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.
