EP.24Recessive mutations in CAV3 - a new differential diagnosis of early-onset neuromuscular disorders

Abstract

Dominant CAV3 mutations account for a very wide phenotypical spectrum, including limb girdle muscular dystrophy (LGMD), rippling muscle disease (RMD), distal myopathy or asymptomatic hyperCKemia. Very few recessive cases have been reported to date with mild clinical features. Here we report a 19-month-old male presenting antenatally with reduced foetal movements from 36/40 and possible polyhydramnios. Family history had been unremarkable except for a history of speech and language delay in 2 siblings. He was delivered by elective Caesarean section at 38 weeks gestation. He was hypotonic at birth and was given facial oxygen and started on intravenous antibiotics until sepsis had been excluded. He quickly established spontaneous breathing and breast feeding. He was re-admitted to hospital when he was 2 months old with bronchiolitis when he was noted to have generalized hypotonia pronounced axially, with significant head lag and scarce antigrativity movements in his legs. There was bilateral talipes but there were no other contractures. DTR were difficult to elicit. He was not dysmorphic and did not have any facial weakness or ophthalmoplegia. CK was elevated up to 7398 IU/L. Brain MRI and cardiac evaluation were normal. His muscle biopsy showed abnormal variation in fibre size, increase in internal nuclei, necrosis and regeneration with modest endomysial chronic inflammation. Molecular analysis revealed a homozygous CAV3 mutation (c.10_17delGAAGAGCA; p.Glu4Hisfs*17) in trans. Further muscle biopsy IHC studies revealed complete caveolin-3 deficiency. Subsequently the patient achieved independent sitting at the age of 8 months, crawled from 1 year and walked independently at 18 months. No rippling of muscle was noted on further examination. This report expands the genetic and clinico-pathological spectrum of CAV3-associated disease, and suggests that recessive CAV3 mutations ought to be considered in the differential diagnosis of early-onset neuromuscular disorders.