Clinical Information

Homocystinuria is an autosomal recessive disorder caused by a deficiency of the enzyme cystathionine beta-synthase. The incidence of homocystinuria is approximately 1 in 200,000 to 335,000 live births. Classical homocystinuria is characterized by a normal presentation at birth followed by failure to thrive and developmental delay. Untreated homocystinuria can lead to ophthalmological problems, intellectual disability, seizures, thromboembolic episodes, and skeletal abnormalities. The biochemical phenotype is characterized by increased plasma concentrations of methionine and homocysteine (free and total) along with decreased concentrations of cystine.

Methylmalonic acidemia (MMA) and propionic acidemia (PA) are defects of propionate metabolism caused by deficiencies in methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. The clinical phenotype includes vomiting, hypotonia, lethargy, apnea, hypothermia, and coma. The biochemical phenotype for MMA includes elevations of propionyl carnitine, methylmalonic acid, and methylcitric acid. Patients with PA will have elevations of propionyl carnitine and methylcitric acid with normal methylmalonic acid concentrations as the enzymatic defect is upstream of methylmalonic-CoA mutase.

Newborn screening for inborn errors of methionine and propionic acid metabolism relies on elevations of methionine and propionyl carnitine. These analytes are not specific for these conditions and are prone to false-positive results, leading to increased cost, stress, and anxiety for families who are subjected to follow-up testing. Homocysteine, methylmalonic acid, and methylcitric acid are more specific markers for inborn errors of methionine and propionic acid metabolism. Molecular genetic testing can be used to confirm a biochemical diagnosis for homocystinuria, methylmalonic acidemia, and propionic acidemia.