Vol.2, No.4, 132-134 (2013) Advances in Alzheimer’s Disease
Copyright © 2013 SciRes. OPEN ACCESS
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
Copyright © 2013 Leila Mansouri et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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
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
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
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
Copyright © 2013 SciRes. OPEN ACCESS
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.
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)
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].
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-
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