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Amino Acid and Organic Acid Metabolism Disorders

by Chin-To Fong, MD

Defects of amino acid transport in the renal tubule are discussed in Congenital Renal Transport Abnormalities. For a more complete listing of amino acid and organic amino acid metabolism disorders, see Table Disorders of Amino Acid and Organic Acid Metabolism.

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 B 12 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 B 12 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/omim ).

Phenylketonuria (PKU)

Phenylketonuria (PKU) is a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine. The primary cause is deficient phenylalanine hydroxylase activity. Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine levels. Treatment is lifelong dietary phenylalanine restriction. Prognosis is excellent with treatment.

PKU is most common among all white populations and relatively less common among Ashkenazi Jews, Chinese, and blacks. Inheritance is autosomal recessive; incidence is about 1/10,000 births among whites.

Pathophysiology

Excess dietary phenylalanine (ie, that not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is an essential cofactor for this reaction. When one of several gene mutations results in deficiency or absence of phenylalanine hydroxylase, dietary phenylalanine accumulates; the brain is the main organ affected, possibly due to disturbance of myelination. Some of the excess phenylalanine is metabolized to phenylketones, which are excreted in the urine, giving rise to the term phenylketonuria. The degree of enzyme deficiency, and hence severity of hyperphenylalaninemia, varies among patients depending on the specific mutation.

Variant forms

Although nearly all cases (98 to 99%) of PKU result from phenylalanine hydroxylase deficiency, phenylalanine can also accumulate if BH4 is not synthesized because of deficiencies of dihydrobiopterin synthase or not regenerated because of deficiencies of dihydropteridine reductase. Additionally, because BH4 is also a cofactor for tyrosine hydroxylase, which is involved in the synthesis of dopamine and serotonin, BH4 deficiency alters synthesis of neurotransmitters, causing neurologic symptoms independently of phenylalanine accumulation.

Symptoms and Signs

Most children are normal at birth but develop symptoms and signs slowly over several months as phenylalanine accumulates. The hallmark of untreated PKU is severe intellectual disability. Children also manifest extreme hyperactivity, gait disturbance, and psychoses and often exhibit an unpleasant, mousy body odor caused by phenylacetic acid (a breakdown product of phenylalanine) in urine and sweat. Children also tend to have a lighter skin, hair, and eye color than unaffected family members, and some may develop a rash similar to infantile eczema.

Diagnosis

  • Routine neonatal screening

  • Phenylalanine levels

In the US and many developed countries, all neonates are screened for PKU 24 to 48 h after birth with one of several blood tests; abnormal results are confirmed by directly measuring phenylalanine levels. In classic PKU, neonates often have phenylalanine levels > 20 mg/dL (1.2 mM/L). Those with partial deficiencies typically have levels < 8 to 10 mg/dL while on a normal diet (levels > 6 mg/dL require treatment); distinction from classic PKU requires a liver phenylalanine hydroxylase activity assay showing activity between 5% and 15% of normal or a mutation analysis identifying mild mutations in the gene.

BH4 deficiency is distinguished from other forms of PKU by elevated concentrations of biopterin or neopterin in urine, blood, CSF, or all 3; recognition is important, and the urine biopterin profile should be determined routinely at initial diagnosis because standard PKU treatment does not prevent neurologic damage.

Children in families with a positive family history can be diagnosed prenatally by using direct mutation studies after chorionic villus sampling or amniocentesis.

Prognosis

Adequate treatment begun in the first days of life prevents all manifestations of disease. Treatment begun after 2 to 3 yr may be effective only in controlling the extreme hyperactivity and intractable seizures. Children born to mothers with poorly controlled PKU (ie, they have high phenylalanine levels) during pregnancy are at high risk of microcephaly and developmental deficit.

Treatment

  • Dietary phenylalanine restriction

Treatment is lifelong dietary phenylalanine restriction. All natural protein contains about 4% phenylalanine. Therefore dietary staples include low-protein natural foods (eg, fruits, vegetables, certain cereals), protein hydrolysates treated to remove phenylalanine, and phenylalanine-free elemental amino acid mixtures. Examples of commercially available phenylalanine-free products include XPhe products (XP Analog for infants, XP Maxamaid for children 1 to 8 yr, XP Maxamum for children > 8 yr); Phenex I and II; Phenyl-Free I and II; PKU-1, -2, and -3; PhenylAde (varieties); Loflex; and Plexy10. Some phenylalanine is required for growth and metabolism; this requirement is met by measured quantities of natural protein from milk or low-protein foods.

Frequent monitoring of plasma phenylalanine levels is required; recommended targets are between 2 mg/dL and 4 mg/dL (120 to 240μmol/L) for children < 12 yr and between 2 mg/dL and 10 mg/dL (120 to 600 μmol/L) for children > 12 yr. Dietary planning and management need to be initiated in women of childbearing age before pregnancy to ensure a good outcome for the child. Tyrosine supplementation is increasingly used because it is an essential amino acid in patients with PKU. In addition, sapropterin is increasingly being used.

For those with BH4 deficiency, treatment also includes tetrahydrobiopterin 1 to 5 mg/kg po tid; levodopa, carbidopa, and 5-OH tryptophan; and folinic acid 10 to 20 mg po once/day in cases of dihydropteridine reductase deficiency. However, treatment goals and approach are the same as those for PKU.

Disorders of Tyrosine Metabolism

Tyrosine is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved in its metabolism lead to a variety of syndromes.

Transient tyrosinemia of the newborn

Transient immaturity of metabolic enzymes, particularly 4-hydroxyphenylpyruvic acid dioxygenase, sometimes leads to elevated plasma tyrosine levels (usually in premature infants, particularly those receiving high-protein diets); metabolites may show up on routine neonatal screening for PKU.

Most infants are asymptomatic, but some have lethargy and poor feeding.

Tyrosinemia is distinguished from PKU by elevated plasma tyrosine levels.

Most cases resolve spontaneously. Symptomatic patients should have dietary tyrosine restriction (2 g/kg/day) and be given vitamin C 200 to 400 mg po once/day.

Tyrosinemia type I

This disorder is an autosomal recessive trait caused by deficiency of fumarylacetoacetate hydroxylase, an enzyme important for tyrosine metabolism.

Disease may manifest as fulminant liver failure in the neonatal period or as indolent subclinical hepatitis, painful peripheral neuropathy, and renal tubular disorders (eg, normal anion gap metabolic acidosis, hypophosphatemia, vitamin D–resistant rickets) in older infants and children. Children who do not die from associated liver failure in infancy have a significant risk of developing liver cancer.

Diagnosis is suggested by elevated plasma levels of tyrosine; it is confirmed by a high level of succinylacetone in plasma or urine and by low fumarylacetoacetate hydroxylase activity in blood cells or liver biopsy specimens. Treatment with 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclo-hexanedione (NTBC) is effective in acute episodes and slows progression.

A diet low in phenylalanine and tyrosine is recommended. Liver transplantation is effective.

Tyrosinemia type II

This rare autosomal recessive disorder is caused by tyrosine transaminase deficiency.

Accumulation of tyrosine causes cutaneous and corneal ulcers. Secondary elevation of phenylalanine, though mild, may cause neuropsychiatric abnormalities if not treated.

Diagnosis is by elevation of tyrosine in plasma, absence of succinylacetone in plasma or urine, and measurement of decreased enzyme activity in liver biopsy.

This disorder is easily treated with mild to moderate restriction of dietary phenylalanine and tyrosine.

Alkaptonuria

This rare autosomal recessive disorder is caused by homogentisic acid oxidase deficiency; homogentisic acid oxidation products accumulate in and darken skin, and crystals precipitate in joints.

The condition is usually diagnosed in adults and causes dark skin pigmentation (ochronosis) and arthritis. Urine turns dark when exposed to air because of oxidation products of homogentisic acid. Diagnosis is by finding elevated urinary levels of homogentisic acid (> 4 to 8 g/24 h).

There is no effective treatment, but ascorbic acid 1 g po once/day may diminish pigment deposition by increasing renal excretion of homogentisic acid.

Oculocutaneous albinism

Tyrosinase deficiency results in absence of skin and retinal pigmentation, causing a much increased risk of skin cancer and considerable vision loss. Nystagmus is often present, and photophobia is common (see Albinism).

Disorders of Branched-Chain Amino Acid Metabolism

Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis.

Maple syrup urine disease

This is a group of autosomal recessive disorders caused by deficiency of one or more subunits of a dehydrogenase active in the 2nd step of branched-chain amino acid catabolism. Although quite rare, incidence is significant (perhaps 1/200 births) in Amish and Mennonite populations.

Clinical manifestations include body fluid odor that resembles maple syrup (particularly strong in cerumen) and overwhelming illness in the first days of life, beginning with vomiting and lethargy, and progressing to seizures, coma, and death if untreated. Patients with milder forms of the disease may manifest symptoms only during stress (eg, infection, surgery).

Biochemical findings are profound ketonemia and acidemia. Diagnosis is by finding elevated plasma levels of branched-chain amino acids (particularly leucine).

Acutely, treatment with peritoneal dialysis or hemodialysis may be required, along with IV hydration and nutrition (including high-dose dextrose). Long-term management is restriction of dietary branched-chain amino acids; however, small amounts are required for normal metabolic function. Thiamin is a cofactor for the decarboxylation, and some patients respond favorably to high-dose thiamin (up to 200 mg po once/day). Liver transplantation is curative.

Isovaleric acidemia

The 3rd step of leucine metabolism is the conversion of isovaleryl CoA to 3-methylcrotonyl CoA, a dehydrogenation step. Deficiency of this dehydrogenase results in isovaleric acidemia, also known as “sweaty feet” syndrome, because accumulated isovaleric acid emits an odor that smells like sweat.

Clinical manifestations of the acute form occur in the first few days of life with poor feeding, vomiting, and respiratory distress as infants develop profound anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Bone marrow suppression often occurs. A chronic intermittent form may not manifest for several months or years.

Diagnosis is made by detecting elevated levels of isovaleric acid and its metabolites in blood or urine.

Acute treatment is with IV hydration and nutrition (including high-dose dextrose) and measures to increase renal isovaleric acid excretion by conjugation with glycine. If these measures are insufficient, exchange transfusion and peritoneal dialysis may be needed. Long-term treatment is with dietary leucine restriction and continuation of glycine and carnitine supplements. Prognosis is excellent with treatment.

Propionic acidemia

Deficiency of propionyl CoA carboxylase, the enzyme responsible for metabolizing propionic acid to methylmalonate, causes propionic acid accumulation.

Illness begins in the first days or weeks of life with poor feeding, vomiting, and respiratory distress due to profound anion gap metabolic acidosis, hypoglycemia, and hyperammonemia. Seizures may occur, and bone marrow suppression is common. Physiologic stresses may trigger recurrent attacks. Survivors may have tubular nephropathies, intellectual disability, and neurologic abnormalities. Propionic acidemia can also be seen as part of multiple carboxylase deficiency, biotin deficiency, or biotinidase deficiency.

Diagnosis is suggested by elevated levels of propionic acid metabolites, including methylcitrate and tiglate and their glycine conjugates in blood and urine, and confirmed by measuring propionyl CoA carboxylase activity in WBCs or cultured fibroblasts.

Acute treatment is with IV hydration (including high-dose dextrose) and nutrition; carnitine may be helpful. If these measures are insufficient, peritoneal dialysis or hemodialysis may be needed. Long-term treatment is dietary restriction of precursor amino acids and odd-chain fatty acids and possibly continuation of carnitine supplementation. A few patients respond to high-dose biotin because it is a cofactor for propionyl CoA and other carboxylases.

Methylmalonic acidemia

This disorder is caused by deficiency of methylmalonyl CoA mutase, which converts methylmalonyl CoA (a product of the propionyl CoA carboxylation) into succinyl CoA. Adenosylcobalamin, a metabolite of vitamin B 12 , is a cofactor; its deficiency also may cause methylmalonic acidemia (and also homocystinuria and megaloblastic anemia). Methylmalonic acid accumulates. Age of onset, clinical manifestations, and treatment are similar to those of propionic acidemia except that cobalamin, instead of biotin, may be helpful for some patients.

Disorders of Methionine Metabolism

A number of defects in methionine metabolism lead to accumulation of homocysteine (and its dimer, homocystine) with adverse effects including thrombotic tendency, lens dislocation, and CNS and skeletal abnormalities.

Homocysteine is an intermediate in methionine metabolism; it is either remethylated to regenerate methionine or combined with serine in a series of transsulfuration reactions to form cystathionine and then cysteine. Cysteine is then metabolized to sulfite, taurine, and glutathione. Various defects in remethylation or transsulfuration can cause homocysteine to accumulate, resulting in disease.

The first step in methionine metabolism is its conversion to adenosylmethionine; this conversion requires the enzyme methionine adenosyltransferase. Deficiency of this enzyme results in methionine elevation, which is not clinically significant except that it causes false-positive neonatal screening results for homocystinuria.

Classic homocystinuria

This disorder is caused by an autosomal recessive deficiency of cystathionine β-synthase, which catalyzes cystathionine formation from homocysteine and serine. Homocysteine accumulates and dimerizes to form the disulfide homocystine, which is excreted in the urine. Because remethylation is intact, some of the additional homocysteine is converted to methionine, which accumulates in the blood. Excess homocysteine predisposes to thrombosis and has adverse effects on connective tissue (perhaps involving fibrillin), particularly the eyes and skeleton; adverse neurologic effects may be due to thrombosis or a direct effect.

Arterial and venous thromboembolic phenomena can occur at any age. Many patients develop ectopia lentis (lens subluxation), intellectual disability, and osteoporosis. Patients can have a marfanoid habitus even though they are not usually tall.

Diagnosis is by neonatal screening for elevated serum methionine; elevated total plasma homocysteine levels are confirmatory. Enzymatic assay in skin fibroblasts can also be done.

Treatment is a low-methionine diet, combined with high-dose pyridoxine (a cystathionine synthetase cofactor) 100 to 500 mg po once/day. Because about half of patients respond to high-dose pyridoxine alone, some clinicians do not restrict methionine intake in these patients. Betaine (trimethylglycine), which enhances remethylation, can also help lower homocysteine; dosage is 100 to 125 mg/kg po bid. Folate 500 to 1000 μg once/day is also given. With early treatment, intellectual outcome is normal or near normal.

Other forms of homocystinuria

Various defects in the remethylation process can result in homocystinuria. Defects include deficiencies of methionine synthase (MS) and MS reductase (MSR), delivery of methylcobalamin and adenosylcobalamin, and deficiency of methylenetetrahydrofolate reductase (MTHFR, which is required to generate the 5-methyltetrahydrofolate needed for the MS reaction). Because there is no methionine elevation in these forms of homocystinuria, they are not detected by neonatal screening.

Clinical manifestations are similar to other forms of homocystinuria. In addition, MS and MSR deficiencies are accompanied by neurologic deficits and megaloblastic anemia. Clinical manifestation of MTHFR deficiency is variable, including intellectual disability, psychosis, weakness, ataxia, and spasticity.

Diagnosis of MS and MSR deficiencies is suggested by homocystinuria and megaloblastic anemia and confirmed by DNA testing. Patients with cobalamin defects have megaloblastic anemia and methylmalonic acidemia. MTHFR deficiency is diagnosed by DNA testing.

Treatment is by replacement of hydroxycobalamin 1 mg IM once/day (for patients with MS, MSR, and cobalamin defects) and folate in supplementation similar to characteristic homocystinuria.

Cystathioninuria

This disorder is caused by deficiency of cystathionase, which converts cystathionine to cysteine. Cystathionine accumulation results in increased urinary excretion but no clinical symptoms.

Sulfite oxidase deficiency

Sulfite oxidase converts sulfite to sulfate in the last step of cysteine and methionine degradation; it requires a molybdenum cofactor. Deficiency of either the enzyme or the cofactor causes similar disease; inheritance for both is autosomal recessive.

In its most severe form, clinical manifestations appear in neonates and include seizures, hypotonia, and myoclonus, progressing to early death. Patients with milder forms may present similarly to cerebral palsy (see Cerebral Palsy (CP) Syndromes) and may have choreiform movements.

Diagnosis is suggested by elevated urinary sulfite and confirmed by measuring enzyme levels in fibroblasts and cofactor levels in liver biopsy specimens. Treatment is supportive.

Urea Cycle Disorders

Urea cycle disorders (UCDs) are characterized by hyperammonemia under catabolic or protein-loading conditions.

Primary UCDs include carbamoyl phosphate synthase (CPS) deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency (argininosuccinic aciduria), and arginase deficiency (argininemia). In addition, N-acetylglutamate synthetase (NAGS) deficiency has been reported. The more “proximal” the enzyme deficiency is, the more severe the hyperammonemia; thus, disease severity in descending order is NAGS deficiency, CPS deficiency, OTC deficiency, citrullinemia, argininosuccinic aciduria, and argininemia.

Inheritance for all UCDs is autosomal recessive, except for OTC deficiency, which is X-linked.

Symptoms and Signs

Clinical manifestations range from mild (eg, failure to thrive, intellectual disability, episodic hyperammonemia) to severe (eg, altered mental status, coma, death). Manifestations in females with OTC deficiency range from growth failure, developmental delay, psychiatric abnormalities, and episodic (especially postpartum) hyperammonemia to a phenotype similar to that of affected males.

Diagnosis

  • Serum amino acid profiles

Diagnosis is based on amino acid profiles. For example, elevated ornithine indicates CPS deficiency or OTC deficiency, whereas elevated citrulline indicates citrullinemia. To distinguish between CPS deficiency and OTC deficiency, orotic acid measurement is helpful because accumulation of carbamoyl phosphate in OTC deficiency results in its alternative metabolism to orotic acid.

Treatment

  • Dietary protein restriction

  • Arginine or citrulline supplementation

  • Sometimes liver transplantation

Treatment is dietary protein restriction that still provides adequate amino acids for growth, development, and normal protein turnover. Arginine has become a staple of treatment. It supplies adequate urea cycle intermediates to encourage the incorporation of more nitrogen moieties into urea cycle intermediates, each of which is readily excretable. Arginine is also a positive regulator of acetylglutamate synthesis. Recent studies suggest that oral citrulline is more effective than arginine in patients with OTC deficiency. Additional treatment is with Na benzoate, phenylbutyrate, or phenylacetate, which by conjugating glycine (Na benzoate) and glutamine (phenylbutyrate and phenylacetate) provides a “nitrogen sink.”

Despite these therapeutic advances, many UCDs remain difficult to treat, and liver transplantation is eventually required for many patients. Timing of liver transplantation is critical. Optimally, the infant should grow to an age when transplantation is less risky (> 1 yr), but it is important to not wait so long as to allow an intercurrent episode of hyperammonemia (often associated with illness) to cause irreparable harm to the CNS.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • R-GENE 10
  • SABRIL
  • DELSYM
  • CYSTADANE
  • CUPRIMINE
  • No US brand name
  • KUVAN
  • LODOSYN
  • LEVOPHED
  • ADRENALIN

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