Elsevier

Revue Neurologique

Volume 175, Issues 1–2, January–February 2019, Pages 81-86
Revue Neurologique

Original article
O'Sullivan–McLeod syndrome: Unmasking a rare atypical motor neuron disease

https://doi.org/10.1016/j.neurol.2018.04.009Get rights and content

Abstract

Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan–McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan–McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3 years was observed, with a mean time delay of 6.6 years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan–McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases.

Introduction

Motor neuron disease (MND) represents a large, increasingly expanding group of neurodegenerative disorders involving compromise of the upper motor neurons (UMNs), lower motor neurons (LMNs), or both. Amyotrophic lateral sclerosis (ALS) represents the most common form of adult-onset MND, whereas spinal muscular atrophy (SMA) is the most common presentation in young, childhood-onset patients. Yet, despite the well-known clinical, neuroimaging, neurogenetic and pathophysiological bases recognized in ALS and SMA, atypical variants have been described, representing rare heterogeneous disorders with a broad range of complex clinical and neuropathological characteristics, including flail-leg and flail-arm syndromes, O'Sullivan–McLeod syndrome, facial-onset sensory and motor neuronopathy (FOSMN) syndrome, and finger extension weakness and downbeat nystagmus (FEWDON) MND [1], [2].

O'Sullivan and McLeod were the first to describe six patients with a history of slowly progressive distal weakness and amyotrophy of the hands and forearms extending over long periods of time (up to 20 years) [3], [4]. These patients also had features suggestive of anterior horn cell compromise during workup evaluations, described by the authors as “chronic distal spinal muscular atrophy” [5]. In fact, clinical, radiological and electrophysiological findings in all those cases were consistent with chronic LMN degeneration restricted bilaterally to cervical myotomes and involving distal muscle groups of the upper limbs with no conduction block, a disorder currently and eponymously known as ‘O'Sullivan–McLeod syndrome’ [3], [4], [5].

This syndrome is characterized clinically by slowly progressive weakness and amyotrophy of the distal parts of the upper limbs, mainly the hands, but sometimes extending into the forearms, in the absence of sensory or pyramidal signs. Most cases are of juvenile or early-adult onset, although late-onset cases starting as late as the fourth decade of life have also been described [3], [5], [6]. The main differential diagnoses include Hirayama disease, distal hereditary motor neuronopathy (or distal spinal muscular atrophy [SMA]) and multifocal motor neuropathy with conduction block [7], [8]. Yet, despite several similarities to Hirayama disease [9], [10] in initial clinical presentation, neurophysiological studies and even neuroimaging studies in some cases, both conditions represent distinct neurodegenerative entities with different pathophysiological mechanisms and distinctive clinical courses and natural histories [11], [12].

Neurophysiological studies of O'Sullivan–McLeod syndrome have revealed chronic denervation with normal nerve conduction studies (NCS) and, rarely, acute denervation findings in distal upper-limb muscle groups [5], [11], [13]. Neuroimaging studies are usually unremarkable, although they can display symmetrical hyperintensity in the anterior horn (the so-called ‘snake-eye sign’) of the cervical spinal cord in T2-weighted sequences [3] and, rarely, focal atrophy of the cervical segment of the spine [14].

Yet, despite this well-defined clinical and neuroimaging profile found in most cases of this rare syndrome as described in the literature from isolated sporadic case reports, few data are available regarding more widely encompassing case series, including typical and atypical clinical, epidemiological, neuroradiological, neurophysiological and neurogenetic findings. Thus, the present report comprises a new case series of seven Brazilian patients with O'Sullivan–McLeod syndrome together with some detailed aspects observed in this group of patients.

Section snippets

Patient selection and evaluation

Seven non-related Brazilian patients with clinical, neurophysiological and neuroradiological findings consistent with a diagnosis of O'Sullivan–McLeod syndrome were identified and assessed from among 885 patients attending the Motor Neuron Disease Unit of the Division of Neuromuscular Diseases, Universidade Federal de São Paulo (UNIFESP), in São Paulo, Brazil, between January 2016 and December 2017. All of their medical records were reviewed, and all of the available subjects were reexamined

Clinical and laboratory findings

A summary of all seven patients’ clinical and laboratory findings is presented in Table 1. Five patients were male, representing a male-to-female ratio of 2.5 to 1 (or 5 to 2). Mean age at onset of symptoms was 34.3 years, with the youngest onset being at age 18 and the oldest at age 55 years. All patients were right-handed and had no previous history of head or spine trauma. The mean time delay from symptom onset to a definitive diagnosis was 6.6 years, ranging from one case of immediate

Discussion

The present case series has revealed important clinical findings in an extremely rare syndrome. Regarding epidemiological aspects, these cases showed a slightly later age of symptom onset compared with other, historical series [4], [6], [15], [21]. Furthermore, one of our patients presented with motor symptoms at age 55, the oldest onset age reported in the literature to our knowledge. As for gender prevalence, our series had a male-to-female ratio of 2.5 to 1, which is slightly higher than the

Conclusion

Our present case series of seven patients with O'Sullivan–McLeod syndrome has demonstrated a slowly progressing distal amyotrophy of the upper limbs, mostly affecting the hands and forearms, that is the result of a sporadic purely lower MND with normal neuroimaging studies. Thus, this series confirms the sporadic nature of the syndrome and the difficulties encountered, in some cases, before a definitive diagnosis can finally be reached. Our findings also extend what was previously considered

Authors’ contributions

PVSS participated in conception and design of study, acquisition and analysis of data, and participated in the writing of the first draft. MAT participated in organization of study and acquisition and analysis of data. FGMN participated in conception and organization of study and review and critique of the manuscript. WBVRP participated in conception and design of study, acquisition and analysis of data, and writing of the first draft. ASBO participated in review and critique of the manuscript.

Competing interest statement

The authors declare that they have nothing to declare regarding interests.

Disclosure of interest

The authors declare that they have no competing interest.

Financial disclosure and funding support

We have nothing to disclose.

No other authors or co-authors contributed to this manuscript. This research received no specific grants from funding agencies in the public, commercial or not-for-profit sectors.

Ethics statement

Our institution's ethics committee approved the project.

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