Lifting the ‘hood’ on autism

A gene-sequencing study of children with autism, described in an advance online publication in Nature Genetics offers a sneak peek at a technique which, combined with other approaches, may explain 40 to 50 percent of the genetic causes of the disorder within just a few years, proposes the study’s lead investigator. This approach, says Evan Eichler of the University of Washington in Seattle, will potentially allow clinicians to “lift the hood on what has gone wrong in each individual child with autism,” with the hope of ultimately devising individually-tailored drug therapies.

Autism spectrum disorders manifest themselves in a wide variety of ways, and researchers believe that they are highly genetically diverse, involving mutations in any of several hundred genes. While studies of twins suggest that as much as 90 percent of autism is genetically based, large-scale genetic screens over the past decade that searched for common genetic variants underlying the disorder have been disappointing. A growing body of evidence suggests that, especially in families with no prior history of the disorder, autism results not from the inheritance of an unfortunate combination of common gene variants, but from rare, spontaneous - or de novo - mutations in the egg or sperm.

Over the past few years, this theory has been supported by numerous microarray studies showing that children with spontaneous autism are more likely than their unaffected siblings to have de novo copy number variants, mutations in which a large chunk of DNA is duplicated or deleted.

Now, in work funded in part by the Simons Foundation, Brian O’Roak, a joint postdoc in Jay Shendure’s and Eichler’s labs at the University of Washington, has sequenced the exome - the protein-coding regions of the genome - of 20 families consisting of one child with an autism spectrum disorder and unaffected parents and siblings. In contrast to most previous studies, which had sufficient resolution to detect only large copy number variants, the new study could detect even point mutations, in which just a single DNA nucleotide is affected. “Our approach has the advantage of taking a snapshot of an individual’s protein-coding genome and quickly identifying the one or two new sporadic mutations they carry,” O’Roak says.

The families in the study were drawn from the Simons Simplex Collection, a large repository of genetic, phenotypic and biological data from families with just one affected child and unaffected parents and siblings.

The collection was created for the express purpose of facilitating the search for rare, de novo autism mutations.

While the 20 children with autism did not have significantly more de novo point mutations than would be expected in the population at large, their mutations were much more disruptive to the proteins they encoded than is typical.

What’s more, a significant number of the mutations occurred in regions of the genome in which mutations are rarely found, probably because these regions are so crucial to bodily functioning that individuals with defects in those regions usually die without reproducing.

Three of the four mutated genes - FOXP1, GRIN2B and SCN1A - have previously been implicated in autism, and are thought to play roles in speech and language disorders, intellectual disability and epilepsy, respectively.

The fourth gene, LAMC3, has not previously been linked to autism, but is known to be expressed in many areas of the cortex and limbic system. “Finding a LAMC3 mutation will probably set the stage for some new research agendas,” Eichler says.

Two of the four children appear to have experienced a genetic double-whammy, having inherited a deleterious mutation from a parent in addition to having a de novo mutation. The child with a FOXP1 mutation also inherited a defective copy of CNTNAP2, another gene that may be involved in language development.

“It’s like getting hit by lightning twice,” Eichler says. That child has severe autism and the greatest language deficit of any individual in the study.

The child with the epilepsy-related SCN1A mutation also inherited from his mother a deletion that increases the risk for epilepsy; and indeed, that child has been diagnosed with epilepsy.

The findings support the ‘multi-hit’ theory of autism, the idea that it may take a combination of mutations in the same pathway to cause severe autism or related disorders.

Studying 20 families is just a start - “a teaser,” as Eichler puts it.

At the same time, the study offers two important proofs of principle: It provides compelling evidence that de novo point mutations may underlie many cases of autism, and it shows that exome-sequencing is an effective way to discover which of the more than 20,000 genes in the human genome are responsible for autism spectrum disorders.

“It’s like having a dartboard with 20,000 candidates - the fact that we could pick off four outstanding candidate genes is a great success,” Eichler says.

“It’s proof on the ground that this technique is fruitful.”

“Within a couple of years, we should have a pretty comprehensive view of the genes that cause autism,” he says.

Source: Anastasia Greenebaum Simons Foundation

Early detection of alcohol dependence

by Dr. R.A.R. Perera

One of the disadvantages of early detection of alcohol dependence is that it makes medical personnel think of physical damage first, where as social problems such as marital breakdown or loss of job are earlier indicators. These are often followed by psychological difficulties such as depression, anxiety or change in personality. Physical disorders generally occur later. Alcohol induced gastritis, ulcer pain, vomiting of blood and cirrhosis are the common medical problems. Alcohol related problems may occur singly but the more and longer and individual drinks the more problems he risks.

An alcohol dependent person has the following main features;

* The dependent drinker drinks to relieve or avoid withdrawal symptoms and drinking increasingly takes priority over other activities.

*The development of tolerance is shown by the dependent person being able to sustain an alcohol intake which would incapacitate the average man. For example blood alcohol concentration of 300 mg% does not indicate a person’s manly ability to hold his drink, but rather his pathological tolerance.\*The dependent drinker becomes liable to withdrawal symptoms after 8-12 hours of abstinence. Each morning he may experience tremor, which varies from shaking of the hands to the whole body, nausea or vomiting, sweating, itching, muscle cramps and mood disorders.

*These withdrawal symptoms are temporarily ‘cured’ by drinking more alcohol. The drinker finds he can no longer control his drinking or be sure of stopping once he has started and drinking after abstinence is likely to lead to reinstatement of the entire episode.

Because of the relatively poor results of treating the established and heavily dependent drinker, emphasis has recently turned towards prevention and early detection, Alcohol related problems are caused by many causes and research has implicated variety of predisposing factors such as heredity, personality and occupation.

Overall per capita consumption is related to the price and availability of alcohol, Wherever alcohol is relatively cheap and widely available (as in Sri Lanka) the per capita consumption is high and alcohol related problems are common.

Since governments control the price and availability of alcohol, the prevalence of alcoholism is not only a medical but also a political question.

Psychologists and doctors are increasingly confronted with the social, psychological and physical consequences of excessive alcohol consumption.

It is not difficult to diagnose the pot-bellied person who shakes as he breathes stale alcohol, but it is difficult to recognize the excessive drinker decade earlier.

There are at risk factors to recognize and alcoholic dependent person.

*Marital problems e.g. Violence towards the family

*Problems at work – repeated absence on Mondays.

*Problem drinkers are much more liable to accident at home, at work and on the roads.

*A relative with alcoholism-alcoholism is a family disease

*High risk occupation – commercial travellers, company directors, entertainers, journalists, soldiers, and doctors.

*Mental disorders-anxiety, depression and attempted suicide

*Physical disorders – gastritis, liver disease

There are some blood tests which will show whether a patient is alcohol dependent.

There are psychological treatment such as aversive therapy and behavioural modification therapy to treat alcohol dependants. These therapies are effective but takes a long time to produce the expected results.

(The writer is a Consultant Psychologist)

Parents, key to children’s drinking

Children who regularly see their parents drink are twice as likely to binge on alcohol themselves, according to a survey.

Youths who are left unsupervised are also more likely to drink, the Joseph Rowntree Foundation report found.

Researchers for Ipsos Mori questioned 5,700 teenagers in England, and found one in four 13-14-year-olds have been drunk more than once, compared to just over half of children (52%) who are 15-16.

Those who said they had seen their parents inebriated were twice as likely to have been drunk several times.

And the odds of a teenager having ever had an alcoholic drink are also greater if their parents do not know where they are on a Saturday night, or if they are allowed to watch 18-rated films unsupervised.

Claire Turner, from the Joseph Rowntree Foundation, said: “This research shows that parents can have more influence on their teenagers’ behaviour than perhaps many assumed.

“Both what parents say and how they behave have a strong impact on their teenagers drinking, drinking regularly, and drinking to excess.”

The survey found the influence of friends is the most significant factor in childhood drinking, as the likelihood of youths drinking to excess more than doubles if they spend more than two nights a week socialising.

Spending every night with friends multiplies the odds of drinking heavily more than four times.

The report concluded that schools are key to distributing information about drinking.

“The findings suggest that efforts to improve drinking behaviour among young people at a national policy level are best directed at supporting and educating parents,” it said.

“This should include positive messages for parents about how they can influence their child’s behaviour and stress the importance of parents’ own drinking and what their children see and think about this.

“Friends are another key area of influence. Schools could help here by challenging incorrect perceptions about the regularity and scale of heavy drinking by peer groups.

“Schools could also be a channel for information, getting targeted messages to parents encouraging actions at specific times in their child’s development.”

Diane Abbott, the Labour health spokeswoman, said: “This report confirms that the Government’s failure to take real action on alcohol pricing is helping to feed an epidemic of teen drinking.

“We should equip young people with the skills they need to resist peer pressure to go out drinking. There are concrete lessons to be learnt from overseas, where tried and tested programmes aim to reduce alcohol and substance abuse through classroom-based education. These types of programmes have had excellent success rates.”

A Department of Health spokesman said: “Alcohol misuse is a major public health issue. We know that teenagers can be especially vulnerable to the harmful effects of drinking.

Courtesy: The Independent

Competing treatments comparable for hearing loss

A relatively new treatment for sudden hearing loss that involves injecting steroids into the middle ear appears to work just as well as the current standard of oral steroids, a study by researchers suggests. The findings could lead to more options for the 1 in 20,000 people who suffer from this often baffling and disabling condition each year.

As the name implies, sudden hearing loss (SHL) is a dramatic loss of hearing that occurs over a short period, usually less than 72 hours.

Often, physicians never figure out the cause of the problem. Though about a third of patients regain some hearing on their own, others suffer a permanent loss if untreated. Patients are more likely to regain their hearing if they’re treated within two weeks of the start of symptoms.

The usual treatment is a course of oral steroids, which are thought to reduce inflammation that might be responsible for the hearing loss.

Some doctors have recently begun treating SHL patients instead with a series of steroid injections delivered through the eardrum and into the middle ear.

In theory, these injections could deliver a heavier dose of steroids directly to the source of the problem, explains John Carey, M.D., a professor in the Department of Otolaryngology Head and Neck Surgery at the Johns Hopkins University School of Medicine.

However, he adds, the relative rarity of this condition and potential for it to improve without treatment left physicians puzzled over how these two treatments compare.

To investigate, he and his colleagues conducted a trial of the two different treatments at 16 academic medical centres across the country. The researchers randomly assigned 250 patients who came into these centres for SHL treatment to receive either a two-week course of oral steroids or four steroid injections spaced out over two weeks.

Before treatment, these patients each had a 50-decibel or greater hearing loss in one of their ears.

Two months after treatment, the researchers tested the study subjects’ hearing again. Results showed that patients treated with oral steroids had an average 30.7-decibel improvement in the affected ear, compared to a 28.7-decibel improvement in those treated with injections. The treatments were comparable for most patients, Carey explains, with the exception of patients with very severe hearing loss (greater than 90 decibels), who tended to have better results with oral steroids.

He adds that both treatments have a variety of pros and cons. For example, oral steroids come with a host of side effects, including insomnia, weight gain and an increase in blood sugar, but have a low cost and can be taken conveniently at home. Steroid injections can avoid these side effects, but are expensive and potentially painful, and need to be performed in a doctor’s office.

“This study suggests that for most SHL patients, oral and injected steroids appear to be equally effective,” Carey says. “This could lead to better options for patients that match their personal preferences.”

He and his colleagues plan to eventually study whether the treatments might be even more effective if they’re given concurrently or sequentially.

This study was funded by a grant from the National Institute on Deafness and Other Communication Disorders.

Source: Johns Hopkins Medicine

Urgent need to fight diseases affecting the world’s poor

Despite significant advancements in increasing distribution and development of vaccines against childhood killer diseases – including pneumococcal disease, rotavirus, and Haemophilus influenzae Type B - global efforts to reduce the burden of infection from neglected tropical diseases (NTDs) has greatly lagged, argues Sabin Vaccine Institute (Sabin) President Dr. Peter Hotez in an article for the June edition of Health Affairs.

NTDs, a group of 17 parasitic infections, represent a significant contributor to global poverty, and have well documented chronic and disabling effects. Yet efforts to develop vaccines for NTDs have not benefited from larger ongoing initiatives to combat major childhood diseases.

In his article Dr. Hotez cites three critical reasons for the lack of interest in “anti poverty” vaccines:

* Though NTDs disable, they do not typically cause high levels of mortality leading some in the public health community to misleadingly conclude that NTDs are not a significant public health threat;

* NTDs predominately occur in rural settings and are largely hidden diseases unknown to the public and infrequently documented; and,

* Pharmaceutical companies are reluctant to make an investment in NTD vaccines because there is no financial incentive. Public-private partnerships increasingly represent an innovative mechanism for developing NTD vaccines, states Dr. Hotez in his article. In particular, manufacturers from middle-income countries are increasingly partnering with U.S. organizations and academic institutions to generate a pipeline of vaccines for NTDs. Sabin’s vaccine development program - currently developing vaccines for human hookworm infection and schistosomiasis - represents one of a limited number of such partnerships. Dr. Hotez concludes by stating that “developing a new generation of antipoverty vaccines represents a highly innovative and meaningful approach to eliminating the world’s neglected diseases, lifting the bottom billion out of poverty, and promoting international diplomacy.”

Source: Richard Hatzfeld Sabin Vaccine Institute

Human retina protein as a light-sensitive magnetic sensor

For migratory birds and sea turtles, the ability to sense the Earth’s magnetic field is crucial to navigating the long-distance voyages, these animals undertake during migration. Humans, however, are widely assumed not to have an innate magnetic sense. Research published in the latest Nature Communications shows that a protein expressed in the human retina can sense magnetic fields when implanted into Drosophila, reopening an area of sensory biology in humans for further exploration.

In many migratory animals, the light-sensitive chemical reactions involving the protein cryptochrome (CRY) are thought to play an important role in the ability to sense the Earth’s magnetic field. In the case of Drosophila, previous studies from the Reppert laboratory have shown that the cryptochrome protein found in these flies can function as a light-dependent magnetic sensor. To test whether the human cryptochrome 2 protein (hCRY2) has a similar magnetic sensory ability, the researchers created a transgenic Drosophila model lacking its native cryptochrome protein but expressing hCRY2 instead. Using a behavioural system Reppert’s group previously developed, they showed that these transgenic flies were able to sense and respond to an electric-coil-generated magnetic field and do so in a light-dependent manner.

These findings demonstrate that hCRY2 has the molecular capability to function in a magnetic sensing system and may pave the way for further investigation into human magnetoreception. “Additional research on magneto sensitivity in humans at the behavioural level, with particular emphasis on the influence of magnetic field on visual function, rather than non-visual navigation, would be informative,” wrote Reppert and his colleagues in the study.

Source: im Fessenden University of Massachusetts Medical School