Ювенильный боковой амиотрофический склероз 4-го типа: клиническое наблюдение и обзор литературы

Juvenile amyotrophic lateral sclerosis (ALS) presents a group of few rare monogenic disorders with onset from early childhood up to 25 years and much more benign course than “classic” ALS. Autosomal dominant ALS type 4 (ALS4) related to SETX gene is one of them. In spite of characteristic combined involvement of central and peripheral motor neurons, ALS4 clinical diagnostics may be difficult, particularly in atypical and/or non‑familial cases and electroneuromyography underestimation. Massive parallel sequencing permits diagnosing majority of cases and performing genetic counselling in families.Aim of this work: to describe non‑familial ALS4 case detected by whole‑exome sequencing and present a review on poorly known disorder.A 21‑year‑old female patient in a consanguineous family was examined; methods: clinical, genealogical, electroneuromyography, peripheral nerves ultrasound; molecular: panel and whole‑exome sequencing, bioinformatical analysis.The girl is an only child and an only patient in a family of Mountain Jews – first cousins. She had spastic paraparesis since age of independent walking (1.5 y.o.) and early feet deformation, her first diagnosis was cerebral palsy. In 12 years spasticity progressed, walking was lost. After orthopedic surgery in 15 years supported walking restored, at that age leg distal amyotrophy developed with no further progressing. Due to electroneuromyography results polyneuropathy was misdiagnosed. In 21 years repeated electroneuromyography excluded polyneuropathy and detected generalized motor neuron impairment and juvenile ALS was suggested. On neurological examination pronounced spastic paraparesis together with peripheral leg paraparesis without sensory impairment were detected; her supported gait was of mixed spastic and paretic types; there were no fasciculations or fibrillations.Whole‑exome sequencing detected a novel heterozygous missense mutation c.4442A>G (p.Lys1481Arg) in SETX exon 10. Sanger familial sequencing was not possible, but DNA finding matching the phenotype supported ALS4 diagnosis. Juvenile ALS4 (SETX gene) is a relatively benign autosomal dominant disease, imitating in different stages other nervous disorders of early and young age; genealogy is not always informative. Along with typical cases (like our patient) clinical variability exists. Electroneuromyography is the main instrumental tool. Methods of massive parallel sequencing are optimal in DNA testing of juvenile ALS.В структуре бокового амиотрофического склероза (БАС) небольшое, но важное место занимают моногенные ювенильные формы с началом в период от раннего детства до 25 лет и характеризующиеся гораздо более доброкачественным течением, чем многофакторный и поздний моногенный БАС. Одна из редких ювенильных форм – аутосомно‑доминантный БАС 4‑го типа (БАС‑4), связанный с геном сенатаксина SETX. Несмотря на характерную картину (сочетанное поражение центральных и периферических мотонейронов), клиническая диагностика БАС‑4 может вызывать трудности, особенно в атипичных и/или несемейных случаях, а также при недостаточном внимании к данным электронейромиографии (ЭНМГ). Высокопроизводительное экзомное секвенирование MPS позволяет диагностировать большинство случаев и проводить медико‑генетическое консультирование в семьях.Цель работы – описать случай БАС‑4, диагностированный методом полноэкзомного секвенирования, и представить обзор литературы, посвященной этой малоизвестной болезни.Обследована пациентка 21 года из инбредной семьи, использованы следующие методы: клинико‑генеалогический, электронейромиография, ультразвуковое исследование периферических нервов, молекулярно‑генетические методы (панельное и полноэкзомное секвенирование, биоинформатический анализ). Девушка – единственный ребенок и единственная больная в семье горских евреев – двоюродных сибсов. С начала ходьбы (1,5 года) отмечались спастический парапарез, ранняя деформация стоп; ходила без опоры; диагностировали детский церебральный паралич. В 12 лет регресс, утратила ходьбу; после ортопедических операций в 15 лет ходит с опорой; с того же возраста наблюдается амиотрофия дистальных отделов ног; прогрессирования нет. По данным ЭНМГ диагностировали полинейропатию. В 21 год при ЭНМГ нейропатия исключена, выявлено поражение сегментарных мотонейронов. В неврологическом статусе: выраженный нижний спастический парапарез в сочетании с периферическим парапарезом без расстройств чувствительности, походка спастико‑паретическая с опорой, фасцикуляций нет. При полноэкзомном секвенировании найдена ранее не описанная гетерозиготная миссенс‑мутация c.4442A>G (p.Lys1481Arg) в экзоне 10 гена SETX. Семейная валидация по Сэнгеру была невозможна, но соответствие ДНК-находки фенотипу позволило диагностировать БАС‑4.Ювенильный БАС‑4 (ген SETX) – относительно доброкачественное заболевание с аутосомно‑доминантным типом наследования, имитирующее на разных этапах другие нервные болезни детского и юношеского возраста; семейный анамнез не всегда информативен. Наряду с типичными случаями (представленное наблюдение) выражено клиническое разнообразие. ЭНМГ – основное инструментальное исследование. Методы высокопроизводительного экзомного секвенирования оптимальны в ДНК‑диагностике ювенильного БАС

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson’s disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

ВОЗМОЖНОСТИ ХИРУРГИЧЕСКОЙ КОРРЕКЦИИ ТРОМБОЗА ВНУТРЕННЕЙ СОННОЙ АРТЕРИИ У ПАЦИЕНТОВ С ОСТРЫМ ИШЕМИЧЕСКИМ ИНСУЛЬТОМ

Objective. To estimate the efficacy of surgical treatment of internal carotid artery (ICA) thrombosis in patients suffered from acute ischemic stroke (AIS).Material and methods. Author operated 25 patients suffered from AIS and ICA thrombosis from 01 Feb, 2014 till 31 Aug, 2016 in Neurosurgical Department of N.V. Sklifosovsky Research Institute for Emergency Medicine. Among them, 15 patients had total thrombosis of ICA and were operated on, 10 patients had partial mural thrombosis or floating thrombus (6 patients were operated on). There were 7 thrombectomies with the removal of intima, 13 superficial temporal artery (STA)-middle cerebral artery (MCA) bypasses, 1 ICA stent installation.Results. The excellent outcomes were seen in 7 (33.4%) patients, good outcomes — in 11 (52.3%) and satisfactory outcomes were observed in 3 (14.3%) patients. The improvement of functional deficit in the early post-operative period was 4.85 scores according to NIHSS, 1.2 scores according to Rankin scale and 2.3 scores according to Rivermead mobility index. The regress of neurological deficit was more significant among patients with severe focal disturbances; better outcomes were among patients operated on within first 3 days from an onset of the disease. There was no significant improvement among non-operated patients at the moment of discharge from hospital. Thrombectomy with the removal of intima performed in 2 (40%) patients with partial mural thrombosis was complicated by repeated thrombosis of ICA. The improvement of cerebral blood supply was verified in 16 (76.2%) operated patients according to the data of cerebral perfusion examination.Conclusions. The early surgical treatment is indicated for patients with acute total thrombosis of ICA. It is possible to perform STA-MCA bypass in case of inability to perform endovascular thrombextraction or open thrombectomy with the removal of intima. The conservative treatment is indicated for patients with partial mural thrombosis while urgent operation is necessary among patient with floating thrombus to decrease the risk of cerebral embolism. Цель. Оценить эффективность хирургического лечения тромбоза внутренней сонной артерии (ВСА) у пациентов с острым ишемическим инсультом (ОИИ).Материал и методы. В период с 1.02.2014 по 31.08.2016 гг. в нейрохирургическом отделении НИИ СП им. Н.В. Склифосовского пролечены 25 пациентов с ОИИ и тромбозом ВСА. У 15 больных выявлен полный тромбоз (все 15 оперированы), у 10 — неполный пристеночный или флотирующий тромб (6 оперированы). Выполнено 7 тромбинтимэктомий (ТИЭ), 13 экстра-интракраниальных микроанастомозов (ЭИКМА), одно стентирование ВСА. Результаты. Отличные исходы получены у 7 (33,4%), хорошие — у 11 (52,3%), удовлетворительные — у 3 (14,3%) больных. Снижение функционального дефицита в раннем послеоперационном периоде состави- ло 4,85 балла по шкале NIHSS, 1,2 балла по шкале Рэнкина и 2,3 балла по индексу мобильности Ривермид. Регресс неврологического дефицита был более выражен у пациентов со значительными очаговыми нарушениями; лучшие исходы имели пациенты, оперированные в первые 3 сут заболевания. У неоперированных пациентов достоверного улучшения к моменту выписки не было. ТИЭ по поводу пристеночных тромбозов в 2 наблюдениях (40%) сопровождалась ретромбозом ВСА. У 16 оперированных пациентов (76,2%) отмечено улучшение кровоснабжения головного мозга по данным исследований его перфузии.Заключение. Пациентам с острым полным тромбозом ВСА показано проведение раннего хирургического лечения. При невозможности проведения эндовазальной тромбэкстракции или открытой ТИЭ предлагается выполнить обходное шунтирование (ЭИКМА). Пациентам с неполным пристеночным тромбозом показано проведение консервативного лечения. Больным с неполным флотирующим тромбозом и высоким риском эмболии в головной мозг показано проведение экстренной операции.

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder