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

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.

• Authors: Masahiro Kawaguchi, Takayuki Sassa, Hiroyuki Kidokoro, Tomohiko Nakata, Kohji Kato, Hideki Muramatsu, Yusuke Okuno, Hiroyuki Yamamoto, Tadashi Kaname, Akio Kihara, Jun Natsume
• Journal: Brain & development (Brain Dev) Vol. 42 Issue 2 Pg. 217-221 (Feb 2020) ISSN: 1872-7131 [Electronic] Netherlands
• PMID: 31837835 (Publication Type: Case Reports)
• Copyright: Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Mixed Function Oxygenases
• fatty acid alpha-hydroxylase

Topics

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