Genetic heterogeneity of motor neuropathies.

Boglarka Bansagi,Mark Greenslade,Jennifer Duff,Natalie Forester,Helen Griffin,Rita Horvath,Angela Pyle,Teresinha Evangelista,Thalia Antoniadi,Roger G Whittaker,Stephanie Kleinle,Anna Bradshaw,Venkateswaran Ramesh,Edit Franko,Hannah Steele,Veronika Boczonadi,Patrick F Chinnery,James Miller,Hanns Lochmüller

doi:10.1212/wnl.0000000000003772

Abstract

Objective:To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.Methods:Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).Results:The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.Conclusions:Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.

Highlights

The prevalence of Distal hereditary motor neuropathy (dHMN) is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66) in the North of England
Diagnosis of dHMN was based on preserved sensory nerve studies with normal or reduced compound motor unit action potentials or neurogenic changes on EMG examination.[2]
We considered HMN plus when motor neuropathy was the leading feature, but was accompanied by other neurologic symptoms

Summary

Methods

Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). Between 2010 and 2015, we selected 105 patients out of 461 diagnosed with inherited neuropathies in our genetic neuropathy clinic at Newcastle Hospitals NHS Foundation, which is the catchment area of a total population of 2.99 million. Inclusion of patients was based on the presence of a motor neuropathy/neuronopathy with no or only subclinical sensory changes on electrophysiology. Some affected family members of patients with a confirmed genetic diagnosis were included in this cohort, even if no electrophysiologic data were available. Participants provided written informed consent, approved by local research ethics committees, for all experiments using human participants and for photographs that may be published

Results

Discussion

Conclusion