Neurocognitive phenotype of isolated methylmalonic acidemia

• Published in: Pediatrics (Evanston) 2012-06, Vol.129 (6), p.e1541-e1551
• Main Authors: O'Shea, Colin J, Sloan, Jennifer L, Wiggs, Edythe A, Pao, Maryland, Gropman, Andrea, Baker, Eva H, Manoli, Irini, Venditti, Charles P, Snow, Joseph
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Amino Acid Metabolism, Inborn Errors - diagnosis; Amino Acid Metabolism, Inborn Errors - epidemiology; Amino Acid Metabolism, Inborn Errors - psychology; Causes of; Child; Child, Preschool; Cognition & reasoning; Cognition Disorders - diagnosis; Cognition Disorders - epidemiology; Cognition Disorders - psychology; Cohort Studies; Convulsions & seizures; Diagnosis; Epilepsy - diagnosis; Epilepsy - epidemiology; Epilepsy - psychology; Female; Genotype & phenotype; Humans; Hyperammonemia; Longitudinal Studies; Male; Metabolic disorders; Methylmalonic acidemia; Neurologic manifestations; Neurologic manifestations of general diseases; Neuropsychological Tests; Neuropsychology; Pediatrics; Phenotype; Risk factors; Young Adult
• ISSN: 0031-4005; 1098-4275
• DOI: 10.1542/peds.2011-1715

Methylmalonic acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition. A diverse cohort with mut, cblA, or cblB subtypes of isolated MMA (N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined. Early-onset mut patients (n = 21) manifested the most severe neurocognitive impairments, with a mean ± SD full-scale IQ (FSIQ) of 71.1 ± 14.75. Late-onset mut patients (n = 6) had a mean FSIQ of 88.5 ± 27.62. cblA (n = 7), cblB (n = 6), and mut patients diagnosed prenatally or by newborn screening (n = 3) obtained mean FSIQs in the average range (100.7 ± 10.95, 96.6 ± 10.92, and 106.7 ± 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ (P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing (n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation. The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present.