual disability, bone marrow suppression, hypoglycemia; ketoacidosis, hyperammonemia, neonatal death Treatment: Controlled leucine intake, glycine, carnitine
3-Methylcrotonyl-CoA carboxylase deficiency	3-Methylcrotonyl CoA carboxylase		Biochemical profile: Elevated 3-hydroxyisovalerate, 3-methylcrontylglycine, and 3-hydroxyisovalerylcarnitine Clinical features: Episodic vomiting, acidosis, hypoglycemia, hypotonia, intellectual disability, coma; sometimes asymptomatic intellectual disability Treatment: Controlled leucine intake (see also Multiple carboxylase deficiency and Biotinidase deficiency, above)
Type I (210200)	α-Subunit	MCCC1 (3q25-q27)*
Type II (210210)	β-Subunit	MCCC2 (5q12-q13)*
3-Methylglutaconic aciduria type I (250950)	3-Methylglutaconyl-CoA hydratase	AUH (9)*	Biochemical profile: Elevated urine 3-methylglutaconate and 3-hydroxyisolvalerate Clinical features: Acidosis, hypotonia, hepatomegaly, speech delay Treatment: Carnitine; benefit of leucine restriction unclear
3-Methylglutaconic aciduria type II (Barth syndrome; 302060)	Tafazzin	TAZ (Xq28)*	Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Myopathy, dilated cardiomyopathy, mitochondrial abnormality, neutropenia, developmental delay Treatment: Pantothenic acid
3-Methylglutaconic aciduria type III (Costeff optic atrophy; 258501)	Not determined	OPA3 (19q13)*	Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Optic atrophy, ataxia, spasticity, choreiform movement Treatment: No effective treatment
3-Methylglutaconic aciduria type IV (250951)	Not determined	Not determined	Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Variable expression, growth and developmental delay, hypotonia, seizures, optic atrophy, deafness, cardiomyopathy, acidosis Treatment: No effective treatment
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (246450)	3-Hydroxy-3-methylglutaryl-CoA lyase	HMGCL (1pter-p33)*	Biochemical profile: Elevated urine 3-hydroxy-3-methylglutarate, 3-methylglutaconate, and 3-hydroxyisovalerate; elevated plasma 3-methylglutarylcarnitine Clinical features: Reye-like syndrome, vomiting, hypotonia, acidosis, hypoglycemia, lethargy, hyperammonemia without ketosis Treatment: Restricted leucine intake, control of hypoglycemia
Mevalonic aciduria (251170, 260920)	Mevalonate kinase	MVK (12q24)*	Biochemical profile: Elevated creatine kinase, transaminase, leukotriene, and urinary mevalonic acid; decreased cholesterol Clinical features: In classic form, short stature, hypotonia, developmental delay, dysmorphic features, cataracts, vomiting, diarrhea, hepatosplenomegaly, arthralgia, lymphadenopathy, cerebral and cerebellar atrophy, anemia, thrombocytopenia, early death In hyper IgD form, recurrent febrile episodes, vomiting, diarrhea, arthralgia, abdominal pain, rash, splenomegaly, elevated serum IgD and IgA levels Treatment: No effective treatment; corticosteroids during acute attacks possibly helpful
Mitochondrial acetoacetyl-CoA thiolase deficiency (607809)	Acetyl-CoA thiolase	ACAT1 (11q22.3-a23.1)*	Biochemical profile: Elevated urine 2-methyl-3-hydroxybutyrate and 2-methylacetoacetate, elevated plasma tiglylglycine Clinical features: Episodes of ketoacidosis, vomiting, diarrhea, coma, intellectual disability Treatment: Low-protein diet, controlled isoleucine intake
Isobutyryl-CoA dehydrogenase deficiency	Isobutyryl-CoA dehydrogenase	Not determined	Biochemical profile: Elevated C-4 carnitine, low free carnitine Clinical features: Anemia, cardiomyopathy Treatment: Carnitine
3-Hydroxyisobutyryl-CoA deacylase deficiency (methacrylic aciduria; 250620)	3-Hydroxyisobutyryl-CoA deacylase	Not determined	Biochemical profile: Elevated S-(2-carboxypropyl)-cysteine and S-(2-carboxypropyl)-cysteamine Clinical features: Growth and developmental delay, dysmorphic feature, vertebral anomaly, CNS malformations, death Treatment: No effective treatment
3-Hydroxyisobutyric aciduria (236795)	3-Hydroxyisobutyrate dehydrogenase	HIBADH (chromosomal location not determined)	Biochemical profile: Elevated urine 3-hydroxyisobutyrate; in 50% patients, elevated lactate Clinical features: Dysmorphic features, CNS malformations, hypotonia, ketoacidosis Treatment: Low-protein diet, carnitine
2-Methylbutyryl glycinuria (600301)	Short branched-chain acyl-CoA dehydrogenase	ACADSB (10q25-q26)*	Biochemical profile: Elevated urine 2-methylbutyrulglycine Clinical features: Hypotonia, muscular atrophy, lethargy, hypoglycemia, hypothermia Treatment: No effective treatment
Ethylmalonic encephalopathy (602473)	Mitochondrial protein of undetermined function	ETHE1 (19q13.32)*	Biochemical profile: Elevated urine ethylmalonic and methylsuccinic acids, elevated serum lactate Clinical features: Retinopathy, acrocyanosis, diarrhea, petechiae, developmental delay, intellectual disability, extrapyramidal symptoms, ataxia, seizures, hyperintense lesions in the basal ganglia Treatment: No effective treatment
Malonic aciduria (248360)	Malonyl-CoA decarboxylase	MLYCD (16q24)*	Biochemical profile: Elevated lactate, malonate, methylmalonate, and malonylcarnitine Clinical features: Hypotonia, developmental delay, hypoglycemia, acidosis Treatment: No effective treatment; low-fat, high-carbohydrate diet Carnitine possibly helpful in some patients
Hypervalinemia or hyperisoleucine-hyperleucinemia (277100)	Mitochondrial branched-chain aminotransferase 2	BCAT2 (19q13)	Biochemical profile: Elevated urine and serum valine Clinical features: Growth retardation Treatment: Controlled valine intake
Disorders of methionine and sulfur metabolism
Homocystinuria (236200)	Cystathionine β-synthase	CBS (21q22.3)*	Biochemical profile: Methioninuria, homocystinuria Clinical features: Osteoporosis, scoliosis, fair complexion, ectopia lentis, progressive intellectual disability, thromboembolism Treatment: Pyridoxine, folate, betaine for unresponsive patients, low methionine diet with some L-cysteine supplementation
Methylenetetrahydrofolate reductase deficiency (236250)	Methylenetetrahydrofolate reductase	MTHFR (1p36.3)*	Biochemical profile: Low to normal plasma methionine, homocystinemia, homocystinuria Clinical features: Varies from asymptomatic to microcephaly, hypotonia, seizures, gait abnormality, and intellectual disability to apnea, coma, and death Treatment: Pyridoxine, folate (folic acid), hydroxycobalamin, methionine, betaine
Methylmalonic acidemia-homocystinuria (cblE; 236270)	Methionine synthase reductase	MTRR (5p15)*	Biochemical profile: Homocystinuria, homocystinemia, low plasma methionine, no methylmalonic aciduria, normal B₁₂ and folate Clinical features: Feeding difficulty, growth failure, intellectual disability, ataxia, cerebral atrophy Treatment: Hydroxycobalamin, folate, L-methionine
Methylmalonic acidemia-homocystinuria (cblG; 250940)	Methylene tetrahydrofolate homocysteine methyltransferase	MTR (1q43)*	Same as methylmalonic acidemia-homocystinuria cblE
Hypermethioninemia (250850)	Methionine adenosyltransferase I and III	MAT1A (10q22)*	Biochemical profile: Elevated plasma methionine Clinical features: Mainly asymptomatic, fetid breath Treatment: None needed
Cystathioninuria (219500)	γ-Cystathionase	CTH (16)*	Biochemical profile: Cystathioninuria Clinical features: Usually normal; intellectual disability reported Treatment: Pyridoxine
Sulfite oxidase deficiency (606887)	Sulfite oxidase	SUOX (12q13)*	Biochemical profile: Elevated urine sulfite, thiosulfate, and S-sulfocysteine; decreased sulfate Clinical features: Developmental delay, ectopia lentis, eczema, delayed dentition, fine hair, hemiplegia, infantile hypotonia, hypertonia, seizures, choreoathetosis, ataxia, dystonia, death Treatment: No effective treatment
Molybdenum cofactor defect (252150)	MOCS1A and MOCS1B proteins	MCOS1 (14q24)*	Biochemical profile: Elevated urinary sulfite, thiosulfate, S-sulfocysteine, taurine, hypoxanthine, and xanthine; decreased sulfate and urate Clinical features: Similar to sulfite oxidase deficiency but also urinary stones Treatment: No effective treatment Low sulfur diet possibly helpful in patients with milder symptoms
	Molybdopterin synthase	MCOS2 (6p21.3)*
	Gephyrin	GEPH (5q21)*
Urea cycle and related disorders
Ornithine-transcarbamoylase (OTC) deficiency (311250)	OTC	OTC (Xp21.1)*	Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures, death In female carriers, variable manifestations, ranging from growth delay, small stature, protein aversion, and postpartum hyperammonemia to symptoms as severe as those in males with the deficiency Treatment: Hemodialysis for emergent hyperammonemic crisis, Na benzoate, Na phenylacetate, Na phenylbutyrate, low-protein diet supplemented with essential amino acid mixture and arginine, citrulline, experimental attempts at gene therapy, liver transplantation (which is curative)
N-Acetylglutamate synthetase deficiency (237310)	N-Acetylglutamate synthetase	NAGS (17q21.31)	Biochemical profile: Similar to OTC deficiency except for normal to low urine orotate Clinical features: Similar to OTC deficiency except carriers are asymptomatic Treatment: Similar to OTC deficiency but also N-carbamylglutamate supplementation
Carbamoyl phosphate synthetase (CPS) deficiency (237300)	Carbamoyl phosphate synthetase	CPS1 (2q35)*	Biochemical profile: Similar to OTC deficiency except for normal to low urine orotate Clinical features: Similar to OTC deficiency except carriers are asymptomatic Treatment: Na benzoate and arginine
Citrullinemia type I (215700)	Argininosuccinic acid synthetase	ASS (9q34)*	Biochemical profile: High plasma citrulline and glutamine, citrullinuria, orotic aciduria Clinical features: Episodic hyperammonemia, growth failure, protein aversion, lethargy, vomiting, coma, seizures, cerebral edema, developmental delay Treatment: Similar to that for OTC deficiency except citrulline supplementation is not recommended
Citrullinemia type II (603814, 603471)	Citrin	SCL25A13 (7q21.3)*	Biochemical profile: Elevated plasma citrulline, methionine, galactose, and bilirubin Clinical features: With neonatal onset, cholestasis resolved by 3 mo With adult onset, enuresis, delayed menarche, sleep reversal, vomiting, delusions, hallucinations, psychosis, coma Treatment: No clear treatment
Argininosuccinic aciduria (207900)	Argininosuccinate lyase	ASL (7cen-q11.2)*	Biochemical profile: Elevated plasma citrulline and glutamine, elevated urine argininosuccinate Clinical features: Episodic hyperammonemia, hepatic fibrosis, elevated liver enzymes, hepatomegaly, protein aversion, vomiting, seizures, intellectual disability, ataxia, lethargy, coma, trichorrhexis nodosa Treatment: Arginine supplementation
Argininemia (107830)	Arginase I	ARG1 (6q23)*	Biochemical profile: Elevated plasma arginine, diaminoaciduria (argininuria, lysinuria, cystinuria, ornithinuria), orotic aciduria, pyrimidinuria Clinical features: Growth and developmental delay, anorexia, vomiting, seizures, spasticity, irritability, hyperactivity, protein intolerance, hyperammonemia Treatment: Low-protein diet, benzoate, phenylacetate
Lysinuric protein intolerance (dibasic aminoaciduria II; 222700)	Dibasic amino acid transporter	SLC7A7 (14q11.2)*	Biochemical profile: Elevated urine lysine, ornithine, and arginine Clinical features: Protein intolerance, episodic hyperammonemia, growth and developmental delay, diarrhea, vomiting, hepatomegaly, cirrhosis, leucopenia, osteopenia, skeletal fragility, coma Treatment: Low-protein diet, citrulline
Hyperornithinemia, hyperammonemia, and homocitrullinemia (238970)	Mitochondrial ornithine translocase	SLC25A15 (13q14)*	Biochemical profile: Elevated plasma ornithine, homocitrullinemia Clinical features: Intellectual disability, progressive spastic paraparesis, episodic confusion, hyperammonemia, dyspraxia, seizures, vomiting, retinopathy, abnormal nerve conduction and evoked potentials, leukodystrophy Treatment: Lysine, ornithine, or citrulline supplementation
Ornithinemia (258870)	Ornithine aminotransferase	OAT (10q26)*	Biochemical profile: Elevated plasma ornithine and urine ornithine, lysine, and arginine; low plasma lysine, glutamic acid, and glutamine Clinical features: Myopia, night blindness, blindness, progressive loss of peripheral vision, progressive gyrate atrophy of choroid and retina, mild proximal hypotonia, myopathy Treatment: Pyridoxine, low-arginine diet, lysine and α-aminoisobutyrate to increase renal loss of ornithine; proline or creatine supplementation
Hyperinsulinism-hyperammonemia syndrome (606762)	Hyperactivity of glutamate dehydrogenase	GLUD1 (10q23.3)*	Biochemical profile: Elevated urine α-ketoglutarate Clinical features: Seizures, recurrent hypoglycemia, hyperinsulinism, asymptomatic hyperammonemia Treatment: Prevention of hypoglycemia
Disorders of proline and hydroxyproline metabolism
Hyperprolinemia, type I (239500)	Proline oxidase (proline dehydrogenase)	PRODH (22q11.2)*	Biochemical profile: Elevated plasma proline and urinary proline, hydroxyproline, and glycine Clinical features: Usually benign; hereditary nephritis, nerve deafness Treatment: None needed
Hyperprolinemia, type II (239510)	Δ1-Pyrroline-5-carboxylate dehydrogenase	P5CDH (1p36)*	Biochemical profile: Elevated plasma proline and pyrroline-5-carboxylate (P5C); elevated urinary P5C, Δ1-pyrroline-5-carboxylate, proline, hydroxyproline, and glycine Clinical features: During childhood, seizures, intellectual disability During adulthood, benign Treatment: None needed
Δ1-Pyrroline-5-carboxylate synthetase deficiency (138250)	Δ1-Pyrroline-5-carboxylate synthetase	PYCS (10q24.3)*	Biochemical profile: Low plasma proline, citrulline, arginine, and ornithine Clinical features: Hyperammonemia, cataracts, intellectual disability, joint laxity Treatment: Avoidance of fasting
Hyperhydroxyprolinemia (237000)	4-Hydroxyproline oxidase	Not determined	Biochemical profile: Hydroxyprolinemia Clinical features: Disease association not proven Treatment: None needed
Prolidase deficiency (170100)	Prolidase	PEPD (19q12-q13.11)*	Biochemical profile: Amino acid profile normal in unhydrolyzed urine, but excessive proline and hydroxyproline in acid-hydrolyzed urine Clinical features: Skin ulcers, frequent infections, dysmorphic features, immunodeficiency, intellectual disability Treatment: Proline supplement, Mn++ and ascorbic acid, essential amino acids, blood transfusion (packed RBC), topical proline and glycine ointment
Disorders of β- and γ-amino acids
Hyper-β-alaninemia (237400)	β-Alanine-α-ketoglutarate aminotransferase	Not determined	Biochemical profile: Elevated urinary β-alanine, taurine, γ-aminobutyrate (GABA), and β-aminoisobutyrate Clinical features: Seizures, somnolence, death Treatment: Pyridoxine
Methylmalonate/malonate semialdehyde dehydrogenase deficiency with 3-amino and 3-hydroxy aciduria (236795)	Methylmalonate/malonate semialdehyde dehydrogenase	ALDH6A1 (14q24.3)*	Biochemical profile: Elevated 3-hydroxyisobutyrate 3-aminoisobutyrate, 3-hydroxypropionate β-alanine, and 2-ethyl-3-hydroxypropionate Clinical features: None to mild Treatment: Not determined
Methylmalonic semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia	Methylmalonic semialdehyde dehydrogenase (see also Branched-chain amino acid metabolism, above)	ALDH6A1 (14q24.1)	Biochemical profile: Moderately elevated urine methylmalonate Clinical features: Developmental delay, seizures Treatment: No effective treatment
Hyper-β-aminoisobutyric aciduria (210100)	D(R)-3-Aminoisobutyrate:pyruvate aminotransferase	Not determined	Biochemical profile: Elevated β-aminoisobutyric acid Clinical features: Benign Treatment: None needed
Pyridoxine dependency with seizures (266100)	Not determined	Specific gene not determined (5q31.2-q31.3)	Biochemical profile: Elevated CSF glutamate Clinical features: Seizure disorder refractory to conventional anticonvulsants, high-pitched cry, hypothermia, jitteriness, dystonia, hepatomegaly, hypotonia, dyspraxia, developmental delay Treatment: Pyridoxine
GABA-transaminase deficiency (137150)	4-Aminobutyrate-α-ketoglutarate aminotransferase	ABAT (16p13.3)*	Biochemical profile: Elevated plasma and CSF GABA and β-alanine, elevated carnosine Clinical features: Accelerated linear growth, seizures, cerebellar hypoplasia, psychomotor delay, leukodystrophy, burst suppression EEG pattern Treatment: No known treatment
4-Hydroxybutyric aciduria (271980)	Succinic semialdehyde dehydrogenase	ALDH5A1 (6p22)*	Biochemical profile: Elevated urinary 4-hydroxybutyrate and glycine Clinical features: Psychomotor retardation, speech delay, hypotonia Treatment: Vigabatrin
Carnosinemia, homocarnosinosis, or both (236130, 212200)	Carnosinase	Specific gene not determined (18q21.3)	Biochemical profile: In carnosinemia phenotype, carnosinuria despite meat-free diet, elevated urine anserine after ingestion of food containing imidazole dipeptides, normal CSF In homocarnosinosis phenotype, elevated CSF homocarnosine, normal serum carnosine Clinical features: Usually benign; reported symptoms probably due to ascertainment bias Treatment: None needed
Disorders of lysine metabolism
Hyperlysinemia (238700)	Lysine:α-ketoglutarate reductase	AASS (7q31.3)*	Biochemical profile: Hyperlysinemia Clinical features: Muscle weakness, seizures, mild anemia, intellectual disability, joint and muscular laxity, ectopia lentis; sometimes benign Treatment: Limited lysine intake
2-Ketoadipic acidemia (245130)	2-Ketoadipic dehydrogenase	Not determined	Biochemical profile: Elevated urine 2-ketoadipate, 2-aminoadipate, and 2-hydroxyadipate Clinical features: Benign Treatment: None needed
Glutaric acidemia type I (231670)	Glutaryl CoA dehydrogenase	(19q13.2)*	Biochemical profile: Elevated urinary glutaric acid and 2-hydroxyglytaric acid Clinical features: Dystonia, dyskinesia, degeneration of the caudate and putamen, frontotemporal atrophy, arachnoid cysts Treatment: Aggressive treatment of intercurrent illness, carnitine, Protein, lysine, and tryptophan restriction possibly helpful
Saccharopinuria (268700)	α-Aminoadipic semialdehyde-glutamate reductase	AASS (7q31.3)*	Biochemical profile: Elevated urine lysine, citrulline, histidine, and saccharopine Clinical features: Intellectual disability, spastic diplegia, short stature, EEG abnormality Treatment: No clear treatment
Disorders of the γ-glutamyl cycle
γ-Glutamylcysteine synthetase deficiency (230450)	γ-Glutamylcysteine synthetase	GGLC (6p12)*	Biochemical profile: Aminoaciduria, glutathione deficiency Clinical features: Hemolysis, spinocerebellar degeneration, peripheral neuropathy, myopathy Treatment: No clear treatment; avoidance of drugs that trigger hemolytic crisis in G6PD deficiency
Pyroglutamic aciduria (5-oxoprolinuria; 266130, 231900)	Glutathione synthetase	GSS (20q11.2)*	Biochemical profile: Elevated urinary, plasma, and CSF 5-oxoproline; increased γ-glutamylcysteine; decreased glutathione level Clinical features: Hemolysis, ataxia, seizures, intellectual disability, spasticity, metabolic acidosis In mild form, no evidence of neurologic damage Treatment: Na bicarbonate or citrate, vitamins E and C, avoidance of drugs that trigger hemolytic crisis in G6PD deficiency
γ-Glutamyltranspeptidase deficiency (glutathionuria; 231950)	γ-Glutamyltranspeptidase	Specific gene not determined (22q11.1-q11.2)	Biochemical profile: Elevated plasma and urinary glutathione Clinical features: Intellectual disability Treatment: No specific treatment
5-Oxoprolinase deficiency (260005)	5-Oxoprolinase	Not determined	Biochemical profile: Elevated urinary 5-oxoproline Clinical features: Probably benign Treatment: None needed
Disorders of histidine metabolism
Histidinemia (235800)	Classic: l-Histidine ammonia-lyase (liver and skin) Variant: l-Histidine ammonia-lyase (liver only)	HAL (12q22-q23)*	Biochemical profile: Elevated plasma histidine Clinical features: Frequently benign; neurologic manifestations in some patients Treatment: Low-protein diet For symptomatic patients only, controlled histidine intake
Urocanic aciduria (276880)	Urocanase	Not determined	Biochemical profile: Elevated urine urocanic acid Clinical features: Probably benign Treatment: None needed
Disorders of glycine metabolism
Nonketotic hyperglycinemia (605899)	Glycine cleavage enzyme system		Biochemical profile: Elevated plasma and CSF glycine Clinical features: In neonatal form, hypotonia, seizures, myoclonus, apnea, death In infantile and episodic forms, seizures, intellectual disability, episodic delirium, chorea, vertical gaze palsy In late-onset form, progressive spastic diplegia, optic atrophy, but no cognitive impairment or seizures Treatment: No effective treatment; in some patients, temporary benefit from Na benzoate and dextromethorphan
	P protein	GLDC (9p22)*
	H protein	GCSH (16q23)*
	T protein	ATM (3p21)*
	L protein	Not determined
Miscellaneous disorders
Sarcosinemia (268900)	Sarcosine dehydrogenase	Specific gene not determined (9q34)	Biochemical profile: Elevated plasma sarcosine Clinical features: Benign; intellectual disability reported Treatment: None needed
D-glyceric aciduria (220120)	D-glycerate kinase	Not determined	Biochemical profile: Elevated urinary D-glyceric acid Clinical features: Chronic acidosis, hypotonia, seizures, intellectual disability Treatment: Bicarbonate or citrate for acidosis
Hartnup disorder (234500)	System B(0) neutral amino acid transporter	SLC6A19 (5p15)*	Biochemical profile: Neutral aminoaciduria Clinical features: Atrophic glossitis, photodermatitis, intermittent ataxia, hypertonia, seizures, psychosis Treatment: Nicotinamide
Cystinuria	Renal dibasic amino acid transporter	—	Biochemical profile: Elevated urinary cystine, lysine, arginine, and ornithine Clinical features: Nephrolithiasis, increased risk of impaired cerebral function Treatment: Maintenance of fluid intake, bicarbonate or citrate, penicillamine or mercaptopropionylglycine
Type I (220100)	Heavy subunit	SLC3A1 (2p16.3)*
Types II and III (600918)	Light subunit	SLC7A9 (19q13.1)*
Iminoglycinuria (242600)	Renal transporter of proline, hydroxyproline, and glycine	Not determined	Biochemical profile: Elevated urinary proline, hydroxyproline, and glycine but normal plasma levels Clinical features: Probably benign Treatment: None needed
Guanidinoacetate methyltransferase deficiency (601240)	Guanidinoacetate methyltransferase	GAMT (19p13.3)*	Biochemical profile: Elevated guanidinoacetate, decreased creatine and phosphocreatine Clinical features: Developmental delay, hypotonia, extrapyramidal movements, seizures, autistic behavior Treatment: Creatine supplementation
Cystinosis	See Table5sec19ch296
*Gene has been identified, and molecular basis has been elucidated. OMIM = online mendelian inheritance in man (see database at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM).

Disorders of Amino Acid and Organic Acid Metabolism

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

Disorders of phenylalanine and tyrosine metabolism
Phenylketonuria (PKU), with classic and mild forms (261600)	Phenylalanine hydroxylase	PAH (12q24.1)*	Biochemical profile: Elevated plasma phenylalanine Clinical features: Intellectual disability, behavioral problems Treatment: Dietary phenylalanine restriction, tyrosine supplementation
Dihydropteridine reductase deficiency (261630)	Dihydropteridine reductase	QDPR (4p15.31)*	Biochemical profile: Elevated plasma phenylalanine, high urine biopterin, low plasma biopterin Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia Treatment: Dietary phenylalanine restriction, tyrosine supplementation, folinic acid, neurotransmitter replacement
Pterin-4α-carbinolamine dehydratase deficiency (264070)	Pterin-4α-carbinolamine dehydratase	PCBD (10q22)*	Biochemical profile: Elevated plasma phenylalanine, high urine neopterin and primapterin, low plasma biopterin Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia Treatment: Dietary phenylalanine restriction, tyrosine supplementation, neurotransmitter replacement
Biopterin synthesis deficiency	GTP-cyclohydrolase (233910)	GCH1 (14q22)*	Biochemical profile: Elevated plasma phenylalanine, low urine biopterin, low (GCH) or high (PTS and SPR) urine neopterin Clinical features: Similar to mild PKU, but if neurotransmitter deficiency is unrecognized, development of intellectual disability, seizures, and dystonia Treatment: Tetrahydrobiopterin and neurotransmitter supplementation
	6-Pyruvoyl-tetrahydropterin synthase (261640)	PTS (11q22-q23)*
	Sepiapterin reductase (182125)	SPR (2p14-p12)*
Tyrosinemia type I (hepatorenal; 276700)	Fumarylacetoacetate hydrolase	FAH (15q23-q25)*	Biochemical profile: Elevated plasma tyrosine, elevated plasma and urinary succinylacetone Clinical features: Cirrhosis, acute liver failure, peripheral neuropathy, Fanconi syndrome Treatment: Dietary phenylalanine, tyrosine, and methionine restriction; 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC); liver transplantation
Tyrosinemia type II (oculocutaneous; 276600)	Tyrosine aminotransferase	TAT (16q22.1-q22.3)*	Biochemical profile: Elevated plasma tyrosine and phenylalanine Clinical features: Intellectual disability, palmoplantar hyperkeratitis, corneal ulcers Treatment: Dietary phenylalanine and tyrosine restriction
Tyrosinemia type III (276710)	4-Hydroxyphenylpyruvate dioxygenase	HPD (12q24-qter)*	Biochemical profile: Elevated plasma tyrosine, elevated urinary 4-hydroxyphenyl derivatives Clinical features: Developmental delay, seizures, ataxia Treatment: Dietary phenylalanine and tyrosine restriction, ascorbate supplementation
Transient tyrosinemia	4-Hydroxyphenylpyruvate dioxygenase	Not genetic	Biochemical profile: Elevated plasma phenylalanine and tyrosine Clinical features: Usually occurring in premature infants; mostly asymptomatic Occasionally poor feeding and lethargy Treatment: Tyrosine restriction and ascorbate supplementation for symptomatic patients only
Hawkinsinuria (140350)	4-Hydroxyphenylpyruvate dioxygenase complex	HPD (12q24-qter)*	Biochemical profile: Mild hypertyrosinemia, elevated urinary hawkinsin Clinical features: Failure to thrive, ketotic metabolic acidosis Treatment: Dietary phenylalanine and tyrosine restriction, ascorbate supplementation
Alkaptonuria (203500)	Homogentisate oxidase	HGD (3q21-q23)*	Biochemical profile: Elevated urine homogentisic acid Clinical features: Dark urine, ochronosis, arthritis Treatment: None; ascorbate supplementation to reduce pigmentation
Oculocutaneous albinism type I (A and B; 203100)	Tyrosinase	TYR (11q21)*	Biochemical profile: No abnormality in plasma and urine amino acids, absent (IA) or decreased (IB) tyrosinase Clinical features: Absent (IA) or decreased (IB) pigment in skin, hair, iris, and retina; nystagmus; blindness; skin cancer Treatment: Protection of skin and eyes from actinic radiation
Disorders of branched-chain amino acid (valine, leucine, isoleucine) metabolism
Maple syrup urine disease, or branched-chain ketoaciduria (248600)	Branched-chain α-ketoacid dehydrogenase complex (BCKD)		Biochemical profile: Elevated plasma valine, leucine, isoleucine, and alloisoleucine Clinical features (molecular forms do not correlate with clinical forms except that a high percentage of type II mutations are associated with thiamin responsiveness): In classic form, hypertonia, seizures, coma, death In intermediate form, intellectual disability, neurologic symptoms, full-blown picture developing with stress In intermittent form, symptoms only with stress (eg, fever, infection) In thiamin-responsive form, features similar to mild intermediate form In E3 subunit deficient form, features similar to intermediate form but accompanied by severe lactic acidosis because E3 is needed for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase Acute treatment: Peritoneal dialysis, hemodialysis, or both; aggressive nutrition management, including high-dose glucose, insulin, and special hyperalimentation Chronic treatment: Dietary branched-chain amino acid restriction, thiamin supplementation as needed
Type IA	BCKD E1α component	BCKDHA (19q13)*
Type IB	BCKD E1β component	BCKDHB (6p22-p21)*
Type II	BCKD E2 component	DBT (1p31)*
Type III	BCKD E3 component	DLD (7q31-q32)*
Propionic acidemia (606054)	Propionyl-CoA carboxylase		Biochemical profile: Elevated plasma glycine, urine methylcitrate, 3-hydroxypropionate, propionylglycine, and tiglylglycine Clinical features: Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth delay, intellectual disability, physical disability Treatment: During acute episodes, high-dose glucose and aggressive fluid resuscitation For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis For long-term management, controlled intake of threonine, valine, isoleucine, and methionine; carnitine supplementation; biotin for responsive patients (see also Multiple carboxylase deficiency and Biotinidase deficiency, below)
Type I	α-Subunit	PCCA (13q32)*
Type II	β-Subunit	PCCB (3q21-q22)*
Multiple carboxylase deficiency (253270)	Holocarboxylase synthetase	HLCS (21q22.1)*	Biochemical profile: Same as for propionic acidemia but also elevated lactate and 3-methylcrotonate Clinical features: Skin rash, alopecia, seizures, hypotonia, developmental delay, ketoacidosis, defective T- and B-cell immunity, hearing loss Treatment: Biotin 5–10 mg/day
Biotinidase deficiency (253260)	Biotinidase	BTD (3p25)*	Similar to multiple carboxylase deficiency
Methylmalonic acidemia (mut defects; 251000)	Methylmalonyl-CoA mutase Mut0 (no enzyme activity) Mut- (some residual enzyme activity)	MUT (6p21)*	Biochemical profile: Elevated plasma glycine; increased urine methylmalonate, 3-hydroxypropionate, methylcitrate, and tiglylglycine Clinical features: Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia, hyperammonemia, bone marrow suppression, growth delay, intellectual disability, and physical disability Treatment: During acute episodes, high-dose glucose and aggressive fluid resuscitation For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis For long-term management, controlled intake of threonine, valine, isoleucine, and methionine; carnitine supplementation; vitamin B₁₂ for patients with mut- type
Methylmalonic acidemia (cblA; 251100)	Mitochondrial cobalamin translocase	MMAA (4q31.1-q31.2)*	Biochemical profile: Similar to methylmalonic acidemia due to mutase deficiency Clinical features: Similar to methylmalonic acidemia due to mutase deficiency Treatment: Responsive to high-dose hydroxycobalamin
Methylmalonic acidemia (cblB; 251110)	ATP:cob(1)alamin adenosyl transferase	MMMB (12q24)*	Biochemical profile: Similar to methylmalonic acidemia due to mutase deficiency Clinical features: Similar to methylmalonic acidemia due to mutase deficiency Treatment: Responsive to high-dose hydroxycobalamin
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (cblC; 277400)	Methylmalonyl-CoA mutase and methylene tetrahydrofolate:homocysteine methyltransferase	Genetically heterogeneous	Biochemical profile: Similar to methylmalonic acidemia cblA and cblB but also homocystinemia, homocystinuria, low methionine, and high cystathionine; normal serum cobalamin Clinical features: Similar to cblA and cblB but also megaloblastic anemia Treatment: Protein restriction, high-dose hydroxycobalamin
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (cblD; 277410)	Not determined	Genetically heterogeneous	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (cblF; 277380)	Defective lysosomal release of cobalamin	Genetically heterogeneous	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (intrinsic factor deficiency; 261000)	Intrinsic factor	GIF (11q13)*	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (Imerslund-Graesbeck syndrome; 261100)	Cubilin (intrinsic factor receptor)	CUBN (10p12.1)*	Similar to methylmalonic acidemia cblC
Methylmalonic acidemia-homocystinuria-megaloblastic anemia (transcobalamin II deficiency; 275350)	Transcobalamin II	TC2 (22q11.2)*	Similar to methylmalonic acidemia cblC
Methylmalonic semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia (603178)	Methylmalonic semialdehyde dehydrogenase (see also disorders of β- and γ-amino acids, below)	ALDH6A1 (14q24.1)	Biochemical profile: Moderate urine methylmalonate Clinical features: Developmental delay, seizures Treatment: No effective treatment
Methylmalonic acidemia-homocystinuria (cblH; 606169)	Not determined	Genetically heterogeneous	Similar to methylmalonic acidemia cblA
Isovaleric acidemia (243500)	Isovaleryl-CoA dehydrogenase	IVD(15q14-q15)*	Biochemical profile: Isovaleryl glycine, 3-hydroxyisovalerate Clinical features: Characteristic sweaty feet odor, vomiting, lethargy, acidosis, intellectual disability, bone marrow suppression, hypoglycemia; ketoacidosis, hyperammonemia, neonatal death Treatment: Controlled leucine intake, glycine, carnitine
3-Methylcrotonyl-CoA carboxylase deficiency	3-Methylcrotonyl CoA carboxylase		Biochemical profile: Elevated 3-hydroxyisovalerate, 3-methylcrontylglycine, and 3-hydroxyisovalerylcarnitine Clinical features: Episodic vomiting, acidosis, hypoglycemia, hypotonia, intellectual disability, coma; sometimes asymptomatic intellectual disability Treatment: Controlled leucine intake (see also Multiple carboxylase deficiency and Biotinidase deficiency, above)
Type I (210200)	α-Subunit	MCCC1 (3q25-q27)*
Type II (210210)	β-Subunit	MCCC2 (5q12-q13)*
3-Methylglutaconic aciduria type I (250950)	3-Methylglutaconyl-CoA hydratase	AUH (9)*	Biochemical profile: Elevated urine 3-methylglutaconate and 3-hydroxyisolvalerate Clinical features: Acidosis, hypotonia, hepatomegaly, speech delay Treatment: Carnitine; benefit of leucine restriction unclear
3-Methylglutaconic aciduria type II (Barth syndrome; 302060)	Tafazzin	TAZ (Xq28)*	Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Myopathy, dilated cardiomyopathy, mitochondrial abnormality, neutropenia, developmental delay Treatment: Pantothenic acid
3-Methylglutaconic aciduria type III (Costeff optic atrophy; 258501)	Not determined	OPA3 (19q13)*	Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Optic atrophy, ataxia, spasticity, choreiform movement Treatment: No effective treatment
3-Methylglutaconic aciduria type IV (250951)	Not determined	Not determined	Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate Clinical features: Variable expression, growth and developmental delay, hypotonia, seizures, optic atrophy, deafness, cardiomyopathy, acidosis Treatment: No effective treatment
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (246450)	3-Hydroxy-3-methylglutaryl-CoA lyase	HMGCL (1pter-p33)*	Biochemical profile: Elevated urine 3-hydroxy-3-methylglutarate, 3-methylglutaconate, and 3-hydroxyisovalerate; elevated plasma 3-methylglutarylcarnitine Clinical features: Reye-like syndrome, vomiting, hypotonia, acidosis, hypoglycemia, lethargy, hyperammonemia without ketosis Treatment: Restricted leucine intake, control of hypoglycemia
Mevalonic aciduria (251170, 260920)	Mevalonate kinase	MVK (12q24)*	Biochemical profile: Elevated creatine kinase, transaminase, leukotriene, and urinary mevalonic acid; decreased cholesterol Clinical features: In classic form, short stature, hypotonia, developmental delay, dysmorphic features, cataracts, vomiting, diarrhea, hepatosplenomegaly, arthralgia, lymphadenopathy, cerebral and cerebellar atrophy, anemia, thrombocytopenia, early death In hyper IgD form, recurrent febrile episodes, vomiting, diarrhea, arthralgia, abdominal pain, rash, splenomegaly, elevated serum IgD and IgA levels Treatment: No effective treatment; corticosteroids during acute attacks possibly helpful
Mitochondrial acetoacetyl-CoA thiolase deficiency (607809)	Acetyl-CoA thiolase	ACAT1 (11q22.3-a23.1)*	Biochemical profile: Elevated urine 2-methyl-3-hydroxybutyrate and 2-methylacetoacetate, elevated plasma tiglylglycine Clinical features: Episodes of ketoacidosis, vomiting, diarrhea, coma, intellectual disability Treatment: Low-protein diet, controlled isoleucine intake
Isobutyryl-CoA dehydrogenase deficiency	Isobutyryl-CoA dehydrogenase	Not determined	Biochemical profile: Elevated C-4 carnitine, low free carnitine Clinical features: Anemia, cardiomyopathy Treatment: Carnitine
3-Hydroxyisobutyryl-CoA deacylase deficiency (methacrylic aciduria; 250620)	3-Hydroxyisobutyryl-CoA deacylase	Not determined	Biochemical profile: Elevated S-(2-carboxypropyl)-cysteine and S-(2-carboxypropyl)-cysteamine Clinical features: Growth and developmental delay, dysmorphic feature, vertebral anomaly, CNS malformations, death Treatment: No effective treatment
3-Hydroxyisobutyric aciduria (236795)	3-Hydroxyisobutyrate dehydrogenase	HIBADH (chromosomal location not determined)	Biochemical profile: Elevated urine 3-hydroxyisobutyrate; in 50% patients, elevated lactate Clinical features: Dysmorphic features, CNS malformations, hypotonia, ketoacidosis Treatment: Low-protein diet, carnitine
2-Methylbutyryl glycinuria (600301)	Short branched-chain acyl-CoA dehydrogenase	ACADSB (10q25-q26)*	Biochemical profile: Elevated urine 2-methylbutyrulglycine Clinical features: Hypotonia, muscular atrophy, lethargy, hypoglycemia, hypothermia Treatment: No effective treatment
Ethylmalonic encephalopathy (602473)	Mitochondrial protein of undetermined function	ETHE1 (19q13.32)*	Biochemical profile: Elevated urine ethylmalonic and methylsuccinic acids, elevated serum lactate Clinical features: Retinopathy, acrocyanosis, diarrhea, petechiae, developmental delay, intellectual disability, extrapyramidal symptoms, ataxia, seizures, hyperintense lesions in the basal ganglia Treatment: No effective treatment
Malonic aciduria (248360)	Malonyl-CoA decarboxylase	MLYCD (16q24)*	Biochemical profile: Elevated lactate, malonate, methylmalonate, and malonylcarnitine Clinical features: Hypotonia, developmental delay, hypoglycemia, acidosis Treatment: No effective treatment; low-fat, high-carbohydrate diet Carnitine possibly helpful in some patients
Hypervalinemia or hyperisoleucine-hyperleucinemia (277100)	Mitochondrial branched-chain aminotransferase 2	BCAT2 (19q13)	Biochemical profile: Elevated urine and serum valine Clinical features: Growth retardation Treatment: Controlled valine intake
Disorders of methionine and sulfur metabolism
Homocystinuria (236200)	Cystathionine β-synthase	CBS (21q22.3)*	Biochemical profile: Methioninuria, homocystinuria Clinical features: Osteoporosis, scoliosis, fair complexion, ectopia lentis, progressive intellectual disability, thromboembolism Treatment: Pyridoxine, folate, betaine for unresponsive patients, low methionine diet with some L-cysteine supplementation
Methylenetetrahydrofolate reductase deficiency (236250)	Methylenetetrahydrofolate reductase	MTHFR (1p36.3)*	Biochemical profile: Low to normal plasma methionine, homocystinemia, homocystinuria Clinical features: Varies from asymptomatic to microcephaly, hypotonia, seizures, gait abnormality, and intellectual disability to apnea, coma, and death Treatment: Pyridoxine, folate (folic acid), hydroxycobalamin, methionine, betaine
Methylmalonic acidemia-homocystinuria (cblE; 236270)	Methionine synthase reductase	MTRR (5p15)*	Biochemical profile: Homocystinuria, homocystinemia, low plasma methionine, no methylmalonic aciduria, normal B₁₂ and folate Clinical features: Feeding difficulty, growth failure, intellectual disability, ataxia, cerebral atrophy Treatment: Hydroxycobalamin, folate, L-methionine
Methylmalonic acidemia-homocystinuria (cblG; 250940)	Methylene tetrahydrofolate homocysteine methyltransferase	MTR (1q43)*	Same as methylmalonic acidemia-homocystinuria cblE
Hypermethioninemia (250850)	Methionine adenosyltransferase I and III	MAT1A (10q22)*	Biochemical profile: Elevated plasma methionine Clinical features: Mainly asymptomatic, fetid breath Treatment: None needed
Cystathioninuria (219500)	γ-Cystathionase	CTH (16)*	Biochemical profile: Cystathioninuria Clinical features: Usually normal; intellectual disability reported Treatment: Pyridoxine
Sulfite oxidase deficiency (606887)	Sulfite oxidase	SUOX (12q13)*	Biochemical profile: Elevated urine sulfite, thiosulfate, and S-sulfocysteine; decreased sulfate Clinical features: Developmental delay, ectopia lentis, eczema, delayed dentition, fine hair, hemiplegia, infantile hypotonia, hypertonia, seizures, choreoathetosis, ataxia, dystonia, death Treatment: No effective treatment
Molybdenum cofactor defect (252150)	MOCS1A and MOCS1B proteins	MCOS1 (14q24)*	Biochemical profile: Elevated urinary sulfite, thiosulfate, S-sulfocysteine, taurine, hypoxanthine, and xanthine; decreased sulfate and urate Clinical features: Similar to sulfite oxidase deficiency but also urinary stones Treatment: No effective treatment Low sulfur diet possibly helpful in patients with milder symptoms
	Molybdopterin synthase	MCOS2 (6p21.3)*
	Gephyrin	GEPH (5q21)*
Urea cycle and related disorders
Ornithine-transcarbamoylase (OTC) deficiency (311250)	OTC	OTC (Xp21.1)*	Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema, spasticity, intellectual disability, seizures, death In female carriers, variable manifestations, ranging from growth delay, small stature, protein aversion, and postpartum hyperammonemia to symptoms as severe as those in males with the deficiency Treatment: Hemodialysis for emergent hyperammonemic crisis, Na benzoate, Na phenylacetate, Na phenylbutyrate, low-protein diet supplemented with essential amino acid mixture and arginine, citrulline, experimental attempts at gene therapy, liver transplantation (which is curative)
N-Acetylglutamate synthetase deficiency (237310)	N-Acetylglutamate synthetase	NAGS (17q21.31)	Biochemical profile: Similar to OTC deficiency except for normal to low urine orotate Clinical features: Similar to OTC deficiency except carriers are asymptomatic Treatment: Similar to OTC deficiency but also N-carbamylglutamate supplementation
Carbamoyl phosphate synthetase (CPS) deficiency (237300)	Carbamoyl phosphate synthetase	CPS1 (2q35)*	Biochemical profile: Similar to OTC deficiency except for normal to low urine orotate Clinical features: Similar to OTC deficiency except carriers are asymptomatic Treatment: Na benzoate and arginine
Citrullinemia type I (215700)	Argininosuccinic acid synthetase	ASS (9q34)*	Biochemical profile: High plasma citrulline and glutamine, citrullinuria, orotic aciduria Clinical features: Episodic hyperammonemia, growth failure, protein aversion, lethargy, vomiting, coma, seizures, cerebral edema, developmental delay Treatment: Similar to that for OTC deficiency except citrulline supplementation is not recommended
Citrullinemia type II (603814, 603471)	Citrin	SCL25A13 (7q21.3)*	Biochemical profile: Elevated plasma citrulline, methionine, galactose, and bilirubin Clinical features: With neonatal onset, cholestasis resolved by 3 mo With adult onset, enuresis, delayed menarche, sleep reversal, vomiting, delusions, hallucinations, psychosis, coma Treatment: No clear treatment
Argininosuccinic aciduria (207900)	Argininosuccinate lyase	ASL (7cen-q11.2)*	Biochemical profile: Elevated plasma citrulline and glutamine, elevated urine argininosuccinate Clinical features: Episodic hyperammonemia, hepatic fibrosis, elevated liver enzymes, hepatomegaly, protein aversion, vomiting, seizures, intellectual disability, ataxia, lethargy, coma, trichorrhexis nodosa Treatment: Arginine supplementation
Argininemia (107830)	Arginase I	ARG1 (6q23)*	Biochemical profile: Elevated plasma arginine, diaminoaciduria (argininuria, lysinuria, cystinuria, ornithinuria), orotic aciduria, pyrimidinuria Clinical features: Growth and developmental delay, anorexia, vomiting, seizures, spasticity, irritability, hyperactivity, protein intolerance, hyperammonemia Treatment: Low-protein diet, benzoate, phenylacetate
Lysinuric protein intolerance (dibasic aminoaciduria II; 222700)	Dibasic amino acid transporter	SLC7A7 (14q11.2)*	Biochemical profile: Elevated urine lysine, ornithine, and arginine Clinical features: Protein intolerance, episodic hyperammonemia, growth and developmental delay, diarrhea, vomiting, hepatomegaly, cirrhosis, leucopenia, osteopenia, skeletal fragility, coma Treatment: Low-protein diet, citrulline
Hyperornithinemia, hyperammonemia, and homocitrullinemia (238970)	Mitochondrial ornithine translocase	SLC25A15 (13q14)*	Biochemical profile: Elevated plasma ornithine, homocitrullinemia Clinical features: Intellectual disability, progressive spastic paraparesis, episodic confusion, hyperammonemia, dyspraxia, seizures, vomiting, retinopathy, abnormal nerve conduction and evoked potentials, leukodystrophy Treatment: Lysine, ornithine, or citrulline supplementation
Ornithinemia (258870)	Ornithine aminotransferase	OAT (10q26)*	Biochemical profile: Elevated plasma ornithine and urine ornithine, lysine, and arginine; low plasma lysine, glutamic acid, and glutamine Clinical features: Myopia, night blindness, blindness, progressive loss of peripheral vision, progressive gyrate atrophy of choroid and retina, mild proximal hypotonia, myopathy Treatment: Pyridoxine, low-arginine diet, lysine and α-aminoisobutyrate to increase renal loss of ornithine; proline or creatine supplementation
Hyperinsulinism-hyperammonemia syndrome (606762)	Hyperactivity of glutamate dehydrogenase	GLUD1 (10q23.3)*	Biochemical profile: Elevated urine α-ketoglutarate Clinical features: Seizures, recurrent hypoglycemia, hyperinsulinism, asymptomatic hyperammonemia Treatment: Prevention of hypoglycemia
Disorders of proline and hydroxyproline metabolism
Hyperprolinemia, type I (239500)	Proline oxidase (proline dehydrogenase)	PRODH (22q11.2)*	Biochemical profile: Elevated plasma proline and urinary proline, hydroxyproline, and glycine Clinical features: Usually benign; hereditary nephritis, nerve deafness Treatment: None needed
Hyperprolinemia, type II (239510)	Δ1-Pyrroline-5-carboxylate dehydrogenase	P5CDH (1p36)*	Biochemical profile: Elevated plasma proline and pyrroline-5-carboxylate (P5C); elevated urinary P5C, Δ1-pyrroline-5-carboxylate, proline, hydroxyproline, and glycine Clinical features: During childhood, seizures, intellectual disability During adulthood, benign Treatment: None needed
Δ1-Pyrroline-5-carboxylate synthetase deficiency (138250)	Δ1-Pyrroline-5-carboxylate synthetase	PYCS (10q24.3)*	Biochemical profile: Low plasma proline, citrulline, arginine, and ornithine Clinical features: Hyperammonemia, cataracts, intellectual disability, joint laxity Treatment: Avoidance of fasting
Hyperhydroxyprolinemia (237000)	4-Hydroxyproline oxidase	Not determined	Biochemical profile: Hydroxyprolinemia Clinical features: Disease association not proven Treatment: None needed
Prolidase deficiency (170100)	Prolidase	PEPD (19q12-q13.11)*	Biochemical profile: Amino acid profile normal in unhydrolyzed urine, but excessive proline and hydroxyproline in acid-hydrolyzed urine Clinical features: Skin ulcers, frequent infections, dysmorphic features, immunodeficiency, intellectual disability Treatment: Proline supplement, Mn++ and ascorbic acid, essential amino acids, blood transfusion (packed RBC), topical proline and glycine ointment
Disorders of β- and γ-amino acids
Hyper-β-alaninemia (237400)	β-Alanine-α-ketoglutarate aminotransferase	Not determined	Biochemical profile: Elevated urinary β-alanine, taurine, γ-aminobutyrate (GABA), and β-aminoisobutyrate Clinical features: Seizures, somnolence, death Treatment: Pyridoxine
Methylmalonate/malonate semialdehyde dehydrogenase deficiency with 3-amino and 3-hydroxy aciduria (236795)	Methylmalonate/malonate semialdehyde dehydrogenase	ALDH6A1 (14q24.3)*	Biochemical profile: Elevated 3-hydroxyisobutyrate 3-aminoisobutyrate, 3-hydroxypropionate β-alanine, and 2-ethyl-3-hydroxypropionate Clinical features: None to mild Treatment: Not determined
Methylmalonic semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia	Methylmalonic semialdehyde dehydrogenase (see also Branched-chain amino acid metabolism, above)	ALDH6A1 (14q24.1)	Biochemical profile: Moderately elevated urine methylmalonate Clinical features: Developmental delay, seizures Treatment: No effective treatment
Hyper-β-aminoisobutyric aciduria (210100)	D(R)-3-Aminoisobutyrate:pyruvate aminotransferase	Not determined	Biochemical profile: Elevated β-aminoisobutyric acid Clinical features: Benign Treatment: None needed
Pyridoxine dependency with seizures (266100)	Not determined	Specific gene not determined (5q31.2-q31.3)	Biochemical profile: Elevated CSF glutamate Clinical features: Seizure disorder refractory to conventional anticonvulsants, high-pitched cry, hypothermia, jitteriness, dystonia, hepatomegaly, hypotonia, dyspraxia, developmental delay Treatment: Pyridoxine
GABA-transaminase deficiency (137150)	4-Aminobutyrate-α-ketoglutarate aminotransferase	ABAT (16p13.3)*	Biochemical profile: Elevated plasma and CSF GABA and β-alanine, elevated carnosine Clinical features: Accelerated linear growth, seizures, cerebellar hypoplasia, psychomotor delay, leukodystrophy, burst suppression EEG pattern Treatment: No known treatment
4-Hydroxybutyric aciduria (271980)	Succinic semialdehyde dehydrogenase	ALDH5A1 (6p22)*	Biochemical profile: Elevated urinary 4-hydroxybutyrate and glycine Clinical features: Psychomotor retardation, speech delay, hypotonia Treatment: Vigabatrin
Carnosinemia, homocarnosinosis, or both (236130, 212200)	Carnosinase	Specific gene not determined (18q21.3)	Biochemical profile: In carnosinemia phenotype, carnosinuria despite meat-free diet, elevated urine anserine after ingestion of food containing imidazole dipeptides, normal CSF In homocarnosinosis phenotype, elevated CSF homocarnosine, normal serum carnosine Clinical features: Usually benign; reported symptoms probably due to ascertainment bias Treatment: None needed
Disorders of lysine metabolism
Hyperlysinemia (238700)	Lysine:α-ketoglutarate reductase	AASS (7q31.3)*	Biochemical profile: Hyperlysinemia Clinical features: Muscle weakness, seizures, mild anemia, intellectual disability, joint and muscular laxity, ectopia lentis; sometimes benign Treatment: Limited lysine intake
2-Ketoadipic acidemia (245130)	2-Ketoadipic dehydrogenase	Not determined	Biochemical profile: Elevated urine 2-ketoadipate, 2-aminoadipate, and 2-hydroxyadipate Clinical features: Benign Treatment: None needed
Glutaric acidemia type I (231670)	Glutaryl CoA dehydrogenase	(19q13.2)*	Biochemical profile: Elevated urinary glutaric acid and 2-hydroxyglytaric acid Clinical features: Dystonia, dyskinesia, degeneration of the caudate and putamen, frontotemporal atrophy, arachnoid cysts Treatment: Aggressive treatment of intercurrent illness, carnitine, Protein, lysine, and tryptophan restriction possibly helpful
Saccharopinuria (268700)	α-Aminoadipic semialdehyde-glutamate reductase	AASS (7q31.3)*	Biochemical profile: Elevated urine lysine, citrulline, histidine, and saccharopine Clinical features: Intellectual disability, spastic diplegia, short stature, EEG abnormality Treatment: No clear treatment
Disorders of the γ-glutamyl cycle
γ-Glutamylcysteine synthetase deficiency (230450)	γ-Glutamylcysteine synthetase	GGLC (6p12)*	Biochemical profile: Aminoaciduria, glutathione deficiency Clinical features: Hemolysis, spinocerebellar degeneration, peripheral neuropathy, myopathy Treatment: No clear treatment; avoidance of drugs that trigger hemolytic crisis in G6PD deficiency
Pyroglutamic aciduria (5-oxoprolinuria; 266130, 231900)	Glutathione synthetase	GSS (20q11.2)*	Biochemical profile: Elevated urinary, plasma, and CSF 5-oxoproline; increased γ-glutamylcysteine; decreased glutathione level Clinical features: Hemolysis, ataxia, seizures, intellectual disability, spasticity, metabolic acidosis In mild form, no evidence of neurologic damage Treatment: Na bicarbonate or citrate, vitamins E and C, avoidance of drugs that trigger hemolytic crisis in G6PD deficiency
γ-Glutamyltranspeptidase deficiency (glutathionuria; 231950)	γ-Glutamyltranspeptidase	Specific gene not determined (22q11.1-q11.2)	Biochemical profile: Elevated plasma and urinary glutathione Clinical features: Intellectual disability Treatment: No specific treatment
5-Oxoprolinase deficiency (260005)	5-Oxoprolinase	Not determined	Biochemical profile: Elevated urinary 5-oxoproline Clinical features: Probably benign Treatment: None needed
Disorders of histidine metabolism
Histidinemia (235800)	Classic: l-Histidine ammonia-lyase (liver and skin) Variant: l-Histidine ammonia-lyase (liver only)	HAL (12q22-q23)*	Biochemical profile: Elevated plasma histidine Clinical features: Frequently benign; neurologic manifestations in some patients Treatment: Low-protein diet For symptomatic patients only, controlled histidine intake
Urocanic aciduria (276880)	Urocanase	Not determined	Biochemical profile: Elevated urine urocanic acid Clinical features: Probably benign Treatment: None needed
Disorders of glycine metabolism
Nonketotic hyperglycinemia (605899)	Glycine cleavage enzyme system		Biochemical profile: Elevated plasma and CSF glycine Clinical features: In neonatal form, hypotonia, seizures, myoclonus, apnea, death In infantile and episodic forms, seizures, intellectual disability, episodic delirium, chorea, vertical gaze palsy In late-onset form, progressive spastic diplegia, optic atrophy, but no cognitive impairment or seizures Treatment: No effective treatment; in some patients, temporary benefit from Na benzoate and dextromethorphan
	P protein	GLDC (9p22)*
	H protein	GCSH (16q23)*
	T protein	ATM (3p21)*
	L protein	Not determined
Miscellaneous disorders
Sarcosinemia (268900)	Sarcosine dehydrogenase	Specific gene not determined (9q34)	Biochemical profile: Elevated plasma sarcosine Clinical features: Benign; intellectual disability reported Treatment: None needed
D-glyceric aciduria (220120)	D-glycerate kinase	Not determined	Biochemical profile: Elevated urinary D-glyceric acid Clinical features: Chronic acidosis, hypotonia, seizures, intellectual disability Treatment: Bicarbonate or citrate for acidosis
Hartnup disorder (234500)	System B(0) neutral amino acid transporter	SLC6A19 (5p15)*	Biochemical profile: Neutral aminoaciduria Clinical features: Atrophic glossitis, photodermatitis, intermittent ataxia, hypertonia, seizures, psychosis Treatment: Nicotinamide
Cystinuria	Renal dibasic amino acid transporter	—	Biochemical profile: Elevated urinary cystine, lysine, arginine, and ornithine Clinical features: Nephrolithiasis, increased risk of impaired cerebral function Treatment: Maintenance of fluid intake, bicarbonate or citrate, penicillamine or mercaptopropionylglycine
Type I (220100)	Heavy subunit	SLC3A1 (2p16.3)*
Types II and III (600918)	Light subunit	SLC7A9 (19q13.1)*
Iminoglycinuria (242600)	Renal transporter of proline, hydroxyproline, and glycine	Not determined	Biochemical profile: Elevated urinary proline, hydroxyproline, and glycine but normal plasma levels Clinical features: Probably benign Treatment: None needed
Guanidinoacetate methyltransferase deficiency (601240)	Guanidinoacetate methyltransferase	GAMT (19p13.3)*	Biochemical profile: Elevated guanidinoacetate, decreased creatine and phosphocreatine Clinical features: Developmental delay, hypotonia, extrapyramidal movements, seizures, autistic behavior Treatment: Creatine supplementation
Cystinosis	See Table5sec19ch296
*Gene has been identified, and molecular basis has been elucidated. OMIM = online mendelian inheritance in man (see database at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM).