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.

Genotypic and phenotypic features of 39 Chinese patients with glycogen storage diseases type I, VI, and IX.

Glycogen storage diseases (GSDs) are abnormally inherited glycogen metabolism mainly affecting the liver, muscles, and heart. Deficiency of proteins involved in glycogen metabolism caused by genetic mutations are responsible for different subtype of GSDs. However, there are still some challenges in diagnosing GSD. This study includes 39 suspected GSDs patients from unrelated families in China. Next-generation sequencing (NGS) was used to investigate the reason for their diseases at the genetic level. Finally, all 39 patients were diagnosed with GSDs, including 20 GSD-Ia, 4 GSD-VI, and 15 GSD IX (12 GSD-IXa patients and 3 GSD-IXb patients). Thirty-two mutations in G6PC1, PYGL, PHKA2, and PHKB genes were identified, with 14 of them being novel variants. The pathogenicity of novel variants was classified according to ACMG guildlines and predicted by in slico algorithms. Mutations p.L216L and p.R83H in G6PC1 gene may be the hot spot mutation in Chinese. Hearing impairment is a rare clinical feature of GSD Ia, which has also been observed in our cohort. The severity of GSD VI and IX was indicated by our patients. Close follow-up should be applied to GSD VI and IX patients. Our findings provided evidence for building the phenotype-genotype of GSDs and expanded the mutation spectrum of related genes.

Gene therapy for glycogen storage diseases.

Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.

The Liver and Glycogen: In Sickness and in Health.

The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation.

[Splicing abnormalities caused by a novel mutation in the PHKA2 gene in children with glycogen storage disease type IX].

Objective: Glycogen storage disease type IX (GSD-IX) is a rare primary glucose metabolism abnormality caused by phosphorylase kinase deficiency and a series of pathogenic gene mutations. The clinical characteristics, gene analysis, and functional verification of a mutation in a child with hepatomegaly are summarized here to clarify the pathogenic cause of the disease. Methods: The clinical data of a child with GSD-IX was collected. Peripheral blood from the child and his parents was collected for genomic DNA extraction. The patient's gene diagnosis was performed by second-generation sequencing. The suspected mutations were verified by Sanger sequencing and bioinformatics analysis. The suspected splicing mutations were verified in vivo by RT-PCR and first-generation sequencing. Results: Hepatomegaly, transaminitis, and hypertriglyceridemia were present in children. Liver biopsy pathological examination results indicated glycogen storage disease. Gene sequencing revealed that the child had a c.285 + 2_285 + 5delTAGG hemizygous mutation in the PHKA2 gene. Sanger sequencing verification showed that the mother of the child was heterozygous and the father of the child was of the wild type. Software such as HSF3.1 and ESEfinder predicted that the gene mutation affected splicing. RT-PCR of peripheral blood from children and his mother confirmed that the mutation had caused the skipping of exon 3 during the constitutive splicing of the PHKA2 gene. Conclusion: The hemizygous mutation in the PHKA2 gene (c.285 + 2_285 + 5delTAGG) is the pathogenic cause of the patient's disease. The detection of the novel mutation site enriches the mutation spectrum of the PHKA2 gene and serves as a basis for the family's genetic counseling.

Diagnosis and follow-up of glycogen storage disease (GSD) type VI from the largest GSD center in China.

Glycogen storage disease (GSD) Type VI is a glycogenolysis disorder caused by variants of PYGL. Knowledge about this disease is limited because only approximately 50 cases have been reported. We investigated the clinical profiles, molecular diagnosis, and treatment outcomes in patients with GSD VI from 2000 to 2021. The main initial clinical features of this cohort include hepatomegaly, short stature, elevated liver transaminases, hypertriglyceridemia, fasting hypoglycemia, and hyperuricemia. After uncooked cornstarch treatment, the stature and biochemical parameters improved significantly (p < 0.05). However, hyperuricemia recurred in most patients during adolescence. Among the 56 GSD VI patients, 54 biallelic variants and two single allelic variants of PYGL were identified, of which 43 were novel. There were two hotspot variants, c.1621-258_2178-23del and c.2467C>T p.(Gln823*), mainly in patients from Southwest and South China. c.1621-258_2178-23del is a 3.6 kb deletion that results in an out-of-frame deletion r.1621_2177del and an in-frame deletion r.1621_2265del. Our data show for the first time that long-term monitoring of uric acid is recommended for older GSD VI patients. This study also broadens the variant spectrum of PYGL and indicates that there are two hot-spot variants in China.

Molecular, Biochemical, and Clinical Characterization of Thirteen Patients with Glycogen Storage Disease 1a in Malaysia.

Background: Glycogen storage disease type 1a (GSD1a) is a rare autosomal recessive metabolic disorder characterized by hypoglycaemia, growth retardation, lactic acidosis, hepatomegaly, hyperlipidemia, and nephromegaly. GSD1a is caused by a mutation in the G6PC gene encoding glucose-6-phosphatase (G6Pase); an enzyme that catalyses the hydrolysis of glucose-6-phosphate (G6P) to phosphate and glucose. Objective: To elaborate on the clinical findings, biochemical data, molecular genetic analysis, and short-term prognosis of 13 GSD1a patients in Malaysia. Methods: The information about 13 clinically classified GSD1a patients was retrospectively studied. The G6PC mutation analysis was performed by PCR-DNA sequencing. Results: Patients were presented with hepatomegaly (92%), hypoglycaemia (38%), poor weight gain (23%), and short stature (15%). Mutation analysis revealed nine heterozygous mutations; eight previously reported mutations (c.155 A > T, c.209 G > A, c.226 A > T, c.248 G > A, c.648 G > T, c.706 T > A, c.1022 T > A, c.262delG) and a novel mutation (c.325 T > C). The most common mutation found in Malaysian patients was c.648 G > T in ten patients (77%) of mostly Malay ethnicity, followed by c.248 G > A in 4 patients of Chinese ethnicity (30%). A novel missense mutation (c.325 T > C) was predicted to be disease-causing by various in silico software. Conclusions: The establishment of G6PC molecular genetic testing will enable the detection of presymptomatic patients, assisting in genetic counselling while avoiding the invasive methods of liver biopsy.

Update on glycogen storage disease: primary hepatic involvement.

PURPOSE OF REVIEW: Glycogen storage disease is a group of disorders primarily characterized by hepatomegaly and fasting hypoglycemia. This group of disorders may also affect the muscle, kidneys, and neurodevelopment. With an overall prevalence of 1 : 20 000, GSDs are disorders that clinicians should diagnose in a timely manner because adequate management can prevent complications, such as neurodevelopmental delay and liver disease [1] . As there are numerous types of GSDs, being able to distinguish one type from another can be overwhelming. In this review, we focus on hepatic GSDs to provide a concise review of clinical presentation, diagnosis, and current management. RECENT FINDINGS: GSDs are considered rare disorders, and one of the main challenges is the delay in diagnosis, misdiagnosis, or under diagnosis. However, with molecular genetic testing now readily available, confirming the diagnosis is no longer as difficult or invasive as it was in the past. SUMMARY: Current therapy for this group of disorders requires maintaining stable glucose levels. Avoiding hypoglycemia, as well as hyperglycemia, is critical in managing these patients. Being able to distinguish the types of GSDs and understanding the specific treatments for each enzymatic defect will optimize patient care.

A very rare case report of glycogen storage disease type IXc with novel PHKG2 variants.

BACKGROUND: Pathogenic mutations in the PHKG2 are associated with a very rare disease-glycogen storage disease IXc (GSD-IXc)-and are characterized by severe liver disease. CASE PRESENTATION: Here, we report a patient with jaundice, hypoglycaemia, growth retardation, progressive increase in liver transaminase and prominent hepatomegaly from the neonatal period. Genetic testing revealed two novel, previously unreported PHKG2 mutations (F233S and R320DfsX5). Functional experiments indicated that both F223S and R320DfsX5 lead to a decrease in key phosphorylase b kinase enzyme activity. With raw cornstarch therapy, hypoglycaemia and lactic acidosis were ameliorated and serum aminotransferases decreased. CONCLUSION: These findings expand the gene spectrum and contribute to the interpretation of clinical presentations of these two novel PHKG2 mutations.

A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis.

Glycogen storage disease type IX (GSD-IX) constitutes nearly a quarter of all GSDs. This ketotic form of GSD is caused by mutations in phosphorylase kinase (PhK), which is composed of four subunits (α, ß, γ, δ). PhK is required for the activation of the liver isoform of glycogen phosphorylase (PYGL), which generates free glucose-1-phosphate monomers to be used as energy via cleavage of the α -(1,4) glycosidic linkages in glycogen chains. Mutations in any of the PhK subunits can negatively affect the regulatory and catalytic activity of PhK during glycogenolysis. To understand the pathogenesis of GSD-IX-beta, we characterized a newly created PHKB knockout (Phkb−/−) mouse model. In this study, we assessed fasting blood glucose and ketone levels, serum metabolite concentrations, glycogen phosphorylase activity, and gene expression of gluconeogenic genes and fibrotic genes. Phkb−/− mice displayed hepatomegaly with lower fasting blood glucose concentrations. Phkb−/− mice showed partial liver glycogen phosphorylase activity and increased sensitivity to pyruvate, indicative of partial glycogenolytic activity and upregulation of gluconeogenesis. Additionally, gene expression analysis demonstrated increased lipid metabolism in Phkb−/− mice. Gene expression analysis and liver histology in the livers of old Phkb−/− mice (>40 weeks) showed minimal profibrogenic features when analyzed with age-matched wild-type (WT) mice. Collectively, the Phkb−/− mouse recapitulates mild clinical features in patients with GSD-IX-beta. Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.

[Genetic analysis of a child with glycogen storage disease type IXa due to a novel variant in PHKA2 gene].

OBJECTIVE: To explore the genetic etiology of a patient with glycogen storage diseases. METHODS: Clinical data of child and his parents were collected. The genes associated with glycogen storage diseases were subjected to high-throughput sequencing to screen the variants. Candidate variant was validated by Sanger sequencing. Pathogenicity of the variant was predicted by bioinformatic analysis. RESULTS: High-throughput sequencing results showed that the boy has carried a hemizygous c.749C>T (p.S250L) variant of the PHKA2 gene. Sanger sequencing verified the results and confirmed that it was inherited from his mother. This variant was unreported previously and predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The patient was diagnosed with glycogen storage disease type IXa due to a novel c.749C>T (p.S250L) hemizygous variant of the PHKA2 gene. High-throughput sequencing can facilitate timely and accurate differential diagnosis of glycogen storage disease type IXa.

Gene therapy for glycogen storage diseases.

The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that affect liver or muscle or both tissues. For example, glucose-6-phosphatase (G6Pase) deficiency in GSD type Ia (GSD Ia) affects primarily the liver and kidney, while acid α-glucosidase (GAA) deficiency in GSD II causes primarily muscle disease. The lack of specific therapy for the GSDs has driven efforts to develop new therapies for these conditions. Gene therapy needs to replace deficient enzymes in target tissues, which has guided the planning of gene therapy experiments. Gene therapy with adeno-associated virus (AAV) vectors has demonstrated appropriate tropism for target tissues, including the liver, heart and skeletal muscle in animal models for GSD. AAV vectors transduced liver and kidney in GSD Ia and striated muscle in GSD II mice to replace the deficient enzyme in each disease. Gene therapy has been advanced to early phase clinical trials for the replacement of G6Pase in GSD Ia and GAA in GSD II (Pompe disease). Other GSDs have been treated in proof-of-concept studies, including GSD III, IV and V. The future of gene therapy appears promising for the GSDs, promising to provide more efficacious therapy for these disorders in the foreseeable future.

From a Single Child to Uniform Newborn Screening: My Lucky Life in Pediatric Medical Genetics.

Mike, a memorable young patient with untreated phenylketonuria, as well as others affected by genetic disorders that could be treated if diagnosed in infancy, launched my six-decade career. This autobiographical article reflects on my childhood, early research, and professional experiences in pediatric genetics. My laboratory research focused on inborn errors of metabolism, including the glycogen storage diseases. My effort to organize newborn screening through the recommended uniform screening panel shaped and standardized newborn screening nationwide. Looking ahead, the expansion of whole-genome and whole-exome sequencing into newborn screening raises ethical and policy issues regarding informed consent procedures and the storage and use of residual blood spots.

Characterization of liver GSD IX γ2 pathophysiology in a novel Phkg2-/- mouse model.

INTRODUCTION: Liver Glycogen Storage Disease IX is a rare metabolic disorder of glycogen metabolism caused by deficiency of the phosphorylase kinase enzyme (PhK). Variants in the PHKG2 gene, encoding the liver-specific catalytic γ2 subunit of PhK, are associated with a liver GSD IX subtype known as PHKG2 GSD IX or GSD IX γ2. There is emerging evidence that patients with GSD IX γ2 can develop severe and progressive liver disease, yet research regarding the disease has been minimal to date. Here we characterize the first mouse model of liver GSD IX γ2. METHODS: A Phkg2-/- mouse model was generated via targeted removal of the Phkg2 gene. Knockout (Phkg2-/-, KO) and wild type (Phkg2+/+, WT) mice up to 3 months of age were compared for morphology, Phkg2 transcription, PhK enzyme activity, glycogen content, histology, serum liver markers, and urinary glucose tetrasaccharide Glcα1-6Glcα1-4Glcα1-4Glc (Glc4). RESULTS: When compared to WT controls, KO mice demonstrated significantly decreased liver PhK enzyme activity, increased liver: body weight ratio, and increased glycogen in the liver, with no glycogen accumulation observed in the brain, quadricep, kidney, and heart. KO mice demonstrated elevated liver blood markers as well as elevated urine Glc4, a commonly used biomarker for glycogen storage disease. KO mice demonstrated features of liver structural damage. Hematoxylin & Eosin and Masson's Trichrome stained KO mice liver histology slides revealed characteristic GSD hepatocyte architectural changes and early liver fibrosis, as have been reported in liver GSD patients. DISCUSSION: This study provides the first evidence of a mouse model that recapitulates the liver-specific pathology of patients with GSD IX γ2. The model will provide the first platform for further study of disease progression in GSD IX γ2 as well as for the evaluation of novel therapeutics.

A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation.

OBJECTIVE: Glycogen storage diseases (GSDs) are severe human disorders resulting from abnormal glucose metabolism, and all previously described GSDs segregate as autosomal recessive or X-linked traits. In this study, we aimed to molecularly characterize the first family with a dominant GSD. METHODS: We describe a dominant GSD family with 13 affected members presenting with adult-onset muscle weakness, and we provide clinical, metabolic, histological, and ultrastructural data. We performed exome sequencing to uncover the causative gene, and functional experiments in the cell model and on recombinant proteins to investigate the pathogenic effect of the identified mutation. RESULTS: We identified a heterozygous missense mutation in PYGM segregating with the disease in the family. PYGM codes for myophosphorylase, the enzyme catalyzing the initial step of glycogen breakdown. Enzymatic tests revealed that the PYGM mutation impairs the AMP-independent myophosphorylase activity, whereas the AMP-dependent activity was preserved. Further functional investigations demonstrated an altered conformation and aggregation of mutant myophosphorylase, and the concurrent accumulation of the intermediate filament desmin in the myofibers of the patients. INTERPRETATION: Overall, this study describes the first example of a dominant glycogen storage disease in humans, and elucidates the underlying pathomechanisms by deciphering the sequence of events from the PYGM mutation to the accumulation of glycogen in the muscle fibers. ANN NEUROL 2020;88:274-282.

PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only.

Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole-exome sequencing or targeted next-generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%-20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH-only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH-only phenotype of PHKA2.

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.

Novel mutations in the PHKB gene in an iranian girl with severe liver involvement and glycogen storage disease type IX: a case report and review of literature.

BACKGROUND: Glycogen storage disease (GSD) type IXb is one of the rare variants of GSDs. It is a genetically heterogeneous metabolic disorder due to deficient hepatic phosphorylase kinase activity. Diagnosis of GSD can be difficult because of overlapping manifestations. Mutation analysis of the genes related to each type of GSD is supposed to be problem-solving, however, the presence of novel mutations can be confusing. In this case report, we will describe our experience with a young girl with the diagnosis of GSD and two novel mutations related to GSD type IXb. CASE PRESENTATION: A 3-year- old girl presented with short stature, hepatomegaly, and liver cirrhosis. No specific diagnosis was made based on laboratory data, so liver biopsy and targeted-gene sequencing (TGS) were performed to find out the specific molecular basis of her disease. It was confirmed that the patient carries two novel variants in the PHKB gene. The variant in the PHKB gene was classified as pathogenic. CONCLUSIONS: This is the first reported case of a dual molecular mutation of glycogen storage disease type IXb in the same patient. Two novel variants in PHKB were identified and one of them was a pathogenic split-site mutation. In conclusion, for the first time, identification of the novel variants in this patient expands the molecular and the phenotype basis of dual variants in GSD-IXb.

Polyglucosan body myopathy 1 may cause cognitive impairment: a case report from China.

BACKGROUND: Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease that can cause skeletal muscle myopathy and cardiomyopathy with or without immunodeficiency due to a pathogenic mutation in the RBCK1 gene. PGBM1 has been reported in only 14 European and American families, and no cognitive impairment phenotype was reported. Its prevalence in Asia is unknown. CASE PRESENTATION: We report a Chinese boy with teenage onset of skeletal muscle myopathy and mild cognitive impairment. Whole-exome sequencing analysis identified a homozygous missense mutation in RBCK1 (c.1411G > A:p.Glu471Lys). A muscle biopsy indicated the accumulation of periodic acid-Schiff-positive material, which could be ubiquitinated by immunohistochemistry with an anti-ubiquitin antibody. In skeletal muscle tissue, HOIL-1 and HOIP protein levels were lower than those in the control, confirming the phenotype of an RBCK1 mutation. MRI revealed abnormal cerebral white matter signals. Immune system and cardiac examination found no abnormalities. The patient was diagnosed with PGBM1 with no effective treatment. CONCLUSIONS: This case from China with a novel homozygous missense mutation in RBCK1 extends the phenotypic spectrum and geographical distribution of PGBM 1, which may cause cerebral white matter changes and cognitive impairment.