Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review

Wladimir Bocca Vieira de Rezende Pinto; Paulo Victor Sgobbi de Souza; Bruno Mattos Lombardi Badia; Igor Braga Farias; José Marcos Vieira de Albuquerque Filho; Eduardo Augusto Gonçalves; Roberta Ismael Lacerda Machado; Acary Souza Bulle Oliveira

doi:10.1590/0004-282X-ANP-2020-0429

Arquivos de Neuro-Psiquiatria, Table of Contents

CC BY-NC-ND 4.0 · Arq Neuropsiquiatr 2021; 79(10): 912-923
DOI: 10.1590/0004-282X-ANP-2020-0429

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Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review

Atrofia muscular espinhal não-5q proximal de início no adulto: uma revisão abrangente

Wladimir Bocca Vieira de Rezende Pinto

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

Paulo Victor Sgobbi de Souza

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

Bruno Mattos Lombardi Badia

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

Igor Braga Farias

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

José Marcos Vieira de Albuquerque Filho

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

Eduardo Augusto Gonçalves

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

Roberta Ismael Lacerda Machado

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

,

Acary Souza Bulle Oliveira

¹Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

› Author Affiliations

Abstract

Background: Adult-onset spinal muscular atrophy (SMA) represents an expanding group of inherited neurodegenerative disorders in clinical practice. Objective: This review aims to synthesize the main clinical, genetic, radiological, biochemical, and neurophysiological aspects related to the classical and recently described forms of proximal SMA. Methods: The authors performed a non-systematic critical review summarizing adult-onset proximal SMA presentations. Results: Previously limited to cases of SMN1-related SMA type 4 (adult form), this group has now more than 15 different clinical conditions that have in common the symmetrical and progressive compromise of lower motor neurons starting in adulthood or elderly stage. New clinical and genetic subtypes of adult-onset proximal SMA have been recognized and are currently target of wide neuroradiological, pathological, and genetic studies. Conclusions: This new complex group of rare disorders typically present with lower motor neuron disease in association with other neurological or systemic signs of impairment, which are relatively specific and typical for each genetic subtype.

RESUMO

Antecedentes: Atrofia muscular espinhal (AME) de início no adulto representa um grupo de doenças neurodegenerativas hereditárias em expansão na prática clínica. Objetivo: Este artigo de revisão sintetiza os principais aspectos clínicos, genéticos, radiológicos, bioquímicos e neurofisiológicos relacionados às formas clássicas e recentemente descritas de AME proximal do adulto. Métodos: Os autores realizaram uma revisão crítica não sistemática descrevendo as principais apresentações de AME proximal de início no adulto. Resultados: Previamente restrito às apresentações de AME tipo 4 associada ao gene SMN1, este grupo atualmente envolve mais de 15 diferentes condições clínicas que compartilham entre si a presença de comprometimento progressivo e simétrico do neurônio motor inferior se iniciando no adulto ou no idoso. Novos subtipos clínicos e genéticos de AME proximal de início no adulto foram reconhecidas e são alvos atuais de estudos direcionados a aspectos neurorradiológicos, patológicos e genéticos. Conclusões: Este novo grupo complexo de doenças raras tipicamente se apresenta com doença do neurônio motor inferior em associação com outros sinais de comprometimento neurológico ou sistêmico, os quais apresentam padrões relativamente específicos para cada subtipo genético.

Keywords:

Muscular Atrophy, Spinal - Neurodegenerative Diseases - Motor Neuron Disease - Neuromuscular Diseases

Palavras-chave:

Atrofia Muscular Espinhal - Doenças Neurodegenerativas - Doença dos Neurônios Motores - Doenças Neuromusculares

Full Text

References

References
1 Souza PVS, Pinto WBVR, Chieia MAT, Oliveira ASB. Clinical and genetic basis of familial amyotrophic lateral sclerosis. Arq Neuro-Psiquiatr. 2015 Dec;73(12):1026-37. https://doi.org/10.1590/0004-282X20150161
2 Garg N, Park SB, Vucic S, Yiannikas C, Spies J, Howells J, et al. Differentiating lower motor neuron syndromes. J Neurol Neurosurg Psychiatry. 2017 Jun;88(6):474-83. https://doi.org/10.1136/jnnp-2016-313526
3 Benarroch L, Bonne G, Rivier F, Hamroun D. The 2021 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2020 Dec;30(12):1008-48. https://doi.org/10.1016/j.nmd.2020.11.009
4 Pinto WBVR, Debona R, Nunes PP, Assis ACD, Lopes CG, Bortholin T, et al. Atypical Motor Neuron Disease variants: still a diagnostic challenge in Neurology. Rev Neurol (Paris). 2019 Apr;175(4):221-32. https://doi.org/10.1016/j.neurol.2018.04.016
5 Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015 Feb;51(2):157-67. https://doi.org/10.1002/mus.24497
6 Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015 Nov;33(4):831-46. https://doi.org/10.1016/j.ncl.2015.07.004
7 Turner MR, Barnwell J, Al-Chalabi A, Eisen A. Young-onset amyotrophic lateral sclerosis: historical and other observations. Brain. 2012 Sep;135(Pt 9):2883-91. https://doi.org/10.1093/brain/aws144
8 Farrar MA, Kiernan MC. The genetics of Spinal Muscular Atrophy: progress and challenges. Neurotherapeutics. 2015 Apr;12(2):290-302. https://doi.org/10.1007/s13311-014-0314-x
9 Zerres K, Rudnik-Schöneborn S. 93^rd ENMC international workshop: non-5q spinal muscular atrophies (SMA) – clinical picture (6-8 April 2001, Naarden, The Netherlands). Neuromuscul Disord. 2003 Feb;13(2):179-83. https://doi.org/10.1016/s0960-8966(02)00211-0
10 Wee CD, Kong L, Sumner CJ. The genetics of spinal muscular atrophies. Curr Opin Neurol. 2010 Oct;23(5):450-8. https://doi.org/10.1097/WCO.0b013e32833e1765
11 Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014 Nov;137(11):2879-96. https://doi.org/10.1093/brain/awu169
12 Souza PVS, Bortholin T, Naylor FGM, Chieia MAT, Pinto WBVR, Oliveira ASB. Motor neuron disease in inherited neurometabolic disorders. Rev Neurol (Paris). 2018 Mar;174(3):115-24. https://doi.org/10.1016/j.neurol.2017.06.020
13 Karakaya M, Storbeck M, Strathmann EA, Vedove AD, Hölker I, Altmueller J, et al. Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. Hum Mutat. 2018 Sep;39(9):1284-98. https://doi.org/10.1002/humu.23560
14 Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology. 2011 Jul;77(4):312-4. https://doi.org/10.1212/WNL.0b013e3182267bd8
15 Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968 Jul;18(7):671-80. https://doi.org/10.1212/wnl.18.7.671
16 Grunseich C, Fischbeck KH. Spinal and bulbar muscular atrophy. Neurol Clin. 2015 Nov;33(4):847-54. https://doi.org/10.1016/j.ncl.2015.07.002
17 Manzano R, Sorarú G, Grunseich C, Fratta P, Zuccaro E, Pennuto M, et al. Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease. J Neurol Neurosurg Psychiatry. 2018 Aug;89(8):808-12. https://doi.org/10.1136/jnnp-2017-316961
18 Querin G, Soraru G, Pradat PF. Kennedy disease (X-linked recessive bulbospinal neuronopathy): a comprehensive review from pathophysiology to therapy. Rev Neurol (Paris). 2017 May;173(5):326-37. https://doi.org/10.1016/j.neurol.2017.03.019
19 Breza M, Koutsis G. Kennedy’s disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease. J Neurol. 2019 Mar;266(3):565-73. https://doi.org/10.1007/s00415-018-8968-7
20 Pradat PF, Bernard E, Corcia P, Couratier P, Jublanc C, Querin G, et al. The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations. Orphanet J Rare Dis. 2020 Apr 10;15(1):90. https://doi.org/10.1186/s13023-020-01366-z
21 Dahlqvist JR, Oestergaard ST, Poulsen NS, Thomsen C, Vissing J. Refining the spinobulbar muscular atrophy phenotype by quantitative MRI and clinical assessments. Neurology. 2019 Feb;92(6):e548-e559. https://doi.org/10.1212/WNL.20200429202004296887
22 Klickovic U, Zampedri L, Sinclair CDJ, Wastling SJ, Trimmel K, Howard RS, et al. Skeletal muscle MRI differentiates SBMA and ALS and correlates with disease severity. Neurology. 2019 Aug;93(9):e895-e907. https://doi.org/10.1212/WNL.20200429202004298009
23 Lombardi V, Bombaci A, Zampedri L, Lu CH, Malik B, Zetterberg H, et al. Plasma pNfH levels differentiate SBMA from ALS. J Neurol Neurosurg Psychiatry. 2020 Feb;91(2):215-7. https://doi.org/10.1136/jnnp-2019-320624
24 Hashizume A, Katsuno M, Suzuki K, Banno H, Takeuchi Y, Kawashima M, et al. Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials. J Neurol. 2019 May;266(5):1211-21. https://doi.org/10.1007/s00415-019-09251-x
25 Fernández-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, et al. A randomised, placebo-controlled trial of dutasteride in spinal and bulbar muscular atrophy. Lancet Neurol. 2011 Feb;10(2):140-7. https://doi.org/10.1016/S1474-4422(10)70321-5
26 Grunseich C, Miller R, Swan T, Glass DJ, El Mouelhi M, Fornaro M, et al. Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomized, placebo-controlled trial. Lancet Neurol. 2018 Dec;17(12):1043-52. https://doi.org/10.1016/S1474-4422(18)30320-X
27 Ikezoe K, Yoshimura T, Taniwaki T, Matsuura E, Furuya H, Yamada T, et al. Autosomal dominant familial spinal and bulbar muscular atrophy with gynecomastia. Neurology. 1999 Dec;53(9):2187-9. https://doi.org/10.1212/wnl.53.9.2187
28 Finkel N. A forma pseudomiopàtica tardia da atrofia muscular progressiva heredo-familial. Arq Neuro-Psiquiatr. 1962 Dec;20(4):307-22. https://doi.org/10.1590/S0004-282X1962000400005
29 Richieri-Costa A, Rogatko A, Levisky R, Finkel N, Frota-Pessoa O. Autosomal dominant late adult spinal muscular atrophy, type Finkel. Am J Med Genet. 1981;9(2):119-28. https://doi.org/10.1002/ajmg.1320090206
30 Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822-31. https://doi.org/10.1086/425287
31 Marques VD, Marques W Jr. Neurophysiological findings of the late-onset, dominant, proximal spinal muscular atrophies with dysautonomia because of the VAPB Pro56Ser mutation. J Clin Neurophysiol. 2008 Aug;25(4):233-5. https://doi.org/10.1097/WNP.0b013e31817ed219
32 Kosac V, Freitas MR, Prado FM, Nascimento O, Bittar C. Familial adult spinal muscular atrophy associated with the VAPB gene: report of 42 cases in Brazil. Arq Neuro-Psiquiatr. 2013 Oct;71(10):788-90. https://doi.org/10.1590/0004-282X20130123
33 Jokela M, Penttilä S, Huovinen S, Hackman P, Saukkonen AM, Toivanen J, et al. Late-onset lower motor neuronopathy: a new autosomal dominant disorder. Neurology. 2011 Jul;77(4):334-40. https://doi.org/10.1212/WNL.0b013e3182267b71
34 Penttilä S, Jokela M, Huovinen S, Saukkonen AM, Toivanen J, Lindberg C, et al. Late-onset spinal motor neuronopathy – a common form of dominant SMA. Neuromuscul Disord. 2014 Mar;24(3):259-68. https://doi.org/10.1016/j.nmd.2013.11.010
35 Müller K, Andersen PM, Hübers A, Marroquin N, Volk AE, Danzer KM, et al. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014 Dec;137(Pt 12):e309. https://doi.org/10.1093/brain/awu227
36 Bannwarth S, Ait-El-Mkadern S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014 Aug;137(Pt 8):2329-45. https://doi.org/10.1093/brain/awu138
37 Penttilä S, Jokela M, Bouquin H, Saukkonen AM, Toivanen J, Udd B. Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Ann Neurol. 2015 Jan;77(1):163-72. https://doi.org/10.1002/ana.24319
38 Pasanen P, Myllykangas L, Poyhonen M, Kiuru-Enari S, Tienari PJ, Laaksovirta H, et al. Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val. Acta Neurol Scand. 2016 May;133(5):361-6. https://doi.org/10.1111/ane.12470
39 Penttilä S, Jokela M, Saukkonen AM, Toivanen J, Palmio J, Lähdesmäki J, et al. CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients. J Neurol Neurosurg Psychiatry. 2017 Mar;88(3):272-7. https://doi.org/10.1136/jnnp-2016-314154
40 Brockmann SJ, Freischmidt A, Oeckl P, Müller K, Ponna SK, Helferich AM, et al. CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency. Hum Mol Genet. 2018 Feb;27(4):706-15. https://doi.org/10.1093/hmg/ddx436
41 Isozumi K, DeLong R, Kaplan J, Deng HX, Iqbal Z, Hung WY, et al. Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Hum Mol Genet. 1996 Sep;5(9):1377-82. https://doi.org/10.1093/hmg/5.9.1377
42 Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010 Feb;42(2):165-9. https://doi.org/10.1038/ng.509
43 Takashima H, Nakagawa M, Nakahara K, Suehara M, Matsuzaki T, Higuchi I, et al. A new type of hereditary motor and sensory neuropathy linked to chromosome 3. Ann Neurol. 1997 Jun;41(6):771-80. https://doi.org/10.1002/ana.410410613
44 Maeda K, Sugiura M, Kato H, Sanada M, Kawai H, Yasuda H. Hereditary motor and sensory neuropathy (proximal dominant form, HMSN-P) among Brazilians of Japanese ancestry. Clin Neurol Neurosurg. 2007 Nov;109(9):830-2. https://doi.org/10.1016/j.clineuro.2007.07.015
45 Patroclo CB, Lino AMM, Marchiori PE, Brotto MWI, Hirata MTA. Autosomal dominant HMSN with proximal involvement: new Brazilian cases. Arq Neuro-Psiquiatr. 2009 Sep;67(3B):892-6. https://doi.org/10.1590/S0004-282X2009000500021
46 Campellone JV. Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P). J Clin Neuromuscul Dis. 2013 Jun;14(4):180-3. https://doi.org/10.1097/CND.0b013e318286165a
47 Stephen CD, Balkwill D, James P, Haxton E, Sassower K, Schmahmann JD, et al. Quantitative oculomotor and nonmotor assessments in late-onset GM2 gangliosidosis. Neurology. 2020 Feb;94(7):e705-e717. https://doi.org/10.1212/WNL.20200429202004298959
48 Kang SY, Song SK, Lee JS, Choi JC, Kang JH. Adult Sandhoff disease with 2 mutations in the HEXB gene presenting as brachial amyotrophic diplegia. J Clin Neuromuscul Dis. 2013 Dec;15(2):47-51. https://doi.org/10.1097/CND.20200429202004290014
49 Chardon JW, Bourque PR, Geraghty MT, Boycott KM. Very late-onset Sandhoff disease presenting as Kennedy disease. Muscle Nerve. 2015 Dec;52(6):1135-6. https://doi.org/10.1002/mus.24775
50 Cachon-Gonzalez MB, Zaccariotto E, Cox TM. Genetics and therapies for GM2 gangliosidosis. Curr Gene Ther. 2018;18(2):68-89. https://doi.org/10.2174/1566523218666180404162622
51 Scarpelli M, Tomelleri G, Bertolasi L, Salviati A. Natural history of motor neuron disease in adult onset GM2-gangliosidosis: a case report with 25 years of follow-up. Mol Genet Metab Rep. 2014 Jul;1:269-72. https://doi.org/10.1016/j.ymgmr.2014.06.002
52 Iwahara N, Hisahara S, Hayashi T, Kawamata J, Shimohama S. A novel lamin A/C gene mutation causing spinal muscular atrophy phenotype with cardiac involvement: report of one case. BMC Neurol. 2015 Feb;15:13. https://doi.org/10.1186/s12883-015-0269-5
53 Rudnik-Schöneborn S, Botzenhart E, Eggermann T, Senderek J, Schoser BG, Schröder R, et al. Mutations of the LMNA gene can mimic autosomal dominant proximal spinal muscular atrophy. Neurogenetics. 2007 Apr;8(2):137-42. https://doi.org/10.1007/s10048-006-0070-0
54 Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004 Jun;74(6):1128-35. https://doi.org/10.1086/421054
55 Rudnik-Schöneborn S, Arning L, Epplen JT, Zerres K. SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy. Neuromuscul Disord. 2012 Mar;22(3):258-62. https://doi.org/10.1016/j.nmd.2011.09.006
56 Scoto M, Rossor AM, Harms MB, Cirak S, Calissano M, Robb S, et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology. 2015 Feb;84(7):668-79. https://doi.org/10.1212/WNL.20200429202004291269
57 Niu Q, Wang X, Shi M, Jin Q. A novel DYNC1H1 mutation causing spinal muscular atrophy with lower extremity predominance. Neurol Genet. 2015 Aug;1(2):e20. https://doi.org/10.1212/NXG.20200429202004290017
58 Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, et al. Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain. 2015 Feb;138(Pt 2):293-310. https://doi.org/10.1093/brain/awu356
59 Beecroft SJ, McLean CA, Delatycki MB, Koshy K, Yiu E, Haliloglu G, et al. Expanding the phenotypic spectrum associated with mutations of DYNC1H1. Neuromuscul Disord. 2017 Jul;27(7):607-15. https://doi.org/10.1016/j.nmd.2017.04.011
60 Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis. 2012 Oct 29;7:83. https://doi.org/10.1186/1750-1172-7-83
61 Jaeger B, Bosch AM. Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience. J Inherit Metab Dis. 2016 Jul;39(4):559-64. https://doi.org/10.1007/s10545-016-9924-2
62 Bashford JA, Chowdhury FA, Shaw CE. Remarkable motor recovery after riboflavin therapy in adult-onset Brown-Vialetto-Van Laere syndrome. Pract Neurol. 2017 Jan;17(1):53-6. https://doi.org/10.1136/practneurol-2016-001488
63 Camargos S, Guerreiro R, Bras J, Mageste LS. Late-onset and acute presentation of Brown-Vialetto-Van Laere syndrome in a Brazilian family. Neurol Genet. 2018 Feb;4(1):e215. https://doi.org/10.1212/NXG.20200429202004290215
64 Di Fonzo A, Ronchi D, Gallia F, Cribiù FM, Trezzi I, Vetro A, et al. Lower motor neuron disease with respiratory failure caused by a novel MAPT mutation. Neurology. 2014 Jun;82(22):1990-8. https://doi.org/10.1212/WNL.20200429202004290476
65 Origone P, Geroldi A, Lamp M, Sanguineri F, Caponnetto C, Cabona C, et al. Role of MAPT in pure motor neuron disease: report of a recurrent mutation in Italian patients. Neurodegener Dis. 2018;18(5-6):310-14. https://doi.org/10.1159/000497820
66 Yu FPS, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis. 2018 Jul;13(1):121. https://doi.org/10.1186/s13023-018-0845-z
67 Messina MF, Messina S, Gaeta M, Rodolico C, Damiano AMS, Lombardo F, et al. Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): an atypical phenotype and review of the literature. Eur J Paediatr Neurol. 2012 Jan;16(1):90-4. https://doi.org/10.1016/j.ejpn.2011.10.005
68 Pedurupillay CRJ, Amundsen SS, Baroy T, Rasmussen M, Blomhoff A, Stadheim BF, et al. Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2. Neuromuscul Disord. 2016 Sep;26(9):570-5. https://doi.org/10.1016/j.nmd.2016.06.457