Novel Mutation in the Inverted Formin 2 Gene in a Family with Hereditary Motor and Sensory Neuropathy, and Nephropathy

Case Study: Mutations in the INF2 gene have been identified as a major cause of autosomal-dominant focal segmental glomerulosclerosis (FSGS) and account for up to 20% of familial FSGS. Investigations of the rare association of HMSN with FSGS revealed the prevalence of INF2 gene mutations in up to 75% if these two conditions coexist. Age at manifestation and the progression of INF2-associated nephropathies are widely variable. However, in the presence of HMSN, a severe renal phenotype develops with early-onset during the first two decades and rapid progression toward end-stage renal disease.

Here, we report the case of a 10-year-old boy, who was transferred to our Neuromuscular Center for the investigation of gait abnormalities, bilateral pes cavus, weakness of distal limb muscles, and reduction of vibratory sensation. Nerve conduction velocity (NCV) studies showed an axonal neuropathy with reduced motor NCV (lower limb motor nerves: 28 m/s; median nerve: 43 m/s) and reduced or not detectable amplitudes of muscle action potentials and sensory nerve action potentials, respectively, measured in the lower limbs. Renal function and morphology were normal. The father of our patient was diagnosed for HMSN in his teens and, in addition, underwent renal transplantation because of the rapidly progressive nephropathy at the age of 17 years.

Because of this familial constellation, investigation of the INF2 gene was performed. We discovered a so far unreported sequence variant in the INF2 gene consisting of a duplication of three base pairs in exon 2 leading to an insertion of asparagine between Tyr117 and Ile118. This mutation was found in our patient and his father, but not in his healthy mother and sister.

HMSN with FSGS is primarily caused by INF2 gene mutations. Because of the rapidly progressive FSGS in INF2-associated neuropathies, the detection of INF2 gene mutations in these patients is of prognostic relevance. However, the prevalence of INF2 gene mutations in HMSN without nephropathy has not been investigated so far.

Keywords: inverted formin 2 (INF2) gene, hereditary motor and sensory neuropathy, focal segmental.