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.

• 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]

  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]

  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]

• 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]

  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]

  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]

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

  An analysis of risk factors for osteoporosis, pain, falls and fractures as well as bone metabolism parameters was conducted in 90 patients with 8 different muscle disorders. 54.6% of patients with pompe disease had a reduction of bone density, including [digital.bibliothek.uni-halle.de]

• 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]

  heart failure Cardiomyopathy: Vacuolar; Cardiomegaly, Biventricular hypertrophy Glycogen: Increased in myocardium Phosphorylase kinase activity: Absent in myocardium Respiratory Failure Pulmonary edema Macroglossia : Some patients Death: 3 weeks to 5 [neuromuscular.wustl.edu]

• Difficulty Climbing Stairs

  climbing stairs Frequent falls Scapular winging Respiratory Frequent infections Respiratory insufficiency Cardio-respiratory failure (death) Respiratory failure/insufficiency Morning headache & day time tiredness Orthopnea ( breathing difficulties when [cuh.nhs.uk]

  No sport activities were possible and the boy had even difficulties climbing stairs due to muscle weakness. Moreover, he complained of chest pain after physical exercise and recurrent nausea. [ojrd.biomedcentral.com]

  […] running 30 (32%) • Difficulty performing sports 22 (23%) • Difficulty climbing stairs 24 (26%) • Difficulty walking 15 (16%) • Difficulty rising from an armchair 11 (12%) • Difficulty rising from a lying position 9 (10%) Fatigue 17 (18%) Muscle soreness [dx.doi.org]

• Respiratory Insufficiency

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

  Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. [dx.doi.org]

  […] failure Late-onset Pompe disease can present at various ages with muscle weakness and respiratory insufficiency. [centogene.com]

• 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]

  apnea ( stopping breathing whilst asleep) Exertional shortness of breath Respiratory infections Gastrointestinal Failure to thrive, feeding difficulties Organomegaly – enlarged liver, spleen & tongue Jaw muscle fatigue & swallowing difficulties At risk [cuh.nhs.uk]

  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]

  apnea Scapular winging Scoliosis Low back pain Muscle weakness Signs & Symptoms Unusual symptoms or clusters of more common symptoms Respiratory insufficiency Gait abnormality 11. • Glycogen storage disease type III • Is an autosomal recessive metabolic [slideshare.net]

  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]

• Dyspnea

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

  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]

  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 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. Non-classic form of infantile-onset Pompe disease usually appears by age 1. [tellmegen.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]

  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]

• 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]

• 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]

  The heart may be abnormally large (cardiomegaly), but affected individuals usually do not experience heart failure. [tellmegen.com]

  The primary end point assessed was heart failure-free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. [ncbi.nlm.nih.gov]

• 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]

  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]

  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]

• Heart Murmur

  Video also includes discussion on echocardiogram, aortic stenosis, heart murmurs, subaortic stenosis, sudden cardiac death, LVH, and more. MedCram: Medical education topics explained clearly including: Respiratory lectures such as Asthma and COPD. [youtube.com]

  One patient's disease was diagnosed and treated at the age of 2 months because of an audible heart murmur. [doi.org]

  A heart murmur may be audible upon physical examination. Enlargement of the left ventricle of the heart may cause obstruction of blood flow and cardiac failure. [encyclopedia.com]

• Hepatomegaly

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

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

  A 4-year old male patient was presented with hepatomegaly and persistently elevated liver enzyme. Liver biopsy revealed swollen hepatocyte filled with glycogen storage, suggesting GSDs. [repository.ajou.ac.kr]

  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]

  Accumulation of glycogen in certain tissues, especially muscles, impairs their function. In 2006, the U.S. [malacards.org]

• Muscle Weakness

  Here, glycogen accumulation mainly affects the heart and skeletal muscles, and affected infants develop progressive cardiomyopathy and muscle weakness. [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]

  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]

  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]

  myopathy)(E05.-＋) G73.6*대사성 질환에서의 근병증(Myopathy in metabolic diseases) 당원축적 질환에서의 근병증(Myopathy in glycogen storage disease)(E74.0＋) 지질축적 장애에서의 근병증(Myopathy in lipid storage disorders)(E75.-＋) G73.7*달리 분류된 기타 질환에서의 근병증(Myopathy in other diseases classified [dic.impact.pe.kr]

• Muscle Cramp

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

  […] due to muscle cramps, rhabdomyolysis Treatment: Carbohydrate administration before exercise, high-protein diet GSD VI (Hers disease; 232700) Liver phosphorylase PYGL (14q21-q22)* Frequency: Rare Onset: Early childhood Clinical features: Benign course [msdmanuals.com]

• Osteoporosis

  /osteopenia Neurological & hearing 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]

  An analysis of risk factors for osteoporosis, pain, falls and fractures as well as bone metabolism parameters was conducted in 90 patients with 8 different muscle disorders. 54.6% of patients with pompe disease had a reduction of bone density, including [digital.bibliothek.uni-halle.de]

  Early treatment also decreases the rate of severe problems such as: Gout Kidney failure Life-threatening low blood sugar Liver tumors Possible Complications These complications can occur: Frequent infection Gout Kidney failure Liver tumors Osteoporosis [mountsinai.org]

  […] disability, epilepsy, cancer, chronic fatigue, lupus, anxiety, inner ear problems, meniere's, vertigo or dizziness, kidney failure requiring dialysis or other renal problems, cirrhosis, hepatitis, or other liver disease, pancreatitis, osteoarthritis, osteoporosis [disability-claims.net]

  […] cramps Symptoms of specific types of glycogen storage diseases include: Type I - Von Gierke Disease Enlarged liver and kidneys Low blood sugar High levels of lactate, fats, and uric acid in the blood Impaired growth and delayed puberty Bone thinning from osteoporosis [chp.edu]

• 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]

  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]

  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]

• 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

  trunk and lower limbs) Gait abnormalities Muscle pain Difficulty climbing stairs Frequent falls Scapular winging Respiratory Frequent infections Respiratory insufficiency Cardio-respiratory failure (death) Respiratory failure/insufficiency Morning headache [cuh.nhs.uk]

  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]

  Pompe’s Disease Infantile onset < 12 months Late onset > 12 months Head lag Enlarged tongue Respiratory insufficiency Delayed motor development Muscle weakness Organomegaly Cardiomegaly/ cardiomyopathy Morning headache Daytime somnolence Shortness of [slideshare.net]

  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]

• Limb Weakness

  Phenotypically, she had weak axial and proximal limb muscles that was worse in the lower limbs with poor chest expansion and subsequently developing decompensated respiratory failure necessitating ventilatory support. [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]

• Intracranial Hemorrhage

  Furthermore, those patients may present with cerebral aneurysm or intracranial hemorrhage, presumably due to glycogen accumulation in cerebral vessels. [symptoma.com]

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.

• Atelectasis

  Course Onset usually several years after leg weakness Eventually occurs in 100% Diaphragm involvement: Common & Early; More symptomatic when supine Sleep disordered breathing: Common Expiration more involved than inspiration Secondary features Basilar atelectasis [neuromuscular.wustl.edu]

• 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]

• Wide QRS Complex

  QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy) (50-92%) The non-classic variant of infantile-onset Pompe disease usually presents within the first year of life and is predominantly characterized by the following 1 : [centogene.com]

• 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]

  In addition, the electrocardiogram (ECG) may show conduction abnormalities including a short PR interval, characteristic tall QRS complexes, and Wolf-Parkinson-White syndrome in some patients. 34, 37, 40, 42 Additional symptoms include macroglossia, hepatosplenomegaly [dx.doi.org]

• Biventricular Hypertrophy

  Before MAD, the ECG revealed biventricular hypertrophy and abnormalities in repolarisation with a ST-elevation of 0.5 mV. [ojrd.biomedcentral.com]

  ECG showed biventricular hypertrophy, although the PR intervals were not significantly shortened. [doi.org]

  ATP depletion Activates glycolysis & fatty acid uptake during hypoxic stress or metabolic demand Non-lysosomal cardiac glycogenosis Clinical Onset: Neonatal Cardiac PR interval: Short Congestive heart failure Cardiomyopathy: Vacuolar; Cardiomegaly, Biventricular [neuromuscular.wustl.edu]

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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