spasms
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Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
- MeSH
- draslíkové kanály Shab genetika MeSH
- kineziny genetika MeSH
- kojenec MeSH
- křeče u dětí diagnóza genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- předškolní dítě MeSH
- proteiny přenášející monosacharidy genetika MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go genetika MeSH
- receptory cytoplazmatické a nukleární genetika MeSH
- represorové proteiny genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole-exome sequencing. A heterozygous amino-acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G-actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G-actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient.
- MeSH
- aktiny metabolismus MeSH
- buňky NIH 3T3 MeSH
- epilepsie genetika MeSH
- kojenec MeSH
- křeče u dětí genetika MeSH
- lidé MeSH
- mikrofilamentové proteiny genetika MeSH
- mutace * MeSH
- myši MeSH
- předškolní dítě MeSH
- sekvenování exomu MeSH
- zvířata MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
Cílem této práce bylo vyšetření a léčba funkčních poruch krční páteře ve vztahu k bolestem hlavy. Jedná se o téma společensky závažné, protože prevalence vertebrogenních bolestí hlavy se podle různých literárních Údajů pohybuje od 2 do 30 %. Vertebrogenní bolesti hlavy patří mezi časté potíže jako jedny z civilizačních chorob. Mezi nejčastější příčiny patří funkční patologie z oblasti krční páteře - kloubní dysfunkce (blokády) hlavových kloubů C0-C1-C1-2-3, C-Th přechodu, blokády 1. žebra, as tím související zvýšené svalové napětí šíjového svalstva. Metoda práce. Vyšetřili jsme funkční poruchy krční páteře ve výše zmíněných segmentech podle přesné metodiky muskuloskeletální medicíny (uznávané Federation International of Musculosceletal medicine). Intenzitu a frekvenci bolestí hlavy jsme hodnotili 10stupňovou analogovou škálou bolesti. Snažili jsme se ověřit možnost ovlivnění těchto bolestí pomocí měkkých technik.
The goals of this contribution are to evaluate functional disturbance of cervical spině and its influence on headache. It is an important topič, because prevalence of cervicocranial syndrome is present from 2 to 30% according to various literatuře sources. CC syndrome belongs to civilisation illnesses. The most frequent source is dysfunction of cervicocranial joints C0-C1 -2-3, C-Th junction, blockade of 1. ribs and jointed muscle spasm. Method: We investigated functional disturbance of cervical spině in above mentioned segments exactly using methods of Musculosceletal Medicine (accepted by tne Federation International of Musculosceletal Medicine). We measured intensity and frequencyof headache by 10 degree'sanaloguescaleof pain. Wetried to bring a proof of possibility of treating these pains by soft tissue techniques.
- MeSH
- bolesti hlavy diagnóza patologie terapie MeSH
- dospělí MeSH
- krční obratle patologie MeSH
- lidé MeSH
- měření bolesti metody MeSH
- nervosvalová blokáda MeSH
- svalová spasticita diagnóza patologie terapie MeSH
- techniky fyzikální terapie metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms during infancy. Both these conditions are quite resistant to pharmacotherapy; thus, a search for new treatments is warranted. METHODS: In this study, we determined the efficacy of two novel neurosteroids, pregnanolone glutamate (PAG) and pregnanolone pyroglutamate (PPG), and tested these drugs in doses of 1-10 mg/kg (ip) against the TMDT syndrome and in our rodent model of infantile spasms. RESULTS: Only PPG in doses 5 and 10 mg/kg suppressed the severity of the TMDT syndrome and TMDT-induced lethality, while the 1 mg/kg dose was without an effect. Interestingly, the 1 mg/kg dose of PPG in combination with 1 mg/kg of diazepam was also effective against TMDT poisoning. Neither PAG nor PPG were effective against experimental spasms in the N-methyl-D-aspartate (NMDA)-triggered model of infantile spasms. CONCLUSIONS: While evidence suggests that PAG can act through multiple actions which include allosteric inhibition of NMDA-induced and glycine receptor-evoked currents as well as augmentation of ɣ-aminobutyric acid subtype A (GABAA) receptor-induced currents, the agent appears to neither have the appropriate mechanistic signature for activity in the infantile spasm model, nor the adequate potency, relative to PPG, for ameliorating the TMDT syndrome. The full mechanisms of action of PPG, which may become a potent TMDT antidote either alone or in combination with diazepam are yet unknown and thus require further investigation.
- MeSH
- diazepam farmakologie MeSH
- hlodavci MeSH
- křeče u dětí * chemicky indukované farmakoterapie MeSH
- kyselina glutamová MeSH
- kyselina pyrrolidonkarboxylová MeSH
- N-methylaspartát toxicita terapeutické užití MeSH
- neurosteroidy * MeSH
- neurotoxické syndromy * MeSH
- pregnanolon škodlivé účinky MeSH
- spasmus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- dospělí MeSH
- elektrokardiografie metody MeSH
- hyperventilace MeSH
- lidé MeSH
- nízká teplota MeSH
- variantní angina pectoris diagnóza MeSH
- zátěžový test MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
