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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Biallelic mutations in the ALS2 gene are associated with a spectrum of autosomal recessive neurodegenerative disorders.
• These disorders include infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2).
• Understanding the genetic basis and phenotypic variability of these conditions is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To investigate the genetic cause of IAHSP in two consanguineous Pakistani families.
• To identify novel mutations within the ALS2 gene responsible for the observed phenotype.
• To analyze the intrafamilial clinical homogeneity associated with specific ALS2 mutations.

Main Methods:

• Linkage analysis and homozygosity mapping were employed to identify regions of interest in affected individuals.
• Targeted sequencing of the ALS2 gene was performed to detect specific mutations.
• Clinical data from eleven affected individuals across two families were collected and analyzed.

Main Results:

• Two novel mutations in the ALS2 gene were identified: a c.194T>C (p.Phe65Ser) missense mutation and a c.2998delA (p.Ile1000*) nonsense mutation.
• These mutations were found in eleven individuals affected with IAHSP from two consanguineous families.
• The study observed a remarkable degree of clinical homogeneity within families carrying the same ALS2 mutation.

Conclusions:

• The identified novel ALS2 mutations are causative of infantile-onset ascending hereditary spastic paralysis (IAHSP).
• The findings highlight the significant role of ALS2 in neurodevelopment and the spectrum of associated motor neuron diseases.
• Specific ALS2 mutations appear to correlate with consistent intrafamilial phenotypes, aiding in understanding disease progression and inheritance patterns.