Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: a French real-life observational study.

Abstract

Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only few studies reported long-term outcomes. We retrospectively analysed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. 64 patients were identified. At diagnosis (median age 4 months), all patients had cardiomyopathy and most had severe hypotonia (57 out of 62 patients, 92%). ERT was initiated in 50 (78%) patients, and stopped later as ineffective in 10 (21%). 37 (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first three years of life and after the age of 12. Persistence of cardiomyopathy during follow-up, and/or the presence of heart failure, were highly associated with an increased risk of death. In contrast, CRIM-negative status (n=16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Beside survival, a decreased of ERT-efficacy appeared after the age of 6 with a progressive decline in motor and pulmonary functions for most survivors. This study reported the long term follow-up of one of the largest cohort of classical IOPD patients and demonstrated high mortality and morbidity rates at long term with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance to develop new therapeutic approaches targeting various aspects of pathogenesis.