C677T and A1298C gene polymorphisms and sporadic early-onset Alzheimer’s disease

doi:10.4236/aad.2013.24018

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Vol.2, No.4, 132-134 (2013) Advances in Alzheimer’s Disease

http://dx.doi.org/10.4236/aad.2013.24018

C677T and A1298C gene polymorphisms and

sporadic early-onset Alzheimer’s disease

Leila Mansouri1, Sarra Klai1*, Najiba Fekih-Mrissa1, Nasreddine Gritli1, Ridha Mrissa2

1Laboratory of Molecular Biology, Department of Hematology, Military Hospital, Tunis, Tunisia;

*Corresponding Author: gksarrah@yahoo.fr

2Department of Neurology, Military Hospital, Tunis, Tunisia

Received 18 August 2013; revised 27 September 2013; accepted 9 October 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Alzheimer’s disease (AD) is a genetically com-

plex and heterogeneous disorder. Although the

clinical manifestations and the pathological fea-

tures have been well elucidated, a clear etiology

of AD is still unknown to this day. In the past few

decades, investigations have elucidated that both

the genetic and the environmental factors are

capable of causing the development of AD. We

report a patient with clinically diagnosed early-

onset Alz heimer's dise ase, age of ons et 45 years.

Genetic analysis revealed two MTHFR hetero-

zygous polymorphisms C677T and A1298C.

Keywords: A1298C MTHF R Mu tat ion ; C 677T

MTHFR Mutation; Early-Onset Alzheimer

1. INTRODUCTION

Alzheimer is the first common cause of dementia [1].

Classification of Alzheimer’s disease (AD) into subtypes

based on the time of onset of the symptoms is still con-

troversial. Clinically, late-onset patients with AD have a

greater degree of memory disturbance, while early-onset

patients have greater degrees of other cognitive dysfunc-

tions and a rapid progression of cognitive deficits rather

than memory disturbance in the early stage of the disease

[2].

The genetic determinants of early-onset (<65 years of

age) Alzheimer’s disease (EOAD) are heterogeneous. [3]

The term early onset (EO) Alzheimer’s disease (AD)

refers to patients who meet the criteria for AD [4] and

show onset of symptoms before the age of 65 years. Com-

pared with the more frequent late onset (LO) AD, EOAD

patients present with a more rapid clinical and cognitive

decline and an earlier multidomain cognitive impairment,

including language, visuospatial, and executive function

deficits .[5]

The role of methylenetetrahydrofolate reductase (MTHFR)

gene polymorphisms as risk factors for the occurrence of

Alzheimer’s disease (AD) is still controversial. A com-

mon C → T polymorphism at position 677 in the me-

thylenetetrahydrofolate reductase gene (MTHFR) has been

recently studied and proposed as AD/dementia risk factor

[6].

2. CASE REPORT

We describe a 53-year-old man diagnosed with very

rapidly progressing early-onset Alzheimer’s disease (EOAD),

age of onset 45 years, and two MTHFR polymorphism

C677T and A1298C were detected. A rapidly progres-

sive neuropsychological deterioration associated with

motor deficits and cerebellar signs dominated the clinical

picture. There’s no family history of AD disease.

The patient presented a progressive alteration of epi-

sodic memory, spatial disorientation, apathy, language

disturbances and neglect of personal care. At 45 years, he

had begun to have episodic memory problems. His wife

reported forgetfulness (losing objects and forgetting meet-

ings, conversations, and receipts), diminished language

fluency and word-finding difficulties.

2.1. Neuropsychological Assessment

Neuropsychological investigation assessed: global cog-

nitive functioning, visuospatial functions, frontal-exe-

cutive functions, and learning with Rey’s word list im-

mediate and delayed recall [4].

2.2. Genetic Analysis

Blood (6 mL) was collected in ethylenediaminetetra-

acetic acid (EDTA) vial. Genomic DNA was extracted

from the leukocytes in the cell pellet by salting out me-

thod [7]. The polymerase chain reaction (PCR) was used

L. Mansouri et al. / Advances in Alzheimer’s Disease 2 (2013) 132-134

133

to type the thermolabile methylene tetrahydropholate re-

ductase (MTHFR) C677T and A1298C polymorphism.

After amplification, the PCR product underwent a re-

verse hybridization. Heterozygous C677T and A1298C

mutations were detected.

3. DISCUSSION

This patient with early-onset Alzheimer’s disease (EOAD)

was reported to be different from those with late onset

Alzheimer’s disease (LOAD) in terms of neuropsycholo-

gical and neuroimaging findings. Patients with EOAD

tend to display more diverse cognitive impairments and

neurological deficits than those with LOAD, such as

language, visuospatial, and executive dysfunctions [8,9],

and extrapyramidal signs, whereas patients with LOAD

present cognitive impairment of the amnesia-predomi-

nant type [10].

Approximately 10% of cases present at an age of onset

before 65 years old, which in turn can bemonogenic fa-

milial AD (FAD) or sporadic early-onset AD (EOAD)

[11].

In the past few decades, investigations have elucidated

that both the genetic and the environmental factors are

capable of causing the development of AD.

5,10-Methylenetetrahydrofolate reductase (MTHFR)

is an important enzyme in the pathway of regulation of

homocysteine (Hcy) concentrations. It can catalyze the

conversion of 5,10-methylenetetrahydrofolate to 5-me-

thyltetrahydrofolate, which is the predominant form of

folate in plasma and provides the methyl group for me-

thionine synthesis through homocysteine remethylation.

The experiment proved that the homozygous mutations

of the MTHFR gene, C → T transition at nucleotide po-

sition 677, could decrease the enzymatic activity and

cause elevation of Hcy level [12]. Significant association

between hyperhomocysteinaemia, MTHFR C677T poly-

morphism and cardiovascular diseases risk has been

identified [13,14].

Since hyperhomocysteinaemia is regarded as a risk

factor of atherosclerotic disease, it may also play an im-

portant role in the development of AD [15]. A large

number of small, individually underpowered, case-con-

trol studies have been performed to assess the associa-

tions between MTHFR C677T polymorphism and AD.

However, the results remain conflicting in many ethnies:

Italy, England, Brazile and other countries [16]. In the

subgroup analysis of ethnicity, The results showed that

MTHFR 677T had an effect of increasing the AD risk for

all model comparisons in East Asians, while no evidence

of association between MTHFR C677T polymorphisms

and AD was observed in Caucasians [17]. On the other

hand there is little known about the A1298C MTHFR

mutation, there are no studies in the literature that ad-

dresses the relationship between this mutation and AD.

The role of methylenetetrahydrofolate reductase (MTHFR)

gene polymorphisms as risk factors for the occurrence of

Alzheimer’s disease (AD) is still controversial. A rela-

tively new approach to the pathogenesis of Alzheimer’s

disease (AD), a typical multifactorial disease, warrants

the study of the interplay between classic AD risk factors

and a number of other contributors causing brain damage

by various mechanisms. Among emerging probable con-

tributors, vascular risk factors [18-20] seem to play an

important role.

Despite these seminal advances in understanding the

genetics and pathophysiology of early-onset familial AD,

several lines of evidence suggest that additional genetic

factors remain to be identified for this form of the dis-

ease. This will then enable a strategy for “early predic-

tion and early prevention” of AD, which forms the cor-

nerstone of genomic medicine [21].

4. CONCLUSION

The absence of effective prophylactic treatments for

AD limits presymptomatic and antenatal testing for ethi-

cal reasons (Hedera, 2001). However, if any of the ex-

perimental prevention or treatment strategies proves to

be effective, molecular diagnosis in risk families will

become very important. Knowledge gained from genetic

studies of AD was and remains the essential prerequisite

for our current understanding of the etiological and

pathophysiological mechanisms leading to neurodegen-

eration in AD as well as for the development of novel

strategies for the treatment and prevention of this dis-

ease.

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