Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia

Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(3-4):260-5. doi: 10.3109/21678421.2015.1125501. Epub 2016 Jan 11.

Abstract

Biallelic mutations of ALS2 cause a clinical spectrum of overlapping autosomal recessive neurodegenerative disorders: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2). We report on eleven individuals affected with IAHSP from two consanguineous Pakistani families. A combination of linkage analysis with homozygosity mapping and targeted sequencing identified two novel ALS2 mutations, a c.194T > C (p.Phe65Ser) missense substitution located in the first RCC-like domain of ALS2/alsin and a c.2998delA (p.Ile1000*) nonsense mutation. This study of extended families including a total of eleven affected individuals suggests that a given ALS2 mutation may lead to a phenotype with remarkable intrafamilial clinical homogeneity.

Keywords: ALS2; alsin; amyotrophic lateral sclerosis; infantile-onset ascending hereditary spastic paralysis (IAHSP).

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Male
  • Mutation / genetics*
  • Pakistan
  • Spastic Paraplegia, Hereditary / genetics*
  • Young Adult

Substances

  • ALS2 protein, human
  • Guanine Nucleotide Exchange Factors

Supplementary concepts

  • Hereditary spastic paralysis, infantile onset ascending