CDG – an update

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Aerobic exercise in children with oxidative phosphorylation defects

Fatigue and exercise intolerance are symptoms in children with metabolic myopathy. Frequently this is combined with muscle pain in children with mitochondrial myopathy. Offering therapeutic advice remains challenging in this patient group. Here we describe five children above the age of four years, with normal intelligence, myopathy, exercise intolerance, motor developmental delay, and fatigue, who were diagnosed with a mitochondrial dysfunction. Based on the positive experience of condition training in adults with mitochondrial disease and inactivity, aerobic exercise training was advised for all the children. Because of the lack of clear protocols for individualized mitochondrial myopathies, regular training was initiated. The Movement Assessment Battery of Children, the Jamar dynamometer for grip force, and the Bruce protocol treadmill test were applied for evaluation. No patient showed significant disease progression on a weekly scheme of strength training or on aerobic training during periods varying between 6 and 18 months. Only one out of the five patients has shown an improvement after a period of structured, aerobic training, demonstrating good compliance and motivation over the course of 18 months. Some patients developed severe muscle pain after explosive exercise. Even in a relatively homogenous, intelligent group of patients and motivated parents, we could not reach full compliance. With our case studies, we would like to draw attention to the importance and pitfalls of movement therapy in children with mitochondrial disease

How to find and diagnose a CDG due to defective N-glycosylation

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Sperm antioxidant biomarkers and their correlation with clinical condition and lifestyle with regard to male reproductive potential

Measurement of sperm oxidative-antioxidant indicators is widely used in the assessment and detection of biochemical causes of male infertility. The main purpose of this study was to identify biomarkers that assist in diagnostics and monitoring of male reproductive potential. We performed the assessment of oxidative-antioxidant malondialdehyde (MDA), glutathione (GSH), and total redox antioxidant potential (TRAP) indicators in seminal plasma, seminogram, clinical condition, and lifestyle of people with reproductive problems. The combined assessment of GSH and TRAP as potential biomarkers of male infertility in semen plasma was characterized by the highest total sensitivity and specificity. Furthermore, we provide evidence that male reproductive potential is significantly correlated with basic sperm parameters, sperm cell membrane integrity, their morphology, lifestyle, eating habits, occupation, and mental health. Our results provide evidence on the importance of oxidative stress and defense against free radicals in diagnosing and monitoring men with infertility that are consistent with previously conducted research. We provide an alternative approach on the possibility of interpreting the combination of the biomarkers that can bring benefits to a multi-threaded approach to the diagnosis and treatment of male infertility

Screeningul dereglărilor congenitale ale glicozilării prin intermediul focusării izoelectrice a transferinei

Institute of Mother and Child, Chisinau, R.M., Tulane Medical School, New Orleans, U.S.A., Translational Metabolic Laboratory, Radboudumc, Nijmegen, NetherlandsBackground. Congenital Disorders of Glycosylation(CDG) are a group of disorders caused by defects in the biosynthesis of glycoprotiens and other glycoconjugates. Incidence is the 1:50.000-1:100.000 population. The golden standard for screening is the isoelectric focusing of transferrin(IEFT) Objective of the study. To performe the screening by IEFT on suspected patients for diagnose the CDG. Material and Methods. About 40 patients of various ages(2mo – 15y) under clinical suspicions for CDG at Institute of Mother and Child were examined by IEFT in colaborations with Radboudumc, Netherlands and U.S.A. The spectrum of clinical presentations of patients was multisystem damage, predominant neurological manifestations Results. Half of patients had an early presentation with hypotonia, hepatomegaly, elevated transaminases, mild hypoglycemia and various changes on cerebral MRI. Eleven children had dysmorphic features, seizures, failure to thrive and mental retardation. Other patients presented coagulations abnormality, cutis laxa, inverted nipples, stroke-like episodes, strabismus, nistagmus and ataxia. Serum samples analyzed by IEFTf: 37 normal, 2 questionable and 1 abnormal paterns. Two samples questionable were the patients with galactosemiaadfructosemia, which give the fals positive results.The last positive sample is performing aditionally for glycomics profiling. Conclusion. The CDG is a rare metabolic disease with multisystem impairement and variety of simptoms that determine miss diagnose. A important step în CDG diagnosis is to exclude secondary abnormality of glycosylation as fructosemia, galactosemia, sever liver disease and transferrin polimorphys.Introducere. Dereglările Congenitale ale Glicozilării (CDG) reprezintă patologii determinate de defectele în biosinteza glicoproteinelor și a altor glicoconjugate, incidența constituind 1:50.000-100.000 de populație. Standardul de aur pentru diagnosticul CDG îl reprezintă Focusarea izoelectrică a Transferinei. Scopul lucrării. Screening-ul pacienților suspecți pentru CDG, pin metoda de Focusare Izoelectrica a Transferinei. Material și metode. Aproximativ 40 de pacienți de diferite vârste (2l-25 ani) suspecți pentru CDG, aflați la evidență în Institutul Mamei și Copilului, au fost examinați prin IEFT, în colaborare cu Centrul Radboudumc, Olanda și S.U.A. Spectrul de manifestări clinice au inclus copilul afectat multisistemic predominant fiind sistemul neurologic. Rezultate. Aproximativ jumătate dintre pacienții din studiu au prezentat hipotonie cu debut precoce, hepatomegalie, transaminaze crescute, episoade de hipoglicemie și diferite modificări ale RMN cerebrală. 8 din pacienți au manifestat trăsături dismorfice, convulsii, retard mintal și reținere în dezvoltarea fizică. Alți pacienți au prezentat dereglări de coagulare, cutis laxa, mameloane inversate, episoade stroke-like, strabism, nistagmus și ataxie. Probele analizate prin metoda IEFT au relevat: 37 normale, 2 suspecte și 1 patern abnormal. Probele fals-pozitive au fost în cazul Galactozemiei și a Fructozemiei. Profilul pozitiv va fi analizat adițional, prin prisma profilului glicomic. Concluzii. CDG reprezintă un grup de patologii rare cu heterogenitate clinică, ceea ce determină subdiagnosticarea acestora. Primordial, în diagnosticul CDG, este excluderea abnormalităților secundare ale glicozilării ca Fructozemia, Galactozemia, hepatopatii și polimorfismul transferinei

PMM2-CDG caused by uniparental disomy: Case reportand literature review

Background Phosphomannomutase 2 deficiency (PMM2-CDG) affects glycosylation pathways such as the N-glycosylation pathway, resulting in loss of function of multiple proteins. This disorder causes multisystem involvement with a high variability among patients. PMM2-CDG is an autosomal recessive disorder, which can be caused by inheriting two pathogenic variants, de novo mutations or uniparental disomy. Case Presentation Our patient presented with multisystem symptoms at an early age including developmental delay, ataxia, and seizures. No diagnosis was obtained till the age of 31 years, when genetic testing was reinitiated. The patient was diagnosed with a complete maternal mixed hetero/isodisomy of chromosome 16, with a homozygous pathogenic PMM2 variant (p.Phe119Leu) causing PMM2-CDG. A literature review revealed eight cases of uniparental disomy as an underlying cause of CDG, four of which are PMM2-CDG. Conclusion Since the incidence of homozygosity for PMM2 variants is rare, we suggest further investigations for every homozygous PMM2-CDG patient where the segregation does not fit. These investigations include testing for UPD or a deletion in one of the two alleles, as this will have an impact on recurrence risk in genetic counselingWe thank the patient described in this case report for all-owing us to share her details, and we thank C. Pérez-Cerdá of the Center of Molecular Biology-Severo Ochoa,Madrid, for her contribution. This work is funded by thegrant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute ofNeurological Diseases and Stroke (NINDS) and theNational Center for Advancing Translational Sciences(NCATS), and the Rare Disorders Consortium DiseaseNetwork (E.M. and S.K.

Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression

Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous inborn errors of metabolism. At present, treatment is available for only one CDG, but potential treatments for the other CDG are on the horizon. It will be vitally important in clinical trials of such agents to have a clear understanding of both the natural history of CDG and the corresponding burden of disability suffered by patients. To date, no multicentre studies have attempted to document the natural history of CDG. This is in part due to the lack of a reliable assessment tool to score CDG’s diverse clinical spectrum. Based on our earlier experience evaluating disease progression in disorders of oxidative phosphorylation, we developed a practical and semi-quantitative rating scale for children with CDG. The Nijmegen Paediatric CDG Rating Scale (NPCRS) has been validated in 12 children, offering a tool to objectively monitor disease progression. We undertook a successful trial of the NPCRS with a collaboration of nine experienced physicians, using video records of physical and neurological examination of patients. The use of NPCRS can facilitate both longitudinal and natural history studies that will be essential for future interventions

Complexitatea diagnosticului Dereglărilor Congenitale ale Glicozilării

Background. Congenital Glycosylation Disorders (CDG) is a group of pathologies caused by the disorder of the glycosylation process of glycoproteins and glycoconjugates with various disabling multisystem impairment mimicking other pathologies. Objective of the study. The aim of this study was to implement the diagnostic algorithm and identify cases of CDG in the cohort of Moldovan patients Material and Method. For the diagnosis of CDG, there were analyzed the serum of 40 patients by isoelectric focusing of transferrin (IEFT) and urine by NMR spectroscopy. Results. The clinical manifestations of the patients included in the study were: hypotonia, hepatomegaly, mild hypoglycemia, increased transaminases, abnormal brain MRI, dysmorphic features, failure to thrive and neurological manifestations. Analyzing the serum by IEFT, 37 were normal profiles, and 3– abnormal profile of the transferrin suspected for CDG. Fructosemia and Galactosemia, considered secondary causes of glycosylation troubles that induce the abnormal IEFT profile suspected for CDG, have been confirmed by biochemical and molecular-genetic analyses in two cases. Another one positive serum will be analyzed by assessing the glycomic profile and confirmation at the DNA level. Conclusion. CDG is a group of rare pathologies with a variety of symptoms that lead to their underdiagnosis. In the process of diagnosing CDG it is mandatory to exclude secondary abnormalities of glycosylation. Introducere. Dereglările Congenitale ale Glicozilării (CDG) reprezintă un grup de patologii determinate de tulburarea procesului de glicozilare a glicoproteinelor, cu afectarea multisistemică variată, dizabilitantă, mimând alte patologii grave. Scopul lucrării. Scopul lucrării a fost implementarea algoritmului de diagnostic și identificarea cazurilor de CDG în cohorta pacienților moldoveni. Material și Metode. Pentru diagnosticul CDG, serul a 40 pacienți a fost analizat prin focusare isoelectrică a transferinei (IEFT) și urina prin spectroscopie RMN. Rezultate. Manifestările clinice ale pacienților incluși în studiu au fost: hipotonie, hepatomegalie, hipoglicemie ușoară, creșterea transaminazelor, modificări ale RMN-ului cerebral, dismorfii, deficit de creștere, manifestări neurologice. În urma analizării serul prin IEFT: 37 - profil normal, 3- profil biochimic al transferinei suspect pentru CDG. Fructozemia și Galactozemia, considerate anormalități secundare ale glicozilării, care induc anormalități în profilul transferinei sugestive pentru CDG, au fost confirmate la nivel biochimic (galactitol în urină) și molecular-genetic în două cazuri. Alt treilea ser pozitiv urmează a fi analizat prin evaluarea profilul glicemic și confirmare ADN. Concluzii. CDG reprezintă un grup de patologii rare, cu o varietate de simptome care determină subdiagnosticarea lor. În proces de diagnosticul al CDG este obligatoriu a exclude anormalitățile secundare ale glicozilării prin teste metabolice și genetice adiționale

Complexity of the diagnosis of congenital disorders of glycosylation

IMSP Institutul Mamei și Copilului, Universitatea de Stat de Medicină şi Farmacie „Nicolae Testemiţanu”, Departamentul Pediatrie, Mayo Clinic, SUA, Congresul consacrat aniversării a 75-a de la fondarea Universității de Stat de Medicină și Farmacie „Nicolae Testemițanu” din Republica Moldova, Ziua internațională a științei pentru pace și dezvoltareIntroduction: Congenital Glycosylation Disorders (CDG) is a group of pathologies caused by the disorder of the glycosylation process of glycoproteins and glycoconjugates with various disabling multisystem impairment mimicking other pathologies. Purpose: The implementation of the diagnostic algorithm and identify cases of CDG in the cohort of Moldovan patients. Material and methods: serum of 40 patients suspected for CDG were analyzed by isoelectric focusing of transferrin (IEFT) and urine by NMR spectroscopy. Results: The clinical manifestations of the patients were: hypotonia, hepatomegaly, mild hypoglycemia, increased transaminases, abnormal brain MRI, dysmorphic features, failure to thrive and neurological manifestations. Conclusions: The variety of symptoms in CDG lead to missdiagnosis other pathologies. In the process of diagnosing CDG it is mandatory to exclude secondary abnormalities of glycosylation.https://stiinta.usmf.md/ro/manifestari-stiintifice/zilele-universitati