Autism research news and opinion
22 July 2014 - 29 July 2014
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Common mutations account for half of autism risk
Jessica Wright
21 July 2014
Common gene variants that have minor
effects may contribute about half the risk of
developing autism, according to a study
published Sunday in Nature Genetics1.
Identifying these variants would require
tens of thousands of samples.
Genetic risk: Using multiple statistical models, researchers have
attributed 59 percent of the risk of developing autism to genetics.
Much of autism research so far has focused
on rare, de novo mutations, which appear
spontaneously in individuals with autism.
These mutations often have strong effects
and so can be straightforward to find — for
example, by comparing the genomes of the
affected individuals with those of their
unaffected family members.
By contrast, common variants are present
in 5 percent or more of the population.
Alone, each variant may have little effect on
an individual, but taken together they can tip the scales toward a particular condition, such as
autism.
Because of their prevalence, definitively linking a particular variant to a disorder requires tens of
thousands of samples.
Rather than pinpoint individual variants, the new study looked at how much common variants
contribute to autism risk overall. The results suggest that roughly 49 percent of the risk of developing
autism can be attributed to common variants, versus 3 percent for rare, de novo variants.
“De novo mutations are extraordinarily important, but we need to consider this other kind of
inherited risk as a critical part of the [genetic] architecture,” says lead researcher Joseph Buxbaum,
director of the Seaver Autism Center at the Icahn School of Medicine at Mount Sinai in New York City.
Family ties:
Several studies have tried to define exactly how much of autism risk can be attributed to inheritance.
These studies often analyze the genomes of twins because identical twins share the same DNA.
However, they don’t always adequately account for the fact that twins also share other factors — such
as the in utero environment, their homes or pediatricians.
“In the world of heritability, which is something of a dark art, twin studies are the darkest of the arts,”
says Stephan Sanders, assistant professor of psychiatry at the University of California, San Francisco.
Perhaps as a result, estimates from twin studies of genetics’ contribution vary widely — ranging from
90 percent in twin studies in the 1980s to only 37 percent in a controversial 2011 twin study.
The new study falls in the middle, estimating the contribution of genetics overall at around 59 percent.
The researchers looked at autism risk across all children born in Sweden between 1982 and 2007,
including 5,689 diagnosed with autism, in a total of 1.6 million families.
The researchers pieced together pedigrees of extended families to an unprecedented level, from firstdegree relatives (parents, siblings) to ninth-degree distant cousins. By looking at autism recurrence
across these families, they calculated that about 52 percent of autism risk is inherited.
In the world of heritability, which is
something of a dark art, twin studies
are the darkest of the arts.
The “magic” of this analysis is that the distant relatives — many of whom don’t even know each other
— are less likely to share a home or other environmental confounds than siblings are, says Kathryn
Roeder, professor of statistics at Carnegie Mellon University in Pittsburgh.
To identify the role of common variants, the researchers looked at more than 500,000 variants shared
among 3,046 unrelated individuals in the population. From this, they estimated that common variants
contribute about 49 percent of autism risk overall. That suggests that only the remaining 3 percent of
risk comes from rare, inherited mutations.
These calculations are estimates, with sizable error rates. A study of Swedish twins published earlier
this month similarly pegged the risk from inherited genetics at 54 percent, however, boosting the
numbers’ credibility2.
“By using a variety of different analytical approaches, the researchers still come up with the same
figure of around 54 percent,” says Louise Gallagher, professor of child and adolescent psychiatry at
Trinity College, Dublin, who was not involved in the study. “The strength [of the new study] is the
large population sample.”
Spontaneous risk:
The new study also calculated the contribution of de novo mutations — which are not included in
estimates of inherited risk — at about 3 percent. This calculation may be an underestimate, say
experts. For example, the analysis includes only mutations found in the coding portion of the genome.
Still, the relatively low contribution from de novo variants belies the importance the field has given to
them so far, says Dan Arking, associate professor at the Institute of Genetic Medicine at John Hopkins
University in Baltimore, who was not involved in the study. “This is bringing people back to the reality
that common variation is explaining most of autism risk,” he says.
Together, all these genetic factors (along with a previously published estimate of recessive mutations)
add up to 59 percent of autism risk.
Although other studies have designated the remainder as ‘environmental’ risk, the researchers say this
category should be considered “unaccounted.” This is because the analysis does not account for
interactions between risk factors — between common and rare variants, for example, or the influence
of environment on gene expression.
De novo mutations may in fact act as a ‘second hit’ that pushes a set of common variants toward
autism, says Buxbaum.
“The inter-relationship between common and rare variation and inherited and de novo variation is
going to be the big thing for the next few years,” he says.
In any case, it’s clear that large numbers of samples can transform autism research — as they have in
work on schizophrenia.
Just five years ago, schizophrenia researchers had access to only a few thousand genomes — enough to
show that common variants are important in the disorder, but not enough to identify any particular
variant — says Benjamin Neale, assistant professor of analytic and translational genetics at
Massachusetts General Hospital.
But after analyzing nearly 40,000 schizophrenia genomes, an international consortium of researchers
identified more than 100 common variants associated with schizophrenia — 83 of which are new links
to the disorder. The researchers published their results yesterday in Nature3.
“The kind of trajectory we’ve seen in schizophrenia suggests what the future of autism genetics may
hold — if we make a strong commitment as a community to increasing sample sizes,” says Neale.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1: Gaugler T. et al. Nat. Genetics Epub ahead of print (2014) PubMed
2: Sandin S. et al. JAMA 311, 1770-1777 (2014) PubMed
3: Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature Epub ahead of
print (2014) Abstract
Autism gene affects brain function early in development
Jessica Wright
28 July 2014
Mutations in a gene linked to intellectual
disability and sometimes autism may lead
to a permanent boost in brain activity
beginning early in development, according
to a study published 18 June in Neuron1.
Signal strength: Brain slices from mice lacking one copy of the
SYNGAP1 gene (bottom) are more excitable (red) than those from
controls (top).
The gene, called SYNGAP1, prevents
connections that send activating signals in
the brain from maturing too early during
the first few weeks of fetal development.
Mutations that inactivate one of two
SYNGAP1 gene copies are a relatively
common cause of intellectual disability but
also frequently lead to epilepsy and, in
about 30 percent of cases, autism.
In 2012, the same researchers showed that
loss of one copy of this gene results in abnormally strong signals and overexcitable brains in mice2.
The boost in activating signals may lead to an imbalance between inhibitory and excitatory activity,
which some researchers have suggested as a cause of autism and epilepsy.
The new study suggests that mutations in SYNGAP1 cause permanent damage to the brain in utero.
Restoring SYNGAP1 in adulthood does not improve symptoms in mice missing a copy of the gene.
Conversely, removing it in adulthood does little damage to their brains and behavior.
“You can lose one copy of SYNGAP1 in adulthood, that’s fine,” says lead researcher Gavin Rumbaugh,
associate professor of neuroscience at the Scripps Research Institute in Jupiter, Florida. “But you
need full expression of the protein in the developmental critical period in order to have cognition
develop and emerge properly.”
The results may seem discouraging for developing treatments. But they suggest that repairing the
mutation in utero may completely mitigate its effects. “If you had a compound that enhanced
SYNGAP1 back up to normal in the critical period, you would essentially cure the disorder,” says
Rumbaugh — although he notes that putting this strategy into practice is decades away.
Excitatory effects:
The study also looked at where in the brain a SYNGAP1 mutation might cause the most damage.
Pyramidal neurons, which send excitatory signals in the forebrain — a part of the brain responsible for
most cognitive function — are most affected.
“Understanding which neuron types are important will help us to understand mechanism and how
these disease genes are working in specific neurons,” says Kimberly Huber, professor of neuroscience
at the University of Texas, Southwestern, who was not involved in the study.
SYNGAP1 has other links to autism as well. For example, it regulates expression of the autism-linked
gene MEF1. And it is a member of a family of genes that dampen activity of the RAS pathway, many of
which, when mutated, also have links to autism.
To home in on the specific effects of SYNGAP1 mutations, the researchers engineered a series of
mouse models that lack one copy of SYNGAP1 either in certain cells or at certain times in
development.
Deleting one copy of SYNGAP1 in the entire mouse brain leads to social deficits, seizures and
problems with learning and memory. Deleting the copy only in pyramidal neurons has the same effect,
underscoring the importance of these neurons. By contrast, mice missing one copy of SYNGAP1 in
inhibitory neurons of the forebrain look normal.
“This is a nice, simple demonstration that you don’t need to have deficits in inhibition to have excess
of excitatory activity,” says Vikaas Sohal, assistant professor of psychiatry at the University of
California, San Francisco. Being able to focus only on excitatory circuits gives researchers a defined
target when it comes to treatments, he adds.
The researchers also engineered mice that express normal levels of SYNGAP1 in pyramidal neurons
but are missing one copy in the rest of the brain. This alleviates the mice’s problems with memory and
learning but not their seizures.
This finding is intriguing because it is often difficult to know whether cognitive deficits are a symptom
in their own right or are the result of frequent seizures, says Huber. “As far as I know, that’s the first
time someone has been able to dissociate a seizure phenotype from cognitive phenotypes,” she says.
“This suggests there are different circuits that are mediating these two different types of behaviors.”
The study also found that enhanced signaling in pyramidal neurons tracks perfectly with memory
problems in the mice. This suggests that researchers should correct this brain signal instead of
watching for changes in behavior, which are harder to assess, says Rumbaugh. “Now the next phase of
the project is to try and figure out how to make these animals better.”
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1: Ozkan E.D. et al. Neuron 82, 1317-1333 (2014) PubMed
2: Clement J.P. et al. Cell 151, 709-723 (2012) PubMed
Severity metric helps studies address autism's variability
Kate Yandell
23 July 2014
A new method for measuring severity in
disorders such as autism can help researchers
correct for the widely varying autism
symptoms among study participants,
according to a paper published 2 May in
NeuroImage1.
The method, called population
characterization of heterogeneity (PUNCH),
lets scientists combine the results of multiple
tests into a single severity score for each
individual. Using severity scores, they can
divide their samples in new ways, allowing
them to detect subgroup characteristics that
might otherwise remain hidden.
Clearer contrast: Differences between the brains of people
with autism and those of controls become more apparent as
autism severity in the sample increases (from left to right).
Researchers first created PUNCH as part of a
larger project to understand differences in
brain images between people with autism and
controls. They hoped to find new ways to
parse their sample, the better to reveal
differences between the groups.
People with autism have widely varying intelligence quotients, language abilities and levels of
repetitive behavior and social difficulties, among other core autism symptoms. This can make it
difficult to home in on the exact differences between people with autism and controls.
For PUNCH’s proof of concept, the researchers analyzed unpublished test results collected in the
broader research program. They used results from nine tests measuring 50 traits, including social
responsiveness, communication, attention and anxiety, in 370 adolescent males with autism and 118
controls. They converted the scores into percentiles of performance in comparison with that of others.
The researchers then calculated how well the scores for each trait distinguish between people with
autism and controls, and weighted them accordingly to produce an overall score. A person who has
more traits that distinguish well between autism and typical development gets a higher overall
severity score than a person with traits that are less distinctive.
The researchers next used PUNCH scores to help analyze brain images from 69 people with autism
and 54 controls. They found that brain differences between people with autism and controls intensify
with autism severity. When the researchers discarded data from people with the lowest PUNCH
scores, or the least severity, they saw more differences than when they looked at the whole autism
group.
The researchers say that using the new severity metric as a filter for their analyses will allow them to
see trends that might otherwise be obscured by mild cases of the disorder. They are applying PUNCH
to a much larger collection of brain images.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1. Tunc B. et al. Neuroimage 98, 50-60 (2014) PubMed
Why inferring autism's causes from epidemiology is
dangerous
Mayada Elsabbagh
29 July 2014
In the past few years, I’ve seen several
reports that suggest that health disparities
in autism are related to social factors such
as culture, race, ethnicity and
socioeconomic status.
Misleading clues: An early study of autism in Africa looked only
at people of high socioeconomic status, but some researchers
mistakenly assumed that only this group was susceptible to the
disorder.
For example, claims abound that a
mother’s ethnicity is associated with
genetic differences that predispose her
children to autism. Or that her country of
birth means she was exposed to harmful
environmental factors that may lead to
autism in her children. Or even that the
stress associated with immigration
increases her risk of having a child with
autism.
Most recently, a study published earlier
this month reported that in Los Angeles
County, children born to mothers who
immigrated from Central or South
America, the Philippines or Vietnam have
an elevated risk of autism. It also concludes that African-American and Hispanic children have higher
rates of autism than do Caucasian children1.
At first glance, these ‘just-so’ stories resemble well-established associations between some single-gene
disorders and certain races or ethnic groups — for example, the link between Tay-Sachs disease and
the Jewish population. But it is far more challenging to identify and explain such disparities in
conditions such as autism, which result from multiple genetic and environmental risk factors.
While working on a World Health Organization-commissioned review of the global prevalence of
autism, I came across many other just-so stories linking factors such as ethnicity, nativity and race to
the prevalence of the condition2. But association does not imply causality, and prevalence data cannot
be used to infer underlying genetic, biological or environmental differences.
Out of Africa:
I was particularly struck by a claim in the review that autism is a rare or even nonexistent condition in
Africa. I was even more surprised to find the origins of this claim in a misinterpretation of Victor
Lotter’s pioneering and insightful case series in Africa3.
A well-known epidemiologist in the 1970s, Lotter traveled to a number of African countries and
described cases of autism that looked remarkably similar to what he had seen in his home country, the
U.K.
Lotter is often misquoted as suggesting that there is a lower prevalence of autism in Africa than in the
U.K., or that autism is associated with high socioeconomic status. He was in fact open about the fact
that he had looked at only a small group of people of high socioeconomic status. He attributed this to
the fact that these families were probably more likely than others to seek help in urban clinics.
As we put together the puzzle pieces of race, culture and biology as risk factors for autism, it is worth
making sure that we aren’t perpetuating this type of misunderstanding. If we do, we risk repeating the
past mistakes of social Darwinism, which attributes individual differences in intelligence, personality
and cultural and social characteristics to a genetic basis.
For example, African-Americans as a group may score consistently lower on tests of intelligence than
other ethnic groups, even after controlling for a wide range of social and economic confounds4. This
has led some people to attribute these results to innate (genetic) differences between races. But
prominent critics of this perspective have challenged not only the quality of the evidence on which
these claims are based but also their underlying assumptions5.
Mistakenly attributing racial
differences [in autism risk] to biology
offers a convenient excuse for political
apathy.
Complex social phenomena cannot be reduced to measurable concepts such as intelligence quotients.
And the association of these measures with race does not imply causality. The lower test scores could
be a result instead of biases in the tests themselves, which in the case of IQ tend to reflect the person’s
ability to take tests in general. What’s more, the skills measured in these tests are by no means
culturally universal.
Mistakenly attributing racial differences to biology offers a convenient excuse for political apathy, in
lieu of sustained efforts to eliminate health and social disparities where possible.
In autism, many studies have similarly tried to link autism risk or prevalence to race, ethnicity and
country of origin.
The stories often lead in two curious directions: Mothers take the lion’s share of the blame. And the
increase in autism risk and severity is seen mostly in non-Caucasians, or those who are born outside
the U.S. or Northern Europe.
In the past decade, social and advocacy pressures have revealed many disparities in autism
prevalence. Indeed, in our global review we found that prevalence estimates are highly variable across
geography and culture. Others’ findings suggest differences in severity of symptoms or in functioning
across racial groups.
We and others have attributed this variability to a range of social factors that influence the
measurement of autism prevalence. These include broadening of the diagnostic criteria of the
condition, the rise in awareness, improved identification and stronger advocacy, alongside the many
methodological differences in prevalence studies.
If differences in prevalence across diverse groups were truly the result of genetics, they would be
immutable. Instead, prevalence estimates are highly variable and amount to snapshots within a given
community at a certain time period.
False assumptions:
The most comprehensive evidence from the U.S. Centers for Disease Control and Prevention confirms
that prevalence across racial groups in the U.S. is a moving target. The pattern of change suggests a
‘catch up’ in diagnosis in groups of individuals who were initially underdiagnosed. This makes
prevalence estimates powerful advocacy tools to signal the unmet needs of various subgroups.
Further problems with claims about differences in prevalence relate to the validity of their constructs.
For example, how is ‘foreign birth’ a biologically meaningful construct? Who or what is the person
foreign to? Where did she come from? Did she choose to leave her home country or was she driven out
by natural or political circumstance?
Similarly, U.S.-defined race categories are limited in capturing the complexity of individual
differences both in biology and in culture. For example, ‘black’ encompasses African-Americans
alongside immigrants from African countries who are a socioculturally distinct group. Neighboring
Canada has dozens of government-recognized ethnic categories that are not collapsible into the U.S.
categories, despite the overlap in ethnic origins between the populations of the two countries.
More often than not, ‘U.S.-born Caucasian’ is used as a reference group of convenience, rather than
one that is logically or statistically justified. Rather than measuring individual differences, we tend to
measure how different everyone else is from this ‘prototypical’ Caucasian Anglo-American or
European group.
What’s more, disparities in access to care and clinician biases are documented phenomena that may
be driving the reports of differences in prevalence. And the lack of a typical comparison group in most
studies leaves open the possibility that tests used to measure IQ or language skills underestimate
these skills in children from certain racial and ethnic groups.
If we accept that race and ethnicity are signs of biological differences in autism, this also opens to the
door to using a child’s skin color to decide his or her prognosis or treatment. We should instead focus
on making access to care more equitable for all children.
Rather than relying on frequency counts, studies investigating questions of culture and ethnicity need
to formulate solid hypotheses based on well-grounded assumptions and the highest-quality data. For
now, evidence suggests that where these disparities exist, they are unlikely to relate to underlying
causes.
As with social Darwinism, our epidemiological just-so stories may inadvertently have socially and
ethically questionable implications. The reality is that what underlies these stories is probably as
complex as life itself.
References:
1: Becerra T.A. et al. Pediatrics 134, e63-71 (2014) PubMed
2: Elsabbagh M. et al. Autism Res. 5, 160-179 (2012) PubMed
3: Lotter V. J. Child Psychol. Psychiatry 19, 231-244 (1978) PubMed
4: Herrnstein R. and C. Murray (1994) The Bell Curve: Intelligence and Class Structure in American
Life New York: Free Press
5: Gould S.J. (1981) The Mismeasure of Man New York: W.W. Norton
Guest blog: Schizophrenia milestone holds lessons for autism
Alan Packer
21 July 2014
A long-awaited report on the largest-ever study to link common variants to the
risk of developing schizophrenia appeared today in Nature1.
This so-called genome-wide association study (GWAS) confirms what some
investigators have been arguing for years: Given cases and controls numbering
in the tens of thousands, researchers can identify a substantial number of
common genetic risk factors for a complex neuropsychiatric disorder.
This is a milestone in the study of schizophrenia, and holds several lessons for
autism researchers as well.
The results are reasonably straightforward. A consortium of dozens of investigators pooled DNA from
nearly 37,000 people with schizophrenia and 113,000 controls and looked for associations of 9.5
million single-nucleotide variants across the genome. They found that 128 variants reach
genome-wide significance, a level of statistical support that makes false-positive associations unlikely.
Of these, 108 map to distinct genomic regions, and 83 are completely new to schizophrenia risk.
Jonathan Flint and Marcus Munafò, authors of an accompanying News & Views article2, regard this
as an advance “of the sort that rewrites textbooks” — and I agree.
Notably, the researchers titled their paper, ‘Biological insights from 108 schizophrenia-associated
genetic loci,’ underscoring the point that the genetic findings are only important insofar as they enable
a better understanding of the underlying biology of the disorder.
So what are the genes and what do they tell us? The researchers highlight pathways that regulate
neuronal function, such as glutamate-dependent neurotransmission and voltage-gated calcium
channels. They also implicate genes involved in immune functions.
In this latter category, the most significant association by far is in the major histocompatibility
complex, which encodes proteins that enable the immune system to recognize foreign molecules.
Others have made this observation before, but it remains largely unexplained in terms of the biology
of schizophrenia risk3.
Genes involved in the immune response to pathogens are also on the list, implicating this process in
the development of the disorder. Finally, it’s worth noting that many of the associated variants
actually lower the risk of developing schizophrenia, which makes these of particular interest as
potential drug targets.
Additive effects:
The subject of drug targets raises the issue that these common variants have small effects, each
altering the risk of developing schizophrenia by 10 percent or less.
This raises the question of whether these really would be good targets for new drugs. The researchers
have one good argument on their side, which is that the list of genome-wide significant hits includes
the type 2 dopamine receptor (DRD2). DRD2 is the target of all effective antipsychotic drugs,
suggesting that even modest genetic associations can identify drug targets of significant clinical
impact.
As for autism, the contrast is clear. Although it is apparent that common variation is an important
component of autism risk4, 5, we can count the number of variants implicated with a high level of
statistical support on one hand.
The number of genotyped autism samples is only in the range of 5,000 to 6,000, and if the genetic
architecture of autism is anything like that of schizophrenia, this lack of statistical power by itself
explains why autism research lags behind in this area.
Fortunately, efforts are ongoing to close this gap. The good news from the schizophrenia GWAS is that
cases ascertained by physicians rather than research-based assessment using time-consuming
methods allowed for a boost in power without introducing what the researchers call “a crippling
degree of heterogeneity.” A similarly broad approach to ascertainment of autism samples should
speed the accumulation of the sample sizes needed for gene discovery.
Finally, the schizophrenia study reveals significant overlap between genes implicated by both common
and rare variant approaches. If this turns out to be true for autism as well, it may help us to solve a
puzzle: that rare, spontaneous — or de novo — mutations in autism are largely restricted to
individuals with below-average intelligence quotients (IQs).
As such, despite the success in identifying rare mutations in autism, we still know almost nothing
about the genetic underpinnings of the disorder in individuals who have average or above-average
IQs. Susceptibility to ‘high-functioning’ autism may be driven by particular constellations of common
variants of weak effect. But we’ll only know that for sure if the field examines groups of the scale that
schizophrenia researchers have so painstakingly assembled.
Alan Packer is senior scientist at the Simons Foundation Autism Research Initiative.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1: Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature Epub ahead of
print (2014) Abstract
2: Flint J. and M. Munafò Nature Epub ahead of print (2014) Abstract
3: Stefansson H. et al. Nature 460, 744-747 (2009) PubMed
4: Gaugler T. et al. Nat. Genet. Epub ahead of print (2014) Abstract
5: Klei L. et al. Mol. Autism 3, 9 (2012) PubMed
Guest blog: Rett outcome is improving with time
Alan K. Percy
25 July 2014
I first learned about Rett syndrome in 1983, when I read the first Englishlanguage description of 35 cases1,2. So much has changed since then, and I
see no reason to think it won’t keep changing.
The 1983 paper led to a flurry of clinical studies aiming to understand the
specific features of this disorder. In 1999, researchers identified the genetic
basis of Rett as mutations in MeCP23. That discovery created a surge in
research to identify the fundamental neural underpinnings and to seek
potential therapies.
An Australian study published in the Orphanet Journal of Rare Diseases
in June supports a series of similar previous studies that are revealing
remarkable changes in the outcome of women with the disorder, including
greater life expectancy and improved overall health4. This is the result of
rising awareness of the medical problems that accompany the disorder.
And it has led to specific therapies, such as physical, occupational and communication strategies,
along with improved nutrition, for these girls and women.
For example, we have better information now about symptoms such as impaired growth,
gastrointestinal problems such as acid reflux and constipation, and a high risk of choking, or
aspiration. This has led clinicians to focus on proper nutrition for women with the syndrome and to
aggressively treat their gastrointestinal problems.
Before this change in clinical practice, a 1997 study of 805 participants reported that nearly half of the
deaths in Rett syndrome occur in women described as frail or debilitated and having frequent
aspiration5. The researchers could not identify an immediate cause of death for one-quarter of the
participants. However, it is likely that it might have been the result of a sudden catastrophic event
such as aspiration or seizure disorder, because of the common occurrence of these problems in this
population. (This is purely speculative on my part; the authors do not go into much more detail, but
they suggest the same reason.)
Better lives:
Since then, researchers have looked in detail at the long-term survival of women with Rett syndrome
who live in the U.S., Canada, Austria and Australia: The bottom line is that survival rates have
improved everywhere.
In 2010, we published a study that included nearly 2,000 participants with Rett syndrome from the
U.S. and Canada6. At least half of these women lived past 50 years of age. Since 2006, we have an
ongoing study now involving more than 900 participants with classic Rett syndrome, whom we
examine at least once every year. This project is part of the National Institute of Child Health and
Human Development’s Rett Syndrome Natural History Study, which aims to gather natural history
data in preparation for clinical trials.
In addition to the individuals with classic Rett syndrome, the study includes 166 girls who have
atypical Rett syndrome, meaning that they meet only some of the criteria for a Rett syndrome
diagnosis.
By contrast, a 2010 study looked at the outcome of the original 22 cases diagnosed by Andy Rett in
1966. The probability of survival to age 25 was 21 percent: 19 of 22 Austrian women with Rett
syndrome had died by 25 years of age7. However, the same report found that 71 percent of more than
332 Australian women had survived past 25 years — results that echo our findings from the U.S. and
Canada.
The Australian study published this month, which includes nearly 400 participants followed for up to
20 years, found 71.5 percent survival past 25 years of age — virtually identical results to the previous
Australian findings4. From our own Natural History Study, we have identified 35 deaths among 855
participants with classic Rett syndrome and 6 of 157 people with atypical Rett. Only one of these
deaths was related to frailty or poor nutrition, yet the possibility of aspiration pneumonia remains.
These results strongly support the need for parents to continue demanding aggressive therapeutic
approaches in order to preserve optimal health — for example, maintaining proper nutrition, treating
gastrointestinal issues and optimizing physical and occupational therapies. It is equally crucial to
remain alert to potential medical issues, to continue implementation of strong therapies and to
maintain a proper level of engagement with family and peers.
Alan K. Percy is professor of pediatrics and neurology at the University of Alabama at Birmingham
School of Medicine.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1.
Rett A. Wien. Med. Wochenschr. 116, 723-726 (1966) PubMed
2.
Hagberg B. et al. Ann. Neurol. 14, 471-479 (1983) PubMed
3.
Amir R.E. et al. Nat. Genet. 23, 185-188 (1999) PubMed
4:
Anderson A. et al. Orphanet J. Rare Dis. 9, 87 (2014) PubMed
5:
Kerr A.M. et al. Eur. Child Adolesc. Psychiatry 6 Suppl 1, 71-74 (1997) PubMed
6:
Kirby R.S. et al. J. Pediatr. 156, 135-138 (2010) PubMed
7:
Freilinger M. et al. Dev. Med. Child Neurol. 52, 962-965 (2010) PubMed