Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations

J Hum Genet. 2016 Jun;61(6):527-31. doi: 10.1038/jhg.2016.9. Epub 2016 Feb 18.


Cerebellar atrophy is recognized in various types of childhood neurological disorders with clinical and genetic heterogeneity. Genetic analyses such as whole exome sequencing are useful for elucidating the genetic basis of these conditions. Pathological recessive mutations in Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase (SEPSECS) have been reported in a total of 11 patients with pontocerebellar hypoplasia type 2, progressive cerebellocerebral atrophy or progressive encephalopathy, yet detailed clinical features are limited to only four patients. We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2. Their development was slightly delayed regardless of normal brain magnetic resonance imaging (MRI) in infancy. The progression of clinical symptoms in these families is evidently slower than in previously reported cases, and the cerebellar atrophy milder by brain MRI, indicating that SEPSECS mutations are also involved in milder late-onset cerebellar atrophy.

MeSH terms

  • Adolescent
  • Alleles*
  • Amino Acid Substitution
  • Amino Acyl-tRNA Synthetases / genetics*
  • Brain / cytology
  • Child
  • Child, Preschool
  • Exome
  • Female
  • Gene Frequency
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mutation*
  • Olivopontocerebellar Atrophies / diagnosis*
  • Olivopontocerebellar Atrophies / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA


  • Amino Acyl-tRNA Synthetases
  • O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, human

Supplementary concepts

  • Pontocerebellar Hypoplasia Type 2
  • Pontocerebellar Hypoplasia Type 3