Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type.

Abnormal neurodevelopment has been widely reported in combined methylmalonic aciduria (MMA) and homocystinuria, cblC type (cblC disease), but neurodevelopmental phenotypes in cblC have not previously been systematically studied. We sought to further characterize developmental neurology in children with molecularly-confirmed cblC. Thirteen children at our center with cblC, born since implementation of expanded newborn screening in New York State, undertook standard-of-care evaluations with a pediatric neurologist and pediatric ophthalmologist. At most recent follow-up (mean age 50 months, range 9-84 months), of twelve children with early-onset cblC, three (25%) had a history of clinical seizures and two (17%) meet criteria for microcephaly. A majority of children had hypotonia and nystagmus. Twelve out of thirteen (92%) underwent neurodevelopmental evaluation (mean age 41 months; range 9-76 months), each child tested with standardized parental interviews and, where possible, age- and disability-appropriate neuropsychological batteries. All patients showed evidence of developmental delay with the exception of one patient with a genotype predictive of attenuated disease and near-normal biochemical parameters. Neurodevelopmental deficits were noted most prominently in motor skills, with relative preservation of socialization and communication skills. Nine children with early-onset cblC underwent magnetic resonance imaging and spectroscopy (MRI/MRS) at mean age of 47 months (range 6-81 months); common abnormalities included callosal thinning, craniocaudally short pons, and increased T2 FLAIR signal in periventricular and periatrial white matter. Our study further characterizes variable neurodevelopmental phenotypes in treated cblC, and provides insights into the etiopathogenesis of disordered neurodevelopment frequently encountered in cblC. Plasma homocysteine and MMA, routinely measured at clinical follow-up, may be poor predictors for neurodevelopmental outcomes. Additional data from large, prospective, multi-center natural history studies are required to more accurately define the role of these metabolites and others, as well as that of other genetic and environmental factors in the etiopathogenesis of the neurologic components of this disorder.

Caution warranted in extrapolating from Boston Naming Test item gradation construct.

The Boston Naming Test (BNT) was designed to present items in order of difficulty based on word frequency. Changes in word frequencies over time, however, would frustrate extrapolation in clinical and research settings based on the theoretical construct because performance on the BNT might reflect changes in ecological frequency of the test items, rather than performance across items of increasing difficulty. This study identifies the ecological frequency of BNT items at the time of publication using the American Heritage Word Frequency Book and determines changes in frequency over time based on the frequency distribution of BNT items across a current corpus, the Corpus of Contemporary American English. Findings reveal an uneven distribution of BNT items across 2 corpora and instances of negligible differentiation in relative word frequency across test items. As BNT items are not presented in order from least to most frequent, clinicians and researchers should exercise caution in relying on the BNT as presenting items in increasing order of difficulty. A method is proposed for distributing confrontation-naming items to be explicitly measured against test items that are normally distributed across the corpus of a given language.