Progressive microcephaly and neurodegeneration are genetically heterogenous conditions, largely associated with genes that are essential for the survival of neurons. In this study, we interrogate the genetic etiology of two siblings from a non-consanguineous family with severe early onset of neurological manifestations. Whole exome sequencing identified novel compound heterozygous mutations in VARS that segregated with the proband: a missense (c.3192G>A; p.Met1064Ile) and a splice site mutation (c.1577-2A>G). The VARS gene encodes cytoplasmic valyl-tRNA synthetase (ValRS), an enzyme that is essential during eukaryotic translation. cDNA analysis on patient derived fibroblasts revealed that the splice site acceptor variant allele led to nonsense mediated decay, thus resulting in a null allele. Three-dimensional modeling of ValRS predicts that the missense mutation lies in a highly conserved region and could alter side chain packing, thus affecting tRNA binding or destabilizing the interface between the catalytic and tRNA binding domains. Further quantitation of the expression of VARS showed remarkably reduced levels of mRNA and protein in skin derived fibroblasts. Aminoacylation experiments on patient derived cells showed markedly reduced enzyme activity of ValRS suggesting the mutations to be loss of function. Bi-allelic mutations in cytoplasmic amino acyl tRNA synthetases are well-known for their role in neurodegenerative disorders, yet human disorders associated with VARS mutations have not yet been clinically well characterized. Our study describes the phenotype associated with recessive VARS mutations and further functional delineation of the pathogenicity of novel variants identified, which widens the clinical and genetic spectrum of patients with progressive microcephaly.
We report a case of rabies encephalomyelitis in a 12-year-old boy who had received anti-rabies vaccine 6 weeks after being bitten by a puppy. The MR (magnetic resonance) imaging helped to differentiate rabies from acute disseminated encephalomyelitis (ADEM). ADEM involves the white matter predominantly, whereas rabies has a predilection for grey matter, that too of midline regions. This report emphasizes the usefulness of MRI in differentiating rabies and ADEM when encephalomyelitis occurs in a vaccinated child.
Glucose transporter type 1 (glut1) deficiency syndrome presents with developmental delay, microcephaly, and recurrent seizures during infancy, as well as cerebrospinal fluid (CSF) hypoglycorrhachia and mutations in the SLC2A1 gene. We describe a baby with microcephaly, global developmental delay, seizures from 3 months of age, and CSF glucose in the lower limit of normal range, with heterozygous p.Glu815Lys mutation of the ATP1A3 gene and no mutation in the SLC2A1 gene. Mutations in ATP1A3 gene are associated with alternating hemiplegia of childhood (AHC). Interestingly the baby developed episodes of recurrent bouts of alternating hemiplegia from 13 months of age. The case is reported to highlight ATP1A3 mutation as a probable etiology for glut1 deficiency like syndrome and AHC. A brief review of literature emphasizing the overlapping paroxysmal and nonparoxysmal symptoms of the two conditions is also included.
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