Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant

Neurol Sci. 2018 Nov;39(11):1917-1925. doi: 10.1007/s10072-018-3526-8. Epub 2018 Aug 21.


Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.

Keywords: ALS2; Alsin; IAHSP; Infantile-onset ascending hereditary spastic paralysis; Natural history.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Family Health*
  • Female
  • Guanine Nucleotide Exchange Factors / genetics*
  • Humans
  • Iran
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / physiopathology*
  • Young Adult


  • ALS2 protein, human
  • Guanine Nucleotide Exchange Factors

Supplementary concepts

  • Hereditary spastic paralysis, infantile onset ascending