Pompe disease (also known as glycogen storage disease type II [GSDII], acid maltase deficiency or GAA deficiency) is an autosomal recessive inherited disorder caused by a mutation in the gene encoding GAA.¹ Deficiency in GAA affects lysosomal-mediated degradation of glycogenesis and results in intralysosomal accumulation of glycogen and disruption of the tissue architecture in various organs, most notably the skeletal muscles, heart and liver.²

Classification

As is the case with other LSDs, Pompe disease presents at different ages and with differing degrees of severity. Pompe disease is classified into two broad categories – infantile and late onset disease – based on age of onset.³

Age of onset, organ involvement and disease severity correlate with residual enzyme activity and genotype – enzyme activity is absent or minimal in infantile disease, but may be reduced to varying degrees (residual enzyme activity 3-30%) in those with late-onset disease.⁴

Early age of onset (within the first months of life) is associated with more severe disease with a shorter survival time. In the infantile-onset form symptoms become apparent within the first few months of life and prognosis is poor such that most patients die within the first year or two of life without treatment.⁵ Patients with classic infantile-onset Pompe disease are further distinguished based on their cross reactive immunological material (CRIM) status – CRIM-negative patients lack any form of endogenous GAA, whereas CRIM-positive patients are able to synthesize some catalytically inactive GAA.⁶

Late-onset Pompe disease generally has a milder phenotype than infantile-onset disease; it can present with symptoms any time after age 1 year.⁷ It is characterised by skeletal myopathy usually in a limb-girdle distribution, and is associated with less cardiac involvement and a more protracted disease course, but eventually leads to respiratory failure.^8,9  The term pseudodeficiency is used to describe patients who have low GAA enzyme activity but who do not develop Pompe disease.⁴

Epidemiology

Epidemiological data for Pompe disease has been derived from gene frequency studies, evaluation of anonymous dried blood spots and population-based screening programs. Based on calculated carrier frequencies the combined incidence of infantile-onset and late-onset Pompe disease was previously estimated to be 1:40,000.¹⁸ More recent data from the US, based on analyses of dried blood spots, indicates an incidence of approximately 1:28,000. Data from the USA estimate the prevalence of pseudodeficiency to be <1%.⁵

Common mutations associated with infantile-onset disease have been detected in people of African descent (c.2560C>T; p.ARg85Ter), Taiwanese (c.1935C>A; p.Asp645Glu) and Dutch (c.del525T; p.Glu176ArgfsTer45 and exon 18 deletion) populations,¹⁰ such that incidence rates may vary from 1:14,000 to 1:600,000, depending on the geographic area or ethnic group being examined.¹ Due to the autosomal recessive inheritance, both genders are equally affected.

Pooled data from population based studies (USA and Austria) and the Taiwanese newborn screening program estimate that 28% of Pompe disease cases are infantile-onset and that 85% of these have associated cardiomyopathy (classic infantile-onset Pompe disease).⁵ About 25% of cases of classic infantile-onset Pompe disease are CRIM-negative, which is associated with worse outcomes.

Incidence of Pompe disease in different populations. 

Adapted from Leslie and Tinkle, GeneReviews (2013)¹⁰

Pathophysiology 

GAA is a lysosomal enzyme responsible for hydrolyzing α-1,4- and α-1,6-glycosidic bonds in glycogen, maltose and isomaltose.¹ Lysosomes are a cell’s disposal system.¹¹ Thus, a deficiency in the GAA enzyme leads to the accumulation of normal glycogen in lysosomes and the cytoplasm. This leads eventually to tissue destruction, and enlargement and dysfunction of involved organs.

Electron microscopy examination of individual myocytes from patients with classical infantile-onset Pompe disease has demonstrated a pathogenic cascade that can be divided into several stages.¹²

Pompe disease pathogenic cascade. 

Adapted from Al Jasmi et al. BMC Neurology (2015) 15:20⁵

In the past decade it has become apparent that this relatively simplistic view of Pompe disease pathophysiology is inadequate. Autophagy – a process in which the cell’s cytoplasm and organelles are sequestered in a double-membrane bound vesicle – facilitates recycling of amino acids, fatty acids and glucose during periods of stress and starvation.¹¹ Several autophagic pathways have been described, of which macroautophagy is of most relevance to Pompe disease.⁹ GAA deficiency results in a secondary defect in the fusion between autophagasomes and lysosomes; as a result, autophagosomes accumulate leading to muscle tissue damage.^13-16

As research continues to look for new therapeutic approaches to Pompe disease, its complex pathological cascade continues to be elucidated. Current understanding is that it may also involve disturbance of calcium homeostasis, mitochondrial abnormalities, dysfunctional autophagy, accumulation of toxic nondegradable materials, and accelerated production of lipofuscin deposits that are unrelated to ageing.¹⁷