Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia

Area of Science:

• Genetics and Neurology
• Molecular Biology
• Neuroscience

Background:

• Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders.
• EXOSC3 gene mutations are typically associated with pontocerebellar hypoplasia type 1 (SCPH1).
• Autosomal recessive inheritance patterns are observed in some forms of HSP.

Purpose of the Study:

• To investigate the genetic cause of autosomal recessive hereditary spastic paraplegia in a consanguineous family.
• To identify novel mutations in the EXOSC3 gene and their associated clinical phenotypes.
• To expand the understanding of the phenotypic spectrum associated with EXOSC3 gene mutations.

Main Methods:

• Family-based genetic analysis utilizing homozygosity mapping.
• Whole exome sequencing (WES) to identify causative mutations.
• Clinical assessment of affected siblings, including neurological examination and cerebral imaging.

Main Results:

• Identified a novel homozygous c.571G>T; p.G191C mutation in the EXOSC3 gene in affected siblings.
• Clinical presentation included delayed motor milestones, early-onset spastic paraplegia, cognitive disability, and cerebellar signs.
• Cerebral imaging revealed enlarged cisterna magna and mild cerebellar vermis hypoplasia/atrophy, with a normal pons.

Conclusions:

• EXOSC3 gene mutations can cause a complicated form of autosomal recessive hereditary spastic paraplegia.
• The phenotypic spectrum of EXOSC3 mutations extends beyond pontocerebellar hypoplasia type 1.
• This study highlights the importance of considering EXOSC3 in the differential diagnosis of hereditary spastic paraplegia, even without pontine abnormalities.