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 a complex repeat motif, (TG)_n(TCTG)_n(CCTG)_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 the PCR repeat-primed assay.

Management: Treatment of manifestations: Ankle-foot orthoses, wheelchairs, or other assistive devices as needed for weakness; routine physical activity appears to help maintain muscle strength and endurance and to control musculoskeletal pain; medications used with some success in myalgia management include mexilitene, gabapentin, pregabalin, nonsteroidal anti-inflammatory drugs, low-dose thyroid replacement, and tricyclic antidepressants; myotonia rarely requires treatment but mexilitene or lamotrigine may be beneficial in some individuals; removal of cataracts or epiretinal membrane that impair vision; defibrillator placement for those with arrhythmias; hormone substitution therapy for endocrine dysfunction; prokinetic agents may be helpful for gastrointestinal manifestations; cognitive behavioral therapy and modafinil may be helpful for fatigue and daytime sleepiness; vitamin D supplementation for those with deficiency; hearing aids for sensorineural hearing loss.

Prevention of secondary complications: Anesthetic risk may be increased and therefore assessment of cardiac and respiratory function before and after surgery are recommended. Prompt treatment of hypothyroidism and vitamin D deficiency to reduce secondary weakness and myotonia.

Surveillance: Annual evaluation with neurologist, occupational therapist, and physical therapist; annual ophthalmology evaluation for posterior subcapsular cataracts and epiretinal membranes; annual EKG, echocardiogram, and 24-hour Holter monitoring to detect/monitor cardiac conduction defects and cardiomyopathy; cardiac MRI per cardiologist; annual measurement of fasting serum glucose concentration, glycosylated hemoglobin level, thyroid hormone levels, and vitamin D; serum testosterone and FSH per endocrinologist.

Agents/circumstances to avoid: Cholesterol-lowering medications when associated with increased weakness.

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 one parent with a CCTG repeat expansion; de novo pathogenic variants have not been reported. Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion. There is no correlation between disease severity and CCTG repeat length. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible once the CCTG repeat expansion has been identified in an affected family member.