This
is a very interesting topic, and unfortunately the research on genetics and
lupus is in it’s infancy. There were
just 3 new genes found by scientists that increase the risk of developing
SLE. There are obviously some
environmental factors that are contributing to the development of lupus, or
trigger lupus, in those with the genetic components needed to get the
disease. Another topic that people with
lupus have questioned is, is there a link between autoimmune diseases and brain
disorders like autism or schizophrenia? I
hope this can help answer some questions.
Genetics
in Lupus
The most common symptoms of lupus are
fever, rash, and arthritis. Women tend to develop lupus more commonly than men,
and people of African descent develop lupus more commonly than people of
European descent.
Lupus is only one of many
"auto-immune" diseases. "Auto" means that the body has an
immune reaction against itself. Rheumatoid arthritis and scleroderma are also
auto-immune diseases.
Given that lupus, rheumatoid
arthritis, and scleroderma are all auto-immune disorders, how do physicians
tell them apart? The answer is surprisingly old-fashioned. In the case of
lupus, physicians compare the patient's symptoms and blood tests to a list of
11 criteria that experts agreed on in 1982. If the patient's data match 4 or
more of the criteria, a diagnosis of lupus can be made.
Auto-immunity causes some, but not
all, symptoms of lupus. Other symptoms are caused by problems cleaning up the
remnants of auto-immune attacks. These remnants are called "immune
complexes" and they circulate in the blood, where they can irritate the
inside wall of blood vessels.
Thus, lupus is more correctly
viewed as arising from problems with control of the immune system. It happens
that these control problems show up as auto-immunity.
|
Can lupus run in families?
Yes. This was first observed in the
1950s. More recent studies show that the brother or sister of a lupus patient
is 25 times more likely to develop lupus than someone in the general
population.
When lupus runs in families, is the
reason genes or environment?
As in most human disease, the answer
appears to be "both." Lupus has strong genetic components. It has
environmental components as well.
Lupus in twins
Studies of twins provide the
clearest insight into the relative importance of genes and environment. For
example, in 1992 researchers looked at 107 pairs of twins in which at least
one twin had lupus.
If lupus were governed only by genes, then every time one identical twin has lupus, the other should have it, too. (Because identical twins have the same genes.) In other words, the "concordance rate" should be 100%. The table shows, however, that there is a 24% concordance between identical twins. This shows that lupus has an environmental component.
If lupus were purely an
environmental condition, then genes should make no difference at all. The
concordance rate would be the same for identical twins and non-identical
twins. The table shows, however, that the concordance rate is more than ten
times higher in identical twins (24%) as compared with non-identical twins
(2%). This shows that lupus has a genetic component.
|
What genes are involved in lupus?
In 95% of cases, genetic
susceptibility to lupus is not caused by a single gene. Multiple genes are
involved. Identifying them has been slow because different genes seem to be at
work in different ethnic groups.
HLA Genes
Because lupus is an auto-immune
disease, scientists first studied genes that control the immune system. The HLA
family of genes, all located on the short arm of chromosome 6 , are important
controllers of the immune system. They are divided into 3 classes:
- HLA class I genes -- These genes have little to do with lupus.
- HLA class II genes -- Many genes in this group are linked to lupus:
- The combination of the DR3 and DQ2 variants, or the DR2 and DQ6 variants raise the risk of lupus by a factor of 2 or 3. These genes account for only a small part of the genetic risk for lupus.
- Many studies of class II genes show no links with lupus. Scientists, therefore, tried dividing lupus into subtypes, according to the results of various blood tests. When they did this, many links between class II genes and lupus subtypes were seen. This suggests that systemic lupus erythematosus is not one disease, but several similar diseases.
- HLA class III genes -- Many genes in this group are linked to lupus:
- The C4A and C2 genes are discussed below, in the section on "complement genes."
- Certain variants of the TNF genes raise the risk of lupus in some ethnic groups.
Complement Genes
Less than 5% of patients with lupus
owe their genetic susceptibility to a single gene. Many of these genes relate
to the body's "complement system." The complement system is part of
the immune system.
- The C1q genes on chromosome 1 sometimes code for a variant of the C1q complement protein that is less efficient than usual. When this happens, lupus can result, especially in children. The C1q protein has both an "attack" function and a "clean-up" function in the immune system. Scientists believe that lupus can be triggered if the remnants of an immune system attack are not cleaned up efficiently.
- Deficiencies of other complement proteins also lead to lupus, including deficiencies of the proteins coded by the C4A and C2 genes on chromosome 6 , and the C1r and C1s genes on chromosome 12.
- The MBL2 gene on chromosome 10 is the blueprint for a protein called mannose binding protein that is similar in shape to C1q. In Spanish and African-American populations, certain variants of this gene are more common in persons with lupus. Combinations of this gene and the C4 gene are more strongly associated with lupus than either gene alone.
Other Genes
- Three studies have scanned the entire human genome for linkages with lupus. One part of the short arm of chromosome 1 was positive in all 3 studies. Other parts were positive in two of three studies. These results were reassuring, because other studies had identified suspicious genes in precisely these areas of chromosome 1:
- The FCGR2A gene influences how the body cleans up the results of immune attacks. Certain variants of this gene raise the risk of kidney disease in African-Americans with lupus.
- The APT1LG1 and ADPRT genes are part of the body's system that controls the lifespan of cells ("apoptosis"). Similar genes in laboratory mice are linked to lupus, but more studies of humans are needed.
- Regions on chromosomes 2, 6, 14, 16, and 20 also came up positive in at least two of the whole-genome studies mentioned above.
- Another powerful genetic effect is gender. Ninety percent of all lupus cases are in women.
Actually, the C1q protein is not a
single protein coded by a single gene. Nature is often more complicated than
it first appears.
Strictly speaking, C1q is the name
for a complex of 3 different types of proteins, called A, B, and C. Each of
these 3 proteins is made from its own gene on chromosome 1 . Six copies of A,
B, and C group together, meaning that C1q is actually a complex of 18
individual proteins! Scientists are not sure whether the A, B, or C gene
causes the problem that leads to lupus.
|
Two heart medications,
procainamide and hydralazine, can trigger an illness that is similar to
systemic lupus erythematosus, but not identical. This illness is called
drug-induced lupus. At least two genes can contribute to susceptibility to
drug-induced lupus:
Drug-induced lupus usually goes
away when the offending medication is stopped, although it sometimes takes
years to resolve completely.
|
What environmental factors are
involved in lupus?
It has been difficult to pin down
the environmental components of lupus. The following factors are the best
known:
- Medications -- As described above, the cardiac medications procainamide and hydralazine can trigger an illness similar to lupus. Of course, most people who take these medications do not develop an illness. We do not know why.
- Ultraviolet radiation -- Sunlight can worsen the skin problems of people with lupus.
- Sex hormones -- Women get lupus more commonly than men. And certain men who have higher-than-normal levels of female sex hormones (due to a medical condition called Klinefelter syndrome) develop lupus at a rate between that of women and other men.
The evidence for other environmental
factors -- including infections, diet, and chemical agents and toxins -- is
weak and inconsistent. Once the genetics of lupus is better clarified, it will
be easier to determine the environmental factors influencing the disease.
When lupus runs in families, why
don't all family members have it?
It helps to frame this question a
little differently.... All members of a family do not have the same height,
weight, and face. So, it makes sense that they don't all have the same
conditions and diseases -- or the same susceptibility to various diseases.
Here again, it's genetic and
environmental differences that explain differences in our appearance and
health. Some family members will inherit genes that predispose to lupus, and
others will not. Some family members will be exposed to environmental agents
that trigger disease, and others will not.
There is no lupus in my family. Does
this mean it will never occur in my family?
No. Anyone can develop lupus. About
90% of people with lupus do not have an immediate family member with lupus. But
if someone in your family does have lupus, you are at greater risk.
How will discoveries about DNA help
people and families with lupus?
Further discoveries about lupus
genes will lead to more individualized medicine. Prevention, diagnosis,
treatment, and prognosis will be personalized, based largely on the strengths
and weaknesses found in a person's genes.
- Treatment -- better use of existing treatments
Several medicines have been approved
to treat lupus. How does your physician know which is best for you? Part of the
answer may be in your genes.
In this article, we've seen how
specific genes influence the development and progression of a complex condition
-- lupus. Similarly, specific genes may influence the responses to different
treatments. Better genetic information could explain why some drugs work better
in some people than others. This will make choosing treatments less
hit-and-miss than in the past.
- Treatment -- discovery of new treatments
Whenever scientists discover a gene
involved in lupus, it's a doorway to designing new treatments. If the gene is
over-active, then scientists can look for ways to turn it off or interfere with
its activity. If the gene is under-active or broken, then scientists can look
for ways to turn it on or increase its activity.
- Prevention, Diagnosis, Prognosis
Prevention, diagnosis, and prognosis
all improve when our ability to calculate risk improves. Scientists believe
genes will tell us a lot about the risk of developing lupus and the progression
of lupus.
Article by DNA Sciences
New Lupus Genes Identified
The analysis of more than 17,000 genetic samples from people of several ethnic groups also pinpointed another 11 genetic regions that may be related to lupus and require further study.
The researchers found that the genes IRF8 and TMEM39a are associated with lupus in European-American, African-American, Gullah (a distinctive group of African-Americans in Georgia and South Carolina) and Asian patients. The gene IKZF3 is only significantly associated with lupus in African-Americans and European-Americans.
The researchers said their findings, which appear in the April 6 issue of the American Journal of Human Genetics, show that the genes that cause lupus aren't always universal.
The next step is to study the three genes to find out exactly what role they play in lupus, said lead author Christopher Lessard, a scientist at the Oklahoma Medical Research Foundation in Oklahoma City.
Lupus affects about 1.5 million Americans, and about 90 percent of patients are women. The disease causes the immune system to become overactive and attack the body's own cells. Symptoms include fatigue, fever, rashes and joint pain.
A combination of environmental and genetic factors cause lupus. Learning more about genetic risk factors may lead to improved diagnosis and treatment of the disease.
-- Robert Preidt
New Clues on Genetic Causes of Autism
http://www.webmd.com/brain/autism/news/20110608/new-clues-on-genetic-causes-of-autism
June 8, 2011 -- Genetic mutations not inherited from parents appear to explain some cases of autism, new research suggests. And the mutations may number in the hundreds.While the new research is a step forward, it is a small puzzle piece. "It could explain up to 2% of all autism cases," says researcher Stephan J. Sanders, MD, a postdoctoral research associate at Yale University's Child Study Center.
Even so, he says the new research -- reported as a trio of studies in the journal Neuron -- provides a solid foundation to a better understanding of the biology of the disorder, eventually leading to better treatments.
In the new research, scientists also found new clues about why boys seem to be more vulnerable to the disorder than girls.
''In combination with some other research studies, this new research shows pretty clearly there is indeed a strong genetic component to autism, and that the individual genes can be identified," say Alan Packer, PhD, associate director for research at the Simons Foundation. It funds autism research and provided the sample populations studied in the new research.
About one in 110 U.S. children has autism or autism spectrum disorder, the neurodevelopmental disorders marked by impaired communication, social interaction problems, repetitive behaviors, and other problems.
Genetic Causes of Autism: Trio of Studies
In two of the new studies, researchers analyzed more than 1,000 families who have one autistic child and unaffected siblings. They evaluated their DNA from blood samples. The researchers used a highly sophisticated technique that can detect duplications or deletions of one or more sections of DNA.These duplications or deletions are called copy number variants or CNVs. If they occur at random, or sporadically, and aren't inherited, they are known as de novo CNVs.
Some CNVs ''are normal parts of being human," Sanders tells WebMD. "It's very difficult to find the ones that matter. We looked for ones that were new in the child.''
They found more new CNVs in autistic children than in unaffected children, which they expected.
They zeroed in on many regions linked with these rare sporadic mutations, Sanders says, confirming previous research on which areas matter. "Basically five regions really stand out now," he says.
These include areas of chromosome 7, 15, 16, 17 and Neurexin 1.
The team estimates ''there are 130-234 CNV regions that could be linked with autism," he says.
The researchers also found that the long arm of chromosome 7, a region associated with Williams syndrome, a genetic disorder in which people are highly social and overly friendly with strangers, may also be associated with autism.
"For a long time it has been known if you have a deletion there, it causes Williams syndrome," Sanders says.
They found the children with autism were more likely to have duplications in this region.
So it appears having a duplication may make you less social -- one of the characteristics of autism.
analyzed the same families. They used a similar approach. n a second study, researchers from Cold Spring Harbor Laboratory and other institutions
They, too, confirmed a contribution from the sporadic mutations. They estimated the number of regions involved even higher, at up to 300.
They also found that girls appear to have a greater resistance to autism from genetic causes than do boys.
''When we looked at affected females, we don't see small mutations, but very large mutations," says Michael Ronemus, PhD, a researcher at Cold Spring Harbor Laboratory. "Girls are more resistant," he says. It appears to take a larger mutation to affect girls with autism compared with boys.
It's long been known that boys are much more likely to get autism than are girls.
In a third report, Ronemus and his colleagues developed a method for analysis of the genetic associations. They used a new method to help identify a network of genes affected by the rare mutations in autism.
"The genes we are finding are typically involved in early brain development, forming connections in the brain," Ronemus says. These genes are related to the development of synapses, the point of connection between two nerve cells, among other tasks, the researchers say.
Genetic Causes of Autism: Implications
While the new research provides more clues to the genetic underpinnings of autism, "the message is not 'go out and get tested,'" says Sanders."We really are not at that stage yet."The new research provides new information ''but also confirms a lot of things we have already known," says Andy Shih, PhD, vice president of scientific affairs for Autism Speaks, an advocacy and research organization.
"It confirms that rare copy number variants are the main risk factors for many families," he says. However, he says, it also confirms that it's still impossible to explain the majority of cases of autism.
The sporadic mutations appear to play more of a role in families with just one child affected, Shih says. Eventually, the genetic findings could be useful information during genetic counseling in families who have one affected child, he says.
The findings are called a critical first step in the eventual goal of developing targeted treatments.
More Autism Diagnoses in High-Tech Areas, Study Finds
Last
Updated: 2011-Jun-24 :: (HealthDay)
FRIDAY,
June 24 (HealthDay News) -- Autism experts have long noted that they meet a lot
of engineers and computer programmers who have autistic children compared to,
say, salespeople. A new study suggests there may be merit to those
observations.Researchers from Cambridge University in England found that nearly three times as many children were diagnosed with an autism spectrum disorder in a region of the Netherlands known as a center of high-tech industry than in two other regions with fewer high-tech jobs.
The possible explanation: Autism is highly heritable -- meaning, it runs in families -- and has a strong genetic component related to a trait called "systemizing," which is a skill for analyzing how systems work and creating them. Workers in high-tech industries -- engineering and computing, for example -- tend to excel at systemizing.
"The theory is that people with autism may have a relative strength in systemizing, or the drive to analyze how systems work, how systems behave, how you can control them and build new ones," said study co-author Rosa Hoekstra, a visiting scientist with the Autism Research Center at Cambridge and an assistant professor of psychology at the Open University in Milton Keynes, England. "In the engineer or physicist or mathematician, these traits are advantageous, but it might cause difficulties in the children and show up as a clinical diagnosis of autism."
Some parents of autistic children have personality traits that are similar to those of autistic people, though not to the degree that they would be considered autistic, she added.
"They can function in society, but they have some personality or cognitive characteristics that are consistent with autism, such as a real preference for routines, or some social difficulties," Hoekstra said.
The study, published June 17 online in the Journal of Autism and Developmental Disorders, has implications for the distribution of services to autistic children, the authors said.
For the study, researchers asked schools in three regions of the Netherlands -- Eindhoven, Haarlem and Utrecht -- for statistics on children with an autism spectrum disorder. Children with autism often struggle with communication and social interactions, exhibit repetitive behaviors and have strong but narrow interests.
All three regions are similar in population size and socioeconomics, but Eindhoven is the Netherland's information technology hub. It's home to Eindhoven University of Technology, the High Tech Campus Eindhoven, and several technology companies, including Philips, ASML, IBM and ATOS Origin.
About 30 percent of jobs in Eindhoven are in technology or ICT compared to 16 percent in Haarlem and 17 percent in Utrecht.
The schools provided diagnostic information on more than 62,500 children. About 2.3 percent (or 229 for every 10,000) children in Eindhoven had autism, almost three times as many as in Haarlem (84 per 10,000) and four times as many as in Utrecht (57 per 10,000).
The rate in the United States is estimated to be about 1 percent.
Dr. Gary Goldstein, president and CEO of the Kennedy Krieger Institute in Baltimore, said the findings mirror his experiences with parents of autistic children. "I haven't met that many high-end people in sales with children with autism, but I met all these very successful people in the backroom processing the data," he said.
And while a doubling or a tripling of the risk is "enormous" in statistical terms, parents should also rest assured that it still means the vast majority of children -- 98 percent -- born to engineers or high-tech types will not have autism.
Researchers acknowledged their study had limitations, including the possibility that parents in the high-tech region were more attuned to the signs of autism and that the kids were more likely to be diagnosed, and that they relied on numbers from the schools but were unable to examine the kids themselves.
They are planning a follow-up study to test for other factors that might explain their finding.
Prior research has found that the mothers of children with autism are more likely to work in highly technical occupations, that autism is more common among the siblings of mathematics students, and that autism is more common among children who have fathers or grandfathers who worked as engineers, according to background information in the study.
"This suggests some link between a talent for systemizing and autism," Hoekstra said.
More information
The U.S. National Institute of Neurological Disorders and Stroke has more on autism.
2011
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advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A
MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified
health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.
Autoimmune disease in mothers with
the FMR1 premutation is associated with seizures in their children with
fragile X syndrome
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955238/
Weerasak Chonchaiya,1,2
Flora Tassone,1,3 Paul Ashwood,1,4 David Hessl,1,5
Andrea Schneider,1,5 Luis Campos,6 Danh V. Nguyen,6
and Randi J. Hagerman
1,7
1,7
1Medical Investigation of Neurodevelopmental Disorders (MIND)
Institute, University of California Davis Health System, 2825 50th Street,
Sacramento, CA 95817 USA
2Division of Growth and Development, Department of
Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital,
Chulalongkorn University, Bangkok, Thailand
3Department of Biochemistry and Molecular Medicine, School of
Medicine, University of California Davis, Davis, CA USA
4Department of Medical Microbiology and Immunology, School of
Medicine, University of California Davis, Davis, CA USA
5Department of Psychiatry and Behavioral Sciences, University
of California Davis Health System, Sacramento, CA USA
6Division of Biostatistics, Department of Public Health
Sciences, School of Medicine, University of California Davis, Davis, CA USA
7Department of Pediatrics, University of California Davis
Health System, Sacramento, CA USA
Randi J. Hagerman, Phone:
+1-916-7030247, Fax: +1-916-7030240, Email: randi.hagerman@ucdmc.ucdavis.edu.
Corresponding author.
Received June 16, 2010; Accepted
August 23, 2010.
This article has been cited by
other articles in PMC.
Abstract
An increased prevalence of
autoimmune diseases in family members of children with autism spectrum
disorders (ASD) has been previously reported. ASD is also a common problem
co-occurring in children with fragile X syndrome (FXS). Why ASD occurs in some
individuals with FXS, but not all, is largely unknown. Furthermore, in
premutation carrier mothers, there is an increased risk for autoimmune
diseases. This study compared the rate of ASD and other neurodevelopmental/behavioral
problems in 61 children with FXS born to 41 carrier mothers who had autoimmune
disease and in 97 children with FXS of 78 carrier mothers who did not have
autoimmune disease. There were no significant differences in the mean age
(9.61 ± 5.59 vs. 9.41 ± 6.31, P = 0.836),
cognitive and adaptive functioning in children of mothers with and without
autoimmune disease. Among children whose mothers had autoimmune disease, the
odds ratio (OR) for ASD was 1.27 (95% CI 0.62–2.61, P = 0.5115).
Interestingly, the OR for seizures and tics was 3.81 (95% CI 1.13–12.86, P = 0.031)
and 2.94 (95% CI 1.19–7.24, P = 0.019), respectively, in
children of mothers with autoimmune disease compared to children of mothers
without autoimmune disease. In conclusion, autoimmune disease in carrier
mothers was not associated with the presence of ASD in their children. However,
seizures and tics were significantly increased in children of mothers with
autoimmune disease. This suggests a potential new mechanism of seizure and tic
exacerbation in FXS related to an intergenerational influence from autoimmunity
in the carrier mother.
Introduction
There is a close connection between
immune function and development of the central nervous system (CNS). Both
systems interact across the life span of an individual so that successful
neurodevelopment requires a normal balance of immune responses (Ashwood et al. 2006; Delneste et al. 1999). Autism spectrum
disorders (ASD) are a complex group of heterogeneous neurodevelopmental
disorders with significant social and communication deficits in which
etiologies are mostly unknown. Recently, altered immunogenetics and a
dysfunctional immune system have been proposed to play a role in at least a
subgroup of children with ASD (Ashwood et al. 2006; Enstrom et al. 2009). In addition, an
increased prevalence of autoimmune disease in family members of children with
idiopathic ASD has been demonstrated in several studies (Atladottir et al. 2009; Comi et al. 1999; Money et al. 1971; Sweeten et al. 2003). Maternal
autoantibodies may also affect fetal brain development during critical periods
of neurodevelopment in a subset of children with ASD (Ashwood and Van de Water 2004; Dalton et al. 2003; Singer et al. 2006). Studies have
shown that when IgG from mothers of children diagnosed with ASD is injected
into pregnant rhesus monkeys, there are behavioral changes in the rhesus
offspring including abnormal stereotypical and hyperactive behaviors, compared
with offspring injected with IgG isolated from mothers of typically developing
children and controls (Martin et al. 2008). These findings
suggest a potential deleterious relationship between exposure to autoantibodies
against the fetal brain during gestation and the risk to develop ASD.
Fragile X syndrome (FXS) is the most
common known single gene cause of autism (Hagerman et al. 2008). The
prevalence of autism in individuals with FXS is approximately 30% (Kaufmann et
al. 2004; Rogers et
al. 2001) and pervasive
developmental disorder-not otherwise specified (PDD-NOS) is seen in an
additional 30% (Harris et al. 2008).
Therefore, the prevalence of ASD is approximately 60% in individuals with FXS
(Hagerman et al. 2008;
Harris et al. 2008). The
mechanism of ASD in FXS is hypothesized to be related to the deficit of FMRP
(the FMR1 protein) which regulates the translation of many genes that
are associated with autism (Chonchaiya et al. 2009; Hagerman et al. 2008; Wang
et al. 2010). Why ASD
occurs in some individuals with FXS, but not all, is largely unknown (Loesch et
al. 2007). Problems
affecting the CNS including seizures, malformations, or other genetic disorders
are more likely to occur in those with FXS and ASD compared with those with FXS
without ASD (Garcia-Nonell et al. 2008). Therefore, the
diagnosis of ASD in those with FXS may also be related to additional risks
including genetic and environmental factors leading to additional brain
dysfunction additive to the FMR1 mutation (Loesch et al. 2007).
The prevalence of autoimmune
diseases including autoimmune thyroid disease, lupus, multiple sclerosis (MS),
and fibromyalgia (with a postulated autoimmune component) are increased in
females with the FMR1 premutation (Buskila and Sarzi-Puttini 2008; Coffey et al. 2008; Di Franco et al. 2010; Greco et al. 2008; Rodriguez-Revenga
et al. 2009; Staines 2004; Zhang et al. 2009). These autoimmune
disorders in some premutation carriers are thought to be related to RNA
toxicity from elevated levels of FMR1 mRNA (Coffey et al. 2008; Greco et al. 2008; Zhang et al. 2009). Maternal autoimmunity
may play an additional role that further contributes to ASD or may be
associated with more severe ASD symptoms along the continuum of social deficits
in their children with FXS. However, the association between autoimmune disease
in mothers and the presence of ASD or other medical and behavioral problems
particularly tics [since tics and Tourette syndrome have a potential autoimmune
etiology through the mechanism of pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infection (PANDAS) (Martino et al. 2009a)] that perhaps
could be influenced by autoimmunity in their children with FXS has not been
studied previously. We therefore investigated whether autoimmune diseases/conditions
in mothers with the FMR1 premutation are associated with ASD or other
problems by comparing the offspring of mothers with and without autoimmune
disease (M + AI and M − AI).
Materials and methods
Subjects
Included in this study were children
with FXS (n = 158) with either the full mutation or mosaicism,
and their mothers (n = 119) whom were seen between 2003 and
2009 at the MIND Institute. This study was approved by the Institutional Review
Board of the University of California, Davis. The children with FXS in this
cohort were divided into children (n = 61) who were born to
mothers who had a history of autoimmune disease and children (n = 97)
whose mothers did not have autoimmune disease.
The diagnosis of autoimmune disease
in the mother was confirmed by a physician and these diseases include
autoimmune thyroid disease, systemic lupus erythematosus (SLE), rheumatoid
arthritis, multiple sclerosis (MS), Sjogren’s syndrome, psoriasis, optic
neuritis, Raynaud’s phenomenon, or fibromyalgia, which has a postulated
autoimmune component in its pathophysiology (Coffey et al. 2008; Di Franco et al. 2010; Greco et al. 2008; Staines 2004; Zhang et al. 2009). Sixty-one
children with FXS with a mean age of 9.61 years (SD 5.59) were born to 41
mothers with a mean age of 40.54 years (SD 7.96) who had experienced
autoimmune disease. They were compared to 97 children with FXS with a mean age
of 9.41 years (SD 6.31), born to 78 mothers with a mean age of
38.62 years (SD 6.46) without a history of clinically defined autoimmune
disease. Most mothers in each group [M + AI and M − AI, 23
(56.1%) vs. 59 (75.6%), respectively] had one child with FXS. There were 16
(39.0%) and 19 (24.4%) M + AI and M − AI, respectively, who
had two children with FXS. Two (4.9%) M + AI had three children with
FXS. Children with the FMR1 premutation born to these mothers were not
included in the study. A description of both mothers and children with FXS are
presented in Tables 1
and and22.
 |
Characteristics of mothers with
the fragile X premutation
|
 |
Characteristics of children with
FXS
|
Study protocol
All subjects underwent a full
medical history and physical examination by a physician with expertise in
fragile X-associated disorders (RJH) after informed consent was obtained. The
medical history covered an extensive review of prenatal, perinatal and
postnatal history and complications, developmental and behavioral variations
and problems for each child including developmental delay or regression of
development, tics (a sudden, repetitive, nonrhythmic, stereotyped motor
movement or vocalization involving discrete muscle groups, such as eye blinking,
shoulder shrugging, throat clearing, etc.; tics symptoms had to appear before
18 years of age and occur before taking stimulant medications if those
with FXS also have co-morbid attention deficit/hyperactivity disorders), sleep
problems (problems falling asleep or waking up at night), clinical seizures
(seizures characteristics, onset, duration, frequency, any co-occurring loss of
consciousness, other neurological deficit, associated symptoms, possible
triggers if they could be defined, electrical activity recorded by an
electroencephalography (EEG) testing, and anticonvulsant medications), other
pertinent medical problems, review of systems, and medications. Autoimmune
diseases/conditions in mothers were thoroughly obtained by self-report after questioning
about all potential autoimmune disorders in the medical history mentioned
above. Sometimes medical records (approximately 30%) of the mothers were
available for review in those with autoimmune problems during the visits at our
clinic; however, these data are not included in the analysis because it was not
consistently obtained. To be documented as having an autoimmune disease in the
mother or developmental, behavioral, and medical problems particularly
seizures, tics, and sleep problems in children with FXS, the subjects had to
have sought medical or pediatric professional help for their problems and to
have been previously diagnosed and/or treated by a physician for each
disease/condition (physician-documented clinical involvement). Each subject underwent
a medical examination that included a head circumference. A large head or
macrocephaly was defined as exceeding 2 standard deviations (SD) above normal
when compared with typically developing children of the same age.
The diagnosis of ASD in those with
FXS was made after the use of standardized measures including the Autism
Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview,
Revised (ADI-R) and the Diagnostic and Statistical Manual of Mental Disorders
(DSM IV) (American Psychiatric Association 2000; Le
Couteur et al. 1989;
Lord et al. 2000)
followed by a team consensus discussion as previously described (Harris et al. 2008).
The developmental or cognitive
abilities were assessed with age appropriate measures, including the Mullen
Scales of Early Learning, the Wechsler Preschool and Primary Scale of
Intelligence-Third Edition (WPPSI-III), the Wechsler Intelligence Scale for
Children-Third Edition (WISC-III), the Wechsler Intelligence Scale for
Children-Fourth Edition (WISC-IV), the Wechsler Abbreviated Scale of
Intelligence (WASI), the Wechsler Adult Intelligence Scale-Third Edition
(WAIS-III) or the Stanford-Binet Intelligence Scale, Fourth Edition. Children’s
adaptive functioning was also assessed using the Vineland Adaptive Behavioral
Scales, Second Edition (Vineland-II) by interviewing the caregivers (Mullen 1995;
Sparrow et al. 2005;
Thorndike et al. 1986;
Wechsler 1991,
1997, 1999, 2002, 2003).
Intellectual disability was defined as IQ less than 70.
Behavioral and emotional problems
including externalizing behaviors (hyperactivity, aggression, and conduct
problems), internalizing behaviors (anxiety, depression, and somatization),
atypicality, withdrawal, attention problems, and adaptive skills (adaptability,
social skills, leadership, activities of daily living, and functional
communication) were completed by a limited percentage of parents for each group
of children with FXS (autoimmune disease vs. no autoimmune disease, 72.1 vs.
54.6%) using Behavior Assessment System for Children (BASC) questionnaire
(Reynolds and Kamphaus 1992, 2004).
Behavior Symptoms Index (BSI), a measure of an overall level of problems
consisting of the hyperactivity, aggression, depression, attention problems,
atypicality and withdrawal scales, was also documented. The BASC parent rating
scale yields T scores with a mean of 50 and a SD of 10. On the clinical
scales, scores from 60 to 69 are in the “at-risk” range and scores of 70 and
above indicate “clinically significant” problems. On the adaptive skill scales
of the BASC, scores from 31 to 40 indicate “at-risk” problems and scores of 30
and lower are considered “clinically significant.” In this study,
externalizing, internalizing behaviors, and BSI scores 60 or above were defined
as having those problems accordingly, whereas deficits in adaptive skills were
defined in which adaptive skills scores are 40 or lower. Table 3
lists the variables investigated statistically between both groups of children.
 |
Neurodevelopmental and behavioral
problems between both groups of children
|
Molecular analysis
A blood sample for measurement of
methylation status, CGG repeat, and FMR1 mRNA levels were obtained from
each subject (both mothers and children with FXS). FMR1 mRNA
quantification, Southern Blot and PCR-based genotyping were performed as
previously described (Tassone et al. 2000; Tassone et al. 2008).
Statistical analysis
Qualitative variables for which
there were specified cut-offs including autoimmune disease in mothers, the
diagnosis of ASD, intellectual disability, seizures, sleep problems, tics,
macrocephaly, externalizing, internalizing behaviors, BSI and deficits in
adaptive skills were rated dichotomously (presence or absence) as demonstrated
in Table 3.
Univariate analysis of continuous variables including age, CGG repeat size, FMR1
mRNA level, activation ratio (AR: the fraction of normal FMR1 allele as
the active allele in female individuals with FXS), IQ, and adaptive functioning
was based on t test. Fisher’s exact test for 2 × 2 contingency
table analyses were used to assess the association between autoimmune status in
the mothers of children with FXS and the diagnosis of ASD. Results are
presented in terms of odds ratio (OR) and 95% confidence interval (95% CI). P
value and 95% confidence interval (CI) relating to the primary hypotheses of
whether there is an association of autoimmune disease in mothers to ASD in
children with FXS was based on a logistic regression model using generalized
estimating equations. This approach accounts for correlation within a family
(i.e. mother–children correlation) in estimates of standard errors, although
this did not make a material difference in the results. Also, models were
explored with adjusting for mother’s age, child’s age, gender, number of
offspring, whether a mother had a child before or after age 35, CGG repeat
numbers, and mRNA levels. All covariates were not significant and adjusted OR
estimates did not differ from OR estimates from models with only the main
variable of interest—the presence of autoimmune disease. Thus, we reported this
simple later model with main effect of interest. An exception is for the variable
gender in the model of BSI outcome (as noted in Table 3;
see “Results”).
However, we did not adjust for multiple testing and the reason for this is that
our original primary hypothesis relates to investigating the association
between autoimmune disease in the mothers and ASD. Neurodevelopmental and
behavioral outcomes, particularly the collection of BASC variables, were
exploratory. BASC T scores were analyzed using general linear model
adjusted for age and accounting for within-in family correlation and variation
among subjects. All P reported are two-sided and the significance level
is 0.05.
Results
Characteristics of subjects
Characteristics of the mothers and
their offspring with FXS are illustrated in Tables 1
and and2,2,
respectively. There was no significant difference in mean age between
M + AI and M − AI [40.54 (SD 7.96) vs. 38.62 (SD 6.46)
years, P = 0.238]. There were no significant differences in
molecular variables including CGG repeats, FMR1 mRNA levels, and AR
between both groups of mothers. The two most common autoimmune disorders in the
mothers were autoimmune thyroid diseases (27/41, 65.9%), and fibromyalgia
(11/41, 26.8%). MS and Raynaud’s phenomenon were present at a similar rate in
the mothers at 12.2% (5/41). Four (4/41, 9.8%) mothers reported to have been
diagnosed with rheumatoid arthritis and three (3/41, 7.3%) mothers reported having
SLE. Other reported autoimmune diseases included Sjogren syndrome (1/41), optic
neuritis (1/41), and psoriasis for each disease (1/41). Of the
41 M + AI, there were 29 who presented with a single autoimmune
disease, whereas a further 12 reported having two or more autoimmune diseases.
Twenty (48.8%) mothers had autoimmune thyroid disease alone and 3 (7.3%)
mothers had been diagnosed with fibromyalgia alone. In 23 (56.1%) mothers, the
mean age of diagnosis with autoimmune disease was 30.26 (SD 9.45) years.
The remainder of the group neither recalled the onset of the autoimmune disease
nor the data for the onset of autoimmune disease in medical records were
collected before the association between autoimmune disease in the mothers and
the presence of ASD in their offspring with FXS was hypothesized.
Of the 41 mothers, 13 stated that
their autoimmune disease occurred during their gestation. However, a precise
ascertainment of the age of onset or diagnosis for each autoimmune disease
based on self-report was very difficult due to the fact that the natural course
of many autoimmune diseases can include a subclinical phase that does not meet
stringent clinical diagnosis (Papi et al. 2007; Poppe and Glinoer 2003; Ulff-Moller et al.
2009).
There was significant difference
neither in the mean age of children with FXS in the two groups [9.61 (SD 5.59)
vs. 9.41 (SD 6.31) years, in children born of M + AI and
M − AI, respectively, P = 0.836] nor in the type of
the fragile X mutation (percentage of full
mutation/mosaic = 78.7/21.3% vs. 79.4/20.6%, P = 0.876].
With regard to gender, there were fewer male children with FXS born to
M + AI when compared with children with FXS of M − AI (60.7
vs. 78.4%, P = 0.016). Mean cognitive ability in both groups
of children with FXS was in a mild range of intellectual disability and was not
significantly different between groups [FSIQ = 62.75 (SD 17.77) vs.
60.80 (SD 17.55), in children born of M + AI and M − AI,
respectively, P = 0.523]. Likewise, the adaptive behavior
composite score documented by the Vineland between both groups of children with
FXS was not significantly different [64.33 (SD 18.51) vs. 63.62 (SD 18.71), in
children born of M + AI and M − AI, respectively, P = 0.847].
Autoimmune disease, ASD, and other
neurodevelopmental problems
Of the 61 children with FXS born to
M + AI, 38 (62.3%) children met the criteria for ASD. Twenty-two
(36.07%) subjects had autism and 16 (26.23%) had PDD-NOS. Of the 32 mothers
with children that had FXS and ASD, autoimmune thyroid disease was present in
22 (67.6%), fibromyalgia in 8 (25.0%), and Raynaud’s phenomenon in 4 (12.5%).
Among children from M + AI, the odds ratio (OR) for FXS and ASD was
1.27 (95% CI 0.62–2.61, P = 0.5115). These data suggest that
autoimmune disease in the mothers may not be a relevant risk factor for autism
in combination with FXS. Other variables including intellectual disability,
sleep problems, and macrocephaly were not different between both groups of
children. However, the rate of tics was significantly higher in the group of
children with FXS born to M + AI (15/58, 25.86%) compared with
M − AI [10/94, 10.64%; OR = 2.94 (95% CI 1.19–7.24), p = 0.019].
Autoimmune disease and seizures
Data about seizures were not
available for three children. However, a higher rate of clinical seizures was
observed in a group of children with FXS born to M + AI (9/60, 15.0%)
when compared with children with FXS of M − AI [4/95, 4.21%;
OR = 3.81 (95% CI 1.13–12.86), P = 0.031]. Details
of the nine children with FXS who have seizures and were born to
M + AI are as follows: age range, 4.17–24 years (median age
9 years); gender, 7 boys and 2 girls; FMR1 mutations, six have the
full mutation and three have mosaicism in the FMR1 gene. Three have more
than one seizures type including complex partial seizures, generalized
seizures, gelastic seizures and absence seizures, four had generalized
tonic-clonic convulsions alone, and two experienced petit mal or absence
seizures alone. Seizures onset ranged from 17 months to 9 years with
a median age of onset at 3 years. With regard to treatment of seizures, seven
subjects reported to take long-term anticonvulsant medications. Four of these
seven subjects took more than one anticonvulsants to control the seizures. Of
these nine children with FXS born to M + AI who developed clinical
seizures, eight mothers had autoimmune thyroid disease. There was no history of
birth asphyxia or neonatal encephalopathy. The cognitive abilities of children
with seizures were similar to the whole group of children with FXS.
Details of four children with FXS
who had seizures born to M − AI are as follows: age range
3.63–17.75 years (median age 8.25 years), gender 3 boys and 1 girl,
all have the full mutation in the FMR1 gene; one reported to have more
than one seizure type including absence, complex partial seizures, and
generalized seizures, one experienced absence seizures alone, one had partial
seizures alone, and one subject was noted to have two episodes of simple
febrile seizures but this child has never taken any medications. Seizures onset
in this group ranged from 2.67 to 5 years with a median age of onset at
3.84 years. Abnormal EEG results were confirmed in all subjects in this
group of children. With regard to anticonvulsant medications, one child has
taken more than one medication to treat the seizures and seizures were well
controlled by one medication in two subjects in this group.
Autoimmune disease and behavioral
problems
Behavioral and emotional problems
documented by BASC were completed in 97 (61.4%) children with FXS in our study.
The children’s age, gender and type of the fragile X mutations were not
significantly different between both groups (children of M + AI and
M − AI). The rate of externalizing behaviors [36.36 vs. 16.98%;
OR = 3.04 (95% CI 1.10–8.38), P = 0.0319] was
increased in children with FXS born to M + AI. T scores of
these behavioral and emotional problems between both groups of children are
illustrated in Table 4.
Children with FXS born to M + AI were likely to have higher T
scores on aggression, internalizing behaviors, depression, withdrawal symptoms,
and BSI when compared with those children with FXS born to M − AI,
even though only withdrawal symptoms and BSI scale reached a significant level
for documenting the problems.
 |
Parent rating scale (T
score) of behavioral and emotional problems documented by BASC between both
groups of children
|
Discussion
This is the first study
investigating the intergenerational association between the presence of
co-morbid ASD, medical problems, and behavioral problems in the children with
FXS of M + AI. Evidence of an increased prevalence of autoimmune
disorders including hypothyroidism, Hashimoto’s thyroiditis, type 1 diabetes,
rheumatoid arthritis, SLE and ulcerative colitis have been reported in parents
of children with idiopathic ASD in previous studies (Atladottir et al. 2009; Comi et al. 1999; Croen et al. 2005; Money et al. 1971; Mouridsen et al. 2007; Sweeten et al. 2003). However, this
finding was not replicated in all studies (Micali et al. 2004). Our clinical
sample of children with FXS did not support this finding. Therefore,
autoimmunity in the mothers may not be significantly associated with ASD in the
offspring with FXS. A mutation in the FMR1 gene alone involves
significant dysregulation of numerous genes whose translation is controlled by
FMRP leading to significant deficits in synaptic plasticity and ASD (Chonchaiya
et al. 2009).
Interesting findings were that the
rates of seizures, tics, and externalizing problems documented by the BASC
which were significantly increased in the group of children with FXS of
M + AI. The overall prevalence of seizures in children with FXS in
both groups of M + AI and M − AI was similar to the 10–20%
rate seizures previously reported in FXS (Berry-Kravis 2002; Musumeci et al. 1999).
The pathophysiology of seizures in
those with FXS is hypothesized to be related to the imbalance of the excitatory
and inhibitory neurotransmitter systems, especially the mGluR5 pathway and the
gamma-aminobutyric acid A (GABAA) pathway in the absence of FMRP.
There is a lower expression of GABA receptors in the fragile X knock out (KO)
mouse (D’Hulst et al. 2006)
and an increased expression of glutamic acid decarboxylase (GAD), the enzyme
responsible for GABA synthesis in the KO mouse (El Idrissi et al. 2005). Interestingly,
other factors including autoimmunity or immune-mediated responses may influence
these pathways leading to seizures. For instance, the presence of autoantibody
to GAD was demonstrated in the sera of non-fragile X patients with early onset
of chronic drug-resistant epilepsy leading to loss of GAD and decreased GABA
synthesis that ultimately contributed to a lower seizure threshold (McKnight et
al. 2005). In
addition, autoantibodies to GluR3B-peptide of
glutamate/α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor
subtype 3 or to a peptide of N-methyl-d-aspartate (NMDA) receptor
subunit 2A (NR2A) subunit of glutamate/NMDA receptors have been found to be
elevated in non-fragile X patients with epilepsy (Ganor et al. 2005). However, there
are no studies of autoimmunity in mothers of children with epilepsy or seizures
available. Moreover, the impact of autoimmunity on seizures in individuals with
FXS has not been studied and our work provides just the first step in this direction.
This study suggests that autoimmunity in the mother may influence the risk of
seizures in the offspring with FXS.
A tic disorder has been reported in
approximately 20% in individuals with FXS (Hagerman 2002). The
pathophysiology of tic disorders is quite complex. There are genetic and
environmental influences that involve a number of brain structures including
basal ganglia, cortico-striato-thalamo-cortical circuits, dopaminergic,
glutamatergic, and the serotoninergic neuronal system (Harris and Singer 2006; Rampello et al. 2006). Although there is
familial aggregation in those with Tourette syndrome, the most severe and
chronic form of a tic disorder, but family members also share common
environmental factors in addition to their similar genetic backgrounds
(O’Rourke et al. 2009).
The potential role of various abnormal immune-mediated responses followed by
different triggers/factors causing or exacerbating tics or Tourette syndrome
has been previously reported in conditions including PANDAS, possible
involvement of non-streptococcal and viral infection in aggravating tics
symptoms, or the presence of different antibodies/auto-antibodies in either
sera or against striatal structures in human subjects, and animal models,
respectively. These antibodies include anti-phospholipid auto-antibodies and
antineuronal antibodies (Martino et al. 2009a; Morer et al. 2008; Rampello et al. 2006). There are no
studies of other autoimmunity in mothers of children with tics or Tourette
syndrome available, although there are family studies that show a higher
incidence of Tourette syndrome in the parents and the etiology in a subgroup of
those with Tourette syndrome includes autoantibodies against the basal ganglia
as mentioned above so this can also be an autoimmune disease itself (Martino et
al. 2009b; O’Rourke
et al. 2009).
Therefore, an increase rate of tics in our study may suggest another potential
hypothesis that future studies should take into account of autoimmunity in the
mothers or the inheritance of autoimmune tendencies in their offspring with FXS
may be related to a higher rate of tics in these children.
Taken together, our findings suggest
that future studies should consider how autoimmunity in the mothers may interact
with the FMR1 mutation to disrupt critical networks in the brain,
particularly GABA and glutamate systems or perhaps through other mechanisms
leading to clinical seizures, tics, and behavioral problems in their offspring
with FXS. Children with FXS born to M + AI may be genetically more
prone to produce antibodies that exacerbate an underlying seizure and tic
tendency in FXS. This hypothesis requires further prospective study with larger
sample sizes.
The weaknesses of our study includes
a clinical sample with an assessment of autoimmune disease that is documented
only by medical history which can be influenced by poor recall, small numbers
of study subjects and the lack of documentation of specific antibodies that may
affect the offspring. However, a possible association between the autoimmunity
in mothers and medical and neurodevelopmental problems in their children with
FXS was assessed years after our routine data collection and therefore was
blinded and unbiased regarding autoimmune disease in the mother. Although there
were gender differences between both groups of offspring, other characteristics
particularly age, molecular data, cognitive abilities, and adaptive functioning
were not significantly different between both groups of offspring. The gender
difference was accounted for in the analyses using logistic regression and
general linear models. However, if we had had more male offspring of
M + AI, it is likely that we would have found more significant
differences between the two groups of children because boys with FXS have a
higher rate of intellectual and behavioral impairments including autism
compared to girls with FXS.
An important limitation of the
current study relates to our statistically significant findings (e.g. seizures,
tics, and BASC behavioral outcome) among our exploratory/secondary variables.
Although these findings suggest specific outcomes to examine in future studies,
these statistically significant findings are not adjusted for multiple testing;
thus, the overall type I error rate is inflated. Mothers provided data
regarding their own medical history and their offspring’s behavioral data, it
is possible that psychological factors, such as anxiety or depression
associated with autoimmune disease or the premutation could have introduced a
negative bias in these behavioral ratings. This point, however, raises another
potential explanation for our findings, specifically high rates of stress and
anxiety associated with raising children with FXS could potentially contribute
to a pro-inflammatory environment that may facilitate autoimmunity tendency in
the premutation mothers (Stojanovich 2010; Stojanovich and
Marisavljevich 2008).
The issue regarding whether or not the autoimmune disease occurred during the
gestation cannot be accurately assessed with this retrospective data.
Therefore, prospectively collected data is needed to investigate risk during
pregnancy and biological markers of immune function should be obtained to
elucidate this possible intergenerational relationship.
In conclusion, autoimmune disease in
mothers was not significantly associated with the presence of ASD in their
children with FXS. However, clinical seizures, tics, and behavioral problems
were significantly increased in children with FXS born to M + AI.
These data suggest an additional mechanism of seizure and tic exacerbation in
FXS related to an intergenerational influence from autoimmunity in the mother.
Acknowledgments
This work was supported by National
Institute of Health Grants HD036071, and HD02274; Neurotherapeutic Research
Institute (NTRI) Grants DE019583, and DA024854; National Institute on Aging
Grants AG032119 and AG032115; National Institute of Mental Health Grant
MH77554; National Center for Resources UL1 RR024146; and support from the
Health and Human Services Administration of Developmental Disabilities Grant
90DD05969. We also thank Antoniya Boyd and Jacky Au from the UC Davis MIND.
Institute for their help with data processing and providing some BASC
questionnaires to the parents, respectively.
Conflict of interest Randi Hagerman has received funding from Seaside
Therapeutics, Roche, Novartis, Neuropharm, Forest, Johnson and Johnson, and
Curemark to carry out treatment trials. There are no other conflicts of
interest from the authors.
Open Access This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits any noncommercial use,
distribution, and reproduction in any medium, provided the original author(s)
and source are credited.
References
- Diagnostic and Statistical Manual of Mental Disorders, text revised, 4th edn. Washington, DC: American Psychiatric Association; 2000.
- Ashwood P, Water J. Is autism an autoimmune disease? Autoimmun Rev. 2004;3:557–562. doi: 10.1016/j.autrev.2004.07.036. [PubMed] [Cross Ref]
- Ashwood P, Wills S, Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006;80:1–15. doi: 10.1189/jlb.1205707. [PubMed] [Cross Ref]
- Atladottir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, Parner ET. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics. 2009;124:687–694. doi: 10.1542/peds.2008-2445. [PubMed] [Cross Ref]
- Berry-Kravis E. Epilepsy in fragile X syndrome. Dev Med Child Neurol. 2002;44:724–728. doi: 10.1111/j.1469-8749.2002.tb00277.x. [PubMed] [Cross Ref]
- Buskila D, Sarzi-Puttini P. Fibromyalgia and autoimmune diseases: the pain behind autoimmunity. Isr Med Assoc J. 2008;10:77–78. [PubMed]
- Chonchaiya W, Schneider A, Hagerman RJ. Fragile X: a family of disorders. Adv Pediatr. 2009;56:165–186. doi: 10.1016/j.yapd.2009.08.008. [PMC free article] [PubMed] [Cross Ref]
- Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R, Bronsky HE, Yuhas J, Borodyanskaya M, Grigsby J, Doerflinger M, Hagerman PJ, Hagerman RJ. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A. 2008;146:1009–1016. [PMC free article] [PubMed]
- Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999;14:388–394. doi: 10.1177/088307389901400608. [PubMed] [Cross Ref]
- Croen LA, Grether JK, Yoshida CK, Odouli R, Water J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch Pediatr Adolesc Med. 2005;159:151–157. doi: 10.1001/archpedi.159.2.151. [PubMed] [Cross Ref]
- D’Hulst C, Geest N, Reeve SP, Dam D, Deyn PP, Hassan BA, Kooy RF. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 2006;1121:238–245. doi: 10.1016/j.brainres.2006.08.115. [PubMed] [Cross Ref]
- Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A. Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol. 2003;53:533–537. doi: 10.1002/ana.10557. [PubMed] [Cross Ref]
- Delneste Y, Herbault N, Galea B, Magistrelli G, Bazin I, Bonnefoy JY, Jeannin P. Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation. J Immunol. 1999;163:3071–3075. [PubMed]
- Di Franco M, Iannuccelli C, Valesini G. Neuroendocrine immunology of fibromyalgia. Ann N Y Acad Sci. 2010;1193:84–90. doi: 10.1111/j.1749-6632.2009.05344.x. [PubMed] [Cross Ref]
- El Idrissi A, Ding XH, Scalia J, Trenkner E, Brown WT, Dobkin C. Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse. Neurosci Lett. 2005;377:141–146. doi: 10.1016/j.neulet.2004.11.087. [PubMed] [Cross Ref]
- Enstrom AM, Water JA, Ashwood P. Autoimmunity in autism. Curr Opin Investig Drugs. 2009;10:463–473. [PubMed]
- Ganor Y, Goldberg-Stern H, Lerman-Sagie T, Teichberg VI, Levite M. Autoimmune epilepsy: distinct subpopulations of epilepsy patients harbor serum autoantibodies to either glutamate/AMPA receptor GluR3, glutamate/NMDA receptor subunit NR2A or double-stranded DNA. Epilepsy Res. 2005;65:11–22. doi: 10.1016/j.eplepsyres.2005.03.011. [PubMed] [Cross Ref]
- Garcia-Nonell C, Ratera ER, Harris S, Hessl D, Ono MY, Tartaglia N, Marvin E, Tassone F, Hagerman RJ. Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorder. Am J Med Genet A. 2008;146A:1911–1916. doi: 10.1002/ajmg.a.32290. [PubMed] [Cross Ref]
- Greco CM, Tassone F, Garcia-Arocena D, Tartaglia N, Coffey SM, Vartanian TK, Brunberg JA, Hagerman PJ, Hagerman RJ. Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis. Arch Neurol. 2008;65:1114–1116. doi: 10.1001/archneur.65.8.1114. [PMC free article] [PubMed] [Cross Ref]
- Hagerman RJ. Physical and behavioral phenotype. In: Hagerman RJ, Hagerman PJ, editors. Fragile X syndrome: diagnosis, treatment and research. 3. Baltimore: The Johns Hopkins University Press; 2002. pp. 3–109.
- Hagerman RJ, Rivera SM, Hagerman PJ. The fragile X family of disorders: a model for autism and targeted treatments. Curr Pediatr Rev. 2008;4:40–52. doi: 10.2174/157339608783565770. [Cross Ref]
- Harris K, Singer HS. Tic disorders: neural circuits, neurochemistry, and neuroimmunology. J Child Neurol. 2006;21:678–689. doi: 10.1177/08830738060210080901. [PubMed] [Cross Ref]
- Harris SW, Hessl D, Goodlin-Jones B, Ferranti J, Bacalman S, Barabato I, Tassone F, Hagerman PJ, Herman K, Hagerman RJ. Autism profiles of males with fragile X syndrome. Am J Mental Retard. 2008;113:427–438. doi: 10.1352/2008.113:427-438. [Cross Ref]
- Kaufmann WE, Cortell R, Kau AS, Bukelis I, Tierney E, Gray RM, Cox C, Capone GT, Stanard P. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet. 2004;129A:225–234. doi: 10.1002/ajmg.a.30229. [PubMed] [Cross Ref]
- Le Couteur A, Rutter M, Lord C, Rios P, Robertson S. Autism diagnostic interview: a standardized investigator-based instrument. J Autism Dev Disord. 1989;19:363–387. doi: 10.1007/BF02212936. [PubMed] [Cross Ref]
- Loesch DZ, Bui QM, Dissanayake C, Clifford S, Gould E, Bulhak-Paterson D, Tassone F, Taylor AK, Hessl D, Hagerman R, Huggins RM. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev. 2007;31:315–326. doi: 10.1016/j.neubiorev.2006.09.007. [PMC free article] [PubMed] [Cross Ref]
- Lord C, Risi S, Lambrecht L, Cook EH, Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30:205–223. doi: 10.1023/A:1005592401947. [PubMed] [Cross Ref]
- Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun. 2008;22:806–816. doi: 10.1016/j.bbi.2007.12.007. [PubMed] [Cross Ref]
- Martino D, Dale RC, Gilbert DL, Giovannoni G, Leckman JF. Immunopathogenic mechanisms in Tourette syndrome: a critical review. Mov Disord. 2009;24:1267–1279. doi: 10.1002/mds.22504. [PubMed] [Cross Ref]
- Martino D, Defazio G, Giovannoni G. The PANDAS subgroup of tic disorders and childhood-onset obsessive-compulsive disorder. J Psychosom Res. 2009;67:547–557. doi: 10.1016/j.jpsychores.2009.07.004. [PubMed] [Cross Ref]
- McKnight K, Jiang Y, Hart Y, Cavey A, Wroe S, Blank M, Shoenfeld Y, Vincent A, Palace J, Lang B. Serum antibodies in epilepsy and seizure-associated disorders. Neurology. 2005;65:1730–1736. doi: 10.1212/01.wnl.0000187129.66353.13. [PubMed] [Cross Ref]
- Micali N, Chakrabarti S, Fombonne E. The broad autism phenotype: findings from an epidemiological survey. Autism. 2004;8:21–37. doi: 10.1177/1362361304040636. [PubMed] [Cross Ref]
- Money J, Bobrow NA, Clarke FC. Autism and autoimmune disease: a family study. J Autism Child Schizophr. 1971;1:146–160. doi: 10.1007/BF01537954. [PubMed] [Cross Ref]
- Morer A, Lazaro L, Sabater L, Massana J, Castro J, Graus F. Antineuronal antibodies in a group of children with obsessive-compulsive disorder and Tourette syndrome. J Psychiatr Res. 2008;42:64–68. doi: 10.1016/j.jpsychires.2006.09.010. [PubMed] [Cross Ref]
- Mouridsen SE, Rich B, Isager T, Nedergaard NJ. Autoimmune diseases in parents of children with infantile autism: a case–control study. Dev Med Child Neurol. 2007;49:429–432. doi: 10.1111/j.1469-8749.2007.00429.x. [PubMed] [Cross Ref]
- Mullen EM. Mullen scales of early learning. Circle Pines: American Guidance Service; 1995.
- Musumeci SA, Hagerman RJ, Ferri R, Bosco P, Dalla Bernardina B, Tassinari CA, Sarro GB, Elia M. Epilepsy and EEG findings in males with fragile X syndrome. Epilepsia. 1999;40:1092–1099. doi: 10.1111/j.1528-1157.1999.tb00824.x. [PubMed] [Cross Ref]
- O’Rourke JA, Scharf JM, Yu D, Pauls DL. The genetics of Tourette syndrome: a review. J Psychosom Res. 2009;67:533–545. doi: 10.1016/j.jpsychores.2009.06.006. [PMC free article] [PubMed] [Cross Ref]
- Papi G, Uberti ED, Betterle C, Carani C, Pearce EN, Braverman LE, Roti E. Subclinical hypothyroidism. Curr Opin Endocrinol Diabetes Obes. 2007;14:197–208. [PubMed]
- Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update. 2003;9:149–161. doi: 10.1093/humupd/dmg012. [PubMed] [Cross Ref]
- Rampello L, Alvano A, Battaglia G, Bruno V, Raffaele R, Nicoletti F. Tic disorders: from pathophysiology to treatment. J Neurol. 2006;253:1–15. doi: 10.1007/s00415-005-0008-8. [PubMed] [Cross Ref]
- Reynolds CR, Kamphaus RW. BASC Behavior Assessment System for Children Manual. Circle Pines: American Guidance Service; 1992.
- Reynolds CR, Kamphaus RW. BASC-2 behavior assessment system for children, 2nd edn. Circle Pines: AGS Publishing; 2004.
- Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xuncla M, Badenas C, Kulisevsky J, Gomez B, Mila M. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 2009;17:1359–1362. doi: 10.1038/ejhg.2009.51. [PMC free article] [PubMed] [Cross Ref]
- Rogers SJ, Wehner EA, Hagerman RJ. The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr. 2001;22:409–417. [PubMed]
- Singer HS, Morris CM, Williams PN, Yoon DY, Hong JJ, Zimmerman AW. Antibrain antibodies in children with autism and their unaffected siblings. J Neuroimmunol. 2006;178:149–155. doi: 10.1016/j.jneuroim.2006.05.025. [PubMed] [Cross Ref]
- Sparrow SS, Cicchetti DV, Balla DA. Vineland adaptive behavior scales. 2. Circle Pines: AGS Publishing; 2005.
- Staines DR. Is fibromyalgia an autoimmune disorder of endogenous vasoactive neuropeptides? Med Hypotheses. 2004;62:665–669. doi: 10.1016/j.mehy.2004.01.003. [PubMed] [Cross Ref]
- Stojanovich L. Stress and autoimmunity. Autoimmun Rev. 2010;9:A271–A276. doi: 10.1016/j.autrev.2009.11.014. [PubMed] [Cross Ref]
- Stojanovich L, Marisavljevich D. Stress as a trigger of autoimmune disease. Autoimmun Rev. 2008;7:209–213. doi: 10.1016/j.autrev.2007.11.007. [PubMed] [Cross Ref]
- Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics. 2003;112:e420. doi: 10.1542/peds.112.5.e420. [PubMed] [Cross Ref]
- Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet. 2000;66:6–15. doi: 10.1086/302720. [PMC free article] [PubMed] [Cross Ref]
- Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ. A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn. 2008;10:43–49. doi: 10.2353/jmoldx.2008.070073. [PMC free article] [PubMed] [Cross Ref]
- Thorndike RL, Hagen E, Sattler J. Stanford–Binet intelligence scale. 4. Itasca: Riverside Publishing; 1986.
- Ulff-Moller CJ, Jorgensen KT, Pedersen BV, Nielsen NM, Frisch M. Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark. J Rheumatol. 2009;36:1903–1909. doi: 10.3899/jrheum.090002. [PubMed] [Cross Ref]
- Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010;7:264–274. doi: 10.1016/j.nurt.2010.05.005. [PubMed] [Cross Ref]
- Wechsler D. Wechsler intelligence scale for children, (WISC-III), 3rd edn. San Antonio: The Psychological Corporation; 1991.
- Wechsler D. Wechsler adult intelligence scale: administration and scoring manual, 3rd edn. San Antonio: Harcourt Assessment; 1997.
- Wechsler D. Wechsler abbreviated scale of intelligence (WASI) San Antonio: Harcourt Assessment; 1999.
- Wechsler D. Wechsler preschool and primary scale of intelligence. 3. San Antonio: The Psychological Corporation; 2002.
- Wechsler D. Wechsler intelligence scale for children. 4. San Antonio: Harcourt Assessment.; 2003.
- Zhang L, Coffey S, Lua LL, Greco CM, Schafer JA, Brunberg J, Borodyanskaya M, Agius MA, Apperson M, Leehey M, Tartaglia N, Tassone F, Hagerman PJ, Hagerman RJ. FMR1 premutation in females diagnosed with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80:812–814. doi: 10.1136/jnnp.2008.160960. [PubMed] [Cross Ref]
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Is autism an autoimmune disease? This article is a pay article so to view in it’s entirety you must go to the website and pay for it.
http://www.sciencedirect.com/science/article/pii/S1568997204001120
- Paul Ashwood,
- Judy Van de Water
, 
- Department of Internal Medicine, Division of Rheumatology, and UC Davis M.I.N.D. Institute, University of California, Davis, 95616, United States
- Accepted 17 July 2004. Available online 3 October 2004.
- http://dx.doi.org/10.1016/j.autrev.2004.07.036, How to Cite or Link Using DOI
- Cited by in Scopus (52)
Abstract
Autism spectrum disorder (ASD) is a spectrum of behavioral anomalies characterized by impaired social interaction and communication, often accompanied by repetitive and stereotyped behavior. The condition manifests within the first 3 years of life and persists into adulthood. There are numerous hypotheses regarding the etiology and pathology of ASD, including a suggested role for immune dysfunction. However, to date, the evidence for involvement of the immune system in autism has been inconclusive. While immune system abnormalities have been reported in children with autistic disorder, there is little consensus regarding the nature of these differences which include both enhanced autoimmunity and reduced immune function. In this review, we discuss current findings with respect to immune function and the spectrum of autoimmune phenomena described in children with ASD.
Autism
tied to autoimmune diseases in immediate family http://www.usatoday.com/news/health/2009-07-12-autism13_N.htm
|
By Liz Szabo, USA
TODAY
Danish researchers have found
another clue to the mysterious causes of autism, according to a study published
online this month in Pediatrics.
In a study of children born in Denmark from 1993 to 2004, doctors
found that many children with autism or related disorders also had a family
history of autoimmune diseases. Autoimmune diseases, such as type 1 diabetes
and rheumatoid arthritis,
develop when antibodies that normally fight infectious organisms instead attack
the body itself.
In the study, doctors examined
patterns of disease among children, mothers, fathers and siblings.
For the first time, researchers
found an increased risk of autism spectrum disorders in children whose mothers
have celiac disease, a digestive condition in which people cannot tolerate
gluten, a protein found in wheat, rye and barley. Autism spectrum disorders
include a range of neurological problems affecting communication and
socializing.
The study also confirms the results
of many earlier papers, says author Hjördis Atladottir of Denmark's University of Aarhus.
For example, doctors found an increased risk of autism in children with a
family history of type 1 diabetes and an increased risk of autism spectrum
disorders in children whose mothers have rheumatoid arthritis.
Researchers say their study leaves
many questions unanswered. But they say it's possible babies are affected by
their mother's antibodies while in the womb. Their mother's disease also may
create an abnormal environment.
Although the study is designed to
find associations among diseases, it is not able to prove that autoimmune
disorders cause autism, says the University of
Washington's Karen Toth, a clinical psychologist who was not involved in
the study.
But Toth says it's possible that the
same genes are involved in autoimmune diseases and autism. Researchers have
known for many years that autism can run in families, Toth says. And scientists
have found genes that may be involved in autism.
Children may also have an increased
risk if they are exposed in the womb to certain drugs — such as thalidomide,
valproic acid or cocaine — or to infectious diseases such as rubella, Toth
says.
Recent studies also have found that
babies born prematurely have higher risks of autism.
Children also are at higher risk if
their fathers are older than 40 or if children have conditions such as epilepsy
or Fragile X syndrome, which causes mental retardation, according to the Mayo Clinic.
People with autoimmune diseases
shouldn't be alarmed, Atladottir says. The vast majority of people with these
conditions do not have children with autism, he says. In the study, only 3,325
of the more than 689,196 children studied were diagnosed with autism spectrum
disorders.
Association of Schizophrenia and
Autoimmune Diseases: Linkage of Danish National Registers
Am J
Psychiatry 2006;163:521-528. 10.1176/appi.ajp.163.3.521
text A A A
OBJECTIVE:
Individuals
with schizophrenia and their relatives tend to have either higher or lower than
expected prevalences of autoimmune disorders, especially rheumatoid arthritis,
celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose
of the study was to estimate the association of schizophrenia with these
disorders as well as a range of other autoimmune diseases in a single large
epidemiologic study. METHOD: The
Danish Psychiatric Register, the National Patient Register, and a register with
socioeconomic information were linked to form a data file that included all
7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their
parents along with a sample of matched comparison subjects and their parents.
The data linkage required that the autoimmune disease occur before the
diagnosis of schizophrenia. RESULTS: A
history of any autoimmune disease was associated with a 45% increase in risk
for schizophrenia. Nine autoimmune disorders had higher prevalence rates among
patients with schizophrenia than among comparison subjects (crude incidence
rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher
prevalence rates among parents of schizophrenia patients than among parents of
comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8).
Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial
cystitis, and Sjögren’s syndrome had higher prevalence rates among patients
with schizophrenia than among comparison subjects and also among family members
of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is
associated with a larger range of autoimmune diseases than heretofore
suspected. Future research on comorbidity has the potential to advance
understanding of pathogenesis of both psychiatric and autoimmune disorders.
Theories on autoimmune
aspects of schizophrenia invoke the notion of early infection by microorganisms
possessing antigens that are so similar to tissue in the CNS that resulting
antibodies act against the brain R1633CJHGHHBA–R1633CJHGHBAC.
Comparisons of schizophrenia patients and healthy subjects have revealed
differences in immunologic parameters R1633CJHCIHBH,
but there have been failures to replicate. There has been repeated evidence of
a genetic locus for schizophrenia in the area of the human leukocyte antigens
(HLA), also with failures to replicate R1633CJHEFBFG–R1633CJHJDGHD.
Obstetric complications have been implicated in schizophrenia, and some have
speculated that infection in the mother produces antibodies that are
transmitted to the fetus, producing autoantibodies that disrupt neural
development and raise risk for schizophrenia R1633CJHIGHAB,
R1633CJHCIEIB.
Schizophrenia patients
or their relatives have been reported to have either higher or lower than
expected prevalences of some autoimmune disorders, including rheumatoid
arthritis R1633CJHCGGIH,
type 1 diabetes R1633CJHCBDAA,
thyroid disorders R1633CJHCBDAA,
R1633CJHIBHIA,
and celiac disease R1633CJHBEJAJ.
This article presents a systematic comparison of the prevalence of 29
autoimmune disorders for all patients in the nation of Denmark diagnosed with
schizophrenia between 1981 and 1998 and their parents along with a group of
healthy subjects and their parents.
Method
Abstract
| Method
| Results
| Discussion
| References
The Registers
Data from Danish
registers were linked using the unique personal identification number that has
been allocated to all residents in Denmark since 1968 R1633CJHFGJDJ.
Socioeconomic information was obtained from the Integrated Database for
Longitudinal Labor Market Research, which was created by linking a number of
employment and education databases R1633CJHECCHE.
The Danish Psychiatric
Register, which records contacts with psychiatric facilities throughout
Denmark, was the source of patients with schizophrenia R1633CJHCIAHE,
R1633CJHJBFFG.
There are no private psychiatric facilities in Denmark, and all treatment is
free of charge. Information on autoimmune diseases originated from the National
Patient Register, which has collected data on all admissions to Danish
hospitals since 1977 R1633CJHFFIEF.
Since 1995 it has included all contacts in emergency rooms and outpatient
clinics. Diagnoses in the psychiatric and patient registers were according to
ICD-8 until the end of 1993 and according to ICD-10 from the beginning of 1994.
The disease categories used here were designed to separate, as much as
possible, syndromes with an autoimmune basis from similar syndromes with other
causes.
The study procedures
were approved by the Danish Data Protection Board and the Johns Hopkins
Bloomberg School of Public Health Committee on Human Research.
Subjects
The 7,704
schizophrenia patients comprised all persons over age 15 admitted to a Danish
psychiatric facility for the first time between 1981 and 1998 with a diagnosis
of schizophrenia and known maternal identity. This group of patients, 66% of
whom were male, has been described elsewhere R1633CJHBAEHA.
For each patient, 25 comparison subjects matched by year of birth and sex were
selected randomly from a 5% sample of the Integrated Database for Longitudinal
Labor Market Research. Comparison subjects were excluded if they had been
admitted to a psychiatric facility before the first admission of the patient.
In 92% of the patients and 96% of the comparison subjects, the father was
known. Socioeconomic and disease information on the patients, comparison
subjects, and their parents relates to the status just before the first contact
with the patient. Wealth of the parents was organized into the highest quartile
of the two parents for each individual, based on the distribution of wealth in
the entire Integrated Database for Longitudinal Labor Market Research.
Statistical Analysis
Statistical methods
included estimation of prevalence proportions in patients and comparison
subjects, and conditional logistic regression analyses that yielded an
incidence rate ratio. The strata for the logistic regression are formed by the
matching variables of year of birth and sex. Multivariate models adjust for
known risk factors for schizophrenia: urbanicity of birth, socioeconomic
status, and family history of schizophrenia. An initial logistic regression
model predicts the occurrence of schizophrenia from prior occurrence of any
of 29 autoimmune diseases. Later models are developed that predict
schizophrenia from the occurrence of each of the specific autoimmune
diseases. Separate prediction models are developed from the autoimmune status
of the patients and from the parents of the patients to suggest effects of
genetics as distinct from environment.
Results
Abstract
| Method
| Results
| Discussion
| References
There were 29
autoimmune diseases with which either the patient or a parent was diagnosed
before the patient had been diagnosed with schizophrenia. t1
shows prevalence data. There were 175, 16, and two patients with one, two, and
three autoimmune diseases, respectively. Schizophrenia was associated with nearly
50% higher lifetime prevalence of one or more autoimmune disorders (t2).
The analysis in t2
adjusts for known risk factors for schizophrenia (as well as controlling for
sex and age in the matching process), revealing relationships that mirror the
scientific literature R1633CJHHBACI.
Nine autoimmune
diseases had higher lifetime prevalence among schizophrenia patients than among
comparison subjects at a 95% level of statistical significance: thyrotoxicosis,
intestinal malabsorption, acquired hemolytic anemia, chronic active hepatitis,
interstitial cystitis, alopecia areata, myositis, polymyalgia rheumatica, and
Sjögren’s syndrome (t3).
Two disorders had sizable incidence rate ratios but did not meet traditional
levels of significance: thyroiditis (incidence rate ratio=3.3) and ankylosing
spondylitis (incidence rate ratio=2.7). Even so-called significant findings
were based on small numbers: a single case of Sjögren’s disorder produced the
incidence rate ratio of 12.5; likewise three cases of acquired hemolytic anemia
produced the large incidence rate ratio of 12.5.
Twelve autoimmune
diseases had higher prevalence among parents of schizophrenia patients than among
parents of comparison subjects: thyrotoxicosis, thyroiditis, type 1 diabetes,
intestinal malabsorption, pernicious anemia, acquired hemolytic anemia,
interstitial cystitis, psoriasis, seropositive rheumatoid arthritis, other
rheumatoid arthritis, dermatomyositis, and Sjögren’s syndrome (t4).
Chronic active hepatitis, alopecia areata, myositis, and polymyalgia rheumatica
were autoimmune disorders with higher prevalences than expected in the
schizophrenia patients but not in their parents.
Discussion
Abstract
| Method
| Results
| Discussion
| References
Five autoimmune
disorders appeared more frequently in patients with schizophrenia prior to
schizophrenia onset as well as in the patients’ parents: thyrotoxicosis,
intestinal malabsorption, acquired hemolytic anemia, interstitital cystitis,
and Sjögren’s syndrome.
The relationship
between intestinal malabsorption, or celiac disease, and schizophrenia was
noticed as early as 1961 R1633CJHBHIJC.
Celiac disease is an immune-mediated reaction to gluten that presents with
diarrhea, weight loss, and abdominal complaints as well as a range of less
common signs and symptoms, including some psychiatric and neurological symptoms
R1633CJHGGBDD,
R1633CJHGBDEJ.
The psychological interpretation for the first case series was reinterpreted by
Dohan R1633CJHECIAJ
as an inherited defect in which the environmental trigger of gluten
precipitated schizophrenia in some individuals. Dohan presented two series of
ecological data supporting the idea: one temporal series from countries in
Europe during World War II R1633CJHECIAJ
and a number of comparisons in the western Pacific based on anthropological
data R1633CJHGDGII.
The literature includes case studies, biological explanations for the
association, and clinical trials of gluten withdrawal (e.g., references R1633CJHGAJGCR1633CJHJEDIF.
Data from the Oxford Record Linkage Study R1633CJHEIHJD
revealed an odds ratio of about three for cross-sectional comorbidity of
schizophrenia and celiac disease, and we have published a short report on
celiac disease and schizophrenia that used a nearly identical dataset to this
one R1633CJHBEJAJ.
Autoimmune thyroiditis
is characterized by hypothyroidism with clinical manifestations of goiter and
lymphocyte infiltration of the gland R1633CJHGJGGI.
Thyrotoxicosis (Graves disease) causes sustained hyperthyroidism with clinical
complications in thyroid-associated ophthalmology and dermopathy R1633CJHJCAAA.
Kraepelin reported clinical observations of enlarged thyroid gland in dementia
praecox R1633CJHJBAFD.
Subsequent clinical evidence has shown an excess of thyroid hormone dysfunction
in schizophrenia, and some have attributed these observations to dysfunction of
the hypothalamus-pituitary-thyroid axis and neuroleptic medications R1633CJHCHDDC–R1633CJHGFGHJ.
Our findings on thyroid disorders confirm prior research R1633CJHCBDAA,
R1633CJHIBHIA,
R1633CJHCDDIE,
R1633CJHHHFJG.
Acquired hemolytic
anemia is the clinical manifestation of the production of antibodies against
red blood cells R1633CJHCAIGB,
R1633CJHDEDAJ.
Our findings on acquired hemolytic anemia are consistent with a prior study R1633CJHCBDAA
that showed an excess of hemolytic anemia in (just two) relatives of
schizophrenia patients compared with the single instance in healthy subjects
(odds ratio=2.02, 95% CI=0.11–121.6).
Interstitial cystitis
is a bladder condition characterized by increased urinary frequency or pelvic
pain R1633CJHJGIJF,
R1633CJHEHAFA.
Although interstitial cystitis has been recently genetically linked to panic
disorder R1633CJHCHCAC,
we are unaware of prior research linking it to schizophrenia. The causes and
pathogenesis for interstitial cystitis are not known.
Sjögren’s syndrome is
characterized by progressive destruction of the exocrine glands, manifesting in
a decrease in the production of saliva and tears R1633CJHFEFBG.
Sjögren’s syndrome generally affects women, and the estimated prevalence varies
from approximately 0.1%–6% R1633CJHJFIBI–R1633CJHBCIBA.
It sometimes occurs with other rheumatic disorders such as systemic lupus
erythematosus, but we are unaware of any prior research linking it to
schizophrenia.
This analysis does not
support certain results in the epidemiologic literature on schizophrenia. For
example, two studies have reported an excess of type I diabetes in the
relatives of individuals with schizophrenia R1633CJHCBDAA,
R1633CJHHHFJG,
consistent with the data reported here in t4;
other studies, however, have reported a negative association between the two
disorders R1633CJHFGECG.
The most consistent
finding in the area of schizophrenia and autoimmune diseases is the negative
relationship with rheumatoid arthritis R1633CJHCGGIH,
R1633CJHBBJGJ,
R1633CJHHHCFB.
The incidence rate ratio for the schizophrenia patients was very close to 1.0
in this analysis, whereas in most other studies rheumatoid arthritis is much
less common in individuals with schizophrenia. Our analysis required that the
rheumatoid arthritis appear before the patient was diagnosed with
schizophrenia, which may have influenced this result, since many cases of
rheumatoid arthritis have onset much later than the age at onset for
schizophrenia. The incidence rate ratio for parents of schizophrenia patients
was greater than 1.0, contrary to the expected direction. There are two small
studies of rheumatoid arthritis in the mothers of schizophrenia patients R1633CJHCBDAA,
R1633CJHFFADF,
which suggest an inverse relationship.
Parallel Genetic Studies of Schizophrenia and Autoimmune Diseases
One of the possible
hypotheses for our observed results is that schizophrenia shares a genetic
diathesis with the family of autoimmune diseases, yielding the nearly 50%
increase in risk for other autoimmune disorders as shown in t2.
For example, Becker and colleagues R1633CJHDACFH
hypothesized that common complex diseases may be a result of the collective
effects of disease-specific loci, common nondisease-specific loci, and specific
environmental triggers, the so-called common variants/multiple diseases
hypothesis. This contrasts slightly with the notion that a single or limited
number of genes specific to each autoimmune disorder might be associated with
schizophrenia—straightforward pleiotropy R1633CJHDCIBH.
The data relevant to these hypotheses, for the most part, come from separate,
parallel genetic research studies of specific disorders. For autoimmune
diseases, a source of general vulnerability may be the HLA system. Association
studies have highlighted the role of HLA genes for certain autoimmune diseases R1633CJHBDFIH,
R1633CJHCFHED.
Case/control and family studies suggest that genes in HLA class II regions
(e.g., HLA-DR3, DQA1, DRB1) are related to thyrotoxicosis and thyroiditis R1633CJHBDFIH,
but the evidence is limited R1633CJHDGJHE.
Several studies have suggested the HLA-related susceptibility for celiac
disease lies in the DQ alleles R1633CJHGCHEH,
R1633CJHJDHGD,
but there is some evidence for linkage with other HLA regions R1633CJHJIHHE,
R1633CJHGDBFE.
There is a line of research on HLA class II (e.g., DQA, DRB1, and DQB1) in
relation to the primary Sjögren’s syndrome R1633CJHHJBAI–R1633CJHDHADG.
Little is known about associations linking HLA and interstitial cystitis. The
epidemiologic association between all these disorders could be a result of 1)
direct involvement of HLA antigens or 2) physical closeness between loci for
the autoimmune disorders and schizophrenia loci in HLA regions.
Outside the HLA
region, the search for variants for common autoimmune diseases has not, as yet,
suggested many clusters related to schizophrenia R1633CJHJDJAE.
An exception is that linkage studies have suggested that schizophrenia and
celiac disease may have genes that are close to each other or identical R1633CJHJDHII,
R1633CJHECCDI.
Another exception is that the HOPA (human opposite paired) gene on chromosome
Xq13, which codes for a coactivator for the T4 receptor and in which mutations
have been found associated with hypothyroidism R1633CJHIJHAA,
has recently been linked with the elevated risk of schizophrenia R1633CJHDHDDD,
R1633CJHHFHDH.
Because the HOPA gene is expressed throughout the CNS and other tissues,
especially in the period of fetal development, the abnormality in the HOPA gene
is hypothesized to raise risk for schizophrenia. Separate association studies
have connected the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene to
schizophrenia R1633CJHFAABG
and to rheumatoid arthritis R1633CJHCIIIB,
and a similar pattern exists for the IL1B gene R1633CJHCAHDJ,
R1633CJHHJHDC.
The CTL-4 gene has been associated with schizophrenia in at least one study R1633CJHGDFBF,
and with type 1 diabetes, autoimmune thyroid diseases, and rheumatoid arthritis
in numerous studies R1633CJHDACFH.
There have also been suggestive association study findings for the IL10 gene R1633CJHGDFGJ
and type 1 diabetes, rheumatoid arthritis, and Sjögren’s syndrome R1633CJHDACFH
as well as for the TNF gene R1633CJHHCBEB
and psoriasis, rheumatoid arthritis, and type 1 diabetes R1633CJHDACFH.
Limitations
These data suffer from
important limitations. The rarity of the autoimmune disorders is problematic,
even for this study that involved an entire nation. Ascertainment was based on
diagnosis received in normal medical specialty settings. There is likely to be
underascertainment, since individuals with many of these disorders will not
always be in attendance at a specialty clinic or inpatient setting. The
argument could be made that schizophrenia, and many autoimmune diseases, are so
serious that they inevitably end up in specialty treatment and the register
system. But some diseases, such as hypothyroid disorder and type 1 diabetes,
may be treated by primary care practitioners and never enter the registers.
However, for any given disease, these biases would exist equally for patients
and comparison subjects, and for parents of both groups; as a consequence the
net effect is to lower the degree of association, making the findings
conservative.
Another explanation
for the low prevalence of autoimmune diseases is that many of them have onset
later than schizophrenia, so that the prevalence in patients is much lower than
what might be expected. These findings—even findings on parents of patients—may
be limited to a subset of autoimmune diseases that have early onset. This
possibility cannot be addressed with these data. Another limitation of the
present study is the fact that the analyses were carried out in subjects
matched by gender, making it impossible to examine gender-related differences,
even though the etiology of autoimmune diseases and of schizophrenia probably
differ by sex R1633CJHFHDCJ,
R1633CJHEHJJH.
Finally, we cannot be certain that treatment for autoimmune disease is not a
risk factor for schizophrenia.
Conclusions from these
analyses, especially when the focus is on individual disorders, must
necessarily be circumspect because of the opportunistic nature of the
statistical analysis. Results reviewed from genetic association and linkage
studies likewise are suggestive at best. On the other hand, findings concerning
celiac disease and autoimmune thyroid diseases are consistent with the
scientific literature, and this analysis is a confirmation based on a stronger
dataset than has existed before. In future clinical studies it may be
interesting to search for a family history of autoimmune diseases, and specific
autoantibodies, in patients with schizophrenia. Eventually, individual or
family disease comorbidity may help to elucidate shared etiologic pathways.
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