Differentiating lower motor neuron syndromes

Nidhi Garg, Susanna B Park, Steve Vucic, Con Yiannikas, Judy Spies, James Howells, William Huynh, José M Matamala, Arun V Krishnan, John D Pollard, David R Cornblath, Mary M Reilly, Matthew C Kiernan, Nidhi Garg, Susanna B Park, Steve Vucic, Con Yiannikas, Judy Spies, James Howells, William Huynh, José M Matamala, Arun V Krishnan, John D Pollard, David R Cornblath, Mary M Reilly, Matthew C Kiernan

Abstract

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Keywords: GENETICS; MOTOR NEURON DISEASE; NEUROIMMUNOLOGY; NEUROPATHY; NEUROPHYSIOLOGY.

Conflict of interest statement

Competing interests: None declared.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Spinobulbar muscular atrophy (Kennedy's disease): (A) facial asymmetry due to asymmetrical facial muscle weakness which is accentuated by pursing the lips; (B) tongue wasting resulting in scalloping of the lateral borders and midline furrowing.
Figure 2
Figure 2
Asymmetric wasting of thenar eminence in a 71-year-old male with an upper limb predominant motor neuropathy associated with anti-GM1 IgM antibody (A). High doses of intravenous immunoglobulin were required to achieve disease stabilisation. The CMAP was unrecordable on the right from APB. The distal APB CMAP on the left was normal, but there was marked dispersion and reduction in CMAP amplitude with stimulation at the elbow (B). A, amplitude; A, area; APB, abductor pollicis brevis; d, duration; CMAP, compound muscle action potential; CV, conduction velocity; NCS, nerve conduction studies.
Figure 3
Figure 3
This 46-year-old man presented with a 20-year history of progressive distal wasting and weakness of the right hand and forearm muscles. Symptoms developed in the left hand 5 years prior to presentation. Upper limb reflexes were depressed. Needle electromyography revealed chronic neurogenic changes in clinically affected muscles. There were no sensory abnormalities. (A and B) Asymmetrical wasting of the hands and forearm affecting C7-T1 musculature with striking preservation of brachioradialis in the right upper limb; (C) sagittal T2-weighted STIR image demonstrating a linear hyperintensity within the cervical cord at C6 and C7 associated with cord atrophy; (D) axial T2-weighted image with ‘snake eyes’ appearance in the anterior horns. STIR, Short TI Inversion Recovery.
Figure 4
Figure 4
Diagnostic algorithm for a patient presenting with a LMN syndrome. ALS, amyotrophic lateral sclerosis; CB, conduction block; dHMN, distal hereditary motor neuropathy; FHx, family history; GBS, Guillain-Barré syndrome; LL, lower limb; LMN, lower motor neuron; MMA, monomelic amyotrophy; MMN, multifocal motor neuropathy; MND, motor neuron disease; NCS, nerve conduction studies; NGS, next-generation sequencing; PMA, progressive muscular atrophy; SBMA, spinobulbar muscular atrophy; SMA, spinal muscular atrophy; UL, upper limb.
Figure 5
Figure 5
Proposed pathogenic mechanisms for LMN syndromes. LMN syndromes may arise from disease processes affecting the anterior horn cell or the motor axon and/or its surrounding myelin. (A) A variety of mechanisms have been implicated in the degenerative and hereditary syndromes including mitochondrial dysfunction, altered RNA processing and impaired axonal transport (see text for further details). (B) Anti-GM1 antibodies may bind to GM1 in the paranodal region leading to disruption of ion channel clusters and paranodal anatomy. Although not a purely LMN syndrome, IgG4 antibodies against NF155 and CNTN1 have recently been described and may similarly disrupt paranodal anatomy resulting in a sensorimotor neuropathy. CNTN1, contactin-1; LMN, lower motor neuron; NF155, neurofascin-155.

References

    1. Prior TW and Russman BS. GeneReviews [internet]: Spinal Muscular Atrophy. (accessed Aug 2016).
    1. Rudnik-Schoneborn S, Hausmanowa-Petrusewicz I, Borkowska J, et al. . The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III. Eur Neurol 2001;45:174–81.
    1. Brahe C, Servidei S, Zappata S, et al. . Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 1995;346:741–2. 10.1016/S0140-6736(95)91507-9
    1. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000;15:228–37. 10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>;2-9
    1. Wirth B, Herz M, Wetter A, et al. . Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am J Hum Genet 1999;64:1340–56. 10.1086/302369
    1. Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain 2014;137(Pt 11):2879–96. 10.1093/brain/awu169
    1. Querin G, Bertolin C, Da Re E, et al. . Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients. J Neurol Neurosurg Psychiatr 2016;87:810–16. 10.1136/jnnp-2015-311305
    1. Mariotti C, Castellotti B, Pareyson D, et al. . Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord 2000;10:391–7. 10.1016/S0960-8966(99)00132-7
    1. Atsuta N, Watanabe H, Ito M, et al. . Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 2006;129(Pt 6):1446–55. 10.1093/brain/awl096
    1. La Spada AR, Wilson EM, Lubahn DB, et al. . Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9. 10.1038/352077a0
    1. Rossor AM, Kalmar B, Greensmith L, et al. . The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatr 2012;83:6–14. 10.1136/jnnp-2011-300952
    1. Irobi J, Dierick I, Jordanova A, et al. . Unraveling the genetics of distal hereditary motor neuronopathies. Neuromolecular Med 2006;8:131–46. 10.1385/NMM:8:1-2:131
    1. Dierick I, Baets J, Irobi J, et al. . Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain 2008;131(Pt 5):1217–27. 10.1093/brain/awn029
    1. Irobi J, Van Impe K, Seeman P, et al. . Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet 2004;36:597–601. 10.1038/ng1328
    1. Sivakumar K, Kyriakides T, Puls I, et al. . Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain 2005;128(Pt 10):2304–14. 10.1093/brain/awh590
    1. Yuki N, Hartung HP. Guillain-Barre syndrome. N Engl J Med 2012;366:2294–304. 10.1056/NEJMra1114525
    1. Vlam L, van der Pol WL, Cats EA, et al. . Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat Rev Neurol 2012;8:48–58. 10.1038/nrneurol.2011.175
    1. Garg N, Heard RNS, Kiers L, et al. . Multifocal motor neuropathy presenting as pseudodystonia. Mov Disord Clin Pract 2016;doi:10.1002/mdc3.12336 10.1002/mdc3.12336
    1. Joint Task Force of the E, the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. J Peripher Nerv Syst 2010;15:295–301.
    1. Van Es HW, Van den Berg LH, Franssen H, et al. . Magnetic resonance imaging of the brachial plexus in patients with multifocal motor neuropathy. Neurology 1997;48:1218–24. 10.1212/WNL.48.5.1218
    1. Gallardo E, Noto Y, Simon NG. Ultrasound in the diagnosis of peripheral neuropathy: structure meets function in the neuromuscular clinic. J Neurol Neurosurg Psychiatr 2015;86:1066–74. 10.1136/jnnp-2014-309599
    1. Vucic S, Black KR, Chong PS, et al. . Multifocal motor neuropathy: decrease in conduction blocks and reinnervation with long-term IVIg. Neurology 2004;63:1264–9. 10.1212/01.WNL.0000140497.85952.FA
    1. Katz JS, Barohn RJ, Kojan S, et al. . Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology 2002;58:615–20. 10.1212/WNL.58.4.615
    1. Vucic S, Black K, Chong PS, et al. . Multifocal motor neuropathy with conduction block: distribution of demyelination and axonal degeneration. Clin Neurophysiol 2007;118:124–30. 10.1016/j.clinph.2006.09.020
    1. Simon NG, Ayer G, Lomen-Hoerth C. Is IVIg therapy warranted in progressive lower motor neuron syndromes without conduction block? Neurology 2013;81:2116–20. 10.1212/01.wnl.0000437301.28441.7e
    1. Donaghy M, Mills KR, Boniface SJ, et al. . Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatr 1994;57:778–83. 10.1136/jnnp.57.7.778
    1. Kiernan MC, Vucic S, Cheah BC, et al. . Amyotrophic lateral sclerosis. Lancet 2011;377:942–55. 10.1016/S0140-6736(10)61156-7
    1. Kim WK, Liu X, Sandner J, et al. . Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology 2009;73:1686–92. 10.1212/WNL.0b013e3181c1dea3
    1. Vucic S, Howells J, Trevillion L, et al. . Assessment of cortical excitability using threshold tracking techniques. Muscle Nerve 2006;33:477–86. 10.1002/mus.20481
    1. Menon P, Geevasinga N, Yiannikas C, et al. . Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol 2015;14:478–84. 10.1016/S1474-4422(15)00014-9
    1. Wijesekera LC, Mathers S, Talman P, et al. . Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology 2009;72:1087–94. 10.1212/01.wnl.0000345041.83406.a2
    1. Vucic S, Kiernan MC. Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatr 2007;78:849–52. 10.1136/jnnp.2006.105056
    1. Menon P, Geevasinga N, Yiannikas C, et al. . Cortical contributions to the flail leg syndrome: pathophysiological insights. Amyotroph Lateral Scler Frontotemporal Degener 2016;17:389–96. 10.3109/21678421.2016.1145232
    1. Yamashita S, Ando Y. Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis. Transl Neurodegener 2015;4:13 10.1186/s40035-015-0036-y
    1. Bali T, Self W, Liu J, et al. . Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatr 2016 Published Online First: 3 Jun 2016. doi: 10.1136/jnnp-2016-313521 10.1136/jnnp-2016-313521
    1. Aksoy H, Dean G, Elian M, et al. . A4T mutation in the SOD1 gene causing familial amyotrophic lateral sclerosis. Neuroepidemiology 2003;22:235–8.
    1. Regal L, Vanopdenbosch L, Tilkin P, et al. . The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. Arch Neurol 2006;63:262–7. 10.1001/archneur.63.2.262
    1. Cervenakova L, Protas II, Hirano A, et al. . Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS). J Neurol Sci 2000;177:124–30. 10.1016/S0022-510X(00)00350-6
    1. Hewitt C, Kirby J, Highley JR, et al. . Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 2010;67:455–61. 10.1001/archneurol.2010.52
    1. Nishimura AL, Mitne-Neto M, Silva HC, 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;75:822–31. 10.1086/425287
    1. Cox LE, Ferraiuolo L, Goodall EF, et al. . Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS ONE 2010;5:e9872 10.1371/journal.pone.0009872
    1. Gourie-Devi M, Nalini A. Long-term follow-up of 44 patients with brachial monomelic amyotrophy. Acta Neurol Scand 2003;107:215–20. 10.1034/j.1600-0404.2003.02142.x
    1. Hirayama K, Tomonaga M, Kitano K, et al. . Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatr 1987;50:285–90. 10.1136/jnnp.50.3.285
    1. Raval M, Kumari R, Dung AA, et al. . MRI findings in Hirayama disease. Indian J Radiol Imaging 2010;20:245–9. 10.4103/0971-3026.73528
    1. Di Muzio A, Delli Pizzi C, Lugaresi A, et al. . Benign monomelic amyotrophy of lower limb: a rare entity with a characteristic muscular CT. J Neurol Sci 1994;126:153–61. 10.1016/0022-510X(94)90266-6
    1. Hamano T, Mutoh T, Hirayama M, et al. . MRI findings of benign monomelic amyotrophy of lower limb. J Neurol Sci 1999;165:184–7. 10.1016/S0022-510X(99)00086-6
    1. O'Sullivan DJ, McLeod JG. Distal chronic spinal muscular atrophy involving the hands. J Neurol Neurosurg Psychiatr 1978;41:653–8. 10.1136/jnnp.41.7.653
    1. Lebouteux MV, Franques J, Guillevin R, et al. . Revisiting the spectrum of lower motor neuron diseases with Snake eyes appearance on magnetic resonance imaging. Eur J Neurol 2014;21:1233–41. 10.1111/ene.12465
    1. Booy R, Tashani M. Edging ever closer to polio eradication. Lancet Glob Health 2016;4:e592–3. 10.1016/S2214-109X(16)30172-3
    1. Howard RS. Poliomyelitis and the postpolio syndrome. BMJ 2005;330:1314–18. 10.1136/bmj.330.7503.1314
    1. Thomson RM, Parry GJ. Neuropathies associated with excessive exposure to lead. Muscle Nerve 2006;33:732–41. 10.1002/mus.20510
    1. Lin C, Park SB, Krishnan AV. Porphyric neuropathy. Handbook of clinical neurology, Vol 115 (3rd series). Peripheral nerve disorders 2013;613–627.
    1. Murphy M, Quinn S, Young J, et al. . Increasing incidence of ALS in Canterbury, New Zealand: a 22-year study. Neurology 2008;71:1889–95. 10.1212/
    1. Talbot K. Monomelic amyotrophy or Hirayama's disease. Pract Neurol 2004;4:362–5. 10.1111/j.1474-7766.2004.00265.x
    1. Drew AP, Blair IP, Nicholson GA. Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies. Curr Mol Med 2011;11:650–65. 10.2174/156652411797536714
    1. Sendtner M. Molecular mechanisms in spinal muscular atrophy: models and perspectives. Curr Opin Neurol 2001;14:629–34. 10.1097/00019052-200110000-00012
    1. Peters OM, Ghasemi M, Brown RH Jr. Emerging mechanisms of molecular pathology in ALS. J Clin Invest 2015;125:1767–79. 10.1172/JCI71601
    1. Turner MR, Swash M. The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey. J Neurol Neurosurg Psychiatr 2015;86:667–73. 10.1136/jnnp-2014-308946
    1. Willison HJ, Yuki N. Peripheral neuropathies and anti-glycolipid antibodies. Brain 2002;125(Pt 12):2591–625. 10.1093/brain/awf272
    1. Mathey EK, Park SB, Hughes RA, et al. . Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatr 2015;86:973–85. 10.1136/jnnp-2014-309697
    1. Uncini A, Kuwabara S. Nodopathies of the peripheral nerve: an emerging concept. J Neurol Neurosurg Psychiatr 2015;86:1186–95. 10.1136/jnnp-2014-310097

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj