Syndrom intelektuálního postižení související s DYRK1A (DYRK1A-related intellectual disability syndrome) je autozomálně dominantní onemocnění charakterizované středním až těžkým intelektuálním postižením, zpožděním vývoje řeči, poruchou autistického spektra a mikrocefalií. Typické jsou kraniofaciální dysmorfie, potíže s krmením, malý vzrůst, hypertonie, poruchy chůze. V kojeneckém věku bývají často febrilní záchvaty, později vývoj epilepsie. Cílem našeho kazuistického sdělení je prezentace 3leté pacientky s tímto syndromem. U naší pacientky bylo vzhledem k vyčerpaným diagnostickým možnostem a neobjasněné příčině intelektuálního postižení provedeno celoexomové sekvenování (WES). Pomocí této metody jsme nalezli heterozygotní patogenní variantu p.R205* v genu DYRK1A, což umožnilo rychlé stanovení kauzální diagnózy. Lze tedy říct, že WES představuje účinný diagnostický nástroj pro detekci mutací, které jsou příčinou různých syndromů spojených s intelektuálním postižením.
DYRK1A-related intellectual disability syndrome is an autosomal dominant disorder characterized by intellectual disability including impaired speech development, autism spectrum disorder, and microcephaly. Affected individuals often have a clinically recognizable phenotype including typical craniofacial dysmorphism, feeding problems, hypertonia, short stature, gait disturbances, and foot anomalies. Other medical concerns relate to febrile seizures in infancy with later development of epilepsy. This case report aims to present a case of a three-year-old girl with DYRK1A syndrome. Since there were no additional diagnostic methods available and the cause of the intellectual disability remained unexplained, we decided to perform whole-exome sequencing (WES). WES led to the identification of heterozygous pathogenic variant p.R205* in DYRK1A gene and enabled us to reach a causal diagnosis in a reasonable time frame. We can conclude, that WES is an efficient diagnostic approach to identify causative genetic variants for syndromes associated with intellectual disability.
- Klíčová slova
- DYRK1A syndrom,
- MeSH
- diferenciální diagnóza MeSH
- komorbidita MeSH
- lidé MeSH
- mentální retardace * diagnóza genetika patologie MeSH
- předškolní dítě MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory genetika MeSH
- sekvenování exomu MeSH
- tyrosinkinasy antagonisté a inhibitory genetika MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.
- MeSH
- dítě MeSH
- dospělí MeSH
- epilepsie diagnóza patologie MeSH
- homocystinurie diagnóza patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mentální retardace diagnóza patologie MeSH
- methylentetrahydrofolátreduktasa (NADPH2) nedostatek MeSH
- mladiství MeSH
- mladý dospělý MeSH
- opožděná diagnóza MeSH
- psychotické poruchy diagnóza patologie MeSH
- retrospektivní studie MeSH
- svalová spasticita diagnóza patologie MeSH
- věk při počátku nemoci MeSH
- záchvaty diagnóza patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- MeSH
- dospělí MeSH
- genetické testování metody MeSH
- lidé MeSH
- mentální retardace genetika patologie MeSH
- neurovývojové poruchy * genetika MeSH
- novorozenec MeSH
- proteinfosfatasa 2C genetika MeSH
- výsledek terapie MeSH
- vývojové poruchy u dětí genetika patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mentální retardace etiologie klasifikace komplikace patologie MeSH
- neurologické vyšetření * metody MeSH
- novorozenec MeSH
- postura těla MeSH
- psychomotorický výkon MeSH
- reflex MeSH
- supinační poloha MeSH
- svalová hypertonie klasifikace MeSH
- svalová hypotonie klasifikace MeSH
- vývoj dítěte klasifikace MeSH
- vývojové poruchy u dětí klasifikace MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- přehledy MeSH
TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.
- MeSH
- DNA vazebné proteiny genetika MeSH
- dospělí MeSH
- fosfodiesterasy genetika MeSH
- geny recesivní genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mentální retardace genetika patologie MeSH
- mutace ztráty funkce genetika MeSH
- spinocerebelární ataxie genetika patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Birk Barel syndrome also known as KCNK9 imprinting syndrome is a rare developmental disorder associated with a loss-of-function variant in KCNK9, an imprinted gene with maternal expression on the 8th chromosome encoding the TASK3 (TWIK-related acidity inhibited K + -channel 3). Only two variants of KCNK9 have been associated with this condition before, both of them leading to the same amino-acid exchange p.Gly236Arg (Barel, 2008, Graham, 2016). We describe a case of a 17-year-old girl presenting with very similar phenotype and pure motor neuropathy with a novel variant c.710C > A: p.Ala237Asp (NM_001282534.1) in KCNK9 found by whole exome sequencing. Our case suggests that Birk Barel syndrome may not be caused only by variants leading to amino-acid exchange p.Gly236Arg but also by other missense variant in this gene and that peripheral motor neuropathy might be a feature of this syndrome.
- MeSH
- draslíkové kanály s dvoupórovou doménou genetika MeSH
- genetická predispozice k nemoci * MeSH
- genomový imprinting genetika MeSH
- kraniofaciální abnormality genetika patologie MeSH
- lidé MeSH
- mentální retardace genetika patologie MeSH
- missense mutace genetika MeSH
- mladiství MeSH
- sekvence aminokyselin genetika MeSH
- sekvenování exomu MeSH
- svalová hypotonie genetika patologie MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
BACKGROUND AND AIM: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. METHODS: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). RESULTS: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl(-)) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl(-): 10 % versus 39 %, p = 0.002; GA1: 26 % versus 73 %, p < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl(-) to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used. CONCLUSIONS: NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl(-). Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.
- MeSH
- dítě MeSH
- dospělí MeSH
- glutaryl-CoA-dehydrogenasa nedostatek metabolismus MeSH
- kojenec MeSH
- kyselina methylmalonová metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mentální retardace metabolismus patologie MeSH
- metabolické nemoci mozku vrozené metabolismus patologie MeSH
- metabolické nemoci mozku metabolismus patologie MeSH
- metabolické nemoci metabolismus patologie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- novorozenecký screening metody MeSH
- předškolní dítě MeSH
- věk při počátku nemoci MeSH
- vitamin B 12 metabolismus MeSH
- vrozené poruchy metabolismu aminokyselin metabolismus patologie MeSH
- vrozené poruchy transportu aminokyselin metabolismus patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chromosome 17q21.31 microdeletion syndrome is a genomic disorder caused by a recurrent 600 kb long deletion. The deletion affects the region of a common inversion present in about 20% of Europeans. The inversion is associated with the H2 haplotype carrying additional low-copy repeats susceptible to non-allelic homologous recombination, and this haplotype is prone to deletion. No instances of 17q21.31 deletions inherited from an affected parent have been reported, and the deletions always affected a parental chromosome with the H2 haplotype. The syndrome is characterized clinically by intellectual disability, hypotonia, friendly behavior and specific facial dysmorphism with long face, large tubular or pear-shaped nose and bulbous nasal tip. We present monozygotic twin sisters showing the typical clinical picture of the syndrome. The phenotype of the sisters was very similar, with a slightly more severe presentation in Twin B. The 17q21.31 microdeletion was confirmed in both patients but in neither of their parents. Potential copy number differences between the genomes of the twins were subsequently searched using high-resolution single nucleotide polymorphism (SNP) and comparative genome hybridisation (CGH) arrays. However, these analyses identified no additional aberrations or genomic differences that could potentially be responsible for the subtle phenotypic differences. These could possibly be related to the more severe perinatal history of Twin B, or to the variable expressivity of the disorder. In accord with the expectations, one of the parents (the mother) was shown to carry the H2 haplotype, and the maternal allele of chromosome 17q21.31 was missing in the twins.
- MeSH
- chromozomální delece MeSH
- dospělí MeSH
- dvojčata monozygotní genetika MeSH
- haplotypy * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- lidské chromozomy, pár 17 genetika MeSH
- mentální retardace genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- studie na dvojčatech MeSH
- MeSH
- lidé MeSH
- mentální retardace * patologie psychologie rehabilitace MeSH
- osoby s mentálním postižením * psychologie rehabilitace MeSH
- postoj MeSH
- sociální opora * MeSH
- sociální prostředí MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
Článek přehledně pojednává o posuzování plné a částečné invalidity u osob s různými stupni mentální retardace. Důraz seklade na důsledné individuální posouzení, odmítá se schematický způsob posouzení.
The article reviews the assessment of a full and partial disability in individuals with different stages of mental retardation. Theconsistent individual assessment is stressed, the schematic way of assessment is refused.
