# INF2‐Related Charcot–Marie–Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights

## TL;DR

This study identifies INF2 mutations as a rare cause of CMT in Japan, highlighting the importance of genetic testing for children with neuropathy and kidney issues.

## Contribution

The study provides new genetic and clinical insights into INF2-related CMT in a Japanese cohort.

## Key findings

- Six pathogenic INF2 variants were identified in eight patients, all located in the diaphanous inhibitory domain.
- All patients exhibited lower limb weakness, sensory disturbances, and kidney dysfunction, with most progressing to end-stage renal disease.
- Demyelinating neuropathy was common, and some patients received unnecessary immunotherapy due to misdiagnosis.

## Abstract

INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot–Marie–Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2‐related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune‐mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole‐exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records.

We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain‐binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end‐stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune‐mediated neuropathy.

Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early‐onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing.