DiagnosisClinical DiagnosisAdult polyglucosan body disease (APBD) is diagnosed in individuals over age 40 years with the following:Progressive neurogenic bladderGait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvementSensory loss predominantly in the distal lower extremitiesMild difficulties in cognition (often executive dysfunction)Typically, but not necessarily, Ashkenazi Jewish heritageFamily history consistent with autosomal recessive inheritanceTestingNeuroimaging. 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 atrophyThe 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 microscopyGlycogen 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 TestingGene. GBE1, the gene encoding 1,4-alpha-glucan-branching enzyme, is the only gene in which mutation is known to cause APBD.Clinical testingSequence 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 DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityGBE1Sequence analysisSequence variants 2>90%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 StrategyEstablishing 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 testing2.Assay of GBE activity in skin fibroblasts or muscle tissue if results from molecular genetic testing need clarification3.Sural nerve biopsy if results from assay of GBE activity need clarificationCarrier 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.Genetically Related (Allelic) DisordersThe 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 failureNon-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]Table 2. GBE1 Mutations by GSD IV PhenotypeView in own windowGSD IV PhenotypeDNA Nucleotide Change
(Alias 1)Protein Amino
Acid ChangeReference
SequencesClassichepaticc.1543C>T
(1633C>T)p.Arg515HisNM_000158​.3
NP_000149​.3c.771T>A
(861T>A)p.Phe257Leuc.1570C>T
(1660C>T)p.Arg524XNon-progressive
hepaticc.986A>C
(1076A>C)p.Tyr329Serc.672 T>Cp.Leu224ProFatal perinatal
neuromuscularc.143+1G>A
(IVS1DS, G>A, +1)(Truncation of last 654
amino acid residues)c.1634A>Gp.His545ArgCongenital
neuromuscularc.992_1619del p.Ser331Ilefs*10
(Exon8-12del)c.1774G>Tp.Glu592X(253 bp del)(Exon4-6 del)c.[708G>C]+[784C>T] 2p.[Gln236His]
+[Arg262Cys] 2 c.691+5G>C
(IVS5DS, G>C, +5)(Exon 5 and 6 skipping)c.1643G>Ap.Trp548XChildhood
neuromuscularc.1883A>Gp.His628ArgCombined hepaticand myopathicc.1571G>A
(1661G>A)p.Arg524GlnCombined hepaticand neuromuscularc.[c.38dupA]+[1571G>A] 2p.[Asp13Glufs*12]
+[Arg524Gln] 2 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. One change in each of the two GBE1 alleles}

Natural HistoryMost 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 injuriesMild 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 CorrelationsNo 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).

Differential DiagnosisPolyglucosan 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:GSD type IV [OMIM 232500] (see Genetically Related Disorders)Double athetosis (Bielschowsky bodies)Normal older persons (corpora amylacea)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.

ManagementEvaluations Following Initial DiagnosisTo 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 bladderAssessment of post-void residual and consultation with a urologist to identify and manage complications of a neurogenic bladderBedside or formal neuropsychometric analysis to assess for early signs of cognitive impairmentTreatment of ManifestationsOptimally, 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 chairsConsideration of antispasmodic bladder medications and in-and-out bladder catheterization vs indwelling bladder catheter depending on urologic findingsBehavioral modification and cognitive aids as neededPrevention of Secondary ComplicationsGait aids and urologic management of neurogenic bladder may prevent falls and urosepsis, respectively.SurveillancePeriodic assessment of the following:Bladder functionGaitSensation in the distal lower extremitiesCognition (e.g., executive function)Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationA 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGBE13p12​.21,4-alpha-glucan-branching enzymeGBE1 homepage - Mendelian genesGBE1Data 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) View in own window 263570POLYGLUCOSAN BODY DISEASE, ADULT FORM; APBD 607839GLYCOGEN BRANCHING ENZYME; GBE1Normal allelic variants. GBE1 has 16 exons.Pathologic allelic variants. See Table 3.Table 3. Selected GBE1 Pathologic Allelic Variants Associated with APBDView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.986A>C
(1076 A>C)p.Tyr329Ser ^{2NM_000158​.3
NP_000149​.3c.[1543C>T]+ [1571G>A] 3(1633 C>T, 1661G>A)p.[Arg515His]+[Arg524Gln] 3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Typically observed in homozygous state in affected individuals3. One change in each of the two GBE1 allelesNormal 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.}