Identification of novel L2HGDH mutation in a large consanguineous Pakistani family- a case report

BMC Med Genet. 2018 Feb 20;19(1):25. doi: 10.1186/s12881-018-0532-x.

Abstract

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a progressive neurometabolic disease of brain caused by mutations of in L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. Cardinal clinical features include cerebellar ataxia, epilepsy, neurodevelopmental delay, intellectual disability, and other clinical neurological deficits.

Case presentation: We describe an index case of the family presented with generalised tonic-clonic seizure, developmental delay, intellectual disability, and ataxia. Initially, the differential diagnosis was difficult to be established and a SNP genome wide scan identified the candidate region on chromosome 14q22.1. DNA sequencing showed a novel homozygous mutation in the candidate gene L2HGDH (NM_024884.2: c.178G > A; p.Gly60Arg). The mutation p.Gly60Arg lies in the highly conserved FAD/NAD(P)-binding domain of this mitochondrial enzyme, predicted to disturb enzymatic function.

Conclusions: The combination of homozygosity mapping and DNA sequencing identified a novel mutation in Pakistani family with variable clinical features. This is second report of a mutation in L2HGDH gene from Pakistan and the largest family with L2HGA reported to date.

Keywords: Cerebellar ataxia; Developmental delay; Epilepsy; Intellectual disability; L-2-hydroxyglutaric aciduria; L2HGDH; Mutation; Pakistan.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alcohol Oxidoreductases / genetics*
  • Amino Acid Sequence
  • Asian People / genetics
  • Ataxia / diagnosis
  • Ataxia / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 14 / genetics
  • Computational Biology
  • Consanguinity*
  • Epilepsy / diagnosis
  • Epilepsy / genetics*
  • Female
  • Homozygote
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Mutation
  • Mutation, Missense
  • Pakistan
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Protein Conformation
  • Seizures / diagnosis
  • Seizures / genetics*
  • Sequence Analysis, DNA

Substances

  • Alcohol Oxidoreductases
  • L2HGDH protein, human