Pompe disease (PD, glycogen storage disease type II, OMIM # 232300) is an autosomal recessive lysosomal storage disease caused by deficiency of acid alpha-glucosidase (GAA) (acid maltase, EC 220.127.116.11) due to mutations in the GAA gene.1 Progressive storage of intra-lysosomal glycogen in skeletal, cardiac, and smooth muscle cells leads to impairment of cellular integrity and function with eventual apoptosis of affected muscle fibers, inflammatory processes, and subsequent replacement through connective tissue.2 Additional systemic metabolic abnormalities may be observed although their clinical relevance is unknown.3
PD represents a continuous clinical spectrum with about one-third of patients presenting during the first months of life or prenatally with hypertrophic cardiomyopathy, muscle hypotonia, and secondary complications, such as respiratory insufficiency, feeding difficulties, and failure to thrive.1,4,5 The remaining two-thirds of patients present as clinical continuum resembling the clinical picture of a limb girdle muscular dystrophy (LGMD) without cardiomyopathy and with variable age of onset ranging from late infancy to adulthood.6 The proximal muscle groups including thigh, pelvic, and shoulder muscles are affected while the distal muscle groups are typically spared.7 The diaphragm in contrast to other genetic causes of LGMD is typically affected in PD contributing to the respiratory insufficiency and CO2 retention in later onset patients.6,8 Importantly, asymptomatic patients with PD have been reported.9 Residual GAA activity correlates with severity of PD, such that infantile onset patients show complete absence of enzyme activity whereas later onset patients retain up to 30 % residual enzyme activity.8
PD is a pan-ethnic disease with an estimated frequency of 1:40,000, although recent reports from newborn screening studies suggest that PD may be more frequent.1,8,10,11 The advent of recombinant human enzyme replacement therapy (ERT) has improved quality of life and reduced morbidity and mortality in the majority of patients with both infantile-onset PD11,12 and later-onset PD.13 Recombinant human GAA (rhGAA) is harvested from Chinese hamster ovary (CHO) cells and exerts its activity after proteolytic cleavage in the lysosomes. The uptake of rhGAA is readily achieved via mannose receptors on macrophages of the liver and spleen.8
The diagnostic path to late-onset PD may be long and extensive for adult patients presenting with muscular symptoms due to the phenotypic overlap with LGMD. Although the presence of clinical clues have been reported in the medical literature, the predominant and first-presenting symptoms are typically muscular in nature.14 Early involvement of the diaphragm causing respiratory insufficiency15–17 as well as cardiac arrythmias18 or vascular involvement19 may increase the clinician’s suspicion for PD. Since late-onset PD lacks a definite clinical phenotype that allows clinicians to clearly differentiate PD from other LGMDs, it is important for physicians to include PD in the differential diagnosis for LGMD considering the availability of ERT.
A diagnosis of infantile-onset PD is readily suspected in any infant with hypertrophic cardiomyopathy, muscular hypotonia, and moderate elevation of creatine kinase (CK) levels.1,4,5 Any delay in diagnosis is not acceptable since it is now well established that an early diagnosis and timely initiation of ERT will have a drastic impact on the natural disease course.12 The delayed start of ERT, even by only a few weeks increases the morbidity in affected infants significantly.11
CK levels are a sensitive marker for PD as CK is moderately elevated in all infants with PD and in more than 95 % of adults with PD.7,8, The remaining 5 % of adults with PD have either very mild disease or, which is more likely, are in the terminal stage of PD with little or no residual skeletal muscle mass. Muscle injury in PD will not only lead to elevations of CK, but also to a release of other muscle enzymes including aldolase, lactate dehydrogenase (LDH), and amino transaminases (AST, ALT). The ratio of AST to ALT in PD is typically close to 1 in contrast to acute rhabdomyolysis where AST/ALT is greater than 3.20 However, elevated transaminases should not be misinterpreted in the context of PD or other myopathies as being secondary to liver disease.20,21
Muscle biopsies have an important place in the diagnostic workup of myopathies where the differential diagnosis may be extensive. However, if PD is considered in a patient based on the clinical phenotype, family history, and/or elevated CK levels, a muscle biopsy may not be used as the first-line diagnostic test. Instead, analysis of GAA activity is preferred for initial screening due to its short turnaround time and non-invasiveness.22 In cases of uncertain or conflicting laboratory test results (enzyme and molecular), muscle biopsies as a second-tier test may guide the physician and provide additional valuable information for the differential diagnosis. Physicians need to be aware that up to 25 % of adult patients with PD may have normal muscle biopsies without pathologic storage of glycogen on periodic acid–Schiff (PAS) staining.22,23