CMT1A; CMT1E; DSS; GAS-3; GAS3; HMSNIA; HNPP; Sp110
Pathogenic variants in the PMP22 gene are associated with autosomal dominant Charcot-Marie-Tooth disease type 1A (CMT1A) (MedGen UID: 75727) and 1E (CMT1E) (MedGen UID: 348419) as well as autosomal dominant hereditary neuropathy with liability to pressure palsies (HNPP) (MedGen UID: 98291).
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An estimated 70%-80% of CMT1 is caused by full PMP22 gene duplications, and approximately an additional 1% is caused by PMP22 sequence changes. PMP22 is the only gene known to be associated with HNPP. Among patients with a positive personal and family history of HNPP, >80% have the common deletion encompassing the PMP22 gene and a minority of patients have other types of pathogenic variants in PMP22.
The PMP22 gene encodes an integral membrane protein called peripheral myelin protein 22. The PMP22 protein is a major component of myelin and is produced in the Schwann cells of the peripheral nervous system.
The PMP22 gene is associated with autosomal dominant Charcot-Marie-Tooth disease type 1A (CMT1A; MedGen UID: 75727), Charcot-Marie-Tooth disease type 1E (CMT1E; MedGen UID: 348419), and hereditary neuropathy with liability to pressure palsies (HNPP; MedGen UID: 98291). Other PMP22-related disorders have also been reported (OMIM: 601097).
CMT1A is a progressive, symmetrical peripheral motor and sensory neuropathy that results in loss of sensation and atrophy of the muscles in the feet, legs, and hands due to demyelination (PMID: 15765265). It is the most common form of CMT (PMID: 16775366). Symptoms typically become apparent between 5 to 25 years of age but can range in age of onset from infancy to 40 years and older. Symptoms usually include balance difficulties, weakness of the muscles in the feet, and structural changes to the feet, such as pes cavus, pes planus, and hammer toes (PMID: 16775366, 24646194). These structural changes and diminished sensory input lead to gait abnormalities such as foot drop, push-off deficit, and an increased risk of ankle injuries and falls (PMID: 21944474). Median motor conduction velocity in affected individuals is typically <38 m/s (PMID: 1301995). Muscle weakness is progressive, moving from the feet to the lower legs, and to the hands. When muscle weakness occurs in the hands, it can affect activities of daily living, such as writing, fastening buttons, and use of doorknobs (PMID: 19774309, 19774309). Musculoskeletal or neuropathic pain in the feet is reported in 20-30% of individuals affected with CMT1A (PMID: 20334975, 20334975). Vestibular abnormalities have been reported in individuals with CMT1A and may also contribute to difficulty with balance (PMID: 23658384). Symptoms of CMT1A vary from person to person and can range from mild to severe in presentation. Fewer than 5% of individuals affected by CMT1A require a wheelchair, and lifespan is not affected (PMID: 15765265).
Patients with CMT1E can have a more severe clinical phenotype than those with CMT1A (PMID: 11118262). CMT1E has been associated with hearing loss, loss of vestibular function, cranial nerve involvement, and liability to pressure palsies (PMID: 16772060, 15992829, 21692910, 15205993).
HNPP is a condition that affects peripheral nerves, making them sensitive to compression (PMID: 8780105). Triggers can include carrying heavy bags, sitting in the same position, or leaning on an elbow (PMID: 9391880, 12453844). These triggers lead to recurrent episodes of acute neuropathy consisting of numbness, tingling, and/or loss of motor function in the location of the affected nerve (PMID: 14755484). Neuropathy episodes can last from several minutes to months, with full recovery achieved approximately 50% of the time. Incomplete recovery is generally not correlated with long-term symptom severity (PMID: 16024889). The most common sites of compression neuropathy include the median nerve in the wrist (causing carpal tunnel syndrome), the peroneal nerve in the knee (causing foot drop), the ulnar nerve at the elbow (causing numbness and weakness of the hand), and the brachial plexus and radial nerves (also causing loss of sensation and tingling in the hand; PMID: 12827539, 12453844). Atypical presentations and symptoms have also been reported, including polyneuropathies, recurrent short-term positional symptoms, generalized cramping and weakness, and proximal muscle involvement (PMID: 10227632, 12439896, 24726093, 19078663, 16906084). Symptoms of HNPP are variable and generally begin in adolescence or young adulthood but have been reported to occur in people as young as 2 years and as old as 70 years of age (PMID: 12499508, 24668782).
The PMP22 gene encodes an integral membrane protein called peripheral myelin protein 22 (PMP22), which is produced in Schwann cells of the peripheral nervous system (PMID: 1556154). The PMP22 protein is a major component of myelin and is involved in the maintenance and stabilization of myelin (PMID: 14755484). PMP22 is also involved in the regulation of growth and differentiation of Schwann cells (PMID: 10697408).
Duplication of the PMP22 gene results in CMT1A, and it is thought that a gene dosage effect plays a role in the demyelinating neuropathy (PMID: 1822787, 1303229, 1303228). The 1.4 Mb recurrent duplication of PMP22 is the result of nonallelic homologous recombination (PMID 24530202).
CMT1E is caused by point mutations or small deletions in the transmembrane domain of PMP22. Changes in this region of the gene alter portions of the PMP22 protein in close proximity to the extracellular component of the protein and are thought to result in toxic gain of function (PMID: 10330345, 16772060, 12578939). The most frequently reported mutation in PMP22 associated with CMT1E with hearing loss is p.Ala67Pro (PMID: 10330345).
HNPP is caused by heterozygous loss-of-function mutations (e.g., frameshifts, deletions, nonsense mutations) in PMP22, and most commonly, by a deletion of the entire gene (PMID: 8422677, 8012388, 16437560, 23224996). Patients with the PMP22 frameshift variant p.Arg95GlyfsTer128 may also exhibit a motor/sensory neuropathy similar to CMT1A (PMID: 9712007).
CMT1A is inherited in an autosomal dominant fashion. This means that an individual with a CMT1A-causing PMP22 gene duplication has a 50% chance of passing on the duplication to their offspring. Genetic testing for PMP22 variants, including gene duplication testing, is available to identify at-risk relatives. Approximately two-thirds of individuals with CMT1A have inherited a PMP22 gene duplication from an affected parent, while the remaining one-third have the condition due to a de novo event (PMID: 15765265, 11835375). Triplications of PMP22 have also been observed and result in more severe symptoms (PMID: 24530202).
CMT1E and HNPP are also inherited as autosomal dominant conditions, resulting in a 50% inheritance risk for the offspring of an affected individual. Genetic testing is available to identify at-risk relatives (PMID: 4285163, 880924, 8355122). Approximately 80% of individuals with HNPP have inherited a pathogenic variant from an affected parent, while 20% have the disorder due to a de novo variant (PMID: 11494267).
Recommended management for individuals with CMT1A and CMT1E includes care by a multidisciplinary team consisting of a neurologist, geneticist/genetic counselor, physical therapist, orthopedic surgeon, and an occupational therapist (PMID: 1560704).
Treatment is symptom-based and includes the following recommendations:
Recent advances in the management of CMT1A include the following:
Management for individuals with HNPP includes the following recommendations:
Review date: March 2018
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Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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