FIG4 – Charcot-Marie-Tooth disease type 4J

Charcot-Marie-Tooth disease type 4J (CMT4J) is a recessive demyelinating peripheral neuropathy caused by biallelic variants in the phosphoinositide phosphatase FIG4. Affected individuals present with progressive proximal and distal muscle weakness, chronic denervation on electromyography, and variable onset in childhood or adulthood. CMT4J should be considered in patients with rapid progression or asymmetrical demyelinating features.

Genetic evidence for FIG4–CMT4J includes at least 19 unrelated probands with compound heterozygous or homozygous FIG4 variants (c.122T>C (p.Ile41Thr)) across multiple cohorts (Neurology • 2024 PMID:39133880). Variant spectrum comprises missense hypomorphic alleles (p.Ile41Thr), loss-of-function frameshifts/splice changes (e.g., c.831_838del (p.Lys278fs)), and initiator codon alterations, with the I41T allele detected at a carrier frequency of 0.1% in Northern Europeans (Brain • 2011 PMID:21705420). No recurrent founder variants beyond I41T have been reported.

Segregation data demonstrate co-segregation of biallelic FIG4 variants with CMT4J in at least 4 families, supporting autosomal recessive inheritance and high penetrance in compound heterozygotes and homozygotes. Population screening of 4000 CMT patients identified FIG4 mutations in ~0.3%, confirming rarity but reproducibility across unrelated cohorts (Brain • 2011 PMID:21705420).

Functional studies reveal that the p.Ile41Thr variant impairs FIG4–VAC14 interaction, causing protein instability and reduced PI(3,5)P2 synthesis. Fibroblasts from CMT4J patients exhibit enlarged endolysosomal vacuoles, rescued by proteasome inhibition or TRPML1 activation (PLoS Genetics • 2011 PMID:21655088). Mouse models expressing Fig4-Ile41Thr transgenes on a null background recapitulate neuropathy phenotypes and demonstrate dose-dependent rescue, underscoring haploinsufficiency as the pathogenic mechanism (Hum Mol Genet • 2016 PMID:26604144).

No studies have convincingly refuted the FIG4–CMT4J link. Experimental concordance across cellular and animal models, plus consistent genotype–phenotype correlations, reinforce causality.

In summary, robust genetic and functional evidence supports a definitive association between FIG4 and Charcot-Marie-Tooth disease type 4J. FIG4 genetic testing aids diagnosis in demyelinating neuropathies, guiding prognosis and potential therapeutic strategies targeting lysosomal Ca2+ channels.

References

• Brain | 2011 | Distinctive genetic and clinical features of CMT4J: a severe neuropathy caused by mutations in the PI(3,5)P2 phosphatase FIG PMID:21705420
• Neurology | 2024 | Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J PMID:39133880
• PLoS Genetics | 2011 | Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J PMID:21655088
• Human Molecular Genetics | 2016 | Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene PMID:26604144

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