Objective: To identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs). Methods: The first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cose-gregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation. Results: dHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family. Conclusions: This study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.
Bibliographical noteFunding Information:
This work was supported by the Association Belge contre les Maladies Neuromusculaire (ABMM)—Aide à la Recherche ASBL and the EU FP7/2007 2013 under grant agreement number 2012—305121 (NEUROMICS), the Medical Research Council (G1002279 to A.H.C.), and the Neurosciences Research Foundation (to A.H.C. and E.L.B.). J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund—Flanders (FWO).
C.G. Salter, D. Beijer, H. Hardy, K.E.S. Barwick, M. Bower, and I. Mademan report no disclosures. P. De Jonghe has served on the editorial board of Acta Neurologica Belgica. T. Deconinck reports no disclosures. M.A. Russell has received research support from the European Foundation for the Study of Diabetes. M.M. McEntagart and B.A. Chioza report no disclosures. R.D. Blakely has received research support from the NIH and SFARI Award (Simons Foundation) and receives license fee/royalty payments from Molecular Devices. J.K. Chilton has received research support from the Northcott Devon Medical Foundation. J. De Bleecker has served on the scientific advisory boards of Sanofi Genzyme and Pfizer and has received travel funding/speaker honoraria from Sanofi Genzyme. J. Baets and E.L. Baple report no disclosures. D. Walk has served on the scientific advisory boards of Pfizer, AstraZeneca, and Acceleron Pharma; has received a consulting fee from Acceleron Pharma; serves on the editorial board of Pain Medicine; has served on speakers’ bureaus of Eli Lilly; and performs clinical consultations and electrodiagnostic studies (50% time) for the University of Minnesota. A.H. Crosby has received research support from the Medical Research Council, Newlife Foundation, Neurosciences Research Foundation, and Spastic Paraplegia Support Group/Diamond Jubilee Fund. Full disclosure form information provided by the authors is available with the full text of this article at Neurology. org/NG.
© 2018 The Author(s).