The pediatric neuro-genetics revolution is here....But ...what can the exome not do?

Does your child have an unknown? The exome is here to stay! 

But...here is what the exome cant do....  JR

10 Things Exome Sequencing Can’t Do–but Why It’s Still Powerful

By Ricki Lewis | May 16, 2012 |  4

The views expressed are those of the author and are not necessarily those of Scientific American.

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Sequencing of the exome – the protein-encoding parts of all the genes – is beginning to dominate the genetics journals as well as headlines, thanks to its ability to diagnose the formerly undiagnosable.

The 2011 Pulitzer Prize in Explanatory Reportinghonored the Milwaukee-Wisconsin Journal Sentinel’s coverage of a 4-year-old whose intestinal disorder was finally diagnosed after sequencing his exome. Once investigators assigned a gene to his symptoms, a bone marrow transplant saved his life. And a just-published study compared the exomes of 12 children with combinations of developmental delay, intellectual disability, and birth defects at the Duke University genetics clinic to reference exomes, revealing 7 mutations, 2 in genes not known to be associated with disease.

In the best-case scenario, mutations revealed by exome sequencing suggest a treatment, as it did for the 4-year-old. But that may be unusual. “We can’t treat most of the Mendelian diseases we know about, so we won’t be able in the near and medium term to treat most of the cases that are diagnosed by sequencing,“ says David Goldstein, PhD, director of the center for human genome variation at Duke and an author of the study. The new National Center for Advancing Translational Sciencesmay add to existing treatments and new drug discovery by providing access to compounds from three major pharmaceutical companies. One study’s reject could be another’s cure.

But for certain types of genetic disorders, exome sequencing won’t help. Understanding what, exactly, an exome is reveals why.

A little less than 2% of the 3.2 billion bases of a human genome encode protein. Most genes consist of sections that are transcribed (into RNA) and translated into protein — these are exons – and sections that are transcribed but are then snipped out before the protein forms – these are introns. The exome, including only exons, is to the genome what a Wikipedia entry about a book is to the actual book. It’s part of the story, albeit an important part.

Admission: Back in the Precambrian period when I was in high school, I read the CliffsNotes version of John Steinbeck’s “The Grapes of Wrath.” I read the actual book many years later, and what a difference! The meager plot summary I read in high school missed the nuances, the connections, the feel and the utter devastation of the final scene.

Analyzing an exome to understand a disease is, in some cases, like reading the CliffsNotes version of a classic book.

The 10 Exceptions

Understanding the limitations of exome sequencing is important because it’s already here. “Be one of the first to get your personal exome sequence,” proclaims 23andMe, about its pilot Exome80x project, offered direct-to-consumer, “for research and educational use only.”'

The first CLIA-certified test, Clinical Diagnostic ExomeTM, became available fromAmbry Genetics earlier this year. A news release announcing the diagnosis of three tough cases calls the technology “essentially a human genome project for an individual patient.” Said CEO Charles Dunlop, “Some of these families have been trying to figure out what was ailing their children for years, and we solved the riddle in weeks.”

But exome sequencing won’t help every family, and here’s my list of reasons why. The technology won’t detect:

1. Genes in all exons. A few exons, such as those buried in stretches of repeats out towards the chromosome tips, aren’t part of exome sequencing chips.

2. Mutations in the handful of genes that reside in mitochondria, rather than in the nucleus.

3. “Structural variants,” such as translocations and inversions, that move or flip DNA but don’t alter the base sequence (detectable other ways).

4. Triplet repeat disorders, such as Huntington’s disease and fragile X syndrome. Their mutations don’t change the DNA base sequence – they expand what’s already there.

5. Other copy number variants will remain beneath the radar, for they too don’t change the sequence, but can increase disease risk.

6. Genes in introns. A mutation that jettisons a base in an intron can have dire consequences: inserting intron sequences into the protein, or obliterating the careful stitching together of exons, dropping gene sections. For example, a mutation in the apoE4 gene, associated with Alzheimer’s disease risk, puts part of an intron into the protein.

7. “Uniparental disomy.” Two mutations from one parent, rather than one from each, appear the same in an exome screen: the kid has two mutations. But whether mutations come from only mom, only dad, or one from each has different consequences for risk to future siblings. In fact, a case of UPD reported in 1988 led to discovery of the cystic fibrosis gene.

8. Control sequences. Much of the human genome tells the exome what to do, like a gigantic instruction manual for a tiny but vital device. For example, mutations in microRNAs cause cancer by silencing various genes, but the DNA that encodes about half of the 1,000 or so microRNAs is intronic – and therefore not on exome chips.

9. Gene-gene (epistatic) interactions. One gene affecting the expression of another can explain why siblings with the same single-gene disease suffer to a different extent. For example, a child with severe spinal muscular atrophy, in which an abnormal protein shortens axons of motor neurons, may have a brother who also inherits SMA but has a milder case thanks to a variant of a second gene that extends axons. Computational tools will need to sort out networks of interacting genes revealed in exome sequencing.

10. Epigenetic changes. Environmental factors can place shielding methyl groups directly onto DNA, blocking expression of certain genes. Starvation during the “Dutch Hunger Winter” of 1945, for example, is associated with schizophrenia in those who were fetuses at the time, due to methylation of certain genes. Exome sequencing picks up DNA sequences – not gene expression.

3 Great Uses for Exome Sequencing

Exome sequencing is of great value in two obvious situations: (a) finding a mutation in a known gene behind an “atypical presentation,” such as Nicholas Volker, the saved Pulitzer boy; and (b), identifying mutations in novel genes, like 2 of the 7 children in the Duke University clinic.

Another application is subtle: exome sequencing reveals incomplete penetrance, a phenomenon in which a person gets lucky. He or she has mutations that should cause a particular trait or illness, but they don’t.

Exome sequencing of parent-child trios can reveal when an apparently healthy parent actually has the same mutation as the sick child, but for some reason escaped the genetic fate. A genetic counselor would use this information in predicting risk for siblings. If mom or dad contributes a mutation, the next kid faces a much higher risk than if the affected child has a new mutation. But there’s a bigger picture. Figuring out how the parent stays healthy can reveal new drug targets, and perhaps even lead to repurposing an existing treatment.

Article here

Girls naturally more protected from autism development

This article explains why boys are four times more likely to develop autism and explains why girls may be naturally more protected from developing autism.

It takes more mutations to trigger autism in women than in men, which may explain why men are four times more likely to have the disorder, according to a study published 26 February in the American Journal of Human Genetics.

The study found that women with autism or developmental delay tend to have more large disruptions in their genomes than do men with the disorder. Inherited mutations are also more likely to be passed down from unaffected mothers than from fathers.

Together, the results suggest that women are resistant to mutations that contribute to autism.

"This strongly argues that females are protected from autism and developmental delay and require more mutational load, or more mutational hits that are severe, in order to push them over the threshold," says lead researcher Evan Eichler, professor of genome sciences at the University of Washington in Seattle. "Males on the other hand are kind of the canary in the mineshaft, so to speak, and they are much less robust."

The findings bolster those from previous studies, but don't explain what confers protection against autism in women. The fact that autism is difficult to diagnose in girls may mean that studies enroll only those girls who are severely affected and who may therefore have the most mutations, researchers note.

"The authors are geneticists, and the genetics is terrific," says David Skuse, professor of behavioral and brain sciences at University College London, who was not involved in the study. "But the questions about ascertainment are not addressed adequately."

Genetic burden:

The new study draws from the Simons Simplex Collection (SSC), a database of families that have one child with autism and unaffected parents and siblings. (This project is funded by the Simons Foundation, SFARI.org's parent organization.) In a 2011 study, researchers found that girls with autism in the SSC tend to have more large duplications or deletions of regions of the genome, called copy number variants (CNVs), than do boys with the disorder, although this disparity does not reach statistical significance2.

For the new study, Eichler and his colleagues cataloged the number of CNVs in 109 girls and 653 boys with autism from the SSC. They found that females are twice as likely as males to carry CNVs that are at least 400 kilobases long. (The larger the CNV, the more likely it is to disrupt important genes.)

When the researchers analyzed only CNVs that encompass risk genes for neurodevelopmental disorders, they found that females with autism are three times as likely as males with the disorder to carry CNVs that encompass these genes.

Females with autism also carry slightly more rare mutations that change a single DNA nucleotide than the men do. These are the "nastiest of nasty mutations," says Eichler, because they interfere with the protein's function.

The researchers saw a similar but smaller effect for CNVs in a larger group of 9,206 males and 6,379 females referred for genetic testing: 75 percent of this group turned out to have developmental delay, intellectual disability or autism.

Women in this group are 1.28 times more likely than men to carry large CNVs that include risk factors for these disorders.

Many autism-linked mutations arise spontaneously, or de novo, and about 80 percent of these come from the father.

Eichler and his colleagues found that women are far more likely than men to transmit the inherited mutations that confer autism risk.

Of the 27 large CNVs the researchers identified in the SSC group, 70 percent, or 19, were inherited from the mother. Mothers had similarly passed down about 57 percent of the 3,561 CNVs detected in the neurodevelopmental group.

Eichler intends to extend this work in a bigger study to assess whether certain mutations are more likely than others to be inherited.

"I think it's really critical to identify these inherited components," he says. "We know they're there, but we need to really focus on identifying the specific genes so we can advise [parents] a little more about recurrence."

However, it's unclear whether this gender bias is the result of genetics or reflects differences in diagnosis or the way females manifest symptoms of the disorder. Girls with autism tend to actively compensate for their symptoms in ways that boys don't, which may account for the discrepancy, says Skuse.

As a result, the females enrolled in studies may tend to be severely affected and carry multiple mutations. "There is some suggestion that higher-functioning females are out there in the general population, but they're not being referred," he says.

The study also does not address why women with autism transmit more mutations, or how they are protected from autism.

"We need to ask what it is about brain development that makes it such that females are protected -- because ultimately that is what we want know," says Aravinda Chakravarti, director of the Center for Complex Disease Genomics at the Johns Hopkins University School of Medicine in Baltimore. "We need to re-create that developmental environment."

The most obvious explanation for autism's gender bias is that because men have only one X chromosome, they are hypersensitive to mutations in this chromosome. In line with this theory, several autism-linked genes are located on the X chromosome. However, most of the mutations that show a gender bias in the new study are not on the X chromosome, suggesting that other factors must be involved.

This article has been modified from the original. An earlier version incorrectly stated that 80 percent of the genetic risk factors for autism arise spontaneously. The exact contribution of spontaneous genetic variants to autism is not known.

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Autism checklist improved for diagnosis in toddlers

A checklist used as a screening tool for autism has successfully been improved for diagnosis in toddlers.

An updated screening tool that physicians administer to parents to help determine if a very young child has autism has been shown to be much more accurate than earlier versions at identifying children who could benefit from further evaluation, according to researchers supported by the National Institutes of Health.

The Modified Checklist for Autism in Toddlers — Revised, with Follow-Up (M-CHAT–R/F) — is a free, two-step screening tool used to detect children likely to have autism. It is intended for use at regular well-child checkups for children 16 to 30 months old. With the M-CHAT-R/F, health care providers can classify a child’s risk of having autism as low, medium or high, on the basis of parents’ answers to 20 questions.

“This checklist can more accurately identify children likely to have autism so they can get the treatment and support they need,” said Alice Kau, Ph.D., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute that funded the study. “Given that the typical autism diagnosis occurs at age 4, it also offers the possibility of detecting autism much earlier — during regular doctor’s visits when a child is 18 months or 2 years old. And earlier intervention has been shown to improve outcomes for children with autism.”

A score in the high-risk range warrants a referral for further evaluation for possible autism. For a child determined to be at medium risk, M-CHAT R/F includes a follow-up questionnaire used soon after the original evaluation to obtain additional information needed to more definitively classify the child as either high risk or low risk.

Based on the M-CHAT-R/F classifications, the researchers found that a smaller proportion of children received a medium- or high-risk assessment (7 percent) than with earlier versions of the checklist (9 percent). However, more total cases of autism were detected with the revised checklist than with earlier versions (67 cases per 10,000 screened vs 45 cases per 10,000 screened).

Of the more than 16,000 children evaluated with the screening tool, 93 percent of the children screened were considered low-risk, 6 percent were in the medium-risk range and 1 percent were considered high-risk.

Of all the children who determined by the test to be at risk after the M-CHAT-R/F follow-up, 95 percent were eventually found to have some form of developmental delay, including more than 47 percent with autism spectrum disorder.

First author Diana L. Robins, Ph.D., of Georgia State University (GSU), in Atlanta, conducted the research with GSU colleague Karís Casagrande, and Marianne Barton, Ph.D., Chi-Ming Chen, Ph.D., Thyde Dumont-Mathieu, M.D., M.P.H., and Deborah Fein, Ph.D., all of the University of Connecticut in Storrs. Dr. Fein was the study’s senior author.

The findings appear in Pediatrics.

The researchers updated an earlier version of the autism screening tool, adding examples, rephrasing some questions and dropping others that previously did not elicit strong responses. Using the revised tool, the researchers worked with health care providers to screen more than 15,000 toddlers considered at low risk for autism.

“Earlier tools cast a wider net, but these refinements will allow health care providers to focus energy where it is needed most and will reduce the number of families who go through additional testing but which ultimately do not need treatment interventions,” said Dr. Fein.

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Preemies may face neurodevelopmental problems

A study shows that preemies born at or earlier than 25 weeks are likely to have extremely low IQ or other neurodevelopmental issues during childhood.

Babies who are born at 25 weeks' gestation or earlier and survive early life have a "substantial likelihood" of having a very low IQ or other neurodevelopmental problems in childhood, researchers said today.

In a review of nine past studies, they found between 24 and 43 percent of extremely premature infants went on to have moderate or severe impairment, depending on just how early the babies were born.

Dr. Henry Lee, from the Division of Neonatal & Developmental Medicine at Stanford University and Lucile Packard Children's Hospital in California, said it's a "very difficult circumstance for the family" when a baby is born between 22 and 25 weeks.

Normal gestation is 37 to 42 weeks. Twenty-two weeks is considered the earliest a baby can be born and still have a chance of surviving. But the odds can be so low, and the risks so high, that some hospitals might not even offer aggressive care to preemies delivered at 22 to 23 weeks, said Lee, who wasn't involved in the new research.

"First of all, they're at high risk of not even surviving, even when everything is done to help them," he told Reuters Health. "Even when they do survive, they have high rates of disability."

By 25 weeks in the womb, a baby's chances of surviving and going on to lead a normal life are thought to be significantly better.

Lee said the new data could be used to help counsel families of extremely premature infants.

"It's hopefully an informed decision that the family makes in terms of how they're going to proceed, whether to try to provide very aggressive, intensive care to these infants or potentially to provide palliative and comfort care," he said.

"The hard part too is there is still uncertainty. Even though there is this risk, there are some infants at each of these gestational ages that will survive and not have disability."

For their analysis, researchers led by Dr. Gregory Moore from The Ottawa Hospital in Ontario, Canada, pooled the results of nine studies that assessed kids born between 22 and 25 weeks' gestation when they were four to eight years old. Most of the studies were conducted in Europe and together they included close to 900 children.

Moderately or severely impaired children were those scoring in the lowest 2 to 3 percent on IQ tests, children with cerebral palsy and those who were fully or mostly deaf or blind.

Studies varied widely in the frequency of impairment they reported, likely based in part on different practices in different regions, the researchers said.

They found that across the board, children were at risk of neurodevelopmental problems - although those risks declined for every extra week in the womb.

Among babies born at 22 weeks, 43 percent were impaired. That compared to 40 percent of those born at 23 weeks, 28 percent born at 24 weeks and 24 percent born at 25 weeks' gestation, the study team reported Monday in JAMA Pediatrics.

About 4 to 5 percent of full-term babies go on to have some type of developmental problem, Moore said, but that includes children with milder impairment as well.

"Although substantial numbers of extremely preterm infants go on to develop moderate to severe (neurodevelopmental impairment), the results are not completely bleak in that over half of the children studied did not go on to develop moderate to severe impairment," Dr. Kimberly Noble, a pediatrician who studies child brain development at Columbia University in New York, said.

Noble, who wasn't involved in the new research, told Reuters Health in an email that it's unclear whether rates of impairment would be similar for U.S. babies born very early.

Moore, also from The Children's Hospital of Eastern Ontario, said the findings were limited by the small number of children born at the earliest gestations included in the studies.

"We don't want these (data) to make a physician automatically say, ‘There's no hope' or, ‘There's no chance,'" he told Reuters Health.

But, he added, "Many parents do think of long-term impairment as a major concern for them, and some parents think of it as a bigger concern than death, for example. For some parents knowing this data and knowing the limitations of it and speaking with a caring neonatologist about it, we would hope that that would help them in their decision making."

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Risks of taking epilepsy drugs while pregnant

Keep in mind ...What does the WHO recommend

Recommendation(s)

• Women with epilepsy should have seizures controlled as well as possible with the minimum dose of antiepileptic drug taken in monotherapy, wherever possible. Antiepileptic drug polytherapy should be avoided. Valproic acid should be avoided if possible.  Strength of recommendation: STRONG
• Folic acid should routinely be taken by women with epilepsy of child bearing age who are on antiepileptic drugs.  Strength of recommendation: STRONG
• Standard breast feeding recommendations remain appropriate for women with epilepsy on the antiepileptic drugs included in this review (phenobarbital, phenytoin, carbamazepine and valproic acid). Strength of recommendation: STRONG
• JR

Risks of taking epilepsy drugs while pregnant

This article discusses the various risks associated with pregnant women taking drugs for epilepsy, such as having a child with developmental delays or showing signs of autism.

Women with epilepsy who take anti-seizure medication while they are pregnant are more likely to later report delays in their child's development and autism symptoms, according to a new study from Norway.

The findings probably won't change the conversation too much between women and their doctors in terms of managing epilepsy during pregnancy, because it's already understood that the medications carry some risks, said Dr. Lewis Holmes, director of the Antiepilepsy Drug Registry at Massachusetts General Hospital, who was not involved in the research.

However, studies like this are badly needed, he added, because women are often asking about risks to their children's development, and "it hasn't really been mapped out."

The researchers could not prove that the anti-epileptic drugs are to blame, but the findings add to other evidence linking the medications to effects on children's development.

Seizure medication taken during pregnancy is already tied to a higher risk of physical malformations in the baby, and the drugs are linked with a greater chance of complications during pregnancy and childbirth.

One study from Denmark earlier this year also found that women who took the epilepsy drug valproate during pregnancy were three times more likely to have a child with an autism spectrum disorder.

"The risk of other effects on fetal development, that is, development and behavior, is less clear," said Dr. Gyri Veiby, lead author of the new study and a researcher at the University of Bergen in Norway.

She said that among all pregnancies, about three to five women out of every 1,000 use anti-epileptic drugs during pregnancy.

"It is reasonable to assume that most (anti-epileptic drugs) have the potential to harm the developing fetus. On the other hand, seizures should also be avoided during pregnancy," Veiby wrote in an email.

"In order to assess whether antiepileptic drug treatment during pregnancy is justified, we need to know as much as possible about the potential risks for the fetus," she said.

Veiby and her colleagues examined data from a large survey of mothers across Norway.

More than 108,000 women filled out a questionnaire asking about the behavior and development of their children at 18 and 36 months of age.

The survey included questions about social, physical and verbal skills, mannerisms, aggression and other traits.

Among the women in the study, 634 had epilepsy and 333 of them took epilepsy medication while they were pregnant - that translated to about 46 percent of the children of epileptic mothers having been exposed to one or more of the medications.

Children whose mothers took epilepsy drugs while pregnant were more likely to score outside the normal range on several developmental measurements, the researchers report in the journal Epilepsia.

For instance, 3.3 percent of three-year-olds whose mothers did not have epilepsy did not meet milestones for physical skills, whereas 7.5 percent of kids exposed to epilepsy drugs in utero failed to meet these milestones.

In addition, 4.8 percent of three-year-olds whose mothers did not have epilepsy scored abnormally on their ability to form sentences, while 11.2 percent of the children whose mothers took anti-seizure medication were delayed in their sentence skills.

The kids whose mothers took epilepsy medication while pregnant were also more likely to have autistic traits - 6 percent - compared to just 1.8 percent of the kids who mothers did not have epilepsy.

A mother's epilepsy itself did not appear to contribute to the heightened risk. Mothers with the condition who did not take any medication were no more likely to have a child with delays than mothers without epilepsy.

Dr. Cynthia Harden, a neurology professor at Hofstra-North Shore LIJ School of Medicine in Hempstead, New York, said it's possible the findings could be explained in part by something called "selection bias."

Mothers who take epilepsy medication while pregnant, for example, might be more concerned and therefore looking out for developmental delays, so they could be more likely to report them.

But Harden also said it's possible the drugs themselves have a negative effect on babies' development.

"There might be something real going on here, but it's possible that the magnitude of the effect is exaggerated by selection bias," said Harden, who is also the director of the Comprehensive Epilepsy Care Center at North Shore-LIJ Medical Group in Great Neck, NY.

Holmes said the findings support parents taking action on cues that their child might have a delay.

"Because there are concerns about subtle effects, I think it's smart to go ahead and think about obtaining some formal testing...as a way of making sure that everything is OK before first grade," Holmes said.

Harden agreed that the study doesn't change the discussion about epilepsy management during pregnancy too much.

Already, patients and physicians are aware of the potential hazards of the drugs, yet "seizures are dangerous, and we cannot permit our patients to have seizures during pregnancy," she said.

Physicians try to reduce the dose of the medication, trim back the treatment to one type of drug if possible, and avoid the use of valproate.

Veiby added that another way to minimize the risks during pregnancy is to plan ahead to figure out the safest treatment strategy, and to avoid unplanned pregnancies.

"Unfortunately, many women on (anti-epileptic drugs) do not receive the appropriate pre-pregnancy counseling," she said.

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Study: In-Vitro fertilization related to slight risk of mental deficit

A new study claims that children born through in-vitro fertilization have a slightly higher risk of having a mental deficit, possibly due to a lower birth weight.

Despite some concerns, children born by in vitro fertilization do not seem to have an increased risk of autism, a large new study finds. They may, however, have a slightly higher-than-normal chance of being intellectually impaired.

The study, reported in the July 3 issue of the Journal of the American Medical Association, looked at more than 2.5 million infants born in Sweden between 1982 and 2007. It found that the nearly 31,000 children conceived via in vitro fertilization (IVF) did not have an increased risk of the developmental disorder autism.

They were, however, 18 percent more likely to have an intellectual disability (which used to be called mental retardation), defined as an IQ lower than 70 and limited abilities in schoolwork .

Experts stressed that the risk is quite low: The rate of intellectual disability among IVF kids was about 46 per 100,000 each year, versus about 40 per 100,000 among kids conceived naturally.

"The vast majority of children born after the different types of IVF treatment will be perfectly healthy," said lead researcher Sven Sandin, of the Karolinska Institute, in Stockholm, and King's College London, in England.

What's more, the risk seemed largely related to the fact that babies born via IVF are often multiples (such as twins or triplets), and, therefore, frequently born preterm or at a low weight. That in itself carries a higher-than-normal risk of intellectual disability.

Experts said the findings suggest that whenever possible, IVF should involve implanting only one embryo in the woman's uterus, rather than the traditional route of implanting at least two.

"From the results of this study, we think that the use of single-embryo transfer should be extended," Sandin said.

An infertility specialist not involved in the study agreed. "I think we should be encouraging more single-embryo transfers," said Dr. Marcelle Cedars, director of reproductive endocrinology at the University of California, San Francisco.

That is happening more often these days, said Cedars, who wrote an editorial published with the study. At her center, she said, more than half of IVF patients have a single embryo implanted -- although that is higher than the national norm.

There is still a chance, however, that certain IVF procedures carry a risk.

Sandin's team found that a specific IVF technique used for male infertility -- called intracytoplasmic sperm injection, or ICSI -- was related to an increased risk of intellectual disability, even among single babies.

Again, the actual rates of intellectual impairment were quite low, Sandin said. But the results suggest there could be something about the intracytoplasmic sperm injection, or fathers' infertility, that contributes to the risk.

"People have for some time been concerned about the ICSI procedure," Cedars said.

That is partly because intracytoplasmic sperm injection is invasive: A single sperm is injected directly into an egg, whereas in standard IVF, sperm fertilize the eggs in a lab dish. "[ICSI] also bypasses the natural selection of sperm" that happens during fertilization, Cedars said, in which sperm compete to penetrate the egg and the fittest one wins.

But an alternative explanation is that male infertility -- which may involve genetically abnormal sperm -- is raising the risk of intellectual disability, rather than some effect of intracytoplasmic sperm injection, Cedars said.

Sandin agreed, but said it's impossible to say for sure based on these findings.

The study corroborates past research that has found no excess risk of autism after IVF. But this is by far the largest and best designed study to look at the question, Cedars said.

"This gives us powerful evidence that there is no association with autism," she said. She added that expectant parents can also be reassured that the risk of intellectual disability linked to intracytoplasmic sperm injection is still very low, even if it's higher than the norm.

Although the study found an association between certain IVF procedures and a higher risk of intellectual disabilities in children, it did not establish a cause-and-effect relationship.

Cedars and Sandin both said more studies are needed to see how children fare after IVF, and to dig for reasons for the current findings on ICSI.

Between 1978 and 2012, about 5 million children worldwide were born via IVF, and the numbers will only increase, Cedars said. And in some countries -- including the United States -- intracytoplasmic sperm injection is being increasingly used in cases in which there is no clear problem with the man's fertility, because there is a perception that it's more efficient.

But that belief, Sandin's team said, is unproven.

Read more here

Outcomes for Children with CP - Early Identification and Comprehensive Management are Important!

This important article starts with great observations that a) early diagnosis is beneficial and b) prognostic information is importance. My problem with the article is that all types of CP are blended together.  
See the bottom for prognostic information. JR

"Parents believe professionals withhold prognostic information in an attempt to protect them from bad news. Research, however, suggests that the absence of prognostic information makes it more difficult, not easier, for parents to cope.

Dissatisfaction with delayed receipt of diagnostic information has been linked to higher rates of parental depression. In qualitative studies, parents advise professionals that they want and need prognostic information to assist them with planning services.

In addition, parents recommend that medical information be presented in “parent-friendly” language to facilitate their understanding and acceptance of information.^"

Clinical prognostic messages from a systematic review on cerebral palsy.

Novak I, Hines M, Goldsmith S, Barclay R.

Source

MSc (Hons), BAppSc (OT), Head of Research, Cerebral Palsy Alliance Research Institute, PO Box 184, Brookvale NSW 2100, Australia. inovak@cerebralpalsy.org.au.

Abstract

OBJECTIVE:

To summarize evidence on the rates of co-occurring impairments, diseases, and functional limitations with cerebral palsy into succinct clinical messages.

METHODS:

A search was conducted of the databases PubMed, Medline, CINAHL, and PsycINFO, and the results were supplemented with hand searches. Two independent reviewers determined whether retrieved abstracts met the following inclusion criteria: human subjects; >90% were children or adults with cerebral palsy; published after 1999; and population-based data. Articles were appraised, analyzing design, participants, level of evidence, rates of impairments, and functional implications. Methodologic quality was rated by using a standardized checklist.

RESULTS:

A total of 1366 papers were identified in the search; 82 were appraised and 30 were included in the meta-analyses. High-level evidence existed, as rated on the Oxford 2011 Levels of Evidence: 97% of prevalence studies were level 1. The data were of a moderate to high quality grade (with the exception of sleep disorders), allowing plain English clinical messages to be developed.

CONCLUSIONS:

Among children with cerebral palsy, 3 in 4 were in pain; 1 in 2 had an intellectual disability; 1 in 3 could not walk; 1 in 3 had a hip displacement; 1 in 4 could not talk; 1 in 4 had epilepsy; 1 in 4 had a behavior disorder; 1 in 4 had bladder control problems; 1 in 5 had a sleep disorder; 1 in 5 dribbled; 1 in 10 were blind; 1 in 15 were tube-fed; and 1 in 25 were deaf.

PMID:

 

23045562

 

[PubMed - in process]

Pediatrics. 2012 Nov;130(5):e1285-312. doi: 10.1542/peds.2012-0924. Epub 2012 Oct 8.

Clinical Prognostic Messages 

From a Systematic Review on 

Cerebral Palsy

TABLE 3

Clinical Messages

Problem	How Common Is This Problem?	Who Is at Risk?	Long-term Implications?	Clinical Recommendations
Behavior	1 in 4 children with cerebral palsy have a behavior disorder (moderate-quality GRADE)	Children with cerebral palsy and an ID are more likely to have behavioral problems (high-quality GRADE)	Unknown	Thorough assessment of behavior is recommended. Also a pain assessment is essential in the presence of behavioral problems, even for children with mild physical impairments.
	The rate of abnormal behavior in children with cerebral palsy is 2 to 4 times higher than the population (moderate-quality GRADE)	Children with cerebral palsy and epilepsy are more likely to have behavioral problems; these children are also more likely to have an intellectual impairment (moderate-quality GRADE)		Pain control may remediate or minimize the behavioral problem.
		Children with cerebral palsy and severe pain are more likely to have behavioral problems (high-quality GRADE)		Standard psychometric IQ assessment is also recommended in the presence of behavioral problems to enable the family to understand the prognosis of the behavioral problem.
		Children with cerebral palsy and milder physical disability are more likely to have behavioral problems than children with severe physical disability (high-quality GRADE)
Bladder and bowel control	1 in 4 children with cerebral palsy do not have bladder control (moderate-quality GRADE)	The risk of bladder and bowel control problems increases with severity of physical disability (moderate-quality GRADE)	Unknown	Medical investigations are warranted as abnormal anatomic findings are common
	The rate of bladder control problems in children with cerebral palsy <4 2="2" 3="3" grade="grade" higher="higher" is="is" low-quality="low-quality" old="old" population="population" td="td" than="than" the="the" times="times" to="to" years="years">	Children with cerebral palsy who are unable to walk or have an ID are most at risk for bladder and bowel control problems (moderate-quality GRADE)		Children with cerebral palsy should be offered standard toilet training but over a longer period of time
	1 in 3 to 4 children with cerebral palsy have constipation (low-quality GRADE)			Prescription of incontinence aides will be required for 1 in 3-4 and this will be for longer periods of time that children without physical disabilities
Dribbling	1 in 5 children with cerebral palsy dribble (moderate-quality GRADE)	Children with severe physical disability are more likely to dribble (moderate-quality GRADE)	Unknown	Social stigma is a major problem arising from dribbling and effective treatments such as Botulinum toxin A or surgical interventions should be explored.
Eating	1 in 15 children with cerebral palsy are tube-fed (moderate-quality GRADE)	Children with a history of poor sucking during infancy are more likely to have feeding problems (moderate-quality GRADE)	Eating skills remain stable in adulthood (high-quality GRADE)	Infants with cerebral palsy and poor sucking should have their eating comprehensively monitored.
	Children with cerebral palsy are 3 times more likely to have feeding problems at 6 months of age (moderate-quality GRADE)	Children with severe physical disability are more likely to need someone to feed them (moderate-quality GRADE) and are more likely to need tube feeding (moderate-quality GRADE).		Swallowing safety should be comprehensively assessed if concerns are reported.
		Children who are nonverbal are more likely to have difficulty feeding (high-quality GRADE)		Weight should also be measured regularly as those with more severe physical disability have higher risk for malnutrition.
Epilepsy	1 in 4 children with cerebral palsy have active epilepsy (high-quality GRADE)	The risk of epilepsy with cerebral palsy increases with severity of physical disability (high-quality GRADE)	Adults with cerebral palsy and epilepsy are less likely to work (high-quality GRADE)	Anti-epileptic medications are usually effective for managing seizures and are considered standard practice for managing epilepsy in children with cerebral palsy
	1 in 3 children with cerebral palsy have had epilepsy at some time (high-quality GRADE)	Children with both sides of the body affected are more likely to have epilepsy (high-quality GRADE)	Children with cerebral palsy are less likely to become seizure-free (low-quality GRADE)
		Children with cerebral palsy and an ID are more likely to have epilepsy (high-quality GRADE)
Hearing	1 in 25 children with cerebral palsy have severe hearing impairment or are deaf (high-quality GRADE)	Children with more severe physical disability are more likely to have a hearing impairment (moderate-quality GRADE)	Unknown	Early screening, assessment, and accommodation for hearing impairment is recommended
Hips and spine	1 in 3 children with cerebral palsy have hip displacement (high-quality GRADE)	Children with both sides of the body affected and who cannot walk are at the greatest risk of hip problems (high-quality GRADE) and scoliosis (low-quality GRADE)	Long-term active hip surveillance reduces the likelihood of progression from hip displacement to hip dislocation (moderate-quality GRADE)	6- to 12-month hip surveillance is recommended and is effective for ensuring access to early treatment. Radiograph and clinical assessment should commence very early. For those who receive hip surveillance the rate of salvage orthopedic surgery is lower
	1 in 10 children with cerebral palsy have hip dislocation without hip surveillance (high- quality GRADE)	The risk of hip abnormalities with cerebral palsy increases with severity of physical disability (high-quality GRADE)
		The risk of associated spinal deformity increases with severity of physical disability (low-quality GRADE)
Intellect	1 in 2 children with cerebral palsy have an ID (moderate-quality GRADE)	Children with more severe physical disability are more likely to have an intellectual impairment (moderate-quality GRADE)	Unknown	Formal assessment and diagnosis of an ID is an important prognostic indicator for walking, bladder control, school performance, and likelihood of independent living
	1 in 4 children with cerebral palsy have a severe ID (moderate-quality GRADE)	Children with dyskinetic cerebral palsy who have an ID are more likely to have a severe ID than those with spastic cerebral palsy (moderate-quality GRADE)		If multiple impairments exist, psychometric screening of intelligence is highly recommended for intervention and school planning
Pain	3 in 4 children with cerebral palsy are in pain (moderate-quality GRADE)	Children and adults with cerebral palsy regardless of level of disability are at risk for pain (high-quality GRADE)	Pain is linked to higher rates of behavioral problems and lower participation (high-quality GRADE)	Parents and children report levels of pain differently and therefore the child’s perceptions should always be sought
		For those who can walk, neck, back, and feet are high-risk pain sites (low-quality GRADE)	Pain increases with age (moderate-quality GRADE)	Investigate a wide range of pain origins (eg, dental, gastrointestinal, muscular, neuropathic, rheumatology, skeletal, tonal)
		Children and adults with contracture are at higher risk of developing pain (moderate-quality GRADE)		Comprehensive pain management should be instigated to minimize the likelihood of secondary behavioral problems from developing
Sleeping	1 in 5 children with cerebral palsy have a sleep disorder (low-quality GRADE)	Children with cerebral palsy and active epilepsy are most at risk for sleep disorders (low-quality GRADE)	Unknown	Through and specialist assessment of sleep problems are recommended
	The rate of sleep disorders in children with cerebral palsy is 5 times higher than the population (low-quality GRADE)	Children with spastic quadriplegia or dyskinesia or a severe visual impairment are more likely to have difficulty initiating and maintaining sleep (low-quality GRADE)		Early treatment of sleep problems (both medical and behavioral) is advisable before secondary academic and behavioral problems emerge or are established
Talking	1 in 4 children with cerebral palsy cannot talk (high-quality GRADE)	Children with more severe physical disability/nonambulatory are more likely to have a speech impairment (high-quality GRADE)	Unknown	Early assessment and recommendations of augmentative and alternative communication options for speech impairment is recommended
	1 in 3 children with cerebral palsy have some speech impairment (high-quality GRADE)	Children with dyskinesia are more likely to have speech problems (high-quality GRADE)
Walking	1 in 3 children with cerebral palsy cannot walk (high-quality GRADE)	Children with cerebral palsy who have 4 limbs affected and/or ID and/or epilepsy and/or a vision impairment have a higher risk of being unable to walk (high-quality GRADE)	Children who walk using aids or cannot walk lose walking function during adolescence (moderate-quality GRADE)	Children who walk using aides and their families should be emotionally prepared for potential loss of motor function in adolescence
	1 in 6 children with cerebral palsy walk using aides (high-quality GRADE)	At age 2 years, children with cerebral palsy who are unable to roll, sit, or pull to stand have a very high risk of being unable to walk (high-quality GRADE)	Ability to walk further declines during later adulthood. (high-quality GRADE)	Children who walk using aides require mobility assessments at the commencement of adolescence to enable prescription of appropriate mobility devices to accommodate declining motor function
	1 in 2 children with cerebral palsy walk independently (high-quality GRADE)	A child’s walking ability at age 12 years is predictive of their walking ability as an adult. (high-quality GRADE)
Vision	1 in 10 children with cerebral palsy have a severe visual impairment or are blind (moderate-quality GRADE)	Children with severe physical disability are more likely to have a visual impairment (high-quality GRADE). Among those with severe physical disability, severe visual impairment occurs more frequently with spasticity than dyskinesia (high-quality GRADE)	Unknown	Early screening, assessment, and treatment of vision impairment is recommended
	1 in 4 children with cerebral palsy have a vision impairment (moderate-quality GRADE)	Children born prematurely with cerebral palsy are more likely than children without cerebral palsy to have visual impairments (high-quality GRADE)

• GRADE system (Guyatt et al [2008])²¹ was as follows: high-quality: further research is very unlikely to change our confidence in the estimate of effect; moderate-quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low-quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; and very-low-quality: any estimate of effect is very uncertain.