Early neurodevelopmental characterization in children with cobalamin C/defect

Abstract

Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12‐48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3‐18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease‐related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment.

Outcomes of patients with cobalamin C deficiency: A single center experience

“…In a recent study, 18 patients with cblC deficiency underwent neurodevelopmental assessments. The study showed progressive deterioration of the neurodevelopment, identified after 24 months of age 8 . It seems that our patient outcomes may be more favorable compared to previous studies.…”

“…Several recent studies reported neurodevelopmental outcomes in children identified with cblC deficiency on NBS 6‐8,18 . Weisfeld‐Adams described 13 patients with early onset disease (oldest 7 years of age), who had GDD/ID (n = 11), hypotonia (n = 11), nystagmus (n = 8), and thin corpus callosum and white matter abnormalities in brain MRI (n = 9) 6 Hypotonia and nystagmus were more common in that study compared to our study cohort.…”

“…In contrast, later onset forms may present with thromboembolic events (eg, stroke), psychosis, and progressive encephalopathy 2,5 . Neurodevelopmental disorders 6‐8 and ophthalmologic involvement (ie, maculopathy, retinopathy) 9,10 are also common.…”

Screening for Methylmalonic and Propionic Acidemia: Clinical Outcomes and Follow-Up Recommendations

“…The phenotype for disorders of cobalamin metabolism is variable but includes global developmental delay, encephalopathy, neurologic symptoms, and cytopenia [ 3 ]. It has been well documented that newborn screening for methylmalonic acidemia and PA improves outcomes, and more recent studies also show improved outcomes for cblC deficiency [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].…”

Investigation on a MMACHC mutant from cblC disease: The c.394C>T variant

“…The disease results in impaired intracellular synthesis of adenosylcobalamin (Ado-Cbl) and methylcobalamin (Me-Cbl), cofactors for the mitochondrial methylmalonyl-CoA mutase (MUT) and cytosolic methionine synthase (MS) enzymes, respectively (1,2). The clinical consequences are devastating and systemic, including pulmonary problems, hemolytic-uremic syndrome, neurocognitive impairment, and degenerative maculopathy (3)(4)(5)(6). The onset may be early (EO) (a few weeks) or late (LO) (second, third decade of life) (7).…”