GDAP1-Related Hereditary Motor and Sensory Neuropathy

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.

1. 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.

2. 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.