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CLINICAL AND BIOCHEMICAL TRACES OF HEREDITARY METABOLIC
DISEASES. ON THE EXAMPLE OF DRUG-RESISTANT EPILEPSY
Yodgorov Jasurbek Jo’rayevich
Bukhara State Medical Institute named after Abu Ali ibn Sino. Bukhara, Uzbekistan.
e-mail:
Annotation:
In this article, we will provide information after studying hereditary metabolic
diseases (HMD) where epilepsy manifests prominently. In the process of analyzing the
database, we identified IMD associated with various types of epilepsy, which we classified
according to the IMD classification based on classical pathophysiology and classified
according to the factors associated with the selected seizure (neonatal seizures, infantile
spasms, myoclonic seizures, and characteristic EEG patterns) and the possibility of treating
the underlying metabolic defect. In addition, we analyzed the clinical severity level to
compare the phenotype with biochemical characteristics, genotype, and delayed initiation of
pyridoxine. As a result, we classified according to the clinical severity scale as follows: 1)
global developmental delay/intellectual disability; 2) age of seizure onset before pyridoxine
treatment; 3) current seizures during treatment. An expanded list of IMD, an overview of the
main clinical signs, and the recommended diagnostic and therapeutic approaches may be
useful for epileptologists and healthcare professionals assisting patients with metabolic
disorders.
Keywords:
Seizures, Epilepsy, Metabolic, Drug-resistant epilepsy, Neurometabolic,
Diagnosis, Treatment.
Аннотация:
В этой статье мы изучим и предоставим информацию о наследственных
метаболических заболеваниях (НМЗ), где эпилепсия проявляется наиболее ярко. В
процессе анализа базы данных были выявлены ИМД, ассоциированные с различными
вариантами эпилепсии, которые мы классифицировали по классификации ИМД,
основанной на классической патофизиологии, и классифицировали по факторам,
связанным с выбранными судорогами (неонатальные судороги, инфантильные спазмы,
миоклонические судороги и характерные ЭЭГ-образцы) и возможности лечения
основного метаболического дефекта. Для сравнения фенотипа с биохимическими
особенностями, генотипом и задержкой инициации пиридоксина мы изучили и
проанализировали степень клинической тяжести. В результате мы классифицировали
по шкале клинической тяжести следующим образом: 1) глобальная задержка
развития/ умственная отсталость; 2) возраст начала судорог до пиридоксина; 3)
текущие приступы при лечении. Расширенный список ИМД, обзор основных
клинических симптомов и рекомендуемые диагностические и терапевтические
подходы могут быть полезны для эпилептологов и медицинских работников,
оказывающих помощь пациентам с метаболическими нарушениями.
Ключевые слова:
Приступы, Эпилепсия, Метаболическая, Лекарственная эпилепсия,
Нейрометаболическая, Диагностика, Лечение.
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Аннотация:
Мақоламида эпилепсия яққол намоён бўладиган ирсий метаболик
касалликлар (ИМК) ҳақида маълумот ўрганиб чиқиб маълумотлар берамиз.
Маълумотлар базасини таҳлил қилиш жараёнида эпилепсиянинг турли хиллари билан
боғлиқ ИМДни аниқлади, уларни классик патофизиологияга асосланган ИМД
таснифига кўра таснифладик ва танланган тутқаноқ билан боғлиқ омиллар (неонатал
тутқаноқлар, инфантил спазмлар, миоклоник тутқаноқлар ва характерли ЭЭГ
намуналари) ва асосий метаболик нуқсонни даволаш имкониятига кўра таснифладик.
Шу қаторда фенотипни биокимёвий хусусиятлар, генотип ва пиридоксин
инициациясининг кечикиши билан таққослаш учун клиник оғирлик даражасини
ўргиним чиқиб таҳлил қилдик. Нитижада клиник оғирлик шкаласи бўйича қуйидагича
классификацияладик: 1) глобал ривожланиш кечикиши/ ақлий заифлик; 2)
пиридоксингача бўлган тутқаноқ бошланиш ёши; 3) даволанишдаги жорий
тутқаноқлар. ИМДнинг кенгайтирилган рўйхати, асосий клиник белгилар шарҳи
ҳамда тавсия этилган диагностик ва терапевтик ёндашувлар метаболик бузилишлари
бўлган беморларга ёрдам кўрсатувчи эпилептологлар ва тиббиёт ходимлари учун
фойдали бўлиши мумкин.
Калит сўзлар:
Хуружлар, Эпилепсия, Метаболик, Дориларга чидамли эпилепси,
Нейрометаболик, Диагностикаси, Даволаш.
Epilepsy is a widespread serious neurological disorder that currently affects more than 70
million people worldwide. People with epilepsy have recurrent causeless seizures, which can
be focal or generalized. To control seizures, several anticonvulsant drugs with different
mechanisms of action and targets can be used, which are beneficial for most patients.
However, it does not significantly change the overall seizure-free outcome of some patients.
Due to drug resistance, some patients still experience uncontrolled seizures. In 2010, the
International League Against Epilepsy defined drug-resistant epilepsy (DCHE) as the failure
of sufficient trials of two resistant, appropriately selected and applied drug schedules with
high resistance (as monotherapy or in combination) to achieve sustained seizure freedom.
The "Categories of Metabolic Traces" aims to provide a complete list of hereditary
metabolic diseases (HIMD) associated with specific medical conditions. The articles
published so far in this series cover the relationship of IMACs with motor disorders, liver
diseases, cardiovascular diseases, changes in mental state, phenotypes of cerebral palsy, skin
diseases, gastrointestinal symptoms, myopathies, tumors, eye phenotypes, kidney and ear
diseases. The 15th review of the series is devoted to hereditary metabolic epilepsy (HME),
in which metabolic disorders become one of the main symptoms of epilepsy. First of all, we
will dwell on the classification of metabolic pathological mechanisms leading to epilepsy
and epileptogenesis. The clinical presentation, methods of diagnosis, and treatment of IME
are described. Our results show that hereditary metabolic epilepsy is more common in the
neonatal period, with infantile spasms or myoclonic seizures. In addition, ~20% of
hereditary metabolic epilepsy that were found to be treated as a result of our search were
mainly associated with the IMD groups "cofactor and mineral metabolism" and
"intermediate metabolism of nutrients." The data provided by this study were differentiated,
including by age, type of seizure, and characteristics of epilepsy patients.
The prognostic effect of the initial age for DRE persisted throughout the entire age range
and was positively correlated with its prognosis; at the onset, older age led to a better
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prognosis. Based on the analyzed data, we witnessed that many studies were focused on
pediatric patients aged 0-18. Among the studies included in this article, most subgroup
analyses were conducted in children with DRE up to 1 year of age. According to the study,
the prognosis of DRE occurrence is presented in newborns and young children aged 0-24
months and 0-30 months, respectively, and in the subsequent study - in both children and
adults. Several studies have shown that the age of onset of the disease is especially common
in children under 1 year of age.
Drug resistance is a major problem in the treatment of epilepsy. Drug-resistant epilepsy
(DRSE) accounts for 30% of all epileptic cases and is a major concern due to
uncontrollability and high workload, mortality rate, and level of involvement. Currently,
numerous studies are being conducted aimed at developing predictors that contribute to the
early detection of DRE in order to facilitate the early initiation of individual treatment.
Although many predictors and risk factors have been identified, currently there are no
standard predictors that can be used to manage the clinical management of DRE. In this
review, we will discuss several potential DRE predictors and related factors that may
become predictors in the future, and analyze the evidence ranking to identify reliable
potential predictors. We report on the treatment outcomes of eleven patients with
pyridoxine-induced epilepsy due to pathogenic variants of ALDH7A1 (PDE-ALDH7A1). In
eight patients with a phenotype from mild to severe (there is no lysine-restricted diet in the
infantile period), the level of α-AASA in urine or plasma increased more than 10 times. The
phenotype ranged from mild to moderate in patients with homozygous cutting variants, and
from moderate to severe in patients with homozygous messenger variants. There was no
correlation between the severity of the phenotype and the degree of proliferation of α-AASA
in urine or genotype. All patients were on a restricted diet with pyridoxine, nine patients
with arginine, and five patients with lysine. Free seizures with pyridoxine occurred in 73%
of patients. In 25% of patients, a mild phenotype was observed during monotherapy with
pyridoxine. 100% of patients on a lysine-restricted diet, which began in the first 7 months of
life, had a mild phenotype. Early onset of a lysine-restricted diet and/or arginine therapy
may have improved neurodevelopmental outcomes in young patients with PDE-ALDH7A1.
RESULT
In this study, we provide comprehensive information about hereditary metabolic disorders,
which are one of the main manifestations of epilepsy. Although the frequency of each of the
individual cases identified in this study is rare, their overall prevalence is significant. In
addition, our results showed that the high probability of IMS in infancy, manifested by
infantile spasms or myoclonic seizures, encourages the study of metabolic etiology in the
applied clinical scenarios. Along with this, we focused on the clinical features and
biochemical signs that can predict DRE. Our analysis of the evidence rating showed that the
mixed type of seizure, SE, absence or poor response to the first ASM, neonatal seizure,
abnormal neuroimaging results, and abnormal neurological examination results, along with
HMGB1 and SCN1A, are reliable predictors of DRE.
With the appearance of these prognoses, drug resistance can be detected early during
treatment, and the diagnosis of DRE may not depend only on the response to drug therapy,
which can allow patients with drug-resistant epilepsy to receive early individualized and
optimized treatment to improve clinical outcomes. However, the use of these predictors in
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clinical practice is hindered by various problems, such as inaccurate reports on the predictive
abilities of some factors. In addition, recent studies of drug-resistant epilepsy included
patients with various confusing factors such as age, sex, and race differences, which led to a
limited generalization of the results for most patients.
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