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.

• Fatigue

  Snapshot A 16-year-old male presents with fatigue and muscle cramps. He recently tried out for the basketball team and has found himself exhausted soon after performing high-intensity sprints. When resting briefly, he said he gets his “second wind.” [medbullets.com]

  Vision Loss, Clinical Obesity, Attention Deficit Hyper Activity or adhd, Bipolar Disorder or Manic Depression, Panic Disorder, schizophrenia, autism, head trauma, memory loss, low iq, mental retardation, learning disability, epilepsy, cancer, chronic fatigue [disability-claims.net]

  In the early morning the child may have low blood sugar which could cause: Paleness Vomiting Extreme fatigue Convulsions The children may also have a mild growth delay. They also may have poor exercise tolerance. [cancercarewny.com]

  The goal of treatment is to avoid muscle fatigue and/or cramps induced by exercise. [chp.edu]

• Pain

  Moreover, he complained of chest pain after physical exercise and recurrent nausea. [ojrd.biomedcentral.com]

  Characterised by painful cramps following sustained exercise. [kmle.co.kr]

  Pain 1990; 41 : 139–150. 138 Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, et al. The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain 2001; 93 : 173–183. 139 McCaffery M. Choosing a faces pain scale. [dx.doi.org]

  Common hereditary enzyme deficiency causing varying degrees of hemolytic anemia; can cause favism, some drug induced hemolytic anemias, and chronic nonspherocytic hemolytic anemia Glycogenosis due to muscle phosphorylase deficiency; characterized by painful [icd9data.com]

  The primary symptom is exercise intolerance, muscle cramping, fatigue and pain depending on the muscle being used. Immediately afterwards they get post exercise red urine due to rhabdomyolysis. [youtube.com]

• Feeding Difficulties

  Symptoms : Difficulty in feeding Difficulty in hearing Feeling distress during normal respiratory activity Non – classical infantile onset Second form of disease i.e. the non – classical occurs when the infant reaches the age of one. [foodnhealth.org]

  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. [symptoma.com]

  The infantile form presents in the first six months of life (typically at between 4-8 weeks) with weakness, hypotonia, respiratory distress, feeding difficulties and heart failure. [patient.info]

  Clinical hallmarks of classic infantile-onset Pompe disease include hypotonia, generalized muscle weakness, cardiomegaly, hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress, and hearing loss. [emedicine.medscape.com]

• Congestive Heart Failure

  Gene therapy remains a potentially effective treatment for the future.[13] Complications In the infantile form, cardiomegaly and congestive heart failure lead to death. [patient.info]

  Congestive heart failure, respiratory failure, and/or aspiration pneumonia are the most frequent causes of death, which usually occurs within 1 year [1]. [path.upmc.edu]

  Congestive heart failure or cardiomegaly is an important finding and suggests the diagnosis. This may be accompanied by a systolic murmur. Hepatomegaly may be present. [emedicine.medscape.com]

  The report in 1984 first suggested that serial echocardiograms might be able to identify individuals with GSD III who have cardiac involvement and are at risk of symptomatic congestive heart failure. [nature.com]

• Poor Feeding

  Infantile-onset disease is characterized by poor feeding and failure to thrive, hypotonia, and an enlarged heart. If untreated, the cardiac manifestations usually cause death in the first year of life. [sema4.com]

  Infantile GSDII presents during the first weeks or months of life with poor feeding, failure to thrive, macroglossia, severe hypotonia, cardiomegaly, mild hepatomegaly, and respiratory insufficiency. [genedx.com]

  Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia).[1] Affected infants may also have poor feeding, failure to gain weight and grow at the expected rate (failure to [rarediseases.info.nih.gov]

  Infantile-onset Pompe disease is suspected in infants with the following 1, 2, 3: Poor feeding/failure to thrive (44-97% of cases) Motor delay/muscle weakness (20-63%) Respiratory concerns (infections/difficulty) (27-78%) Cardiac problems (shortened PR [centogene.com]

  Diagnosis[edit] In the early-onset form, an infant will present with poor feeding causing failure to thrive, or with difficulty breathing. The usual initial investigations include chest X ray, electrocardiogram and echocardiography. [en.wikipedia.org]

• Splenomegaly

  Patients have also organomegaly (hepatomegaly, splenomegaly, macroglossia) and feeding difficulties. [ncbi.nlm.nih.gov]

  Early infancy; rarely, the neonatal period, late childhood, or adulthood (manifesting as a variant nonprogressive or a neuromuscular form) Clinical features:Hepatomegaly with progressive cirrhosis and hypoglycemia, esophageal varices, and ascites; splenomegaly [msdmanuals.com]

  In these storage disorders, however, splenomegaly is massive and helps in the differential diagnosis.43 Hypoglycemia can also be used to distinguish GSD from other metabolic abnormalities. [nature.com]

  Occasional (29-5%) HP:0002205 22 hepatomegaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0002240 23 myopathy 58 31 occasional (7.5%) Occasional (29-5%) HP:0003198 24 respiratory insufficiency 31 HP:0002093 25 hearing impairment 31 HP:0000365 26 splenomegaly [malacards.org]

  Splenomegaly, liver cirrhosis, doll facies, osteoporosis, neurologic disease, elevated serum lactate, metabolic acidosis and renal tubular acidosis have been described very rarely. [wjgnet.com]

• Respiratory Insufficiency

  Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. [eurekaselect.com]

  Later onset forms are characterized by skeletal muscle weakness, respiratory insufficiency and hepatomegaly. Cardiac involvement is usually absent or mild. [genedx.com]

  It causes a slowly progressive myopathy which is ultimately fatal, usually because of respiratory insufficiency. Despite the wide variability in clinical manifestations, one and the same enzyme, lysosomal acid maltase, is deficient in both forms. [repub.eur.nl]

• Sleep Apnea

  Symptoms : Sleep apnea Facing difficulty in breathing Consistent weakness of the muscles Liver enlargement Hyperlordosis Diagnosis of Pompe Disease ECG i.e. electro cardio gram and Chest X – ray can be used for diagnosis of pompe disease. [foodnhealth.org]

  Clinical manifestations of late-onset Pompe disease include the following 1: Progressive proximal muscle weakness (95%) Respiratory insufficiency Exercise intolerance Exertional dyspnea Orthopnea Sleep apnea Hyperlordosis and/or scoliosis (childhood and [centogene.com]

  Patients present with frequent respiratory infections, respiratory distress, orthopnea, sleep apnea, somnolence, morning headaches. As respiratory failure progress, assisted ventilation is required. [ncbi.nlm.nih.gov]

  Treatment of respiratory insufficiency and obstructive sleep apnea should be followed with some type of monitoring so as to document its effectiveness. [dx.doi.org]

  Muscle weakness may interfere with normal daily activities, and respiratory insufficiency is often associated with sleep apnea. Death usually results from respiratory failure. [emedicine.medscape.com]

• Dyspnea

  Spirometry and similar measures may reveal a reduced respiratory capacity despite the absence of dyspnea. [symptoma.com]

  Patients presenting with either a limb‐girdle syndrome or dyspnea secondary to diaphragm weakness should undergo further testing, including evaluations of muscle strength, motor function, and pulmonary function. [dx.doi.org]

  Clinical manifestations of late-onset Pompe disease include the following 1: Progressive proximal muscle weakness (95%) Respiratory insufficiency Exercise intolerance Exertional dyspnea Orthopnea Sleep apnea Hyperlordosis and/or scoliosis (childhood and [centogene.com]

  A 52-year-old woman presented to our clinic due to dyspnea on exertion, severe general weakness, and hepatomegaly. Hypertrophic cardiomyopathy was diagnosed based on echocardiogram findings. [dbpia.co.kr]

  MalaCards based summary : Glycogen Storage Disease Ii, also known as glycogen storage disease type ii, is related to danon disease and wolff-parkinson-white syndrome, and has symptoms including dyspnea and weakness. [malacards.org]

• Failure to Thrive

  It is characterized by a failure to thrive, cardiorespiratory difficulties and weakness with hypotonia, and leads to death within the first two years of life. The muscular form may occur in childhood or even in adults. [repub.eur.nl]

  Infantile-onset disease is characterized by poor feeding and failure to thrive, hypotonia, and an enlarged heart. If untreated, the cardiac manifestations usually cause death in the first year of life. [sema4.com]

  Infantile GSDII presents during the first weeks or months of life with poor feeding, failure to thrive, macroglossia, severe hypotonia, cardiomegaly, mild hepatomegaly, and respiratory insufficiency. [genedx.com]

  Affected infants may also fail to gain weight and grow at the expected rate (failure to thrive) and have breathing problems. If untreated, this form of Pompe disease leads to death from heart failure in the first year of life. [ghr.nlm.nih.gov]

• Dysphagia

  Oropharyngeal dysphagia in infants and children with infantile Pompe disease. Dysphagia. 2009 Sep 10. [Medline]. Musumeci O, la Marca G, Spada M, et al. LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population. [emedicine.medscape.com]

  Oropharyngeal dysphagia in infants and children with infantile pompe disease. Dysphagia. 2010; 25 :277–83. [ PubMed : 19763689 ] Kallwass H, Carr C, Gerrein J, Titlow M, Pomponio R, Bali D, Dai J, Kishnani P, Skrinar A, Corzo D, Keutzer J. [ncbi.nlm.nih.gov]

• Macroglossia

  Infantile GSDII presents during the first weeks or months of life with poor feeding, failure to thrive, macroglossia, severe hypotonia, cardiomegaly, mild hepatomegaly, and respiratory insufficiency. [genedx.com]

  The presentation may include one or a few of the following: muscle weakness/hypotonia motor delay hypertrophic cardiomyopathy hepatomegaly macroglossia failure to thrive respiratory infections Late-onset disease often manifests itself with proximal muscle [radiopaedia.org]

  Patients have also organomegaly (hepatomegaly, splenomegaly, macroglossia) and feeding difficulties. [ncbi.nlm.nih.gov]

  Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia).[1] Affected infants may also have poor feeding, failure to gain weight and grow at the expected rate (failure to [rarediseases.info.nih.gov]

  About half of such patients also have macroglossia. Congestive heart failure, respiratory failure, and/or aspiration pneumonia are the most frequent causes of death, which usually occurs within 1 year [1]. [path.upmc.edu]

• Cardiomegaly

  Gene therapy remains a potentially effective treatment for the future.[13] Complications In the infantile form, cardiomegaly and congestive heart failure lead to death. [patient.info]

  The clinical presentation of Pompe disease encompasses a wide range of phenotypes but all include various degrees of cardiomegaly. [themedicalbiochemistrypage.org]

  Firstly, the hepatomegaly and cardiomegaly were diagnosed. Then an infantile form of Pompe disease was found. The patient got enzyme replacement therapy without positive result. [dspace.bsu.edu.ru]

  Cardiomegaly (reported in 92% of patients), hypotonia (88%) cardiomyopathy (88%) respiratory distress (78%), muscle weakness (63%) were the most common findings ( 7 ). [ncbi.nlm.nih.gov]

  Infantile GSDII presents during the first weeks or months of life with poor feeding, failure to thrive, macroglossia, severe hypotonia, cardiomegaly, mild hepatomegaly, and respiratory insufficiency. [genedx.com]

• Hepatomegaly

  Patients have also organomegaly (hepatomegaly, splenomegaly, macroglossia) and feeding difficulties. [ncbi.nlm.nih.gov]

  Later onset forms are characterized by skeletal muscle weakness, respiratory insufficiency and hepatomegaly. Cardiac involvement is usually absent or mild. [genedx.com]

  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 [ommbid.mhmedical.com]

  Symptoms are relatively mild; hepatomegaly, increased liver glycogen, and decreased leukocyte phosphorylase are present. Liver shrinkage occurs in response to glucagon. [kmle.co.kr]

  Firstly, the hepatomegaly and cardiomegaly were diagnosed. Then an infantile form of Pompe disease was found. The patient got enzyme replacement therapy without positive result. [dspace.bsu.edu.ru]

• Hearing Impairment

  impairment Osteoporosis/osteopenia Treatment Enzyme replacement therapy (ERT) Until recently in the UK treatment for Pompe disease was limited to supportive therapy. [cuh.nhs.uk]

  impairment 31 HP:0000365 26 splenomegaly 31 HP:0001744 27 fever 31 HP:0001945 28 abnormality of the cardiovascular system 58 Very frequent (99-80%) 29 abnormality of metabolism/homeostasis 58 Very frequent (99-80%) 30 elevated serum creatine phosphokinase [malacards.org]

• Muscle Weakness

  Muscle weakness may also interfere with everyday life; patients may need a wheelchair or become unable to live independently. [symptoma.com]

  The juvenile form presents later in childhood with delayed motor development, muscle weakness and hypotonia. The adult form usually presents as skeletal and respiratory muscle weakness. The typical age of presentation is 20-40 years. [patient.info]

  Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects. [ghr.nlm.nih.gov]

  Figure 2 Muscle weakness in adults with Pompe disease. [dx.doi.org]

• Myopathy

  At late-onset, the spectrum of vacuolar myopathy is more divergent, ranging from almost normal to severe. [ncbi.nlm.nih.gov]

  Patients at the other end of the spectrum present in the third to seventh decade, usually with a slowly progressive proximal myopathy. [ommbid.mhmedical.com]

  The glycogen accumulation leads to myopathy / progressive muscle weakness, notably limb-girdle muscle weakness. The myopathy may also cause respiratory distress, and Pompe disease often presents as exercise intolerance. [youtube.com]

  Homepage Rare diseases Search Search for a rare disease Glycogen storage disease due to acid maltase deficiency Disease definition Glycogen storage disease due to acid maltase deficiency (AMD) is an autosomal recessive trait leading to metabolic myopathy [orpha.net]

• Muscle Cramp

  The signs and symptoms of Pompe disease may include: Low blood sugar Enlarged liver (hepatomegaly) Enlarged heart (cardiomegaly) and blockages of some vessels leaving the heart Enlarged tongue Slow growth Muscle cramps Progressive muscle weakness (including [mda.org.au]

  cramps during exercise Extreme fatigue after exercise Burgundy-colored urine after exercise Types VI, IX - Hers' Disease Liver enlargement occurs, but diminishes with age Low blood sugar Type VII- Tarui's Disease Muscle cramps with exercise Anemia Type [chp.edu]

  Snapshot A 16-year-old male presents with fatigue and muscle cramps. He recently tried out for the basketball team and has found himself exhausted soon after performing high-intensity sprints. When resting briefly, he said he gets his “second wind.” [medbullets.com]

  The primary symptom is exercise intolerance, muscle cramping, fatigue and pain depending on the muscle being used. Immediately afterwards they get post exercise red urine due to rhabdomyolysis. [youtube.com]

• Proximal Muscle Weakness

  Progressive proximal muscle weakness including major impairment of respiratory function dominates the picture. Death results usually from complications associated with respiratory failure. [ommbid.mhmedical.com]

  weakness, which may be interpreted as clumsiness 2. [radiopaedia.org]

  Proximal muscle weakness may eventually lead to the inability to walk independently and the need for a wheelchair. [avrobio.com]

  We present a case of adult-onset Pompe’s disease with progressive proximal muscles weakness over 5 years and respiratory failure on admission, requiring prolonged mechanical ventilation. [hindawi.com]

  Late-onset GSD II is characterized by proximal muscle weakness and respiratory compromise. Adults with late-onset GSD II typically present with proximal muscle weakness between the second and sixth decades of life. [emedicine.medscape.com]

• Myalgia

  There are 11 hereditary disorders of glycogen metabolism affecting muscle alone or together with other tissues, and they cause two main clinical syndromes: episodic, recurrent exercise intolerance with cramps, myalgia, and myoglobinuria; or fixed, often [ncbi.nlm.nih.gov]

  myoglobinuria "Second wind" phenomenom rapid relief of fatigue and myalgia secondary to increase blood flow, improved free fatty acid delivery, and liver glucose utilization Sucrose before exercise may improve symptoms Evaluation Von Gierke disease [medbullets.com]

  II deficiency Most common cause of recurrent myoglobinuria Myoglobinuria occurs after moderate exercise or prolonged fasting Mitochondrial disorders Complex III, or I or IV Premature fatigue or breathlessness after normal activities of daily living Myalgias [neuromuscular.wustl.edu]

• Dark Urine

  •About one half of all patients will have experienced myoglobinuria (dark urine) following intense exercise. 21. [slideshare.net]

  Half of the affected patients present a massive increase of creatine kinase (CK) and a crisis of rhabdomyolysis with myoglobinuria (dark urine) after intense exercise, caused by the necrosis of the muscular fibers. [heighpubs.org]

• Headache

  Society, California Medical Association, California Neurology Society, International Headache Society, San Francisco Medical Society, San Francisco Neurological Society Disclosure: Nothing to disclose. [emedicine.medscape.com]

  Patients present with frequent respiratory infections, respiratory distress, orthopnea, sleep apnea, somnolence, morning headaches. As respiratory failure progress, assisted ventilation is required. [ncbi.nlm.nih.gov]

  One patient in the placebo group withdrew owing to headaches. [doi.org]

• Limb Weakness

  Electromyography may be used initially to distinguish Pompe from other causes of limb weakness. The findings on biochemical tests are similar to those of the infantile form, with the caveat that the creatinine kinase may be normal in some cases. [en.wikipedia.org]

  Two weeks prior to admission, she had worsening bilateral upper and lower limbs weakness with reduced effort tolerance and breathing difficulties, rendering her unable to walk. Within a day, her breathing worsened necessitating assisted ventilation. [hindawi.com]

  The symptoms begin at any age in adulthood and may resemble muscular dystrophies; progressive difficulty in walking, and proximal limb weakness which was greater in the arms than the legs. Upper and lower motor neurons are involved. [wjgnet.com]

• Gowers Sign

  The patient presented unmistakable signs of muscular atrophy in the upper and lower limbs, as well as positive Gowers' sign. Levels of creatinkinase in serum were high. His functional respiratory capacity was diminished. [ncbi.nlm.nih.gov]

  sign Joint contractures Cardiac hypertrophy (childhood onset) The current worldwide prevalence of Pompe disease is estimated at 1 in 5,000 to 10,000 people 4, 5. [centogene.com]

• Areflexia

  0001945 28 abnormality of the cardiovascular system 58 Very frequent (99-80%) 29 abnormality of metabolism/homeostasis 58 Very frequent (99-80%) 30 elevated serum creatine phosphokinase 58 Very frequent (99-80%) 31 generalized hypotonia 31 HP:0001290 32 areflexia [malacards.org]

  A few other mutations are also thought to be neuroprotective. 211 Individuals with at least one p.Q292K mutation had later-onset neurologic abnormalities such as mental retardation, expressive language delay, areflexia, and abnormal retinal findings. [dx.doi.org]

• Absent Deep Tendon Reflex

  deep tendon reflexes Metabolic Features: fever of central origin Abdomen Spleen: splenomegaly Cardiovascular Heart: cardiomegaly wolf-parkinson-white syndrome shortened p-r interval on ekg huge qrs complexes Muscle Soft Tissue: proximal muscle weakness [malacards.org]

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.

• Huge QRS Complexes

  qrs complexes Muscle Soft Tissue: proximal muscle weakness weakness firm muscles myopathic pattern on emg Laboratory Abnormalities: elevated serum creatine kinase elevated ast and ldh, especially infantile-onset presence of vacuoles on muscle biopsy [malacards.org]

• Short PR Interval

  ECG: short PR interval and elevated QRS complexes in the infantile form. [patient.info]

  The electrocardiogram typically shows short PR intervals and tall QRS complexes; true Wolf-Parkinson-White syndrome has been reported in some patients. [ncbi.nlm.nih.gov]

  ECG shows a short PR interval as well as very tall QRS complexes. [dx.doi.org]

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.

1. Dos Santos OC, Schultz R. The infantile-onset form of Pompe disease: an autopsy diagnosis. Autops Case Rep. 2015; 5(4):45-51.
2. Moreland RJ, Jin X, Zhang XK, et al. Lysosomal acid alpha-glucosidase consists of four different peptides processed from a single chain precursor. J Biol Chem. 2005; 280(8):6780-6791.
3. De Filippi P, Saeidi K, Ravaglia S, et al. Genotype-phenotype correlation in Pompe disease, a step forward. Orphanet J Rare Dis. 2014; 9:102.
4. Kroos M, Hoogeveen-Westerveld M, van der Ploeg A, Reuser AJ. The genotype-phenotype correlation in Pompe disease. Am J Med Genet C Semin Med Genet. 2012; 160c(1):59-68.
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