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Homocystinuria is an autosomal recessive disorder caused by a deficiency of the enzyme cystathionine beta-synthase. The incidence of homocystinuria is approximately 1 in 350,000 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, mental retardation, 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.
Second-tier assay of newborn screening specimens when abnormal propionyl carnitine or methionine concentrations are identified in a primary newborn screen
Elevated homocysteine, methylcitric acid, or methylmalonic acid concentrations are indicative of an underlying metabolic disorder.
In a Mayo study that analyzed 200 unaffected neonates, clear clinical discrimination was observed when compared to patients with defects of propionate or methionine metabolism. The 99.5 percentile, determined from the analysis of 200 dried blood spots of unaffected controls, for methylmalonic acid (MMA), methylcitric acid (MCA), and homocysteine (HCY), are 1.58 nmol/mL, 0.62 nmol/mL, and 9.9 nmol/mL, respectively, providing clear clinical discrimination from patients with defects of propionate or methionine metabolism (eg, methylmalonic acidemia: MMA=31.9 nmol/mL; propionic acidemia: MCA=12.8 nmol/mL; homocystinuria: HCY=189 nmol/mL).
A metabolic specialist should always be involved in the care of an affected patient
Homocysteine: <15.0 nmol/mL
Methylmalonic acid: <5.0 nmol/mL
Methylcitric acid: <1.0 nmol/mL
An interpretive report will also be provided.
1. Rinaldo P, Hahn S, Matern D: Tietz Textbook of Clinical Chemistry. Fifth Edition. Edited by CA Burtis, ER Ashwood, DE Burns. St. Louis MO, Elsevier Sanders Company, 2006, pp 2207-2247
2. Watkins D, Rosenblatt DS: Cobalamin and inborn errors of cobalamin absorption and metabolism. Endocrinologist 2001;11:98-104