Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration

Brain Dev. 2020 Feb;42(2):217-221. doi: 10.1016/j.braindev.2019.11.006. Epub 2019 Dec 16.

Abstract

FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins. Here we report a 10-year-old Japanese boy with FAHN having novel heterozygous mutations in FA2H. The patient presented with a spastic gait since the age of 5 years and was unable to walk without a cane by the time he was 8 years old. Brain MRI demonstrated a partial thinning of the corpus callosum, slight reduction of cerebellar volume, and posterior dominant periventricular leukodystrophy. Whole exome sequencing revealed two novel missense mutations in FA2H with compound heterozygous inheritance (NM_024306, p.Val149Leu, and p.His260Gln mutations). The enzyme activities of the p.Val149Leu and p.His260Gln variants were 60%-80% and almost 0%, respectively. Our cell-based enzyme assay demonstrated partial functionality for one of the variants, indicating a milder phenotype. However, considered along with previous reports, there was no definite relationship between the disease severity and residual enzyme activity measured using a similar method. Further research is needed to precisely predict the phenotypic severity of this disorder.

Keywords: Fatty acid 2-hydroxylase; Fatty acid hydroxylase-associated neurodegeneration; Hereditary spastic paraplegia; Spastic paraplegia type 35.

Publication types

  • Case Reports

MeSH terms

  • Brain / metabolism
  • Child
  • Demyelinating Diseases / diagnostic imaging
  • Demyelinating Diseases / genetics
  • Demyelinating Diseases / metabolism
  • Gait / genetics
  • Heredodegenerative Disorders, Nervous System / diagnostic imaging
  • Heredodegenerative Disorders, Nervous System / genetics*
  • Heredodegenerative Disorders, Nervous System / metabolism
  • Heterozygote
  • Humans
  • Japan
  • Magnetic Resonance Imaging
  • Male
  • Mixed Function Oxygenases / genetics*
  • Mixed Function Oxygenases / metabolism
  • Mutation
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism
  • Spastic Paraplegia, Hereditary / diagnostic imaging
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism

Substances

  • Mixed Function Oxygenases
  • fatty acid alpha-hydroxylase

Supplementary concepts

  • Fatty Acid Hydroxylase-Associated Neurodegeneration