Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

A novel mutation, outside of the candidate region for diagnosis, in the inverted formin 2 gene can cause focal segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a histological pattern that has several etiologies, including genetics. The autosomal dominant form of FSGS is a heterogenic disease caused by mutations within three known genes: α-actinin 4 (ACTN4), canonical transient receptor potential 6 (TRPC6), and the inverted formin 2 (INF2) gene. More recently, INF2 mutations have also been attributed to Charcot-Marie-Tooth neuropathy associated with FSGS. Here we performed direct sequencing, histological characterization, and functional studies in a cohort of families with autosomal dominant FSGS. We detected a novel mutation in exon 6 of the INF2 gene outside of the exon 2-4 candidate region used for rapid diagnosis of autosomal dominant FSGS. This new mutation is predicted to alter a highly conserved amino-acid residue within the 17th α-helix of the diaphanous inhibitory domain of the protein. A long-term follow-up of this family indicated that all patients were diagnosed in adulthood, as opposed to early childhood, and progression to end-stage renal disease was at different times without clinical or electrodiagnostic evidence of neuropathy. Thus, this novel mutation in INF2 linked to nonsyndromic FSGS indicates the necessity for full gene sequencing if no mutation is found in the current rapid-screen region of the gene.