Myotonic Dystrophy Type 2

Excerpt

Clinical characteristics: Myotonic dystrophy type 2 (DM2) is characterized by myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects, insulin-insensitive type 2 diabetes mellitus, and other endocrine abnormalities. While myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third to fourth decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and proximal and axial weakness of the neck flexors and the hip flexors. Subsequently, weakness occurs in the elbow extensors and finger flexors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. In a subset of individuals, calf hypertrophy in combination with brisk reflexes is notable.

Diagnosis/testing: The diagnosis of DM2 is established in a proband by identification of a heterozygous pathogenic expansion of a CCTG repeat within the complex repeat motif of (TG)_n(TCTG)_n(CCTG)_n(TCTG')_n in CNBP. The number of CCTG repeats in a pathogenic expansion ranges from approximately 75 to more than 11,000, with a mean of approximately 5,000 repeats. The detection rate of a CNBP CCTG expansion is more than 99% with the combination of routine PCR, Southern blot analysis, and PCR repeat-primed assay.

Management: Treatment of manifestations: Ankle-foot orthoses, wheelchairs, or other assistive devices as needed for weakness; regular physical activity and exercise training appears to help maintain muscle strength and endurance and to control musculoskeletal pain; myotonia, especially of the legs, can require treatment and mexiletine or lamotrigine may be beneficial; medications used with some success in myalgia management include mexiletine, gabapentin, pregabalin, nonsteroidal anti-inflammatory drugs, cannabinoids, low-dose thyroid replacement, and tricyclic antidepressants; removal of cataracts or epiretinal membrane that impair vision; education regarding sleep hygiene; cognitive behavioral therapy and modafinil may be helpful for fatigue and daytime sleepiness; vitamin D supplementation for those with deficiency; treatment of diabetes and or dietary management per endocrinologist for insulin sensitivity and type 2 diabetes; lipid-lowering drugs for hyperlipidemia; hormone therapy for endocrine dysfunction; hearing aids for sensorineural hearing loss; treatment of arrhythmia and cardiomyopathy per cardiologist with defibrillator placement for those with arrhythmias; prokinetic agents may be helpful for gastrointestinal manifestations; vaccinations, respiratory training, and cough assist with noninvasive ventilation as needed; cognitive behavioral therapy and psychotropic medications as needed; standard treatment per oncologist for any cancers.

Surveillance: Annual evaluation with neurologist, occupational therapist, and physical therapist; annual ophthalmology evaluation for posterior subcapsular cataracts and epiretinal membranes; assessment for sleep issues, polysomnography to identify sleep apnea, and serum vitamin D every six months; annual assessment of body mass index, clinical manifestations of diabetes mellitus, and thyroid disorders; measurement of fasting serum glucose, glycosylated hemoglobin level, thyroid hormone levels, and lipid panel annually; serum testosterone, inhibin B, luteinizing hormone, follicle-stimulating hormone, and dehydroeipandosterone sulfate annually in males; audiometry evaluation every six months; annual assessment for palpitations, syncope, dyspnea, orthopnea, and edema; annual EKG, 24-hour Holter monitoring, and echocardiogram to detect/monitor cardiac conduction defects and cardiomyopathy; cardiac MRI per cardiologist; assess for gastrointestinal manifestations and respiratory issues using the Respicheck assessment annually; pulmonary function test, cough peak flow, and nocturnal oximetry/capnometry annually; assessment of cardiac and respiratory function before and after surgery; assess for learning difficulties, memory deficits, executive dysfunction, and affective disorders as clinically indicated; neuropsychological testing and brain MRI as clinically indicated; annual assessment for clinical manifestations of associated tumors and follow standard population tumor screening guidelines.

Agents/circumstances to avoid: Cholesterol-lowering medications when associated with increased weakness; medications that can exacerbate myotonia (depolarizing muscle relaxants). Monitor ventilation before, during, and after anesthesia.

Genetic counseling: DM2 is inherited in an autosomal dominant manner. To date, all individuals whose biological parents have been evaluated with molecular genetic testing have had a parent with a pathogenic CNBP CCTG repeat expansion; de novo pathogenic CCTG repeat expansions have not been reported. Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion. The CCTG repeat expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages. There is no confirmed maternal or paternal preference for contraction or expansion. Anticipation is not confirmed in DM2. To date, there is no significant correlation between CCTG repeat size and age of onset of weakness or other measures of disease severity. Once the pathogenic CNBP CCTG repeat expansion has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.