199 Proceedings of the Meeting Course on Type II Glycogenosis: a network for the treatment of Pompe disease S1.2 The pediatrician and the early onset Pompe disease Simona Fecarotta, Giancarlo Parenti, Serena Ascione, Giuseppe Montefusco, Generoso Andria Department of Pediatrics, Federico II University of Naples E-mail: andria@unina.it Pompe disease (PD) is a rare metabolic myopathy. It is caused by the defciency of the lysosomal enzyme acid alpha glucosidase (GAA), with a consequent generalized storage of glycogen, particularly in the heart, skeletal muscle and liver. It has been reported an overall incidence of 1 in 40.000 live birth, with a different frequency in different races. The infantile form has an incidence of 1 in 138.000 among Caucasians. The disease is characterized by phenotypic and biochemi- cal heterogeneity with variable age of onset, from infantile to adult age and varying levels of residual enzyme activity, which are inversely related to the severity of clinical manifestations. The disease is also characterized by wide genetic heterogene- ity, and more than 200 different mutations of different severity have been described with variable genotype-phenotype corre- lations. In infantile Pompe disease the most affected muscles are the heart, respiratory and proximal skeletal muscles of the limbs. The clinical onset may occur in the frst weeks/months of life. Patients with the classic infantile phenotype may present with severe cardiomegaly, hypertrophic cardiomyopathy and heart failure, which are associated with generalized muscle weak- ness and delay in motor development. Pulmonary involvement is characterized by recurrent respiratory infections and respi- ratory failure. Malnutrition, poor growth, feeding diffculties, macroglossia and hepatomegaly are also evident. Biochemi- cal investigations reveal hypertransaminasemia with increased creatine phosphokinase (CPK). Studies of the natural history show that clinical manifesta- tions are progressive, with poor prognosis and early exitus due to cardiorespiratory complications. Data from the International Pompe disease Registry (1) show that the most frequent muscle symptoms are hypotonia, inability to deambulation, weakness of proximal limbs muscles. Pneumonia and respiratory distress are commonly reported in various age groups, while heart fail- ure is prevalent in younger patients. In fact, severe heart involvement is typical of the classic infantile form and it can be detected by simple and cheap di- agnostic investigations as chest x-ray and ECG that guide the diagnostic suspicion. Chest x-ray shows severe cardiomegaly and ECG reveals suggestive abnormalities like short PR, large QRS voltage, repolarization abnormalities and signs of left ven- tricular hypertrophy. Echocardiogram shows hypertrophic car- diomyopathy. Cardiac manifestations are absent or very mild in non clas- sic infantile and juvenile forms. Juvenile patients may present with progressive muscle weakness, myalgias, scapular winging and spine stiffness in combination with recurrent respiratory in- fections, respiratory failure, nocturnal apneas and complications such as scoliosis or feeding problems. Diffculties in differential diagnosis may determine a vari- able diagnostic delay. A simple diagnostic algoritm in infantile forms has been proposed by national and international guide- lines (2, 3). GAA enzymatic assay should be frstly performed in patients showing hypertrophic cardiomyopathy in combina- tion with generalized hypotonia, hypertransaminasemia and incresased CPK. Muscle biopsy may show glycogen storage, but its usefulness in the diagnostic approach is controversial in infantile patients. GAA enzymatic assay should be performed in lymphocytes, fbroblasts or muscle biopsy. Recently innovative methods, such as measurement of GAA activity in dried blood spots by tandem mass spectroscopy, can be used to investigate suspected patients and in newborns screening programs. Moreover a tetra glucose oligomer designated as Glc4 has been shown to be elevated in both urine and plasma of PD patients and it could be used as a non-invasive marker for diagnosis and monitoring of therapeu- tic response. Diagnosis of PD is confrmed by molecular analysis of GAA gene and identifcation of causative mutations is also helpful for familial screening and prenatal diagnosis. Although Pompe disease is a hereditary myopathy it is characterized by multisystem involvement; management of patients is multidisciplinary, involving different specialists. In classic infantile PD patients cardiac involvement is serious and cardiac supportive treatment is often needed. Respiratory involvement is due to concomitant factors as muscle weak- ness, reduced thoracic compliance, poor cough and recurrent infections. Respiratory support is one of the most critical forms of management for Pompe disease, as most patients experience some form of respiratory compromise, and respiratory failure is the most common cause of premature death. Other interventions may include special forms of physical therapy to strengthen weakened respiratory muscles, as well as aggressive manage- ment of infections. Physical therapy has an important role to prevent contractures and deformity. As growth failure and feed- ing diffculties are common in children with PD, nutritional intervention is required. Recently videofuoroscopic study of swallowing demonstrated that pediatric PD patients show oropharyngeal dysphagia with airway invasion and poor cough refex. Videofuoroscopic assessment of dysphagia should be recommended in PD pediatric patients to establish the need for supportive treatment. Similarly hearing loss is now increasingly recognized in classic infantile patients and periodical hearing assessment should be performed. In conclusion multidisciplinary follow-up, coordinated by a metabolic pediatrician or a pediatric neurologist, is needed in PD patients for early identifcation and supportive treatment of multi-organ complications. References 1. Byrne BJ, Kishnani PS, Case LE, et al. Pompe disease: design, methodology, and early fndings from the Pompe Registry. Mol Genet Metab 2011;103:1-11. 2. Bembi B, Cerini E, Danesino C, et al. Management and treatment of glycogenosis type II. Neurology 2008;71(23 Suppl 2):S12-36. 3. Bembi B, Cerini E, Danesino C, et al. Diagnosis of glycogenosis type II. Neurology 2008;71(23 Suppl 2):S4-11.