Stage I: Rule-Out Dashboard Secondary Findings in Adults

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1 Stage I: Rule-Out Dashboard GENE/GENE PANEL: DNM2 DISORDER: DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy HGNC ID: 2974 OMIM ID: ACTIONABILITY PENETRANCE 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? Yes No Patient Management Surveillance or Screening 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? UNKWN SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? Family Management Circumstances to Avoid ( 1 of above) NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? 3. Is the result actionable in an undiagnosed adult with the genetic condition? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 Signif/Burden of Condition GENE/GENE PANEL: DNM2 DISORDER: DNM2-Related Intermediate Charcot-Marie- Tooth Neuropathy 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 Clinical Features (Signs/symptoms) 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. DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI- CMTB) is a rare cause of CMT. Up to 3.4% of CMT (in which CMT1A, 1B, and 1X have already been excluded) is caused by a DNM2 pathogenic variant. CMT hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy resulting from involvement of peripheral nerves and affecting the motor system and/or the sensory system. DI-CMTB is considered a dominant intermediate form of CMT neuropathy given its autosomal dominant inheritance and intermediate findings between a demyelinating and axonal neuropathy using electrophysiologic criteria using nerve conduction velocities. DI-CMTB has a classic, mild to moderately severe Charcot-Marie-Tooth hereditary neuropathy phenotype that often includes pes cavus foot deformity (high instep), depressed tendon reflexes, distal muscle weakness and atrophy, and sensory loss. Some individuals require braces or other walking aids and 3% of individuals with DI-CMTB become wheelchair bound. Other findings include asymptomatic neutropenia and early-onset cataracts (often noted in childhood before age 15 years). (1-3) (1, 2) Natural History (Important subgroups & survival/recovery) It is usually not possible to differentiate between DI-CMTB, other intermediate forms of CMT, and most CMT2 types based on clinical findings, unless cataract and/or neutropenia (occasional findings in DI-CMTB) are present. Individuals with CMT experience symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade. Age of onset varies greatly among affected individuals and ranges from age two to 50 years. (1, 2) 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. To establish the extent of disease and needs in an individual diagnosed with DI-CMTB, the following evaluations are recommended: neurological examination; electrophysiological studies to establish a baseline; complete blood count with absolute neutrophil count (to evaluate for neutropenia); ophthalmologic examination for cataract; and consultation with a medical geneticist and/or genetic counselor. (Tier 4) Patient Management No treatment reverses or slows the natural progression of DI-CMTB. Treatment of DI-CMTB is symptomatic and involves evaluation and management by a multidisciplinary team that includes neurologists, orthopedic surgeons, and physical and occupations therapists. Due to the great phenotypic variability, disease treatment should be tailored to the individual s needs. These treatments may include: ankle/foot orthoses; orthopedic surgery; forearm crutches/canes/wheelchairs; treatment of musculoskeletal pain with acetaminophen or NSAIDS; and career and employment counseling. (Tier 4) Physical therapies such as stretching and exercise are recommended to prevent secondary complications such as foot contractures, acquired deformities, difficulty walking, and, in severe cases, inability to ambulate. (Tier 4) 2

3 A systematic review of exercise interventions for individuals with CMT (not DI-CMTB specifically) identified 9 studies of 134 individuals with CMT (3 randomized trials, 5 quasiexperimental, 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 intervention for increasing ankle range of motion. (Tier 1) (4, 5) Surveillance Family Management Preoperative assessment for co-morbidities and autonomic denervation is recommended. During surgical positioning, transport and mobilization, cautious positioning and protection (6) of pressure points is recommended to avoid nerve compression. Neuromuscular block monitoring during surgery is also recommended. (Tier 4) Surveillance includes regular evaluation by a multidisciplinary team to determine neurologic status and function disability. (Tier 4) 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) Medications that are 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 and should be avoided by all patients with CMT, including those who are asymptomatic; other medications may pose moderate to significant risk. (Tier 4) Circumstances to Avoid Avoiding succinylcholine, a muscle relaxant used for anesthesia, is recommended. (Tier 4) 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) Obesity should be avoided as it makes walking more difficult. (Tier 4) (6) (7) (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 3

4 GENE/GENE PANEL: DNM2 DISORDER: DNM2-Related Intermediate Charcot-Marie- Tooth Neuropathy Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) Autosomal dominant Information on the prevalence of DNM2 pathogenic variants was not identified. 34 individuals were examined among a cohort of 6 families with an identified DNM2 pathogenic variant. The mean age of onset was 16 years, ranging from 2 to 50 years. Of the 34 family members with an identified DNM2 pathogenic variant, 32 had signs of neuropathy. Among the two individuals reporting no symptoms of neuropathy (aged 18 and 23), one had hematological abnormalities and cataracts, the second was found to have some mild features of CMT upon examination. Two families had associated neutropenia, and 1 family developed early-onset cataracts. (Tier 3) No information on relative risk was identified. Expressivity Age of onset and symptoms can vary even within the same family. (Tier 3) (2, 8) 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 setting of recommended care? Chance to Escape Clinical Detection Evaluation may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. (Tier 4) (2, 8, 9) (1, 2, 4-6) Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score Demyelinating peripheral neuropathy / Regular medical evaluations 1 3C IN Not Scored IN DNM2 Demyelinating peripheral neuropathy / Avoidance of vincristine, paclitaxel, succinylcholine 1 3C 3C 2 9CC To see the scoring key, please go to: 4

5 Date of Search (MM.DD.YYYY): References 1. Bird TD. Charcot-Marie-Tooth Hereditary Neuropathy Overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al., editors. GeneReviews(R). Seattle (WA) Zuchner S, Tao F. DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al., editors. GeneReviews(R). Seattle (WA) Barreto LC, Oliveira FS, Nunes PS, de Franca Costa IM, Garcez CA, Goes GM, et al. Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review. Neuroepidemiology. 2016;46(3): Sman AD, Hackett D, Fiatarone Singh M, Fornusek C, Menezes MP, Burns J. Systematic review of exercise for Charcot-Marie-Tooth disease. Journal of the peripheral nervous system : JPNS. 2015;20(4): Rose KJ, Burns J, Wheeler DM, North KN. Interventions for increasing ankle range of motion in patients with neuromuscular disease. The Cochrane database of systematic reviews. 2010:Cd Errando C, Pasha T, Pareyson D. Anaesthesia recommendations for patients suffering from Charcot-Marie-Tooth disease Orphan Anesthesia [Internet] [cited Orphanet. 7. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. Journal of the neurological sciences. 2006;242(1-2): Kniffin C, McKusick V. CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE B; CMTDIB. OMIM [Internet] [cited OMIM. 9. Claeys KG, Zuchner S, Kennerson M, Berciano J, Garcia A, Verhoeven K, et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain. 2009;132(Pt 7):