T.P.16: Clinical and molecular characteristics of 33 patients with Late Onset Pompe Disease (LOPD): Unusual phenotypes, novel mutations and therapeutic responses

Abstract

Pompe disease is a rare metabolic myopathy due to mutations in the gene encoding acid alpha-glucosidase (GAA) involved in glycogen degradation. Two clinical presentations can occur: infantile form and late-onset form. Herein, we describe a cohort of 33 late-onset Pompe disease (LOPD) patients diagnosed at our centre from 1997 to date. Our aim is to present clinical and functional data collected in this long time lapse and to describe unusual clinical and genetic features. LOPD diagnosis was made with muscle GAA residual activity assay and GAA sequence analysis. At follow-up patients underwent motor, respiratory, cardiac and muscle MRI evaluations. Motor performances were tested with Walton Gardner-Medwin, MRC, GSGC, 6MWT. Respiratory function was assessed through FVC% in upright and supine position 19 males, 14 females. The onset symptom was asymptomatic hyperckemia in 13 patients (39%), proximal weakness in 19 (57%) and respiratory failure in 1 (3%). Atypical clinical features were observed in 4 patients: a 66year-old female with a severe distal muscle weakness; a 70-year-old male with mesial temporal sclerosis; a 46-years-old male with severe hearing loss and a 52-year-old male with leukoencephalopathy. The median age at diagnosis was 38years, median diagnostic delay 8.3years. GAA sequence analysis showed the common IVS1–13T>G mutation in all patients associated, in 25 patients, with a second mutation. Two brothers were IVS1–13T>G homozygous and 1 patient had a new mutation (c.2395C>G). In the remaining 8 no second mutation was found. 17 patients started enzyme replacement therapy (ERT). Our study confirms LOPD clinical and genetic heterogeneity. The atypical features encountered may contribute to expand the clinical aspects of the disease highlighting its multisystemic nature. Early diagnosis allows, when indicated, earlier ERT initiation even if, in our cohort, treatment responses were variable and not clearly correlated with diagnostic delay.