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
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Tyrosinemie typ 1 (TYR 1) je vzácné autosomálně recesivní onemocnění z okruhu dědičných poruch metabolismu aminokyselin. Podkladem jsou bialelické mutace v genu FAH, vedoucí k poruše aktivity fumarylacetoacetáthydrolázy, klíčového enzymu v metabolismu tyrosinu. U dětí s TYR 1 dochází alternativní metabolickou cestou k nadprodukci toxických metabolitů, především sukcinylacetonu a fumarylacetoacetátu, které poškozují hepatocyty a tubulární buňky ledvin. Klinicky se TYR 1 projevuje akutní formou jaterního a renálního selhávání v kojeneckém věku nebo chronicky rozvojem jaterní fibrózy, cirhózy, křivice a hepatocelulárního karcinomu v kojeneckém nebo batolecím věku, časté jsou i porfyrické krize. Biochemická diagnostika je založena na průkazu zvýšených hladin sukcinylacetonu v krvi i moči, eventuálně doprovázených elevací tyrosinu a stoupající hladinou alfa-fetoproteinu. Diagnostiku je třeba potvrdit na molekulární úrovni. V léčbě se používá nitisinon, který blokuje produkci toxických metabolitů, v kombinaci s nízkobílkovinnou dietou suplementovanou směsí esenciálních aminokyselin bez tyrosinu a fenylalaninu. Pokud konzervativní terapie nezabrání progresi jaterního selhávání nebo rozvoji hepatocelulárního karcinomu, je indikována transplantace jater. V našem sdělení předkládáme klinický průběh onemocnění u 10měsíčního chlapce, u kterého se onemocnění projevilo hepatopatií, melénou a hepatocelulárním karcinomem. Kromě nitisinonu a diety byla nutná chemoembolizace přívodné jaterní arterie v oblasti nejrychleji rostoucího karcinomu, která umožnila získat čas na přípravu k transplantaci jater. Po úspěšné transplantaci byla metabolická léčba ukončena, chlapec prospívá a je v dobrém klinickém stavu.
Tyrosinemia type 1 is a rare metabolic disease with autosomal recessive inheritance caused by biallelic mutations in the FAH gene, leading to impaired activity of fumarylacetoacetate hydrolase, a key enzyme in tyrosine metabolism. In children with TYR 1, an activation of alternative metabolic pathway leads to an overproduction of toxic metabolites, mainly succinylacetone and fumarylacetoacetate, which damage hepatocytes and renal tubular cells. Clinically, TYR 1 presents with acute progression to liver and renal failure at an early age or chronically with the development of liver fibrosis, cirrhosis, rickets and hepatocellular carcinoma, manifestations of porhyria crisis are also common. Biochemical diagnosis is based on evidence of increased levels of succinylacetone in the blood and urine, accompanied by an elevation of tyrosine and rising level of alpha-fetoprotein. The diagnosis must be confirmed at the molecular level. The treatment is based on an administration of nitisinone, which blocks the production of toxic metabolites in combination with a low-protein diet supplemented with a mixture of essential amino acids without tyrosine and phenylalanine. If conservative therapy does not prevent the progression of liver failure or the development of hepatocellular carcinoma, liver transplantation is indicated. We present the clinical course of the disease in a 10-month-old boy with TYR1, manifesting with hepatopathy, melena, and hepatocellular carcinoma. In addition to nitisinone and diet, chemoembolization of the supplying hepatic artery in the area of the fastest-growing carcinoma was necessary, which enabled us to gain time to prepare liver transplantation. After a successful transplant, the boy is in a good clinical condition.
- MeSH
- chemoembolizace metody MeSH
- hepatocelulární karcinom chirurgie diagnóza MeSH
- kojenec MeSH
- lidé MeSH
- transplantace jater metody MeSH
- tyrosinemie * diagnóza komplikace terapie MeSH
- výsledek terapie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.
Formation of oriented myofibrils is a key event in musculoskeletal development. However, the mechanisms that drive myocyte orientation and fusion to control muscle directionality in adults remain enigmatic. Here, we demonstrate that the developing skeleton instructs the directional outgrowth of skeletal muscle and other soft tissues during limb and facial morphogenesis in zebrafish and mouse. Time-lapse live imaging reveals that during early craniofacial development, myoblasts condense into round clusters corresponding to future muscle groups. These clusters undergo oriented stretch and alignment during embryonic growth. Genetic perturbation of cartilage patterning or size disrupts the directionality and number of myofibrils in vivo. Laser ablation of musculoskeletal attachment points reveals tension imposed by cartilage expansion on the forming myofibers. Application of continuous tension using artificial attachment points, or stretchable membrane substrates, is sufficient to drive polarization of myocyte populations in vitro. Overall, this work outlines a biomechanical guidance mechanism that is potentially useful for engineering functional skeletal muscle.
- MeSH
- dánio pruhované * genetika MeSH
- kosterní svaly * fyziologie MeSH
- morfogeneze MeSH
- myoblasty fyziologie MeSH
- myofibrily fyziologie MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Leber hereditary optic neuropathy is a primary mitochondrial disease characterized by acute visual loss due to the degeneration of retinal ganglion cells. In this study, we describe a patient carrying a rare missense heteroplasmic variant in MT-ND1, NC_012920.1:m.4135T>C (p.Tyr277His) manifesting with a typical bilateral painless decrease of the visual function, triggered by physical exercise or higher ambient temperature. Functional studies in muscle and fibroblasts show that amino acid substitution Tyr277 with His leads to only a negligibly decreased level of respiratory chain complex I (CI), but the formation of supercomplexes and the activity of the enzyme are disturbed noticeably. Our data indicate that although CI is successfully assembled in the patient's mitochondria, its function is hampered by the m.4135T>C variant, probably by stabilizing CI in its inactive form. We conclude that the m.4135T>C variant together with a combination of external factors is necessary to manifest the phenotype.
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Pathogenic variants in the ATAD3A gene lead to a heterogenous clinical picture and severity ranging from recessive neonatal-lethal pontocerebellar hypoplasia through milder dominant Harel-Yoon syndrome up to, again, neonatal-lethal but dominant cardiomyopathy. The genetic diagnostics of ATAD3A-related disorders is also challenging due to three paralogous genes in the ATAD3 locus, making it a difficult target for both sequencing and CNV analyses. RESULTS: Here we report four individuals from two families with compound heterozygous p.Leu77Val and exon 3-4 deletion in the ATAD3A gene. One of these patients was characterized as having combined OXPHOS deficiency based on decreased complex IV activities, decreased complex IV, I, and V holoenzyme content, as well as decreased levels of COX2 and ATP5A subunits and decreased rate of mitochondrial proteosynthesis. All four reported patients shared a strikingly similar clinical picture to a previously reported patient with the p.Leu77Val variant in combination with a null allele. They presented with a less severe course of the disease and a longer lifespan than in the case of biallelic loss-of-function variants. This consistency of the phenotype in otherwise clinically heterogenous disorder led us to the hypothesis that the severity of the phenotype could depend on the severity of variant impact. To follow this rationale, we reviewed the published cases and sorted the recessive variants according to their impact predicted by their type and the severity of the disease in the patients. CONCLUSION: The clinical picture and severity of ATAD3A-related disorders are homogenous in patients sharing the same combinations of variants. This knowledge enables deduction of variant impact severity based on known cases and allows more accurate prognosis estimation, as well as a better understanding of the ATAD3A function.
Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism that leads to severe liver, kidney, and neurological dysfunction. Newborn screening (NBS) can enable a timely diagnosis and early initiation of treatment. We presented the follow up of the only two Slovenian patients diagnosed with HT1. Metabolic control was monitored by measuring tyrosine, phenylalanine and succinylacetone from dried blood spots (DBSs). Retrograde screening of HT1 was performed from DBSs taken at birth using tandem mass spectrometry. First patient was diagnosed at the age of 6 months in the asymptomatic phase due to an abnormal liver echogenicity, the other presented at 2.5 months with an acute liver failure and needed a liver transplantation. The first was a compound heterozygote for a novel FAH intronic variant c.607-21A>G and c.192G>T whereas the second was homozygous for c.192G>T. At the non-transplanted patient, 66% of tyrosine and 79% of phenylalanine measurements were in strict reference ranges of 200-400 μmol/L and >30 μmol/L, respectively, which resulted in a favorable cognitive outcome at 3.6 years. On retrograde screening, both patients had elevated SA levels; on the other hand, tyrosine was elevated only at one. We showed that non-coding regions should be analyzed when clinical and biochemical markers are characteristic of HT1. DBSs represent a convenient sample type for frequent amino acid monitoring. Retrograde diagnosis of HT1 was possible after more than three years of birth with SA as a primary marker, complemented by tyrosine.
- Publikační typ
- kazuistiky MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Mitochondrial disorders (MD) with estimated incidence 1:4000 are caused by disturbances of oxidative phosphorylation system (OXPHOS) and represent genetically and clinically heterogeneous group of diseases with significant impact on morbidity and mortality. OXPHOS biogenesis is under dual genetic control, mitochondrial DNA (mtDNA) and nuclear genome. Subgroup of MD is characterized by mtDNA instability. MtDNA deletions may be caused by mutations in nuclear genes essential for mtDNA stability or may arise secondary to other primary disease in affected tissues. In the project we will elucidate genetic bases of mitochondrial DNA instability in 55 patients, to identify novel factors responsible for presence of deleted mtDNA molecules found in patient tissues and characterize their pathogenic mechanism. The results will significantly contribute to quality of clinical management and genetic counseling in patients. Obtained results improve understanding of mitochondrial biology and may be further utilized for development of effective therapy for these severe disorders.
Mitochondriální onemocnění (MO), jejichž odhadovaná incidence je 1:4000, jsou způsobena poruchou jednoho či více komplexů oxidativní fosforylace (OXPHOS) a tvoří klinicky heterogenní skupinu závažných chorob s významným vlivem na morbiditu a mortalitu. OXPHOS je pod kontrolou jak jaderného genomu, tak i mitochondriální DNA (mtDNA). Podskupina MO je typická výskytem instability mtDNA. Delece v mtDNA mohou být způsobeny jak mutacemi v jaderných genech nezbytných pro stabilitu mtDNA nebo mohou vznikat sekundárně z důvodu jiného onemocnění v postižené tkáni. V projektu se zaměříme na objasnění příčin instability mtDNA u skupiny pacientů, budeme hledat nové faktory zodpovědné za vznik četných delecí v mtDNA v tkáních pacientů a budeme charakterizovat patogenní mechanismy. Výsledky projektu výrazně přispějí ke zlepšení péče o pacienty a kvalitnímu genetickému poradenství v postižených rodinách. Projekt dále přispěje k lepšímu pochopení mitochondriální biologie a nové poznatky mohou být využity k rozvoji účinné terapie pro tato závažná mitochondriální onemocnění.
- Klíčová slova
- mitochondriální DNA, mitochondrial DNA, vzácná onemocnění, mtDNA instabilita, mitochondriální onemocnění, exomové sekvenování, OXPHOS, molekulární podstata, mtDNA instability, mitochondrial disorders, exome sequencing, mtDNA deletions, OXPHOS, molecular basis, rare disease,
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
