Early epileptic encephalopathy associated with stxbp1 mutations: clinical description of nine novel mutation carriers Текст научной статьи по специальности «Клиническая медицина»

КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ И НАБЛЮДЕНИЯ

КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ И НАБЛЮДЕНИЯ

© КОЛЛЕКТИВ АВТОРОВ, 2017 УДК 616.853-036.1-092

Sharkov A.A.13 4, Dadali E.L.2, Konovalov F.A.3, Akimova I.A.2, Sharkova I.V.2, Golovteev A.L.4, Bakhtin I.S.5, Belousova E.D1.

EARLY EPILEPTIC ENCEPHALOPATHY ASSOCIATED WITH STXBP1 MUTATIONS: CLINICAL DESCRIPTION OF NINE NOVEL MUTATION CARRIERS

'Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, 125412, Moscow, Russia

2Federal State budgetary institution «Research centre for medical genetics», 115478, Moscow, Russia 3Genomed Ltd., 115093, Moscow, Russia 4Epilepsy-center Ltd., 127566, Moscow, Russia

5State budgetary institution of health care Children's Regional Clinical Hospital. 350000, Krasnodar, Russia

Introduction: Early infantile epileptic encephalopathy is a group of genetically heterogeneous diseases caused by mutations in more than 50 genes, including the gene STXBP1 responsible for the development of EIEE type 4 (OMIM 612164). Material and methods: We included 196patients with unexplained EE. Prior diagnostic screening including at least brain MRI and metabolic screening was negative for all patients. Mutation analysis was underway exome sequencing on Illumina NextSeq 500 using TruSightOne V1.1 DNA enrichment.

Results: Nine novel STXBP1 point mutations were identified in nine unrelated patients: c.1588G>T (p.Glu530Ter), c.1206T>A (p.Tyr402Ter), c.430G>T (p.Val144Phe), c.1217G>A (p.Arg406His), c.1217G>T (p.Arg406Leu), c.784G>T (p.Asp262Tyr), c.1162C>T (p.Arg388Ter), c.1216C>T (p.Arg406Cys), c.1439C>T (p.Pro480Leu). Analysis of parental DNA showed that all mutations arose de novo. Polyphen2 analysis predicts all missense mutations to be possibly or probably damaging. Epilepsy onset was within the first 2.5 months of age for 8 patients and more later onset (10 month) for 1 case. EEG at onset was normal in 4 patients, but later in all patients had epileptic activity (focal or multifocal in 6 patients, hypsarrhythmia in 2 case and burst-suppression pattern - 1). More frequent seizure types was focal seizures (3 cases) and epileptic spasms (6 cases), in addition, of these, 4 patients had generalized or facial myoclonic jerks, 2 - hypomotor seizures. The mostfrequent neurologicalfindings in all patients was muscle hypotonia, of these, one patient had spastic tetraparesis. All patients had some degree of intellectual disability (profound - 6, severe - 2, mild - 1). All patients were treated with more than 3 antiepileptic drugs (AEDs) (steroid treatment and ACTH included), but only 1 patient had spontaneous seizure-free within 1 year after seizure onset, other patients had good but temporary effect on hormone therapy, vigabatrin, levetiracetam or valproic acid.

Discussion: We can observe focal seizures and focal EEG findings in the epilepsy determined by genetics. Diagnostic criteria early epileptic encephalopathy without structural brain lesion should start the search of genetic etiology of the epilepsy.

Keywords: epileptic encephalopathy, early onset epileptic encephalopathy, STXBP1, epilepsy genetic, epilepsy.

For citation: Sharkov A.A., Dadali E.L., Konovalov F.A., Akimova I.A., Sharkova I.V, Golovteev A.L., Bakhtin I.S., Belousova E.D. Early Epileptic Encephalopathy Associated With STXBP1 Mutations: Clinical Description Of Nine Novel Mutation Carriers. Nevrologicheskiy Zhurnal (Neurological Journal) 2017; 22 (4): 182-189 (Russian). DOI: http://dx.doi.org/10.18821/1560-9545-2017-22-4-182-189.

For correspondence: Sharkov Artem A., neurologist, researcher, Department psychoneurology and epileptol-ogy Research and Clinical Institute for Pediatrics at the Pirogov Russian National Research Medical University, email: [email protected]

Conflict of interest. The authors declare no conflict of interest. Acknowledgments. The study had no sponsorship. Information about authors: Sharkov A.A., http://orcid.org/0000-0002-0980-2638 Dadali E.L., http://orcid.org/0000-0001-5602-2805 Konovalov F.A., http://orcid.org/0000-0001-6414-436X Akimova I.A., http://orcid.org/0000-0002-9092-6581 Sharkova I.V., http://orcid.org/0000-0002-5819-4835 Golovteev A.L., http://orcid.org/0000-0001-6468-5350 Bakhtin I.S., http://orcid.org/0000-0003-3962-565X Belousova E.D., http://orcid.org/0000-0003-3594-6974

Шарков А.А.1,3,4, Дадали Е.Л.2, Коновалов Ф.А.3, Акимова И.А.2, Шаркова И.В.2, Головтеев А.Л.4, Бахтин И.С.5, Белоусова Е.Д1.

КЛИНИКО-ГЕНЕТИЧЕСКИЕ ХАРАКТЕРИСТИКИ РАННЕЙ ЭПИЛЕПТИЧЕСКОЙ ЭНЦЕФАЛОПАТИИ 4-го ТИПА, ОБУСЛОВЛЕННОЙ МУТАЦИЯМИ В ГЕНЕ STXBP1

NEVROLOGICHESKIY ZHURNAL, № 4, 2017 DOI: http://dx.doi.org/10.18821/1560-9545-2017-22-4-182-189

RESEARCHES AND CASE REPORTS

'Научно-исследовательский клинический институт педиатрии им. Ю.Е. Вельтищева ФГБУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» МЗ РФ, 125412, Москва, Россия;

2ФГБУ «Медико-генетический научный центр», 115478, Москва, Россия

3ООО «Геномед», 115093, Москва, Россия

4ООО «Эпилепси-центр», 127566, Москва, Россия

5ГБУЗ «Детская Краевая Клиническая Больница», 350000, Краснодар, Россия

Введение. Ранняя эпилептическая энцефалопатия (РЭЭ) - это группа генетически гетерогенных заболеваний, вызванных мутациями более чем в 50 генах, включая ген STXBP1, ответственный за развитие РЭЭ типа 4 (OMIM 612164).

Материал и методы. Группу больных составили дети (n = 196) первых лет жизни с не диагностированными эпилептическими энцефалопатиями. Предварительное диагностическое обследование, включавшее МРТ головного мозга и метаболический скрининг, было отрицательным для всех пациентов. Поиск мутаций проводили с использованием высокопроизводительного экзомного секвенирования на Illumina NextSeq 500 с платформой TruSightOne V1.1. Результаты. 9 каузативных мутаций в гене STXBP1 были идентифицированы у 9 несвязанных между собой пациентов: c.1588G>T (p.Glu530Ter), c.1206T>A (p.Tyr402Ter), c.430G>T (p.Val144Phe), c.1217G>A (p.Arg406His), c.1217G>T (p.Arg406Leu), c.784G>T (p.Asp262Tyr), c.1162C>T (p.Arg388Ter), c.1216C>T (p.Arg406Cys), c.1439C>T (p.Pro480Leu). Анализ родительской ДНК показал, что все мутации возникли de novo. Дебют приступов наблюдали у 8 пациентов в первые 2,5 мес жизни, в 1 случае - с более поздним началом в 10 мес. ЭЭГ на момент дебюта была нормальной у 4 пациентов, но позже у всех больных наблюдалась эпилептическая активность (региональная или мультирегиональная у 6 пациентов, гипсаритмия в 2 случаях и паттерн «вспышка-подавление» - ещё в одном). Наиболее частыми типами приступов были фокальные приступы (3 случая) и эпилептические спазмы (6 случаев); кроме того, у 4 пациентов также наблюдали генерализованные или лицевые миоклонии, ещё в 2 случаях - гипомо-торные приступы. Наиболее распространённым неврологическим симптомом у всех пациентов была мышечная гипотония, у 1 также отмечался спастический тетрапарез. У всех больных отмечена та или иная степень задержки психомоторного развития (глубокая - 6, тяжёлая - 2, лёгкая - 1). Все пациенты получали 3 и более схем лечения (включая терапию гормонами), но только у 1 пациента наблюдалась устойчивая ремиссия в течение года, у других выявлен кратковременный положительный эффект на фоне лечения гормонами, вигабатрином, леветира-цетамом или вальпроевой кислотой.

Обсуждение. Фокальный характер приступов и ЭЭГ в начале заболевания может наблюдаться и при генетически обусловленных эпилепсиях. При отсутствии явных структурных поражений головного мозга в совокупности с критериями РЭЭ крайне важно проводить генетическую диагностику.

Ключевые слова: эпилептическая энцефалопатия; ранние эпилептические энцефалопатии; STXBP1; генетика эпилепсии; эпилепсия.

Для цитирования: Шарков А.А., Дадали Е.Л., Коновалов Ф.А., Акимова И.А., Шаркова И.В., Голов-теев А.Л., Бахтин И.С., Белоусова Е.Д. Клинико-генетические характеристики ранней эпилептической энцефалопатии 4 типа, обусловленной мутациями в гене STXBP1. Неврологический журнал 2017; 22(4): 182-189 (Russian). DOI: http://dx.doi.org/10.18821/1560-9545-2017-22-4-182-189.

Для корреспонденции: Шарков Артём Алексеевич, врач-невролог, научный сотрудник отдела психоневрологии и эпилептологии Научно-исследовательского клинического института педиатрии им. Ю.Е. Вельтищева ФГБУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» МЗ РФ, е-mail: [email protected]

Received 01.03.17 Accepted 27.06.17

Introduction

Early epileptic encephalopathy (EEE) is a group of genetically heterogeneous diseases featured by manifestation in infancy, multiform and intractable seizures, and «aggressive» interictal epileptiform activity associated with severe developmental delay. Proportion of EEE among all forms of childhood epilepsy varies between 7% [1] and 15% [2], and approximately 40% of seizures occur during the first 3 years of life due to epileptic encephalopathies [3].

Even though this group of epilepsies is heterogeneous in etiology, genetic factors have a high impact. Thus, Trump et al. having carried out the exome sequencing in the group of patients with early childhood epilepsy, which was characterized by a severe developmental delay, genetic variants of EEE were diagnosed in 18% of cases. The detection frequency of hereditary variants of EEE was increased among patients with seizures onset during the first 2 months of life [4]. In other studies the efficiency of high-throughput sequencing reached 46.2%

[5]. Probably the sensitivity of genetically diagnostic is dependent on strict including criterias.

Recently over 50 early epileptic encephalopathy genes have been already identified. Protein products of responsible for the manifestations of EEE genes have a variety of functions, provide of the action potential and the functioning of the neurons of the cerebral cortex. About 70% of cases of EEE are caused by mutations in eight genes: SCN1A, SCN2A, SCN8A, STXBP1, MECP2, CDKL5, FOXG1, KCNQ2 [4]. One of these genes is STXBP1, which localized on chromosome 9q34.11, is responsible for the manifestations of EEE Type 4. The first description of this type of EEE was made by Saitsu et al. in 2008. They found a mi-crodeletion affecting the locus of the STXBP1 gene in a patient with clinical manifestations of Ohtahara syndrome. The subsequent molecular genetic analysis conducted heterozygous mutations in this gene in 4 more patients with the similar clinical presentation [6]. The gene-encoded syntaxin-binding protein 1 (also known

КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ И НАБЛЮДЕНИЯ

as MUNC18-1) is predominantly expressed in brain and plays an important role in the fusion of presynaptic membrane vesicles [7].

Today more than 100 different mutations have been identified in the STXBP1 gene, leading to the development of the disease: missense, nonsense, splice site, frameshift, whole gene deletions and large microdele-tions affecting the gene locus. Estimated pathogenet-ic mechanism for epilepsies due to mutations of the STXBP1 gene is haploinsufficiency, when one functional gene copy is absence, and, consequently, protein product is decreased. It is expected that STXBP1 protein lack have a greater impact on GABAergic inter-neurons. This lead to result in epileptic network and seizures [8].

Recently number of papers about clinical manifestations in STXBP1 epilepsy has increased. EEE type 4 have been described in the most cases, but few authors described more broad the phenotypic spectrum of STXBP1 mutations to nonsyndromic epilepsy, intellectual disability, and autism, juvenile parkinsonism, focal cortical dysplasia or mitochondrial complex

I deficiency [9, 10, 11, 12, 13]. However, we have not found works dedicated to the EEE type 4 in the Russian literature. The aim of this research is describing the clinical and genetic characteristics of patients from the Russian population with early epileptic en-cephalopathies caused by mutations in the STXBP1 gene.

Material and methods

We screened 196 children of the first years of life, who had at least three of the four criteria for early epileptic encephalopathy: (1) the onset of seizures in the first year of life; (2) the developmental delay; (3) epileptiform activity on the EEG (burst-suppression pattern, classical or modified hypsarrhythmia, background slowing, multiregional abnormalities); (4) therapy-resistant seizures.

All examined children didn't have clear clinical and neuroimaging signs of the newborns hypoxic-ischemic encephalopathy, and we supposed the genetic nature of the disease. The epileptic seizures varied widely: focal seizures, generalized myoclonic and tonic-clonic seizures, epileptic (infantile) spasms.

Mutation analysis was underway exome sequencing on Illumina NextSeq 500 with an average coverage of 70-100x. We used gene panel containing 560 genes, which are responsible for the occurrence of diseases and syndromes with seizures. We validated all detected mutation in the STXBP1 gene by Sanger sequencing in patients and their parents.

We performed Video-EEG monitoring using international «10-20» system with additional ECG and EMG electrodes. International classification were used for classification of EEG patterns, interictal epileptiform activity was divided into regional, multiregional, lateral-ized and generalized.

Brain MRI was performed with magnetic field induction of 1.5 or 3 Tesla, we used by the epileptological protocol in some cases [14].

Results and discussion

eEE variant was established in 92 of the 196 patients (47%) after exome sequencing by gene panel. STXBP1 -epilepsy was diagnosed in 9 patients (5 boys and 4 girls) from unrelated families, aged 6 months to 1.5 years, which was 9.8% of all patients with the specified diagnosis. Prior to the genetic analysis one patient was diagnosed early myoclonic epilepsy, two - epileptic (infantile) spasms, three - cryptogenic epilepsy, and the others were diagnosed with symptomatic focal epilepsy.

We found 9 mutations in the STXBP1 gene, 6 were missense mutations, 3 were nonsense mutations. Analysis of parental DNA showed that all mutations arose de novo. Six identified mutations were previously described in the literature in patients with EEE, and three mutations (two missens and one nonsense) have been described for the first time.

Epilepsy onset varied from 3 days to 10 months of life and was within the first 2.5 months of age for 8 patients. Early onset is typical for hereditary EEE [8]. But recently Stamberger et al. showed a broad spectrum of clinical manifestations onset. However, they described 8 patients with childhood-onset epilepsy with first seizures occurring at up to 12 years of age [11]. The clinical and genetic characteristics of our patients are presented in Table 1.

All patients had some degree of intellectual disability (ID), 5 patients had profound ID, 3 - severe, and only one patient had an insignificant developmental delay. Similar data have been obtained by other authors who found some degree of ID in all patients with type 4 EEE, where almost 88% patients had a profound or severe degree of intellectual disability. Even a rapid control of seizures did not associate to significant ID improvement [11, 15]. It is suggested that protein product of the STXBP1 gene had direct influence on the intellectual development regardless of intensity of epileptiform activity.

Diffuse muscular hypotonia have been reported in all patients, in 8 cases was not focal neurological symptoms, and 1 showed spastic tetraparesis. The most frequent neurologic symptoms have been associated with EEE type 4, including muscle hypotonia, extrapyramidal and cerebellar symptoms (e.g. ataxia and dyskinesia), spasticity [11].

Semiotics of seizures varied widely: epileptic spasms were prevalent in 6 patients, along with focal seizures or asymmetric spasms were in four cases. Seizures were predominantly focal clonic-tonic or versive seizures in other 3 cases. Furthermore, four patients had myoclonus predominantly in the facial musculature. Clinical manifestations in onset started with hypomotor seizures, followed by epileptic spasms, focal tonic, generalized and myoclonic seizures in 2 patients. We did not find a relationship between severity of clinical symptoms and the type of mutations in the gene, this data agrees with other authors [11, 16].

Six patients had a pathological change in the EEG at the time of seizures onset (modified hypsarrhythmia was in 2 patients, slow background without discharg-

RESEARCHES AND CASE REPORTS

Table 1 .

Clinical and genetic characteristics of patients with EEE type 4.

Patient, gender BVV, m BMA, f GDD, m KMK, f KEA, f TDD, m BKK, f BLV, m LAA, f

Not described, Described, Not described, Described, Described, Not described, Described, Described, Described,

Mutation p.Glu530Ter p.Tyr402Ter p.Val144Phe p.Arg406Leu p.Arg406His p.Asp262Tyr p.Arg388Ter P.Arg406Cys p.Pro480Leu

c.1588G>T c.1206T>A c.430G>T At the 1st day -aspiration with c.1217G>T Not aggr., c.1217G>A Not aggr., at 1 c.784G>T c.1162C>T c.1216C>T Pregnancy on the background of fetoplacental insufficiency, chronic hepatitis B. Childbirth c.1439C>T

Perinatal history Not aggr. Not aggr. colostrum. At the 5th day - in the normal condition weight at birth 2,700 g month - muscle hypotension Not aggr. Not aggr. - emergency CS at the 34th week. Body weight - 2,030 g. Ventilator - 1 day, probe nutrition - 3 days Not aggr.

Age of first seizures 2.5 months 1 month after vaccination 4th day of life 3111 day of life 2 months 10 months with subfebrile temperature 3111 day of life 2 months 2 months

Initial epileptic manifestations Flexor tonic spasms with eye deviation left, serial Generalized tonic seizures with eye deviation left Generalized myoclonus Generalized tonic-clonic seizures (GTCS) Focal seizures with right head version followed by GTCS Hypomotor seizures Generalized clonic seizures Generalized my-oclonus of facial musculature Hypomotor seizures, focal seizures with left head version

Evolution of the type of seizures, response to treatment

Reduction by 50% after PB for 2 months.

Reduction by 30% after pyridoxine for 2 weeks

1 month 5 days - asymmetric spasms with variable lateralization, serial.

Short-term seizure-free after LVT for 3 months

2nd week of life - serial asymmetric flexor and extensor spasms

with right-sided 2nd week of life -emphasis. epileptic spasms.

Reduction by 50% after LVT + VGB for 1 month.

sACTH -

1 month - hypomotor seizures.

At 2 months seizure-free after VPA and rare

At 4 months remission after VPA+L-karniten for 1 month.

Reduction by 50% after VGB.

seizure-free for 4 relapses against months. high temperature

Cancelation treatment after 1 year of life

Mental retardation, additional neurological signs

profound; axial hypotonia

profound; axial hypotonia

severe; axial hypotonia

profound; axial hypotonia

severe; axial hypotonia

Seizure-free after VPA for 4 months.

At 1.5 years relapse with focal seizures and left head version followed by GTCS.

Seizure-free after increased doses of VPA for 8 months.

At 2 years 10 months - focal versive seizures

of variable lateralization + serial generalized myoclonus

severe; axial hypotonia

At 2 weeks joined myoclonus of facial musculature.

At 1 month -asymmetric tonic seizures with right-sided emphasis, right head version, right-sided mouth angle deviation, eyelid myoclonus.

At 1.5 months

short-term seizure-free after LVT for 10 days.

At 6 months seizure-free after VGB

mild; axial hypotonia

Reduction by 50% after VPA.

At 4 months -epileptic spasms, up to several episodes a day.

LMT+VPA - decreased seizures by 30% for 2 months.

At 3 months -epileptic spasms (symmetrical and asymmetric), up to 20 episodes a day.

Reduction by 60% after DMS for 1 month.

VGB - reduction Reduction by reduction by 50% after VGB 50%. for 3 months.

Pulse-therapy MPS - reduction by 80%

Reduction by 30% after PMP

profound; axial hypotonia, spastic tetraparesis

profound; axial hypotonia

Abbreviations: PB - phénobarbital, VGB - vigabatrin, LVT - levetiracetam, VPA ACTH, MPS - methylprednisolone, DMS - dexamethasone, CS - cesarean section.

valproic acid, LMT - lamotrigine, sACTH - synthetic

es - in 1 case, irregular multiregional discharges was in 1 patient, burst-suppression pattern - in 1 patient), normal bioelectric activity of the brain was recorded in other cases. But later all patients had epileptiform activity or increasing high voltage slow waves in follow-up EEG. We observed stable regional emphasis for both interictal and ictal epileptiform activity in 4 cases. In fact long-term EEG monitoring (>24 h) showed re-

gional epileptiform activity to both left and right hemispheres in almost all cases. EEG changes in the in patients with EEE type 4 are given in Table 2.

Our results about EEG findings correspond to other published data. In most patients with EEE type 4 multiregional or regional epileptiform activity on EEG was described, hypsarrhythmia and burst-suppression pattern was noted less often. However, in some cases

КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ И НАБЛЮДЕНИЯ

Таблица 1

Клинико-генетические характеристики больных с РЭЭ 4-го типа

БВВ, БМА, ГДД, КМК, КЕА, ТДД, БКК, БЛВ, ЛАА,

мужской мужской мужской женский женский мужской женский мужской женский

Мутация

Дебют

Не описана, p.Glu530Ter c.1588G>T

Перинатальный анамнез

Описана, p.Tyr402Ter c.1206T>A

Не отягощен Не отягощен

2,5 мес

Не описана, p.Val144Phe с.4300>Т

на 1-е сутки - аспирация молозивом, остановка дыхания. Выписан домой на 5-е сутки в удовлетворительном состоянии

В 1 мес на фоне прививки

4-е сутки

Описана, p.Arg406Leu c.1217G>T

Не отягощен, вес при рождении 2700 г

3-е сутки

Описана, p.Arg406His c.1217G>A

Не отягощен, при осмотре в 1 мес отмечалась мышечная гипотония

2 мес

Не описана, p.Asp262Tyr c.784G>T

Описана, p.Arg388Ter c.1162C>T

Не отягощен Не отягощен

В 10 мес на фоне субфебрильной температуры

3-е сутки

Описана, Р.Arg406Cys с.1216С>Т

Беременность на фоне ХФПН, хр. гепатита В. Роды экстренные на 34-й неделе; масса тела - 2030 г. На ИВЛ - 1 сут,

на зондовом питании - 3 сут

2 мес

Описана, p.Pro480Leu c.1439C>T

Не отягощен

2 мес

Флексорные то- Генерализован-

Семиотика нические спаз- ный тонический приступов на мы с девиацией приступ с

момент дебюта глаз влево, девиацией глаз серийные влево

Генерализован-Генерализован- ные тонико-ные миоклонии клонические приступы

Фокальные приступы с версией головы вправо с последующими ГТКС

Гипомоторные приступы

Генерализованные клониче-ские приступы

Генерализованные миоклонии периорбиталь-ной мускулатуры

Гипомоторные

приступы, фокальные приступы с версией головы влево

Эволюция типа приступов,

ответ на лечение

Урежение на 50% на фоне PB 2 мес

Редукция приступов на 30% на фоне пиридоксина -2 нед

1 мес 5 дней асимметричные спазмы переменной латерализации, серийные.

Непродолжительная ремиссия на LVT - 3 мес

С 2 нед серийные асимметричные флексорные и экстензорные спазмы с акцентом справа.

Урежение приступов на 50% на фоне LVT +

VGB -1 мес, sACTH -

ремиссия 4 мес, спонтанная ремиссия в 1 год

С 2 нед -эпилептические спазмы.

С 1 мес -гипомоторные приступы.

С 2 мес - ремиссия на фоне VPA, с редкими рецидивами на фоне высокой температуры

С 4 мес - ремиссия на фоне приёма VPA и левокарнитина, в течение 1 мес.

VGB - редукция на 50%

Ремиссия на фоне приёма VPA - 4 мес.

Рецидив в 1,5 года с присоединением фокальных приступов с версией головы влево и ГТКС.

Ремиссия на фоне увеличения доз - 8 мес.

Рецидив в 2 года 10 мес - фокальные версивные приступы переменной латерализации, каскадные генерализованные миоклонии

На 2-й неделе жизни - присоединились мио-клонии лицевой мускулатуры.

В 1 мес -асимметричные тонические приступы, акцент справа, с версией головы и отклонением угла рта вправо, миоклонус век.

В 1,5 мес кратковременная ремиссия на фоне LVT - 10 дней, в 6 мес ремиссия на фоне VGB - по настоящее время

VPA - урежение на 50%.

В 4 мес -эпилептические спазмы, до нескольких серий

в день. LMT + VPA -урежение на 30% на 2 мес.

VGB - уменьшение тяжести приступов, уре-жение на 50%.

Пульс-терапия MPS - урежение на 80%

С 3 мес -эпилептические спазмы (симметричные и асимметричные), до 20 серий в день. DMS - уреже-ние на 60% в течение 1 мес. VGB - уреже-ние на 50% в течение 3 мес. РМР - уреже-ние на 30%

Степень задержки психомоторного развития, неврологический статус

Выраженная. Диффузная гипотония

Выраженная. Диффузная гипотония

Умеренная. Диффузная гипотония

Выраженная. Диффузная гипотония

Умеренная. Диффузная гипотония

Умеренная. Диффузная гипотония

Лёгкая. Диффузная гипотония

Выраженная. Диффузная гипотония, спастический тетрапарез

Выраженная. Диффузная гипотония

Примечание. PB - фенобарбитал; VGB - вигабатрин; LVT - леветирацетам; VPA - вальпроевая кислота; LMT -синтетический АКТГ; MPS - метилпреднизолон; DMS - дексаметазон.

ламотриджин; sACTH -

RESEARCHES AND CASE REPORTS

EEG features in patients with EEE type 4.

Table 2.

Patient, gender BVV, m BMA, f GDD, m KMK, f KEA, f TDD, m BKK, f BLV, m LAA, f

EEG at onset

Modified Without epilep- Slow back- Without epilep-hypsarrhythmia tiform activity ground tiform activity

Regional epi-

Without epilep- Without epilep- leptic activity in tiform activity tiform activity T4-C4, C3-T3, T3 and 02

Burst - suppression pattern

Regional epileptic activity in C3-F3

Evolution of EEG picture

Unchanged

Diagnosis before genetic diagnosis

Epileptic spasms, West syndrome

Multiregional spike-wave complexes

Cryptogenic epilepsy

At 7 months - continuous delta slow and discharges in T6-P4-O2 (dominance) and in T5-P3-O1

At 6 months -slowing of the background

Early myo-clonic epilepsy

Cryptogenic epilepsy

At 2.5 months - slowing of the background, discharges in C4-P4

Symptomatic focal epilepsy

At 1.5 years -slowing of the background.

At 2.5 years - slow background during wakefulness. Epileptiform activity in T4-F8 during sleep.

Ictal pattern in O1, O2, T4-F8,

generalized discharges (independently).

Symptomatic focal epilepsy

At 2 and 5 months -without the epileptiform activity during wakefulness.

At 1 year - regional epileptiform activity and delta-slow in T6-P4-O2 and in T5-O1 during wakefulness. «FREDs» during a sleep in T6-P4-O2 and T5-O1.

Symptomatic focal epilepsy

At 4 months -burst-suppression pattern.

At 1 year - modified hypsarrhythmia with multiregional activity and episodes

of diffuse electrodecre-ments

Epileptic spasms, West syndrome

At 3 months

- hypsarrhyth-

mia.

At 11 months

- multiregional discharges and high-amplitude

slow waves

Cryptogenic epilepsy

Таблица 2

Характеристика особенностей изменения ЭЭГ у больных с РЭЭ 4-го типа

БВВ, БМА, ГДД, КМК, КЕА, ТДД, БКК, БЛВ, ЛАА,

мужской мужской мужской женский женский мужской женский мужской женский

ЭЭГ на момент дебюта приступов Модифицированная гипсаритмия Без эпилеп-тиформной активности Замедление фоновой ритмики Без эпилеп-тиформной активности Без эпилеп-тиформной активности Без эпилеп-тиформной активности Региональная эпиактивность в Т4-С4, С3-Т3, Т3 и 02 Паттерн «вспышка-подавление» Региональная эпиактивность в C3-F3

В 2 и

Эволюция ЭЭГ-картины

Диагноз до постановки генетического диагноза

Без изменений

Мультирегиональные комплексы спайк-волна

Эпилептические спазмы, синдром Веста

Крипто-генная эпилепсия

В 7 мес -продолженное дельта замедление, спайки,

разряды в Т6-Р4-О2 (доминирует) и в Т5-Р3-О1

Ранняя мио-клоническая эпилепсия

В 6 мес -замедление фоновой ритмики

Криптогенная эпилепсия

В 1,5 года - за- 5 мес - без

медление фоно- эпактивности в

вой ритмики. бодрствовании.

В 2,5 года -

В 2,5 мес замедление В 1 год -

- дельта-за- фоновой рит- региональная

медление и мики бодрство- эпилептиформ-

временами вания. Во сне ная активность

продолженные эпиактивность в в структуре

комплексы Т4^8. Паттерны замедления

ОМВ в С4-Р4 приступов из вТ6-Р4-О2

О1, О2, Т4^8, и в Т5-О1 в

генерализован- бодрствовании.

ные разряды FREDs во сне

(независимо) в Т6-Р4-О2 и

Т5-О1

Симптоматиче- Симптоматиче- Симптоматиче-

ская фокальная ская фокальная ская фокальная

эпилепсия эпилепсия эпилепсия

В 4 мес

- паттерн «вспышка-подавление».

В 1 год

- модифицированная гипсаритмия с мультирегиональной активностью и эпизодами диффузного

электродекремента

Эпилептические спазмы, синдром Веста

В 3 мес -гипсаритмия,

11 мес -мультирегиональные разряды на фоне выраженного замедления фоновой активности

Криптогенная эпилепсия

КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ И НАБЛЮДЕНИЯ

normal background without epileptiform activity or a nonspecific burst of slow waves were able to recorded [11, 16].

Delayed myelination was described on brain MRI in 4 cases (along with thin corpus callosum was described in 2 cases), others didn't have significant changes. Only in one case with using MRI 3 Tesla by epileptological protocol we suggested focal dysgyria in the left parietooccipital region, most likely is the focal cortical dysplasia, which was congruent with regional ictal and interictal activity on the EEG. In recent publications, Barcia et al. described cortical atrophy in all patients with mutations in the STXBP1 gene, including thin corpus callosum and abnormal myelination patterns on the brain MRI [16]. According to Stamberger et al., atro-phic changes were described in about one-third of all cases, and thin corpus callosum or hypomyelination in only 16.5% cases. MRI for almost 47% of patients was reported as normal [11].

All our patients were treated with more than 3 an-tiepileptic drugs (AEDs) (including hormone therapy and polytherapy). Period of seizure freedom with the use of AEDs ranged from 10 days to 1 year. The most effective reported therapy (but with temporary effect) were hormonal therapy, levetiracetam, vigabatrin or valproic acid. In 2 patients we observed spontaneous longer period of seizure freedom, subsequently treatment with AEDs eventually could be discontinued. However, one of these patients had relapsed refractory epilepsy (without any positive effect on variable drug therapy) after 8 months a seizure-free period.

The dramatic response of seizures to some AEDs has been repeatedly reported in the several published data such as levetiracetam [15], vigabatrin [17] or sodium valproate. In principle, seizure freedom was achieved only in 43% of patients aged 1 month to 4 years [11]. In addition to drug therapy, one patient became seizurefree after neurosurgical resection of focal cortical dys-plasia type 1a [13]. A positive effect in some patients is also noted on the ketogenic diet [18].

We show the clinical and genetic features of EEE type 4 from patient BLV, 1.5 year old boy.

The child was born from the 5th pregnancy occurred against the background of chronic hepatitis, at the 34th week by emergency cesarean section. His mother had gestosis and fetoplacental insufficiency. The weight at birth was 2,030 g, length 45 cm. Apgar score was 6/8 points. We observed seizures onset at the age of 2 months from multiple facial myoclonias. Valproic acid I.V. in a dose of 30 mg/kg decreased seizures frequency, but did not completely stop it. At 4 months of age flexor epileptic spasms added. The child was treated with sodium valproate and lamotrigine, which was followed by the seizures reduction, but patient had developmental delay. Consequently, he received vigabatrin and later methylprednisolone pulse therapy followed by a short-term reduction of seizures on 80%.

When the child was examined at the age of 1.5 years, he had body hypotrophy, his weight was 6 kg, height -80 cm and head circumference - 44 cm. His psychomotor development was severely impaired. He didn't have

eye contact, never spoke. He didn't keep head, turn over and play toys. At examination, patient had vertical nystagmus, a converging alternating strabismus, a decrease in pharyngeal and palatal reflexes, spastic tetraparesis, equinovarus deformation. ECG showed a moderate sinus arrhythmia, he had ultrasound signs of moderate hepatosplenomegaly, rotation and increased size of the kidneys. Initial EEG recordings showed no physiologic background activity and burst-suppression pattern. During the follow-up at 1.5 years EEG showed a modified hypsarrhythmia. The brain MRI showed hypoxic lesions in the region of the posterior horns of the 4th ventricle. Next gene sequencing by gene panel revealed missense mutation p.1216C>T (p. Arg406Cys) in the STXBP1 gene, and that was present neither in the parental DNA nor in control subjects.

Thus, mutations in the STXBP1 gene are one of the most common causes of EEE, but can also lead to an isolated delay in mental development. The pronounced genetic heterogeneity of EEE and the similarity of their clinical manifestations and EEG features, varied seizures semiology and the significant size of the genes responsible for early-onset epileptic encephalopathies makes more cost-effective and time-effective targeted gene panels like alternative to Sanger sequencing of individual genes for the epilepsy genetic diagnosis.

We can observe focal seizures and focal EEG findings in the epilepsy determined by genetics. Diagnostic criteria early epileptic encephalopathy without structural brain lesion should start the search of genetic etiology of the epilepsy.

Hereditary variants of EEE has a low efficiency AEDs treatment, however, in some cases of EEE type 4 the most effective drugs may be levetiracetam, vigabatrin and valproic acid.

Financing. Without financial support. Conflict of interest. None of the authors has any conflict of interest to disclose.

Л И Т Е РАТ У РА (пп. 2-18 см. REFERENCES)

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NEVROLOGICHESKIY ZHURNAL, № 4, 2017 DOI: http://dx.doi.org/10.18821/1560-9545-2017-22-4-182-189

RESEARCHES AND CASE REPORTS

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