RESUMO
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.
Assuntos
Glucanos , Doença de Depósito de Glicogênio , Músculo Esquelético , Proteômica , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Pessoa de Meia-Idade , Glucanos/metabolismo , Doença de Depósito de Glicogênio/metabolismo , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Masculino , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/genética , Glucosiltransferases , Glicoproteínas , Doenças do Sistema NervosoRESUMO
BACKGROUND: Glycogen storage disease type IX is a rare disorder that can cause a wide variety of symptoms depending on the specific deficiency of the phosphorylase kinase enzyme and the organs it affects. CASE PRESENTATION: A 4-and-a-half-year-old Caucasian girl was referred to our clinic with a liver biopsy report indicating a diagnosis of glycogen storage disease. Prior to being referred to our clinic, the patient had been under the care of pediatric gastroenterologists. The patient's initial symptoms included chronic abdominal pain, constipation, and elevated liver transaminase. With the help of the pediatric gastroenterologists, cholestasis, Wilson disease, and autoimmune hepatitis were ruled out. Given that glycogen storage diseases type I and type III are the most common, we initially managed the patient with frequent feedings and a diet that included complex carbohydrates such as a corn starch supplement and a lactose restriction. Following an unfavorable growth velocity and hepatomegaly during the follow-up period, genetic analysis was conducted, which revealed a novel mutation of the phosphorylase kinase regulatory subunit beta gene- a c.C412T (P.Q138x) mutation. As the diagnosis of glycogen storage disease type IX was confirmed, the treatment regimen was altered to a high protein diet (more than 2 g/kg/day) and a low fat diet. CONCLUSION: Given the mild and varied clinical manifestations of glycogen storage disease type IX, it is possible for the diagnosis to be overlooked. It is important to consider glycogen storage disease type IX in children who present with unexplained hepatomegaly and elevated transaminase levels. Furthermore, due to the distinct management of glycogen storage disease type IX compared with glycogen storage disease type I and glycogen storage disease type III, genetic analysis is essential for an accurate diagnosis.
Assuntos
Doença de Depósito de Glicogênio Tipo I , Doença de Depósito de Glicogênio , Pré-Escolar , Feminino , Humanos , Dor Abdominal/etiologia , Constipação Intestinal , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/diagnóstico , Doença de Depósito de Glicogênio Tipo I/genética , Hepatomegalia/patologia , Irã (Geográfico) , Fígado/patologia , Mutação , Fosforilase Quinase/genética , Fosforilase Quinase/metabolismo , TransaminasesRESUMO
Multiple lung cysts are one of the major features of Birt-Hogg-Dubé syndrome (BHD), but little is known about their nature and pathogenesis. We report a case of a woman diagnosed with BHD lung cysts who exhibited pulmonary interstitial glycogenosis (PIG), a mesenchymal abnormality hitherto undescribed in this disease, in specimens resected at 14 and 29 years of age. Histopathologically, oval to spindle clear cells were seen in the subepithelial interstitial tissue of septal structures and the walls of the cysts. They had abundant periodic acid-Schiff-positive cytoplasmic glycogen. Immunohistochemically, these cells were positive for a few markers of mesenchymal stem cell-like lineage, including vimentin, CD44, and CD10, and negative for markers of epithelial or specific mesenchymal differentiation; these results were consistent with the reported immunophenotype of PIG cells. These PIG cells were more abundant in her specimen at age 14 years than in the second specimen from adulthood. The present case suggests that BHD lung cysts belong to a group of pulmonary developmental disorders characterized by combined PIG and alveolar simplification/cystic change. Disorders with PIG may persist until adulthood and may be of clinical and pathological significance.
Assuntos
Síndrome de Birt-Hogg-Dubé , Cistos , Doença de Depósito de Glicogênio , Doenças Pulmonares Intersticiais , Pneumopatias , Pneumotórax , Humanos , Feminino , Adulto , Adolescente , Síndrome de Birt-Hogg-Dubé/complicações , Síndrome de Birt-Hogg-Dubé/genética , Pneumotórax/diagnóstico , Pneumotórax/etiologia , Pneumotórax/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Pneumopatias/patologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/patologia , Cistos/complicações , Cistos/genética , Doença de Depósito de Glicogênio/complicações , Doença de Depósito de Glicogênio/patologiaRESUMO
Lafora disease is a rare disorder caused by loss of function mutations in either the EPM2A or NHLRC1 gene. The initial symptoms of this condition are most commonly epileptic seizures, but the disease progresses rapidly with dementia, neuropsychiatric symptoms, and cognitive deterioration and has a fatal outcome within 5-10 years after onset. The hallmark of the disease is the accumulation of poorly branched glycogen in the form of aggregates known as Lafora bodies in the brain and other tissues. Several reports have demonstrated that the accumulation of this abnormal glycogen underlies all the pathologic traits of the disease. For decades, Lafora bodies were thought to accumulate exclusively in neurons. However, it was recently identified that most of these glycogen aggregates are present in astrocytes. Importantly, astrocytic Lafora bodies have been shown to contribute to pathology in Lafora disease. These results identify a primary role of astrocytes in the pathophysiology of Lafora disease and have important implications for other conditions in which glycogen abnormally accumulates in astrocytes, such as Adult Polyglucosan Body disease and the buildup of Corpora amylacea in aged brains.
Assuntos
Doença de Depósito de Glicogênio , Doença de Lafora , Adulto , Humanos , Idoso , Doença de Lafora/genética , Doença de Lafora/patologia , Astrócitos/patologia , Glicogênio , Neurônios/patologia , Doença de Depósito de Glicogênio/patologia , Ubiquitina-Proteína LigasesRESUMO
Adult polyglucosan body disease (APBD) is caused by bi-allelic pathogenic variants in GBE1 and typically shows middle age onset urinary symptoms followed by progressive gait disturbances and possibly cognitive decline. Here we present a Belgian cohort of four patients from three families showing both classical and atypical signs of APBD. By clinical phenotyping, detailed neuroimaging of both central nervous system and skeletal muscle, genetic and biochemical testing, we confront our findings with the classical presentation of adult polyglucosan body disease and emphasize the importance of a multidisciplinary approach when diagnosing these patients.
Assuntos
Doença de Depósito de Glicogênio , Doenças do Sistema Nervoso , Pessoa de Meia-Idade , Adulto , Humanos , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/genética , Sistema Nervoso Central , Músculo Esquelético/patologiaRESUMO
Congenital lobar emphysema (CLE)/congenital alveolar overdistension/congenital lobar overinflation or infantile lobar emphysema is a rare developmental anomaly of the lower respiratory tract which is characterised by hyperinflation of one or more of the pulmonary lobes. Histopathology may be variable, which may show abnormality in the cartilage, granulation tissue, mucosal folds, etc. We report a rare underlying histopathology in a preterm neonate with CLE. This entity referred to as pulmonary interstitial glycogenosis (PIG) is a group of heterogeneous lung disease affecting the lung parenchyma and is characterised by the presence of glycogen laden cells in the lung interstitium. This impairs the gas exchange and typically manifest as tachypnoea, retractions, hypoxia and increased respiratory support. Our case report highlights the association of CLE and PIG and a review of literature. One should always have a detailed histopathology in children presenting with CLE to rule out PIG.
Assuntos
Enfisema , Doença de Depósito de Glicogênio , Doenças Pulmonares Intersticiais , Enfisema Pulmonar , Humanos , Enfisema Pulmonar/complicações , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/congênito , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Doença de Depósito de Glicogênio/complicações , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/patologiaRESUMO
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.
Assuntos
Doença de Depósito de Glicogênio , Criança , Família , Testes Genéticos , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutação , Fosforilase Quinase/genéticaRESUMO
Muscle Glycogenosis type 0 (GSD0B) is an extremely rare disorder first recognized in 2007 in three siblings with childhood onset and severe cardiomyopathy. Since then, a few cases with severe cardiac involvement and premature death have been reported. We describe two unrelated cases presenting with an adult-onset myopathy with no heart involvement. Clinical features were quite similar in both patients, mainly characterized by early fatigability, myalgia and muscle weakness. Muscle biopsy revealed marked glycogen depletion in nearly all myofibers. Biochemical assay demonstrated a marked reduction of Glycogen Synthase (GS) activity. Sequence analysis of GYS1 revealed two new variants: a homozygous G to C substitution in the splice donor consensus site (c.678+1G>C) in patient1 and a homozygous missense variant c.630G>C in exon 3 (p. Asp145His) in patient 2. This study describes a new phenotype of muscle GSD0B presenting with adult onset, proximal myopathy, no cardiac abnormalities and a quite benign disease course. This report highlights the importance of a systematic diagnostic approach that includes muscle morphology and enzymatic assay to facilitate the identification of adult patients with GSD0B.
Assuntos
Cardiomiopatias , Doença de Depósito de Glicogênio , Doenças Musculares , Cardiomiopatias/diagnóstico , Cardiomiopatias/genética , Cardiomiopatias/patologia , Criança , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Glicogênio Sintase/deficiência , Glicogênio Sintase/genética , Humanos , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/patologia , FenótipoRESUMO
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.
Assuntos
Doença de Depósito de Glicogênio , Hipoglicemia , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Humanos , Recém-Nascido , Fígado/patologia , Mutação , Fosforilase Quinase/genéticaRESUMO
A 26-year-old Asian woman with persistent muscle weakness was diagnosed with polymyositis based on biopsy findings at another hospital 11 years ago. However, her symptoms fluctuated repeatedly under treatment with prednisone and immunosuppressive agents, and worsened 2 months prior to the current presentation. A second muscle biopsy suggested metabolic myopathy, and genetic testing revealed a novel c.1074C > T variant in the glycogen synthase 1 gene (GYS1), which is implicated in muscle glycogen storage disease type 0. However, no abnormalities in glycogen deposition were found by biopsy; rather, muscle fibers exhibited large intracellular lipid droplets. Furthermore, muscle strength was greatly restored and circulating levels of creatine kinase indicative of muscle degeneration greatly reduced by vitamin B2 treatment. Therefore, the final diagnosis was lipid storage myopathy.
Assuntos
Doença de Depósito de Glicogênio , Doenças Musculares , Polimiosite , Adulto , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Humanos , Erros Inatos do Metabolismo Lipídico , Lipídeos , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Distrofias Musculares , Mutação , Polimiosite/diagnóstico , Polimiosite/genéticaRESUMO
BACKGROUND: We report a case of the neonatal interstitial lung disease pulmonary interstitial glycogenosis in a girl with Jacobsen syndrome. While Jacobsen syndrome is caused by a deletion on the long arm of chromosome 11 and is genetically confirmed, pulmonary interstitial glycogenosis is of unknown etiology and is diagnosed by lung biopsy. Pulmonary interstitial glycogenosis has not previously been described in association with Jacobsen syndrome. CASE PRESENTATION: A term newborn small for gestational age Caucasian girl presented with respiratory distress, pulmonary hypertension, congenital heart defects, immunodeficiency, and thrombocytopenia. She was diagnosed with Jacobsen syndrome, but also had pulmonary interstitial glycogenosis, which contributed to significant morbidity. There was striking clinical improvement after steroid treatment of the pulmonary interstitial glycogenosis. CONCLUSIONS: Interstitial lung disease should be considered as a differential diagnosis when respiratory distress and hypoxemia in the perinatal period worsens or persists despite standard treatment. Importantly, pulmonary interstitial glycogenosis may be treatable with corticosteroids. Whether there is a genetic link between pulmonary interstitial glycogenosis and Jacobsen syndrome is still unknown.
Assuntos
Doença de Depósito de Glicogênio , Hipertensão Pulmonar , Síndrome da Deleção Distal 11q de Jacobsen , Doenças Pulmonares Intersticiais , Biópsia , Feminino , Doença de Depósito de Glicogênio/complicações , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/patologia , Humanos , Recém-Nascido , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológicoRESUMO
Herein, we aimed to present a child with extremely severe hypertriglyceridemia (ESHTG) secondary to diabetic ketoacidosis concomitant with type IX glycogen storage disease (GSD). Extremely severe hypertriglyceridemia (10 700 mg/dL) was detected through the apparent lipemic appearance of the sampled blood in a 17-year-old male patient with severe diabetic ketoacidosis. In spite of insulin infusion, the patient's clinical condition deteriorated to acute pancreatitis. Single sessions of therapeutic plasma exchange (TPE) along with insulin treatment have successfully intercepted the progression of the state of acute pancreatitis. The patient was also diagnosed with type IX GSD on the basis of the genetic analyses performed for the potential underlying metabolic diseases. In conclusion, underlying metabolic diseases, such as glycogen storage disease, should be investigated in patients with diabetic ketoacidosis accompanied by severe hypertriglyceridemia. If ESHTG does not relieve despite insulin infusion, and/or acute pancreatitis occurs as a complication, TPE should be kept in mind.
Assuntos
Complicações do Diabetes/complicações , Cetoacidose Diabética/etiologia , Cetoacidose Diabética/terapia , Doença de Depósito de Glicogênio/complicações , Doença de Depósito de Glicogênio/terapia , Hipertrigliceridemia/terapia , Troca Plasmática/métodos , Adolescente , Cetoacidose Diabética/fisiopatologia , Doença de Depósito de Glicogênio/patologia , Humanos , MasculinoRESUMO
AIMS: Several neurodegenerative and neuromuscular disorders are characterised by storage of polyglucosan, consisting of proteins and amylopectin-like polysaccharides, which are less branched than in normal glycogen. Such diseases include Lafora disease, branching enzyme deficiency, glycogenin-1 deficiency, polyglucosan body myopathy type 1 (PGBM1) due to RBCK1 deficiency and others. The protein composition of polyglucosan bodies is largely unknown. METHODS: We combined quantitative mass spectrometry, immunohistochemical and western blot analyses to identify the principal protein components of polyglucosan bodies in PGBM1. Histologically stained tissue sections of skeletal muscle from four patients were used to isolate polyglucosan deposits and control regions by laser microdissection. Prior to mass spectrometry, samples were labelled with tandem mass tags that enable quantitative comparison and multiplexed analysis of dissected samples. To study the distribution and expression of the accumulated proteins, immunohistochemical and western blot analyses were performed. RESULTS: Accumulated proteins were mainly components of glycogen metabolism and protein quality control pathways. The majority of fibres showed depletion of glycogen and redistribution of key enzymes of glycogen metabolism to the polyglucosan bodies. The polyglucosan bodies also showed accumulation of proteins involved in the ubiquitin-proteasome and autophagocytosis systems and protein chaperones. CONCLUSIONS: The sequestration of key enzymes of glycogen metabolism to the polyglucosan bodies may explain the glycogen depletion in the fibres and muscle function impairment. The accumulation of components of the protein quality control systems and other proteins frequently found in protein aggregate disorders indicates that protein aggregation may be an essential part of the pathobiology of polyglucosan storage.
Assuntos
Doença de Depósito de Glicogênio , Proteômica , Glucanos/metabolismo , Doença de Depósito de Glicogênio/metabolismo , Doença de Depósito de Glicogênio/patologia , Humanos , Músculo Esquelético/patologia , Fatores de Transcrição , Ubiquitina-Proteína Ligases/metabolismoAssuntos
Adenoma de Células Hepáticas , Doença de Depósito de Glicogênio , Neoplasias Hepáticas , Adenoma de Células Hepáticas/patologia , Doença de Depósito de Glicogênio/complicações , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/patologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapiaRESUMO
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.
Assuntos
Doença de Depósito de Glicogênio/genética , Hepatomegalia/genética , Hipoglicemia/genética , Fosforilase Quinase/genética , Acidemia Propiônica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/patologia , Hepatomegalia/diagnóstico , Hepatomegalia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/patologia , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/epidemiologia , Acidemia Propiônica/patologia , Sequenciamento do Exoma , Adulto JovemRESUMO
Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade®/modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.
Assuntos
Modelos Animais de Doenças , Terapia Genética/métodos , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio/terapia , RNA Mensageiro/genética , Animais , Linhagem Celular Tumoral , Citocinas/sangue , Citocinas/metabolismo , Glucose-6-Fosfatase/metabolismo , Glicogênio/metabolismo , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/patologia , Células HeLa , Humanos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/administração & dosagem , Nanopartículas/química , RNA Mensageiro/administração & dosagem , RNA Mensageiro/química , Resultado do Tratamento , Triglicerídeos/metabolismoRESUMO
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.
Assuntos
Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/fisiopatologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/fisiopatologia , Adulto , Encéfalo/patologia , Doença de Depósito de Glicogênio/patologia , Humanos , Músculo Esquelético/patologia , Doenças do Sistema Nervoso/patologia , Nervos Periféricos/patologia , Fenótipo , Medula Espinal/patologiaRESUMO
BACKGROUND: Glycogen storage diseases (GSD) type VI and IX are caused by liver phosphorylase system deficiencies and the two types are clinically indistinguishable. AIM: As the role of liver biopsy is increasingly questioned, we aim to assess its current value in clinical practice. METHODS: We retrospectively reviewed children with diagnosis of GSD VI and IX at a paediatric liver centre between 2001 and 2018. Clinical features, molecular analysis and imaging were reviewed. Liver histology was reassessed by a single histopatologist. RESULTS: Twenty-two cases were identified (9 type VI, 9 IXa, 1 IXb and 3 IXc). Features at presentation were hepatomegaly (95%), deranged AST (81%), short stature (50%) and failure to thrive (4%). Liver biopsy was performed in 19 patients. Fibrosis varied in GSD IXa with METAVIR score between F1-F3 and ISHAK score of F2-F5. METAVIR score was F2-F3 in GSD VI and F3-F4 in GSD IXc. Hepatocyte glycogenation, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining were also demonstrated. CONCLUSIONS: Although GSD VI and IX are considered clinically mild, chronic histological changes of varying severity could be seen in all liver biopsies. Histopathological assessment of the liver involvement is superior to biochemical parameters, but definitive classification requires a mutational analysis.
Assuntos
Doença de Depósito de Glicogênio Tipo VI/patologia , Doença de Depósito de Glicogênio/patologia , Biópsia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio Tipo VI/diagnóstico , Doença de Depósito de Glicogênio Tipo VI/genética , Hepatomegalia/etiologia , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND/AIMS: Glycogen synthesis and storage are normal hepatocyte functions. However, glycogenosis, defined as excess hepatocyte glycogen visible by routine H&E light microscopy, has not been well characterized in nonalcoholic fatty liver disease (NAFLD). METHODS: Glycogenosis in NAFLD liver biopsies was graded as "none", "focal" (in <50% of hepatocytes), or "diffuse" (in ≥50% of hepatocytes). Clinical and pathological variables associated with glycogenosis were assessed. 2047 liver biopsies were prospectively analysed. RESULTS: In adults and children, any glycogenosis was present in 54% of cases; diffuse glycogenosis was noted in approximately 1/3 of cases. On multiple logistic regression analysis, adults with glycogenosis tended to be older (P = .003), female (P = .04), have higher serum glucose (P = .01), and use insulin (P = .02). Adults tended to have lower steatosis scores (P = .006) and lower fibrosis stages (P = .005); however, unexpectedly, they also tended to have more hepatocyte injury including ballooning (P = .003). On multiple logistic regression analysis, paediatric patients with glycogenosis were more likely to be Hispanic (P = .03), have lower body weight (P = .002), elevated triglycerides (P = .001), and a higher fasting glucose (P = .007). Paediatric patients with glycogenosis also had less steatosis (P < .001) than those without. CONCLUSIONS: Glycogenosis is common in adult and paediatric NAFLD, and is associated with clinical features of insulin resistance. Glycogenosis is important to recognize histologically because it may be misinterpreted as ballooning, and when diffuse, confusion with glycogen storage disorders or glycogenic hepatopathy must be avoided. The newly observed dichotomous relationship between glycogenosis and increased liver cell injury but decreased steatosis and fibrosis requires further study.
Assuntos
Doença de Depósito de Glicogênio , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Adulto , Criança , Feminino , Fibrose , Doença de Depósito de Glicogênio/patologia , Humanos , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based. MAIN OUTCOME: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.