TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy

Area of Science:

• Neurology
• Genetics
• Rare Diseases

Background:

• Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder.
• FOSMN shares clinical and pathological features with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD).
• The genetic underpinnings of FOSMN and the utility of genetic testing remain underexplored compared to ALS/FTD.

Purpose of the Study:

• To investigate the genetic profile of a patient diagnosed with FOSMN.
• To explore the role of transactive response DNA-binding protein (TDP-43/TARDBP) in FOSMN pathogenesis.
• To assess the relevance of TARDBP mutations in FOSMN compared to other ALS/FTD-associated genes.

Main Methods:

• Clinical evaluation of a 66-year-old woman presenting with facial pain, dysphagia, and dysarthria.
• Diagnostic workup included neuroimaging (brain and cervical MRI), electrophysiological studies (nerve conduction studies and EMG).
• Next-generation sequencing (NGS) of an ALS/FTD gene panel was performed.

Main Results:

• The patient was diagnosed with FOSMN.
• A novel N390D variant in the TDP-43/TARDBP gene was identified in the patient.
• Literature review indicated that TARDBP mutations are more common in FOSMN than in ALS/FTD, while C9ORF72 and SOD1 mutations are rare or absent in FOSMN.

Conclusions:

• FOSMN exhibits a strong pathological and genetic association with TDP-43.
• Genetic testing panels for ALS/FTD that include TARDBP should be considered for patients diagnosed with FOSMN.
• This finding aids in understanding the genetic landscape of FOSMN and its relationship with TDP-43 proteinopathies.