Sandbox:Vellayat

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vellayat Ali M.B.B.S[2]

Overview

Glycogen Storage Disease Type IV

Synonyms: GSD IV, Andersen Disease, Brancher deficiency; Amylopectinosis; Glycogen Branching Enzyme Deficiency, Glycogenosis IV

 

Overview:

 

Historical Perspective:  

- In 1952, B Illingworth and GT Cori observed accumulation of an abnormal glycogen (resembling amylopectin) in the liver of a patient with von Gierke’s Disease. They postulated this finding to a different type of enzymatic deficiency, and thus to a different type of glycogen storage disease.[1]

- In 1956, DH Andersen, an American pathologist and pediatrician, reported the first clinical case of the disease as "familial cirrhosis of the liver with storage of abnormal glycogen".[2]

- In 1966, BI Brown and DH Brown clearly demonstrated the deficiency of glycogen branching enzyme (alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase) in a case of Type IV glycogenosis.[3]

 

Classification

There is no established system for the classification of GSD Type IV. The deficiency of GBE affecting the liver, the brain, the heart, and skeletal muscles leads to variable clinical presentations. Based on organ/tissue involvement, age of onset and clinical features, Andersen disease can be segregated into various forms [16] as below:

Form of Presentation	Age of  Onset	Clinical Features
Classic Hepatic Form     Neuromuscular form      A-Perinatal             B-Congenital         C-Late childhood form        D-Adult form	0-18 Mo         In utero      At birth          0-18 yrs    >18-21 yrs (any age in adulthood)	Infants present with failure to thrive, and hepatosplenomegaly. Progresses to portal hypertension, ascites, and liver failure, leading to death by 5 years of age.[17]     Prenatal symptoms include, polyhydramnios, hydrops fetalis, and decreased fetal movement; at birth severe hypotonia is observed requiring mechanical ventilation for respiratory support. [18][19] Cardiac findings like progressive cardiomyopathy may also be present.[19]  Newborns may have severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration and neuronal involvement, leading to death in early infancy. [21]     Presents in childhood at any age with myopathy as exercise intolerance, and cardiopathy as exertional dyspnea; and congestive heart failure in progressed cases. [21].   May present as isolated myopathy [23] or as Adult Polyglucosan Body Disease (APBD) [22]

Adult polyglucosan body disesase (APBD)

 

- Adult polyglucosan body disease is one of the neuromuscular variant of GSD Type IV.

- Typically, the first clinical manifestation is of urinary incontinence (secondary to neurogenic bladder), followed by gait disturbance (due to spastic paraplegia) and lower limb paresthesias (due to axonal neuropathy). [15]

Pathophysiology:

Pathogenesis:

-       Glycogen storage disease type IV is an autosomal recessive genetic disorder which results due to deficiency of glycogen branching enzyme (GBE).[4]

-       During Glycogenesis, the branching enzyme introduces branches to growing glycogen chains by transferring α-1,4-linked glucose monomers from the outer end of a chain into an α-1,6 position of the same or neighboring glycogen chain. [6]

-       Deficiency of GBE affects the branching process, yielding a polysaccharide which has fewer branching points and longer outer chains, thus resembling amylopectin. This new amylopectin-like structure is also known as polyglucosan. [7]

-       The enzyme deficiency affects all the bodily tissues; but liver, heart, skeletal muscles, and the nervous system are mostly affected.

-       The abnormally branched glycogen accumulates as intracytoplasmic non membrane-bound inclusions in hepatocytes, myocytes, and neuromuscular system; where it increases osmotic pressure within cells, causing cellular swelling and death.[8][9]

-       The altered structure also renders glycogen to become less soluble, and this is thought to lead into a foreign body reaction causing fibrosis, and finally culminating in liver failure. [10][11]

-       In skeletal muscle, accumulation leads to muscle weakness, fatigue, exercise intolerance, and muscular atrophy. [12]

-       Regarding the heart, a wide spectrum of cardiomyopathy from dilated to hypertrophic and from asymptomatic to decompensated heart failure may occur. [13]

-       Although exact mechanism is not known, glycogen deposition in the myocardium is thought to initiate signaling pathways which cause sarcomeric hypertrophy, resulting in hypertrophic cardiomyopathy.[14] 

   

Molecular Genetics:

   •     Glycogen branching enzyme is a 702 amino acid protein encoded by GBE1 gene mapped to chromosome 3p12.2 and is transmitted as an autosomal recessive trait. [21][5] HUGO Gene Nomenclature Committee https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:4180 The Universal Protein Resource (UniProt) http://www.uniprot.org/uniprot/Q04446

    •       Mutations in the GBE1 are responsible for enzymatic deficiency, and so far 40 pathogenic variants have been identified in individuals with GSD IV or adult-onset polyglucosan body disease (APBD).PMID: 23285490 

CAUSES: 

The cause of GSD type IV is variable deficiency of glycogen branching enzyme. The deficiency is due to various mutations of GBE1 gene encoding the single polypeptide protein. 

Differential Diagnosis:

Comparisons may be useful for a differential diagnosis as a number of other disease conditions with clinical features may present similar to those associated with GSD Type IV.

Presenting as hepatomegaly in infancy, the following glycogen metabolism disorders should be differentiated from GSD Type IV;

-GSD Type I

-GSD Type III

-GSD Type VI

-Hepatic Phosphorylase b Kinase Deficiency

Metabolic disorders presenting with muscle weakness/myopathy during infancy should also be considered;

Muscle glycogen synthase deficiency (GSD0b)

Lysosomal acid maltase deficiency (GSD II)

Glycogen debrancher deficiency (GSD III)

Muscle phosphorylase deficiency (GSD V)

Aldolase A deficiency (GSD XII)

Glycogenin-1 deficiency (GSD XV)

 

EPIDEMIOLOGY:

FREQUENCY- The frequency of all glycogen storage diseases is estimated to be 1 in 20,000 to 25,000 live births, while GSD IV is estimated to occur in 1 in 600,000 to 800,000 individuals worldwide.  NORD GHR https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-iv#statistics

SEX- Males and females appear to be affected in relatively equal numbers [NORD] because the deficiency of glycogen-branching enzyme activity is inherited as an autosomal-recessive trait.

RACE- Familial aggregation is observed in about 30% of adult polyglucosan body disease cases especially among Ashkenazi Jewish populations. NORD

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FOR OVERVIEW:

Glycogen storage disease type IV (GSD-IV; Andersen disease; Brancher deficiency; Amylopectinosis; Glycogen branching enzyme deficiency) was first described by Andersen[102] in 1956 as "familial cirrhosis of the liver with storage of abnormal glycogen" and, in 1966, a deficiency of amylo-1, 4 to 1, 6-transglucosidase (glycogen branching enzyme) was reported[103]. Without glycogen branching enzyme, the glycogen cannot be branched and abnormal glycogens resembling an amylopectin-like structure (polyglucosan), which is harmful for cells, accumulate in various tissues including hepatocytes and myocytes[104,105]. The gene of the enzyme was mapped to chromosome 3p12 in 1993[105]. Mutation in the same gene causes adult polyglucosan body disease. It represents 0.3% of all glycogen storage diseases, and is transmitted as an autosomal recessive trait[106].

Clinical Features:GSD-IV is clinically extremely heterogeneous, owing in part to variation in tissue involvement 104,106]. The existence of tissue specific isozymes may be responsible for remarkable phenotypic variability of the disease.

-         In the classical hepatic form, the patient appears normal at birth. But the disease rapidly progresses, early in life, to cirrhosis, and causes death due to liver failure between 3 and 5 years of age[102]. Affected children present with failure to thrive, hepatosplenomegaly and cirrhosis in the first 18 mo of age. Rarely, the hepatic disease is non-progressive or slowly progressive[107]. In non-progressive hepatic form patients may present with hepatosplenomegaly and a mild elevation of serum transaminases. Generally patients do not show any further progression of disease and growth is normal and liver enzymes may return to normal[107].

-         In multiple system involvement, the deficiency of the enzyme was detected in both muscle and the liver[108]. This includes peripheral myopathy with or without cardiomyopathy, neuropathy, and liver cirrhosis. The age of onset ranges from neonatal to adult age[109].

-         The neuromuscular presentation is divided into 4 groups according to age at onset[110].  

A.    In perinatal (fetal) form, which may cause hydrops fetalis and polyhydroamnios, the affected baby shows arthrogryposis of the limbs due to akinesia[111]. The presence of cervical cystic hygroma during pregnancy may be a warning sign of the disease[106]. Prenatal diagnosis is possible by determining enzyme activity or chorionic villi sampling. Death is inevitable in the neonatal period. Liver cirrhosis and hepatic failure have not been described.

B.    In congenital form, the patients have severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration and neuronal involvement[104,112-114]. Liver involvement is not severe and the child dies in early infancy. Childhood neuromuscular form presents with myopathy or cardiopathy starting at any age[110,115]. The main presenting symptoms are exercise intolerance, exertional dyspnea and congestive heart failure in progressed cases. The disorder may be limited to muscle tissue and serum creatine kinase may be normal.

C.    In adult form, there is isolated myopathy or polyglucosan body disease. 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. The disease may present as pyramidal tetraparesis, peripheral neuropathy, early neurogenic bladder, extrapyramidal symptoms and seizures, and cognitive impairment terminating in dementia[111].

DIAGNOSIS:

Diagnosis can be made by studying enzyme activity in erythrocytes[116,117]. Ultrastructural examination of the central nervous system and skeletal muscle reveals amylopectin-like inclusions both in neurons and muscular fibers. MRIshows white matter abnormalities[118]. Histological examination of the liver shows hepatocellular periodic-acid Schiff positive, diastase-resistant inclusions of the abnormal glycogen deposits The enzyme deficiency can usually be demonstrated in the liver, leukocytes, erythrocytes and fibroblasts although normal leukocyte enzyme activity may be detected in patients with cardioskeletal myopathy[104]. Microscopic examination of tissues, demonstration of enzyme deficiency and mutation analysis confirm the diagnosis of GSD-IV

Glycogen storage disease type IV. Liver biopsy shows diffuse deposition of PAS positive amylopectin like material in hepatocytes (PAS stain).

The only effective therapeutic approach presently available for GSD-IV patients with progressive liver disease is liver transplantation. Liver transplantation may be helpful not only for liver disease but also for muscular involvement[60,119,120]. This may be due to systemic microchimerism after liver allotransplantation and amelioration of pancellular enzyme deficiencies.

 

 

 

 

 

 

 

 

 

References

 

1.Structure of glycogens and amylopectins. III. Normal and abnormal human glycogen.

ILLINGWORTH B, CORI GT.

J Biol Chem. 1952 Dec;199(2):653-60

2. Familial cirrhosis of the liver with storage of abnormal glycogen.

ANDERSEN DH

Lab Invest. 1956 Jan-Feb; 5(1):11-20.

3. Lack of an alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase in a case of type IV glycogenosis.

Brown BI, Brown DH.

Proc Natl Acad Sci U S A. 1966 Aug;56(2):725-9. 

4. Hum Mol Genet. 2011 Feb 1;20(3):455-65. doi: 10.1093/hmg/ddq492. Epub 2010 Nov 12.

Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV. Lee YC¹, Chang CJ, Bali D, Chen YT, Yan YT.

5. Acta Myol. 2011 Oct; 30(2): 96–102.

PMCID: PMC3235878 Progress and problems in muscle glycogenoses

S. Di Mauro and R. Spiegel¹ 

6. Hum Mol Genet. 2015 Oct 15;24(20):5667-76. doi: 10.1093/hmg/ddv280. Epub 2015 Jul 21. 

7. PubMed: 15019703

Tay SK, Akman HO, Chung WK, Pike MG, Muntoni F, Hays AP, Shanske S, Valberg SJ, Mickelson JR, Tanji K, DiMauro S. Fatal infantile neuromuscular presentation of glycogen storage disease type IV. Neuromuscul Disord. 2004;14:253–60. 

8. Isolation of human glycogen branching enzyme cDNAs by screening complementation in yeast.

Thon VJ, Khalil M, Cannon JF

J Biol Chem. 1993 Apr 5; 268(10):7509-13.

9. Hum Pathol. 2012 Jun;43(6):943-51. doi: 10.1016/j.humpath.2011.10.001. Epub 2012 Feb 2. 

10. DOI: 10.1056/NEJM199101033240111

11. Severe cardiopathy enzyme deficiency in branching

Serenella Servidei, M.D., Roger E. Riepe, M.D., Claire Langston, M.D.,Lloyd Y: Tani, M.D., J. Timothy Bricker, M.D., Naoma Crisp-Lindgren, M.D.,Henry Travers, M.D., Dawna Armstrong, M.D., and

Salvatore DiMauro, M.D. 

12. National Organization for Rare Disorders (NORD): rarediseases.org/rare-diseases/andersen-disease-gsd-iv/

13. http://dx.doi.org/10.1155/2012/764286

14. DOI: 10.1056/NEJMra0902923 

15. Ann Neurol. 2012 Sep;72(3):433-41. doi: 10.1002/ana.23598. Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.

Mochel F¹, Schiffmann R, Steenweg ME, Akman HO, Wallace M, Sedel F, Laforêt P, Levy R, Powers JM, Demeret S, Maisonobe T, Froissart R, Da Nobrega BB, Fogel BL, Natowicz MR, Lubetzki C, Durr A, Brice A, Rosenmann H, Barash V, Kakhlon O, Gomori JM, van der Knaap MS, Lossos A. 

16. American Journal of Medical Genetics 139A:118–122 (2005)  

17. Bao, Y., Kishnani, P., Wu, J.-Y., Chen, Y.-T. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J. Clin. Invest. 97: 941-948, 1996. 

18. Neonatal presentation of lethal neuromuscular glycogen storage disease type IV L F Escobar, S Wagner, M Tucker & J Wareham Journal of Perinatology 32, 810–813 (2012) doi:10.1038/jp.2011.178 

19. Neonatal type IV glycogen storage disease associated with “null” mutations in glycogen branching enzyme 1 Andreas R.Janecke MD Susanne Dertinger MD Uwe-Peter Ketelsen MD Lothar Bereuter MD Burkhard Simma MD Thomas Müller MD Wolfgang Vogel MD Felix A. Offner MD

https://doi.org/10.1016/j.jpeds.2004.07.024  

20. Magoulas PL, El-Hattab AW. Glycogen Storage Disease Type IV. 2013 Jan 3. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK115333/  

21. World J Gastroenterol. 2007 May 14; 13(18): 2541–2553.

Published online 2007 May 14. doi:  10.3748/wjg.v13.i18.2541 PMCID: PMC4146814 Glycogen storage diseases: New perspectives Hasan Özen 

22. Glycogen branching enzyme deficiency in adult polyglucosan body disease.

Bruno C, Servidei S, Shanske S, Karpati G, Carpenter S, McKee D, Barohn RJ, Hirano M, Rifai Z, DiMauro S 

Ann Neurol. 1993;33(1):88.  

23. Adult polyglucosan body myopathy.

Goebel HH, Shin YS, Gullotta F, Yokota T, Alroy J, Voit T, Haller P, Schulz A

J Neuropathol Exp Neurol. 1992 Jan; 51(1):24-35. 

24. Ann Neurol. Author manuscript; available in PMC 2015 Feb 16.

Ann Neurol. 2012 Sep; 72(3): 433–441. doi:  10.1002/ana.23598 PMCID: PMC4329926 NIHMSID: NIHMS415710

Adult Polyglucosan Body Disease: Natural History and Key Magnetic Resonance Imaging Findings

Fanny Mochel, MD, PhD,^1,2,3,4 Raphael Schiffmann, MD,⁵ Marjan E. Steenweg, MD,⁶ Hasan O. Akman, PhD,⁷ Mary Wallace, RD,⁵ Frédéric Sedel, MD, PhD,^1,3,8 Pascal Laforêt, MD,^3,9 Richard Levy, MD, PhD,^4,10,11 J. Michael Powers, MD,¹² Sophie Demeret, MD,⁸ Thierry Maisonobe, MD,¹³ Roseline Froissart, PhD,¹⁴ Bruno Barcelos Da Nobrega, MD,¹⁵ Brent L. Fogel, MD, PhD,¹⁶ Marvin R. Natowicz, MD, PhD,¹⁷ Catherine Lubetzki, MD, PhD,^1,4,8 Alexandra Durr, MD, PhD,¹² Alexis Brice, MD,^1,2,4,8 Hanna Rosenmann, PhD,¹⁸ Varda Barash, PhD,¹⁹ Or Kakhlon, PhD,¹⁸ J. Moshe Gomori, MD,²⁰ Marjo S. van der Knaap, MD, PhD,⁶ and Alexander Lossos, MD¹⁸ 

25. PMID 8274116

Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV.

Lee YC¹, Chang CJ, Bali D, Chen YT, Yan YT.

5. Acta Myol. 2011 Oct; 30(2): 96–102.

PMCID: PMC3235878 Progress and problems in muscle glycogenoses

S. DiMauro and R. Spiegel¹ 

6. Hum Mol Genet. 2015 Oct 15;24(20):5667-76. doi: 10.1093/hmg/ddv280. Epub 2015 Jul 21. 

7. Neuromusc. Disord. 14: 253-260, 2004. [PubMed: 15019703