Polyglucosan Body Research Articles

Coexisting adult polyglucosan body disease with frontotemporal lobar degeneration with transactivation response DNA-binding protein-43 (TDP-43)-positive neuronal inclusions

Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is one of the most common pathological findings associated with the clinical FTLD syndromes. However, molecular characterization with genetic sequencing and protein expression techniques are recognizing many new subtypes for FTLDs. FTLDs are diverse and new nomenclature schemes have been proposed based on the molecular defects that are being discovered (Mackenzie et al., 2010, Acta Neuropathologica, 119, 1). Adult polyglucosan body disease (APBD) is a very rare disorder associated with systemic neurological signs and symptoms including progressive dementia with executive dysfunction and motor neuron disease. We report the clinical course of an individual with a clinical FTLD and the as yet unreported findings of coexistent APBD with FTLD-U and transactivation response DNA-binding protein-43 (TDP-43)-positive inclusions at autopsy (or more accurately, FTLD-TDP). It is unclear if these distinct findings are coincidental in this individual, or if pathogenic pathways may intersect to promote these coexisting pathologies.

Corpora Amylacea and Unexpected Death: A Case of Adult Polyglucosan Body Disease Diagnosed at Forensic Autopsy

Adult polyglucosan body disease (APBD) is a rare neurodegenerative condition characterized by typical onset in middle age, progressive neurological impairment that is heterogeneous between cases, and death within 1-14 years of diagnosis. The histopathologic hallmark of the disease is massive deposition of corpora amylacea (designated polyglucosan bodies in this context) in the central nervous system, and variable deposition of similar material in other sites. While the cause of the disease is as yet unknown, recent research has identified mutations in proteins involved in glycogen metabolism in a subset of cases. In this paper, we present a case of unexpected death wherein APBD was diagnosed at forensic autopsy. This represents the first report of an unexpected death due to this disease reported in the medical and forensic literature.

Adult Polyglucosan Body Disease Masquerading as “ALS With Dementia of the Alzheimer Type”

We describe an exceptional clinical picture, namely, cognitive impairment of the Alzheimer disease type in a man who later developed manifestations typical of amyotrophic lateral sclerosis and who was subsequently found to have adult polyglucosan body disease (APGBD) upon postmortem neuropathologic explorations. The combined occurrence of amyotrophic lateral sclerosis and cognitive impairment of the Alzheimer disease type in APGBD has not been reported before. This case also underlines the diverse clinical presentation of this rare clinicopathologic entity (namely APGBD) and highlights the importance of recognizing the unusual association of clinical features in making the diagnosis.

Le cerveau de Vacher et les savants, deuxième partie. Résultats de l’autopsie

The eminent scientists who examined Vacher's brain did not discover evidence of any brain disease known at that time. The results of the histological tests which revealed numerous corporea amylacea, which were not hitherto taken into account, suggest various hypothesis; in order of likehood: the role of cerebral-meningeal lesions, a temporal lobe epilepsy, a familial neurodegenerative disease, such as a polyglucosan body disease. These diagnostic formulations, which propose an organic lesion underlying Vacher's troubles, would support those who argued in favour of his insanity.

Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease

Lafora disease (LD) is caused by mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of polyglucosan inclusions called Lafora Bodies (LBs). Malin knockout (KO) mice present polyglucosan accumulations in several brain areas, as do patients of LD. These structures are abundant in the cerebellum and hippocampus. Here, we report a large increase in glycogen synthase (GS) in these mice, in which the enzyme accumulates in LBs. Our study focused on the hippocampus where, under physiological conditions, astrocytes and parvalbumin-positive (PV+) interneurons expressed GS and malin. Although LBs have been described only in neurons, we found this polyglucosan accumulation in the astrocytes of the KO mice. They also had LBs in the soma and some processes of PV+ interneurons. This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function. Our results emphasize the relevance of the laforin–malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD.

Mapping of Purkinje Neuron Loss and Polyglucosan Body Accumulation in Hereditary Cerebellar Degeneration in Scottish Terriers

A hereditary cerebellar degenerative disorder has emerged in Scottish Terriers. The aims of this study were to describe and quantify polyglucosan body accumulation and quantify Purkinje neurons in the cerebellum of affected and control dogs. The brains of 6 affected Scottish Terriers ranging in age from 8 to 15 years and 8 age-matched control dogs were examined histopathologically. Counts of Purkinje neurons and polyglucosan bodies were performed in control and affected dogs on cerebellar sections stained with periodic acid-Schiff. Affected dogs showed a significant loss of Purkinje neurons compared with control dogs (vermis: P < .0001; hemisphere: P = .0104). The degeneration was significantly more pronounced dorsally than ventrally (P < .0001). There were significantly more polyglucosan bodies in the ventral half of the vermis when compared with the dorsal half (P < .0001) in affected dogs. In addition, there were more polyglucosan bodies in the ventral half of the vermis in affected dogs than in control dogs (P = .0005). Polyglucosan bodies in all affected dogs stained positively with toluidine blue and alcian blue. Immunohistochemically, polyglucosan bodies in affected dogs were positive for neurofilament 200 kD and ubiquitin and negative for glial fibrillary acidic protein, synaptophysin, neurospecific enolase, vimentin, and S100; the bodies were negative for all antigens in control dogs. Ultrastructurally, polyglucosan bodies in 1 affected dog were non-membrane-bound, amorphous structures with a dense core. This study demonstrates significant Purkinje cell loss and increased polyglucosan bodies in the cerebellum of affected Scottish Terriers.

Adult Polyglucosan Body Disease: A Rare Presentation with Chronic Liver Disease and Ground-Glass Hepatocellular Inclusions

Liver involvement in genetic and metabolic disorders may result in intrahepatic accumulation of specific precursors or byproducts, which have distinctive features on light microscopy. The "polyglucosan disorders" are diseases in which polyglucosan (abnormal glycogen with decreased branching) is formed and deposited in various tissues because of decreased or absent glycogen branching enzyme activity. These disorders include Lafora disease (myoclonus epilepsy) and type IV glycogen storage disease. Polyglucosan deposits in both conditions result in ground-glass hepatocellular inclusions resembling those seen in chronic hepatitis B virus infection. In the present report, we describe a case of the rare, adulthood form of glycogen branching enzyme deficiency, adult polyglucosan body disease (APBD), in which abnormal serum liver tests prompted a liver biopsy. The pathologic findings of periportal ground-glass hepatocellular inclusions, mild chronic portal inflammation, and periportal fibrosis are not well described in APBD, but resemble the chronic changes that have been reported in Lafora disease. The differential diagnosis of ground-glass hepatocytes and the genetic basis of APBD are discussed.

Lafora bodies in skeletal muscle are fiber type specific

Glycogen is the largest soluble cytosolic macromolecule, containing up to 55,000 glucoses per molecule. It is formed by glycogen synthase (GS) and branching enzyme (BE), which acting coordinately lead to branching after every sixth glucose and ultimately to a spherical shape that allows solubility. Polyglucosans are malformed glycogen molecules containing much less branching. They precipitate and accumulate into polyglucosan bodies (PB). PB characterize adult polyglucosan body disease (APBD) and Lafora disease (LD). In APBD, PB form in and often obstruct axons. APBD is an axonopathy with upper and lower motor neuron signs and no epilepsy. In LD, PB, called Lafora bodies (LB), occupy neuronal perikarya and dendrites. LD is a progressive myoclonus epilepsy, with no long tract or peripheral nerve deficits. APBD is caused by BE deficiency. LD is caused by mutations in the EPM2A and EPM2B genes encoding respectively the laforin phosphatase and the malin ubiquitin E3 ligase, which regulates laforin. In LD, glycogen becomes progressively phosphorylated, a pathologic process normally prevented by laforin. The charged phosphates unfold glycogen, expose its hydrophobic regions, and lead it to precipitate. GS precipitates with glycogen, but BE does not. Subsequent extension by GS unchecked by branching would convert the glycogen to polyglucosan.1,2 The next step in LD research is to understand the basis of the progressive phosphorylation. What is known is …

Adult Polyglucosan Body Disease (APBD): Anaplerotic diet therapy (Triheptanoin) and demonstration of defective methylation pathways

APBD is a rare disorder most often affecting adults of Ashkenazi Jewish origin due to partial deficiency of the glycogen brancher enzyme (GBE). It is characterized by progressive involvement of both the central and peripheral nervous systems and deposition of amylopectin-like polyglucosan bodies. There have been no metabolic derangements that might suggest effective therapy nor have there been any clinical improvements for control of its relentless progression. The APBD patients, in this study, experienced stabilization of disease progression, and limited functional improvement in most patients with dietary triheptanoin. Due to a plateau in clinical improvement, the reduced plasma creatinine and methionine levels prompted evaluation of other plasma methylation intermediates in this complex integrated pathway system: decreased S-adenosylmethionine (SAM) (p<0.002), increased S-adenosylhomocysteine (p<0.001), elevated creatine (p=0.001) and increased free choline (p<0.001). Plasma levels of homocysteine and guanidinoacetate were normal. Impaired metabolism of choline and creatine may relate to the progressive dysmyelination and progressive muscle weakness associated with APBD. The partial deficiency of GBE appears to produce a secondary energy deficit possibly related to inadequate reserves of normal glycogen for efficient degradation to free glucose. Dysfunctional regulation of glycogen synthase (GS) may result in continued synthesis and deposition of polyglucosan bodies. This investigation has demonstrated, for the first time, arrest of clinical deterioration with limited functional recovery with triheptanoin diet therapy and the existence of significant derangement of methylation pathways that, when corrected, may lead to even greater therapeutic benefits.

Parahippocampal Corpora Amylacea

Corpora amylacea (CA) normally accumulate within perivascular, subpial, and subependymal astrocytic processes. CA are associated with a number of conditions including normal aging, hippocampal sclerosis associated with temporal lobe epilepsy, multiple sclerosis, Lafora-type progressive myoclonic epilepsy, and adult polyglucosan body disease. Reports of massive localized accumulation of CA in the brain outside of these conditions are rare. A 49-year-old woman, with a long-standing history of migraine headaches, presented to her primary care provider for increased headache duration. Brain magnetic resonance imaging (MRI) revealed a left parahippocampal lesion, suggestive of low-grade glioma. Given the MRI suggestive of left parahippocampal glioma, left-sided frontotemporal craniotomy was performed for resection of the lesion. Specimens obtained during the operation revealed focal high-density accumulation of CA with no evidence of neoplasm, ischemia, or hypoxic injury. This case illustrates the possibility that localized high-density CA accumulation can present as an intrinsic lesion on brain MRI. CA should be included in the differential diagnosis for patients presenting with brain MRI suggestive of nonenhancing space-occupying lesions.

Glycogen metabolism

ATP= : adenosine triphosphate; cAMP= : cyclic adenosine monophosphate; GBE= : glycogen branching enzyme; GSK= : glycogen synthase kinase; PTG= : protein targeting to glycogen. Brain glycogen metabolism provides a typical example of metabolic coupling between neurons and astrocytes. Glycogen is almost exclusively localized in astrocytes and serves as an endogenous source of energy for these cells and for neurons. Neural activity leads to release of glutamate and other neurotransmitters that trigger mobilization of energy from glycogen in astrocytes. Glycogenolysis in astrocytes leads to the production of lactate, which serves as an energy substrate for the active neurons. Although the functional role of glycogen in the brain is incompletely understood, there is experimental evidence that glycogen is able to sustain neuronal activity during energy deprivation or in the setting of hypoxia, ischemia, hypoglycemia, or seizures. Whereas neurons also have the enzymatic machinery to synthesize glycogen, in normal conditions this process is actively inhibited, and this prevents glycogen- triggered damage of these cells. Abnormal glycogen metabolism has been typically associated with muscle disorders, but may also underlie some disorders affecting the CNS. Inability to inhibit glycogen synthesis in neurons is the basis for Lafora disease and impaired activity of glycogen branching enzyme occurs in adult polyglucosan body disease. The focus of this short review is on some physiologic aspects of brain glycogen metabolism and their clinical correlations. These topics have been comprehensively reviewed elsewhere.1–7 ### Glycogen metabolism in astrocytes. In adult brain, glycogen is predominantly present in astrocytes. Glycogen is a spherical and highly branched polymer comprising up to approximately 53,000 glycosyl units. It is synthesized from a core consisting of a peptide called glycogenin and proglycogen, which serves as a stable intermediate that is converted into macroglycogen, the storage form of glycogen.8,9 Glycogen synthesis from glucose depends on the activity of glycogen synthase, which catalyzes formation of α-1,4-glycosidic linkage of the polymer, and glycogen branching enzyme, which introduces the α-1,6-glycosidic branch points. Degradation occurs in the cytosol through …

Adult polyglucosan body disease (APBD): Anaplerotic diet therapy (triheptanoin) and demonstration of defective methylation pathways

Adult polyglucosan body disease (APBD): Anaplerotic diet therapy (triheptanoin) and demonstration of defective methylation pathways

Characterisation of Lafora-like bodies and other polyglucosan bodies in two aged dogs with neurological disease

Canine Lafora disease is a genetic disorder of carbohydrate metabolism characterised by neurological signs and accumulation of a type of polyglucosan body (PGB), the Lafora body (LB), in the brain and other organs. Normal canine ageing is associated with accumulation of PGBs in the brain, especially those corresponding to corpora amylacea (CA). In this study, two aged dogs that presented with progressive tremors, ataxia and paraplegia had abundant PGBs throughout the brain, mainly in the hypothalamus and molecular layer of the cerebellum. Hypothalamic and cerebellar PGBs from both cases had lower alcohol-resistant metachromasia than CA when stained with toluidine blue. Immunohistochemical studies of these PGBs against neurone-specific enolase (NSE), glial fibrillary acid protein (GFAP), 200 KDa neurofilaments, S-100, Tau, ubiquitin and heat shock proteins 25 and 70, showed some differences to CA.

Adult polyglucosan body disease: Proton magnetic resonance spectroscopy of the brain and novel mutation in the GBE1 gene

Adult polyglucosan body disease (APBD) is characterized by the accumulation of insoluble glucose polymers within the central and peripheral nervous systems. A common missense mutation in the glycogen branching enzyme (GBE1) gene has been identified in Ashkenazi patients with APBD. We report on a non-Jewish patient with APBD on whom we performed proton magnetic resonance spectroscopic imaging of the brain. GBE activity in fibroblasts was markedly reduced, and a novel heterozygous mutation was identified in the GBE1 gene. Our findings widen the spectrum of APBD genotypes, underline the importance of performing GBE analysis in all APBD patients, and suggest that brain white matter degeneration in APBD may result from tissue damage involving axons and myelin.

Polyglucosan body disease myopathy: An unusual presentation

Polyglucosan body disease (PBD) is a slowly progressive adult-onset glycogen storage disorder that typically affects upper and lower neurons. Myopathy, as a complication of PBD has been reported rarely and clinically manifests as chronic limb-girdle muscle weakness. We report an unusual case of PBD myopathy presenting as an asymmetric motor syndrome that clinically overlapped with amyotrophic lateral sclerosis, further expanding the phenotype of this disorder.

A Case of Adult Polyglucosan Body Disease

Adult polyglucosan body disease (APBD) is a rare neurological disease, characterized by adult onset (fifth to seventh decades), progressive sensorimotor or pure motor peripheral neuropathy, upper motor neuron symptoms, neurogenic bladder, and cognitive impairment. APBD is confirmed by a sural nerve biopsy that shows the widespread presence of polyglucosan bodies in the nerve. We report a 70 year old male patient who exhibited progressive weakness in all extremities and dementia. His electrodiagnostic studies showed sensorimotor polyneuropathy and muscle pathology that consisted of polyglucosan bodies located in small peripheral nerves. This is the first case of APBD reported in Korea.

Stable neuropsychological deficits in adult polyglucosan body disease

We describe a 61-year-old woman who gradually developed deficits of balance, gait, and the ability to negotiate movement in space, together with an unusual pattern of cognitive deficits. A series of non-invasive investigations over three years including EEG, CT, MRI, PET and serial neuropsychological review had not provided a diagnosis. Significantly, the four neuropsychological assessments had revealed no progressive decline in cognition. Brain biopsy revealed an abundance of corpora amylacea, and a diagnosis of adult polyglucosan body disease (APBD) was made. This case contributes to the body of knowledge about the cognitive manifestations of this rare disease, and the stability of its functional impact over time.

Cognitive impairment in neuromuscular disorders

Several studies have suggested the presence of central nervous system involvement manifesting as cognitive impairment in diseases traditionally confined to the peripheral nervous system. The aim of this review is to highlight the character of clinical, genetic, neurofunctional, cognitive, and psychiatric deficits in neuromuscular disorders. A high correlation between cognitive features and cerebral protein expression or function is evident in Duchenne muscular dystrophy, myotonic dystrophy (Steinert disease), and mitochondrial encephalomyopathies; direct correlation between tissue-specific protein expression and cognitive deficits is still elusive in certain neuromuscular disorders presenting with or without a cerebral abnormality, such as congenital muscular dystrophies, congenital myopathies, amyotrophic lateral sclerosis, adult polyglucosan body disease, and limb-girdle muscular dystrophies. No clear cognitive deficits have been found in spinal muscular atrophy and facioscapulohumeral dystrophy.

Adult polyglucosan body disease: A case report of a manifesting heterozygote

A 62-year-old man developed progressive gait instability, bladder dysfunction, proximal weakness, distal sensory loss, and mild cognitive impairment over 6 years. Neurologic examination revealed upper and lower motor neuron dysfunction in the lower extremities, with distal sensory loss. Electrodiagnostic studies, magnetic resonance imaging of the brain, and sural nerve biopsy were consistent with adult polyglucosan body disease. Biochemical and genetic analyses demonstrated reduced glycogen brancher enzyme levels associated with a heterozygous point mutation (Tyr329Ser or Y329S) in the glycogen brancher enzyme gene on chromosome 3. Mutational heterozygosity in the glycogen brancher enzyme gene has not been previously reported as a cause for this rare disease. A review of the clinical presentation, pathogenesis, etiology, and diagnosis of this disease is presented.

Fatal infantile neuromuscular presentation of glycogen storage disease type IV

Glycogen storage disease type IV or Andersen disease is an autosomal recessive disorder due to deficiency of glycogen branching enzyme. Typically, glycogen storage disease type IV presents with rapidly progressive liver cirrhosis and death in childhood. Variants include a cardiopathic form of childhood, a relatively benign myopathic form of young adults, and a late-onset neurodegenerative disorder (adult polyglucosan body disease). A severe neuromuscular variant resembling Werdnig-Hoffmann disease has also been described in two patients. The objective was to describe two additional infants with the neuromuscular variant and novel mutations in the GBE1 gene. Branching enzyme assay, Western blot, RT-PCR and sequencing were performed in muscle biopsies from both patients. The cDNA of patient 1 was subcloned and sequenced to define the mutations. Muscle biopsies showed accumulation of periodic acid Schiff-positive, diastase-resistant storage material in both patients and increased lysosomal enzyme activity in patient 1. Branching enzyme activity in muscle was negligible in both patients, and Western blot showed decreased branching enzyme protein. Patient 1 had two single base pair deletions, one in exon 10 (1238delT) and the other in exon 12 (1467delC), and each parent was heterozygous for one of the deletions. Patient 2 had a large homozygous deletion that spanned 627 bp and included exons 8–12. Patient 1, who died at 41 days, had neurophysiological and neuropathological features of Spinal Muscular Atrophy. Patient 2, who died at 5 1 2 weeks, had a predominantly myopathic process. The infantile neuromuscular form of glycogen storage disease type IV is considered extremely rare, but our encountering two patients in close succession suggests that the disease may be underdiagnosed.