ITPR3‐associated neuropathy: Report of a further family with adult onset intermediate Charcot–Marie–Tooth disease.

Background and Purpose: ITPR3 encodes type 3 inositol‐tri‐phosphate receptor (IP3R3), a protein expressed in Schwann cells, predominantly in the paranodal region, and involved in the regulation of Ca2+ release from the endoplasmic reticulum. Dominant variants in ITPR3 have recently been recognized as a rare cause of intermediate Charcot–Marie–Tooth disease (CMT). Methods: We collected the clinical data of a family with autosomal dominant neuropathy whose proband was diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) for many years. The genetic diagnosis was achieved by whole exome sequencing. Results: The proband developed symmetrical sensory–motor neuropathy with demyelinating features at 32 years old. He was diagnosed with CIDP and received numerous immunomodulatory treatments. However, his condition progressed, leading to severe proximal leg and hand atrophy that confined him to a wheelchair at 60 years. The patient's two sons began to exhibit symptoms suggestive of neuropathy shortly after age 30 years, and the condition was reoriented as inherited. Exome sequencing identified a heterozygous c.4271C > T variant in the ITPR3 gene segregating with the disease. Nerve conduction studies showed a combination of demyelinating and axonal features that vary by nerve, disease duration, and patient. A uniform thickening of the nerves was identified on nerve echography, as was distal symmetric fatty infiltration in lower limb muscle imaging. Conclusions: The c.4271C > T ITPR3 variant causes a late onset CMT that can be considered an intermediate CMT. Considering the electrophysiological findings and the distribution of IP3R3, we hypothesize that this variant could start as nodal dysfunction that progresses to widespread nerve degeneration. [ABSTRACT FROM AUTHOR]