Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (p < 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (p < 0.0001). Nine out of 33 patients died (p = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.

• MeSH
• dítě MeSH
• fenotyp * MeSH
• fosfotransferasy (fosfomutasy) * genetika   nedostatek   MeSH
• genetické asociační studie MeSH
• kardiomyopatie genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• stupeň závažnosti nemoci MeSH
• vrozené poruchy glykosylace * genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.

• MeSH
• 3-oxo-5-alfa-steroid-4-dehydrogenasa metabolismus   genetika   MeSH
• dolichol * metabolismus   biosyntéza   MeSH
• glykosylace MeSH
• lidé MeSH
• membránové proteiny metabolismus   genetika   MeSH
• missense mutace MeSH
• vrozené poruchy glykosylace metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PMM2-CDG is the most prevalent type of congenital disorders of glycosylation (CDG). It is caused by pathogenic variants in the gene encoding phosphomannomutase 2 (PMM2), which converts mannose-6-phosphate to mannose-1-phosphate and thus activates this saccharide for further glycosylation processes. Defective glycosylation can lead to an abnormal accumulation of unfolded proteins in endoplasmic reticulum (ER) and cause its stress. The ER is a key compartment for glycosylation, and its connection and communication with mitochondria has been described extensively in literature. Their crosstalk is important for cell proliferation, calcium homeostasis, apoptosis, mitochondrial fission regulation, bioenergetics, autophagy, lipid metabolism, inflammasome formation and unfolded protein response. Therefore, in the present study we posed a question, whether defective glycosylation leads to bioenergetic disruption. Our data reveal possible chronic stress in ER and activated unfolded protein response via PERK pathway in PMM2-CDG fibroblasts. Presumably, it leads to bioenergetic reorganization and increased assembly of respiratory chain complexes into supercomplexes together with suppressed glycolysis in PMM2-CDG patient cells. These changes cause alterations in Krebs cycle, which is tightly connected to electron transport system in mitochondria. In summary, we present data showing metabolic adaptation of cells to glycosylation defect caused by various pathogenic variants in PMM2.

• MeSH
• fibroblasty metabolismus   MeSH
• fosfotransferasy (fosfomutasy) * genetika   MeSH
• glykosylace MeSH
• lidé MeSH
• vrozené poruchy glykosylace * patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Úvod: Dědičné poruchy metabolismu (DPM) sacharidů představují heterogenní skupinu více než 250 různých onemocnění způsobených porušenou syntézou, transportem či odbouráváním galaktózy, fruktózy, glukózy, disacharidů, glykogenu, glykosaminoglykanů a glykoproteinů/glykolipidů. Jednotlivé DPM sacharidů jsou sice vzácné, ale celkový výskyt v populaci je > 1 : 5000. Diagnostika není součástí laboratorního novorozeneckého screeningu a závisí na klinickém podezření, biochemickém a hematologickém vyšetření a indikaci selektivního metabolického screeningu. Materiál a metody: Práce shrnuje klinické, diagnostické a terapeutické aspekty nejčastějších DPM sacharidů u > 360 pacientů diagnostikovaných na našem pracovišti. Výsledky: Klinické projevy u dětí s DPM sacharidů jsou heterogenní a u řady poruch se mohou překrývat. První příznaky u DPM galaktózy a fruktózy začínají akutními projevy jaterního selhávání s postižením tubulárních funkcí ledvin a Fanconiho syndromem. Většina jaterních glykogenóz (GSD) začíná hepatomegalií, poruchou růstu, atakami hypoglykemií po 2,5–3hodinovém lačnění, hepatopatií, dyslipidemií a laktátovou acidózou, ale i neutropenií (GSD Ib) nebo jaterním selháním (GSD IV). Svalové glykogenózy se manifestují hypotonií a kardiomyopatií (GSD II) a svalovou slabostí a myalgiemi s atakami rhabdomyolýz (GSD V). Fenotyp jaterních a svalových GSD se překrývá s poruchou fosfoglukomutázy 1. Porucha transportu glukózy a galaktózy (GLUT2) spojuje fenotyp GSD s nefropatií při Fanconiho syndromu. Poruchy metabolismu sacharidů v komplexních molekulách způsobují mukopolysacharidózy (MPS) a dědičné poruchy glykosylace (CDG). Klinicky charakteristické pro skupinu MPS a CDG jsou kraniofaciální dysmorfie, encefalopatie, hepato/splenomegalie, porucha růstu, kostní deformity, postižení myokardu a srdečních chlopní, hernie, recidivující otitidy a chronická rýma. Závěr: Včasná diagnóza je nezbytná pro úspěšnou léčbu. Zahrnuje dietní opatření, mezi která patří bezlaktózová a nízkogalaktózová dieta (galaktosemie), nízkofruktózová dieta (intolerance fruktózy), antihypoglykemický režim s přídavkem nevařených škrobů (jaterní formy GSD), zvýšený příjem bílkovin (GSD III) nebo ketogenní dieta (GLUT1). Některé poruchy glykosylace (CDG) lze léčit pomocí manózy nebo galaktózy. V léčbě dětí s MPS se používá enzymová substituční terapie (ERT) a transplantace hematopoietickými kmenovými buňkami.

Introduction: Inherited metabolic disorders (IMD) of carbohydrates represent a heterogeneous group of >250 different diseases caused by impaired synthesis, transport or degradation of galactose, fructose, glucose, disaccharides, glycogen, glycosaminoglycans and glycoproteins/glycolipids. Individual IMD of carbohydrates are rare, but the overall incidence in the population is >1:5 000. Their diagnosis, except galactosemia in some countries is not part of laboratory neonatal screening of IMD and depends on clinical suspicion, biochemical and haematological analyses, and indication of selective metabolic screening. Material and methods: We summarize our experiences with the clinical, diagnostic, and therapeutic aspects of the most common IMD of carbohydrates in >360 patients diagnosed at our institution. Results: Clinical manifestations in children with IMD of carbohydrates are heterogeneous and may overlap with several diseases. The first symptoms of IMD of galactose and fructose begin with acute manifestations of liver failure with impaired renal tubular functions and Fanconi syndrome. Most liver glycogenoses (GSD) begin with hepatomegaly, growth failure, attacks of hypoglycaemia after 2.5-3 hours of fasting, hepatopathy, dyslipidaemia and lactic acidosis, but also neutropenia (GSD Ib) or liver failure (GSD IV). Muscle glycogenoses are presented by hypotonia and cardiomyopathy (GSD II) and muscle weakness and myalgia with attacks of rhabdomyolysis (GSD V). Hepatic and muscle GSD phenotype overlaps with phosphoglucomutase 1 deficiency. Glucose-galactose transport (GLUT2) disorder links GSD phenotype to nephropathy with Fanconi syndrome. IMD of carbohydrates in complex molecules cause mucopolysaccharidoses (MPS) and congenital disorders of glycosylation (CDG). Clinically characteristic of the MPS and CDG group are craniofacial dysmorphy, encephalopathy, hepato/splenomegaly, growth disorder, bone deformities, involvement of the myocardium and heart valves, hernia, recurrent otitis, and chronic rhinitis. Conclusion: Early diagnosis is essential for successful treatment. Dietary intervention includes a lactose-free and low-galactose diet (galactosemia), a low-fructose diet (fructose intolerance), an anti-hypoglycaemic regimen with the addition of uncooked starches (liver GSDs), increased protein intake (GSD III), or a ketogenic diet (GLUT1). Some congenital disorders of glycosylation (CDG) can be treated with mannose or galactose. Enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation are used in the treatment of children with MPS.

• MeSH
• dítě MeSH
• galaktosemie diagnóza   terapie   MeSH
• glykogenóza diagnóza   terapie   MeSH
• intolerance fruktózy diagnóza   terapie   MeSH
• lidé MeSH
• mukopolysacharidózy * diagnóza   terapie   MeSH
• vrozené poruchy glykosylace diagnóza   terapie   MeSH
• vrozené poruchy metabolismu sacharidů * diagnóza   terapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.

• MeSH
• aminokyseliny metabolismus   MeSH
• fosfotransferasy (fosfomutasy) * genetika   MeSH
• glykosylace MeSH
• lidé MeSH
• lipidy MeSH
• vrozené poruchy glykosylace * genetika   terapie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

• MeSH
• dítě MeSH
• glykosylace MeSH
• hydrolasy MeSH
• kojenec MeSH
• lidé MeSH
• Niemannova-Pickova nemoc typu C * MeSH
• oxysteroly * MeSH
• vakuolární protonové ATPasy * MeSH
• vrozené poruchy glykosylace * MeSH
• žlučové kyseliny a soli MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Congenital Disorders of Glycosylation (CDG) represents a large group of severe inherited metabolic diseases that are caused by impaired biosynthesis of glycoproteins and glycolipids.The complexity of glycosylation pathways determines the occurrence of a large number of CDG types - currently more than 100 were described. Glycoproteins constitutes more than 50% of total protein. Their impaired biosynthesis has critical impact on the functioning of the whole organism and manifests with severe clinical symptoms with high child mortality (about 25%). The project aims are i) to elucidate the etiology of the disease in patients with suspected CDG to provide early genetic counseling in affected families; ii) to analyse profile of dolichol metabolites in the urine in order to extend the selective CDG screening in CR; iii) to study the impact of CDG on the energetic metabolism with effort to understand the pathophysiology of disease; iii) to study impaired glycosylation in the background of various pathologies in order to find a specific biomarker reflecting the current state of nutrition.

Dědičné poruchy glykosylace (CDG) představují rozsáhlou skupinu závažných dědičných metabolických onemocnění, které jsou způsobeny poruchou biosyntézy glykoproteinů a glykolipidů Složitost glykosylačních drah předurčuje výskyt velkého množství typů CDG – v současnosti jich bylo popsáno >100 a jsou objevovány stále nové. Glykoproteiny tvoří >50 % všech proteinů s obrovskou funkční rozmanitostí, jejich porušená biosyntéza má kritický dopad na fungování celého organismu. Projevuje se vážnými klinickými příznaky s vysokou mírou dětské úmrtnosti (cca 25%). Cílem projektu je: a) objasnit etiologii nemoci u pacientů s podezřením na CDG s cílem umožnit včasné genetické poradenství v postižených rodinách; b) zavedením analýzy profilu isoforem dolicholů v moči rozšířit spektrum selektivního skríningu CDG chorob v ČR; c) studovat dopad poruch glykosylace na energetický metabolismus se snahou přesněji pochopit rozvoj nemoci;.d) studovat biochemické souvislosti dysregulace glykosylace na pozadí různých patologických stavů s cílem najít specifický biomarker odrážející aktuální stav výživy

• MeSH
• biologické markery MeSH
• časná diagnóza MeSH
• diagnostické techniky molekulární MeSH
• dolichol moč   MeSH
• energetický metabolismus MeSH
• lidé MeSH
• mitochondrie MeSH
• nutriční stav MeSH
• vrozené poruchy glykosylace diagnóza   etiologie   MeSH
• Check Tag
• lidé MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• genetika, lékařská genetika
• vnitřní lékařství
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Congenital disorders of glycosylation (CDG) are inherited metabolic diseases caused by defects in the genes important for the process of protein and lipid glycosylation. With the ever growing number of the known subtypes and discoveries regarding the disease mechanisms and therapy development, it remains a very active field of study. SCOPE OF REVIEW: This review brings an update on the CDG-related research since 2017, describing the novel gene defects, pathobiomechanisms, biomarkers and the patients' phenotypes. We also summarize the clinical guidelines for the most prevalent disorders and the current therapeutical options for the treatable CDG. MAJOR CONCLUSIONS: In the majority of the 23 new CDG, neurological involvement is associated with other organ disease. Increasingly, different aspects of cellular metabolism (e.g., autophagy) are found to be perturbed in multiple CDG. GENERAL SIGNIFICANCE: This work highlights the recent trends in the CDG field and comprehensively overviews the up-to-date clinical recommendations.

• MeSH
• glykosylace MeSH
• lidé MeSH
• lipidy genetika   MeSH
• metabolické sítě a dráhy MeSH
• metabolismus lipidů MeSH
• mutace MeSH
• proteiny genetika   metabolismus   MeSH
• vrozené poruchy glykosylace genetika   metabolismus   patologie   terapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

• MeSH
• adrenální insuficience diagnóza   etiologie   patofyziologie   MeSH
• dítě MeSH
• dospělí MeSH
• fosfotransferasy (fosfomutasy) krev   genetika   MeSH
• glykosylace MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• systém hypofýza - nadledviny fyziologie   MeSH
• vrozené poruchy glykosylace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene. Patients manifest with severe neurologic, cardiac, musculoskeletal and ophthalmic phenotype in combination with dysmorphic features, and almost half of them die before or during the neonatal period. CASE PRESENTATION: A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment. Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth. Transferrin isoelectric focusing revealed a type 1 pattern. Funduscopy showed hypopigmentation and optic disc pallor. Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging. The presence of optic nerve hypoplasia was also supported by magnetic resonance imaging. A gene panel based next-generation sequencing and subsequent Sanger sequencing identified compound heterozygosity for two novel variants c.116del p.(Pro39Argfs*40) and c.1060 C > T p.(Arg354Cys) in ALG3. CONCLUSIONS: Our study expands the spectrum of pathogenic variants identified in ALG3. Thirty-three variants in 43 subjects with ALG3-CDG have been reported. Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia.

• MeSH
• degenerace retiny * MeSH
• fenotyp MeSH
• kojenec MeSH
• lidé MeSH
• mannosyltransferasy genetika   MeSH
• novorozenec MeSH
• oči MeSH
• předškolní dítě MeSH
• vrozené poruchy glykosylace * genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH