Pompe Disease is a rare and fatal genetic disorder of glycogen storage, characterized by low levels of the alpha glucosidase (GAA) enzyme. The symptoms and severity of the disease vary according to the amount of deficiency of GAA. Early onset or infantile Pompe disease is the most severe form of the condition, and is characterized by almost complete deficiency (<1% activity) of the enzyme. The infant starts to show symptoms of feeding problems, absence of weight gain, muscle weakness, floppiness, head lag, respiratory problems, enlarged tongues, and grossly enlarged heart by the first few months of being born. The childhood onset form of the disease is seen when the enzyme activity is about 10%. The symptoms in this case, appear in early childhood, and progress slower than in the infantile form. Late onset or adult onset Pompe disease is characterized by <40% of normal GAA activity and develops much later in life, sometimes as late as in the sixth decade. This is a much less severe condition, and the heart is usually not enlarged. Death, in all cases, is usually due to cardiac and/or respiratory complications. In the USA, one in every 40,000 births is estimated to be affected with Pompe disease. Some race specific variation is seen, with African Americans showing a higher incidence than Caucasians.
Based on the clinical symptoms alone, it may be a difficult to diagnose Pompe disease. Differential diagnoses include spinal muscular atrophy I, Danon disease, endocardial fibroelastosis, and carnitine deficiency. However, the condition can be easily diagnosed based on the GAA levels in the blood and muscles. Usually, a skin biopsy culture is used for this purpose. It is also possible to screen for mutations in the GAA gene. As of now, no specific treatment is available for Pompe disease. Treatment is mostly supportive and symptomatic. Clinical trials have been performed for an enzyme replacement therapy, and it shows promise for the immediate future. Gene therapy for the defective GAA gene is also an option being looked into. Prognosis for the patients depends upon the severity of the disease. The infantile form is generally fatal, with most children succumbing to the illness within the first decade of their life. The childhood onset form is also associated with a reduced life expectancy.
The GAA enzyme functions in breaking down glycogen into glucose, thereby enabling the ready supply of energy for the body cells. More than 70 different mutations have so far been identified in the GAA gene to date. These mutations prevent the GAA enzyme from carrying out its normal function, resulting in accumulation of glycogen all over the body. The heart and muscles are the most severely affected tissues, and cardiac and respiratory problems ensue.
Bashan et al. (1988) conducted a retrospective study on 18 patients with alpha-glucosidase deficiency who have been diagnosed during a period of 15 years in Palestine. All patients were Palestinian Arabs, with the exception of two siblings from a Jewish Iraqi family [See: Palestine > Bashan et al., 1988].
Venugopalan et al. (2002) reported a case of type II glycogen storage disorder (Pompe disease) who presented with cardiac failure. The patient was a three month old Omani baby born to consanguineous parents, who was referred with heart failure, recurrent chest infections and failure to thrive. He was noted to have respiratory distress since birth. There was no similar history in the family. Clinically, he was tachypneic, tachycardic, with no dysmorphic features, had cardiomegaly with normal heart sounds, hepatomegaly of 3-4 cm, hypotonic but with no other neurological deficit. A grade 2/6 ejection systolic murmur was best heard over the pulmonary area. He was managed in an intensive care unit with anti-heart failure therapy, antibiotics and other supportive measures. After hospital stay of one week, he was discharged, but was noted by the parents to have poor weight gain and poor spontaneous activity. In addition, he had two episodes of lower respiratory tract infection which required hospitalization. Further evaluation revealed developmental age of one month, clinical evidence of pulmonary hypertension, severe hypotonia with just elicitable deep tendon reflexes, and bilateral anterior polar cataract. Investigations confirmed the cardiomegaly by chest X-ray. Biventricular hypertrophy with right axis deviation and normal PR interval was evident on ECG. Echo Doppler studies showed hypertrophy of the right and left ventricular walls, as well as the interventricular septum but with no obstruction, as the left ventricular outflow gradient was normal. Left ventricular ejection fraction of 55% with dystolic dysfunction was also detected with mild mitral and tricuspid regurgitation. Blood investigations revealed elevated creatine kinase of 410 U/l, elevated liver enzymes, but normal ammonia, and lactate. Tandem Mass spectrometry did not reveal any metabolic diseases. Electromyography showed a mixed myopathic and neurogenic pattern, and examination of muscle biopsy revealed a severe type pf vacuolar myopathy with p-aminosalicylic acid positive glycogen granules (which were membrane bound when examined with an electron microscope) in the vacuoles replacing myofibrils in many fibers. These findings had confirmed the diagnosis of lysosomal storage disease, infantile type II glycogenosis. His condition improved after management with anti-heart failure therapy and supportive and symptomatic measures. The patient was discharged after counseling the parents, but he died at the age of six months from fulminant chest infection.
Bashan et al. (1988) conducted a retrospective study on 18 patients with alpha-glucosidase deficiency who have been diagnosed during a period of 15 years. All patients were Palestinian Arabs, with the exception of two siblings from a Jewish Iraqi family. Clinically all patients had the infantile type (Pompe's disease), except one who had the juvenile type. Muscle glycogen content varied from 4 to 17% wet weight. Muscle alpha-glucosidase activity was zero in 10 of 17 patients examined. Among the seven patients in whom residual activity was present, the highest value was 18% of normal. Leukocyte alpha-glucosidase activity was highly variable, making this tissue unfit for enzymatic diagnosis of the disease. A marked heterogeneity was found in pH profiles of muscle and leukocyte alpha-glucosidase activity.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. GSD was found in 17/248 patients. The diagnosis was confirmed in all cases of GSD by measuring enzymatic activity in leukocytes, cultured fibroblasts or liver biopsy. Among GSD cases in this cohort, 3 cases from a single family were found to have GSD II. The estimated incidence of GSD IA in this cohort was 2 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Hamdan et al. (2008) reported the case of a 35-week neonate whose older sibling died of infantile Pompe disease (PD). The first sign of the disease was detected at 32 weeks of gestation, when fetal echocardiography showed hypertrophic cardiomyopathy. Then the diagnosis was confirmed after birth through enzyme assay. The patient was homozygous for a mutation in the 8th intron of GAA. This mutation is a splice site mutation (c.1327-2A>G) which is classified among the most deleterious sequence variations in GAA. It is worth mentioning that the patient responded very well to enzyme replacement therapy (ERT) that was started at 18 hours of age. ERT normalized cardiac abnormalities neurodevelopmental indicators. Two years later, Hamdan et al. (2010) studied the cases of three patients (2 males and 1 female) with PD in UAE. Two of these patients had a sibling with PD. Mutational analysis revealed two types of mutations in the GAA gene; c.1327-2A>G and c.340insT. These patients were selected by screening fetuses diagnosed with hypertrophic cardiomyopathy between 2006 and 2009. Enzyme replacement therapy was applied in these cases with varying degrees of success.
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