Glycogen Branching Enzyme Deficiency Research Articles

Myofiber-type-dependent 'boulder' or 'multitudinous pebble' formations across distinct amylopectinoses.

At least five enzymes including three E3 ubiquitin ligases are dedicated to glycogen's spherical structure. Absence of any reverts glycogen to a structure resembling amylopectin of the plant kingdom. This amylopectinosis (polyglucosan body formation) causes fatal neurological diseases including adult polyglucosan body disease (APBD) due to glycogen branching enzyme deficiency, Lafora disease (LD) due to deficiencies of the laforin glycogen phosphatase or the malin E3 ubiquitin ligase and type 1 polyglucosan body myopathy (PGBM1) due to RBCK1 E3 ubiquitin ligase deficiency. Little is known about these enzymes' functions in glycogen structuring. Toward understanding these functions, we undertake a comparative murine study of the amylopectinoses of APBD, LD and PGBM1. We discover that in skeletal muscle, polyglucosan bodies form as two main types, small and multitudinous ('pebbles') or giant and single ('boulders'), and that this is primarily determined by the myofiber types in which they form, 'pebbles' in glycolytic and 'boulders' in oxidative fibers. This pattern recapitulates what is known in the brain in LD, innumerable dust-like in astrocytes and single giant sized in neurons. We also show that oxidative myofibers are relatively protected against amylopectinosis, in part through highly increased glycogen branching enzyme expression. We present evidence of polyglucosan body size-dependent cell necrosis. We show that sex influences amylopectinosis in genotype, brain region and myofiber-type-specific fashion. RBCK1 is a component of the linear ubiquitin chain assembly complex (LUBAC), the only known cellular machinery for head-to-tail linear ubiquitination critical to numerous cellular pathways. We show that the amylopectinosis of RBCK1 deficiency is not due to loss of linear ubiquitination, and that another function of RBCK1 or LUBAC must exist and operate in the shaping of glycogen. This work opens multiple new avenues toward understanding the structural determinants of the mammalian carbohydrate reservoir critical to neurologic and neuromuscular function and disease.

Application of preimplantation genetic diagnosis in 91 equine ICSI embryos

Preimplantation genetic diagnosis (PGD) of in vitro-produced (IVP) equine embryos has been reported in research and clinical settings. In the previous reports, 4-16% biopsied samples failed to yield PCR results of disease-causing genes. There is little information on the feasibility of a second biopsy and refreezing of those PGD-failed frozen IVP equine embryos. In this report, we evaluated biopsy results from 91 IVP equine embryos produced from 2018 to 2022 and tested for hereditary equine regional dermal asthenia (HERDA), glycogen branching enzyme deficiency (GBED) and hyperkalemic periodic paralysis (HYPP) genes. We also examined the pregnancy and foaling rates of twice biopsied-frozen (2BF) embryos by comparing them with fresh or once biopsied-frozen (1BF) embryos. IVP embryos were produced by intracytoplasmic sperm injection and in vitro culture of shipped immature oocytes. Biopsy of embryos was performed as previously reported with minor modifications (Choi et al., Reprod Fertil Dev 2016;28:1382-1389). Biopsies were kept frozen for a maximum of 7 days and shipped to the University of California, Davis for genetic analysis. A total of 15 fresh, 39 1BF and 5 2BF IVP embryos were transferred to recipients at embryo transfer facilities. The non-transferred vitrified embryos, 12 1BF and 1 2BF IVP embryos, were kept frozen accordingto owners’ instructions. Among the 91 IVP biopsies, 7 (8%) failed to yield PCR results and 84 samples were genetically analyzed; 14 (24%) were homozygous for HERDA in 58 samples, 4 (21%) were homozygous for GBED in 19 samples and 0 were homozygous for HYPP in 7 samples. The molecular sexes of 84 samples were 44 males and 40 females. Among the 7 2BF IVP biopsies, 1 failed to yield PCR results and 6 were genetically analyzed; 1 was homozygous for GBED. The molecular sexes of 6 2BF samples were 1 male and 5 females. The pregnancy rates of fresh, 1BF and 2BF IVP embryos were not significantly different among groups (60% (9/15), 64% (25/39) and 80% (4/5), respectively, Fisher's exact test). Of these, 3 pregnancies from 1BF were removed from the foaling rate calculation because of unknown and ongoing pregnancies. The foaling rates of fresh, 1BF and 2BF IVP embryos were not significantly different among groups (47% (7/15), 33% (12/36) and 60% (3/5), respectively, Fisher's exact test). Out of 22 foals analyzed, all matched with molecular genders. In summary, PGD for disease-causing genes can be further improved by a second biopsy and refreezing of frozen IVP equine embryos. In addition, two biopsy-freezing cycles of IVP equine embryos were not detrimental to in vivo embryo development.

O18: A path forward for patients with glycogen branching enzyme deficiency: Consensus on diagnosing and managing glycogen storage disease type IV*

O18: A path forward for patients with glycogen branching enzyme deficiency: Consensus on diagnosing and managing glycogen storage disease type IV*

Prevalence of Genetic Mutations in Horses With Muscle Disease From a Neuromuscular Disease Laboratory

Deleterious genetic variants are an important cause of skeletal muscle disease. Immunohistochemical evaluation of muscle biopsies is standard for the diagnosis of muscle disorders. The prevalence of alleles causing hyperkalemic periodic paralysis (HYPP), malignant hyperthermia (MH), polysaccharide storage myopathy 1 (PSSM1), glycogen branching enzyme deficiency (GBED), myotonia congenita (MC), and myosin heavy chain myopathy (MYHM) in horses with muscle disease is unknown. Archived slides processed for immunohistochemical analysis from 296 horses with muscle disease were reviewed blinded and clinical information obtained. DNA isolated from stored muscle samples from these horses were genotyped for disease variants. Histological findings were classified as myopathic in 192, neurogenic in 41, and normal in 63 horses. A third of the population had alleles that explained disease which constituted 45% of the horses with confirmed histological myopathic process. Four of six muscle disease alleles were identified only in Quarter horse breeds. The allele causing PSSM1 was detected in other breeds, and MC was not detected in these samples. The My allele, associated with susceptibility for MYHM, was the most common (62%) with homozygotes (16/27) presenting a more severe phenotype compared to heterozygotes (6/33). All cases with the MH allele were fatal upon triggering by anesthesia, stress or concurrent myopathy. Both, muscle histological and genetic analyses are essential in the investigation of muscle disease, since 10% of the horses with muscle disease and normal histology had a muscle disease causing genetic variant, and 63% of histologically confirmed muscle with alterations had no known genetic variants.

EP035: Genotype-phenotype correlation of glycogen storage disease type IV

Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disease caused by glycogen branching enzyme deficiency, encoded by GBE1. The deficiency results in variable clinical features, age of onset, and disease severity. GSD IV is arbitrarily divided into several subtypes based on the continuum of symptoms. The most common Classic Hepatic subtype presents in the first few months of life with hepatomegaly, followed by rapid deterioration into cirrhosis and lethal liver failure requiring liver transplant.

73 Preimplantation genetic diagnosis of glycogen branching enzyme deficiency and sex determination in equine in vitro-produced embryos.

Reproduction, Fertility and Development is an international journal publishing original research , review and comment in the fields of reproduction and developmental biology in humans, domestic animals and wildlife

Alleviation of a polyglucosan storage disorder by enhancement of autophagic glycogen catabolism.

This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan‐reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image‐based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

Alteration of mitochondrial function in the livers of mice with glycogen branching enzyme deficiency

Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme gene (GBE1) that lead to the accumulation of aberrant glycogen in affected tissues, mostly in the liver. To determine whether dysfunctional glycogen metabolism in GSD IV affects other components of cellular bioenergetics, we studied mitochondrial function in heterozygous Gbe1 knockout (Gbe1+/−) mice. Mitochondria isolated from the livers of Gbe1+/− mice showed elevated respiratory complex I activity and increased reactive oxygen species production, particularly by respiratory chain complex III. These observations indicate that GBE1 deficiency leads to broader rearrangements in energy metabolism and that the mechanisms underlying GSD IV pathogenesis may include more than merely mechanical cell damage caused by the presence of glycogen aggregates.

GBE1‐related disorders: Adult polyglucosan body disease and its neuromuscular phenotypes

Adult polyglucosan body disease (APBD) represents a complex autosomal recessive inherited neurometabolic disorder due to homozygous or compound heterozygous pathogenic variants in GBE1 gene, resulting in deficiency of glycogen-branching enzyme and secondary storage of glycogen in the form of polyglucosan bodies, involving the skeletal muscle, diaphragm, peripheral nerve (including autonomic fibers), brain white matter, spinal cord, nerve roots, cerebellum, brainstem and to a lesser extent heart, lung, kidney, and liver cells. The diversity of new clinical presentations regarding neuromuscular involvement is astonishing and transformed APBD in a key differential diagnosis of completely different clinical conditions, including axonal and demyelinating sensorimotor polyneuropathy, progressive spastic paraparesis, motor neuronopathy presentations, autonomic disturbances, leukodystrophies or even pure myopathic involvement with limb-girdle pattern of weakness. This review article aims to summarize the main clinical, biochemical, genetic, and diagnostic aspects regarding APBD with special focus on neuromuscular presentations.

Hallmarks of oxidative stress in the livers of aged mice with mild glycogen branching enzyme deficiency

Glycogen branching enzyme (GBE1) introduces branching points in the glycogen molecule during its synthesis. Pathogenic GBE1 gene mutations lead to glycogen storage disease type IV (GSD IV), which is characterized by excessive intracellular accumulation of abnormal, poorly branched glycogen in affected tissues and organs, mostly in the liver. Using heterozygous Gbe1 knock-out mice (Gbe1+/−), we analyzed the effects of moderate GBE1 deficiency on oxidative stress in the liver. The livers of aged Gbe1+/− mice (22 months old) had decreased GBE1 protein levels, which caused a mild decrease in the degree of glycogen branching, but did not affect the tissue glycogen content. GBE1 deficiency was accompanied by increased protein carbonylation and elevated oxidation of the glutathione pool, indicating the existence of oxidative stress. Furthermore, we have observed increased levels of glutathione peroxidase and decreased activity of respiratory complex I in Gbe1+/− livers. Our data indicate that even mild changes in the degree of glycogen branching, which did not lead to excessive glycogen accumulation, may have broader effects on cellular bioenergetics and redox homeostasis. In young animals cellular homeostatic mechanisms are able to counteract those changes, while in aged tissues the changes may lead to increased oxidative stress.

Efficient correction of a deleterious point mutation in primary horse fibroblasts with CRISPR-Cas9

Phenotypic selection during animal domestication has resulted in unwanted incorporation of deleterious mutations. In horses, the autosomal recessive condition known as Glycogen Branching Enzyme Deficiency (GBED) is the result of one of these deleterious mutations (102C > A), in the first exon of the GBE1 gene (GBE1102C>A). With recent advances in genome editing, this type of genetic mutation can be precisely repaired. In this study, we used the RNA-guided nuclease CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats/CRISPR-associated protein 9) to correct the GBE1102C>A mutation in a primary fibroblast cell line derived from a high genetic merit heterozygous stallion. To correct this mutation by homologous recombination (HR), we designed a series of single guide RNAs (sgRNAs) flanking the mutation and provided different single-stranded donor DNA templates. The distance between the Cas9-mediated double-stranded break (DSB) to the mutation site, rather than DSB efficiency, was the primary determinant for successful HR. This framework can be used for targeting other harmful diseases in animal populations.

Guaiacol as a drug candidate for treating adult polyglucosan body disease.

Adult polyglucosan body disease (APBD) is a late-onset disease caused by intracellular accumulation of polyglucosan bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays showed that guaiacol lowers basal and glucose 6-phosphate-stimulated glycogen synthase (GYS) activity. Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged GBE1-knockin mice. Guaiacol's curative effects can be explained by its reduction of polyglucosans in peripheral nerve, liver, and heart, despite a short half-life of up to 60 minutes in most tissues. Our results form the basis to use guaiacol as a treatment and prepare for the clinical trials in APBD.

Case of Neonatal Fatality from Neuromuscular Variant of Glycogen Storage Disease Type IV.

Glycogen storage disease type IV (GSD-IV), or Andersen disease, is a rare autosomal recessive disorder that results from the deficiency of glycogen branching enzyme (GBE). This in turn results in accumulation of abnormal glycogen molecules that have longer outer chains and fewer branch points. GSD-IV manifests in a wide spectrum, with variable phenotypes depending on the degree and type of tissues in which this abnormal glycogen accumulates. Typically, GSD-IV presents with rapidly progressive liver cirrhosis and death in early childhood. However, there is a severe congenital neuromuscular variant of GSD-IV that has been reported in the literature, with fewer than 20 patient cases thus far. We report an unusual case of GSD-IV neuromuscular variant in a late preterm female infant who was born to non-consanguineous healthy parents with previously healthy children. Prenatally, our patient was found to have decreased fetal movement and polyhydramnios warranting an early delivery. Postnatally, she had severe hypotonia and respiratory failure, with no hepatic or cardiac involvement. Extensive metabolic and neurological workup revealed no abnormalities. However, molecular analysis by whole-exome sequencing revealed two pathogenic variants in the GBE1 gene. Our patient was thus a compound heterozygote of the two pathogenic variants: one of these was inherited from the mother [p.L490WfsX5 (c.1468delC)], and the other pathogenic variant was a de novo change [p.E449X (c.1245G>T)]. As expected in GSD-IV, diffuse intracytoplasmic periodic acid-Schiff-positive, diastase-resistant inclusions were found in the cardiac myocytes, hepatocytes, and skeletal muscle fibers of our patient.

A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome.

Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. This was a two-site, randomized crossover trial of 23 patients (age 35-73years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389±164m (range 95-672; n=19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6m; 95% confidence interval (CI) -11 to 22; p=0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4years. We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity. ClinicalTrials.gov Identifier: NCT00947960.

Prevalence of the Glycogen Branching Enzyme Deficiency Mutation in Quarter Horses in Brazil

Glycogen branching enzyme deficiency (GBED) is a fatal autosomal inherited disease affecting horses and caused by a nonsense mutation (c.102C>A) in the GBE1 gene. This disease strongly impairs the glycogen metabolism of affected animals resulting in abortion or early death of foals. Although understanding the prevalence of heterozygous for GBED is imperative to estimate the impact of the disease, prevalence studies have yet to be performed in Brazil. The aim of this study was to determine the prevalence of heterozygous of the GBED mutation in a population of Quarter Horses in Brazil. Blood samples were obtained from 742 animals competing in distinct disciplines including cutting, halter, race, reining, and barrel racing. All samples were submitted to DNA purification, amplification, and sequencing of the target fragment. The overall GBED prevalence of carriers was 7.95% (59/742). The prevalence of heterozygotes by discipline was considered higher in cutting (19.75% [32/162]) and reining (10% [16/160]) subgroups followed by barrel racing (5% [8/160]) and halter (3% [3/100]) horses. There were none heterozygous in the racing subgroup. These results demonstrate the GBED causative mutation in the Brazilian Quarter Horse herd and suggest the occurrence of the disease. Therefore, GBED is a disease that should be considered in the differential diagnosis of abortion and stillbirths, especially if suspect foals are products of two heterozygous. Besides testing aborted foals for the GBED mutation, the molecular diagnosis should be recommended to owners and breeders, at least for those breeding the at-most-risk subgroups of horses, to guiding their mating selections and, therefore, prevent the transmission of the mutation.

Systemic Correction of Murine Glycogen Storage Disease Type IV by an AAV-Mediated Gene Therapy.

Deficiency of glycogen branching enzyme (GBE) causes glycogen storage disease type IV (GSD IV), which is characterized by the accumulation of a less branched, poorly soluble form of glycogen called polyglucosan (PG) in multiple tissues. This study evaluates the efficacy of gene therapy with an adeno-associated viral (AAV) vector in a mouse model of adult form of GSD IV (Gbe1ys/ys). An AAV serotype 9 (AAV9) vector containing a human GBE expression cassette (AAV-GBE) was intravenously injected into 14-day-old Gbe1ys/ys mice at a dose of 5 × 1011 vector genomes per mouse. Mice were euthanized at 3 and 9 months of age. In the AAV-treated mice at 3 months of age, GBE enzyme activity was highly elevated in heart, which is consistent with the high copy number of the viral vector genome detected. GBE activity also increased significantly in skeletal muscles and the brain, but not in the liver. The glycogen content was reduced to wild-type levels in muscles and significantly reduced in the liver and brain. At 9 months of age, though GBE activity was only significantly elevated in the heart, glycogen levels were significantly reduced in the liver, brain, and skeletal muscles of the AAV-treated mice. In addition, the AAV treatment resulted in an overall decrease in plasma activities of alanine transaminase, aspartate transaminase, and creatine kinase, and a significant increase in fasting plasma glucose concentration at 9 months of age. This suggests an alleviation of damage and improvement of function in the liver and muscles by the AAV treatment. This study demonstrated a long-term benefit of a systemic injection of an AAV-GBE vector in Gbe1ys/ys mice.

Response to energy stress in fibroblasts from patients with glycogen branching enzyme deficiency

Response to energy stress in fibroblasts from patients with glycogen branching enzyme deficiency

Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design.

Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. Mutations in the GBE1 gene lead to the heterogeneous early-onset glycogen storage disorder type IV (GSDIV) or the late-onset adult polyglucosan body disease (APBD). To better understand this essential enzyme, we crystallized human GBE1 in the apo form, and in complex with a tetra- or hepta-saccharide. The GBE1 structure reveals a conserved amylase core that houses the active centre for the branching reaction and harbours almost all GSDIV and APBD mutations. A non-catalytic binding cleft, proximal to the site of the common APBD mutation p.Y329S, was found to bind the tetra- and hepta-saccharides and may represent a higher-affinity site employed to anchor the complex glycogen substrate for the branching reaction. Expression of recombinant GBE1-p.Y329S resulted in drastically reduced protein yield and solubility compared with wild type, suggesting this disease allele causes protein misfolding and may be amenable to small molecule stabilization. To explore this, we generated a structural model of GBE1-p.Y329S and designed peptides ab initio to stabilize the mutation. As proof-of-principle, we evaluated treatment of one tetra-peptide, Leu-Thr-Lys-Glu, in APBD patient cells. We demonstrate intracellular transport of this peptide, its binding and stabilization of GBE1-p.Y329S, and 2-fold increased mutant enzymatic activity compared with untreated patient cells. Together, our data provide the rationale and starting point for the screening of small molecule chaperones, which could become novel therapies for this disease.

A Modified Enzymatic Method for Measurement of Glycogen Content in Glycogen Storage Disease Type IV.

Deficiency of glycogen branching enzyme in glycogen storage disease type IV (GSD IV) results in accumulation of less-branched and poorly soluble polysaccharides (polyglucosan bodies) in multiple tissues. Standard enzymatic method, when used to quantify glycogen content in GSD IV tissues, causes significant loss of the polysaccharides during preparation of tissue lysates. We report a modified method including an extra boiling step to dissolve the insoluble glycogen, ultimately preserving the glycogen content in tissue homogenates from GSD IV mice. Muscle tissues from wild-type, GSD II and GSD IV mice and GSD III dogs were homogenized in cold water, and homogenate of each tissue was divided into two parts. One part was immediately clarified by centrifugation at 4°C (STD-prep); the other part was boiled for 5min then centrifuged (Boil-prep) at room temperature. When glycogen was quantified enzymatically in tissue lysates, no significant differences were found between the STD-prep and the Boil-prep for wild-type, GSD II and GSD III muscles. In contrast, glycogen content for GSD IV muscle in the STD-prep was only 11% of that in the Boil-prep, similar to wild-type values. Similar results were observed in other tissues of GSD IV mice and fibroblast cells from a GSD IV patient. This study provides important information for improving disease diagnosis, monitoring disease progression, and evaluating treatment outcomes in both clinical and preclinical clinical settings for GSD IV. This report should be used as an updated protocol in clinical diagnostic laboratories.

Branching Enzyme Deficiency

The neuromuscular presentation of glycogen branching enzyme deficiency includes a severe infantile form and a late-onset variant known as adult polyglucosan body disease. Herein, we describe 2 patients with adult acute onset of fluctuating neurological signs and brain magnetic resonance imaging lesions simulating multiple sclerosis. A better definition of this new clinical entity is needed to facilitate diagnosis. To describe the clinical presentation and progression of a new intermediate variant of glycogen branching enzyme deficiency and to discuss genotype-phenotype correlations. Clinical, biochemical, morphological, and molecular study of 2 patients followed up for 6 years and 8 years at academic medical centers. The participants were 2 patients of non-Ashkenazi descent with adult acute onset of neurological signs initially diagnosed as multiple sclerosis. Clinical course, muscle and nerve morphology, longitudinal study of brain magnetic resonance imaging, and glycogen branching enzyme activity and GBE1 molecular analysis. Molecular analysis showed that one patient was homozygous (c.1544G>A) and the other patient was compound heterozygous (c.1544G>A and c.1961-1962delCA) for GBE1 mutations. Residual glycogen branching enzyme activity was 16% and 30% of normal in leukocytes. Both patients manifested acute episodes of transient neurological symptoms, and neurological impairment was mild at age 45 years and 53 years. Brain magnetic resonance imaging revealed nonprogressive white matter lesions and spinocerebellar atrophy similar to typical adult polyglucosan body disease. GBE1 mutations can cause an early adult-onset relapsing-remitting form of polyglucosan body disease distinct from adult polyglucosan body disease in several ways, including younger age at onset, history of infantile liver involvement, and subacute and remitting course simulating multiple sclerosis. This should orient neurologists toward the correct diagnosis.