NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Adult Polyglucosan Body Disease

, MD
Associate Professor of Neurology
Mayo Clinic
Rochester, Minnesota

Initial Posting: ; Last Update: December 19, 2013.

Summary

Disease characteristics. Adult polyglucosan body disease (APBD) is characterized by adult-onset progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, and mild cognitive difficulties (often executive dysfunction).

Diagnosis/testing. Diagnosis is based on clinical examination, MRI of the brain and spinal cord, sural nerve biopsy showing characteristic polyglucosans within nerve tubes, assay of glycogen brancher enzyme (GBE) activity in skin fibroblasts or muscle tissue, and molecular genetic testing of GBE1, the only gene in which mutations are known to cause APBD.

Management. Treatment of manifestations: Optimally, care is provided by a team including specialists in physical medicine rehabilitation, urology, and behavioral neurology or psychology. Management focuses on use of gait safety devices; antispasmodic bladder medications and in-and-out bladder catheterization or an indwelling bladder catheter; behavioral modification and cognitive aids as needed.

Prevention of secondary complications: Gait aids to prevent falls and urologic management to prevent urosepsis.

Surveillance: Periodic assessment of bladder function, gait, sensation in the distal lower extremities, and cognition.

Genetic counseling. APBD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known; however, requests for prenatal testing for adult-onset conditions such as APBD are uncommon.

Diagnosis

Clinical Diagnosis

Adult polyglucosan body disease (APBD) is diagnosed in individuals over age 40 years with the following:

  • Progressive neurogenic bladder
  • Gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement
  • Sensory loss predominantly in the distal lower extremities
  • Mild difficulties in cognition (often executive dysfunction)
  • Typically (but not necessarily), Ashkenazi Jewish heritage
  • Family history consistent with autosomal recessive inheritance

Testing

Neuroimaging. MRI of the brain and spinal cord reveals the following:

  • Paraventricular, subcortical, and deep white matter changes that may include involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, and anterior medulla (including the olives) often extending to the level of the cervical-medullary junction [Klein et al 2004]
  • Cerebral, cerebellar, and spinal cord atrophy

The imaging features are slowly progressive when followed serially.

Electrophysiologic testing is nonspecific:

  • Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified.
  • Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy.

Sural nerve biopsy reveals characteristic polyglucosans within nerve tubes. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals.

Additional tissues with pathologic polyglucosan accumulation in APBD:

  • Muscle: diastase-resistant, PAS-positive material is characteristic.
  • Muscle and nerve: small inflammatory infiltrates may be seen in both.
  • Axillary skin: within apocrine gland luminal cells, scattered filamentous and granular intracytoplasmic inclusions characteristic of polyglucosan bodies on electron microscopy

Glycogen brancher enzyme (GBE) activity is most commonly assayed in skin fibroblast cultures, but may also be assayed in muscle tissue. In persons of Ashkenazi Jewish heritage with APBD associated with mutations in GBE1, reduced GBE activity is observed.

Note: (1) The level of abnormal activity varies by laboratory, but is generally less than the control range. (2) Some affected individuals (particularly persons who are not of Ashkenazi Jewish heritage) have normal GBE activity [Cafferty et al 1991, Bruno et al 1993, Matsumuro et al 1993]. (3) Children with glycogen storage disease (GSD) type IV typically have no enzyme activity (see Genetically Related Disorders).

Molecular Genetic Testing

Gene. GBE1, the gene encoding 1,4-alpha-glucan-branching enzyme, is the only gene in which mutations are known to cause APBD.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Adult Polyglucosan Body Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
GBE1Sequence analysisSequence variants 4, 5>90% 6

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. A homozygous GBE1 mutation, p.Tyr329Ser, is the most common finding in Ashkenazi Jewish persons [Lossos et al 1998]. Of the two non-Ashkenazi-Jewish persons studied with low GBE activity, one was a compound heterozygote for two GBE1 mutations (p.Arg515His and p.Arg524Gln) [Ziemssen et al 2000] and the other had a presumed polymorphism (p.Val160Ile) [Klein et al 2004].

6. Some individuals with deficient GBE activity do not have identified mutations in GBE1 [Klein et al 2004]. It remains unclear whether other genes that may downregulate GBE1 or GBE1 intronic or promotor mutations or other unknown theoretic mechanisms account for this observation.

Testing Strategy

To confirm/establish the diagnosis in a proband. In individuals with characteristic clinical findings and MRI findings of the brain and spinal cord, the following order of testing is recommended:

1.

Molecular genetic testing

2.

Assay of GBE activity in skin fibroblasts or muscle tissue if results from molecular genetic testing need clarification

3.

Sural nerve biopsy if results from assay of GBE activity need clarification

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Rarely, affected heterozygotes have been reported [Ubogu et al 2005, Massa et al 2008].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Most individuals with adult polyglucosan body disease (APBD) present after age 40 years with unexplained progressive neurogenic bladder, gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly in the distal lower extremities, and mild cognitive difficulties (often executive dysfunction). Delay in diagnosis is common because multiple sclerosis and primary urologic dysfunction are most commonly considered first.

More than 30 individuals of Ashkenazi and non-Ashkenazi Jewish heritage have been reported [Ziemssen et al 2000, Klein et al 2004].

The most common findings:

  • Neurogenic bladder. Urinary incontinence is often the first sign of APBD.
  • Gait difficulties. Age of onset and severity vary among affected individuals; some individuals eventually require gait aids and possibly wheel chair.
  • Sensory loss in the distal lower extremities. Typically mild but can be severe enough to lead to painless foot injuries
  • Mild cognitive difficulty (e.g., executive dysfunction). Varies in severity and progression with many affected individuals having mild involvement. Cognitive difficulties have not been well-studied to date.

Although longevity has not been formally studied against matched age and other disease controls, APBD likely shortens life expectancy. However, with good gait safety, bladder management, and supportive care many have years of productive life without major incident.

Heterozygotes. Manifesting carriers have been reported, including one carrier of the mutation p.Tyr329Ser [Ubogu et al 2005, Massa et al 2008].

Genotype-Phenotype Correlations

No clear association of phenotype with mutation type and severity is known.

Loose association is recognized between the extent of GBE deficiency and disease severity, i.e., childhood and infantile GSD IV are often worse in those with lower or undetectable GBE activity.

Certain mutations seem to be reserved to given phenotypes (see GSD IV, Table 3 [pdf]).

Prevalence

More than 30 affected individuals of Ashkenazi Jewish heritage and non-Ashkenazi Jewish heritage (i.e., of Italian and German descent) have been reported [Ziemssen et al 2000, Klein et al 2004]. Persons of other ethnic groups and races are predicted to be at risk as well.

Differential Diagnosis

Polyglucosan bodies. In adult polyglucosan body disease (APBD), the polyglucosan bodies consist of acellular homogenous periodic acid-Schiff (PAS)-positive material with diastase-resistant glucose polymers and are seen in the central and peripheral nervous system.

Polyglucosans also occur in the following disorders:

Clinical distinction between these disorders is possible by neurologic history and examination.

White matter changes on MRI. In individuals with APBD, MRI shows increased T2 signal in the paraventricular white matter and possibly the brain stem, which may have a similar appearance to that seen in multiple sclerosis (see Multiple Sclerosis Overview). However, the images in APBD typically do not enhance.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with adult polyglucosan body disease (APBD), the following evaluations are recommended:

  • MRI of the brain and spinal column to exclude other treatable causes of gait spasticity and neurogenic bladder
  • Assessment of post-void residual and consultation with a urologist to identify and manage complications of a neurogenic bladder
  • Bedside or formal neuropsychometric analysis to assess for early signs of cognitive impairment
  • Medical genetics consultation

Treatment of Manifestations

Optimally, care is provided by a team that includes specialists in physical medicine rehabilitation, urology, and behavioral neurology or psychology (i.e., behavioralists) who can provide the following:

  • Gait safety devices including canes and wheel chairs
  • Consideration of antispasmodic bladder medications and in-and-out bladder catheterization vs indwelling bladder catheter depending on urologic findings
  • Behavioral modification and cognitive aids as needed

Prevention of Secondary Complications

Gait aids and urologic management of neurogenic bladder may prevent falls and urosepsis, respectively.

Surveillance

Periodic assessment of the following:

  • Bladder function
  • Gait
  • Sensation in the distal lower extremities
  • Cognition (e.g., executive function)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A randomized controlled trial of trihepatnoin for APBD is ongoing. See Author Notes.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Adult polyglucosan body disease (APBD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. The offspring of an individual with APBD are obligate heterozygotes (carriers) for a disease-causing mutation in GBE1.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests are not common for prenatal testing for adult-onset conditions such as APBD. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Adult Polyglucosan Body Disease Research Foundation (APBDRF)
    8 West 37th Street
    Suite 901
    New York NY 10018
    Phone: 212-290-2546
    Fax: 212-643-0963
    Email: info@APBDRF.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Adult Polyglucosan Body Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
GBE13p12​.21,4-alpha-glucan-branching enzymeGBE1 databaseGBE1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Adult Polyglucosan Body Disease (View All in OMIM)

263570POLYGLUCOSAN BODY DISEASE, ADULT FORM; APBD
607839GLYCOGEN BRANCHING ENZYME; GBE1

Normal allelic variants. GBE1 has 16 exons.

Pathogenic variants. See Table 2.

Table 2. Selected GBE1 Pathogenic Variants Associated with APBD

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.986A>C
(1076 A>C)
p.Tyr329Ser 2NM_000158​.3
NP_000149​.3
c.[1543C>T]+ [1571G>A] 3
(1633 C>T, 1661G>A)
p.[Arg515His]+[Arg524Gln] 3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Typically observed in homozygous state in affected individuals

3. One change in each of the two GBE1 alleles

Normal gene product. The 1,4-alpha-glucan-branching enzyme has 702 amino acids. It functions in the synthesis of glycogen by adding branches to the glycogen molecule.

Abnormal gene product. GBE1 mutations result in accumulation of abnormally branched glycogen molecules.

References

Literature Cited

  1. Alegria A, Martins E, Dias M, Cunha A, Cardoso ML, Maire I. Glycogen storage disease type IV presenting as hydrops fetalis. J Inherit Metab Dis. 1999;22:330–2. [PubMed: 10384399]
  2. Andersen DH. Familial cirrhosis of the liver with storage of abnormal glycogen. Lab Invest. 1956;5:11–20. [PubMed: 13279125]
  3. Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J Clin Invest. 1996;97:941–8. [PMC free article: PMC507139] [PubMed: 8613547]
  4. Bruno C, Servidei S, Shanske S, Karpati G, Carpenter S, McKee D, Barohn RJ, Hirano M, Rifai Z, DiMauro S. Glycogen branching enzyme deficiency in adult polyglucosan body disease. Ann Neurol. 1993;33:88–93. [PubMed: 8494336]
  5. Cafferty MS, Lovelace RE, Hays AP, Servidei S, Dimauro S, Rowland LP. Polyglucosan body disease. Muscle Nerve. 1991;14:102–7. [PubMed: 1847989]
  6. Cox PM, Brueton LA, Murphy KW, Worthington VC, Bjelogrlic P, Lazda EJ, Sabire NJ, Sewry CA. Early-onset fetal hydrops and muscle degeneration in siblings due to a novel variant of type IV glycogenosis. Am J Med Genet. 1999;86:187–93. [PubMed: 10449659]
  7. Ferguson IT, Mahon M, Cumming WJ. An adult case of Andersen's disease--Type IV glycogenosis. A clinical, histochemical, ultrastructural and biochemical study. J Neurol Sci. 1983;60:337–51. [PubMed: 6579239]
  8. Greene HL, Brown BI, McClenathan DT, Agostini RM, Taylor SR. A new variant of type IV glycogenosis: deficiency of branching enzyme activity without apparent progressive liver disease. Hepatology. 1988;8:302–6. [PubMed: 3162725]
  9. Guerra AS, van Diggelen OP, Carneiro F, Tsou RM, Simoes S, Santos NT. A juvenile variant of glycogenosis IV (Andersen disease). Eur J Pediatr. 1986;145:179–81. [PubMed: 3464425]
  10. Klein CJ, Boes CJ, Chapin JE, Lynch CD, Campeau NG, Dyck PJ, Dyck PJ. Adult polyglucosan body disease: case description of an expanding genetic and clinical syndrome. Muscle Nerve. 2004;29:323–8. [PubMed: 14755501]
  11. Lossos A, Meiner Z, Barash V, Soffer D, Schlesinger I, Abramsky O, Argov Z, Shpitzen S, Meiner V. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol. 1998;44:867–72. [PubMed: 9851430]
  12. Massa R, Bruno C, Martorana A, de Stefano N, van Diggelen OP, Federico A. Adult polyglucosan body disease: proton magnetic resonance spectroscopy of the brain and novel mutation in the GBE1 gene. Muscle Nerve. 2008;37:530–6. [PubMed: 17994551]
  13. Matsumuro K, Izumo S, Minauchi Y, Inose M, Higuchi I, Osame M. Chronic demyelinating neuropathy and intra-axonal polyglucosan bodies. Acta Neuropathol. 1993;86:95–9. [PubMed: 8396840]
  14. McConkie-Rosell A, Wilson C, Piccoli DA, Boyle J, DeClue T, Kishnani P, Shen JJ, Boney A, Brown B, Chen YT. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis. 1996;19:51–8. [PubMed: 8830177]
  15. McMaster KR, Powers JM, Hennigar GR, Wohltmann HJ, Farr GH. Nervous system involvement in type IV glycogenosis. Arch Pathol Lab Med. 1979;103:105–11. [PubMed: 284761]
  16. Schröder JM, May R, Shin YS, Sigmund M, Nase-Hüppmeier S. Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type IV glycogenosis). Acta Neuropathol. 1993;85:419–30. [PubMed: 7683169]
  17. Ubogu EE, Hong ST, Akman HO, Dimauro S, Katirji B, Preston DC, Shapiro BE. Adult polyglucosan body disease: a case report of a manifesting heterozygote. Muscle Nerve. 2005;32:675–81. [PubMed: 16007674]
  18. Zellweger H, Mueller S, Ionasescu V, Schochet SS, McCormick WF. Glycogenosis. IV. A new cause of infantile hypotonia. J Pediatr. 1972;80:842–4. [PubMed: 4502299]
  19. Ziemssen F, Sindern E, Schröder JM, Shin YS, Zange J, Kilimann MW, Malin JP, Vorgerd M. Novel missense mutations in the glycogen-branchin enzyme gene in adult polyglucosan body disease. Ann Neurol. 2000;47:536–40. [PubMed: 10762170]

Chapter Notes

Author Notes

A randomized controlled trial of trihepatnoin for APBD at:

Institute of Metabolic Disease
Baylor Research Institute
Dallas, Texas
Principal Investigator: Raphael Schiffmann, MD
Contact person: Mary Wallace, MS, RD, LD (Co-investigator)
Tel: 214-820-4533
Email: MaryWall@BaylorHealth.edu

Acknowledgments

The author thanks the APBD research foundation for trying to advance understanding and care of individuals affected by this disorder.

Revision History

  • 19 December 2013 (me) Comprehensive update posted live
  • 23 July 2009 (ck) Revision: clinical trial information
  • 2 April 2009 (et) Review posted live
  • 1 October 2008 (ck) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK5300PMID: 20301758
PubReader format: click here to try

Views

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

  • Glycogen Storage Disease Type IV[GeneReviews<sup>®</sup>. 1993]
    Glycogen Storage Disease Type IV
    Magoulas PL, El-Hattab AW. GeneReviews<sup>®</sup>. 1993
  • Glycogen Storage Disease Type II (Pompe Disease)[GeneReviews<sup>®</sup>. 1993]
    Glycogen Storage Disease Type II (Pompe Disease)
    Leslie N, Tinkle BT. GeneReviews<sup>®</sup>. 1993
  • Congenital Muscular Dystrophy Overview[GeneReviews<sup>®</sup>. 1993]
    Congenital Muscular Dystrophy Overview
    Sparks S, Quijano-Roy S, Harper A, Rutkowski A, Gordon E, Hoffman EP, Pegoraro E. GeneReviews<sup>®</sup>. 1993
  • Arylsulfatase A Deficiency[GeneReviews<sup>®</sup>. 1993]
    Arylsulfatase A Deficiency
    Fluharty AL. GeneReviews<sup>®</sup>. 1993
  • ALS2-Related Disorders[GeneReviews<sup>®</sup>. 1993]
    ALS2-Related Disorders
    Bertini ES, Eymard-Pierre E, Boespflug-Tanguy O, Cleveland DW, Yamanaka K. GeneReviews<sup>®</sup>. 1993
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...