ARTICLE
Auteur(s) : M Mousain-Bosc1, M
Roche2, A Polge2, D Pradal-Prat1,
J Rapin3, JP
Bali4
1Explorations Fonctionnelles du Système Nerveux,
Centre Hospitalier Universitaire Carémeau, Nîmes
2Laboratoire de Biochimie, Centre Hospitalier
Universitaire Carémeau, Nîmes
3Département de Pharmacologie, Université de Bourgogne,
Dijon
4Laboratoire de Biochimie, Faculté de Pharmacie,
Montpellier (France)
For over 30 years, parents have given high doses of pyridoxine and
Mg2+ to their children and have observed improved social
responsiveness. B6 and Mg2+ have received more
scientific support than any other biological intervention for
behavioural disorders (for review, see [1]). There are studies from
18 different research groups showing that B6 and Mg2+
are beneficial to about half of autistic individuals, with no
significant adverse effects. Eleven of these studies involved a
double-blind placebo design which documented decreases in
behavioral problems, improvements in appropriate behavior, and
normalization of brain wave activity and urine biochemistry. There
is also evidence that B6 and Mg2+ may reduce seizure
activity. Parent reports confirm improvement in attention,
learning, speech/language, and visual contact [2-5]. More recently,
in a pilot study of a moderate dose multivitamin/mineral supplement
for children with autistic spectrum disorder, Adams et al. [6]
found significant improvements in sleep and gastrointestinal
problems compared to the placebo group. Despite all these data, the
intervention of Mg-B6 remains controversial and contradictory
studies have been published [7, 8]. In a recent meta-analysis of
all studies published from 1960s, Nye et al. [9] concluded that,
“Due to the small number of studies, the methodological quality of
studies, no recommendation can be advanced regarding the use of
B6-Mg as a treatment for autism”. Together with the fact that both
the American Psychiatric Association and the American Academy of
Pediatrics have stated that megavitamin treatment for learning
disabilities and autism is not justified, these findings explain
the lack of clinical studies about the use of magnesium and vitamin
B6 (Mg-B6) in the treatment of autism.However, recently, new data
concerning a possible association between Mg-B6 supplementation,
neurobehavioural symptoms, and the Mg2+ status of
children have been published, opening a new way of research in this
domain: the first one from Liebscher et al. [10] suggested that
patients with attention deficit hyperactivity disorders should be
considered as potentially Mg-deficient as regards to a wrong
interpretation of the serum Mg test (tetanic patients have lower Mg
values than normals). The second one from Kozielec et al. [11, 12]
reported for the first time an intraerythrocyte magnesium depletion
in hyperactive children; we recently published similar data [13].
In order to study the effect of Mg-B6 for treating social,
communication and behavioural responses of children with pervasive
developmental disorders or autism in connection with the
magnesium/calcium status of the child, we designed an open study on
33 children with PDD syndrome. Our results showed a statistically
significant improvement of the symptoms after Mg-B6 supplementation
together with a rise in Erc-Mg values.
Patients and methods
Patients and treatment
Thirty-three children (1-10 year-old, mean: 4 ± 2, 21 boys, 12
girls) were followed over a period of about 24 months. All children
presented clinical symptoms of pervasive developmental disorders
(signs of autism), as described in DSM-IV [14] (at least 3 from the
4 groups) :
- – group “loss of social interactions”: visual contact,
connection with equals, delight partition, social reciprocity,
- – group “loss of communication”: delayed communication,
no communication, stereotyped language, social mimicking,
- – group “stereotyped restricted behaviour”: stereotyped
interests, customs, motor affectation, handling things,
- – group “abnormal or delayed functioning”: social
interactions, language, symbolic games.
Each symptom, evaluated at the same time, was scored from 0 to 4
by the physician, after discussion with parents and teachers, and
the values for each symptom were statistically compared before and
after Mg-B6 treatment either individually or within each group of
symptoms. As defined in DSM-IV, an improvement in PDD under
treatment is observed when scored values of at least 3 of the four
groups of symptoms decreased (improvement was defined as a
difference in cumulated scored value under treatment higher than
5).
The control group contained 36 children (mean age: 4.37 ± 2
y.o., 14 girls and 22 boys) somatically and behavioury healthy,
devoided of any sign of neuropathology or of a pathology known to
influence magnesium homeostasis. These children did not receive any
Mg-B6 therapy; they were selected as regard to their normal
behavior at school with parental agreement.
A Mg-B6 regimen (6 mg/kg/d Mg, 0.6 mg/kg/d
vit. B6) was established in all PDD children (mean duration: 8
± 5 months). No other medical treatment was given before and during
the Mg-B6 treatment period.
Serum Mg2+ (S-Mg) and intra-erythrocyte
Mg2+ (Erc-Mg) were measured by a colorimetric assay
(chlorophosphonazo III) [9] (Erc-Mg) in an INTEGRA automate (Roche
Diagnostics) and blood ionized Ca2+ concentrations by
electrometric assay (i-Ca) (Bayer Diagnostics). To perform Erc-Mg
measurements, red blood cells (RBC) were washed 3 times in 0.9%
NaCl, centrifuged, and RBC (1 mL pellet) were lysed in
2 mL water for 15 min at + 4°C. Then, 1 mL 20%
trichloracetic acid was added, the mix was stirred on vortex and
centrifuged. The supernatant (1/4 dilution) was used to measure
Erc-Mg. When repeated four times in healthy children at one month
periods, Erc-Mg values varied by 12% around initial values. This
method was adapted on an INTEGRA automate after calibration with
the atomic absorption assay. Biological parameters, including s-Mg,
Erc-Mg, and i-Ca, were measured at the first clinical visit of the
child; then, after two months treatment. The following evaluations
depended on the frequency of the visits (every six months, for
instance). Of course, the control group, only containing healthy
children, was not treated by Mg-B6.
Statistics
All statistical analyses were done after testing all variables of
interest to determine whether they are approximately normally
distributed: two different types of tests for normality were used;
Shapiro-Wilk and Shapiro-Francia. Since the majority of the
variables are not normally distributed, the non-parametric paired
Wilcoxon signed-rank test was used to compare values between before
and after treatment. For the comparison of Erc-Mg values for PDD
children, and their parents versus control children, the
non-parametric Mann & Whitney test was applied. Significance at
p < 0.05.
Results
Tables 1 and 3( Table 1 )( Table 2 )( Table 3
) report mean ± SD values for biological (table 1) and
clinical (table 3) data of the patients before and after Mg-B6
supplementation.
Erc-Mg values are lower in PDD children and their parents as
compared to controls
In PDD children, while s-Mg and i-Ca did not statistically differ
from control children, Erc-Mg values were significantly lower as
compared to those from control group (2.17 ± 0.4 mmol/L, n = 33,
versus 2.73 ± 0.23 mmol/L, n = 36) (p < 0.05) (( figure 1 ) and
table 1). Sixteen on thirty-three (48%) of PDD children showed
Erc-Mg values less than 2.27 mmol/L (mean-2SD of control children).
In addition, mothers and fathers of PDD children, together (n = 7)
or separately (n = 16) showed statistically significant lower
Erc-Mg values than control children (2.16 ± 0.38 mmol/L, n = 23,
and 2.19 ± 0.33 mmol/L, n = 12) (p < 0.05, respectively)
(table 2). When we tried to correlate Erc-Mg values from PDD
children to those of their mothers, a statistically significant
correlation appeared (r2= 0.2243, p < 0.05) ((
figure 2
)).
Table 1 Biological characteristics of PDD children
under treatment: Mean ± SD values of Erc-Mg, i-Ca, and s-Mg
(mmol/L) are reported.
|
Age (years)
|
4.03 ± 1.93
|
|
Duration of Mg-B6 treatment (months)
|
8 ± 5.8
|
|
Erc-Mg (mmol/L)
|
Control children
|
2.73 ± 0.23
|
|
Children before treatment
|
2.17 ± 0.4
|
|
Children after treatment
|
2.42 ± 0.41
|
|
Ratio after/before
|
1.18 ± 0.34
|
|
Mothers
|
2.16 ± 0.38
|
|
Fathers
|
2.19 ± 0.33
|
|
i-Ca (mmol/L)
|
Before treatment
|
1.21 ± 0.08
|
|
After treatment
|
1.20 ± 0.05
|
|
Ratio after/before
|
1.00 ± 0.1
|
|
s-Mg before treatment (mmol/L)
|
0.89 ± 0.06
|
Table 2 Comparison between Erc-Mg values from PDD
children and their parents. Mean ± SD Erc-Mg values (mmol/L) in
control and in PDD children, their mothers and fathers are
reported. Erc-Mg was measured as indicated in figure 1.
Statistical comparison was done using Mann & Whitney non
parametric test. Statistical significance at p = 0.05.
|
Control
|
PDD Children
|
Mothers
|
Fathers
|
|
Children (36)
|
(29)
|
(23)
|
(12)
|
|
Erc-Mg values (mmol/L)
|
2.73 ± 0.23
|
2.17 ± 0.40
|
2.16 ± 0.38
|
2.19 ± 0.33
|
|
Significance versus controls (p)
|
-
|
0.001
|
0.001
|
0.001
|
|
Significance versus PDD children (p)
|
0.001
|
-
|
NS
|
NS
|
|
Number of cases of patients with Erc-Mg < 2,27 mmol/L
(-2 s.d.)
|
0
|
18 (62%)
|
14 (61%)
|
9 (75%)
|
Table 3 Clinical characteristics of PDD children under
treatment: Mean ± SD scored values for each symptom in the PDD
children’s group, as described in DSM-IV, are reported.
|
PDD symptom
|
N
|
Mean ± SD score value before
|
Number of children with score > 3
|
Mean ± SD score value after
|
Number of children with score > 3
|
|
Social interactions
|
|
Visual contact
|
33
|
3.33 ± 0.89
|
26
|
1.36 ± 1.19
|
6
|
|
Connection with equals
|
33
|
3.12 ± 0.74
|
28
|
1.51 ± 1.00
|
6
|
|
Delight partition
|
33
|
3.03 ± 0.81
|
25
|
1.54 ± 1.06
|
6
|
|
Social reciprocity
|
33
|
3.30 ± 0.68
|
29
|
1.51 ± 1.06
|
6
|
|
Cumulated score values
|
33
|
12.61 ± 3.01
|
-
|
5.94 ± 4.10
|
-
|
|
Loss of communication
|
|
Delayed communication
|
33
|
3.39 ± 0.50
|
33
|
2.00 ± 1.00
|
9
|
|
No communication
|
33
|
3.09 ± 0.72
|
26
|
1.54 ± 0.87
|
4
|
|
Stereotyped language
|
33
|
2.85 ± 0.71
|
24
|
1.54 ± 1.09
|
6
|
|
Social mimicking
|
33
|
3.27 ± 0.75
|
29
|
1.39 ± 1.05
|
5
|
|
Cumulated score values
|
|
12.61 ± 2.16
|
-
|
6.48 ± 3.77
|
-
|
|
Stereotyped restricted behavior
|
|
Stereotyped interest
|
33
|
3.03 ± 1.16
|
24
|
1.27 ± 0.91
|
3
|
|
Customs
|
33
|
1.88 ± 1.36
|
12
|
0.64 ± 0.82
|
1
|
|
Motor affectation
|
33
|
2.36 ± 1.14
|
17
|
1.00 ± 0.90
|
3
|
|
Things handling
|
33
|
1.88 ± 1.17
|
10
|
1.03 ± 1.04
|
3
|
|
Cumulated score values
|
|
12.61 ± 2.16
|
-
|
6.48 ± 3.77
|
-
|
|
Abnormal or delayed functioning
|
|
Social interactions
|
33
|
3.26 ± 0.89
|
28
|
1.80 ± 1.22
|
10
|
|
Language
|
33
|
3.39 ± 0.62
|
29
|
1.90 ± 1.22
|
10
|
|
Symbolic games
|
33
|
3.13 ± 0.88
|
27
|
1.66 ± 1.15
|
9
|
|
Cumulated score values
|
|
12.61 ± 2.16
|
-
|
6.48 ± 3.77
|
-
|
ERC-Mg values increased under Mg-B6 supplementation
In PDD children who received a Mg-B6 supplementation for at least
two months, a statistically significant rise in Erc-Mg values was
observed (2.42 ± 0.41 (after) versus 2.17 ± 0.4 mmol/l (before),
Wilcoxon test p = 0.0198) (table 4( Table
4 ))), but these values were still lower than for controls
(2.73 ± 0.23 mmol/L) (( figure 1 ) and
table 1). 11/17 (65%) of children showed increased Erc-Mg
values after treatment. No statistically significant variation
under Mg-B6 treatment has been observed either in s-Mg (Wilcoxon
test p = 0.14) or in i-Ca (Wilcoxon test p = 0.088). When the Mg
supply was stopped, Erc-Mg values return to low levels in about 2
months.
Table 4 Effect of Mg-B6 treatment in PDD
childrenStatistical comparisons of biological parameters between
after versus before treatment. Since majority of the variables are
not normally distributed, the non-parametric paired Wilcoxon
signed-rank test was used to compare values between before and
after treatment. Statistical significance at p = 0.05.
|
Comparison after versus before Mg-B6 treatment
|
Wilcoxon test
|
|
Erc-Mg
|
z = -2.330
|
|
Prob > z = 0.0198
|
|
i-Ca(2+)
|
z = 1.706
|
|
Prob > z = 0.0880, NS
|
|
Social interactions
|
z = 5.074
|
|
Prob > z = 0.0000
|
|
Loss of communication
|
z = 5.061
|
|
Prob > z = 0.0000
|
|
Stereotyped restricted behavior
|
z = 5.119
|
|
Prob > z = 0.0000
|
|
Abnormal/delayed functioning
|
z = 4.726
|
|
Prob > z = 0.0000
|
Evolution of PDD clinical symptoms under Mg-B6
supplementation
In PDD children, Mg-B6 treatment for at least 2 months modified the
clinical symptoms of the disease (( figure 3 ) and
table 3): namely, social interactions (mean cumulated score
values: 5.94 ± 4.10 versus 12.61 ± 3.01 before treatment, p <
0.0001) and communication (mean cumulated score values: 6.48 ± 3.77
versus 12.61 ± 2.16 before treatment, p < 0.0001), stereotyped
behavior (mean cumulated score values: 6.48 ± 3.77 versus 12.61 ±
2.16 before treatment, p < 0.0001) and abnormal functioning
(mean cumulated score values: 6.48 ± 3.77 versus 12.61 ± 2.16
before treatment, p < 0.0001) were statistically reduced
(table 3). For each of the analyses above, the paired t-test
gave similar values to that found with the Wilcoxon signed rank
test, although the non parametric tests are prefered due to the
clearly non-normal data. 23/33 (social interactions), 24/33
(communication), 18/33 (stereotyped behavior) and 17/33 (abnormal
functioning) of PDD children showed a difference in cumulated
scored value under treatment higher than 5, value defined to
consider an improvement in the symptoms. Twenty on thirty-three
(60%) of PDD children improved under Mg-B6 treatment (improvement
for 3 of the four groups of symptoms). Among these 20 children who
improved under treatment, 8/12 exhibited increased Erc-Mg levels.
The main clinical observation in all patients was the improvement
in social behaviour.
Duration of treatment
Children were treated with Mg-B6 from 2 to 40 months. Two months
Mg-B6 supplementation did not induce a statistically significant
rise in Erc-Mg values, and only small changes in children’s
behaviour. These changes became significant after 6 months
treatment. When the magnesium treatment was stopped, clinical
symtoms of the disease reappeared in few weeks.
Discussion
Magnesium is known to be essential for number of physiological and
biochemical central and peripheral processes. Associated to vitamin
B6, it has been proposed for many years as a nutritional factor
which could be used in the treatment of autism. The neurobiological
basis of such a treatment supposes the existence of an impairment
in the neuronal Mg2+ pathway which could be reversed
under Mg-B6 therapy. Mg2+ acts as an ionic membrane
regulator and modulator of ion transfer through membrane channels.
In the brain, it has been shown that traumatic injury causes a
decline in Mg2+ concentrations, focally as well as in
blood circulation, and contributes to the development of neurologic
deficit [15]. Similarly, brain ischemia caused a decline in
intracellular free Mg2+ concentrations [16] and
magnesium salt administration improved motor outcome in this
situation [17]. One of its most important modes of action is to
inhibit the glutamate N-methyl-D-aspartate (NMDA) channel [18]. The
activity of this channel generates an influx of calcium and, in
turn, leads to an excitotoxic cell death and apoptosis [15]. In the
same way, abnormal dietary deficiency of Mg2+ as well as
abnormalities in Mg2+ metabolism play important roles in
different types of heart diseases and Mg2+ influences
catecholamine signaling in such diseases [19].
Recently, in primary autistic children, using positive emission
tomography (PET), Zilbovicius et al. [20, 21] observed in 16/21 of
children a significant decrease in cerebral blood flow localized at
the temporal lobes level. Taken together with the fact that
Mg2+ was shown to increase blood pressure [22] and that
brain from rats fed with low Mg2+ diets are more
susceptible to permanent brain focal ischemia [23], we can
hypothesize that intracellular Mg2+ depletion could be
responsible, at least in part, for some central activity disorders
observed in PDD/autistic children.
In our study, an intra-erythrocyte Mg2+ depletion was
evidenced in almost half of the PDD children. To explain such a
phenomenon, two hypotheses can be proposed:
- – a metabolic inhibition of membrane
Na+/K+ ATPase (observed in autism [24]) with
a concomitant rise in intracellular Ca2+ and decrease in
intracellular Mg2+;
- – a genetic defect in magnesium transport through the
plasma membrane (Na+-Mg2+ exchanger [25, 26]
or TRPM chanzymes [27]).
As Erc-Mg can be considered as representative of some
intracellular Mg concentrations, a decrease in Erc-Mg without
changes in serum Mg concentrations could be interpreted as an
alteration of Mg2+ transport through plasma membrane.
The demonstration that TRPM7 is critical for Mg2+
homeostasis evoked the possibility that mutation of TRPM channels
may cause disease in humans as a result of reduced intracellular
Mg2+ levels: mutations were found in the case of
hypomagnesemia with secondary hypocalcemia disease [28], and, in
this case, symptoms associated with TRPM6 mutations were improved
by supplementation with high Mg2+ doses, in agreement
with increased Mg2+ entry through the passive mode of
Mg2+ influx. This genetic hypothesis was also supported
by our data showing a positive correlation between low Erc-Mg
values in PDD children and their mothers. Similarly,
Feillet-Coudray et al. have found that, in mice genetically
selected for low magnesium levels, Mg efflux from erythrocytes was
significantly increased; the genetic regulation of erythrocyte
Mg2+ content depends on the modifications of
Mg2+ influx [29, 30]. To confirm such an hypothesis, a
genetic study of PDD children’s families clearly has to be
developed.
When PDD children were supplemented with Mg-B6 treatment, Erc-Mg
values increased more or less and only in 65% of children. The
failure to get normal Erc-Mg values under Mg-B6 treatment supports
the hypothesis of a defect in Mg2+ transport in
erythrocytes: in sickle cell disease, Mg pidolate supplementation
was found to decrease Na+/Mg2+ exchanger activity with a
partial rise in Mg2+ and K+ contents of erythrocytes
[31]. Doses of Mg-B6 and duration of the treatment, which have not
been taken into account in our study, could also be involved in
explaining such an observation. Concerning the respective roles of
pyridoxine and Mg2+ in these observations, it was
classically admitted that Mg2+ is associated to
pyridoxine to decrease the irritable side-effects of the B6 therapy
and that B6 is the main factor involved in the improvement of
clinical symptoms in autistic patients. Following Erc-Mg values
during Mg-B6 treatment, we bring here evidence of the role of
Mg2+ itself in this therapy. In addition, in mothers of
PDD children who had pregnancy disturbances, a preventive Mg-B6
therapy seems to be required.
Mg-B6 treatment of PDD children was shown to ameliorate symptoms
of the disease: three of the four main groups of clinical signs
described in DSM-IV were significantly reduced and we found for the
first time that 8/12 of children who improved under treatment
showed higher Erc-Mg values. Persons only slightly deficient in
magnesium become irritable, high-strung, sensitive to noise,
hyperexcitable, apprehensive, and belligerent. If the deficiency is
more severe, or prolonged, they may develop twitching, tremors,
irregular pulse, insomnia, muscle weakness, jerkiness, and leg and
foot cramps. These symptoms can also been found in some cases of
PDD/autism. Although this study was an opened non-controlled study,
we found a relationship between clinical signs of PDD/autism and a
biological parameter Erc-Mg. However, we were unable to establish
any correlation between improvement of symptoms and increase in
Erc-Mg. Various possibilities can explain this lack of
correlation:
- – Erc-Mg is probably not the best biological parameter
to follow the relationship between magnesium homeostasis and
neurological dysfunctions of PDD/autism; contradictory reports have
been published on the use of Erc-Mg as index of Mg2+
status [32, 33]. New biological tests which could help to study
genetic alterations of magnesium transport (lymphocytes…) have to
be tested;
- – Other neurofunctional disorders may be involved in
autism, such as a decrease in temporal blood flow. Even if low
Erc-Mg levels have been shown to be related to decrease in blood
pressure, there is no evidence to associate in all cases blood
pressure and cerebral blood flow.
Conclusion
This study brings new information about the therapeutic role of a
Mg-B6 regimen in children with PDD syndrome. This effect seems to
be associated, at least in part, to a cellular Mg2+
depletion, as evidenced by intra-erythrocyte Mg2+
measurements. Children with pervasive developmental disorders
(including autism) exhibit low Erc-Mg levels. Parents frequently
showed similar low Erc-Mg values suggesting a genetic defect in
Mg2+ transport. Installing a Mg-B6 supplementation for
some weeks restored higher intra-erythrocyte Mg2+ values
and significantly reduced the clinical symptoms of these diseases.
Acknowledgements
The authors would like to express their thanks to parents and
teachers of the children included in this study for their permanent
support. They are grateful to all the staff of Centre Hospitalier
Universitaire of Nîmes and to Dr Jean Durlach (Association
pour le Développement des Recherches sur le Magnesium, Paris) for
his interest to our work. They would like to acknowledge
Sanofi-Aventis for its interest and financial support. They also
would express their thanks to Dr Joan Ryan (Melbourne,
Australia) for her help in statistical determinations.
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