Maple syrup urine disease, or branched-chain ketoaciduria (248600†)

Branched-chain alpha-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 alpha-ketoglutarate dehydrogenase

Acute treatment:

Chronic treatment: Dietary branched-chain amino acid restriction, thiamin supplementation as needed

Emergency plan for acute illness, which may provoke a metabolic crisis

Liver transplantation

Type IA

BCKD E1alpha component

Type IB

BCKD E1beta component

Type II

BCKD E2 component

Type III

BCKD E3 component

Propionic acidemia (606054†)

Propionyl-CoA carboxylase

Biochemical profile:

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, protein restriction

For extreme hyperammonemia, may need hemodialysis or peritoneal dialysis.

Intermittent courses of antibiotics considered for reduction of propionic acid load from intestinal bacteria

Emergency plan for acute illness, which may provoke a metabolic crisis

Type I

Alpha-subunit

Type II

Beta-subunit

Multiple carboxylase deficiency (253270†)

Holocarboxylase synthetase

Biochemical profile: Same as for propionic acidemia but also elevated lactate and 3-methylcrotonate

Clinical features: Rash, alopecia, seizures, hypotonia, developmental delay, ketoacidosis, defective T- and B-cell immunity, hearing loss

Treatment:

Biotinidase deficiency (253260†)

Biotinidase

Clinical features similar to multiple carboxylase deficiency

Treatment:

Methylmalonic acidemia (mut defects; 251000†)

Methylmalonyl-CoA mutase

Mut0 (no enzyme activity)

Mut- (some residual enzyme activity)

Biochemical profile:

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, aggressive fluid resuscitation, and protein restriction

Close monitoring for stroke, renal failure, and acute pancreatitis

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

Intermittent courses of antibiotics considered for reduction of propionic acid load from intestinal bacteria

Emergency plan for acute illness, which may provoke a metabolic crisis

Methylmalonic acidemia (cblA; 251100†)

Mitochondrial cobalamin translocase

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(I)alamin adenosyl transferase

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 (cblC; 277400†)

Methylmalonyl-CoA mutase and methionine synthase

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 aciduria and homocystinuria (cblD; 277410†)

Methylmalonyl-CoA mutase and methionine synthase

Similar to methylmalonic aciduria and homocystinuria cblC

Methylmalonic aciduria and homocystinuria (cblF; 277380†)

Defective lysosomal release of cobalamin

Similar to methylmalonic aciduria and homocystinuria cblC

Intrinsic factor deficiency (261000†)

Intrinsic factor

Megaloblastic anemia

Megaloblastic anemia 1 (Imerslund-Grasbeck syndrome; 261100†)

Cubilin (intrinsic factor receptor)

Megaloblastic anemia

Transcobalamin II deficiency (275350†)

Transcobalamin II

Methylmalonic aciduria, megaloblastic anemia, and pancytopenia

Methylmalonate semialdehyde dehydrogenase deficiency with mild methylmalonic acidemia (603178†)

Methylmalonate semialdehyde dehydrogenase (see also disorders of beta- and gamma-amino acids, below)

Biochemical profile: Moderate urine methylmalonate

Clinical features: Developmental delay, seizures

Treatment: No effective treatment

Isovaleric acidemia (243500†)

Isovaleryl-CoA dehydrogenase

Biochemical profile:

Clinical features: Characteristic sweaty feet odor, vomiting, lethargy, acidosis, intellectual disability, bone marrow suppression, hypoglycemia; ketoacidosis, hyperammonemia, neonatal death

Treatment:

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†)

Alpha-subunit

Type II (210210†)

Beta-subunit

3-Methylglutaconic aciduria type I (250950†)

3-Methylglutaconyl-CoA hydratase

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

Biochemical profile: Elevated urine 3-methylglutaconate and 3-methylglutarate

Clinical features: Myopathy, dilated cardiomyopathy, mitochondrial abnormality, neutropenia, developmental delay

Treatment:

Elamipretide has shown positive effect in early clinical trials.

3-Methylglutaconic aciduria type III (Costeff optic atrophy syndrome; 258501†)

Not determined

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

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

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 (610377†), Hyper-IgD syndrome (260920†)

Mevalonate kinase

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: Corticosteroids during acute attacks; sometimes benefit from IL-1 blockade, tumor necrosis factor blockade, and stem cell transplantation

Mitochondrial acetoacetyl-CoA thiolase deficiency (607809†)

Acetyl-CoA thiolase

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 (611283†)

Isobutyryl-CoA dehydrogenase

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

Biochemical profile: Elevated SS

Clinical features: Growth and developmental delay, dysmorphic feature, vertebral anomaly, central nervous system malformations, death

Treatment: No effective treatment

3-Hydroxyisobutyric aciduria (236795†)

3-Hydroxyisobutyrate dehydrogenase

Biochemical profile: Elevated urine 3-hydroxyisobutyrate; in 50% patients, elevated lactate

Clinical features: Dysmorphic features, central nervous system malformations, hypotonia, ketoacidosis

Treatment: Low-protein diet, carnitine

2-Methylbutyryl glycinuria (610006†)

Short branched-chain acyl-CoA dehydrogenase

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

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

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 (277100†)

Valine transaminase

Biochemical profile: Elevated urine and serum valine

Clinical features: Growth retardation

Treatment: Controlled valine intake