The Role of Environmental and Genetical Factors

in both Migraine Headaches and Multiple

Sclerosis

Haniyeh Rahbar Kafshboran Young Researchers and Elite Club/Tabriz Branch/Islamic Azad University, Tabriz, Iran

Email: h_rahbar_67@yahoo.com

Abbas Nikravesh Department of Molecular Sciences/Faculty of Medicine/North Khorasan University of Medical Sciences, Bojnurd, Iran

Email: nikraveshabbas2@gmail.com

Abstract—Multiple sclerosis (MS) is a chronic inflammatory

process, which aetiology is not yet completely understood.

Studies investigating a proposed association between

multiple sclerosis (MS) and migraine have produced

conflicting results especially in young female and a great

range in the prevalence rate of migraine in MS patients.

Also, studies suggest migraine as a risk factor for

appearance and developing the MS and the severity of

disease. Since the fact that the environmental and genetic

factors play role in the pathology of both mentioned illnesses,

in this study we compared the role of some these factors in

both migraine and MS.

Index Terms—migraine, multiple sclerosis, genetics,

environment

I. INTRODUCTION

The first report of severe headaches in MS referred to

1993 and a patient with a single lesion in PAG

(Periaqueductal gray). Since then, scientists had been

published numerous papers about the relation of migraine

and MS [1]. The exact etiology and pathogenesis of

migraine headaches are not entirely understood yet, but it

also can be comorbid in other neurological diseases like

multiple sclerosis, and can affect the diagnosis,

radiological evaluation, treatment, and quality of life of

these patients [1]. The relation of migraine headaches and

multiple sclerosis are not clearly recognized, but the most

satisfying assumption is the link of these disorders in the

brain stem lesions and inflammatory processes [1]. Paola

Tortorella et al. (2006) reported that MS patients with

migraine showed an increased number of lesions in the

red nucleus (RN) and substantianigra (SN). In that study

MRI-based techniques were used and suggest that

demyelinating lesions in the brain stem might be among

the factors responsible for the presence of migraine in

patients with MS [2]. In 2005, Gee JR et al. showed a

linear correlation between the presence of migraine-like

headaches and numbers of lesion locations. Also, they

Manuscript received July 25, 2014; revised December 1, 2014.

determined the prevalence of migraine-like headaches in

patients with MS and note that 55.6% of patients suffer

from headache, of which 61.7% had migraine, 25.3%

had tension-type headaches and 13% had the features of

both migraine and tension type headaches [3]. Despite the

fact that patients with MS have shown migraine

headaches as a symptom of illness, Martínez Sobrepera et

al. present the history of migraine as a risk factor for MS

[4]. In addition, other studies confirm this finding and

recognize migraine as a risk factor for developing the MS

[5].

II. MIGRAINE

Migraine defines as a neurovascular disorder that can

seriously influence the quality of life. Also, it was

positioned among the world's most disabling illnesses by

the world health organization [6]. Patients with migraine

experience recurrent attacks of severe headache

associated with neurological and autonomic symptoms [7]

that usually last about 4-72 hours. Also, they suffering of

other clinical characteristics of migraine like the presence

of nausea, emesis, phonophobia and photophobia [8].

Clinically, migraine was classified as two main types:

migraine with aura (MA) and migraine without aura (MO)

[6]. In migraine with aura there are transient neurologic

symptoms like scotomas, scintillations, fortification

spectra, etc, which initiates or accompanies pain attacks

[8]. MO is three times more common than MA [7].

Migraine has different prevalence in various populations

because it can be affected by age, sex, ethnic origin, and

income [6]. Generally, the prevalence of migraine

increases until almost 35 - 40 years of age; afterwards

starts to decrease to a lower level [9]. After puberty and

because of the sexual hormones, prevalence increases

more in girls than in boys [10]. The prevalence of

migraine in developed countries populations is lower than

the others for examples in Europeans and Americans 6-

8% of men and 15-18% of women experience migraine

each year, but in Turkey, these percentages are extension

to 10% in men and 22% in women [11].

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doi: 10.12720/jolst.2.2.82-85

III. CAUSES OF MIGRAINE AND MS

There are some problems in diagnosing of both MS

and migraine, like case reports (it means that not all of

patients with these illnesses have a positive family

history), misdiagnosing or delayed diagnosing especially

in MS, and transient symptoms especially in migraine [1].

Despite these problems various studies were done and

they were indicated that both MS and migraine disorders

are multi factorial and heterogeneous, it means that

several genetic and environmental factors play a role in

the pathogenesis of them [12], [13], [8], [14]. There are

some genetic compounds that can active the underlying

mechanism causing the symptoms of MS like migraine

[9]. According to family and twin studies, a significant

role suggested for genetic factors in migraine and MA

introduces as the most heritable subtype of migraine that

there is 40- 65% heredity between these patients [6]. Also,

linkage analysis and association studies suggest several

chromosomal loci and candidate genes that are implicated

in migraine [13].

A. Enviromental Factors in Migraine and MS

MS and its symptoms are the result of interactions

between genes and environment; it is necessary to

understand the environmental factors which can be

effective in the foundation and development of both MS

and migraine headaches [15]. Numerous environmental

factors were introduced to be effective in MS; among

them some also have been proposed to increase the risk

of migraine wholly or somewhat. Effective environmental

risk factors include:

Sunlight and ultraviolet radiation: it was shown that

greater exposure to them has protective effects against

MS [16], but it is suggested that light interference might

improve the phenotypes of migraine [17].

Vitamin D: it is proven that vitamin D deficiency is a

crucial factor to develop MS in patients, but it does not

known as an effective agent for migraine and there are

only a few reports that declare vitamin D therapy can

cause an improvement in migraine frequency and

duration [1].

Infective agents like Epstein–Barr and other viruses:

Epstein–Barr virus/mononucleosis, human herpes virus 6

and varicella zoster are examples for effective viral

infections in MS, but among them just the Epstein–Barr

virus has reported as a possible risk factor for migraine

[1].

Organic solvents: Chronic exposure to the solvents

can effect on central nervous system and demonstrate

degenerative changes. Due to this fact, it is suspected to

have relation with MS [18] and migraine [19].

Psychological stress: There is too many papers which

were reports an association between stressful lives and

the frequencies of neurologic diseases like migraine [20]

and MS [21].

Dietary fat: A trial by Paul Crawford et al. in 2006

showed that dietary habits with low fat intake help to

decreasing the frequencies of migraine headaches [22],

but another study on women showed that there is a null

association between the amount or types of dietary fat

intake and increasing the risk of MS [23]. Until now,

various papers investigate the dietary fat especially

saturated fats as an eventual risk factor for MS, but they

achieved inconsistent results [24].

Dietary antioxidants: Vegetables, fruits, and other

foods which are rich in vitamin C, vitamin E, carotenoids,

thiamine, riboflavin, and other antioxidant compounds

can reduce the risk of MS by neutralizing the reactive

oxygen species and other free radicals that can damage

the nervous system [24]. In 2011, Ülkü Özbey et al.

illuminated the pivotal role of oxidative stress in migraine

pathogenesis, according to this study a diet rich in

antioxidants were suggested to help the patients which is

suffering from migraine headaches [25].

Smoking: smoking may increase the risk of MS and

other autoimmune disease [16], but it does not have any

association with migraine headaches [1].

B. Genetic Factors in Migraine and MS

Like most neurodegenerative diseases, MS has a

complex etiology [26] including heterogeneity,

incomplete penetrance, polygenic inheritance,

environmental risk factors, and genetic predisposition that

the complexity of this disease determines the location and

size of the lesions [27] which can influence the

occurrence of migraine headaches in patients [2].

Similarly, migraine shows heterogeneity and

multifactorial mode of inheritance in which there are

gene×gene or gene×environment interactions [27].

Previous studies demonstrate familial aggregation of MS

which is related to genetic sharing rather than familial

identical environment [15]. Nevertheless, migraine has

more genetic capacity than MS. Migraine is assumed as

an autosomal dominant disease with variable penetration

[1]. Here, there are some genes which are found to be

associated with migraine/ MS or both of them:

(Tumor Necrosis F actor gene): TNF gene which

also called as TNF-α, was mapped on human

chromosome 6p21.3, and located between HLA classes I

and II genes, encodes a multifunctional pro-inflammatory

cytokine that belongs to the tumor necrosis factor (TNF)

superfamily [28]. This cytokine is involved in the

regulation of a wide spectrum of biological processes

including cell proliferation, differentiation, apoptosis,

lipid metabolism, and coagulation. Due to these

proficiencies, TNF has been implicated in the

pathogenesis of infectious and autoimmune disorders,

including MS [29]. Also, TNF is mediated inflammatory

responses in the brain as a pro-inflammatory cytokine [28]

and increased levels of TNF were considered in plasma

during migraine attacks which plays a role in promoting

the headaches [30].

MTHFR (Methylene Tetra Hydro F olate Reductase

(NAD(P)H) gene): MTHFR is a coding gene on human

chromosome 1p36.3 that the expression of it produces

methylene tetra hydro folate reductase enzyme. The

enzyme MTHFR catalyzes a reduction reaction in which

5,10-methylenetetrahydrofolate converted to 5-

methylenetetrahydrofolate, a co-substrate for

homocysteine remethylation to methionine [31], which is

the precursor of S-adenosyl methionine (SAM) essential

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Journal of Life Sciences and Technologies Vol. 2, No. 2, December 2014

TNF

for CNS myelination [32]. Genetic variation in this gene

influences susceptibility to occlusive vascular disease,

neural tube defects, colon cancer and acute leukemia.

Transition of C to T at nucleotide 677 is one of the

common mutations of MTHFR gene. By this mutation,

alanine amino acid changes to valine which causes a

reduction in enzyme activity. This reduction will be more

sensible if both alanine change; it means that the activity

of Val/Val homozygote enzyme is less than the Ala/Val

heterozygote state [33]. Hence, functional genetic

variants which influence MTHFR activity like MTHFR

C677T can enhance the risk of migraine [34]; also, it

could be considered an attractive candidate for disease

which involves myelin like MS [24].

However, it should be added that both migraine and

MS are complex multifactorial disorders that many other

genetic factors have been shown to play significant or

partial role in their pathogenesis.

IV. CONCLUSION

According to the data obtained from previous

statistical studies, it is proven that frequency of migraine

headaches is three times higher in MS patients than the

normal people of the populations [35]. A study on

Japanese MS patients confirms the increased likelihood

of migraine headaches specially migraine without aura

[34]. Therefore, reasons of the presence of migraine

headaches in MS patients should be taken into

consideration. Previous studies revealed that the presence

of CN lesions and midline plaques in MS patients is

related to the outbreak of migraine headaches [3]. Also,

some studies indicated that migraine like headaches can

increase the risk of MS [5].

As the respect to the fact, that the exact etiology and

pathogenesis of both migraine and MS has not been fully

understood. Further studies should be focused on the co-

occurrence of them for better recognition of the involved

gene variants, the role of environmental factors and the

interaction mechanism of them. Perception of migraine

headaches in MS patients can help us to improving our

diagnostic skills and care of these patients. In addition,

such studies can create new ways to prevent and cure

these two debilitating diseases.

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Haniyeh Rahbar Kafshboran is from Tabriz,

Iran. I graduated MSc of Genetics from Zabol University in 2013 and BSc of plant biology

from Tabriz University in 2010. My thesis title in MSc was “Association study of TNF-α

polymorphism in patients with inflammatory

bowel disease in north-west of Iran”, and in BSc was “Comparison of free radical

scavenging activity of phenolic extracts of various population of Artemisia spicigera”.

My research field and interest is molecular medical genetics.

Abbas Nikravesh, Assistant professor in

Molecular Genetics in North Khorasan University of Medical Sciences, Bojnurd, Iran.

I am interested in the teaching of some Genetic

courses such an Medical genetics which I currently more focus on it with moved to

Medical Faculty and established a Genetic Counseling Center to more involved with

Genetics diseases. My favorite research area is

Genetics of Multiple sclerosis; so far, I supervised more than ten theses of Master students of Genetics major in

this subject ended to promising results and interesting publications.

852014 Engineering and Technology Publishing

Journal of Life Sciences and Technologies Vol. 2, No. 2, December 2014