Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 3.0.0
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: PMP22, MPZ, LITAF, EGR2, NEFL
• Condition: Charcot - Marie - Tooth Disease, Type 1
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• PMP22 ⇔ 0019011 (charcot-marie-tooth disease type 1): Moderate Actionability
• PMP22 ⇔ 0019011 (charcot-marie-tooth disease type 1): Moderate Actionability
• MPZ ⇔ 0019011 (charcot-marie-tooth disease type 1): Moderate Actionability
• LITAF ⇔ 0019011 (charcot-marie-tooth disease type 1): Moderate Actionability
• EGR2 ⇔ 0019011 (charcot-marie-tooth disease type 1): Moderate Actionability
• NEFL ⇔ 0019011 (charcot-marie-tooth disease type 1): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: PMP22 ⇔ 0019011 (OMIM:118220) PMP22 ⇔ 0019011 (OMIM:118300) MPZ ⇔ 0019011 (OMIM:118200) LITAF ⇔ 0019011 (OMIM:601098) EGR2 ⇔ 0019011 (OMIM:607678) NEFL ⇔ 0019011 (OMIM:607734)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Impairments in muscle strength, range of motion, mobility, and balance / Evaluation by specialists to guide exercise and strength training programs	1	3C	1A	3	8CA
Demyelinating peripheral neuropathy / Avoidance of neurotoxic drugs	1	3C	2N	3	9CN

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause of neuropathy. The prevalence of CMT type 1 (CMT1) has been estimated at 10.6 in 100,000. CMT1 prevalence in adult populations ranged from 4.2 to 9.3 in 100,000 and in a pediatric population was 8.0 in 100,000. CMT1A is the most common subtype representing 60% to 70% of CMT1. CMT1 prevalence varies greatly in different populations and countries. Most prevalence studies have been conducted in Europe. [1, 2, 3]

Clinical Features

The CMT1 subtypes (CMT1A – CMT1F), 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, loss of reflexes, and slow nerve conduction velocity. The typical presenting symptom of CMT1 is weakness of the feet and ankles. Weakness and atrophy of the intrinsic muscles of the foot cause such deformities as pes cavus, cavovarus, pes planus, hammer or claw toes, and Achilles tendon retraction. Individuals may also display sensory signs, mainly alterations in vibration and tactile sensitivity. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration but can also include impaired sensation of pain/pinprick, temperature, and joint position. Muscle stretch reflexes may be reduced or absent, particularly in the lower limbs. Childhood symptoms include limb weakness, mobility and balance problems, muscle cramps, and foot deformity. The typical affected adult has bilateral foot drop, symmetric atrophy of muscles below the knee, atrophy of intrinsic hand muscles, and absent or hypoactive tendon reflexes in both upper and lower extremities. The proximal muscles usually remain strong. A rather specific sign of CMT1 is the thickening and beading of the peripheral nerves, which can be felt or even seen through the skin. Patients with CMT frequently report pain, fatigue, and cramps. Less frequently, patients may present cranial neuropathies, tremor, scoliosis, muscle cramps, hip dysplasia, and contractures.
CMT1B can manifest a demyelinating phenotype similar to CMT1A or severe childhood forms manifesting with motor developmental delay and a phenotype of congenital hypomyelinating neuropathy. [2, 4, 5, 6]

Natural History

Individuals with CMT1 usually become symptomatic in the first or second decade of life; age of onset ranges from infancy to the fourth and subsequent decades. Most patients with CMT1A present with the classic phenotype in early childhood. The average age of onset of clinical symptoms is 12.2 +/- 7.3 years. The disease frequently presents a slowly progressive course. The initial manifestations frequently involve the lower limbs, with weakness and progressive muscle atrophy of the distal muscles. This results in difficulty running and toe and heel walking, and frequent falls. Over the years, the disease typically progresses to affect the upper limbs, leading to problems with fine motor skills. As the disease progresses, the distal muscles of the legs and those in the lower third of the thigh may atrophy. Affected individuals experience long plateau periods without obvious deterioration. Life span is not shortened. The vast majority of patients are independent and maintain the ability to walk autonomously for much of their lives. Fewer than 5% of individuals become wheelchair dependent. Up to one-third of patients report new or worsening of neuropathic symptoms (including reduced strength and sensitivity, cramps, and pain) during pregnancy, although these improve after delivery in half of patients. [2, 4, 5, 6, 7]

2. How effective are interventions for preventing harm?

Patient Management

No disease-modifying treatment is currently available for CMT, although proper management of symptoms is essential. This may include pharmacological treatments, rehabilitation, and orthopedic treatment. A multidisciplinary approach, adapted to each patient’s characteristics, is essential. (Tier 2) [2]

Nerve conduction studies are recommended in all patients with clinical suspicion of CMT, and provide relevant data for the diagnosis, classification, and prognosis. It is important to conduct a detailed neurophysiological study that includes both sensory and motor nerves in the upper and lower limbs, examining both proximal and distal nerve segments. (Tier 2) [2]

In children with CMT, the use of progressive resistance exercise of the ankle dorsiflexors to improve muscle strength and slow progression of muscle weakness is recommended. A randomized controlled trial (RCT) of targeted progressive resistance exercise enrolled children aged 6 to 17 years with CMT. Participants were randomized to the exercise group (n=30; 80% with CMT1) or sham group (n=30; 87% with CMT1). Children in the exercise group received 6 months of progressive resistance training to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength (expressed as a Z score). No measurable effect of exercise was observed at 6 months or 12 months. At 24 months, the mean Z score for dorsiflexion strength increased from -2.5 to -2.3 in the exercise group and decreased from -2.1 to -2.6 in the sham group (p=0.04). There was no evidence of overwork weakness or harmful effects of resistance training on muscle morphology assessed by MRI. Secondary functional outcome measures (disability, gait, and ankle stability) did not produce a measurable effect between exercise and sham groups. (Tier 1) [8]

The degree of muscle weakness must be assessed with the Medical Research Council (MRC) scale and/or dynamometry. A tailored strength training program should be encouraged, under the supervision of the child’s treating physician and/or allied health clinician. The clinician should provide guidance to ensure that the exercise program is carried out safely, monitor progress and modify the program as appropriate. Strength training of proximal/core muscles (trunk, hip, and shoulder girdle) should be encouraged. Exercise should cease temporarily, and the exercise regimen should be modified, if there are any signs of exercise-induced muscle damage. (Tier 2) [2, 8, 9]

Rehabilitation therapy should be initiated early to identify and improve functional deficits. Rehabilitation therapy should be delivered by a multidisciplinary team including a physiatrist, a physiotherapist, an occupational therapist, and an orthotic/prosthetic technician. An orthopedic surgeon should be included from the early stages. Stretching of joints prone to contracture should form part of rehabilitation management. Serial casting or serial night casting should be used to improve ankle dorsiflexion range of motion in children who have restricted joint range of motion. (Tier 2) [2, 8, 9]

Activities such as balance retraining or core and postural strengthening tailored to the individual should be used to improve balance. Child-appropriate or adolescent-appropriate recreational activities (e.g., dance) may be used to improve balance. (Tier 2) [2, 8]

Several systematic reviews of exercise interventions or rehabilitation therapy in CMT have been published.
•A systematic review of RCTs investigating the effectiveness of exercise in individuals with CMT identified six studies (pooled n=214). The mean age of participants was 38.5 (+13) years, and 83% were diagnosed with CMT1A. Moderate-quality evidence (one trial of 60 children) suggested that strengthening the ankle dorsiflexors minimizes the progression of weakness at 24 months in children with CMT1A (p=0.041) but does not improve function. For outcomes related to hips and knees, quality of the evidence ranged from very low to low.
•A systematic review of exercise interventions for individuals with CMT identified 9 studies of 134 individuals with CMT (60 of whom had CMT1A) with an average age of 38 years (3 RCTs, 5 quasi-experimental, 1 case report). Although most studies identified changes in one or more outcome measurements across exercise modalities, the majority were non-significant. Significant effects included improvements in strength (mainly knee flexion and extension, 4 studies), functional activities (6-minute walk in 3 studies), and physiological adaptations following exercise. Compliance (i.e., number of completed sessions throughout the intervention) was high (>80%, 5 studies).
•A systematic review of physiotherapy treatment for CMT identified 5 studies (4 RCTs ranging from 32 to 62 patients and 1 cohort of 20 patients). All evidence pointed to the effectiveness of physiotherapy in CMT, as it is associated with an increase of strength or endurance and improvement in timing of execution of activities of daily living. Three of these studies reported on strength in the knee.
•A systematic review of interventions for increasing ankle range of motion in patients with neuromuscular diseases identified 2 studies that assessed the effect of night splinting in 26 children and adults with CMT1A. There were no statistically or clinically significant differences between wearing a night splint and not wearing a night splint. (Tier 1) [10, 11, 12, 13]

Anticonvulsants such as gabapentin and pregabalin may be used for the treatment of positive sensory symptoms. The underlying cause of musculoskeletal pain should be assessed and managed as appropriate. Physical therapy such as stretching and strengthening should be used for musculoskeletal pain. Non-pharmaceutical approaches should be used in conjunction with prescribed medications in chronic pain and, if available, within a specialized multidisciplinary health care team. (Tier 2) [2, 8]

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 but can be difficult if upper limbs are affected. (Tier 4) [3]

Close neurological, gynecological, and obstetric follow-up is recommended for individuals with CMT who are pregnant. (Tier 2) [2]

Surveillance

Follow-up of patients with CMT should be performed at least annually, by a multidisciplinary team specifically formed to meet the needs of each individual patient. Follow-up should include a neurological examination, with assessment of muscle strength. (Tier 2) [2, 9]

A hip X-ray should be considered in all children to screen for hip dysplasia. There was no agreement as to how frequently radiologic surveillance should be performed. (Tier 2) [8]

Baseline pulmonary function testing should be undertaken in children with severe forms of CMT including those with symptoms of sleep-disordered breathing, recurrent lower respiratory tract infections, scoliosis, and those who are non-ambulant when they are able to complete this reliably (usually from the age of 5-6 years). Children at high risk for having respiratory deficits should be referred to a respiratory physician/sleep physician for ongoing management. (Tier 2) [2, 8]

Sleep disorders such as sleep apnea and restless leg syndrome should be evaluated by targeted history-taking, and a polysomnography study may be performed when necessary. (Tier 2) [2]

Symptoms such as pain, fatigue, and cramps should be assessed periodically. (Tier 2) [2]

Circumstances to Avoid

Obesity should be avoided because it makes walking more difficult. (Tier 4) [4, 14]

Caution should be exercised, and patients should be informed about potentially neurotoxic drugs that may worsen their symptoms. A review concluded that use of vincristine (30 included papers), and possibly paclitaxel (6 included papers), can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in individuals with CMT. (Tier 2) [2]

Avoiding succinylcholine, a muscle relaxant used for anesthesia, is recommended. (Tier 4) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [4]

Prevalence of Genetic Variants

Information on the prevalence of pathogenic variants associated with CMT1 was not identified in unselected populations.

The proportion caused by a de novo pathogenic variant varies depending on the involved gene. In a study of 1,206 probands, de novo variants were identified in 1.3% of individuals with a PMP22 duplication (CMT1A) and 25% of those with a variant in MPZ (CMT1B). (Tier 3) [4]

CMT1A caused by a duplication of PMP22 is the most common subtype representing 60% to 70% of CMT1. (Tier 3) [1]

In a study using data from a national CMT registry, of the 740 diagnosed with CMT, 364 (49.2%) had duplications in PMP22 (CMT1A), 40 (5.4%) had variants in MPZ (CMT1B), 7 (0.9%) had pathogenic variants in PMP22 (CMT1E), and one individual had a pathogenic variant in NEFL (CMT1F). The rate of genetic diagnosis was 96% in CMT1. (Tier 5) [15]

Penetrance

Penetrance of CMT1 is almost 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) [14]

Slow nerve conduction velocity (NCV) is 100% penetrant independent of age. (Tier 3) [7]

A study of 81 children with CMT1A (mean age 8.5 years, range 2-16 years) reported that 34.5% had pes cavus and 26% had pes planus. When the cohort was divided into three 5-year age groups, the prevalence of pes cavus clearly increased from early childhood (11%) to adolescence (63%), but there remained a group of children with normal and even planus feet in the older age groups. Compared to age-equivalent norms, foot strength declined from the age of 4 years. The following was also reported:
•Foot pain: 27%
•Foot/leg cramps: 36%
•Ankle instability during walking: 72%
•Frequent tripping: 63%
•Frequent falls: 47%
•Generalized joint hypermobility: 39.5%
•Difficulty heel-walking: 84%
•Difficulty toe-walking: 4% (significantly associated with increasing age)
•Foot drop: 4% (Tier 5) [16]

In a patient-reported lifestyle study that included 937 adults with self-reported CMT1A the mean age of participants was 45 years (range 18 to 83 years). Almost 60% of participants reported at least moderate problems with mobility. Anxiety was reported by 39% and depression was reported by 38%. Over 40% reported using insoles and/or ankle or leg braces. (Tier 5) [17]

An international consortium study of individuals with inherited neuropathies (median age of 40 years with a range from 1 to 93) analyzed the prevalence of ankle and foot deformities in 845 individuals with CMT1A. The following was reported:
•Pes cavus: 63%
•Hammer toes: 29%
•Pes planus (7%)
•Any foot surgery: 30% (Tier 5) [18]

In a CMT registry study that included 740 individuals with CMT the mean age was 48.2 ± 16 years (range 1–91, 24 patients were <18 years). The clinical features amongst those with CMT1A (n=332) and CMT1B (n=39) were reported as:
•Delayed milestones (walked after 15 months): CMT1A (10%), CMT1B (24.3%)
•Difficulty walking: CMT1A (71.4%), CMT1B (62.2%)
•Difficulties with buttons (proxy for upper limb involvement): CMT1A (52.7%), CMT1B (45.9%)
•Burning/tingling in feet/hands: CMT1A (30.4%), CMT1B (40.5%)
•Decreased ability to feel: CMT1A (46.4%), CMT1B (51.4%)
•Arthritic-like pain: CMT1A (15.9%), CMT1B (10.8%)
•Foot deformities: CMT1A (92.2%), CMT1B (81.1%)
•Scoliosis: CMT1A (20.8%), CMT1B (10.8%).
•Hip dysplasia: CMT1A (2.4%), CMT1B (2.7%) (Tier 5) [15]

Relative Risk

Information regarding relative risk was not identified.

Expressivity

Variation in clinical presentation is wide, ranging from patients with severe distal atrophy and marked hand and foot deformity to individuals whose only finding is pes cavus and minimal muscle weakness. (Tier 3) [6]

Most patients with CMT1A present with the classic phenotype. The phenotype associated with CMT1E is variable, ranging from severe early-onset forms to milder late-onset forms. (Tier 3) [2]

Clinical variability may be observed both between and within families, even within the same genotype. There is significant intra- and interfamilial variability in the rate of disease progression. (Tier 4) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

Potential interventions include examinations (physical exam, nerve conduction studies), physical therapy/exercise/strength training/stretching, X-ray to screen for hip dysplasia and avoidance of certain medications. Nerve conduction studies are generally well tolerated and pose little risk to patients of serious adverse events. Mild procedural pain and discomfort are very common (≥1 in 10 persons). The discomfort, or mild pain experienced by some patients, following the application of electrical stimulation during nerve conduction studies is transient and self-limiting and will not initiate or aggravate pre-existing symptoms beyond the duration of the actual investigation. [19]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Mild disease may go unrecognized by the affected individual and physician. CMT1 identification may be challenging when there is no family history. (Tier 4) [5, 14]

The partial overlap of clinical and electrodiagnostic features of CMT with other peripheral neuropathies may lead to misdiagnosis. (Tier 3) [1]

CMT has clinical overlap with several hereditary neuropathies, systemic hereditary diseases presenting predominantly with peripheral neuropathy, and distal myopathies. (Tier 4) [2]

In a patient-reported lifestyle study that included 937 individuals with self-reported CMT1A, the time difference between symptom onset and diagnosis was a mean of 11.3 years (median of 6 years). (Tier 5) [17]

Date of Search: 05.28.2014 (updated 03.19.2024)

Reference List

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19. Gechev A, Kane NM, Koltzenburg M, Rao DG, van der Star R. Potential risks of iatrogenic complications of nerve conduction studies (NCS) and electromyography (EMG). Clin Neurophysiol Pract. (2016) 1(2467-981X):62-66.