Atypical forms of motor neuron disease: a review of the problem and clinical cases

Atypical forms of motor neuron disease represent a rare and diverse group of neurodegenerative disorders that differ from classical amyotrophic lateral sclerosis in terms of clinical presentation, genetic background, neuroimaging features, progression rate, and distribution of motor involvement. Diagnostic criteria of these variants include onset at a young or middle age, restriction to a specific anatomical region (bulbar or spinal), exclusive involvement of either the upper or lower motor neuron, the degree of motor neuron degeneration, absence of specific neuroimaging phenomena in certain subtypes, frequent association with other neurological symptoms (e.g., dystonia, parkinsonism, cerebellar ataxia, cognitive impairment), and slow progression. Depending on the predominant site of involvement, this pathology can be divided into two major categories: affecting the upper and lower motor neuron. The first group includes primary lateral sclerosis and Mills syndrome. The lower motor neuron group comprises a broader and more heterogeneous spectrum, including progressive bulbar palsy, progressive muscular atrophy, facial onset sensory and motor neuronopathy syndrome, flail arm syndrome, Hirayama disease (monomelic amyotrophy), O’Sullivan-McLeod syndrome, flail leg syndrome, and finger extension weakness and downbeat nystagmus motor neuron disease. A concise clinical characterization of each variant is provided. This article describes original clinical cases of two atypical motor neuron disease variants, i.e. O’Sullivan-McLeod syndrome and flail leg syndrome, analyzed in the context of a comprehensive literature review. Both cases, characterized by lower (peripheral) motor neuron involvement, underscore the heterogeneity of clinical presentation and the complexity of the diagnostic process, illustrating the necessity of a broad, multimodal diagnostic approach and emphasizing the importance of dynamic patient monitoring. In such scenarios, time itself becomes a key diagnostic factor.