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Glycogen Storage Disease Type 2

Pompe Disease

Glycogen storage disease type 2, sometimes also referred to as Pompe disease, is a genetic disorder inherited as an autosomal recessive trait. Lack of lysosomal acid α-glucosidase results in the accumulation of glycogen within the cell organelles, and this may cause cardiac and skeletal muscle damage as well as neurologic deficits.

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Presentation

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]
  • […] falciforma cea mai frecventa hemoglobinopatie è crize de siklizare è alterari acute ale starii generale, febra F dureri toracice, lombare, ale membrelor, urina inchisa la culoare F insuficienta renala, cardiaca, simptome cerebrale, deces precoce è copii - splenomegalie[rasfoiesc.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]
Respiratory Insufficiency
  • Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent.[eurekaselect.com]
  • In case of respiratory insufficiency, ventilatory assistance should be provided. Respiratory muscle strength training may delay the need for the latter.[symptoma.com]
  • Later onset forms are characterized by skeletal muscle weakness, respiratory insufficiency and hepatomegaly. Cardiac involvement is usually absent or mild.[genedx.com]
  • 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]
  • insufficiency Cardio-respiratory failure (death) Respiratory failure/insufficiency Morning headache & day time tiredness Orthopnea ( breathing difficulties when laying down) Sleep apnea ( stopping breathing whilst asleep) Exertional shortness of breath[cuh.nhs.uk]
Sleep Apnea
  • 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]
  • 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]
  • 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]
  • Weakness: Older adults; Legs & Trunk; Running & Sports Muscle discomfort: Cramps May present with high CK but normal strength Weakness Symmetric Respiratory failure Presenting feature in 5% to 30%: Often with other signs Symptoms: Headache; Somnolence; Dyspnea[neuromuscular.wustl.edu]
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]
  • Fatigue: an important feature of late-onset Pompe disease. J Neurol 2007; 254:941-945. Thurberg B. Insights into the pathophysiology of Pompe disease. Clin Ther 2008;30 Suppl 1:S3. McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM).[rarediseases.org]
  • The goal of treatment is to avoid muscle fatigue and/or cramps induced by exercise.[chp.edu]
  • Symptoms may range from mild fatigue to temporarily incapacitating fatigue with muscle cramping. Late-onset cases may begin showing symptoms of progressive muscle weakness at 60–70 years of age.[encyclopedia.com]
Feeding Difficulties
  • 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]
  • 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]
  • The main clinical findings include floppy baby appearance, delayed motor milestones and feeding difficulties. Moderate hepatomegaly may be present.[en.wikipedia.org]
  • History In the infantile form, the caregiver may report feeding difficulties and difficulty breathing. [7] The child may also have an enlarged tongue and poor muscle tone. An intermediate form manifests with muscle weakness in childhood.[emedicine.medscape.com]
  • difficulties Organomegaly – enlarged liver, spleen & tongue Jaw muscle fatigue & swallowing difficulties At risk of food aspiration Weight stability Other Osteoporosis/osteopenia Neurological & hearing impairment Osteoporosis/osteopenia Treatment Enzyme[cuh.nhs.uk]
Congestive Heart Failure
  • 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]
  • 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 Arrhythmia Variant with no cardiac involvement: Longer survival Liver involvement Pulmonary: Pneumonia Motor Hypotonia (88%) Respiratory distress (80%) Weakness (60%) Anesthesia 18 Succinylcholine: Increased risk Arrhythmia Hyperkalemia[neuromuscular.wustl.edu]
  • 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]
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]
Poor Feeding
  • 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]
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.[emedicine.medscape.com]
  • ., Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy. J Inherit Metab Dis, 2011. 29.[rarediseases.org]
  • Distal weakness more improved than proximal Better pulmonary function Some muscles remain weak Late onset: Mild improvement or disease stabilization reported Course after treatment Improvement: Over months May develop new weakness: Face; Dysarthria; Dysphagia[neuromuscular.wustl.edu]
Macroglossia
  • Patients have also organomegaly (hepatomegaly, splenomegaly, macroglossia) and feeding difficulties.[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]
  • 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]
  • Facial features include macroglossia , wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone.[en.wikipedia.org]
  • Neonatal Cardiac PR interval: Short Congestive heart failure Cardiomyopathy: Vacuolar; Cardiomegaly, Biventricular hypertrophy Glycogen: Increased in myocardium Phosphorylase kinase activity: Absent in myocardium Respiratory Failure Pulmonary edema Macroglossia[neuromuscular.wustl.edu]
Cardiomegaly
  • The heart may be abnormally large (cardiomegaly), but affected individuals usually do not experience heart failure.[ghr.nlm.nih.gov]
  • Over time, cardiomegaly with LV thickening occurs, eventually leading to outflow tract obstruction. Glycogen storage in skeletal muscle leads to hypotonia and weakness.[emedicine.medscape.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]
  • It also has a unique clinical presentation depending on age at onset, ranging from fatal hypotonia and cardiomegaly in the neonate to muscular dystrophy in adults.[emedicine.medscape.com]
Hepatomegaly
  • Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.[ghr.nlm.nih.gov]
  • Although each patient can present individual peculiarities, the most characteristic symptoms are muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.[tellmegen.com]
  • Patients have also organomegaly (hepatomegaly, splenomegaly, macroglossia) and feeding difficulties.[ncbi.nlm.nih.gov]
  • Moreover, those patients may show hepatomegaly and respiratory insufficiency, and they usually don't meet developmental milestones. Their parents often report feeding difficulties.[symptoma.com]
  • Later onset forms are characterized by skeletal muscle weakness, respiratory insufficiency and hepatomegaly. Cardiac involvement is usually absent or mild.[genedx.com]
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]
Muscle Weakness
  • Muscle weakness may also interfere with everyday life; patients may need a wheelchair or become unable to live independently.[symptoma.com]
  • Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.[ghr.nlm.nih.gov]
  • The muscle weakness in this disorder leads to serious breathing problems, and most children with non-classic infantile-onset Pompe disease live only into early childhood.[tellmegen.com]
  • GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease.[ncbi.nlm.nih.gov]
  • Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent.[eurekaselect.com]
Myopathy
  • At late-onset, the spectrum of vacuolar myopathy is more divergent, ranging from almost normal to severe.[ncbi.nlm.nih.gov]
  • 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]
  • Although each patient can present individual peculiarities, the most characteristic symptoms are muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.[tellmegen.com]
  • He was diagnosed with pompe disease after detection of myopathy on EMG due to muscle weakness in the legs and hips. He was started on myozyme vials once every 15 days.[scirp.org]
  • The adult form consists of a slowly progressive proximal myopathy.[icd10data.com]
Muscle Cramp
  • 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]
  • When they do occur, symptoms include: Enlarged liver in infancy Mild growth delay Anxiety, sweating, confusion, or seizures associated with low blood sugar Type 7: Common symptoms of Type 7 include: Muscle cramps and tenderness with exercise Muscle fatigue[cancercarewny.com]
  • Muscle weakness and muscle cramps are the most common symptoms of these types.[my.clevelandclinic.org]
  • 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]
Proximal Muscle Weakness
  • Proximal muscle weakness may eventually lead to the inability to walk independently and the need for a wheelchair.[avrobio.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]
  • muscle weakness (esp. 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[cuh.nhs.uk]
Myalgia
  • , 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]
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]
  • . 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]
  • 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]
Intracranial Hemorrhage
  • Furthermore, those patients may present with cerebral aneurysm or intracranial hemorrhage, presumably due to glycogen accumulation in cerebral vessels.[symptoma.com]
Intracranial Hemorrhage
  • Furthermore, those patients may present with cerebral aneurysm or intracranial hemorrhage, presumably due to glycogen accumulation in cerebral vessels.[symptoma.com]

Workup

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.

Short PR Interval
  • 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]

Treatment

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].

Prognosis

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].

Etiology

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].

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

  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.
  5. van Capelle CI, van der Meijden JC, van den Hout JM, et al. Childhood Pompe disease: clinical spectrum and genotype in 31 patients. Orphanet J Rare Dis. 2016; 11(1):65.
  6. Turaça LT, de Faria DO, Kyosen SO, et al. Novel GAA mutations in patients with Pompe disease. Gene. 2015; 561(1):124-131.
  7. Lim JA, Li L, Raben N. Pompe disease: from pathophysiology to therapy and back again. Front Aging Neurosci. 2014; 6:177.
  8. Malicdan MC, Noguchi S, Nonaka I, Saftig P, Nishino I. Lysosomal myopathies: an excessive build-up in autophagosomes is too much to handle. Neuromuscul Disord. 2008; 18(7):521-529.
  9. Raben N, Roberts A, Plotz PH. Role of autophagy in the pathogenesis of Pompe disease. Acta Myol. 2007; 26(1):45-48.
  10. Prater SN, Banugaria SG, DeArmey SM, et al. The emerging phenotype of long-term survivors with infantile Pompe disease. Genet Med. 2012; 14(9):800-810.
  11. Strothotte S, Strigl-Pill N, Grunert B, et al. Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial. J Neurol. 2010; 257(1):91-97.
  12. van der Ploeg AT, Clemens PR, Corzo D, et al. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010; 362(15):1396-1406.
  13. Manganelli F, Ruggiero L. Clinical features of Pompe disease. Acta Myol. 2013; 32(2):82-84.
  14. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006; 8(5):267-288.
  15. Jones HN, Moss T, Edwards L, Kishnani PS. Increased inspiratory and expiratory muscle strength following respiratory muscle strength training (RMST) in two patients with late-onset Pompe disease. Mol Genet Metab. 2011; 104(3):417-420.
  16. Taglia A, Picillo E, D'Ambrosio P, Cecio MR, Viggiano E, Politano L. Genetic counseling in Pompe disease. Acta Myol. 2011; 30(3):179-181.

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Last updated: 2018-06-21 18:23