title: Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type.
abstract: 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.
authors: Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: james.weisfeld-adams@mssm.edu.
authors: James D
authors: JD
authors: Weisfeld-Adams
authors: H Allison
authors: HA
authors: Bender
authors: Anna
authors: A
authors: Miley-Åkerstedt
authors: Tamiesha
authors: T
authors: Frempong
authors: Nina L
authors: NL
authors: Schrager
authors: Keyur
authors: K
authors: Patel
authors: Thomas P
authors: TP
authors: Naidich
authors: Victoria
authors: V
authors: Stein
authors: Jessica
authors: J
authors: Spat
authors: Stephanie
authors: S
authors: Towns
authors: Melissa P
authors: MP
authors: Wasserstein
authors: Inga
authors: I
authors: Peter
authors: Yitzchak
authors: Y
authors: Frank
authors: George A
authors: GA
authors: Diaz
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000178:diet therapy / Q000503:physiopathology*; D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006712:Homocystinuria / Q000175:diagnosis* / Q000178:diet therapy / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D010088:Oxidoreductases; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; C508359:MMACHC protein, human; D010088:Oxidoreductases
keywords: Cobalamin C; Homocystinuria; MMACHC; Methylmalonic acidemia; Neurodevelopment; Newborn screening