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

Abstract

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.

Keywords: ITPR3; intermediate CMT; late onset CMT; node of Ranvier; nodo‐paranodopathy.

FIGURE 1

Family pedigree. All cases are numbered as they are referenced in the article and tables. Squares represent men, and circles are women. Filled squares signify affected individuals. The proband is indicated with an arrow. Patients and family members who received a clinical, electrophysiological, and/or imaging evaluation are identified with the symbols c, e, and i, respectively. −/−, not carrying the p.Thr1424Met variant of ITPR3. +/−, heterozygous carrier of the variant.

FIGURE 2

Magnetic resonance imaging of Patients III‐1 at 42 years (a and b) and III‐2 at 35 years (c and d) in axial T1 sequences of legs and feet. Note the symmetric fat infiltration of intrinsic, flexor, and extensor muscles of the feet in both patients. Individual III‐1, with greater clinical and neurophysiological involvement, also showed involvement of the gastrocnemius, and the peroneal musculature to a lesser degree following a length‐dependent pattern.

FIGURE 3

Ultrasonography of peripheral nerves from Patient III‐2, showing uniform enlargement. (a) Ulnar nerve at brachial level. (b) Median nerve at forearm.