FOSMN syndrome: novel insight into disease pathophysiology.

Abstract

To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome. Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability. Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral-caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches. Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms.