Acidemia, Propionic & Methylmalonic

Key Features

• Propionic acidemia is due to a defect in the biotin-containing enzyme propionyl-CoA carboxylase

• Methylmalonic aciduria is due to a defect in methylmalonyl-CoA mutase, in either the mutase apoenzyme or in defects of its cofactor, adenosyl-B₁₂ coenzyme

• Some disorders of intracellular vitamin B₁₂ metabolism affect only the synthesis of adenosyl-B₁₂ (Cbl A, B, or D), whereas in others (Cbl C, D, F, J, X), the synthesis of methyl-B₁₂ is also blocked, and hence homocysteine is also elevated in blood in addition to methylmalonic acid

• All forms of propionic and methylmalonic acidemia are autosomal recessive traits (except for X-linked Cbl X) and can be diagnosed in utero

Clinical Findings

• Clinical symptoms vary according to the location and severity of the enzyme block

• Children with severe blocks have

  • Acute, life-threatening metabolic ketoacidosis

  • Hyperammonemia

  • Coma

  • Bone marrow depression in early infancy

  • Metabolic acidosis

  • Vomiting

  • Failure to thrive during the first few months of life

• Most patients with severe disease have mild or moderate mental retardation

• Late complications

  • Pancreatitis

  • Cardiomyopathy

  • Basal ganglia stroke

  • Interstitial nephritis (most common in methylmalonic aciduria)

Diagnosis

• Laboratory findings consist of increases in urinary organic acids derived from propionyl-CoA or methylmalonic acid

• Hyperglycinemia can be present

• In some forms of abnormal vitamin B₁₂ metabolism, homocysteine can be elevated

• Confirmation is by molecular analysis or by assays in fibroblasts

Treatment

• Patients with enzyme blocks in B₁₂ metabolism usually respond to pharmacologic doses of vitamin B₁₂ given subcutaneously or intramuscularly

• Vitamin B₁₂ nonresponsive methylmalonic acidemia and propionic acidemia require

  • Amino acid restriction

  • Strict prevention of catabolism

  • Carnitine supplementation to enhance propionylcarnitine excretion

• Intermittent metronidazole can help reduce the propionate load from the gut

• In the acute setting, hemodialysis or hemofiltration may be needed

• Combined liver-renal transplantation is an option for patients with renal insufficiency

• Liver transplantation has shown promise for patients with life-threatening cardiomyopathy