Clinical characteristics.

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.

Diagnosis/testing.

Diagnosis of GDAP1-HMSN is based on clinical findings and confirmed by detection on molecular genetic testing of either biallelic pathogenic variants in GDAP1 in those with autosomal recessive inheritance or a heterozygous pathogenic variant in those with autosomal dominant inheritance.

Management.

Treatment of manifestations: Treatment is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. Treatment may include: daily heel cord stretching exercises to prevent Achilles tendon shortening, ankle/foot orthoses, orthopedic surgery, forearm crutches or canes, wheelchairs, treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents, and career and employment counseling.

Surveillance: Regular evaluation by the multidisciplinary team to determine neurologic status and functional disability.

Agents/circumstances to avoid: Drugs and medications known to cause nerve damage; obesity.

Genetic counseling.

GDAP1-HMSN is usually inherited in an autosomal recessive (AR) manner; autosomal dominant (AD) inheritance is also observed.

• AR inheritance: 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 relatives is possible once the pathogenic variants in an affected family member have been identified.
• AD inheritance: Offspring of an individual with AD GDAP1-HMSN have a 50% risk of inheriting the GDAP1 pathogenic variant from their affected parent.

Prenatal testing for pregnancies at increased risk for GDAP1-HMSN and preimplantation genetic testing are possible for families in which the pathogenic variant(s) have been identified.

Suggestive Findings

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) should be suspected in individuals with the following clinical and nerve conduction velocity findings.

Clinical findings

• Early onset of peripheral neuropathy, presenting especially with foot deformities, muscle wasting, and involvement of the sensory nerves resulting in decreased appreciation of touch, pain, and vibration. Proximal weakness usually comes later.
• Disability within the first and second decade of life consisting of foot deformity, difficulty walking and claw hand deformity.
• Vocal cord paresis manifest as a hoarse voice
• Mild-to-moderate scoliosis
• Occasional involvement of cranial nerves sometimes resulting in facial weakness.

Nerve conduction velocities (NCVs)

• Motor NCVs
  • Most commonly are consistent with an axonal neuropathy with normal NCVs and reduced amplitudes [Sevilla et al 2003].
  • Occasionally are consistent with either a demyelinating neuropathy with slowed NCVs (<38 m/s) [Baxter et al 2002, Nelis et al 2002, Ammar et al 2003, De Sandre-Giovannoli et al 2003] or an intermediate range (30-40 m/s) [Senderek et al 2003].
• Sensory NCVs are moderately reduced.

Establishing the Diagnosis

The diagnosis of HMSN is established in a proband with typical clinical findings; the diagnosis of GDAP1-HMSN is established by the detection of either biallelic GDAP1 pathogenic variants (in those with autosomal recessive inheritance) or a heterozygous GDAP1 pathogenic variant pathogenic variant (in those with autosomal dominant inheritance) (see Table 1) on molecular genetic testing.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GDAP1-HMSN is broad, individuals with the distinctive findings described in Suggestive Findings may be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other hereditary motor and sensory neuropathies are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) can be inherited in either an autosomal recessive (AR) manner (more common) or an autosomal dominant (AD) manner. The phenotype of AR GDAP1-HMSN is more severe than that of AD GDAP1-HMSN.

Genotype-Phenotype Correlations

Possible genotype-phenotype correlations have been reported but are not common enough to be confirmed. An exception is the founder variant in eastern Europe, p.Leu239Phe, which appears to be associated with a comparably milder phenotype [Kabzińska et al 2010].

The GDAP1 pathogenic variant, p.Glu222Lys, may be uniquely associated with both AR GDAP1-HMSN and (in rare cases) AD GDAP1-HMSN [Kabzińska et al 2014].

Co-occurrence of pathogenic variants in genes causing two different types of HMSN. The co-occurrence of two HMSN-related pathogenic variants presumably resulted in an additive effect and suggests consideration of simultaneous variants in two HMSN-related genes as an explanation in unusual or severe cases:

• GDAP1 and MFN2. Kostera-Pruszczyk et al [2014] reported a child with severe HMSN who was found to be heterozygous for the GDAP1 pathogenic variant, p.His123Arg, and the MFN2 pathogenic variant, p.Thr236Met. The co-occurrence of pathogenic variants in these two genes was also reported by Cassereau et al [2011] and Vital et al [2012].
• GDAP1 and PRX. Auer-Grumbach et al [2008] reported two novel GDAP1 and PRX variants associated with early-onset HMSN.

Penetrance

Reduced penetrance has been reported in AD GDAP1-HMSN. Several heterozygotes have been reported to be mildly affected or asymptomatic at an advanced age [Zimoń et al 2011].

Nomenclature

Hereditary motor and sensory neuropathy is most commonly referred to by the eponymous name, "Charcot-Marie-Tooth (CMT) neuropathy" or "Charcot-Marie-Tooth disease."

Based on an older classification system in which subtypes were defined by clinical parameters such as mode of inheritance, clinical findings, neuropathy type (defined by electrophysiologic findings), and involved gene, GDAP1-related hereditary motor and sensory neuropathy has been referred to in the past as:

• CMT4A, autosomal recessive, demyelinating HMSN
• CMT2H, autosomal recessive, axonal HMSN
• CMTRIA, autosomal recessive, intermediate HMSN
• CMT2K, autosomal dominant, axonal HMSN

However, classification using these clinically defined parameters becomes difficult when pathogenic variants in a single gene (e.g., GDAP1) are associated with more than one mode of inheritance (e.g., both autosomal dominant and autosomal recessive inheritance), and/or more than one neuropathy type (axonal, demyelinating, and/or intermediate). To disambiguate, the general term GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is used in this GeneReview. For further review of nomenclature, see the Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Prevalence

Currently, autosomal recessive GDAP1-HMSN is considered one of the most common autosomal recessive hereditary neuropathies.

Molecular genetic testing has shown the following proportion of individuals with HMSN (also known as CMT) with GDAP1 pathogenic variants:

• Three of 69 (4.3%) unrelated Czech individuals with autosomal recessive CMT [Baránková et al 2007]
• Eight of 197 (5.4%) individuals in an Italian population with CMT [Manganelli et al 2014]
• Five of 174 (2.8%) families from Europe with autosomal recessive CMT screened for thirteen genes known to be associated with AR-HMSN [Zimoń et al 2015]
• 1% of 1000 individuals with an inherited peripheral neuropathy in Japan [Yoshimura et al 2017]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN), the following evaluations are recommended:

• Neurologic examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• Physical therapy and occupational therapy assessments regarding muscle weakness and gait and need for ankle foot orthoses, walking aids, and/or a wheelchair [Kennedy et al 2016]
• Speech therapy assessment if hoarseness is present or vocal cord paresis is suspected
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Individuals with GDAP1-HMSN are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Corrado et al 2016, McCorquodale et al 2016]. Treatment is symptomatic and may include the following [Mathis et al [2015]:

• Daily heel cord stretching exercises to prevent Achilles tendon shortening.
• Exercise within the affected individual's capability
  Note: (1) Fatigue may improve with exercise; (2) unconfirmed anecdotal observations suggest benefit from the stimulant modafinil [Carter et al 2006, Ramdharry et al 2012].
• Ankle/foot orthoses (AFOs) to correct foot drop and aid walking [Guillebastre et al 2011, Phillips et al 2012]
• Orthopedic surgery to correct severe pes cavus deformity [Boffeli & Tabatt 2015, Faldini et al 2015, Ferraro et al 2017]
• Forearm crutches or canes for gait stability
• Wheelchair for mobility because of gait instability
• Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory drugs [Kroenke et al 2009]
• Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin [Shy 2006, Bril et al 2011, Ribiere et al 2012, Jeong et al 2013]
• Weight control to avoid obesity, which has a negative effect on gait and balance
• Career and employment counseling because of persistent weakness of hands and/or feet
• Individual psychotherapy, group therapy, and/or antidepressant medication for depression [Cordeiro et al 2014]

Treatment may require involvement of specialists to evaluate and manage potential complications, including the following:

• Lower urinary tract involvement [Krhut et al 2014]
• Obstructive sleep apnea and restless legs [Boentert et al 2014]
• Pulmonary compromise and/or phrenic nerve involvement [Aboussouan et al 2007]
• Vocal cord paresis
• Hip dysplasia [Bamford et al 2009, Novais et al 2014]

Note: No special diet (including supplements with essential fatty acids, vitamin E, or creatine) has been shown to be beneficial [Mathis et al 2015].

Surveillance

Regular evaluations to determine:

• Neurologic status and need for treatment (or change in treatment) for musculoskeletal and/or neuropathic pain;
• Functional disability and need for change in physical therapy regime and/or augmentative devices for activities of daily living and mobility;
• Need for change in diet to control weight;
• Need to involve specialists to evaluate and treat potential complications.

Agents/Circumstances to Avoid

The following should be avoided:

• Obesity because of its negative effect on gait and balance
• Medications that are toxic or potentially toxic to persons with HMSN (CMT) ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website for an up-to-date list.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and knowledge about agents/circumstances to avoid.

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

Therapies Under Investigation

Mathis et al [2015] discuss more speculative possible future therapies for HMSN including neurotrophic factors, targeting transport defects, enhancement of autophagy-lysosomal pathways, and neuroregeneration.

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.

Mode of Inheritance

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is inherited in an autosomal recessive manner (AR GDAP1-HMSN) or, less frequently, autosomal dominant manner (AD GDAP1-HMSN).

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with AR GDAP1-HMSN are obligate heterozygotes for a GDAP1 pathogenic variant.
• Heterozygotes are typically asymptomatic (see Clinical Description).

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not heterozygous.
• The phenotype is generally consistent among family members with the same genotype; however, intrafamilial variability has been observed in one family with AR GDAP1-HMSN [Azzedine et al 2003].
• Heterozygotes are typically asymptomatic (see Clinical Description).

Offspring of a proband. The offspring of an individual with AR GDAP1-HMSN are obligate heterozygotes for a GDAP1 pathogenic variant and are typically asymptomatic (see Clinical Description).

Other family members. Each sib of the proband's parents are at a 50% risk of being heterozygous for a GDAP1 pathogenic variant.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with AD GDAP1-HMSN have an affected parent.
• The proportion of cases caused by a de novo pathogenic variant is unknown.
• Molecular genetic testing of the parents for the GDAP1 pathogenic variant identified in the proband is recommended.
• If the GDAP1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (though theoretically possible, no instances of germline mosaicism have been reported).

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

• If a parent of the proband has the GDAP1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial clinical variability and reduced penetrance have been observed [Zimoń et al 2011].
• If the GDAP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with AD GDAP1-HMSN has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the GDAP1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the GDAP1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Author History

Thomas D Bird, MD (2017-present)
Jeffery M Vance, MD, PhD; University of Miami (2004-2017)
Stephan Züchner, MD; University of Miami (2004-2017)

Revision History

• 30 March 2017 (bp) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 3 June 2010 (me) Comprehensive update posted live
• 6 March 2007 (jv) Revision: prenatal testing available
• 23 June 2006 (ca) Comprehensive update posted live
• 11 May 2004 (me) Review posted live
• 23 February 2004 (jv,sz) Original submission