Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing.

Glycogen storage diseases (GSDs) are known as complex disorders with overlapping manifestations. These features also preclude a specific clinical diagnosis, requiring more accurate paraclinical tests. To evaluate the patients with particular diagnosis features characterizing GSD, an observational retrospective case study was designed by performing a targeted gene sequencing (TGS) for accurate subtyping. A total of the 15 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Eight genes namely SLC37A4, AGL, GBE1, PYGL, PHKB, PGAM2, and PRKAG2 were detected to be responsible for the onset of the clinical symptoms. A total number of 15 variants were identified i.e. mostly loss-of-function (LoF) variants, of which 10 variants were novel. Finally, diagnosis of GSD types Ib, III, IV, VI, IXb, IXc, X, and GSD of the heart, lethal congenital was made in 13 out of the 14 patients. Notably, GSD-IX and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency) patients have been reported in Iran for the first time which shown the development of liver cirrhosis with novel variants. These results showed that TGS, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate and high-throughput results for diagnosing and sub-typing GSD and related diseases.

Metabolic Profiling in Human Fibroblasts Enables Subtype Clustering in Glycogen Storage Disease.

Glycogen storage disease subtypes I and III (GSD I and GSD III) are monogenic inherited disorders of metabolism that disrupt glycogen metabolism. Unavailability of glucose in GSD I and induction of gluconeogenesis in GSD III modify energy sources and possibly, mitochondrial function. Abnormal mitochondrial structure and function were described in mice with GSD Ia, yet significantly less research is available in human cells and ketotic forms of the disease. We hypothesized that impaired glycogen storage results in distinct metabolic phenotypes in the extra- and intracellular compartments that may contribute to pathogenesis. Herein, we examined mitochondrial organization in live cells by spinning-disk confocal microscopy and profiled extra- and intracellular metabolites by targeted LC-MS/MS in cultured fibroblasts from healthy controls and from patients with GSD Ia, GSD Ib, and GSD III. Results from live imaging revealed that mitochondrial content and network morphology of GSD cells are comparable to that of healthy controls. Likewise, healthy controls and GSD cells exhibited comparable basal oxygen consumption rates. Targeted metabolomics followed by principal component analysis (PCA) and hierarchical clustering (HC) uncovered metabolically distinct poises of healthy controls and GSD subtypes. Assessment of individual metabolites recapitulated dysfunctional energy production (glycolysis, Krebs cycle, succinate), reduced creatinine export in GSD Ia and GSD III, and reduced antioxidant defense of the cysteine and glutathione systems. Our study serves as proof-of-concept that extra- and intracellular metabolite profiles distinguish glycogen storage disease subtypes from healthy controls. We posit that metabolite profiles provide hints to disease mechanisms as well as to nutritional and pharmacological elements that may optimize current treatment strategies.

Genotypic and clinical analysis of 49 Chinese children with hepatic glycogen storage diseases.

BACKGROUND: Glycogen storage disease (GSD) is a relatively rare inborn metabolic disorder, our study aims to investigate the genotypic and clinical feature of hepatic GSDs in China. METHODS: The clinical and genotypic data of 49 patients with hepatic GSDs were collected retrospectively and analyzed. RESULTS: After gene sequencing, 49 patients were diagnosed as GSDs, including GSD Ia (24 cases), GSD IIIa (11 cases), GSD IXa (8 cases), GSD VI (3 cases) and GSD Ib (3 cases). About 45 gene variants of G6PC, AGL, PHKA2, PYGL, and SLC37A4 were detected; among which, 22 variants were unreported previously. c.648G>T (p. Leu216Leu) of G6PC exon 5 is the most common variant for GSD Ia patients (20/24,83.33%）, splice variant c.1735+1G>T of AGL exon 13 is relatively common among GSD IIIa, while novel variant accounts for the majority of GSD IXa and GSD VI patients. As for clinical features, there was no significant difference in the onset age among group GSD Ia, GSD IIIa, and GSD IXa, but the age at diagnosis and average disease duration from diagnosis of GSD Ia were significantly higher than GSD IIIa and GSD IXa. Body weight of GSD patients was basically normal, but growth retardation was relatively common among them, especially for GSD Ia patients; and renomegaly was only found in GSD Ia. Besides, serum cholesterol, triglyceride, lactic acid, and uric acid in GSD Ia were significantly higher than those with GSD IIIa and IXa (p < 0.05); but ALT, AST, CK, and LDH of GSD III and GSD IXa were significantly higher when compared to GSD Ia (p < 0.05). CONCLUSIONS: All hepatic GSDs patients share similarity in clinical and biochemical spectrum, but delayed diagnosis and biochemical metabolic abnormalities were common in GSD Ia. For family with GSD proband, pedigree analysis and genetic testing is strongly recommended.

Distensión abdominal y estancamiento ponderoestatural como forma de presentación de diferentes tipos de glucogenosis / Different glycogen storage diseases presenting as abdominal distention and growth and weight retardation

No disponible

Large animal models and new therapies for glycogen storage disease.

Glycogen storage diseases (GSD), a unique category of inherited metabolic disorders, were first described early in the twentieth century. Since then, the biochemical and genetic bases of these disorders have been determined, and an increasing number of animal models for GSD have become available. At least seven large mammalian models have been developed for laboratory research on GSDs. These models have facilitated the development of new therapies, including gene therapy, which are undergoing clinical translation. For example, gene therapy prolonged survival and prevented hypoglycemia during fasting for greater than one year in dogs with GSD type Ia, and the need for periodic re-administration to maintain efficacy was demonstrated in that dog model. The further development of gene therapy could provide curative therapy for patients with GSD and other inherited metabolic disorders.

Exercise in muscle glycogen storage diseases.

Glycogen storage diseases (GSD) are inborn errors of glycogen or glucose metabolism. In the GSDs that affect muscle, the consequence of a block in skeletal muscle glycogen breakdown or glucose use, is an impairment of muscular performance and exercise intolerance, owing to 1) an increase in glycogen storage that disrupts contractile function and/or 2) a reduced substrate turnover below the block, which inhibits skeletal muscle ATP production. Immobility is associated with metabolic alterations in muscle leading to an increased dependence on glycogen use and a reduced capacity for fatty acid oxidation. Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal muscle substrate metabolism in ways that are beneficial for patients with GSD, such as improving exercise tolerance and increasing fatty acid oxidation. In addition, a regular exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs. We review the studies that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise.

Modificación del Almidón de maiz y sus efectos en el tratamiento de niños con glucogenosis / Modification of starch corn and its effects on the treatment of children with glycogenosis

Introducción: El almidón de maíz (AM) está indicado en el manejo de niños con glucogenosis hepática (GH).Objetivo: Describir la respuesta clínica en siete niños con GH I y III, del Hospital Pablo Tobón Uribe de Medellín, Colombia, al cambiar el AM de uso alimenticio (UA), por AM de pureza farmacológica (PF). Metodología: Estudio observacional, retrospectivo, descriptivo realizado en 51 meses en el que se comparan pruebas bioquímicas y evolución clínica de siete niños ambulatorios con GH, quienes recibían AMUA y se les cambió a AMPF, por recaída en sus controles bioquímicos, relacionados con el cambio en la composición del AM tradicional, al que se le adicionó una mezcla de vitaminas y minerales. Resultados: Se incluyeron 3 niñas y 4 niños entre 13 y 148 meses, 3 con GH I y 4 con GH III, que recibían AMUA, y luego de cambiar a AMPF, presentaron mejoría clínica y bioquímica así: glucemia en ayunas de 77 mg/dL (48-90) a 85 (68-119) mg/dL, ALT de 390 U/L (47-1410) a 159 (47-345) U/L y triglicéridos de 487 (186-1797) mg/dL a 240 (112-614) mg/dL.Conclusiones: El AMPF en niños con GH I y III, demostró resultados mejores, que los obtenidos con el AMUA. La evidencia bioquímica y clínica, permite recomendar su utilización en el tratamiento actual de los pacientes con estos tipos de GH.

Introduction: Corn starch (CS) is indicated for the management of children with liver glucogenosis (LG). Objective: To describe the clinic outcome in 7 children with LG I and III, from Hospital Pablo Tobón Uribe from Medellín, Colombia, to change food (F) CS by the pharmacological purity (PP) CS. Methods: Observational, retrospective, descriptive study performed in 51 months comparing biochemical and clinical course of 7 children outpatient with LG, those receiving FCS and were switched to PPCS by relapse in biochemical controls related to the change in the composition of the traditional commercial CS, which was added a mixture of vitamins and minerals. Results: Were included 3 girls and 4 boys between 13 and 148 months, 3 with LG I and 4 with LG III, receiving FCS, and after switching to PPCS, they improved the biochemical tests and clinical status. Conclusions: PPCS in children with LG I and III, showed better results than those obtained with FCS. The biochemical and clinical evidence both to recommend its use in the current treatment of patients with these types of LG.

Progress and problems in muscle glycogenoses.

In this selective review, we consider a number of unsolved questions regarding the glycogen storage diseases (GSD). Thus, the pathogenesis of Pompe disease (GSD II) is not simply explained by excessive intralysosomal glycogen storage and may relate to a more general dysfunction of autophagy. It is not clear why debrancher deficiency (GSD III) causes fixed myopathy rather than exercise intolerance, unless this is due to the frequent accompanying neuropathy. The infantile neuromuscular presentation of branching enzyme deficiency (GSD IV) is underdiagnosed and is finally getting the attention it deserves. On the other hand, the late-onset variant of GSD IV (adult polyglucosan body disease APBD) is one of several polyglucosan disorders (including Lafora disease) due to different etiologies. We still do not understand the clinical heterogeneity of McArdle disease (GSD V) or the molecular basis of the rare fatal infantile form. Similarly, the multisystemic infantile presentation of phosphofructokinase deficiency (GSD VII) is a conundrum. We observed an interesting association between phosphoglycerate kinase deficiency (GSD IX) and juvenile Parkinsonism, which is probably causal rather than casual. Also unexplained is the frequent and apparently specific association of phosphoglycerate mutase deficiency (GSD X) and tubular aggregates. By paying more attention to problems than to progress, we aimed to look to the future rather than to the past.

Inborn errors of carbohydrate metabolism.

Glycogen storage diseases (GSD) and inborn errors of galactose and fructose metabolism are the most common representatives of inborn errors of carbohydrate metabolism. In this review the focus is set on the current knowledge about clinical symptoms, diagnosis and treatment. Hepatomegaly and hypoglycaemia are the main findings in liver-affecting GSD like type I, III and IX. Diagnosis is usually made by non invasive investigations, e.g. mutation analysis. In GSD I, a carbohydrate balanced diet with frequent meals and nocturnal continuous tube feeding or addition of uncooked corn starch are the mainstays of treatment to prevent hypoglycaemia. Liver transplantation has been performed in different types of GSD. It should only be considered in high risk patients e.g. with substantial cirrhosis. Many countries have included classical galactosaemia in their newborn screening programs. A lactose-free infant formula can be life-saving in affected neonates whereas a strict fructose-restricted diet is indicated in hereditary fructose intolerance.

[Metabolic myopathies - an overview]. / Metabolische Myopathien - ein Uberblick.

Metabolic disorders of energy production characterise the group of rare, mainly autosomal recessively inherited metabolic muscular diseases which are often associated with multi-systemic symptoms. In this report, an update on the clinics, pathophysiology, pathomorphology and current treatment options of metabolic myopathies will be given. Beyond classic phenotypes of these disorders, one should be aware of oligosymptomatic patients who can be easily missed. The relevant gene mutations and the pathophysiology and pathomorphology they cause are now known for almost all these metabolic diseases. Establishing the correct diagnosis has become even more important since highly specific therapy options are now available for at least some of these inherited disorders, e.g. enzyme replacement therapy in Pompe disease.

[Hypoglycemia and endocrine effects of adults' inborn errors of metabolism]. / Hypoglycémies et manifestations endocriniennes des maladies héréditaires du métabolisme chez l'adulte.

Inborn errors of metabolism (IEM) are rare diseases, most often inherited as an autosomal recessive disorder. They may be associated with endocrine dysfunction, the most frequent of them being disorders of carbohydrate metabolism (hypoglycemia, diabetes). The endocrinologist might be led to screen these complications in a patient whose diagnosis has been done during childhood. In some rare cases, he should evoke the diagnosis in front of an endocrine disorder most often associated to a multisystemic involvement. This spreading field is new, not yet very well known in adulthood. Long-term consequences of IEM on fertility and bone metabolism are still poorly understood. Diagnosis orientation relies on a few specific lab investigations encompassing blood lactate, free fatty acids and 3-hydroxy-butyrate, ammoniemia, carnitine and acylcarnitines, aminoacid and urinary organic chromatography. Hyperinsulinism, glycogenosis, fatty acid ss-oxydation, carnitine cycle and glycosylation (CDG syndrome) disorders, fructose intolerance, tyrosinemia, organic aciduria may explain hypoglycemia. These diagnosis should be evoked in front of unexplained adult hypoglycemia. Diabetes is related to iron overload, mitochondriopathy and thiamine sensitive diabetes. Clinical spectrum of some forms of IEM switch from hypoglycemia in childhood to diabetes in adulthood. Mitochondriopathies can be associated to all types of endocrine disorders, the most frequent being diabetes and dysthyroidism. Hypothyroidism is encountered in mitochondriopathies, cystinosis and primary hyperoxaluria. Hypogonadism is almost constant in galactosemia, frequent in CDG syndromes, cystinosis and iron overload. Most of the time, a specialized advice is required, which is one of the mission of reference centres.

Nutritional therapy for glycogen storage diseases.

Glycogen storage diseases (GSDs) are a group of inherited disorders characterized by enzyme defects that affect the glycogen synthesis and degradation cycle, classified according to the enzyme deficiency and the affected tissue. The understanding of GSD has increased in recent decades, and nutritional management of some GSDs has allowed better control of hypoglycemia and metabolic complications. However, growth failure and liver, renal, and other complications are frequent problems in the long-term outcome. Hypoglycemia is the main biochemical consequence of GSD type I and some of the other GSDs. The basis of dietary therapy is nutritional manipulation to prevent hypoglycemia and improve metabolic dysfunction, with the use of continuous nocturnal intragastric feeding or cornstarch therapy at night and foods rich in starches with low concentrations of galactose and fructose during the day and to prevent hypoglycemia during the night.

Combined liver-kidney transplantation in glycogen storage disease Ia: a case beyond the guidelines.

Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder due to hepatic glucose-6-phosphatase deficiency. Although great progress has been made in managing affected patients, severe hypoglycemia, lactic acidosis, hyperlipidemia, hepatic cytolysis, and impaired kidney function are frequent. Liver transplantation is the only radical treatment, for which the main indications are hepatic adenomatosis, hepatocellular carcinoma, or severe hepatic dysfunction. We present the case of a patient with end-stage renal disease without focal hepatic lesions and with moderate hepatic metabolic control, and we explain how combined liver-kidney transplantation (LKT) made it possible to correct the metabolic defects responsible for the impaired glucose homeostasis, liberalize the diet, and give birth to a healthy child after an uneventful pregnancy. Patients with end-stage renal disease that resulted from GSD Ia should be considered for LKT even in the absence of hepatic lesions with the aim of improving their quality of life.

Serum lipid and lipoprotein profile of patients with glycogen storage disease types I, III and IX.

With current dietary therapy, life expectancy in glycogen storage disease (GSD) has improved considerably and more children reach adulthood. Notwithstanding intensive dietary therapy, moderate to severe hyperlipidaemia is still observed frequently. There is limited information about the type and extent of hyperlipidaemia. We studied the lipid profile in 20 patients, aged 8-54 years, of the three (types I, III and IX) most common forms of adult GSD. Hyperlipidaemia was shown to be type-specific, affecting predominantly patients with GSD type Ia, who showed marked combined hypercholesterolaemia and hypertriglyceridaemia. By contrast, a heterogeneous distribution of HDL was found in patients with GSD I and III. There was no significant difference in Apo Al and Apo B concentrations between groups. In addition, mass measurements of the fractions of VLDL1, VLDL2 and IDL were raised in all patients with GSD Ia by comparison with all other patients with GSD. Patients with GSD type Ia have lipid concentrations and individual mass measurements that are consistent with ranges found in patients who have a significant risk of atherosclerosis. Accumulated evidence, however, suggest GSD type Ia patients do not have an increased risk of atherosclerotic cardiovascular disease (CVD) but the reason remains unknown. Intervention to reduce their lipid levels could therefore be on the basis of seeking to prevent the risk of pancreatitis rather than that of CVD.

The natural course of non-classic Pompe's disease; a review of 225 published cases.

Pompe's disease is a neuromuscular disorder caused by deficiency of lysosomal acid alpha-glucosidase. Recombinant human alpha- glucosidase is under evaluation as therapeutic drug. In light of this development we studied the natural course of cases not fitting the definition of classic infantile Pompe's disease. Our review of 109 reports including 225 cases shows a continuous spectrum of phenotypes. The onset of symptoms ranged from 0 to 71 years. Based on the available literature, no criteria to delineate clinical sub-types could be established.A common denominator of these cases is that first symptoms were related to or caused by muscle weakness. In general, patients with a later onset of symptoms seemed to have a better prognosis. Respiratory failure was the most frequent cause of death. CK, LDH, ASAT, ALAT and muscle glycogen levels were frequently but not always elevated. In most cases a muscle biopsy revealed lysosomal pathology, but normal muscle morphology does not exclude Pompe's disease. In 10% of the cases in which the enzyme assay on leukocytes was used, a normal alpha-glucosidase activity was reported. Data on skeletal muscle strength and function, pulmonary function, disability, handicap and quality of life were insufficiently reported in the literature. Studies of non-classic Pompe's disease should focus on these aspects, before enzyme replacement therapy becomes generally available.