Facial onset sensory and motor neuronopathy (FOSMN) is a rare neurological disorder that combines features of both sensory neuropathy and motor neuron disease. Its clinical resemblance to trigeminal neuralgia and amyotrophic lateral sclerosis (ALS) often leads to delayed or incorrect diagnosis. Recent evidence suggests that FOSMN may represent a sensory-onset variant within the ALS spectrum, characterised by the addition of cranial and limb sensory involvement. The present report highlights this diagnostic challenge and emphasises that FOSMN can occur with prominent sensory symptoms and cranial nerve dysfunction even in the absence of significant bulbar features. Recognising this pattern broadens the classical understanding of motor neuron diseases, which are traditionally viewed as purely motor disorders. Awareness of such presentations and the use of targeted neurophysiological tests, particularly blink reflex studies, are essential for accurate diagnosis and better characterisation of this rare and evolving disease spectrum.

Facial onset sensory and motor neuronopathy (FOSMN) syndrome is a rare neurodegenerative disorder initially characterized by facial sensory deficits, which later progress to motor deficits in a rostral-caudal distribution. This study investigated the prevalence, clinical features, and prognosis of FOSMN syndrome and compared these aspects with those of bulbar-onset amyotrophic lateral sclerosis (ALS) within a single institutional cohort of motor neuron diseases. We identified four patients with FOSMN syndrome who had been misclassified as having bulbar-onset ALS, representing approximately 2 % of such ALS cases. The median age of onset for FOSMN syndrome was similar to that of bulbar-onset ALS. However, patients with FOSMN syndrome were often diagnosed at more advanced stages and had lower ALS Functional Rating Scale-revised (ALSFRS-R) scores. Despite the slower progression of FOSMN syndrome, therapeutic interventions such as gastrostomy or non-invasive ventilation were frequently required. In conclusion, this study provides detailed clinical profiles of patients with FOSMN syndrome and deepens our understanding of a heterogeneous group of neurodegenerative disorders.

Motor neuron disease (MND) represents a broad and heterogeneous group of disorders involving the upper or lower motor neurons, represented mainly by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Rare atypical variants of MND-ALS include flail arm syndrome (FA), flail leg syndrome (FL), facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) and long-standing and juvenile MND-ALS. In this article, we present a review of diagnostic criteria and the differential diagnosis for MND, focusing on ALS.

In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS. OM samples were collected from patients with (a) sporadic motor neuron diseases (MND), including spinal ALS (n = 35), bulbar ALS (n = 18), primary lateral sclerosis (n = 10), and facial onset sensory and motor neuronopathy (n = 2); (b) genetic MND, including carriers of C9orf72exp (n = 6), TARDBP (n = 4), SQSTM1 (n = 3), C9orf72exp + SQSTM1 (n = 1), OPTN (n = 1), GLE1 (n = 1), FUS (n = 1) and SOD1 (n = 4) mutations; (c) other neurodegenerative disorders (OND), including Alzheimer's disease (n = 3), dementia with Lewy bodies (n = 8) and multiple system atrophy (n = 6); and (d) control subjects (n = 22). All samples were subjected to SAA analysis for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light chain (NfL) were also assessed in a selected number of patients. TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND patients and 3/22 controls. Surprisingly, one presymptomatic individual also tested positive. As expected, OM of genetic non-TDP-43-related MND tested negative. Interestingly, fluorescence values from non-MND samples that tested positive were consistently and significantly lower than those obtained with sporadic and genetic MND. Furthermore, among TDP-43-positive samples, the lag phase observed in MND patients was significantly longer than that in non-MND patients. Plasma TDP-43 levels were significantly higher in sporadic MND patients compared to controls and decreased as the disease progressed. Similarly, plasma NfL levels were higher in both sporadic and genetic MND patients and positively correlated with disease progression rate (ΔFS). No significant correlations were detected between TDP-43_SAA findings and the biological, clinical, or neuropsychological parameters considered. The OM of a subset of patients with sporadic MND can trigger seeding activity for TDP-43, as previously observed in genetic MND. Thus, TDP-43_SAA analysis of OM can improve the clinical characterization of ALS across different phenotypes and enhance our understanding of these diseases. Finally, plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.