P.17.1 Phenotypic variation within 22 families with Pompe disease

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α -glucosidase (GAA) leading to glycogen accumulation in different tissues. Pompe disease has a broad clinical spectrum, in which the phenotype can vary widely, even in patients with a similar GAA genotype. The aim of this study was to describe phenotypic variation among siblings with non-classic Pompe disease in the Netherlands. We identified 22 families consisting of two or three siblings (50 patients: 42 adults and eight children). All carried the most common mutation c.-32-13T>G in combination with another pathogenic mutation. Siblings typically all had symptom onset either in childhood or in adulthood, however, there was a wide variation in age of symptom onset between siblings (median difference of nine years). Presenting symptoms were similar across siblings in 14 families and limb girdle weakness was most frequently reported. In certain families ptosis, bulbar weakness or scapular winging were present in all siblings. The majority of wheelchair and/or ventilator dependent patients had an ambulant or non-ventilated sibling; half of these less affected siblings had a longer disease duration. Gender, GAA activity and co-morbidity did not appear to explain differences in phenotype between siblings. Since the course of disease and its severity in some families varied to the same extent as seen in unrelated patients with an identical genotype, other factors like epigenetic and environmental effects are likely to influence the clinical presentation and disease course. Additional studies are needed to identify these factors, as possible prognostic factors for disease course and outcome on ERT of an individual patient.