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 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

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

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

Congenital disorders of glycosylation (CDG) represent a wide range of >140 inherited metabolic diseases, continually expanding not only with regards to the number of newly identified causative genes, but also the heterogeneity of the clinical and molecular presentations within each subtype. The deficiency of ATP6AP1, an accessory subunit of the vacuolar H+ -ATPase, is a recently characterised N- and O-glycosylation defect manifesting with immunodeficiency, hepatopathy and cognitive impairment. At the cellular level, the latest studies demonstrate a complex disturbance of metabolomics involving peroxisomal function and lipid homeostasis in the patients. Our study delineates a case of two severely affected siblings with a new hemizygous variant c.221T>C (p.L74P) in ATP6AP1 gene, who both died due to liver failure before reaching 1 year of age. We bring novel pathobiochemical observations including the finding of increased reactive oxygen species in the cultured fibroblasts from the older boy, a striking copper accumulation in his liver, as well as describe the impact of the mutation on the protein in different organs, showing a tissue-specific pattern of ATP6AP1 level and its posttranslational modification.

• MeSH
• fatální výsledek MeSH
• fenotyp MeSH
• kojenec MeSH
• lidé MeSH
• měď metabolismus   MeSH
• metabolomika MeSH
• mutace MeSH
• nemoci jater diagnóza   genetika   metabolismus   MeSH
• oxidační stres genetika   MeSH
• posttranslační úpravy proteinů MeSH
• sourozenci MeSH
• syndromy imunologické nedostatečnosti diagnóza   genetika   metabolismus   MeSH
• vakuolární protonové ATPasy nedostatek   genetika   MeSH
• vrozené poruchy glykosylace diagnóza   genetika   metabolismus   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436G>A, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome.

• MeSH
• 3-oxo-5-alfa-steroid-4-dehydrogenasa chemie   genetika   MeSH
• dítě MeSH
• fenotyp MeSH
• homozygot MeSH
• lidé MeSH
• membránové proteiny chemie   genetika   MeSH
• mutace genetika   MeSH
• oči patologie   MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• vrozené poruchy glykosylace enzymologie   genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH

• MeSH
• cévní mozková příhoda MeSH
• dítě MeSH
• fosfotransferasy * chemie   nedostatek   MeSH
• kanálopatie genetika   MeSH
• lidé MeSH
• nemoci mozečku diagnostické zobrazování   MeSH
• prognóza MeSH
• vápníkové kanály genetika   MeSH
• vrozené poruchy glykosylace diagnostické zobrazování   genetika   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

RFT1-CDG is a rare N-glycosylation disorder. Only 6 children with RFT1-CDG have been described, all with failure to thrive, feeding problems, hypotonia, developmental delay, epilepsy, decreased vision, deafness and thrombotic complications. We report on two young adult siblings with RFT1-CDG, compound heterozygotes for the novel missense mutations c.1222A>G (p.M408V) and c.1325G>A (p.R442Q) in RFT1 gene. Similar to the previously described patients, these siblings have profound intellectual disability but no feeding problems or failure to thrive. Their epilepsy is well controlled and coagulopathy is mild without clinical consequences. In addition, visual acuity is normal in both patients and hearing impairment is present only in one. Our findings extend the phenotype associated with RFT1-CDG.

• MeSH
• exony MeSH
• heterozygot MeSH
• lidé MeSH
• membránové glykoproteiny genetika   MeSH
• mladý dospělý MeSH
• mutace * MeSH
• sourozenci * MeSH
• vrozené poruchy glykosylace diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Congenital disorders of glycosylation (CDG) represent an expanding group of inherited diseases. One of them, ALG8 deficiency (CDG Ih), leads to protein N-glycosylation defects caused by malfunction of glucosyltransferase 2 (Dol-P-Glc:Glc1-Man(9)-GlcNAc(2)-P-P-Dol glucosyltransferase) resulting in inefficient addition of the second glucose residue onto lipid-linked oligosaccharides. So far, only five patients have been described with ALG8 deficiency. We present a new patient with neonatal onset. The girl was born at the 29th week of gestation complicated by oligohydramnios. Although the early postnatal adaptation was uneventful (Apgar score 8 and 9 at 5 and 10 min), generalized oedema, multifocal myoclonic seizures, and bleeding due to combined coagulopathy were present from the first day. Diarrhoea progressing to protein-losing enteropathy with ascites and pericardial effusion developed in the third week of life. Pharmacoresistant seizures and cortical, cerebellar and optic nerve atrophy indicated neurological involvement. No symptoms of liver disease except coagulopathy were observed; however, steatofibrosis with cholestasis was found at autopsy. The girl died at the age of 2 months owing to the progressive general oedema, bleeding and cardio-respiratory insufficiency. Molecular analysis revealed two heterozygous mutations in the ALG8 gene: c.139A>C (p.T47P) and the novel mutation c.1090C>T (p.R364X). Conclusion: The prognosis of patients with ALG8 deficiency is unfavourable. The majority of affected children have early onset of the disease with heterogeneous symptoms including multiple organ dysfunction, coagulopathy and protein-losing enteropathy. Neurological impairment is not a general clinical symptom, but it has to be taken into consideration when thinking about ALG8 deficiency.

• MeSH
• fatální výsledek MeSH
• glukosyltransferasy nedostatek   genetika   MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé MeSH
• missense mutace * MeSH
• mutační analýza DNA MeSH
• mutantní proteiny genetika   MeSH
• novorozenec MeSH
• substituce aminokyselin MeSH
• vrozené poruchy glykosylace diagnóza   enzymologie   genetika   MeSH
• ztučnělá játra enzymologie   genetika   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH