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Glycogen storage disease, type II(GSD2)

MedGen UID:
5340
Concept ID:
C0017921
Disease or Syndrome
Synonyms: ACID ALPHA-GLUCOSIDASE DEFICIENCY; Acid maltase deficiency disease; Aglucosidase alfa; Alpha-1,4-glucosidase deficiency; Cardiomegalia glycogenica diffusa; Deficiency of alpha-glucosidase; Deficiency of lysosomal alpha-glucosidase; Glucosidase acid-1,4-alpha deficiency; Glycogen storage disease type 2; Glycogen Storage Disease Type II (Pompe Disease); GLYCOGENOSIS, GENERALIZED, CARDIAC FORM; GSD II; GSD2; POMPE DISEASE
SNOMED CT: Glycogen storage disease, type II (274864009); Pompe's disease (274864009); Pompe disease (274864009); Glycogen storage disease due to acid maltase deficiency (274864009); Alpha-1,4-glucosidase acid deficiency (274864009); Glycogenosis due to acid maltase deficiency (274864009); Glycogenosis type II (274864009); Glycogen heart disease (274864009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GAA (17q25.3)
 
Monarch Initiative: MONDO:0009290
OMIM®: 232300
Orphanet: ORPHA365

Disease characteristics

Excerpted from the GeneReview: Pompe Disease
Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression. Infantile-onset Pompe disease (IOPD; individuals with onset before age 12 months with cardiomyopathy) may be apparent in utero but more typically onset is at the median age of four months with hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy. Without treatment by enzyme replacement therapy (ERT), IOPD commonly results in death by age two years from progressive left ventricular outflow obstruction and respiratory insufficiency. Late-onset Pompe disease (LOPD; including: (a) individuals with onset before age 12 months without cardiomyopathy; and (b) all individuals with onset after age 12 months) is characterized by proximal muscle weakness and respiratory insufficiency; clinically significant cardiac involvement is uncommon. [from GeneReviews]
Authors:
Nancy Leslie  |  Laurie Bailey   view full author information

Additional descriptions

From OMIM
Pompe disease, also known as glycogen storage disease II (GSD2), is the prototypic lysosomal storage disease. In the classic infantile form, cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal muscles dominates the clinical picture (Matsuishi et al., 1984).  http://www.omim.org/entry/232300
From MedlinePlus Genetics
Researchers have described three types of Pompe disease, which differ in severity and the age at which they appear. These types are known as classic infantile-onset, non-classic infantile-onset, and late-onset.

Pompe disease is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally.

The late-onset type of Pompe disease may not become apparent until later in childhood, adolescence, or adulthood. Late-onset Pompe disease is usually milder than the infantile-onset forms of this disorder and is less likely to involve the heart. Most individuals with late-onset Pompe disease experience progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure.

The classic form of infantile-onset Pompe disease begins within a few months of birth. Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects. Affected infants may also fail to gain weight and grow at the expected rate (failure to thrive) and have breathing problems. If untreated, this form of Pompe disease leads to death from heart failure in the first year of life.

The non-classic form of infantile-onset Pompe disease usually appears by age 1. It is characterized by delayed motor skills (such as rolling over and sitting) and progressive muscle weakness. The heart may be abnormally large (cardiomegaly), but affected individuals usually do not experience heart failure. 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.  https://medlineplus.gov/genetics/condition/pompe-disease

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Sinus tachycardia
MedGen UID:
11700
Concept ID:
C0039239
Disease or Syndrome
Heart rate of greater than 100 beats per minute.
Wolff-Parkinson-White pattern
MedGen UID:
12162
Concept ID:
C0043202
Disease or Syndrome
Wolff-Parkinson-White syndrome is a condition characterized by abnormal electrical pathways in the heart that cause a disruption of the heart's normal rhythm (arrhythmia).\n\nThe heartbeat is controlled by electrical signals that move through the heart in a highly coordinated way. A specialized cluster of cells called the atrioventricular node conducts electrical impulses from the heart's upper chambers (the atria) to the lower chambers (the ventricles). Impulses move through the atrioventricular node during each heartbeat, stimulating the ventricles to contract slightly later than the atria.\n\nPeople with Wolff-Parkinson-White syndrome are born with an extra connection in the heart, called an accessory pathway, that allows electrical signals to bypass the atrioventricular node and move from the atria to the ventricles faster than usual. The accessory pathway may also transmit electrical impulses abnormally from the ventricles back to the atria. This extra connection can disrupt the coordinated movement of electrical signals through the heart, leading to an abnormally fast heartbeat (tachycardia) and other changes in heart rhythm. Resulting symptoms include dizziness, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, and fainting (syncope). In rare cases, arrhythmias associated with Wolff-Parkinson-White syndrome can lead to cardiac arrest and sudden death. The most common arrhythmia associated with Wolff-Parkinson-White syndrome is called paroxysmal supraventricular tachycardia.\n\nComplications of Wolff-Parkinson-White syndrome can occur at any age, although some individuals born with an accessory pathway in the heart never experience any health problems associated with the condition.\n\nWolff-Parkinson-White syndrome often occurs with other structural abnormalities of the heart or underlying heart disease. The most common heart defect associated with the condition is Ebstein anomaly, which affects the valve that allows blood to flow from the right atrium to the right ventricle (the tricuspid valve). Additionally, the heart rhythm problems associated with Wolff-Parkinson-White syndrome can be a component of several other genetic syndromes, including hypokalemic periodic paralysis (a condition that causes episodes of extreme muscle weakness), Pompe disease (a disorder characterized by the storage of excess glycogen), Danon disease (a condition that weakens the heart and skeletal muscles and causes intellectual disability), and tuberous sclerosis complex (a condition that results in the growth of noncancerous tumors in many parts of the body).
Right axis deviation
MedGen UID:
534422
Concept ID:
C0232296
Finding
A kind of abnormal ventricular axis in the EKG whereby the QRS axis falls between +90 degrees and 180 degrees, or beyond +100 degrees if the adult range is used.
Shortened PR interval
MedGen UID:
105466
Concept ID:
C0520878
Finding
Reduced time for the PR interval (beginning of the P wave to the beginning of the QRS complex). In adults, normal values are 120 to 200 ms long.
Dilatation of the cerebral artery
MedGen UID:
1386760
Concept ID:
C4476540
Anatomical Abnormality
The presence of a localized dilatation or ballooning of a cerebral artery.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Subarachnoid hemorrhage
MedGen UID:
11625
Concept ID:
C0038525
Disease or Syndrome
Hemorrhage occurring between the arachnoid mater and the pia mater.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Abnormal CNS myelination
MedGen UID:
866800
Concept ID:
C4021152
Anatomical Abnormality
An abnormality of myelination of nerves in the central nervous system.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
Difficulty descending stairs
MedGen UID:
644568
Concept ID:
C0560085
Finding
Reduced ability to desscend stairs.
Firm muscles
MedGen UID:
342558
Concept ID:
C1850656
Finding
Diaphragmatic paralysis
MedGen UID:
1632032
Concept ID:
C4551685
Finding
The presence of a paralyzed diaphragm.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
Pleural effusion
MedGen UID:
10805
Concept ID:
C0032227
Disease or Syndrome
The presence of an excessive amount of fluid in the pleural cavity.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Increased muscle glycogen content
MedGen UID:
409660
Concept ID:
C1968729
Finding
An increased amount of glycogen in muscle tissue.
Increased circulating NT-proBNP concentration
MedGen UID:
1385064
Concept ID:
C4477024
Finding
An elevated level of circulating N-terminal part of the prohormone of B-type natriuretic peptide (BNP).
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.
Increased circulating creatine kinase MB isoform
MedGen UID:
1690106
Concept ID:
C5139211
Finding
An increased concentration of the MB isoform of creatine kinase in the blood circulation.
Reduced muscle alpha-1,4-glucosidase activity
MedGen UID:
1054136
Concept ID:
CN376600
Finding
Activity of the enzyme alpha-1,4-glucosidase activity in muscle tissue is below the lower limit of normal.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.

Term Hierarchy

Follow this link to review classifications for Glycogen storage disease, type II in Orphanet.

Professional guidelines

PubMed

Bellotti AS, Andreoli L, Ronchi D, Bresolin N, Comi GP, Corti S
Mol Neurobiol 2020 Feb;57(2):1259-1280. Epub 2019 Nov 12 doi: 10.1007/s12035-019-01820-5. PMID: 31713816
Bosman L, Hoeks SE, González Candel A, van den Hout HJM, van der Ploeg AT, Staals LM
Paediatr Anaesth 2018 May;28(5):428-435. Epub 2018 Mar 25 doi: 10.1111/pan.13361. PMID: 29575534
Chien YH, Hwu WL, Lee NC
Pediatr Neonatol 2013 Aug;54(4):219-27. Epub 2013 Apr 28 doi: 10.1016/j.pedneo.2013.03.009. PMID: 23632029

Curated

American College of Medical Genetics ACT SHEET, Newborn Screening ACT Sheet- Pompe Disease (Glycogen Storage Disease type II), 2022

American College of Medical Genetics and Genomics, Algorithm, Pompe disease: acid alpha-glucosidase deficiency, 2022

Recent clinical studies

Etiology

Hannah WB, Derks TGJ, Drumm ML, Grünert SC, Kishnani PS, Vissing J
Nat Rev Dis Primers 2023 Sep 7;9(1):46. doi: 10.1038/s41572-023-00456-z. PMID: 37679331
Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforêt P, Toscano A, Castelli J, Díaz-Manera J, Goldman M, van der Ploeg AT, Bratkovic D, Kuchipudi S, Mozaffar T, Kishnani PS; PROPEL Study Group
Lancet Neurol 2021 Dec;20(12):1027-1037. doi: 10.1016/S1474-4422(21)00331-8. PMID: 34800400
Davison JE
J Mother Child 2020 Oct 2;24(2):3-8. doi: 10.34763/jmotherandchild.20202402si.2001.000002. PMID: 33554498Free PMC Article
Reuser AJJ, van der Ploeg AT, Chien YH, Llerena J Jr, Abbott MA, Clemens PR, Kimonis VE, Leslie N, Maruti SS, Sanson BJ, Araujo R, Periquet M, Toscano A, Kishnani PS, On Behalf Of The Pompe Registry Sites
Hum Mutat 2019 Nov;40(11):2146-2164. Epub 2019 Aug 7 doi: 10.1002/humu.23878. PMID: 31342611Free PMC Article
Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ
Nat Rev Dis Primers 2018 Oct 1;4(1):27. doi: 10.1038/s41572-018-0025-4. PMID: 30275469

Diagnosis

Labella B, Cotti Piccinelli S, Risi B, Caria F, Damioli S, Bertella E, Poli L, Padovani A, Filosto M
Biomolecules 2023 Aug 22;13(9) doi: 10.3390/biom13091279. PMID: 37759679Free PMC Article
Hannah WB, Derks TGJ, Drumm ML, Grünert SC, Kishnani PS, Vissing J
Nat Rev Dis Primers 2023 Sep 7;9(1):46. doi: 10.1038/s41572-023-00456-z. PMID: 37679331
Davison JE
J Mother Child 2020 Oct 2;24(2):3-8. doi: 10.34763/jmotherandchild.20202402si.2001.000002. PMID: 33554498Free PMC Article
Taverna S, Cammarata G, Colomba P, Sciarrino S, Zizzo C, Francofonte D, Zora M, Scalia S, Brando C, Curto AL, Marsana EM, Olivieri R, Vitale S, Duro G
Aging (Albany NY) 2020 Aug 3;12(15):15856-15874. doi: 10.18632/aging.103794. PMID: 32745073Free PMC Article
van der Ploeg AT, Reuser AJ
Lancet 2008 Oct 11;372(9646):1342-53. doi: 10.1016/S0140-6736(08)61555-X. PMID: 18929906

Therapy

Labella B, Cotti Piccinelli S, Risi B, Caria F, Damioli S, Bertella E, Poli L, Padovani A, Filosto M
Biomolecules 2023 Aug 22;13(9) doi: 10.3390/biom13091279. PMID: 37759679Free PMC Article
Blair HA
Drugs 2023 Jun;83(8):739-745. doi: 10.1007/s40265-023-01886-5. PMID: 37184753Free PMC Article
Davison JE
J Mother Child 2020 Oct 2;24(2):3-8. doi: 10.34763/jmotherandchild.20202402si.2001.000002. PMID: 33554498Free PMC Article
Meena NK, Raben N
Biomolecules 2020 Sep 18;10(9) doi: 10.3390/biom10091339. PMID: 32962155Free PMC Article
van der Ploeg AT, Reuser AJ
Lancet 2008 Oct 11;372(9646):1342-53. doi: 10.1016/S0140-6736(08)61555-X. PMID: 18929906

Prognosis

Hannah WB, Derks TGJ, Drumm ML, Grünert SC, Kishnani PS, Vissing J
Nat Rev Dis Primers 2023 Sep 7;9(1):46. doi: 10.1038/s41572-023-00456-z. PMID: 37679331
Meena NK, Raben N
Biomolecules 2020 Sep 18;10(9) doi: 10.3390/biom10091339. PMID: 32962155Free PMC Article
Reuser AJJ, van der Ploeg AT, Chien YH, Llerena J Jr, Abbott MA, Clemens PR, Kimonis VE, Leslie N, Maruti SS, Sanson BJ, Araujo R, Periquet M, Toscano A, Kishnani PS, On Behalf Of The Pompe Registry Sites
Hum Mutat 2019 Nov;40(11):2146-2164. Epub 2019 Aug 7 doi: 10.1002/humu.23878. PMID: 31342611Free PMC Article
Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ
Nat Rev Dis Primers 2018 Oct 1;4(1):27. doi: 10.1038/s41572-018-0025-4. PMID: 30275469
van der Ploeg AT, Reuser AJ
Lancet 2008 Oct 11;372(9646):1342-53. doi: 10.1016/S0140-6736(08)61555-X. PMID: 18929906

Clinical prediction guides

Kishnani PS, Diaz-Manera J, Toscano A, Clemens PR, Ladha S, Berger KI, Kushlaf H, Straub V, Carvalho G, Mozaffar T, Roberts M, Attarian S, Chien YH, Choi YC, Day JW, Erdem-Ozdamar S, Illarioshkin S, Goker-Alpan O, Kostera-Pruszczyk A, van der Ploeg AT, An Haack K, Huynh-Ba O, Tammireddy S, Thibault N, Zhou T, Dimachkie MM, Schoser B; COMET Investigator Group
JAMA Neurol 2023 Jun 1;80(6):558-567. doi: 10.1001/jamaneurol.2023.0552. PMID: 37036722Free PMC Article
Kishnani PS, Kronn D, Brassier A, Broomfield A, Davison J, Hahn SH, Kumada S, Labarthe F, Ohki H, Pichard S, Prakalapakorn SG, Haack KA, Kittner B, Meng X, Sparks S, Wilson C, Zaher A, Chien YH; Mini-COMET Investigators
Genet Med 2023 Feb;25(2):100328. Epub 2022 Dec 21 doi: 10.1016/j.gim.2022.10.010. PMID: 36542086
Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforêt P, Toscano A, Castelli J, Díaz-Manera J, Goldman M, van der Ploeg AT, Bratkovic D, Kuchipudi S, Mozaffar T, Kishnani PS; PROPEL Study Group
Lancet Neurol 2021 Dec;20(12):1027-1037. doi: 10.1016/S1474-4422(21)00331-8. PMID: 34800400
Diaz-Manera J, Kishnani PS, Kushlaf H, Ladha S, Mozaffar T, Straub V, Toscano A, van der Ploeg AT, Berger KI, Clemens PR, Chien YH, Day JW, Illarioshkin S, Roberts M, Attarian S, Borges JL, Bouhour F, Choi YC, Erdem-Ozdamar S, Goker-Alpan O, Kostera-Pruszczyk A, Haack KA, Hug C, Huynh-Ba O, Johnson J, Thibault N, Zhou T, Dimachkie MM, Schoser B; COMET Investigator Group
Lancet Neurol 2021 Dec;20(12):1012-1026. doi: 10.1016/S1474-4422(21)00241-6. PMID: 34800399
Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-onset Pompe Disease
Muscle Nerve 2012 Mar;45(3):319-33. Epub 2011 Dec 15 doi: 10.1002/mus.22329. PMID: 22173792Free PMC Article

Recent systematic reviews

Dalmia S, Sharma R, Ramaswami U, Hughes D, Jahnke N, Cole D, Smith S, Remmington T
Cochrane Database Syst Rev 2023 Dec 12;12(12):CD012993. doi: 10.1002/14651858.CD012993.pub2. PMID: 38084761Free PMC Article
Roger AL, Sethi R, Huston ML, Scarrow E, Bao-Dai J, Lai E, Biswas DD, El Haddad L, Strickland LM, Kishnani PS, ElMallah MK
Expert Opin Biol Ther 2022 Sep;22(9):1117-1135. Epub 2022 Apr 27 doi: 10.1080/14712598.2022.2067476. PMID: 35428407Free PMC Article
van Kooten HA, Roelen CHA, Brusse E, van der Beek NAME, Michels M, van der Ploeg AT, Wagenmakers MAEM, van Doorn PA
Neuromuscul Disord 2021 Feb;31(2):79-90. Epub 2020 Nov 9 doi: 10.1016/j.nmd.2020.10.009. PMID: 33386209
Schoser B, Bilder DA, Dimmock D, Gupta D, James ES, Prasad S
BMC Neurol 2017 Nov 22;17(1):202. doi: 10.1186/s12883-017-0983-2. PMID: 29166883Free PMC Article
Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-onset Pompe Disease
Muscle Nerve 2012 Mar;45(3):319-33. Epub 2011 Dec 15 doi: 10.1002/mus.22329. PMID: 22173792Free PMC Article

Supplemental Content

Table of contents

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    Practice guidelines

    • PubMed
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    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics ACT SHEET, Newborn Screening ACT Sheet- Pompe Disease (Glycogen Storage Disease type II), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Pompe disease: acid alpha-glucosidase deficiency, 2022

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