SEPTIN9 – Amyotrophic Neuralgia

Hereditary neuralgic amyotrophy, a disorder characterized by recurrent, episodic neuropathies affecting the brachial plexus, has been robustly associated with mutations in SEPTIN9. This disorder follows an autosomal dominant pattern and presents with clinical features that include severe pain, motor weakness, and distinctive dysmorphic traits such as hypotelorism (PMID:20019224).

Multiple independent case reports have demonstrated segregation of SEPTIN9 mutations within affected families. For instance, several studies describe families with recurrent neuropathic episodes, where affected individuals present with both typical neuralgic features and, in some cases, additional findings like vocal cord paralysis and platelet dysfunction. An illustrative mutation, reported as c.316C>T (p.Arg106Trp), is consistently observed in these families (PMID:22981636; PMID:28503616).

Genetic evidence from multi-patient studies further reinforces the association. Cohort analyses have identified multiple pathogenic variants, including missense and genomic duplications, across several unrelated pedigrees. Data from these studies, including one that identified mutations in six families and another that documented seven distinct SEPT9 duplications, underlines the strong genetic contribution to amyotrophic neuralgia (PMID:16186812; PMID:19939853).

Functional assessments have provided supporting evidence at the molecular level. Studies demonstrate that pathogenic SEPTIN9 variants disrupt septin filament formation and alter interactions with partner proteins such as SEPT4 and SEPT11, leading to impairment in cytoskeletal dynamics and cellular signaling (PMID:17546647). These findings align with the clinical phenotype observed in affected patients.

The integration of genetic and functional data establishes a coherent narrative linking recurrent mutations in SEPTIN9—most notably c.316C>T (p.Arg106Trp)—with the pathogenesis of amyotrophic neuralgia. This robust evidence supports the use of genetic testing for diagnostic decision-making and reinforces its clinical utility for patient management and genetic counseling.

Key Take‑home sentence: The recurrent c.316C>T (p.Arg106Trp) mutation in SEPTIN9 constitutes a strong genetic basis for amyotrophic neuralgia, enabling precise diagnosis and targeted clinical management.

References

• Journal of neurology, neurosurgery, and psychiatry • 2010 • Phenotypic spectrum of hereditary neuralgic amyotrophy caused by the SEPT9 R88W mutation PMID:20019224
• Nature genetics • 2005 • Mutations in SEPT9 cause hereditary neuralgic amyotrophy PMID:16186812
• Journal of medical genetics • 2010 • Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy PMID:19939853
• Neurology • 2009 • SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy PMID:19451530
• Human mutation • 2007 • SEPT9 sequence alternations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/SEPT11 and resistance to Rho/Rhotekin-signaling PMID:17546647

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