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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]
Fatigue
  • 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]
  • 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]
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 main clinical findings include floppy baby appearance, delayed motor milestones and feeding difficulties. Moderate hepatomegaly may be present.[en.wikipedia.org]
  • 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
  • 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 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]
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]
  • 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 / cramps 16 (17%) Respiratory failure 1 (1%) Clinical features Ptosis[dx.doi.org]
Difficulty Walking
  • walking 15 (16%) • Difficulty rising from an armchair 11 (12%) • Difficulty rising from a lying position 9 (10%) Fatigue 17 (18%) Muscle soreness / cramps 16 (17%) Respiratory failure 1 (1%) Clinical features Ptosis 22 (23%) Bulbar muscle weakness d[dx.doi.org]
Respiratory Insufficiency
  • Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent.[dx.doi.org]
  • Later onset forms are characterized by skeletal muscle weakness, respiratory insufficiency and hepatomegaly. Cardiac involvement is usually absent or mild.[genedx.com]
  • In case of respiratory insufficiency, ventilatory assistance should be provided. Respiratory muscle strength training may delay the need for the latter.[symptoma.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]
  • 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]
  • 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]
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]
  • Patients have also organomegaly (hepatomegaly, splenomegaly, macroglossia) and feeding difficulties.[ncbi.nlm.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]
  • Facial features include macroglossia, wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone.[en.wikipedia.org]
  • Macroglossia, mild hepatomegaly, feeding difficulties, and significantly delayed motor milestones are also typical manifestations of this rapidly progressive form; most patients do not survive beyond the first year of life and die from cardiac failure[dx.doi.org]
Cardiomegaly
  • 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]
  • 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]
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]
  • 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]
  • Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.[ghr.nlm.nih.gov]
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]
  • 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]
  • Glycogen storage disease type II (GSD H) is an autosomal recessive myopathy. Early and late-onset phenotypes are distinguished - infantile, juvenile and adult.[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]
  • However, experience has shown that relying solely on visualizing a periodic acid-Schiff-positive vacuolar myopathy to identify late-onset Pompe disease often leads to false-negative results and subsequent delays in identification and treatment of the[ncbi.nlm.nih.gov]
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]
  • 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]
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]
  • 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]
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]
  • Voermans and B.G.M. van Engelen, The yield of diagnostic work-up of patients presenting with myalgia, exercise intolerance, or fatigue, Neuromuscular Disorders, 27, 3, (243), (2017).[dx.doi.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]
Intracranial Hemorrhage
  • Furthermore, those patients may present with cerebral aneurysm or intracranial hemorrhage, presumably due to glycogen accumulation in cerebral vessels.[symptoma.com]
Areflexia
  • 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]
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]
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]
  • ECG shows a short PR interval as well as very tall QRS complexes.[dx.doi.org]
  • 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[dx.doi.org]

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: 2019-07-11 20:08