ACTIONABILITY KNOWLEDGE REPOSITORY ACTIONABILITY CURATION INTERFACE

Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Incomplete (Consensus scoring is Incomplete) Curation Status (Adult): Released 1.0.0

GENE/GENE PANEL: PMP22, MPZ, LITAF, EGR2, NEFL
Condition: Charcot - Marie - Tooth Disease, Type 1
Mode(s) of Inheritance: Autosomal Dominant
Actionability Rationale
This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.
Final Consensus Scoresa
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Demyelinating peripheral neuropathy (PMP22) / Regular medical evaluations
1
3C
0C
3
7CC
Demyelinating peripheral neuropathy (PMP22) / Avoidance of Vincristine
1
3C
3C
3
10CC
Demyelinating peripheral neuropathy (MPZ, LITAF, EGTR2, NEFL) / Regular medical evaluations
1
3C
0C
3
7CC
Demyelinating peripheral neuropathy (MPZ, LITAF, EGTR2, NEFL) / Avoidance of Vincristine
1
3C
3C
3
10CC

 
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 Condition
The overall prevalence of hereditary neuropathies is estimated at approximately 30:100,000 population. The prevalence of CMT1 is 15:100,000-20:100,000.
1
Clinical Features
(Signs / symptoms)
The CMT1 subtypes, identified solely by molecular findings, are often clinically indistinguishable. CMT1A (70%-80% of CMT1) is associated with PMP22. CMT1B (6%-10% of CMT1) is associated with MPZ. CMT1C (1%-2% of CMT1) is associated with LITAF, and CMT1D (<2% of CMT1) is associated with EGR2. CMT1E (<5% of CMT1) is associated with PMP22. CMT2E/1F (<5% of CMT1) is associated with NEFL.
 
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 and bilateral foot drop.
 
Musculoskeletal or neuropathic pain is reported in some cases.
 
Small studies have reported sleep apnea in CMT1 patients.
 
Other findings in CMT1 individuals include impotence, hip dysplasia, pulmonary insufficiency, deafness or early hearing loss, and lower-limb muscle atrophy and fatty infiltration.
1 2 3 4
Natural History
(Important subgroups & survival / recovery)
The average age of onset of clinical symptoms among CMT1A patients is five to 25 years.
 
Men and women are equally disabled by CMT1.
 
The disease does not decrease life span.
1 2 3
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
No treatment reverses or slows the natural progression of CMT.
 
At diagnosis the following evaluations are recommended: physical examination, nerve conduction velocity (NCV), family history, and medical genetic consultation. (Tier 4)
1
Daily heel cord stretching exercises to prevent Achilles’ tendon shortening are desirable. (Tier 4)
1
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)
4
Surveillance
Information on the effectiveness of the surveillance recommendation(s) below was not provided.
 
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
Circumstances to Avoid
Obesity should be avoided because it makes walking more difficult. (Tier 4)
1
Vincristine, a chemotherapy agent, should be avoided by all persons with CMT, including those who are asymptomatic. Other medications may pose moderate to significant risk. (Tier 4)
1 3
Avoiding succinylcholine, a muscle relaxant used for anesthesia, is recommended. (Tier 4)
4
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Variants
The prevalence of mutations associated with CMT1 was unavailable.
 
 
Penetrance
(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
 
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information regarding relative risk was unavailable.
 
 
Expressivity
Inter- and intra-familial phenotypic variability is common. Cases of mosaicism have been identified (Tier 3)
1 2 3
4. What is the Nature of the Intervention?
Nature of Intervention
Examinations (physical exam, NCV, family history, genetics consultation) and interventions (heel cord stretching) are non-invasive.
 
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
 
 
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; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1358
2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1B; CMT1B. MIM: 118200: 2012 Nov 26. World Wide Web URL: http://omim.org.
3. 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.
4. 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
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