MMACHC gene mutation in familial hypogonadism with neurological symptoms

Gene. 2015 Dec 15;574(2):380-4. doi: 10.1016/j.gene.2015.08.029. Epub 2015 Aug 14.


Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy. After bioinformatic analysis and Sanger sequencing validation, we identified compound heterozygous mutations: c.482G>A (p.R161Q) and c.609G>A (p.W203X) in MMACHC gene in this pedigree. MMACHC was previously confirmed to be responsible for methylmalonic aciduria (MMA) combined with homocystinuria, cblC type (cblC disease), a hereditary vitamin B12 metabolic disorder. Biochemical and gas chromatography-mass spectrometry (GC-MS) examinations in this pedigree further supported the cblC disease diagnosis. These results indicated that hypergonadotropic hypogonadism may be a novel clinical manifestation of cblC disease, but more reports on additional patients are needed to support this hypothesis.

Keywords: Homocystinuria; Hypogonadism; MMACHC; Methylmalonic aciduria; cblC.

Publication types

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

MeSH terms

  • Adult
  • Base Sequence
  • Carrier Proteins / genetics*
  • Humans
  • Hypogonadism / complications
  • Hypogonadism / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Nervous System Diseases / complications
  • Nervous System Diseases / genetics*
  • Oxidoreductases
  • Pedigree


  • Carrier Proteins
  • MMACHC protein, human
  • Oxidoreductases