S1.2 The pediatrician and the early onset Pompe disease

Pompe disease (PD) is a rare metabolic myopathy. It is caused by the deficiency 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 biochemical 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 heterogeneity, and more than 200 different mutations of different severity have been described with variable genotype-phenotype correlations. 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 first 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 weakness and delay in motor development. Pulmonary involvement is characterized by recurrent respiratory infections and respiratory failure. Malnutrition, poor growth, feeding difficulties, macroglossia and hepatomegaly are also evident. Biochemical investigations reveal hypertransaminasemia with increased creatine phosphokinase (CPK). Studies of the natural history show that clinical manifestations 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 failure 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 diagnostic 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 ventricular hypertrophy. Echocardiogram shows hypertrophic cardiomyopathy. Cardiac manifestations are absent or very mild in non classic infantile and juvenile forms. Juvenile patients may present with progressive muscle weakness, myalgias, scapular winging and spine stiffness in combination with recurrent respiratory infections, respiratory failure, nocturnal apneas and complications such as scoliosis or feeding problems. Difficulties in differential diagnosis may determine a variable diagnostic delay. A simple diagnostic algoritm in infantile forms has been proposed by national and international guidelines (2, 3). GAA enzymatic assay should be firstly performed in patients showing hypertrophic cardiomyopathy in combination 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, fibroblasts 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 therapeutic response. Diagnosis of PD is confirmed by molecular analysis of GAA gene and identification 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 weakness, 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 management of infections. Physical therapy has an important role to prevent contractures and deformity. As growth failure and feeding difficulties are common in children with PD, nutritional intervention is required. Recently videofluoroscopic study of swallowing demonstrated that pediatric PD patients show oropharyngeal dysphagia with airway invasion and poor cough reflex. Videofluoroscopic 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 identification and supportive treatment of multi-organ complications.