Caveolinopathies – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: The caveolinopathies, a group of muscle diseases, can be classified into five phenotypes, which can be seen in different members of the same family:

1. Limb-girdle muscular dystrophy 1C (LGMD1C), characterized by onset usually in the first decade, mild-to-moderate proximal muscle weakness, calf hypertrophy, positive Gower sign, and variable muscle cramps after exercise

2. Isolated hyperCKemia (i.e., elevated serum concentration of creatine kinase (CK) in the absence of signs of muscle disease) (HCK)

3. Rippling muscle disease (RMD), characterized by signs of increased muscle irritability, such as percussion-induced rapid contraction (PIRC), percussion-induced muscle mounding (PIMM), and/or electrically silent muscle contractions (rippling muscle)

4. Distal myopathy (DM), observed in one individual only

5. Hypertrophic cardiomyopathy (HCM), without skeletal muscle manifestations

Diagnosis/testing: CAV3, which encodes caveolin-3, a muscle-specific membrane protein and the principal component of caveolae membrane in muscle cells in vivo, is the only gene in which pathogenic variants are known to cause caveolinopathies. Sequence analysis identifies pathogenic variants in more than 99% of affected individuals.

Management: Treatment of manifestations: Aggressive supportive care to preserve muscle function, maximize functional ability and treat complications, especially in those with the LGMD phenotype; weight control to avoid obesity; physical therapy and stretching exercises to promote mobility and prevent contractures; use of mechanical aids such as canes, walkers, orthotics, and wheelchairs as needed to help ambulation and mobility; social and emotional support.

Prevention of secondary complications: In individuals with isolated HCK, special precautions during surgical procedures and anesthesia because of possible risk for malignant hyperthermia (MH).

Surveillance: Periodic monitoring of spine, respiratory function, cardiac function, mobility, and muscle function based on individual needs.

Genetic counseling: Most caveolinopathies are inherited in an autosomal dominant manner; they may also be inherited in an autosomal recessive manner.

Autosomal dominant caveolinopathies: Most affected individuals have an affected parent; the proportion of cases caused by de novo pathogenic variants is unknown, but probably small. Each child of an individual with an autosomal dominant caveolinopathy has a 50% chance of inheriting the pathogenic variant.

Autosomal recessive caveolinopathies: The parents of an affected child are obligate heterozygotes (carriers) and therefore carry one mutated allele; heterozygotes can be asymptomatic or can display modest elevation of serum CK concentration and/or calf hypertrophy. At conception, each sib of an individual with autosomal recessive caveolinopathy 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 is possible if both pathogenic variants have been identified in the family.

Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member.