Abstract
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.
Highlights
Retrograde degeneration of the upper motor neurons (UMN) of the pyramidal tracts due to biallelic pathogenic ALS2 (OMIM * 606352) variants has been associated with a clinical continuum ranging from infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225) to juvenile forms without lower motor neuron (LMN) involvement
Mutations in the ALS2 gene have been associated with a phenotypic spectrum ranging from infantile forms with both UMN and LMN involvement (IAHSP) to juvenile forms with (JALS/ALS2) or without (JPLS) LMN involvement [1,2,3,4, 11, 12]
Approximately 50 ALS2 pathogenic variants have been reported in individuals with
Summary
Retrograde degeneration of the upper motor neurons (UMN) of the pyramidal tracts due to biallelic pathogenic ALS2(OMIM * 606352) variants has been associated with a clinical continuum ranging from infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM # 607225) to juvenile forms without lower motor neuron (LMN) involvement 10 Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. 12 Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. The ALS2 (alsin Rho guanine nucleotide exchange factor) gene, known as KIAA1563, is located at 2q33.1 and encodes at least two isoforms of the alsin protein, a long form with 1657 amino acids and a short form with 396 amino acids. Both forms are ubiquitously expressed in various tissues, including the brain and spinal cord [1, 2]. Alsin plays a role in endosomal and mitochondrial trafficking as well as cytoskeleton maintenance and endocytosis [5,6,7,8,9]
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