Brain Circuit Alterations and Cognitive Disability in Late-Onset Cobalamin D Disorder.

Javier De Las Heras,Antonio Jimenez-Marin,Marta Venecia Diaz-Fernandez,Rafael Pulido,Leire Torices,Jesus M. Cortes,Daniela Ramos-Usuga,Ibai Diez,Alberto Cabrera,Caroline E. Nunes-Xavier,Juan Carlos Arango-Lasprilla

doi:10.3390/jcm9040990

Abstract

Neuroimaging studies describing brain circuits’ alterations in cobalamin (vitamin B12)-deficient patients are limited and have not been carried out in patients with inborn errors of cobalamin metabolism. The objective of this study was to assess brain functionality and brain circuit alterations in a patient with an ultra-rare inborn error of cobalamin metabolism, methylmalonic aciduria, and homocystinuria due to cobalamin D disease, as compared with his twin sister as a healthy control (HC). We acquired magnetic resonance imaging (including structural, functional, and diffusion images) to calculate brain circuit abnormalities and combined these results with the scores after a comprehensive neuropsychological evaluation. As compared with HC, the patient had severe patterns of damage, such as a 254% increment of ventricular volume, pronounced subcortical and cortical atrophies (mainly at striatum, cingulate cortex, and precuneus), and connectivity alterations at fronto-striato-thalamic circuit, cerebellum, and corpus callosum. In agreement with brain circuit alterations, cognitive deficits existed in attention, executive function, inhibitory control, and mental flexibility. This is the first study that provides the clinical, genetic, neuroanatomical, neuropsychological, and psychosocial characterization of a patient with the cobalamin D disorder, showing functional alterations in central nervous system motor tracts, thalamus, cerebellum, and basal ganglia, that, as far as we know, have not been reported yet in vitamin B12-related disorders.

Highlights

Cobalamin, or vitamin B12, is a water-soluble vitamin present in animal products such as meat, fish, eggs, and milk [1]
The cobalamin D disorder is an autosomal recessive disease of cbl metabolism caused by mutations in the MMADHC gene [4] that can result in isolated homocystinuria, isolated methylmalonic aciduria, or the combined form, methylmalonic aciduria and homocystinuria (MMA/healthy control (HC)) [7]
MMA/HC due to cobalamin D (cblD) disease was confirmed by genetic testing, which showed a novel MMADHC mutation (c.438-442delAGAGT; p.F161fsX14) in heterozygosis with the mutation (c.748C > T, p.R250X)

Summary

Introduction

Cobalamin (cbl), or vitamin B12, is a water-soluble vitamin present in animal products such as meat, fish, eggs, and milk [1]. Inborn errors of cbl—cofactor synthesis comprise a group of rare disorders affecting multiple steps between the lysosomal release of cbl and the synthesis of adenosylcobalamin in the mitochondria and methylcobalamin in the cytosol [4]. The cobalamin D (cblD) disorder is an autosomal recessive disease of cbl metabolism caused by mutations in the MMADHC gene [4] that can result in isolated homocystinuria, isolated methylmalonic aciduria, or the combined form, methylmalonic aciduria and homocystinuria (MMA/HC) [7]. A few patients with cblD defect have been described because it is one of the rarest inborn disorders of cbl metabolism. Most patients affected by inborn errors of cbl metabolism present in the neonatal period with seizures, hypotonia, lethargy megaloblastic anemia, and developmental delay [8]. Late-onset forms are extremely rare and difficult to diagnose because they may present with rather nonspecific psychiatric and behavioral symptoms along with different degrees of cognitive impairment [9]

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