Asymptomatic and oligosymptomatic states of dysferlinopathy

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Dysferlinopathy is a phenotypically heterogeneous, inherited, progressive muscular dystrophy caused by mutations in the DYSF gene. Dysferlinopathy is marked by elevated serum creatine kinase (CK) and can in some cases manifest as hyperCKemia in asymptomatic or low-symptom states. Here, we describe the clinical signs and symptoms and laboratory and imaging results with quantitative MRI analysis of eight pediatric patients at asymptomatic and oligosymptomatic states of dysferlinopathy (aged 3–14 years). Seven of them with a same homozygous mutation and one with a compound heterozygous mutation in the DYSF gene. Based on this case series, we propose two stages of dysferlinopathy disease progression. The first state is asymptomatic hyperCKemia laboratory syndrome of myocytolysis, which is marked by an increase in CK (>1.5 times the upper limit of normal (ULN)) and lactic dehydrogenase (LDH). Second state (oligosymptomatic): increasing CK (2.7–12.6 × ULN), LDH, alanine aminotransferase (ALT), and myoglobin; minimal or moderate signs of fatty muscle infiltration, displacement of the center of support to the back of the foot during plantography; slight afterload fatigue of the calf muscles; slight decrease in muscle strength (imperceptible to the patient) and decrease in Achilles reflexes. Taken together, isolated hyperCKemia (asymptomatic stage) and oligosymptomatic patients form a single continuum of pre-manifest cases.