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.

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).

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 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.

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.

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. See the Charcot-Marie-Tooth Association website (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 in the US and EU Clinical Trials Register in Europe 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.

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 Testing

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

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. While decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.

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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

• 19 September 2019 (ma) Chapter retired: Covered in Charcot-Marie-Tooth Hereditary Neuropathy Overview
• 8 August 2013 (me) Review posted live
• 1 April 2013 (vd) Original submission