Razi Journal of Medical Sciences
مجله علوم پزشکی رازی
RJMS
Medical Sciences
http://rjms.iums.ac.ir
39
journal39
2228-7043
2228-7051
en
jalali
1401
12
1
gregorian
2023
3
1
30
1
online
1
fulltext
fa
مروری بر بیماری آمیوتروفیک لاترال سکروزیس (ALS) و وضعیت ژنتیکی آن
An Overview of Amyotrophic Lateral Sclerosis (ALS) and Its Genetic Status
ژنتیک
Genetic
مروري
review article
<div style="text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="direction:rtl"><span style="unicode-bidi:embed"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">بیماری نورودجنراتیو </span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">آمیوتروفیک­لاترال­سکروزیس (</span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Amyotrophic lateral sclerosis</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">-</span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">) شایعترین بیماری کشنده نورون­های حرکتی است. سن شروع بیماری معمولاً 60-50 سال و متوسط سن زنده ماندن بعد از شروع علائم، سه تا پنج سال است. وقوع و شیوع آن به ترتیب 2-1 و 7-2 در 100000 میباشد. بیماری </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> معمولاً اسپورادیک (</span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">SALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">) است اما </span></span></span></span><span lang="AR-SA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">حدود 13-1% موارد خانوادگی </span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">(</span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">FALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">)</span></span></span></span><span lang="AR-SA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> می­باشند.</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> تابه حال بیش از 40 ژن عامل بیماری شناخته شدهاست. جهش در اغلب این ژنها نادر است، با این وجود دو ژن </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">C9orf72</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> و </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">SOD1</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> به ترتیب بیشترین میزان جهش را در بیماران نشان داده­اند. </span></span></span></span></span></span></span></span></span></span></span></span></div>
<div style="text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="direction:rtl"><span style="unicode-bidi:embed"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">با توجه به عملکرد ژنهای شناخته شده، به نظر میرسد فرایندهایی مانند استرس اکسیداتیو، اختلال در انتقال آکسونی و اتوفاژی، تجمع پروتئینها، سمیت ناشی از گلوتامات و اختلال در متابولیسم </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">RNA</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">، در پاتولوژی بیماری نقش دارند. بررسیهای اپیدمیولوژیکی و ژنتیکی در ایران نشان میدهد که (الف) وقوع بیماری در سال برابر 42/0 به ازاء 100000 نفر و شیوع آن برابر 57/1 در هر 100000 می­باشد. (ب) برخلاف جوامع اروپایی، که بیشتر بیماران </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">FALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">، جهش در </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">C9orf72</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> دارند، در بیماران </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">FALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> ایرانی، درصد قابل توجهی از این بیماران (حدود 30%) جهش در ژن </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">SOD1</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> دارند و جهش در </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">C9orf72</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> تنها در موارد معدود از بیماران مشاهده شده است. این وضعیت در کشورهای آسیای شرق مانند ژاپن، چین و تایلند گزارش شدهاست. (ج) سرعت پیشرفت بیماری در بیمارانی که داروی ریلوزول مصرف میکنند در مقایسه با گروهی که دارو نمیگیرند، اختلاف معنی­داری نشان میدهد. </span></span></span></span></span></span></span></span></span></span></span></span></div>
<div style="text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="direction:rtl"><span style="unicode-bidi:embed"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">درک پاتوژنز </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS</span></span></span></span><span style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black"> در توسعهی روشهای تشخیصی و ارائه درمانهای موثر جدید، بسیار ضروری است. بنابراین این مقاله نکاتی را پیرامون علائم </span></span></span></span><span dir="LTR" style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS</span></span></span></span><span lang="FA" style="font-size:10.0pt"><span style="line-height:115%"><span b="" mitra="" style="font-family:"><span style="color:black">، ژنتیک بیماری و وضعیت آن در ایران ارائه خواهد کرد.</span></span></span></span></span></span></span></span></span></span></span></span></div>
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<div style="text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Amyotrophic Lateral Sclerosis (ALS) is the most common fatal motor neuron disease characterized by involvement of the combination of upper (UMNs) and lower (LMNs) motor neurons. The degeneration of LMNs and UMNs leads rapidly to progressive muscle atrophy and paralysis, dysphagia, dysarthria, fasciculations, muscle cramps, and finally death due to respiratory failure. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS is an adult-onset neurodegenerative disease; its age at onset (AAO) is usually 50-60 years. However, AAO of the disease is variable (1 - 94 years old). Mean survival of patients with ALS has been reported as 3-5 years from the disease onset. However, 10-20% of patients survive more than 10 years. The incidence and prevalence of ALS in the European population is 1–2 and 2-7 people per 100,000, respectively. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Due to the great clinical variability in ALS manifestations, the diagnosis of ALS can be challenging. Thus, the El Escorial criteria were developed based on clinical data to ALS diagnosis.</span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS can be categorized into different forms:</span></span></span></span></span></span></span></span></span></span></div>
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<li style="margin-left: 8px; margin-bottom: 13px; text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"></span></span><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">It can be classified into familial and sporadic based on the presence and absence of other patients in the family. Most ALS cases are sporadic (SALS) and only about 1-13% of ALS cases are familial (FALS). </span></span></span></span></span></span></span></span></span></span></li>
<li style="margin-left: 8px; margin-bottom: 13px; text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"></span></span><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">It can be sub-grouped based on the mode of inheritance of the disease; autosomal dominant, autosomal recessive, X-linked, mitochondrial or <i>de novo</i>.</span></span></span></span></span></span></span></span></span></span></li>
<li style="margin-left: 8px; margin-bottom: 13px; text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"></span></span><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS can be categorized based on the age at onset of the disease: juvenile ALS; age at onset below 25 years, and adult ALS; the onset age is over 25 years old - usually the onset age of the disease is over 45 years old.</span></span></span></span></span></span></span></span></span></span></li>
<li style="margin-left: 8px; margin-bottom: 13px; text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"></span></span><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">ALS can be classified based on the locus and gene involved in the development of the disease. To date, more than 40 ALS-causative genes have been identified. These loci are only responsible for about two-thirds of FALS and about 10% of SALS. </span></span></span></span></span></span></span></span></span></span></li>
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<div style="text-align: justify;"><span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Molecular analyses of the known ALS genes have demonstrated that their encoded proteins are involved in several physiological pathways, including, oxidative stress, axonal transport, autophagy, proteins folding, glutamate excitotoxicity, RNA metabolism and involvement of non-neuronal cells (microglia, astrocytes and oligodendrocytes).</span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Among the ALS-causative known genes, five genes including <i>SOD1</i>, <i>C9orf72</i>, <i>TARDBP</i>, <i>FUS</i>/<i>TLS</i> and <i>TBK1</i> seem to more important and account for about 15% of all ALS patients. Meanwhile, mutations of <i>SOD1</i> and <i>C9orf72</i> genes are detected in a significant percent of patients. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Superoxide dismutase 1 gene - <i>SOD1</i> - is the first gene identified for ALS disease. Mutations of this gene have been observed in 20% (12-23%) of FALS cases and about 3% (1-7%) of SALS patients. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">The repetitive sequence of six nucleotides (GGGGCC; G4C2)<sub>n</sub> in intron 1 of the <i>C9orf72</i> gene was also associated with ALS. The number of G4C2 repeats in healthy people is less than 23, while in affected individuals, the number of these repetitions was more than 23 and up to 1500 and even more. The dynamics of such repetitions in this gene may be an explanation for the phenotypic variability and different penetrance of the disease in these families. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">The cause of most ALS cases is not yet known, but it is certain that several cellular functions are disturbed in the motor neurons of these patients, which can probably lead to the degeneration of these neurons. It is clear that most of the genes responsible for ALS do not exclusively play a role in the development of this disease, and mutations in these genes are not only involved in the development of ALS, but also can result in the occurrence of other neurodegenerative disorders like frontotemporal dementia (FTD), hereditary spastic paraplegia (HSP), Parkinson disease, progressive supranuclear palsy, ataxia, corticobasal syndrome, and Huntington disease-like syndrome. So, understanding the pathogenesis of ALS is essential in developing diagnostic methods and providing new effective treatments in the clinical trials. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black">Here, we reviewed the clinical, epidemiologic and genetic of ALS and briefly explained those in Iran. Our results showed (a) the average incidence and prevalence of ALS were 0.42/100 000, and 1.57/100 000, respectively. (b) In contrast to European countries, mutations of <i>SOD1</i> are the common cause of ALS in Iranian FALS patients; they are causative in approximately 30% of the FALS cases but mutations of <i>C9orf72</i> are rare. (c) A significant difference in disease progression rate is observed between patients who used riluzole and those who did not. </span></span></span></span></span></span></span></span></span></span><br>
<span style="font-size:11pt"><span style="text-justify:kashida"><span style="text-kashida:0%"><span style="tab-stops:10.5pt"><span style="line-height:115%"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="line-height:115%"><span new="" roman="" style="font-family:" times=""><span style="color:black"></span></span></span></span></span></span></span></span></span></span></div>
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آمیوتروفیکلاترالسکروزیس, SOD1, C9orf72, ایران
Amyotrophic lateral sclerosis, ALS, SOD1, C9orf72, Iran
244
263
http://rjms.iums.ac.ir/browse.php?a_code=A-10-6882-1&slc_lang=fa&sid=1
Aida
Ghasemi
آیدا
قاسمی
3900319475328460074917
0000000163867961
No
MA, Genetics Research Center, University of Social Welfare & Rehabilitation Sciences, Tehran, Iran
کارشناسی ارشد، مرکز تحقیقات ژنتیک، دانشگاه علوم توانبخشی و سلامت اجتماعی، تهران، ایران
Elahe
Elahi
الهه
الهی
3900319475328460074918
0000000268972223
No
Professor, Faculty of Science, Tehran University, Tehran, Iran
استاد، پردیس علوم، دانشکده زیست شناسی، دانشگاه تهران، تهران، ایران
Mohamad
Rohani
محمد
روحانی
3900319475328460074919
0000000254091804
No
Associate Professor, Rasool- Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
دانشیار، بیمارستان حضرت رسول اکرم، دانشگاه علوم پزشکی ایران، تهران، ایران
Bahram
Haghi Ashtiani
بهرام
حقی آشتیانی
3900319475328460074920
000000023373740X
No
Assistant Professor, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
استادیار، بیمارستان فیروزگر، دانشگاه علوم پزشکی ایران، تهران، ایران
Afagh
Alavi
آفاق
علوی
afaghalavi@gmail.com
3900319475328460074921
0000000303902475
Yes
Associate Professor, Genetics Research Center, University of Social Welfare & Rehabilitation Sciences, Tehran, Iran
دانشیار، مرکز تحقیقات ژنتیک، دانشگاه علوم توانبخشی و سلامت اجتماعی، تهران، ایران