TRPV4 – Neuronopathy, Distal Hereditary Motor, Autosomal Dominant 8

Neuronopathy, distal hereditary motor, type VIII is an exceedingly rare autosomal dominant disorder characterized by progressive distal muscle weakness and atrophy without sensory impairment. We describe a pediatric proband with prenatal clubfoot, bilateral knee valgus, pelvic tilt, and inability to walk unaided, diagnosed by exome sequencing to carry a heterozygous TRPV4 c.805C>T (p.Arg269Cys) variant consistent with disease pathogenesis (PMID:38562133).

The c.805C>T (p.Arg269Cys) variant arose in one unrelated proband without available segregation, supporting autosomal dominant inheritance; no additional affected relatives were reported. Functional and structural analyses of ankyrin-repeat domain TRPV4 mutations, including p.Arg269Cys, demonstrate altered channel glycosylation, membrane trafficking defects, and gain-of-function calcium influx consistent with neuropathy mechanisms (PMID:22702953). While this represents limited clinical evidence, the concordant molecular data provide a mechanistic link to guide diagnostic testing.

References

• Frontiers in Pediatrics • 2024 • Case Report: TRPV4 gene mutation causing neuronopathy, distal hereditary motor, type VIII. PMID:38562133
• Biochemistry • 2012 • Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. PMID:22702953

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