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 mutation is known to cause APBD.

Clinical testing

• Sequence analysis. 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].
  
  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 occult GBE1 intronic or promotor mutations or other unknown theoretical mechanisms account for this observation.

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
GBE1	Sequence analysis	Sequence variants 2	>90%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The only other disorder known to be associated with mutations in GBE1 is GSD type IV. In GSD type IV:

• GBE activity is typically undetectable or minimally detectable, whereas in APBD GBE activity is reduced or normal.
• Multiple homozygous or compound heterozygous GBE1 mutations have been identified [Andersen 1956, Zellweger et al 1972, McMaster et al 1979, Ferguson et al 1983, Guerra et al 1986, Greene et al 1988, Schröder et al 1993, Bao et al 1996, McConkie-Rosell et al 1996, Alegria et al 1999, Cox et al 1999].

The phenotype associated with GSD IV spans a spectrum that includes the following forms (subtypes) based on age of presentation, clinical manifestations, and severity:

• Classic hepatic form (Andersen disease) [Andersen 1956, Bao et al 1996]: progressive hepatosplenomegaly with portal hypertension, ascites, and liver failure
• Non-progressive hepatic form [Greene et al 1988, McConkie-Rosell et al 1996]
• Fatal perinatal neuromuscular form [Alegria et al 1999, Cox et al 1999]
• Congenital neuromuscular form [Zellweger et al 1972, McMaster et al 1979]
• Childhood neuromuscular form [Guerra et al 1986, Schröder et al 1993]
• Childhood combined hepatic and myopathic form: Liver transplantation has shown variable benefit for survival [Selby et al 1991].
• Adult neuromuscular with isolated myopathy form [Ferguson et al 1983]

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 Tables 2 and 3).

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.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are generally asymptomatic. One manifesting carrier has been reported [Ubogu et al 2005, Massa et al 2008].

Sibs of a proband

• 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.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are generally asymptomatic. One manifesting carrier has been reported [Ubogu et al 2005, Massa et al 2008].

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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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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]
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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]
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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. Selby R, Starzl TE, Yunis E, Brown BI, Kendall RS, Tzakis A. Liver transplantation for type IV glycogen storage disease. N Engl J Med. 1991;324:39–42. [PMC free article: PMC3091357] [PubMed: 1984162]
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20. 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]

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 authors thank the APBD research foundation for trying to advance understanding and care of individuals affected by this disorder.

Revision History

• 23 July 2009 (ck) Revision: clinical trial information
• 2 April 2009 (et) Review posted live
• 1 October 2008 (ck) Original submission