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Environmental factors brain development and intelligence in adulthood.

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24. Serafini B, Rosicarelli B, Franciotta D, et al. Dysregulated
Epstein-Barr virus infection in the multiple sclerosis brain. J
Exp Med 2007;204:2899 –2912.
25. Willis SN, Stadelmann C, Rodig SJ, et al. Epstein-Barr virus
infection is not a characteristic feature of multiple sclerosis
brain. Brain advance access, doi:10.1093/brain/awp200.
26. Gulley ML, Glaser SL, Craig FE, et al. Guidelines for interpreting EBER in situ hybridization and LMP1 immunohistochemical tests for detecting Epstein-Barr virus in Hodgkin lymphoma. Am J Clin Pathol 2002;117:259 –267.
DOI: 10.1002/ana.21842
Environmental Factors,
Brain Development, and
Intelligence in Adulthood
Cognitive abilities in adulthood are highly dependent
on normal brain development during gestation. Disorders of the highly complex processes of brain development are associated with various degrees of cognitive
deficiency and autistic spectrum disorder. These conditions have a prevalence close to 1 or 2% of the population, with mild mental retardation 10 times more
common than severe retardation. Identification of the
causes of these problems is of prime importance for
both the family and society, because some etiologies
may be preventable. An underlying cause can be identified in 65 to 75% of patients. Identified causes are
genetic in 30 to 40% of diagnosed cases, structural
malformations (some genetic) in 15 to 20% of cases,
and complications of prematurity and perinatal conditions in 15 to 25% of cases. Other etiologies are related to environmental, behavioral, or socioeconomic
factors.1,2 The negative impact of exposure to alcohol
on future cognitive ability has been clearly demonstrated, and malnutrition, and maternal exposure to
cigarette smoking and street drugs are also suspected to
be detrimental.3 X-rays have a negative impact, whereas
the role of industrial toxins and of pharmaceutical molecules remains uncertain.4 Finally, early viral infections
of the fetus may induce abortion or changes to the
brain parenchyma, leading to severe cognitive deficits,
whereas cytomegalovirus (CMV) infection later in gestation may lead to isolated hearing loss or to moderate
cognitive disability (a direct causal link being difficult
to demonstrate epidemiologically). Despite careful evaluations, the cause remains elusive in 25 to 35% of
cases, particularly in those with mild mental defects.
Some of these cases are undoubtedly due to genetic
266
Annals of Neurology
Vol 66
No 3
September 2009
changes, which are now easier to detect with new techniques, such as comparative genomic hybridization arrays, but others may be related to environmental factors, which would require large epidemiological studies
to be identified.
In this issue of Annals of Neurology, Eriksen et al ask a
very provocative question: could a flu pandemic that occurred 20 years ago have decreased the ultimate cognitive ability of individuals who were in the early phase of
gestation during the epidemic?5 The authors did not aim
to identify major mental deficiencies in this study. Instead, they looked for a moderate reduction of cognitive
abilities in apparently normal young men who were undergoing medical and cognitive evaluation for compulsory military service. The main outbreak of Hong Kong
flu in Norway occurred between November 1969 and
January 1970, and the overall clinical attack rate was estimated at between 15 and 40% of the population.
However, no information was available about the specific rate for pregnant women or the intensity of symptoms in pregnant women, although flu is generally
thought to be clinically more severe during pregnancy.6
The sample consisted of ⬎200,000 men born between
1967 and 1973. After adjustment for parental educational level, paternal age, and percentage of premature
and small for gestational age children, the young men
who were born between July and October 1970 were
found to have a significantly lower score on the cognitive test battery than young men born during any other
period, including the same months in previous and subsequent years. These findings suggest that a bout of flu
early in pregnancy may affect the cognitive ability of the
mature subject evaluated 20 years later. This finding will
no doubt engender considerable controversy. Let us assume that the intelligence test data used in this study are
sufficiently robust and reliable in terms of both their reproducibility and their comparability with well-validated
measures of intelligence. The authors carefully justify
their findings. The most important question concerns
the extent of the reduction of performance on a standard
intelligence quotient (IQ) scale. This is difficult to evaluate, because individual results cannot be linked with
individual information about exposure to flu during gestation. The authors of this paper assume an exposure
rate of 20% in pregnant women and their fetuses. Consequently, they suggest that flu during pregnancy may
decrease the IQ of the offspring by 3 to 7 points as measured on a standard IQ scale. However, during the periods considered, almost 10% of the population did not
undergo military service because they had already died,
or for other reasons such as psychiatric illness or cognitive impairment. The authors could not control for this
potential bias. In this regard, it would be most interesting to determine whether severe brain malformations
leading to early death, severe mental retardation, psychiatric illness, or milder cognitive impairment were more
frequent in individuals born during the 4 months identified than at other times.
Consideration of the percentage decrease in cognitive ability in a general population may be a powerful
way of indentifying new causes of abnormal brain development. Indeed, with this method, it is possible to
include large numbers of subjects systematically, improving confidence intervals.
What mechanism is responsible of the observed effect? This point is carefully discussed by the authors.
One possibility is mother-to-child transmission of the
virus, as for rubella, CMV, varicella-zoster virus, or
human immunodeficiency virus-1 infection, in a
small percentage of infected women (influenced by
the specific virus and the intensity of viremia, the socalled “viral load”). As for other viruses, following flu
pandemics, increases in spontaneous abortions and
brain malformations have been described. However,
the relatively small decrease in IQ described here in
otherwise apparently normal individuals seems less
consistent with direct viral replication in the fetal
brain as the underlying cause. Instead, it suggests a
role for indirect factors linked to the maternal illness
(including soluble factors of inflammation and the
consequences of transient breathing or eating difficulties in the mother) early in gestation.
Marc Tardieu, MD, PhD
Yann Mikaeloff, MD, PhD
Assistance Publique Hôpitaux de Paris
Hôpital Bicêtre, Université Paris Sud
Inserm Units 802 and 822
Le Kremlin Bicêtre, France
Potential conflict of interest: Nothing to report.
References
1. Kinsbourne M, Wood FB. Disorders of mental development. In:
Menkes JH, Sarnat HB, Maria BL, eds. Child Neurology. 7th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:
1097–1155.
2. Hackman DA, Farah MJ. Socioeconomic status and the developing brain. Trends Cogn Sci 2009;13:65–73.
3. Alati R, Macleod J, Hickman M, et al. Intrauterine exposure to
alcohol and tobacco use and childhood IQ: findings from a
parental-offspring comparison within the Avon Longitudinal
Study of Parents and Children. Pediatr Res 2008;64:659 – 666.
4. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet 2006;368:2167–2178.
5. Eriksen W, Sundet JM, Tambs K. Register data suggest lower
intelligence in men born the year after flu pandemic. Ann Neurol 2009;66:284 –289.
6. Rothberg MB, Haessler SD, Brown RB. Complications of viral
influenza. Am J Med 2008;121:258 –264.
DOI: 10.1002/ana.21781
Gene Therapy for Muscular
Dystrophy Reaches Human
Clinical Trial
Limb-girdle muscular dystrophies (LGMDs) are a
group of primary inherited muscle diseases, many of
which present in childhood and exhibit a lethal progression resulting in premature death. More than a
dozen LGMDs have been recognized as genetically distinct so far; of these, ␣-sarcoglycan deficiency
(LGMD2D) is among the more common.1 In this issue of the Annals of Neurology, Mendell et al2 report a
first-in-man study of viral vector-mediated gene delivery to muscle toward the ultimate goal of gene therapy
for patients with LGMD2D.
Although the clinical and pathological presentation
of muscular dystrophy was first described in the medical literature in the 19th century,3 identification of a
specific molecular defect as the cause of a muscular
dystrophy phenotype first occurred with the discovery
of dystrophin deficiency as the cause of Duchenne
muscular dystrophy (DMD) in 1987.4 The identification of other muscle membrane proteins, including
the sarcoglycans, soon followed, enhancing our understanding of the biochemical structure of the sarcolemma (Fig 1).5– 8 Identification of mutations in
genes coding for individual proteins that are localized
to the sarcolemma or are localized elsewhere in the
muscle cell as direct causes of the clinical phenotype
of muscular dystrophy led to subdivisions of the
LGMD diseases based on a genetic classification. The
discovery that muscular dystrophies are single-gene
defects in muscle membrane proteins generated the
hopeful anticipation among researchers, patients, and
their families that a gene replacement approach using
gene therapy could be rapidly developed as an effective treatment for muscular dystrophy.
Over the past 20 years, researchers have actively pursued gene replacement strategies for the treatment of
muscular dystrophy in preclinical animal studies. Several nonviral and viral vectors can be used for gene delivery to striated muscle tissue. Experimentation has
uncovered advantages and limitations of each vector
system. Significant experimental hurdles, including inefficient gene delivery, immune rejection, vector toxicity, and other problems, have challenged many talented
research groups. Nonetheless, despite some setbacks,
there have been many advances and multiple creative
approaches. The adeno-associated viral (AAV) vector,
used in the Mendell et al. study, has emerged in preclinical studies as the viral vector with the most prom-
Clemens: Gene Therapy for MD
267
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