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. 2017 Mar 28;88(13):1226-1234.
doi: 10.1212/WNL.0000000000003772. Epub 2017 Mar 1.

Genetic heterogeneity of motor neuropathies

Boglarka Bansagi  1 , Helen Griffin  1 , Roger G Whittaker  1 , Thalia Antoniadi  1 , Teresinha Evangelista  1 , James Miller  1 , Mark Greenslade  1 , Natalie Forester  1 , Jennifer Duff  1 , Anna Bradshaw  1 , Stephanie Kleinle  1 , Veronika Boczonadi  1 , Hannah Steele  1 , Venkateswaran Ramesh  1 , Edit Franko  1 , Angela Pyle  1 , Hanns Lochmüller  1 , Patrick F Chinnery  1 , Rita Horvath  2
Affiliations

Genetic heterogeneity of motor neuropathies

Boglarka Bansagi et al. Neurology. .

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.

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Figures

Figure 1
Figure 1. Clinical heterogeneity of different forms of hereditary motor neuropathy (HMN)
Distal hereditary motor neuropathy (dHMN) (top 2 rows), motor Charcot-Marie-Tooth disease 2 (CMT2) (third row), and HMN plus (bottom row): (A) patients 2 and 3: GARS; (B) patient 19: IGHMBP2; (C) patient 23: TRPV4; (D) patient 32: IGHMBP2; (E) not yet diagnosed dHMN; (F) patient 18: DYNC1H1; (G) patient 10: SYT2; (H) patient 16: BICD2; (I, J) not yet diagnosed spinal muscular atrophy lower extremity dominance; (K) patient 42: AARS; (L) patient 39: AARS; (M) family 22: DNM2; (N) patient 51: FUS; (O) patient 53: ATP7A; (P) patient 57: TBX5; (Q) patient 58: STAT5B; (R) not yet diagnosed HMN plus.
Figure 2
Figure 2. Identified genes in our hereditary motor neuropathy (HMN) patient cohort
(A) Spectrum and distribution of mutated genes detected in our cohort within the 3 phenotypic groups. (B) Overlapping clinical phenotypes related to the identified genes and key additional clinical features associated. *Upper motor neuron involvement. ALS = amyotrophic lateral sclerosis.
Figure 3
Figure 3. Diagnostic flow chart and mutation detection rates in our hereditary motor neuropathy (HMN) cohort
CMT = Charcot-Marie-Tooth disease; dHMN = distal hereditary motor neuropathy; WES = whole exome sequencing.
Figure 4
Figure 4. Pathomechanisms of genes reported in hereditary motor neuropathy (HMN)
See this image and copyright information in PMC

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