FGD4 – Charcot-Marie-Tooth disease type 4H

Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating neuropathy caused by biallelic mutations in FGD4, which encodes FRABIN, a Cdc42‐specific RhoGEF essential for Schwann cell myelination (PMID:17564959). Affected individuals present in infancy or early childhood with slowly progressive distal muscle weakness, sensory loss, myelin outfoldings on nerve biopsy, and variable scoliosis and cranial nerve involvement.

FGD4-related CMT4H has been reported in twelve unrelated probands across eight consanguineous and nonconsanguineous families (PMID:17564959, PMID:26400421). Segregation analysis documented eight additional affected relatives with consistent biallelic FGD4 variants (PMID:34148957). Inheritance is autosomal recessive with homozygous or compound heterozygous alleles.

Variant spectrum comprises loss‐of‐function alleles including splice‐site (c.837-1G>A), nonsense (c.1135C>T (p.Arg379Ter)), and frameshift mutations (c.514_515insG (p.Asn172ArgfsTer3)) as well as rare missense substitutions in RhoGEF and PH domains (p.Arg577Gln) (PMID:23550889, PMID:34148957). No recurrent founder variant has been identified, reflecting genetic heterogeneity across Japanese, Mediterranean, Tunisian, Korean, and Spanish cohorts.

Functional assays in rat Schwann cells demonstrated that truncated FRABIN mutants reduce microspike formation, implicating impaired actin remodeling in pathogenesis (PMID:17564959). A Schwann cell–specific Fgd4 knockout mouse model recapitulates focal hypermyelination and myelin outfoldings; mechanistic studies revealed disrupted endocytic trafficking via SNX3 and upregulated NRG1‐type III/ERBB2/3 signalling, which were partially rescued by niacin treatment (PMID:36314052).

No conflicting reports have refuted the association; all studies consistently link FGD4 loss-of-function to CMT4H. The integrated genetic and functional evidence supports a Strong gene–disease association by ClinGen criteria, with Strong genetic evidence and Moderate experimental data.

Key take-home: Biallelic FGD4 variants are a robust diagnostic marker for CMT4H and mechanistic insights into FRABIN function guide therapeutic exploration.

References

• American journal of human genetics • 2007 • Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H. PMID:17564959
• Annals of human genetics • 2015 • Charcot-Marie-Tooth Disease Type 4H Resulting from Compound Heterozygous Mutations in FGD4 from Nonconsanguineous Korean Families. PMID:26400421
• Annals of human genetics • 2013 • A novel mutation in FGD4/FRABIN causes Charcot Marie Tooth disease type 4H in patients from a consanguineous Tunisian family. PMID:23550889
• Internal medicine (Tokyo, Japan) • 2021 • Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening. PMID:34148957
• Brain • 2023 • Imbalance of NRG1-ERBB2/3 signalling underlies altered myelination in Charcot-Marie-Tooth disease 4H. PMID:36314052

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