Clinical characteristics: The spectrum of ANO5 muscle disease is a continuum that ranges from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. The most typical presentation is limb-girdle muscular dystrophy type 2L (LGMD2L) with late-onset proximal lower-limb weakness in the fourth or fifth decade (range 15-70 years). Less common is Miyoshi-like disease (Miyoshi muscular dystrophy 3) with early-adult-onset calf distal myopathy (around age 20 years). Incidental hyperCKemia may be present even earlier. Initial symptoms are walking difficulties, reduced sports performance, and difficulties in standing on toes as well as nonspecific exercise myalgia and/or burning sensation in the calf muscles. Muscle weakness and atrophy are frequently asymmetric. Cardiac findings can include cardiomyopathy and arrhythmias and/or left ventricular dysfunction. Bulbar or respiratory symptoms have not been reported. Females have milder disease manifestations than males. Disease progression is slow in both the LGMD and distal forms; ambulation is preserved until very late in the disease course. Life span is normal.
Diagnosis/testing: The diagnosis of ANO5 muscle disease is established in a proband with identification of biallelic pathogenic variants in ANO5 on molecular genetic testing.
Management: Treatment of manifestations: No definitive treatments for the limb-girdle muscular dystrophies exist. Management is tailored to the individual. To assist with decreased mobility, the following are suggested: weight control to avoid obesity, physical therapy to promote mobility and prevent contractures, and use of mechanical aids to help ambulation and mobility.
Surveillance: Evaluate muscle strength and functional status every six to 12 months.
Agents/circumstances to avoid: Heavy muscle force training of weak muscles. The use of statins, which can induce muscle pain and worsen muscle weakness should be avoided, but if absolutely necessary for the health of the individual, use requires extra monitoring of clinical status especially at the beginning of treatment.
Genetic counseling: ANO5 muscle disease is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members, prenatal diagnosis for a pregnancy at increased risk and preimplantation testing are possible if the pathogenic variants in the family have been identified.
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