Calpainopathy

Clinical characteristics: Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles. Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, laxity of the abdominal muscles, Achilles tendon shortening, and scoliosis. Affected individuals typically do not have cardiac involvement or intellectual disability.

Three autosomal recessive calpainopathy phenotypes have been identified based on the distribution of muscle weakness and age at onset:

1. Pelvifemoral limb-girdle muscular dystrophy (LGMD) (Leyden-Möbius LGMD) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle, with onset that may occur as early as before age 12 years or as late as after age 30 years

2. Scapulohumeral LGMD (Erb LGMD) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle

3. HyperCKemia, usually observed in children or young individuals, in which individuals are asymptomatic and have high serum creatine kinase (CK) concentrations

The autosomal dominant form of calpainopathy is clinically variable, ranging from almost asymptomatic to wheelchair dependence after age 60 years in a few individuals; phenotype is generally milder than the recessive form.

Diagnosis/testing: The diagnosis of calpainopathy is established by identification of biallelic pathogenic variants in CAPN3 or a dominantly acting heterozygous CAPN3 pathogenic variant by molecular genetic testing. Muscle biopsy showing absent or severely reduced calpain-3 on immunoblot analysis can confirm the diagnosis if molecular testing is inconclusive.

Management: Treatment of manifestations: Physical therapy and stretching exercises to promote mobility and prevent contractures; supervised strengthening and gentle low-impact aerobic exercise; nutrition management as needed to maintain appropriate weight for height; mobility aids such as canes, walkers, orthotics, and wheelchairs to help maintain independence; knee-ankle-foot orthoses while sleeping to prevent contractures; positioning and seating devices to prevent scoliosis; surgery for foot deformities, scoliosis, and Achilles tendon contractures as needed; scapular fixation as needed for scapular winging; annual influenza vaccine; prompt treatment of chest and respiratory infections; nocturnal ventilator assistance as needed; respiratory aids to treat chronic respiratory insufficiency in late stages of the disease; social, emotional, and family support for care decisions.

Surveillance: Monitor muscle strength, joint range of motion, and orthopedic complications annually; assess for nocturnal hypoventilation annually; pulmonary evaluation as needed with forced vital capacity assessed in the sitting and supine position; examination of cardiac function in those with advanced disease as needed; assess need for social work support at each visit.

Agents/circumstances to avoid: Strenuous and excessive muscle exercise; obesity and excessive weight loss; physical trauma, bone fractures, and prolonged immobility. Avoid succinylcholine and halogenated anesthetic agents when possible; avoid cholesterol-lowering agents (e.g., statins) when possible.

Evaluation of relatives at risk: It is appropriate to clarify the status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of evaluation and subsequent surveillance.

Genetic counseling: Calpainopathy is typically inherited in an autosomal recessive manner. Less commonly, calpainopathy is inherited in an autosomal dominant manner.

1. Autosomal recessive inheritance: If both parents are known to be heterozygous for a pathogenic variant associated with autosomal recessive calpainopathy, each sib of an affected individual has at conception 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. Once the CAPN3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives is possible.

2. Autosomal dominant inheritance: Each child of an individual with autosomal dominant calpainopathy has a 50% chance of inheriting the CAPN3 pathogenic variant.

Once the CAPN3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for calpainopathy are possible.