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Charcot-Marie-Tooth Neuropathy Type 4H

Synonyms: Charcot-Marie-Tooth Disease Type 4H, CMT4H
, PhD
Inserm/Aix-Marseille Université
UMR S910
Génétique Médicale et Génomique Fonctionnelle
Faculté de Médecine de la Timone
Marseille, France

Initial Posting: .

Summary

Clinical characteristics.

Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is a demyelinating form of CMT that is characterized by early onset (usually before age 3 years; range: birth to age 10 years) and slow progression. The degree of distal muscle weakness and amyotrophy varies between affected individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement. Neuropathic pain has not been reported. To date, findings in18 individuals with molecularly confirmed CMT4H from 13 families have been reported.

Diagnosis/testing.

CMT4H is suspected in individuals with typical findings of CMT (distal amyotrophy, foot deformities), early onset, and slow progression. Motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs) are abnormal. The diagnosis is established by the presence of biallelic FGD4 pathogenic variants.

Management.

Treatment of manifestations: Often management is by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment is symptomatic and may include: ankle/foot orthoses (AFOs); physiotherapy (daily heel cord stretching exercises and physical activity to prevent contractures and help preserve flexibility); surgery to correct severe pes cavus deformity and/or spine deformities; and forearm crutches, canes, and/or wheelchairs for mobility. Musculoskeletal pain may be treated with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs).

Surveillance: Regular (annual) evaluation to determine neurologic status and functional disability.

Agents/circumstances to avoid: Obesity because it makes walking more difficult; medications that are toxic or potentially toxic to persons with CMT.

Genetic counseling.

CMT4H is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Clinical Diagnosis

Formal diagnostic guidelines for Charcot-Marie-Tooth type 4H (CMT4H) do not exist.

Note: Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [Shy et al 2005, Murphy et al 2011], their limited ability to measure disability and severity of the disease in children under age ten years [Haberlová & Seeman 2010, Pagliano et al 2011] makes their use in the diagnosis of early childhood-onset disease like CMT4H problematic.

The diagnosis of Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is suspected in individuals with findings typically observed in CMT (distal amyotrophy, foot deformities) and the following (see also Table 1):

  • Early onset. The imprecise retrospective data available indicate that symptoms typically appear before age three years, with a range presumed to be birth to ten years.
  • Slow progression. Despite early onset, the disease is stable with only very slow progression.
  • Scoliosis; onset before age ten years (observed in some, but not all, affected individuals)
  • Abnormal motor nerve conduction velocities (MNCVs) and sensory nerve conduction velocities (SNCVs). In the lower limbs, MNCVs were non-recordable in 8/9 individuals tested and severely reduced in one; SNCVs were non-recordable in 8/8 individuals tested. In the upper limbs, MNCVs were non-recordable in 3/16 and severely reduced in 13/16; SNCVs were non-recordable in 8/9 and reduced in one (for details see Table 2 [pdf]).
  • Family history consistent with autosomal recessive inheritance. Parental consanguinity is common; parents are not affected unless multigenerational consanguinity exists. Note: Disease severity and disability vary even within the same family (i.e., among individuals with the same pathogenic variants).

The diagnosis of CMT4H is established in individuals with biallelic FGD4 pathogenic variants [De Sandre-Giovannoli et al 2005, Delague et al 2007, Reddy et al 2008] (Table 1).

Table 1.

Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 4H

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
FGD4Sequence analysis 4Sequence variants 513/13 6
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

The test method does not allow detection or large genomic rearrangements within FGD4. However, except for deletions/duplications in CMT1A, large genomic rearrangements are not known as frequent molecular defects in CMT disease.

6.

Individuals with CMT4H or autosomal recessive demyelinating CMT with clinical signs consistent with CMT4H [Delague et al 2007, Stendel et al 2007, Fabrizi et al 2009, Houlden et al 2009, Hayashi et al 2013]. Almost all pathogenic variants described to date were homozygous and in individuals born to consanguineous parents.

Note: When molecular genetic testing is not available, sural nerve biopsy can be considered; however, histologic findings are not specific to CMT4H, and thus not confirmatory.

Histologic findings consistent with the diagnosis of CMT4H. Moderate to severe loss of myelinated fibers, mainly affecting large caliber fibers, probably secondary to a demyelination-remyelination process is observed in all individuals with CMT4H undergoing nerve biopsy reported to date (see Table 2 [pdf]). The remaining fibers usually have features of congenital hypomyelination (e.g., myelin thickening) and other signs of altered myelination (e.g., onion bulbs and myelin outfoldings). Although myelin outfoldings are not specific to CMT4H, they are observed in only a few CMT subtypes (CMT4B1, CMTB2, and CMT4F), and thus could support molecular genetic testing of FGD4.

Clinical Characteristics

Clinical Description

Charcot-Marie-Tooth neuropathy type 4H (CMT4H), an autosomal recessive demyelinating form of CMT, is characterized by early onset and slow progression. The most common findings observed in published reports of 18 affected individuals from 13 families with molecularly confirmed CMT4H are summarized in Table 3 (see Table 2 [pdf] for a comprehensive summary).

The degree of distal muscle weakness and amyotrophy varies between affected individuals as does the presence or absence and severity of foot deformities, scoliosis, and sensory involvement.

Although individuals with CMT do experience neuropathic pain that is usually moderate, preferentially located in the extremities, and symmetric [Ribiere et al 2012], neuropathic pain has not been documented in CMT4H.

Table 3.

Clinical Characteristics of CMT4H in 18 Individuals from 13 Families

Patient 1OriginAge in Yrs at First Symptoms / Last ExamAge in Mos at WalkingDistal MusclesFoot Deformity 4Scoliosis 5Distal Sensory Loss 6Functional ImpairmentReference
Weakness 2Muscle Atrophy 3
Ia 7Lebanon1-2 / 15Delayed, 15-36++++++++++++Moderate to severe: unsteady gait, walking w/out aidDelague et al [2007]
Ib 7Lebanon1-2 / 18Delayed, 15-36+++++++-++Mild: unsteady gait, walking w/out aid
Ic 7Lebanon4 / 1312++++++++++UnknownStendel et al [2007]
IIAlgeria2 / unknownUnknown++++++UnknownModerate: walking w/out aid, waddling gaitDelague et al [2007]
IIITurkey<1 / 30Delayed++++++-+UnknownStendel et al [2007]
IVTurkey2 / unknownDelayed, 26+++---Unknown
VTamil9 / unknown16++---Unknown
VIaNorthern IrelandChildhood 8 / 58Unknown+++-++Moderate: walking w/out aid at 58 yrsHoulden et al [2009]
VIbNorthern IrelandChildhood 9 / 50Unknown++Unknown+-++Severe: at 50, walking w/2 crutches or wheelchair
VIIItaly<1 / 2017+++++Moderate: unsteady gait w/steppageFabrizi et al [2009]
VIIILebanon5 / 2114+++-Moderate: walking w/out aidBaudot et al [2012]
IXAlgeriaUnknownUnknownUnknownUnknownUnknownUnknownUnknownUnknown
XaTunisia3 / 616+++++++-Walking on tiptoesBoubaker et al [2013]
XbTunisia3 / 18Normal+++++++++
XcTunisia3 / 22Normal++++++++++Spine surgery at age 16
XIJapanChildhood / unknownUnknownUnknownUnknown+UnknownUnknownWalked w/out assistance until 65 years; severe gait disturbance from 68 yrsHayashi et al [2013]
XIIJapanBirth / unknown11UnknownUnknown+UnknownUnknownAbnormal gait from 3 yrs
XIIIJapan4 / unknown14UnknownUnknownUnknownUnknownUnknownFrequent falls from age 4 years; walked w/limp from 6 yrs

For further information see Table 2 (pdf).

1.

Roman numerals = family; letters = sibs

2.

- = not affected; + = mild in the lower extremities; ++ = marked in the lower extremities; +++ = also affected the hands and forearms

3.

- = affected; + = mild; ++ = severe

4.

- = no deformities; + = pes cavus and hammer toes; ++ = pes equinus and toes retraction

5.

- = none; + = mild; ++ = severe; +++ = surgery required

6.

- = no deficit; + = decreased sensibility; +++ = no sensibility

7.

Patients Ia, Ib, and Ic are from three different branches of the same Lebanese family. See also Table 5.

8.

Difficulty running and poor balance

9.

Clumsiness

Genotype-Phenotype Correlations

No genotype-phenotype correlations can be established in the 18 affected individuals from 13 families with molecularly confirmed CMT4H; remarkably, individuals homozygous for nonsense or frameshift variants do not have more severe manifestations than individuals with missense variants (summarized in detail in Table 2 [pdf]).

Prevalence

CMT4H is rare and it is difficult to estimate its prevalence. Only 13 families with molecularly confirmed CMT4H have been published to date.

Table 4 summarizes the proportion of individuals with CMT4H in published studies of CMT4. These studies have shown that FGD4 pathogenic variants are most commonly homozygous variants identified in consanguineous families.

Table 4.

Proportion of Individuals with CMT4H in Published Studies

# of Individuals with CMT4H / Total # of Individuals with CMT4# of Individuals with CMT4H / # of Individuals in the Study w/an Identified Pathogenic VariantReferences
3/103 (~3%)3/7 (43%)Hayashi et al [2013]
2/45 (~4.5%) 12/28 (7%)Baets et al [2011]
4/63 (~6.3%)2UnknownStendel et al [2007]
1/12 (~8.3%)UnknownHoulden et al [2009]
5/108 (~4.6%)UnknownDelague et al [2007]; Delague, personal communication
1.

The proportion of CMT4H is probably higher than indicated, as a number of individuals in this series have autosomal dominant inheritance.

2.

All affected individuals had (1) demyelinating sensorimotor neuropathy with onset in the first decade and (2) at least one of the following: (a) parental consanguinity or at least one other affected sib; (b) severely slowed NCVs (<15 m/s for the motor median nerve); (c) prominent scoliosis; and (d) myelin outfoldings on nerve biopsy. No parents of affected individuals had clinical or neurophysiologic findings of CMT.

Differential Diagnosis

See Charcot-Marie-Tooth Neuropathy.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Charcot-Marie-Tooth neuropathy type 4H (CMT4H), the following evaluations are recommended:

  • Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, sensory loss, and skeletal deformities. In children with CMT, one should use the CMTPedS score defined by Burns et al [2012], a reliable, well-tolerated, valid, and sensitive global measure of disability for children with CMT from the age of 3 years [Burns et al 2012].
    Although the CMT Neuropathy Score (CMTNS) and CMTNS version 2 (CMTNS2) are widely used in the diagnosis of CMT [Shy et al 2005, Murphy et al 2011], they have shown limited potential in measuring disability and disease severity in children younger than age ten years [Haberlová & Seeman 2010, Pagliano et al 2011].
    The transition from the CMTPedS in childhood to the CMTNS2 in adulthood has been evaluated [Burns et al 2013]; together, the two measures provide a continuum for lifelong measurement of disability in patients with CMT.
  • Orthopedic consultation to evaluate skeletal deformities such as foot deformities (pes cavus) and scoliosis and to determine the need for a surgery and/or ankle/foot orthoses
  • Clinical genetics consultation and/or pediatric neurology consultation

Treatment of Manifestations

Individuals with CMT4H are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 1995, Grandis & Shy 2005].

Treatment is symptomatic and may include the following:

  • Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [Carter et al 1995]
  • Physiotherapy with daily heel cord stretching exercises to help prevent Achilles' tendon shortening and physical activity adapted to the abilities of each individual to prevent contractures and help preserve flexibility
  • Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000, Ward et al 2008]
  • Surgery to correct spine deformities
  • Forearm crutches or canes for gait stability
  • Wheelchairs as needed because of gait instability
  • Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) [Carter et al 1998]

Surveillance

Appropriate surveillance includes annual evaluation by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability.

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 4H (CMT4H) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CMT4H are obligate heterozygotes (carriers) for a pathogenic variant in FGD4.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CMT4H are possible.

Requests for prenatal testing for conditions which (like CMT4H) do not affect intellect and have some treatment available are rare. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association CMT France
    France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@cmtausa.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    Email: info@hnf-cure.org
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • TREAT-NMD
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 (0)191 241 8617
    Fax: 44 (0)191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Netherlands
    Phone: 31 35 5480481
    Fax: 31 35 5480499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Charcot-Marie-Tooth Neuropathy Type 4H: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 4H (View All in OMIM)

609311CHARCOT-MARIE-TOOTH DISEASE, TYPE 4H; CMT4H
611104FYVE, RhoGEF, AND PH DOMAIN-CONTAINING PROTEIN 4; FGD4

Gene structure. FGD4 comprises 17 exons, of which 14 are coding exons. The gene covers a genomic region of about 14 kb. There are several isoforms, but the major transcript (NM_139241.2) is 2931 bp long (2301 bp of coding sequence). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. 14 FGD4 pathogenic variants have been described in 13 families. FGD4 single-nucleotide variants have been described (occurring throughout the gene), including missense, nonsense, frameshift, splice site, and splicing variants.

See Table 5 for FGD4 allelic variants.

Table 5.

FGD4 Variants Identified in the 13 Reported Families

FamilyOriginConsanguinityDNA Nucleotide Change
(Alias 1)
Location in the GenePredicted Protein ChangeReference
Ia, Ib 2LebanonYesc.893T>G 3Exon 7p.Met298ArgfsTer8 3Delague et al [2007]
Ic 2LebanonYesc.893T>G 3Exon 7p.Met298Arg 3Stendel et al [2007]
IIAlgeriaYesc.893T>CExon 7p.Met298ThrDelague et al [2007]
IIITurkeyYesc.670C>Tp.Arg224TerStendel et al [2007]
IVTurkeyYesc.1628_1629delGA
(1627_1628delGA or
1626_1627delAG)
Exon 13p.Glu543GlyfsTer5
VTamilSporadicc.1756G>TExon 14p.Gly586Ter
VINorthern IrelandYesc.823C>TExon 6p.Arg275TerHoulden et al [2009]
VIIItalyYesc.1762-2A>GIntron 14p.Tyr587fsTer14Fabrizi et al [2009]
VIILebanonYesc.1698G>AExon 14p.Met566IleBaudot et al [2012]
IXAlgeriaYesc.1325G>AExon 10p.Arg442His
XTunisiaYesc.514_515dupG
(514_515insG)
Exon 4p.Ala172GlyfsTer27Boubaker et al [2013]
XIJapanYes/noc.1888_1892delAAAGG
(1890_1894del)
Exon 15p.Lys630AsnfsTer5Hayashi et al [2013]
XIIJapanYes/noc.[837-2A>G + 1132+1G>A]Intron 6/intron 8p.[Trp279fsTer + Tyr355fsTer2]
XIIIJapanNo/unknownc.837-1G>AIntron 6p.Glu280LysfsTer23

For further information see Table 2 (pdf).

Reference sequences: NM_139241​.2 and NP_640334​.2

1.

Variant designation that does not conform to current naming conventions

2.

Two individuals from different branches of the same Lebanese family

3.

Stendel et al [2007] described c.893T>G as a missense variant leading to p.Met298Arg substitution, but Delague et al [2007] simultaneously described the same pathogenic variant in two other branches from the same Lebanese family and demonstrated that it is, in fact, a splicing variant predicted to result in a truncated protein of 305 amino acids instead of the full-length 766 residues (p.298MetfsTer8), or in total absence of the protein.

Normal gene product. FGD4 encodes FRABIN (FGD1-related F-actin binding protein), a 766-amino acid protein (NP_640334.2) (105 kd), with five functional domains: a N-terminal F-actin binding domain, one DH (Dbl homology) domain, two PH (pleckstrin homology) domains, and one cysteine-rich FYVE domain [Delague et al 2007].

DH domains were first identified in the Dbl protein (and are present in many proteins where they play a key role in the catalysis of GDP to GTP exchange); while PH and FYVE domains are mainly involved in interactions with different forms of phosphoinositides.

FRABIN is a Rho GDP/GTP nucleotide exchange factor (RhoGEF), specific for Cdc42, a member of the Rho family of small GTP binding proteins (Rho GTPases) [Obaishi et al 1998, Umikawa et al 1999]. Rho GTPases play a key role in regulating signal transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division [Jaffe & Hall 2005, Etienne-Manneville & Hall 2002].

The role of FRABIN in peripheral nerve is not well known; however, overexpression of Frabin in embryonic rat spinal motoneurons and rat RT4 schwannoma cells showed that Frabin co-localizes with F-actin in neurite tips and growth cones, and induces the formation of filopodia-like microspikes [Delague et al 2007, Stendel et al 2007].

Also, a recent study in a mouse model of CMT4H [Horn et al 2012] has shown that Frabin regulates the RhoGTPase Cdc42 and endocytosis in Schwann cells.

Abnormal gene product. Most FGD4 pathogenic variants described to date are predicted to be loss-of-function variants. In particular, nonsense, frameshift, splice site and splicing variants are predicted to lead to either a truncated protein or to complete absence of FRABIN. No data describing the effect of the pathogenic variants at the protein level in individuals with CMT4H have been published to date.

References

Literature Cited

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Suggested Reading

  • Dubourg O, Azzedine H, Verny C, Durosier G, Birouk N, Gouider R, Salih M, Bouhouche A, Thiam A, Grid D, Mayer M, Ruberg M, Tazir M, Brice A, LeGuern E. Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:75–86. [PubMed: 16775368]
  • Kabzinska D, Hausmanowa-Petrusewicz I, Kochanski A. Charcot-Marie-Tooth disorders with an autosomal recessive mode of inheritance. Clin Neuropathol. 2008;27:1–12. [PubMed: 18257469]

Chapter Notes

Author Notes

Author’s Team

My team leads translational research in the field of Inherited Peripheral Neuropathies (mostly Charcot-Marie-Tooth disease), a group of neuromuscular disorders affecting peripheral nerve. Our aim is to better understand the genetics and physiopathology of this group of diseases. We focus our research on autosomal recessive forms of these diseases, by studying large consanguineous families. By using traditional positional cloning strategies, combined to high-throughput Next Generation Sequencing strategies, we identify new defective genes in Inherited Peripheral Neuropathies. We further study the physiopathology of these diseases, by developing different models, in order to identify potential therapeutic strategies for these diseases. We study in particular two CMT subtypes: CMT4H, caused by pathogenic variants in FGD4/FRABIN and AR-CMT2A, caused by pathogenic variants in LMNA.

In close relationship with the Molecular Genetics Department of The Children’s Hospital “La Timone,” we develop innovative diagnosis strategies.

Revision History

  • 8 August 2013 (me) Review posted live
  • 1 April 2013 (vd) Original submission
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