Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: PMP22, MPZ, LITAF, EGR2, NEFL
Condition: Charcot - Marie - Tooth Disease, Type 1
GENEDISEASE PAIRS: PMP22118220 PMP22118300 MPZ118200 LITAF601098 EGR2607678 NEFL607734
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. Estimates of the prevalence of CMT range from 9.7/100,000 in Serbia to 82.3/100,000 in Norway. The prevalence of CMT type 1 (CMT1) has been estimated from 15:100,000-20:100,000. The prevalence of CMT1A (the most common subtype) is approximately 10:100,000.
1 2 3
Clinical Features
(Signs / symptoms)
The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable.
 
The classic phenotype of CMT1 is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. It is usually slowly progressive and often associated with pes cavus foot deformity (high instep) and bilateral foot drop. Clinical severity is variable, ranging from extremely mild disease that goes unrecognized by patient or physician, to considerable weakness and disability, with fewer than 5% of individuals becoming wheelchair dependent. The typical presenting symptom of CMT1 is weakness of the feet and ankles. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance), atrophy of intrinsic hand muscles, and absent tendon reflexes in both upper and lower extremities. The proximal muscles usually remain strong. Variable scoliosis may develop during adolescence.
 
Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet, but many affected individuals are unaware of this symptom. Pain, especially in the feet, is reported by 20%-30% of individuals. The pain is often musculoskeletal in origin but may be neuropathic in some cases.
 
Other observed findings in CMT1 individuals include: vestibular impairment, sleep apnea, restless leg syndrome, episodic pressure palsies, impotence, hip dysplasia, pulmonary insufficiency, deafness or early hearing loss, and lower-limb muscle atrophy and fatty infiltration.
1 4 5 2
Natural History
(Important subgroups & survival / recovery)
Individuals with CMT1 usually become symptomatic between ages of five and 25; age of onset ranges from infancy (resulting in delayed walking) to the fourth and subsequent decades. Affected individuals experience long plateau periods without obvious deterioration. The disease does not decrease life span.
 
Women have been reported to have earlier onset of symptoms (8.6 versus 14 years) and higher deterioration of quality of life compared to affected men.
1 4 5 2
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with CMT1, the following evaluations are recommended: physical examination, nerve conduction velocity (NCV), family history, and medical genetic consultation (Tier 4)
1
No treatment reverses or slows the natural progression of CMT. Treatment of CMT1 is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, physiatrist, orthopedic surgeons, and physical and occupational therapists. These treatments may include: ankle/foot orthoses; orthopedic surgery; forearm crutches/canes/wheelchairs; exercise as tolerated; serial night casting to help increase ankle flexibility; treatment of musculoskeletal pain with acetaminophen or NSAIDS; treatment of neuropathic pain with tricycle antidepressants or drugs such as carbamazepine or gabapentin; and career and employment counseling. Daily heel cord stretching exercises to prevent Achilles’ tendon shortening are desirable. (Tier 4)
1 2
A systematic review of exercise interventions for individuals with CMT identified 9 studies of 134 individuals with CMT (3 randomized trials, 5 quasi-experimental, 1 case report). This review found that although benefits appear to be gained from exercise in strength and function in some studies, most outcomes reported were not statistically significant. The authors concluded that the optimal exercise modality and intensity for people with CMT, the clinical relevance of the changes observed, and the safety of exercise in these patients is still unclear. A review of four RCTs (149 patients with neuromuscular disease) found no benefit of any studied intervention (night splits, prednisone, orthopedic surgery) for sustainably increasing ankle range of motion. (Tier 1)
6 7
Preoperative assessment for co-morbidities and autonomic denervation is recommended. During surgical positioning, transport and mobilization, cautious positioning and protection of pressure points is recommended to avoid nerve compression. Neuromuscular block monitoring during surgery is also recommended. (Tier 4)
5
Surveillance
Individuals should be evaluated regularly by a team comprising physiatrists, neurologists, and physical and occupational therapists to determine neurologic status and functional disability. (Tier 4)
1
Individuals should undergo regular foot examination for pressure sores. (Tier 4)
1
Family Management
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being affected. (Tier 4)
1
Circumstances to Avoid
Obesity should be avoided because it makes walking more difficult. (Tier 4)
1 8
Over 30 medications have been identified as toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Vincristine and paclitaxel (chemotherapeutic agents) pose a definite high risk of nerve damage and should be avoided by all patients with CMT, including those who are asymptomatic. (Tier 4)
1
Avoiding succinylcholine, a muscle relaxant used for anesthesia, is recommended. (Tier 4)
5
A review of case reports addressing CMT and toxic medication effects identified 22 reports (30 patients) addressing vincristine toxicity. 18 of 30 patients developed marked sensory symptoms or new onset weakness, with some developing dysarthria and dysphagia. Nearly all reports describe eventual improvement, but frequently not to baseline levels. These cases occurred in both adults (15) and children (15). Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30) and were only recognized following administration of vincristine; however, 10 cases, in retrospect, had overt clinical signs or a close relative with known CMT. A review of the CMT North American Database (including 209 individuals) identified 19 medications associated with clinical worsening. The majority of cases reviewed did not have information on genotype of CMT subtype; however, of those cases with identified subtypes the vast majority were CMT1A. (Tier 5)
9
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
Information on the prevalence of pathogenic variants associated with CMT1 was not identified. However, the prevalence of CMT type 1 (CMT1) has been estimated from 15:100,000-20:100,000. The estimated proportion of CMT1 cases related to each subtype include: CMT1A (70%-80%; PMP22), CMT1B (6%-10%; MPZ), CMT1C (1%-2%; LITAF), CMT1D (<2%; EGR2), CMT1E (<5%; PMP22), and CMT2E/1F (<5%; NEFL). (Tier 3)
1
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Penetrance of CMT1 is usually nearly 100%, but the wide range in age onset and severity may
 
result in under-recognition of individuals with mild or late-onset disease. (Tier 4)
1 2 8
A study of 109 persons (mean age 22 years; range 1-60 years) from completely ascertained sibships from 15 unrelated families, concluded that penetrance (as indicated by physical examination and nerve conduction) was 28% complete in the first decade and essentially complete by the middle of the third decade. However, this study was conducted prior to the introduction of genetic testing and was based on an assumption that 50% of sibships should be affected. Overall 48% of individuals were found to be affected (44% affected with probands excluded). The average age of onset was 12.2 years with a standard deviation of 7.3. The mean age at time of diagnosis was 18.3 years (range 3 to 54 years). (Tier 3)
4
Information regarding relative risk was not identified.
 
 
Expressivity
Inter- and intra-familial phenotypic variability is common. (Tier 3)
4
4. What is the Nature of the Intervention?
Nature of Intervention
Potential interventions include examinations (physical exam, electrophysiological, ophthalmologic, family history, genetics consultation), physical therapy/stretching, and avoidance of certain medications.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Mild disease may go unrecognized by the affected individual and physician. (Tier 4)
1
 
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Demyelinating peripheral neuropathy / Regular medical evaluations
1
3C
IN
Not Scored
IN
Demyelinating peripheral neuropathy / Avoidance of Vincristine, paclitaxel, succinylcholine
1
3C
3C
2
9CC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. TD Bird. Charcot-marie-tooth hereditary neuropathy overview. 1998 Sep 28 [Updated 2016 Sep 01]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1358
2. Charcot-Marie-Tooth disease type 1. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=65753
3. Barreto LC, Oliveira FS, Nunes PS, de Franca Costa IM, Garcez CA, Goes GM, Neves EL, de Souza Siqueira Quintans J, de Souza Araujo AA. Epidemiologic study of charcot-marie-tooth disease: a systematic review. Neuroepidemiology. (2016) 46(3):157-65.
4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Charcot-marie-tooth disease, demyelinating, type 1a; cmt1a. MIM: 118220: 2016 Jun 23. World Wide Web URL: http://omim.org.
5. Anaesthesia recommendations for patients suffering from charcot-marie-tooth disease. (2014) Website: http://www.orphananesthesia.eu/de/erkrankungen/zu-erledigen/doc_view/139-charcot-marie-tooth-disease.html
6. Sman AD, Hackett D, Fiatarone Singh M, Fornusek C, Menezes MP, Burns J. Systematic review of exercise for charcot-marie-tooth disease. J Peripher Nerv Syst. (2015) 20(4):347-62.
7. Rose KJ, Burns J, Wheeler DM, North KN. Interventions for increasing ankle range of motion in patients with neuromuscular disease. Cochrane Database Syst Rev. (2010)
8. Aretz S, Rautenstrauss B, Timmerman V. Clinical utility gene card for: hmsn/hnpp hmsn types 1, 2, 3, 6 (cmt1,2,4, dsn, chn, gan, ccfdn, hna); hnpp. Eur J Hum Genet. (2010) 18(9).
9. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in charcot marie tooth disease. J Neurol Sci. (2006) 242(1-2):47-54.
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