Atypical MND phenotypes and comparison between two clinical series

ABSTRACT Motor neuron disease (MND) refers to an heterogenous and expanding group of neurodegenerative disorders distinguished by the progressive degeneration of motor neurons, specifically the anterior horn cells (lower motor neurons) and/or the giant pyramidal Betz cells (upper motor neurons) with the most common forms represented by amyotrophic lateral sclerosis (ALS). Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease or Charcot’s disease, is a progressive neurodegenerative disorder that falls under the larger category of motor neuron diseases. The pathognomonic feature is given by the targeting and degeneration of two distinct types of motor neurons: upper motor neurons (“I motor neuron”) located in the cerebral cortex, and the lower motor neurons (“II motor neuron”) found in the brainstem and spinal cord. ALS is clinically characterized by increased muscle tone, muscle fasciculations and gradual weakness caused by progressive and worsening muscle atrophy. This results in difficulties with speech, swallowing and eventually breathing (although these manifestations may sometimes occur not only in late stages but also as initial symptoms). Even in advanced stages, the disease solely affects the motor system while leaving other neurological functions unaffected as sensory, sexual and sphincter functions are generally spared. On the other hand, cognitive impairment has been reported in up to 50% of patients, especially in some genetic forms, demonstrating that non motor system can also be involved. Furthermore, ALS does not impair internal organs (such as the hearth, liver, and kidneys) or the five senses (sight, hearing, smell, taste, touch). Although ALS remains the most common type of adult-onset neurodegenerative motor neuron disease, other common forms, which differently involve either upper or lower motor neurons, include progressive bulbar palsy (PBS), which presents with signs of involvement of motor neurons located in the brainstem, progressive muscular atrophy (PMA), where there is exclusive involvement of lower motor neurons, and primary lateral sclerosis (PLS), which is characterized by pure involvement of upper motor neurons. The phenotype being quite heterogeneous, is one of the reasons why the diagnosis is so difficult. In fact, despite these well-known common MND forms, nowadays a big challenge in clinical practice has been represented by the so-called atypical variants of MND including flail-leg syndrome, flail-arm syndrome, facial-onset sensory and motor neuropathy (FOSMN), finger extension weakness and downbeat nystagmus (FEWDON) and long lasting and juvenile MND-ALS. Indeed, they make difficult the path to reach a proper diagnosis due to their atypical features and frequently require an extensive complementary workup for differential diagnosis with other pathologies of neurodegenerative type. This study aims to analyse the features of atypical phenotypes of motor neurons disorders (MND), of which ALS is the most common, from Veneto and Piemonte regions of Italy, to improve the diagnosis which face the heterogenicity of MNDs phenotypes as main obstacle. In particular, the phenotypes taken in consideration for the study include flail-arm syndrome (FAS), flail-leg syndrome (FLS), facial-onset sensory and motor neuropathy (FOSMN), Hirayama disease (HD) and primary lateral sclerosis (PLS).