Thompson & Thompson Genetics in Medicine, 8th Edition

Case 8. Charcot-Marie-Tooth Disease Type 1a (PMP22 Mutation or Duplication, MIM 118220)

Autosomal Dominant


• Genetic heterogeneity

• Gene dosage

• Recombination between repeated DNA sequences

Major Phenotypic Features

• Age at onset: Childhood to adulthood

• Progressive distal weakness

• Distal muscle wasting

• Hyporeflexia

History and Physical Findings

During the past few years, J.T., an 18-year-old woman, had noticed a progressive decline in her strength, endurance, and ability to run and walk. She also complained of frequent leg cramps exacerbated by cold and recent difficulty stepping over objects and climbing stairs. She did not recollect a precedent illness or give a history suggestive of an inflammatory process, such as myalgia, fever, or night sweats. No other family members had similar problems or a neuromuscular disorder. On examination, J.T. was thin and had atrophy of her lower legs, mild weakness of ankle extension and flexion, absent ankle reflexes, reduced patellar reflexes, footdrop as she walked, and enlarged peroneal nerves. She had difficulty walking on her toes and could not walk on her heels. The findings from her examination were otherwise normal. As part of her evaluation, the neurologist requested several studies, including nerve conduction velocities (NCVs). J.T.'s NCVs were abnormal; her median NCV was 25 m/sec (normal, >43 m/sec). Results of a subsequent nerve biopsy showed segmental demyelination, myelin sheath hypertrophy (redundant wrappings of Schwann cells around nerve fibers), and no evidence of inflammation. The neurologist explained that these results were strongly suggestive of a demyelinating neuropathy such as type 1 Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy type 1. Explaining that the most common cause of type 1 Charcot-Marie-Tooth disease is a duplication of the peripheral myelin protein 22 gene (PMP22), the neurologist requested testing for this duplication. This test confirmed that J.T. had a duplicated PMP22 allele and type 1A Charcot-Marie-Tooth disease.


Disease Etiology and Incidence

The Charcot-Marie-Tooth (CMT) disorders are a genetically heterogeneous group of hereditary neuropathies characterized by chronic motor and sensory polyneuropathy. CMT has been subdivided according to patterns of inheritance, neuropathological changes, and clinical features. By definition, type 1 CMT (CMT1) is an autosomal dominant demyelinating neuropathy; it has a prevalence of approximately 15 in 100,000 and is also genetically heterogeneous. CMT1A, which represents 70% to 80% of CMT1, is caused by increased dosage of PMP22 secondary to duplication of the PMP22 gene on chromosome 17. De novo duplications account for 20% to 33% of CMT1A cases; of these, more than 90% arise during male meiosis.


PMP22 is an integral membrane glycoprotein. Within the peripheral nervous system, PMP22 is found in compact but not in noncompact myelin. The function of PMP22 has not been fully elucidated, but evidence suggests that it plays a key role in myelin compaction.

Dominant negative mutations within PMP22 or increased dosage of PMP22 can each cause this peripheral polyneuropathy. Increased dosage of PMP22 arises by tandem duplication of a 1.5-Mb region in 17p11.2 flanked by repeated DNA sequences that are approximately 98% identical. Misalignment of these flanking repeat elements during meiosis can lead to unequal crossing over and formation of one chromatid with a duplication of the 1.5-Mb region and another with the reciprocal deletion. (The reciprocal deletion causes the disease hereditary neuropathy with pressure palsies [HNPP].) An individual inheriting a chromosome with the duplication will have three copies of a normal PMP22 gene and thus overexpress PMP22 (see Chapter 6).

Overexpression of PMP22 or expression of dominant negative forms of PMP22 results in an inability to form and to maintain compact myelin. Nerve biopsy specimens from severely affected infants show a diffuse paucity of myelin, and nerve biopsy specimens from more mildly affected patients show segmental demyelination and myelin sheath hypertrophy. The mechanism by which PMP22 overexpression causes this pathological process remains unclear.

The muscle weakness and atrophy observed in CMT1 result from muscle denervation secondary to axonal degeneration. Longitudinal studies of patients have shown an age-dependent reduction in the nerve fiber density that correlates with the development of disease symptoms. In addition, evidence in murine models suggests that myelin is necessary for maintenance of the axonal cytoskeleton. The mechanism by which demyelination alters the axonal cytoskeleton and affects axonal degeneration has not been completely elucidated.

Phenotype and Natural History

CMT1A has nearly full penetrance, although the severity, onset, and progression of CMT1 vary markedly within and among families. Many affected individuals do not seek medical attention, either because their symptoms are not noticeable or because their symptoms are accommodated easily. On the other hand, others have severe disease that is manifested in infancy or in childhood.

Symptoms of CMT1A usually develop in the first two decades of life; onset after 30 years of age is rare. Typically symptoms begin with an insidious onset of slowly progressive weakness and atrophy of the distal leg muscles and mild sensory impairment (Fig. C-8). The weakness of the feet and legs leads to abnormalities of gait, a dropped foot, and eventually foot deformities (pes cavus and hammer toes) and loss of balance; it rarely causes patients to lose their ability to walk. Weakness of the intrinsic hand muscles usually occurs late in the disease course and, in severe cases, causes claw hand deformities because of imbalance between flexor and extensor muscle strength. Other associated findings include decreased or absent reflexes, upper extremity ataxia and tremor, scoliosis, and palpably enlarged superficial nerves. On occasion, the phrenic and autonomic nerves are also involved.


FIGURE C-8 Distal leg muscle wasting in an older man with the PMP22 duplication. See Sources & Acknowledgments.

In electrophysiological studies, the hallmark of CMT1A is uniform slowing of NCVs in all nerves and nerve segments as a result of demyelination. The full reduction in NCVs is usually present by 2 to 5 years of age, although clinically apparent symptoms may not be manifested for many years.


Although the diagnosis of CMT1 is suspected because of clinical, electrophysiological, and pathological features, a definitive diagnosis often depends on detection of a mutation. Inflammatory peripheral neuropathies are frequently difficult to distinguish from CMT1 and HNPP and, before the advent of molecular testing many patients with inherited neuropathies were treated with immunosuppressants and experienced the associated morbidity without improvement of their neuropathy.

Treatment focuses on symptomatic management because curative therapies are currently unavailable for CMT1. Paralleling disease progression, therapy generally follows three stages: strengthening and stretching exercises to maintain gait and function, use of orthotics and special adaptive splints, and orthopedic surgery. Further deterioration may require use of ambulatory supports such as canes and walkers or, in rare, severely affected patients, a wheelchair. All patients should be counseled to avoid exposure to neurotoxic medications and chemicals.

Inheritance Risk

Because the PMP22 duplication and most PMP22 point mutations are autosomal dominant and fully penetrant, each child of an affected parent has a 50% chance for development of CMT1A. The variable expressivity of the PMP22 duplication and PMP22 mutations, however, makes prediction of disease severity impossible.

Questions for Small Group Discussion

1. Genomic deletions and duplications frequently arise by recombination between repetitive sequences within the human genome (see Chapter 6). Name three disorders caused by deletion after presumed recombination between repetitive sequences. Which of these deletions are associated with a reciprocal duplication? What does the identification of a reciprocal duplication suggest about the mechanism of recombination? What does the absence of a reciprocal duplication suggest?

2. In general, genomic duplications are associated with less severe disease than genomic deletions. Duplication of a PMP22 allele, however, usually causes more severe disease than deletion of a PMP22 allele does. Discuss possible reasons for this.

3. Name two other diseases that are caused by a gene dosage effect.


Bird TD. Charcot-Marie-Tooth neuropathy type 1. [Available from]

Harel T, Lupski JR. Charcot-Marie-Tooth disease and pathways to molecular based therapies. Clin Genet. 2014;86:422–431.