Charcot-Marie-Tooth Disease, Type 4H

Last update 08 May 2025

Basic Info

Synonyms

CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL RECESSIVE, TYPE 4H, CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, AUTOSOMAL RECESSIVE, TYPE 4H, CHARCOT-MARIE-TOOTH DISEASE, TYPE 4H

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Introduction

Charcot-Marie-Tooth disease, type 4H (CMT4H) is a demyelinating CMT peripheral sensorimotor polyneuropathy. It has been described in 10 individuals from two large consanguineous families from Lebanon and Algeria. Onset occurs within the first two years of life with slowly progressive muscle weakness in the distal extremities. Other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. CMT4H is caused by mutations in the FGD4 gene (12p11.1). Transmitted in an autosomal recessive manner.

Clinical Trials associated with Charcot-Marie-Tooth Disease, Type 4H

NCT05902351

/ RecruitingNot Applicable

Global Registry for Inherited Neuropathies Natural History Study for Charcot Marie Tooth Disease

The goal of this Natural History Study for Charcot-Marie-Tooth is to acquire, record, and analyze patient-reported data and associated genetic reports, Electronic Health Records (EHRs) and clinical notes to identify the burden, diagnostic journey, and prevalence of disease that will aid scientists in their work toward finding a cure.
Participants will be asked to complete a Natural History Survey.

Start Date01 Nov 2013

Sponsor / Collaborator

Hereditary Neuropathy Foundation, Inc.

100 Clinical Results associated with Charcot-Marie-Tooth Disease, Type 4H

100 Translational Medicine associated with Charcot-Marie-Tooth Disease, Type 4H

0 Patents (Medical) associated with Charcot-Marie-Tooth Disease, Type 4H

Literatures (Medical) associated with Charcot-Marie-Tooth Disease, Type 4H

02 Jan 2024·Journal of Neuromuscular Diseases

A Novel Mutation in Frabin (FGD4) Causing a Mild Phenotype of CMT4H in an Indian Patient

Article

Author: Kulanthaivelu, Karthik ; Nashi, Saraswati ; Vengalil, Seena ; Nalini, Atchayaram ; Polavarapu, Kiran ; Nishadham, Vikas ; Chickabasaviah, Yasha T. ; Saini, Jitender ; Santhoshkumar, Rashmi ; Sanka, Sai Bhargava ; Bardhan, Mainak ; Anjanappa, Ram Murthy

Charcot-Marie-Tooth disease 4H(CMT4H) is an autosomal recessive demyelinating form of CMT caused by FGD4/FRABIN mutations. CMT4H is characterized by early onset and slowly progressing motor and sensory deficits in the distal extremities, along with foot deformities. We describe a patient with CMT4H who presented with rapidly progressing flaccid quadriparesis during the postpartum period, which improved significantly with steroid therapy. Magnetic resonance imaging and ultrasonography demonstrated considerable nerve thickening with increased cross-sectional area in the peripheral nerves. A nerve biopsy revealed significant demyelination and myelin outfolding. This is the first report of an Indian patient with a novel homozygous nonsense c.1672C>T (p.Arg558Ter) mutation in the FGD4 gene, expanding the mutational and phenotypic spectrum of this disease.

02 May 2023·Brain

Imbalance of NRG1-ERBB2/3 signalling underlies altered myelination in Charcot–Marie–Tooth disease 4H

Article

Author: Castro, Christel ; Roeckel-Trévisiol, Nathalie ; Quintana, Patrice ; El-Bazzal, Lara ; Gadacha, Jihane ; Borg, Jean-Paul ; Delague, Valérie ; Bernard-Marissal, Nathalie ; Lenfant, Nicolas ; Mégarbané, André ; Bartoli, Marc ; Lembo, Frédérique ; Estève, Clothilde ; Ghata, Adeline ; Roubertoux, Pierre L ; Lévy, Nicolas ; Poitelon, Yannick

AbstractCharcot–Marie–Tooth (CMT) disease is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells of the peripheral nervous system (PNS) and caused by more than 100 genes. We previously identified mutations in FGD4 as responsible for CMT4H, an autosomal recessive demyelinating form of CMT disease. FGD4 encodes FRABIN, a GDP/GTP nucleotide exchange factor, particularly for the small GTPase Cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin figures called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in Schwann cell myelination, we generated a knockout mouse model (Fgd4SC–/–), with conditional ablation of Fgd4 in Schwann cells. We show that the specific deletion of FRABIN in Schwann cells leads to aberrant myelination in vitro, in dorsal root ganglia neuron/Schwann cell co-cultures, as well as in vivo, in distal sciatic nerves from Fgd4SC–/– mice. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ERBB2/3 signalling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two-hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that the loss of FRABIN impairs endocytic trafficking, which may contribute to the defective NRG1 type III/ERBB2/3 signalling and myelination. Using RNA-Seq, in vitro, we identified new potential effectors of the deregulated pathways, such as ERBIN, RAB11FIP2 and MAF, thereby providing cues to understand how FRABIN contributes to proper ERBB2 trafficking or even myelin membrane addition through cholesterol synthesis. Finally, we showed that the re-establishment of proper levels of the NRG1 type III/ERBB2/3 pathway using niacin treatment reduces myelin outfoldings in nerves of CMT4H mice.Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ERBB2/3 NRG1signalling and myelination and opens future therapeutic strategies based on the modulation of the NRG1 type III/ERBB2/3 pathway to reduce CMT4H pathology and more generally other demyelinating types of CMT disease.

01 May 2022·Veterinary Pathology

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4

Article

Author: Neeley, Catherine ; Dittmer, Keren E. ; Reynolds, Edwardo ; Littlejohn, Mathew D. ; Garrick, Dorian J. ; Perrott, Matthew R.

Charcot-Marie-Tooth disease (CMT) is a hereditary sensory and motor peripheral neuropathy that is one of the most common inherited neurological diseases of humans and may be caused by mutations in a number of different genes. The subtype Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutations in the FGD4 (FYVE, RhoGEF, and PH domain-containing 4) gene. A previous genome-wide association study involving 130,783 dairy cows found 6 novel variants, one of which was a homozygous splice site mutation in the FGD4 gene. Descendants of carriers were genotyped to identify 9 homozygous Holstein Friesian calves that were raised to maturity, of which 5 were euthanized and sampled for histopathology and electron microscopy at 2 and 2.5 years of age. Three control Holstein Friesian animals were raised with the calves and euthanized at the same time points. No macroscopic lesions consistent with CMT4H were seen at necropsy. Microscopically, peripheral nerves were hypercellular due to hyperplasia of S100-positive Schwann cells, and there was onion bulb formation, axonal degeneration with demyelination, and increased thickness of the endoneurium. On electron microscopy, decreased axonal density, onion bulb formations, myelin outfoldings, and increased numbers of mitochondria were present. These changes are consistent with those described in mouse models and humans with CMT4H, making these cattle a potential large animal model for CMT.

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Charcot-Marie-Tooth Disease, Type 4H

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