Glycogen Storage Disease Type 2

Infants suffering from severe GAA deficiencies usually develop first symptoms at the age of one or two months; progressive hypertrophic cardiomyopathy and hypotonia are the hallmarks of classic infantile GSD2. The latter may be more pronounced in arms and legs or occur in a generalized form ("floppy infants"). Moreover, those patients may show hepatomegaly and respiratory insufficiency, and they usually don't meet developmental milestones. Their parents often report feeding difficulties.

Both non-classic infantile GSD2 and late-onset Pompe disease are characterized by skeletal muscle weakness. Affected individuals often suffer from limb-girdle syndrome and claim walking difficulties. Dyspnea secondary to diaphragm or respiratory muscle weakness may also be observed. In advanced stages of the disease, patients often depend on a wheelchair and ventilatory assistance. Furthermore, those patients may present with cerebral aneurysm or intracranial hemorrhage, presumably due to glycogen accumulation in cerebral vessels.

The determination of GAA activity in blood or fibroblasts is considered the gold standard for diagnosis of GSD2 [13]. In general, pediatric patients diagnosed with the classic infantile form of the disease show less than 3% of residual enzymatic activity, whereas late-onset GSD2 is associated with 3-30% of physiological GAA activity. Such results are diagnostic of Pompe disease.

Histopathological analyses of muscle biopsy specimens may prompt a strong suspicion of GSD2, but this diagnostic approach is less sensitive than the aforementioned assessment of enzymatic activity. If performed, increased glycogen contents and buildup of autophagic vacuoles may be observed. Normal muscle biopsies don't exclude GSD2.

Additionally, standard analyses of blood samples are recommended. Creatine kinase levels are often elevated and in young patients, it is not uncommon to measure increased serum concentrations of hepatic enzymes.

Upon diagnosis of GSD2, radiographic images of the chest should be obtained in order to identify cardiac lesions, and pulmonary function tests should be conducted to assess the involvement of respiratory muscles. Spirometry and similar measures may reveal a reduced respiratory capacity despite the absence of dyspnea.

Since GSD2 is provoked by a deficiency in GAA, causative treatment should aim at replacing this enzyme: Recombinant human GAA has been available for a few years and ERT has become the treatment of choice. Both pediatric and adult patients receive cumulative doses of 20-40 mg alglucosidase alfa per kg body weight via biweekly infusion [10] [11]. As has been indicated above, significant improvements of the patients' prognoses are most likely in case of classic infantile GSD2 if ERT is initiated early.

Further therapy is supportive.

• Standard procedures are often applied to treat hypertrophic cardiomyopathy, but inotropes, ACE-inhibitors and diuretics may be contraindicated [14].
• Progression of muscle weakness may be delayed by regular physical therapy, but patients may nevertheless require a wheelchair at a later time.
• Infants presenting with feeding difficulties may require specialized diets or gastric feedings in order to assure their development and to avoid aspiration pneumonia. Dietary adjustments may also be indicated in case of late-onset GSD2.
• If patients develop contractures, they may need aggressive medication or even surgery.
• In case of respiratory insufficiency, ventilatory assistance should be provided. Respiratory muscle strength training may delay the need for the latter [15].

Classic infantile GSD2 is the most severe form of the disease and its outcome largely depends on the patients condition at the time of diagnosis. If ERT is initiated at an early age - ideally during the first six months of life when muscle damage is not yet severe - cardiac function, motor skill development and survival can be significantly improved [10]. Since ERT has only been available for a few years, long-term outcomes have not yet been evaluated. If left untreated, affected infants often die from hypertrophic cardiomyopathy during their first year of life.

With regards to late-onset GSD2, progressive muscle weakness may eventually affect the respiratory musculature and patients may then depend on ventilation or die from respiratory failure. Also, blunted swallowing reflexes may lead to life-threatening aspiration pneumonia. Muscle weakness may also interfere with everyday life; patients may need a wheelchair or become unable to live independently. Although ERT has been reported to be less efficient in patients suffering from this form of the disease, it may mildly improve lung function and motor skills [11] [12].

In GSD2 patients, glycogen accumulates in lysosomes of distinct tissues owing to a deficiency in GAA. The enzyme GAA is an 1,4- and 1,6-α-glucosidase that catalyzes the hydrogenation of the respective glycosidic bonds of glycogen to glucose. GAA consists of different peptides which do, however, originate from one single 105-kDa precursor. Post-translational modification, specifically proteolytic cleavage in lysosomes, yields smaller peptides of sizes 3.9, 10.3, 19.4 and 70 kDa [2].

The gene encoding for GAA is located on the long arm of chromosome 17, and GSD2 may be triggered by distinct mutations of the corresponding sequence. So far, dozens of mutations of the GAA gene have been described and while there is a strong correlation between the number of affected alleles and disease severity, this does not apply for individual mutations. The disease is inherited with an autosomal recessive trait, but two patients sharing the same genotype don't necessarily present at the same age with similar symptoms [3]. The following general statements can be made [4]:

• Patients suffering from classic infantile GSD2 carry two mutated GAA alleles. GAA activity is either not detectable or very low. Glycogen accumulation primarily affects the heart and patients rapidly develop life-threatening hypertrophic cardiomyopathy.
• If GAA activity is less severely reduced, patients may not develop any symptoms until adolescence or adulthood. They may then be diagnosed with late-onset GSD2. Interestingly, in these patients, glycogen accumulation mainly occurs in skeletal muscle while the heart is generally spared.

Of note, infants may also develop non-classic infantile GSD2. This form of the disease is characterized by progressive skeletal muscle weakness and early death due to respiratory failure. These pediatric patients show minor cardiac lesions or none at all [5].

Estimates regarding the overall incidence of GSD2 vary between 1 per 14,000 and 1 per 250,000 live births [6]. Significant differences between determined geographic regions have been reported, e.g., very low incidence rates in Australia when compared with Europe or North America, but have not yet been explained [3]. With regards to gender predilections, contradictory findings have been published. According to some studies, males are affected more frequently than females. Because GSD2 is inherited with an autosomal trait, there is no obvious explanation for this observation besides secondary gender-related factors [5]. Since any one genotype may be associated with distinct phenotypes, the influence of further genetic or environmental factors is very likely, and the aforementioned hypothesis is thus plausible.

Accumulation of glycogen within lysosomes causes progressive enlargement of those cell organelles. This may cause pressure-induced damage of affected tissues. Eventually, lysosomes may rupture. Subsequent release of lysosomal enzymes, protons and macromolecules further interferes with cell and organ function, and for a long time, it has been assumed that this space-occupying and self-destructive process is the main pathomechanism of GSD2 [7]. However, more recent findings demonstrate the need for a broader perspective.

Lysosomes fulfill a myriad of functions [8]:

• They supply nutrients and molecules required for repair processes.
• They inactivate surface receptors and are thus involved in numerous intracellular pathways.
• They may inactivate intracellular pathogens and are involved in antigen processing.
• They degrade supernumerary or damaged organelles in a process referred to as autophagy.

The latter seems to be of particular importance for GSD2 pathogenesis. It has been hypothesized that lysosomes may be recognized as damaged organelles in very early stages of the disease, when an enlargement did not yet take place [9]. This may cause an autophagic buildup, i.e., the formation of large areas of autophagic activity that disrupt tissue structure. Skeletal muscle and neuronal tissues display enhanced autophagic activity even under physiological conditions [8], and this observation may account for the fact that those tissues are preferentially affected by GSD2. Moreover, dysfunctional autophagy in skeletal muscle may explain why ERT is successful in case of cardiac lesions, but may not remedy skeletal muscle myopathy: trafficking of the recombinant enzyme may be altered and the drug may be degraded in autophagosomes [9].

GSD2 is inherited in an autosomal recessive manner. Thus, affected families may benefit from genetic counseling [16]. Carrier detection is possible and should be realized if such families wish to procreate; molecular techniques are applied to this end. Prenatal diagnosis may be offered. Neonates who may have inherited a defective allele should be tested as early as possible in order to initiate ERT before the onset of symptoms.

Glycogen storage disease type 2 (GSD2) has first been described by the Dutch pathologist Joannes C. Pompe and in his honor, it is also referred to as Pompe disease [1]. Similar to other types of glycogen storage diseases, deficiency or absence of a single enzyme accounts for the cell's inability to degrade glycogen into glucose, i.e., to carry out glycogenolysis. In case of GSD2, the responsible enzyme is the lysosomal acid α-glucosidase (GAA), which is active in lysosomes of many different tissues. This enzyme has also been named acid maltase and thus, acid maltase deficiency is yet another designation of GSD2. GSD2 is the only glycogen storage disease resulting from a deficient lysosomal metabolism.

Despite GAA being an ubiquitous enzyme, dysfunction of striated muscle cells and cardiac cells are most typical for GSD2. In case of complete or near-complete GAA deficiency, infants may show first symptoms when only being a few months old, and this form of GSD2 is associated with a high mortality. If enzyme replacement therapy (ERT) is not initiated in a timely manner, those patients die from hypertrophic cardiomyopathy during the first year of life. Progressive accumulation of glycogen within lysosomes of skeletal muscle cells may cause symptom onset during adolescence or adulthood, with largely varying disease progression. Patients may merely suffer from mild forms of the disease, or may eventually die from respiratory failure due to respiratory muscle insufficiency or aspiration pneumonia. Such differences may partially be explained by varying degrees of GAA deficiency. Unfortunately, ERT has proven less efficient in reversing skeletal muscle abnormalities, and only supportive treatment can be provided in such cases.

Glycogen storage disease type2 (GSD2) is a hereditary disorder sometimes also referred to as Pompe disease or acid maltase deficiency. In fact, the latter designation reveals the pathophysiological basis of GSD2: the reduced activity of a determined enzyme. This enzyme is called acid maltase or acid α-glucosidase (GAA) and is responsible for the breakdown of glycogen, a molecule that stores energy, to glucose. If this enzyme cannot be produced in appropriate quantities due to mutations of the encoding gene, glycogen accumulates in cell organelles, which eventually interferes with cell, tissue and organ function.

Complete or near-complete absence of GAA provokes symptom onset in infants of only few months of age. Here, glycogen accumulation mainly affects the heart and skeletal muscles, and affected infants develop progressive cardiomyopathy and muscle weakness. An early diagnosis allows for the initiation of therapy before irreversible damage occurs and significantly improves cardiac function, motor skill development and survival. If left untreated, those infants often die before they become one year old.

Less severe reductions of GAA activity result in late-onset GSD2. Adolescents or adults may experience progressive muscle weakness, breathing and walking difficulties. Eventually, they may depend on artificial ventilation and may require a wheelchair. Their life expectancy is reduced when compared with the general population.

Causative treatment consists in regular application of the deficient enzyme, and this therapy is known as enzyme replacement therapy. Furthermore, supportive measures may be taken to compensate for cardiac and skeletal muscle lesions and to delay disease progression. Such measures may comprise physical therapy, medication and possibly surgery.

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