JNNP Online First, published on December 21, 2016 as 10.1136/jnnp-2016-313526 Neuromuscular J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-313526 on 21 December 2016. Downloaded from REVIEW Differentiating lower motor neuron syndromes Nidhi Garg,1 Susanna B Park,1 Steve Vucic,2 Con Yiannikas,3 Judy Spies,1 James Howells,1 William Huynh,1,4 José M Matamala,1 Arun V Krishnan,4 John D Pollard,1 David R Cornblath,5 Mary M Reilly,6 Matthew C Kiernan1 ▸ Additional material is ABSTRACT MND from other relatively indolent conditions, published online only. To view Lower motor neuron (LMN) syndromes typically present such as SMA and immune neuropathies. The please visit the journal online (http://dx.doi.org/10.1136/ with muscle wasting and weakness and may arise from pattern of weakness should be documented, includ- jnnp-2016-313526). pathology affecting the distal motor nerve up to the level ing (1) symmetry versus asymmetry, (2) proximal of the anterior horn cell. A variety of hereditary causes versus distal involvement, (3) upper versus lower 1Brain and Mind Centre, Sydney Medical School, are recognised, including spinal muscular atrophy, distal limb predominance and (4) presence versus absence The University of Sydney, hereditary motor neuropathy and LMN variants of of bulbar involvement. Nerve conduction studies Sydney, New South Wales, familial motor neuron disease. Recent genetic advances and electromyography (EMG) are essential to Australia have resulted in the identification of a variety of disease- confirm that the disorder is neurogenic and should 2Departments of Neurology and Neurophysiology, causing mutations. Immune-mediated disorders, focus on assessing (1) the pattern of involvement, Westmead Hospital, including multifocal motor neuropathy and variants of including symmetry and length dependence, (2) The University of Sydney, chronic inflammatory demyelinating polyneuropathy, presence of focal motor conduction block or Sydney, New South Wales, account for a proportion of LMN presentations and are demyelinating features and (3) the presence or Australia important to recognise, as effective treatments are absence of subclinical sensory abnormalities. 3Department of Neurology, Concord and Royal North available. The present review will outline the spectrum of Imaging, genetic testing, antibody markers and Shore Hospitals, The University LMN syndromes that may develop in adulthood and advanced neurophysiological techniques are useful of Sydney, Sydney, New South provide a framework for the clinician assessing a patient adjuncts and form an extension of the clinical Wales, Australia presenting with predominantly LMN features. assessment. The present review will examine LMN 4Prince of Wales Clinical School, The University of syndromes from a clinical perspective as well as New South Wales, Sydney, providing an overview of current understanding of copyright. New South Wales, Australia pathophysiological mechanisms. 5Department of Neurology, INTRODUCTION Johns Hopkins School of Lower motor neuron (LMN) syndromes are clinic- Medicine, Baltimore, Maryland, ally characterised by muscle atrophy, weakness and Late-onset SMA USA fl 6MRC Centre for hypore exia without sensory involvement. They SMA represents a group of genetic disorders result- Neuromuscular Diseases, may arise from disease processes affecting the ing in the degeneration of anterior horn cells in the National Hospital for anterior horn cell or the motor axon and/or its sur- spinal cord and motor nuclei in the brainstem Neurology and Neurosurgery rounding myelin. Neuromuscular junction path- causing progressive, predominantly proximal and UCL Institute of fl Neurology, London, UK ology and muscle disorders may mimic a LMN muscle weakness with reduced or absent re exes. disorder and form part of the differential diagnosis. They are classified into four types on the basis of Correspondence to LMN syndromes can be broadly classified as age of onset and clinical course (SMA I–IV).1 SMA Professor Matthew C Kiernan, hereditary, sporadic or immune-mediated. I and II are defined by onset in infancy. SMA III is http://jnnp.bmj.com/ Brain and Mind Centre, Immune-mediated neuropathies, such as multifocal a milder phenotype with signs of weakness present- The University of Sydney, fl 94 Mallett Street motor neuropathy (MMN) and chronic in amma- ing at or after 1 year of age with patients attaining 1 Camperdown, Sydney, tory demyelinating polyneuropathy (CIDP) are the ability to walk unaided. It is associated with NSW 2050, Australia; important to distinguish from sporadic and heredi- significant variability in the age of onset, disease matthew.kiernan@sydney. tary forms, as treatments are available. LMN pre- progression and ambulatory period with some edu.au sentations of motor neuron disease (MND) are patients only developing walking difficulties in 2 on September 24, 2021 by guest. Protected Received 22 September 2016 most often sporadic, but several genetic mutations adulthood. Adult-onset SMA (SMA IV) typically Accepted 21 November 2016 have been described which can be associated with presents in the third or fourth decade of life with a LMN preponderance. Other hereditary forms of slowly progressive and relatively benign course.3 LMN syndromes include the spinal muscular atro- Respiratory insufficiency may occur in SMA IV, but phies (SMAs) and distal hereditary motor neuropa- is usually mild and life expectancy is normal.1 thies (dHMNs). The increasing availability of The vast majority of SMA is autosomal recessive next-generation sequencing (NGS), including the (AR) in inheritance and related to mutations in the ability for multiple genes to be sequenced in paral- SMN1 gene located on chromosome 5q13. Most lel, has resulted in an increase in the discovery of cases are homozygous for a deletion of exon 7 novel genetic mutations. (94%), but a small percentage are compound het- To cite: Garg N, Park SB, The clinical evaluation of a patient presenting erozygous for a deletion in SMN1 and an intragenic Vucic S, et al. J Neurol with a LMN syndrome includes a thorough assess- mutation of SMN1.4 Targeted molecular genetic Neurosurg Psychiatry fi Published Online First: ment of disease onset and progression. This is par- testing is the rst-line investigation for SMA to [please include Day Month ticularly important to ascertain as a rapid rate of detect homozygous deletions of SMN1 exon 7 Year] doi:10.1136/jnnp- decline may support a diagnosis of MND and gene. However, if only a single deletion is detected, 2016-313526 remains an important factor in distinguishing sequencing the SMN1 gene should be performed to Garg N, et al. J Neurol Neurosurg Psychiatry 2016;0:1–10. doi:10.1136/jnnp-2016-313526 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence. Neuromuscular J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-313526 on 21 December 2016. Downloaded from assess for a point mutation. Overall, 4–5% of patients with clin- Despite significant advances in molecular genetics, a disease- ically typical SMA have no identifiable mutation in SMN1.5 causing mutation is only identified in ∼15% of patients with a Non-5q SMA can be inherited in an autosomal dominant (AD), typical presentation of dHMN.13 Mutations in the HSPB1, AR or X-linked pattern with marked clinical and genetic hetero- HSPB8 and BSCL2 genes are the most frequent causes of AD geneity. NGS technology has facilitated the discovery of a dHMN. Mutations in HSPB1 and HSPB8 are associated with a number of non-5q causative genes associated with SMA.6 classical length-dependent motor neuropathy beginning in the lower limbs which may present in childhood (dHMN type I) or adulthood (dHMN type II).14 Several phenotypes associated Spinobulbar muscular atrophy (Kennedy’s disease) with mutations in BSCL2 have been described and include (1) Spinobulbar muscular atrophy or Kennedy’s disease is the most dHMN type II with a length-dependent motor neuropathy, (2) common adult-onset SMA. It is a polyglutamine genetic dis- dHMN V presenting with a predominantly upper limb distal order caused by a CAG trinucleotide repeat expansion in the phenotype, (3) dHMN with pyramidal signs and (4) Silver syn- androgen receptor gene on the X-chromosome.7 Degeneration drome with atrophy of the intrinsic hand muscles, pyramidal of motor neurons in the spinal cord and brainstem results in a 14 signs and lower limb spasticity. The upper limb-onset pheno- slowly progressive disorder characterised by weakness and type (dHMN V) may also result from mutations in GARS with atrophy of facial, bulbar and limb muscles without upper motor most cases presenting in their second decade with progressive neuron (UMN) signs (figure 1). Cramps, leg weakness, tremor weakness and wasting of the thenar eminence and first dorsal and orolingual fasciculations (see online supplementary video 15 interossei muscles. Cramping and pain in the hands on expos- S1) with bulbar symptoms are the most common presenting 15 ure to cold may be an early manifestation. The GARS mutation symptoms. The syndrome affects only men, although female may also present with a classical length-dependent neuropathy carriers may experience mild symptoms such as cramps.8 beginning in the lower limbs, further highlighting the variabi- Symptom onset is typically between 30 and 50 years of age, but lity in genotype–phenotype correlations. It remains unclear why there is marked variability in age of presentation.9 Weakness is mutations in ubiquitously