Development of the APBD-SQ, a novel patient-reported outcome for health-related quality of life in adult polyglucosan body disease.

Adult polyglucosan body disease (APBD) is a rare autosomal recessive glycogen storage disorder that leads to slowly progressive multi-organ dysfunction in adulthood. A novel disease-specific patient-reported outcome measure was created and administered to assess symptom burden and health-related quality of life (HR-QOL) in APBD. Thirty-six participants between 30 and 79 years of age (83% ≥60 years, 56% male) completed the anonymous questionnaire independently or with a caregiver proxy (75% self-report). Unemployment predicted an 18.3 (95% CI: 2.8, 33.8; p = 0.028) higher composite disease severity score and a 28.8 (95% CI: 8.2, 49.4; p = 0.010) higher composite HR-QOL score. Use of one or more assistive devices also predicted a 29.3 (95% CI: 8.3, 50.4; p = 0.011) higher composite disease severity score and a 41.8 (95% CI: 10.9, 72.8; p = 0.013) higher composite HR-QOL score. Proxy survey completion predicted a 19.4 (95% CI: 4.1, 34.7; p = 0.020) higher composite disease severity score compared to self-report. Older age at survey completion predicted a 27.4 higher composite HR-QOL score (95% CI: 2.5, 52.4; p = 0.039) for participants in their sixties compared to those between 30 and 59 years old. The development of the Adult Polyglucosan Body Disease questionnaire on Symptom burden and health-related Quality of life (APBD-SQ) marks an important stride forward in capturing the patient experience as a tool for disease monitoring and future research.

Incidence and characterization of polyglucosan bodies in the cerebella of montserrat orioles (Icterus oberi).

Polyglucosan bodies are accumulations of insoluble glucose polymers and proteins that form intracytoplasmic inclusions in the brain, large numbers of which can be indicative of neurodegenerative diseases such as Lafora disease. Montserrat orioles (Icterus oberi) are an icterid passerine endemic to Montserrat with conservation populations maintained in captivity abroad. We demonstrate that polyglucosan bodies are unusually abundant in the cerebellar molecular and Purkinje cell layers and cerebellar peduncles of captive-bred and wild-caught Montserrat orioles. The bodies are periodic acid-Schiff positive and diastase resistant and label with concanavalin A and for ubiquitin, consistent with those seen in humans. We found no association of the polyglucosan bodies with concurrent neurological lesions or clinical signs, nor with EPM2A and EPM2B gene mutations associated with Lafora disease. We conclude that an abundance of cerebellar polyglucosan bodies may be a normal finding in aged Montserrat orioles and not a threat to the captive breeding population.

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-Cage Behavior.

Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 months, and ∼12 months of age, malin-deficient mice ("KO") and wild-type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age-dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home-cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

Phenotypic and genotyping spectrum of two Iranian cases with RBCK1-associated polyglucosan body myopathy.

Glycogen storage diseases (GSDs) are a group of metabolic disorders affecting glycogen metabolism, with polyglucosan body myopathy type 1 (PGBM1) being a rare variant linked to RBCK1 gene mutations. Understanding the clinical diversity of PGBM1 aids in better characterization of the disease. Two unrelated Iranian families with individuals exhibiting progressive muscle weakness underwent clinical evaluations, genetic analysis using whole exome sequencing (WES), and histopathological examinations of muscle biopsies. In one case, a novel homozygous RBCK1 variant was identified, presenting with isolated myopathy without cardiac or immune involvement. Conversely, the second case harbored a known homozygous RBCK1 variant, displaying a broader phenotype encompassing myopathy, cardiomyopathy, inflammation, and immunodeficiency. Histopathological analyses confirmed characteristic skeletal muscle abnormalities consistent with PGBM1. Our study contributes to the expanding understanding of RBCK1-related diseases, illustrating the spectrum of phenotypic variability associated with distinct RBCK1 variants. These findings underscore the importance of genotype-phenotype correlations in elucidating disease mechanisms and guiding clinical management. Furthermore, the utility of next-generation sequencing techniques in diagnosing complex neurogenetic disorders is emphasized, facilitating precise diagnosis and enabling tailored genetic counseling for affected individuals and their families.

Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.

AIMS: Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions, including Lafora disease (EPM2A, EPM2B), adult polyglucosan body disease (APBD, GBE1), polyglucosan body myopathies associated with RBCK1 deficiency (PGBM1, RBCK1) or glycogenin-1 deficiency (PGBM2, GYG1). While the storage material primarily comprises glycans, this study aimed to gain deeper insights into the protein components by proteomic profiling of the storage material in glycogenin-1 deficiency. METHODS: We employed molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies and muscle homogenate, immunohistochemistry and western blot analyses in muscle tissue from a 45-year-old patient with proximal muscle weakness from late teenage years due to polyglucosan storage myopathy. RESULTS: The muscle tissue exhibited a complete absence of glycogenin-1 due to a novel homozygous deep intronic variant in GYG1 (c.7+992T>G), introducing a pseudo-exon causing frameshift and a premature stop codon. Accumulated proteins in the polyglucosan bodies constituted components of glycogen metabolism, protein quality control pathways and desmin. Muscle fibres containing polyglucosan bodies frequently exhibited depletion of normal glycogen. CONCLUSIONS: The absence of glycogenin-1, a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin, mirroring findings in RBCK1 deficiency. These results suggest shared pathogenic pathways across different diseases exhibiting polyglucosan storage. Such insights have implications for therapy in these rare yet devastating and presently untreatable disorders.

A case of polyglucosan body myopathy caused by an RBCK1 gene variant and literature review.

OBJECTIVE: To analyze the clinical and genetic characteristics of a patient with Polyglucosan body myopathy 1 (PGBM1) caused by a novel compound heterozygous variant in the RBCK1 gene. METHODS: The clinical data of the patient were collected, next-generation sequencing technology was used to determine the exome sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing. RESULTS: Through whole-exome sequencing, we found that there were c.919G>T; p. (Glu307*) and c.723_730dup; p. (Glu244fs) variants of the RBCK1 gene in the patient, inherited from his parents, constituting a compound heterozygous variation. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the two variants were rated as pathogenic, but there were no comparable cases. Previous literature reported 24 patients with RBCK1 gene variants, involving a total of 20 myocardial and 18 skeletal muscle cases. CONCLUSIONS: The patient was twice diagnosed with cardiac insufficiency, neglecting the usual manifestations of muscle weakness, resulting in misdiagnosis. Later, novel variants in the RBCK1 gene were discovered through whole-exome sequencing, and symptomatic treatment was given after diagnosis. The importance of whole-exome sequencing technology in disease diagnosis and genetic counseling was emphasized.

A United States-based patient-reported adult polyglucosan body disease registry: initial results.

Background: Adult Polyglucosan Body Disease (APBD) is an ultra-rare, genetic neurodegenerative disorder caused by autosomal recessive mutations in the glycogen branching enzyme gene. Knowledge of the demographic and clinical characteristics of APBD patients and the natural history of the disease is lacking. We report here initial results from a patient-reported registry of APBD patients. Objectives: (1) Maximize the quality of the APBD Registry survey data; (2) provide an initial report on APBD disease progression and natural history using these data; and (3) specify next steps in the process for testing potential new therapies. Design: Data are from members of the APBD Research Foundation (New York), surveyed from 2014 by the Columbia APBD Patient/Family (CAP) Registry. Inclusion criteria are: disease onset at age 18+ and progressive clinical triad of peripheral neuropathy, spasticity, and neurogenic bladder. Methods: Genetic testing results were used when available. Respondents found to not have APBD in clinical records were excluded. All changes and exclusions were recorded in a database edit log. Results are reported in frequency tables, bar graphs, time plots, and heat maps. Results: The 96 respondents meeting inclusion criteria were predominantly (96.8%) White, highly educated (89.3% at least some college education), and mostly (85.1%) of Ashkenazi Jewish descent. 57.1% had at least one parent born in the United States, with at least one grandparent from Europe (excluding Russia; 75.4%), the United States (42.1%), or Russia (33.3%). 37.2% reported a family history of APBD, and 33.3% had an affected sibling. Median APBD onset age was 51 [Interquartile range (IQR) 11], and median age of diagnosis 57 (IQR 10.5). The 75 reported prior misdiagnoses were mainly peripheral neuropathy (43, 60.6%) and spinal stenosis (11, 15.1%). Conclusion: Although from a demographically constricted survey, the results provide basic clinical information for future studies to develop treatments for APBD.

A United States based patient-reported adult polyglucosan body disease registry: initial results Adult Polyglucosan Body Disease, or APBD, is an ultra-rare neurological disorder caused by mutations of the GBE1 gene. While potential therapies exist, to establish if they work we need a "natural history" study that shows the normal path of the disease. Our goal was to provide the first patient-reported natural history study of APBD. We analyzed survey data from 96 patients recruited by the APBD Research Foundation (New York), aged 18 or older, who self-reported having APBD. We maximized data quality by using results from genetic testing when these were available, and by excluding respondents if we could not review clinical records confirming they had APBD. More than 95% of our 96 patients were white. They were highly educated: 89% had at least some college education. Most (85%) were of Ashkenazi Jewish descent. More than half (57.1%) had a parent born in the United States. Many had at least one grandparent from Europe (excluding Russia) (75.4%), the United States (42.1%), or Russia (33.3%). More than a third (37%) reported a family history of APBD, and a third reported that they had a brother or a sister with a history of the disease. Their average age at APBD onset was 51, and their average age at APBD diagnosis was 57. Previous misdiagnoses were common: 75 were reported. Most were for peripheral neuropathy (60.6%) or spinal stenosis (16.7%). Although our data come from a survey of patients who are demographically similar, they provide a report on the characteristics of patients with APBD and basic information that is essential for studies to develop treatments for the disease.

Severe neuromuscular forms of glycogen storage disease type IV: Histological, clinical, biochemical, and molecular findings in a large French case series.

Glycogen storage disease type IV (GSD IV), also called Andersen disease, or amylopectinosis, is a highly heterogeneous autosomal recessive disorder caused by a glycogen branching enzyme (GBE, 1,4-alpha-glucan branching enzyme) deficiency secondary to pathogenic variants on GBE1 gene. The incidence is evaluated to 1:600 000 to 1:800 000 of live births. GBE deficiency leads to an excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues (liver, skeletal muscle, heart, nervous system, etc.). Diagnosis is often guided by histological findings and confirmed by GBE activity deficiency and molecular studies. Severe neuromuscular forms of GSD IV are very rare and of disastrous prognosis. Identification and characterization of these forms are important for genetic counseling for further pregnancies. Here we describe clinical, histological, enzymatic, and molecular findings of 10 cases from 8 families, the largest case series reported so far, of severe neuromuscular forms of GSD IV along with a literature review. Main antenatal features are: fetal akinesia deformation sequence or arthrogryposis/joint contractures often associated with muscle atrophy, decreased fetal movement, cystic hygroma, and/or hydrops fetalis. If pregnancy is carried to term, the main clinical features observed at birth are severe hypotonia and/or muscle atrophy, with the need for mechanical ventilation, cardiomyopathy, retrognathism, and arthrogryposis. All our patients were stillborn or died within 1 month of life. In addition, we identified five novel GBE1 variants.

Expanding the phenotype of RBCK1-associated polyglucosan body myopathy type 1.

Polyglucosan body myopathy-1 (PGBM1) is an extremely rare glycogen storage diseases that leads to muscle weakness and cardiomyopathy due to the accumulation of polyglucosan bodies. The clinical presentation appears to be partially dependent on the genetic mutation, but no clear genotype/phenotype correlation is currently possible. We describe a 7 year old patient, who initially presented with recurrent vomiting and respiratory infections until her first year of life. Diagnostic workup revealed an achalasia and the whole exome sequencing revealed an homozygous RBCK1 (RANBP2-type and C3HC4-type zinc finger containing 1) variant (c.896_899delAGTG) located in exon 7 (mid-domain), which has also been described in 4 patients with PGBM1. The unusual presentation with gastrointestinal and respiratory symptoms before the development of progressive muscle weakness expands the phenotype of this disease.

Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder.

Inadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is histologically characterized by the accumulation of structurally abnormal glycogen (polyglucosan bodies) in multiple cell types. How insufficient GBE1 activity causes the disease phenotype of APBD is poorly understood. We hypothesized that proteomic analysis of tissue from GBE1-deficient individuals would provide insights into GBE1-mediated pathobiology. In this discovery study, we utilized label-free LC-MS/MS to quantify the proteomes of lymphoblasts from 3 persons with APBD and 15 age- and gender-matched controls, with validation of the findings by targeted MS. There were 531 differentially expressed proteins out of 3,427 detected between APBD subjects vs. controls, including pronounced deficiency of GBE1. Bioinformatic analyses indicated multiple canonical pathways and protein-protein interaction networks to be statistically markedly enriched in APBD subjects, including: RNA processing/transport/translation, cell cycle control/replication, mTOR signaling, protein ubiquitination, unfolded protein and endoplasmic reticulum stress responses, glycolysis and cell death/apoptosis. Dysregulation of these processes, therefore, are primary or secondary factors in APBD pathobiology in this model system. Our findings further suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD.

Mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN.

HOIL-1L and SHARPIN are two essential regulatory subunits of the linear ubiquitin chain assembly complex (LUBAC), which is the only known E3 ligase complex generating linear ubiquitin chains. In addition to their LUBAC-dependent functions, HOIL-1L and SHARPIN alone play crucial roles in many LUBAC-independent cellular processes. Importantly, deficiency of HOIL-1L or SHARPIN leads to severe disorders in humans or mice. However, the mechanistic bases underlying the multi-functions of HOIL-1L and SHARPIN are still largely unknown. Here, we uncover that HOIL-1L and SHARPIN alone can form homo-dimers through their LTM motifs. We solve two crystal structures of the dimeric LTM motifs of HOIL-1L and SHARPIN, which not only elucidate the detailed molecular mechanism underpinning the dimer formations of HOIL-1L and SHARPIN, but also reveal a general mode shared by the LTM motifs of HOIL-1L and SHARPIN for forming homo-dimer or hetero-dimer. Furthermore, we elucidate that the polyglucosan body myopathy-associated HOIL-1L A18P mutation disturbs the structural folding of HOIL-1L LTM, and disrupts the dimer formation of HOIL-1L. In summary, our study provides mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN mediated by their LTM motifs, and expands our understandings of the multi-functions of HOIL-1L and SHARPIN as well as the etiology of relevant human disease caused by defective HOIL-1L.

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-cage Behavior.

Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ~6-7 months and ~12 months of age, malin deficient mice ("KO") and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using an in vitro assay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

Glycogen storage disease type IV without detectable polyglucosan bodies: importance of broad gene panels.

Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, the other with talipes and feeding problems. All developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. Our cases expand the phenotypic spectrum of neuromuscular GSD IV, highlight that congenital myopathy and limb girdle weakness can be caused by mutations in GBE1, and emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy.

Treatment-responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy.

BACKGROUND: Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, and include sporadic late onset nemaline myopathy, light chain amyloid myopathy, and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy-associated myopathy (MGAM) in a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) patient. METHOD: Case report. RESULTS: A 51-year-old woman presented with a 6-month history of progressive bilateral foot drop, lower limb edema, and a 15-lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length-dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinating and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen-filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next-generation sequencing of glycogen storage and polyglucosan body myopathy-related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant. CONCLUSIONS: This patient expands a spectrum of MGAM. Recognition of this condition and other subtypes of MGAM is of utmost important because they are treatable.

Metabolic Myopathies in the Era of Next-Generation Sequencing.

Metabolic myopathies are rare inherited disorders that deserve more attention from neurologists and pediatricians. Pompe disease and McArdle disease represent some of the most common diseases in clinical practice; however, other less common diseases are now better-known. In general the pathophysiology of metabolic myopathies needs to be better understood. Thanks to the advent of next-generation sequencing (NGS), genetic testing has replaced more invasive investigations and sophisticated enzymatic assays to reach a final diagnosis in many cases. The current diagnostic algorithms for metabolic myopathies have integrated this paradigm shift and restrict invasive investigations for complicated cases. Moreover, NGS contributes to the discovery of novel genes and proteins, providing new insights into muscle metabolism and pathophysiology. More importantly, a growing number of these conditions are amenable to therapeutic approaches such as diets of different kinds, exercise training protocols, and enzyme replacement therapy or gene therapy. Prevention and management-notably of rhabdomyolysis-are key to avoiding serious and potentially life-threatening complications and improving patients' quality of life. Although not devoid of limitations, the newborn screening programs that are currently mushrooming across the globe show that early intervention in metabolic myopathies is a key factor for better therapeutic efficacy and long-term prognosis. As a whole NGS has largely increased the diagnostic yield of metabolic myopathies, but more invasive but classical investigations are still critical when the genetic diagnosis is unclear or when it comes to optimizing the follow-up and care of these muscular disorders.

Deciphering the Polyglucosan Accumulation Present in Lafora Disease Using an Astrocytic Cellular Model.

Lafora disease (LD) is a neurological disorder characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of insoluble forms of glycogen (polyglucosan bodies, or PGBs) in the brain. The accumulation of PGBs is causative of the pathophysiological features of LD. However, despite the efforts made by different groups, the question of why PGBs accumulate in the brain is still unanswered. We have recently demonstrated that, in vivo, astrocytes accumulate most of the PGBs present in the brain, and this could lead to astrocyte dysfunction. To develop a deeper understanding of the defects present in LD astrocytes that lead to LD pathophysiology, we obtained pure primary cultures of astrocytes from LD mice from the postnatal stage under conditions that accumulate PGBs, the hallmark of LD. These cells serve as novel in vitro models for studying PGBs accumulation and related LD dysfunctions. In this sense, the metabolomics of LD astrocytes indicate that they accumulate metabolic intermediates of the upper part of the glycolytic pathway, probably as a consequence of enhanced glucose uptake. In addition, we also demonstrate the feasibility of using the model in the identification of different compounds that may reduce the accumulation of polyglucosan inclusions.

A synonymous codon variant altering splicing of RBCK1 expands the phenotype and genotype spectra of polyglucosan body myopathy 1.

Polyglucosan body myopathy type 1 (PGBM1, OMIM #615895.) is a rare autosomal recessive disorder caused by RBCK1 mutations. The patients displayed polyglucosan accumulation in skeletal and cardiac muscles, giving rise to loss of ambulation and heart failure with or without immune system dysregulation. So far, only 24 patients have been reported, all of whom exhibited symptoms before adulthood. Here, we reported the first case of an adult-onset PGBM1 patient with a novel compound heterozygous RBCK1 gene mutation consisting of a nonsense and synonymous variant affecting splicing.

Polyglucosan body disease in an aged chimpanzee (Pan troglodytes).

A 57-year-old female chimpanzee presented with a brief history of increasing lethargy and rapidly progressive lower-limb weakness that culminated in loss of use. Postmortem examination revealed no significant gross lesions in the nervous system or other organ systems. Histological analysis revealed round, basophilic to amphophilic polyglucosan bodies (PGBs) in the white and gray matter of the cervical, thoracic, lumbar, and coccygeal regions of spinal cord. Only rare PGBs were observed in forebrain samples. The lesions in the spinal cord were polymorphic, and they were positively stained with hematoxylin, periodic acid Schiff, Alcian blue, toluidine blue, Bielschowsky silver, and Grocott-Gomori methenamine-silver methods, and they were negative for von Kossa and Congo Red stains. Immunohistochemical evaluation revealed reactivity with antibodies to ubiquitin, but they were negative for glial fibrillary acidic protein, neuron-specific enolase, neurofilaments, tau protein, and Aß protein. Electron microscopy revealed non-membrane-bound deposits composed of densely packed filaments within axons and in the extracellular space. Intra-axonal PGBs were associated with disruption of the axonal fine structure and disintegration of the surrounding myelin sheath. These findings are the first description of PGBs linked to neurological dysfunction in a chimpanzee. Clinicopathologically, the disorder resembled adult PGB disease in humans.