Abstract-Text (inkl. Referenzen)

Introduction: Neurons require dynamic intracellular trafficking networks in response to cellular stress. The dynein complex is essential for retrograde axonal transport of damaged components for autophagolysosomal processing. Pathogenic heterozygous variants in its core component, cytoplasmic dynein heavy chain (DYNC1H1), are associated with axonal motor neuropathy, including Charcot-Marie-Tooth disease type 2O (CMT2O). Axonal CMT2 neuropathies form a heterogeneous group with motor and/or sensory neuropathies, yet there are no reports of sensory neuropathies with DYNC1H1 variants to this date.

Methods: We recruited patients through international collaborations and patient networks. We present clinical, molecular and imaging data on the age-related neuromuscular spectrum.

Results: We followed up over 30 unreported cases with pathogenic variants in DYNC1H1 (ages 0-58 years). In addition to motor neuropathy, we identified several cases with novel age-related, progressive sensory neuropathy after the second decade of life, including tingling and numbness in patients with antecedent twitching, trembling, and tremors. We discuss DYNC1H1-related axonal motor sensory neuropathy in the context of CMT2 disorders and its life-long continuum in age-related progression of neuromuscular disorders.

Conclusion: These findings extend the clinical, molecular and imaging spectrum of pathogenic DYNC1H1 variants, and facilitate genetic counselling and anticipatory guidance of patients.