BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. DISCUSSION: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.
- MeSH
- činnosti denního života MeSH
- dospělí MeSH
- elektroencefalografie MeSH
- epilepsie * MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace MeSH
- pohybové poruchy * genetika MeSH
- proteiny Munc18 * genetika MeSH
- záchvaty genetika MeSH
- Check Tag
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism. MATERIAL AND METHODS: We present a cohort of paediatric patients with pathogenic variants of WD-Repeat Domain 45 gene (WDR45). The diagnosis was established by targeted panel sequencing of genes associated with epileptic encephalopathies (n = 9) or by Sanger sequencing of WDR45 (n = 1). Data on clinical characteristics, molecular-genetic findings and other performed investigations were gathered from all participating centres. Markers of iron metabolism were analysed in 6 patients. RESULTS: Ten children (3 males, 7 females, median age 8.4 years) from five centres (Prague, Berlin, Vogtareuth, Tubingen and Cologne) were enrolled in the study. All patients manifested first symptoms (e.g. epilepsy, developmental delay) between 2 and 31 months (median 16 months). Seven patients were seizure-free (6 on antiepileptic medication, one drug-free) at the time of data collection. Neurological findings were non-specific with deep tendon hyperreflexia (n = 4) and orofacial dystonia (n = 3) being the most common. Soluble transferrin receptor/log ferritin ratio was elevated in 5/6 examined subjects; other parameters of iron metabolism were normal. CONCLUSION: Severity of epilepsy often gradually decreases in BPAN patients. Elevation of soluble transferrin receptor/log ferritin ratio could be another biochemical marker of the disease and should be explored by further studies.
- MeSH
- biologické markery krev MeSH
- dítě MeSH
- epilepsie krev genetika metabolismus MeSH
- fenotyp MeSH
- lidé MeSH
- mentální retardace krev genetika metabolismus MeSH
- neurodegenerativní nemoci krev genetika metabolismus MeSH
- pohybové poruchy krev genetika metabolismus MeSH
- poruchy metabolismu železa krev genetika metabolismus MeSH
- transportní proteiny genetika MeSH
- železo krev MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Diisopropylfluorophosphate exerts its toxic effect by irreversibly inhibiting acetylcholinesterase. This results in over-stimulation of central and peripheral cholinergic activity. The aim of the present study was to evaluate the possible preventive effects of acute treatment with reversible acetylcholinesterase inhibitor galantamine against the signs of cholinergic toxic syndrome provoked by diisopropylfluorophosphate, such as hypothermia, muscular fasciculations, oral dyskinesia and decreased locomotor performance in a rat model of intoxication. The effects of these two anticholinesterases on acetylcholinesterase activity and on the expression of mRNA of the immediate early response gene c-fos in the brain were assessed by histochemical acetylcholinesterase staining and by in situ hybridization, respectively. Diisopropylfluorophosphate induced rapidly progressing hypothermia, muscular fasciculations, oral dyskinesia and decreased locomotor performance. The increased cholinergic cortical and hippocampal activity due to irreversible acetylcholinerase inhibition were indicated by the increased c-fos mRNA autoradiographic signal and by the inhibition of acetylcholinesterase staining, respectively. Galantamine by itself provoked transient and relatively weak inhibition of the acetylcholinesterase staining, while it did not induce increased c-fos mRNA expression or significant behavioural signs of cholinergic toxicity. Galantamine significantly reduced the rate of the onset, but not the maximal hypothermia induced by diisopropylfluorophosphate. Importantly, all the above-mentioned behavioural and neurochemical effects of diisopropylfluorophosphate were significantly reduced by galantamine. These results indicate that the acute pre-treatment with galantamine may have prophylactic effects against the intoxication by diisopropylfluorophosphate.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- fascikulace chemicky indukované genetika patologie patofyziologie MeSH
- galantamin farmakologie MeSH
- isofluorofát toxicita MeSH
- krysa rodu rattus MeSH
- messenger RNA genetika metabolismus MeSH
- mozek účinky léků enzymologie patologie patofyziologie MeSH
- neuroprotektivní látky farmakologie MeSH
- pohybová aktivita účinky léků MeSH
- pohybové poruchy genetika patologie patofyziologie MeSH
- potkani Wistar MeSH
- protoonkogenní proteiny c-fos genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- tělesná teplota účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Iron is an essential element necessary for energy production, DNA and neurotransmitter synthesis, myelination and phospholipid metabolism. Neurodegeneration with brain iron accumulation (NBIA) involves several genetic disorders, two of which, aceruloplasminemia and neuroferritinopathy, are caused by mutations in genes directly involved in iron metabolic pathway, and others, such as pantothenate-kinase 2, phospholipase-A2 and fatty acid 2-hydroxylase associated neurodegeneration, are caused by mutations in genes coding for proteins involved in phospholipid metabolism. Phospholipids are major constituents of myelin and iron accumulation has been linked to myelin derangements. Another group of NBIAs is caused by mutations in lysosomal enzymes or transporters such as ATP13A2, mucolipin-1 and possibly also beta-galactosidase and alpha-fucosidase. Increased cellular iron uptake in these diseases may be caused by impaired recycling of iron which normally involves lysosomes. Abnormal iron utilization by mitochondria, as has been proposed in Friedreich's ataxia, is another possible mechanism of iron accumulation. Other, more common degenerative movement disorders, such as Parkinson's disease, Huntington's disease, multiple system atrophy and progressive supranuclear palsy also exhibit increased brain iron content. Finally, brain iron deficiency has been implicated in restless legs syndrome. This review provides an update on recent findings related to genetics, pathogenic mechanisms, diagnosis, and treatment of movement disorders associated with dysregulation of brain iron. We also propose a new classification of NBIAs.
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab. ; 31 cm
Defects in the BSCL 2 (Bernardinelli-Seip congenital lipodystrophy 2) gene were recently found in patients with hereditary motor neuropathy (HMN). Only patients with the pure motor neuropathy will be selected from the available database of patients withhereditary neuropathy. Selected probands will be examined with direct sequencing of all 10 coding exons of the BSCL 2 gene. Clinical and electrophysiological data will be completed in these patients. This study will lead to improvement of the diagnosticpossibilities of the HMN condition and also to a more complex care for HMN patients. Results of the study will specify phenotype and genotype variability of hereditary motor neuropathy.
Porucha BSCL 2 (Bernardinelli-Seip congenital lipodystrophy 2) genu byla nedávno objevena u pacientů s hereditární motorickou neuropatií (dHMN) a poslední studie ukázala, že mutace v BSCL2 jsou nacházeny nejčastěji ze všech dosud známých genů spojených sdHMN. Ze shromáždeného souboru pacientů s hereditárními neuropatiemi budou vybráni pacienti s čistě motorickým typem neuropatie a budou vyšetřeni pomocí přímého skvenování všech 10 kódujících exonů BSCL 2 genu. U pacientů budou doplněna klinická a genealogická data. Studie povede k upřesnění fenotypové a genotypové variability u pacientů s HMN, zlepší diagnostické možnosti a umožní komplexní péči u tohoto neurogenetického onemocnění.
- MeSH
- Charcotova-Marieova-Toothova nemoc MeSH
- dědičné degenerativní poruchy nervového systému MeSH
- exony MeSH
- hereditární motorické a senzitivní neuropatie diagnóza MeSH
- kongenitální generalizovaná lipodystrofie MeSH
- lipodystrofie MeSH
- mutační analýza DNA MeSH
- pohybové poruchy genetika MeSH
- transkripční faktory časné růstové odpovědi MeSH
- Geografické názvy
- Česká republika MeSH
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- neurologie
- biologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
- MeSH
- achondroplazie diagnóza genetika patofyziologie MeSH
- lidé MeSH
- osteoartróza diagnóza genetika patofyziologie MeSH
- osteogenesis imperfecta diagnóza genetika patofyziologie MeSH
- pohybové poruchy genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Neurology in practice ; issue 8
ii35 s. : il., tab. ; 30 cm
- MeSH
- chromozomální aberace diagnóza genetika MeSH
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mentální retardace genetika vrozené MeSH
- mladiství MeSH
- pohybové poruchy genetika vrozené MeSH
- pruhování chromozomů MeSH
- vývojové poruchy u dětí diagnóza genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- kongresy MeSH
