Spectrum of Clinical Variability with SEPT9 Gene Mutation in Hereditary Neuralgic Amyotrophy: Understanding the Pathogenesis Using Molecular Dynamics Simulation Study.

Background: Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominant disorder characterized by episodes of severe pain and amyotrophy affecting the brachial plexus as well as other sites. Mutations in the SEPTIN9 gene have been identified as genetic abnormality for HNA. Although the genetic mutations are known, their pathogenesis for the causation of this disorder is not exactly elucidated.

Objective: In this study, we have investigated the phenotypic and genetic features in a large pedigree with HNA.

Methods: We report the clinical spectrum and genetic analysis of a family with 9 affected members. Clinical heterogeneity has been reported in the individuals having mutations in SEPTIN9 gene. After taking informed consent, we have done genetic analysis of 6 affected and 4 unaffected members of the family to identify the molecular abnormalities of SEPTIN9 gene.

Results and conclusions: Genetic analysis has identified the presence of NM_001113491.2:p.Arg106Trp mutation in SEPTIN9 gene. The same mutation has been identified in 6 affected members of the family. Molecular simulation study has revealed that the mutation has significantly altered the conformation of septin-9 protein, thereby impairing the microtubule binding and bundling ability. Although the affected members shared a common recurrent mutation, they have a wide spectrum of clinical variability. This may be due to the variable penetrance of the mutation and different epigenetic influences in the family. This is the first genetically confirmed case series of HNA reported from India.