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  1. At present, “Pompe disease” stands for the very broad clinical spectrum of glycogen storage disease type II (GSDII) including infantile, childhood, and adult variants. The name “acid maltase deficiency” (AMD) is also used. Pompe disease is one of more than 10 different GSDs (see Chap. 71: Glycogen Storage Diseases) and also one of nearly 60 different lysosomal disorders (see Chaps. 134154: Lysosomal Disorders [Part 16]). Pompe disease results from acid α-glucosidase (GAA) deficiency and is transmitted as an autosomal recessive trait.

  2. The clinical presentation of Pompe disease encompasses a range of phenotypes all of which include varying degrees of myopathy but differ with regard to age of onset, extent of organ involvement, and rate of progression. The most severe is the classic-infantile-onset disease, described by Pompe in 1932 and delineated prior to discovery of the deficiency of acid α-glucosidase (acid maltase), with cardiomyopathy, hypotonia, hepatomegaly, and death due to cardiorespiratory failure, usually before 1 year of age. Patients at the other end of the spectrum present in the third to seventh decade, usually with a slowly progressive proximal myopathy. Between these two extremes of the clinical spectrum there is a heterogeneous group, formerly termed childhood and juvenile variants, generally with onset after early infancy, a predominance of skeletal muscle involvement, usually without cardiac involvement, and a more slowly progressive course as compared with classic-infantile Pompe disease. Progressive proximal muscle weakness including major impairment of respiratory function dominates the picture. Death results usually from complications associated with respiratory failure.

  3. At the cellular level, the acid α-glucosidase deficiency results in intralysosomal accumulation of normally structured glycogen in numerous tissues. The accumulation is most marked in the skeletal muscles, the heart, and the liver of infants with classic-infantile Pompe disease. In children and adults with more slowly progressing forms of Pompe disease the heart and liver are virtually unaffected, and the intralysosomal accumulation of glycogen in muscle is of lesser magnitude. The pathology can vary in different muscles, and can be revealed by CT scans and MRI. As a result of muscle damage, patients across the clinical spectrum, but most so affected infants, usually have elevated blood plasma levels of creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Glc4 is often present in the urine.

  4. The diagnosis “Pompe disease” is confirmed by the finding of a complete deficiency of acid α-glucosidase activity in all classic-infantile cases or a markedly reduced activity (usually <30% of average normal) in all other cases—in leukocytes, cultured skin fibroblasts, or muscle tissue. Blood spots can also be used for measuring the acid α-glucosidase activity and are most useful for screening purposes such as in newborn screening and in screening of patient populations with undiagnosed limb-girdle weakness or hyper CK-emia. The diagnosis “Pompe disease” can also be established by DNA analysis provided that a pathogenic sequence variant is found in each of the two acid α-glucosidase alleles. DNA analysis is the only means for definitive carrier detection; the enzyme activity assay is unreliable for this purpose. Prenatal diagnosis can be performed by measuring the acid α-glucosidase activity in chorionic villus biopsies or in cultured amniotic cells. Prenatal diagnosis by DNA analysis is also possible and reliable when the familial mutations are known. Preimplantation diagnosis can in principle be offered.

  5. The acid α-glucosidase gene has been localized to human chromosome 17q25 and designated GAA. It contains 20 exons in approximately 20 kb of genomic DNA. Both the cDNA and the entire gene have been sequenced and characterized. The cDNA for human acid α-glucosidase is over 3.6 kb, with 2859 nucleotides (nt) of coding sequence, a 3' untranslated region of approximately 550 bp and a 5' untranslated region of at least 218 bp. The coding region predicts 952 amino acids in a non-glycosylated protein of 105.37 kDa with an amino terminal ...

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