Rapid diagnosis of methylmalonic and propionic acidemias: quantitative tandem mass spectrometric analysis of propionylcarnitine in filter-paper blood specimens obtained from newborns.

Methylmalonic acidemias (MMAs) and propionic acidemias (PAs) comprise a group of congenital disorders of branched-chain amino acid metabolism (1). PA is caused by deficiency of propionyl-CoA carboxylase, whereas MMA results from deficiency of either methylmalonyl-CoA mutase or defects in the production of adenosylcobalamin. Deficiency of vitamin B12, a cofactor for methylmalonyl-CoA mutase, will also produce signs and symptoms consistent with MMA (2)(3)(4). Other biochemically closely related disorders are the cobalamin (Cbl) defects, classified as forms A through G (5). Clinical signs and symptoms include failure to thrive, metabolic acidosis, persistent ketotic episodes, hypoglycemia, hypotonia, hyperammonemia, and neurologic symptoms (6). Children with PA, MMA, or Cbl disorders often present with acute illness as neonates or infants. Treatment of MMA and PA includes careful monitoring and limitation of branched-chain amino acid intake (4) as well as possible supplementation with biotin, vitamin B12, and l-carnitine (7). Tests for the diagnosis of MMA and PA are most often performed on urine, plasma, and whole-blood samples and involve gas chromatographic–mass spectrometric analysis of organic acids (8)(9)(10)(11). Tandem mass spectrometry (MS/MS) has been used to semiquantitatively identify presymptomatic and affected infants (12)(13)(14)(15)(16)(17). Confirmation of these test results may involve enzymatic or DNA analysis (1). We report the validation of a high-throughput method for the analysis of acylcarnitine butyl esters in infants with these disorders and include the results from a prospective study of the occurrence of PA and MMA in nearly 1 million newborns screened using MS/MS. Dried filter-paper blood samples were obtained from newborns (908 543 specimens) and infants ≥7 days of age (255 specimens). Samples were prepared and analyzed for acylcarnitines as butyl esters by electrospray MS/MS as …

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