Original articleO'Sullivan–McLeod syndrome: Unmasking a rare atypical motor neuron disease
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.
References (23)
Motor neuropathies and lower motor neuron syndromes. Rev Neurol (Paris)
(2017)Benign focal amyotrophy. Rev Neurol (Paris)
(2017)- et al.
Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature
J Neurol Sci
(1980) - et al.
Genetics of Amyotrophic Lateral Sclerosis. Rev Neurol (Paris)
(2017) - et al.
Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update
J Neurol Sci
(2014) - et al.
Differential diagnosis and atypical subsets of amyotrophic lateral sclerosis
Rev Neurol
(2006) - et al.
Differentiating lower motor neuron syndromes
J Neurol Neurosurg Psychiatry
(2017) - et al.
Slowly progressive spinal muscular atrophy of the hands (O'Sullivan-McLeod syndrome): clinical and magnetic resonance imaging presentation
J Neurol
(2000) - et al.
Distal chronic spinal muscular atrophy involving the hands
J Neurol Neurosurg Psychiatry
(1978) Chronic distal spinal amyotrophy localized to the both upper limbs (O'Sullivan and McLeod type). Rev Neurol (Paris)
(1984)
Bilateral distal muscular atrophy of upper limbs (O'Sullivan-McLeod syndrome). Case report
Rev Bras Neurol
Cited by (5)
Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases
2023, CONTINUUM Lifelong Learning in NeurologyMovement Disorders in Childhood, Third Edition
2022, Movement Disorders in Childhood, Third EditionA case report of O′Sullivan‑McLeod syndrome
2021, Chinese Journal of Internal Medicine/Zhonghua Neike ZazhiA Curious Case of Acute Onset Bilateral Hand Weakness in a Youth Hockey Player: A Case Report
2020, American Journal of Physical Medicine and Rehabilitation