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Branched-Chain Amino Acid Metabolism Disorders

By Lee M. Sanders, MD, MPH, Stanford University

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Patient Education

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.

There are numerous disorders of branched-chain amino acid metabolism ( see Table) as well as many other amino acid and organic acid metabolism disorders. Also see Approach to the Patient With a Suspected Inherited Disorder of Metabolism.

Branched-Chain Amino Acid* Metabolism Disorders

Disease (OMIM Number)

Defective Proteins or Enzymes

Defective Gene or Genes (Chromosomal Location)

Comments

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 protein restriction, high-dose glucose, insulin, and special hyperalimentation; close monitoring for cerebral edema and acute pancreatitis

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 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)

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, protein restriction

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)

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

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, carnitine

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, 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

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

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

*The branched-chain amino acids are valine, leucine, and isoleucine.

Gene has been identified, and molecular basis has been elucidated.

OMIM = online mendelian inheritance in man (see the OMIM database ).

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 smells like 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 of maple syrup urine disease is by finding elevated plasma levels of branched-chain amino acids (particularly leucine). (Also see testing for suspected inherited disorders of metabolism.)

Acutely, treatment of maple syrup urine disease with peritoneal dialysis or hemodialysis may be required, along with IV hydration and nutrition (including protein restriction and high-dose dextrose). Patients should be closely monitored for cerebral edema and acute pancreatitis. 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). An emergency plan for how to manage acute illness, which may provoke a metabolic crisis, should be in place. 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 of isovaleric acidemia is made by detecting elevated levels of isovaleric acid and its metabolites in blood or urine. (Also see testing for suspected inherited disorders of metabolism.)

Acute treatment of isovaleric acidemia 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 of propionic acidemia 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. (Also see testing for suspected inherited disorders of metabolism.)

Acute treatment of propionic acidemia is with IV hydration (including high-dose dextrose), nutrition, and protein restriction; carnitine may be helpful. If these measures are insufficient, peritoneal dialysis or hemodialysis may be needed. Long-term propionic acidemia 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. Intermittent courses of antibiotics should be considered for reducing a proprionic acid load resulting from intestinal bacteria. An emergency plan for how to manage acute illness, which may provoke a metabolic crisis, should be in place.

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 B12, 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.

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