Research Team first to Map Autism-Risk Genes by Function

Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to increased autism risk. Where do you start?

UCLA neuroscientists may have an answer. They are the first to map groups of autism-risk genes by function, and to identify where and when these genes normally play major roles in early brain development.

In addition, they discovered disturbances in neural circuits that define key pathways between parts of the cerebral cortex.

The research suggests that these early disruptions are created by mutations in genes during fetal brain development and are not a result of autism itself.

Published in the Nov. 21 edition of Cell, the findings will help scientists understand how genetic changes cause autism on a molecular level and prioritize targets for future studies.

"Identifying gene variants that boost risk is only the first step of unraveling a disease," explained lead author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behaviour.

"We need to figure out where genetic changes appear in the brain, at what stages during development and which biological processes they disrupt. Only then will we understand how mutations cause autism."

Using an online atlas called BrainSpan, the authors charted gene activity in the developing brain before birth.

In particular, they examined what happens during gene expression —when genes copy data from DNA to RNA in order to create proteins.

Geschwind and his colleagues found high activity in risk genes during two processes critical to early brain development.

"We found that gene variants are expressed in the developing brain when cells define their future identities and roles in neural circuits," first author Neelroop Parikshak, a graduate student researcher in Geschwind's lab.

"Therefore, changes in the genes influence the brain's wiring by altering the synapse and shaping how neurons transmit signals to each other."

The mutated genes also interfered with how the brain's layers and halves relate to one another, a phenomenon confirmed by previous imaging studies of the autistic brain.

"We discovered gene-related disruption of circuits that connect the autistic brain's layers and hemispheres to each other," explained Geschwind, who is director of the UCLA Neurogenetics Program and the Center for Autism Research and Treatment and co-director of the Center for Neurobehavioral Genetics at UCLA.

 "Our finding suggests that the mutated genes caused the miswiring; it's not a result of having the disease itself."

The UCLA team also demonstrated that while autism and intellectual disability share similar risk genes, the genes behave uniquely, showing for the first time how the two disorders differ.

"People often lump intellectual disability together with autism, because the disorders' risk genes overlap," said Parikshak.

"We showed that these genes have unique expression patterns in different brain regions at varying times during brain development.

"Genes linked to intellectual disability influence many biological processes in the body," he added. "But genes tied to autism tend to affect specific functions, such as the connections between brain regions that are essential to many human-specific behaviours, like speech and language."

The UCLA study will reap immediate benefits in the near future, when neuroscientists sequence the genomes of several thousand people for genetic mutations linked to autism and intellectual disability.

"We've made our analysis publically available to allow other researchers to expand upon our study and explore the data in detail," said Geschwind.

"We believe this will mark an important step forward in understanding the biology behind autism and other neurodevelopmental disorders."

ADHD: FDA approves first brain wave test (NEBA)

Christy Foreman

US regulators on Monday approved the first brain wave test for attention deficit hyperactivity disorder, saying it may improve the accuracy of diagnoses by medical experts.

Cases of ADHD are on the rise in the United States, as are the number of prescriptions for stimulants doled out to young people who appear to have difficulty concentrating or controlling impulses.

The new test, known as the Neuropsychiatric EEG-Based Assessment Aid (NEBA) System, measures electrical impulses given off by neurons in the brain.

A 15-20 minute test calculates the ratio of certain brain wave frequencies known as theta and beta waves in children age six to 17.

"The theta/beta ratio has been shown to be higher in children and adolescents with ADHD than in children without it," the US Food and Drug Administration said.

"Diagnosing ADHD is a multistep process based on a complete medical and psychiatric exam," cautioned Christy Foreman, director of the Office of Device Evaluation at the FDA's Center for Devices and Radiological Health.

"The NEBA System along with other clinical information may help health care providers more accurately determine if ADHD is the cause of a behavioral problem."

The FDA said the test "can help confirm an ADHD diagnosis" or help decide if further treatment should focus on "other medical or behavioral conditions that produce symptoms similar to ADHD."

The FDA approved the device after a reviewing it as a new and "low- to moderate-risk medical device."

Studies supplied by the manufacturer evaluated 275 patients using both the NEBA system and other standard protocols for diagnosing ADHD which include behavioral questionnaires, behavioral and IQ testing and physical exams.

An independent review found the device "aided clinicians in making a more accurate diagnosis of ADHD when used in conjunction with a clinical assessment for ADHD, compared with doing the clinical assessment alone," the FDA said.

The device is made by NEBA Health in Augusta, Georgia.

ADHD is believed to occur in five to 10 percent of US children. A recent analysis of US government data by the New York Times found that as many as one in five teenage boys is diagnosed with the disorder.

A study in the journal Pediatrics last year found a 46 percent rise in ADHD prescriptions from 2002 to 2010.

Diabetes: First paediatric-focused calculator

Nationwide Children's Hospital recently developed an online resource to help parents manage their child's diabetes more effectively and care for their health at home.

The "Diabetes Calculator for Kids," a first of its kind electronic tool geared toward the pediatric patient, allows parents, caregivers and the adolescent patient themselves to create an individualised chart which calculates the correct insulin dosage that should be given prior to eating.

Diabetes, which affects nearly 1 in every 400 children and adolescents in the United States, is a disease that is characterised by a high blood glucose or "sugar" level.

Managing a child's diabetes requires the proper balance between insulin dose, food and activity on a daily basis. It is important to keep the child's blood sugars within a target range at all times.

Modern insulin therapy involves administering rapid-acting insulin before each meal and adjusting the dose based on the current blood glucose level and how much food will be eaten.

The Diabetes Calculator for Kids, available for any patient who uses insulin, creates an individualised chart for rapid-acting insulin bolus dosage in five easy steps.

After the parent or patient completes those steps online, a customised chart is produced that can be emailed or printed off.

It provides the parent, caregiver or patient an easy way to look up the correct insulin dosage based on current blood glucose, without having to do the math each time.

David Repaske

"The goal is to provide an additional tool to empower families to successfully manage their child's diabetes at home in order to provide as normal a life as possible for that child," said David Repaske, MD, PhD, chief of Endocrinology, Metabolism & Diabetes at Nationwide Children's and also a faculty member at The Ohio State University College of Medicine.

"The chart can also be printed out and taken to school or given to a sitter to ensure accurate insulin dosing without the need to learn the formula and do the math for each dose."

Nationwide Children's always recommends that parents consult with their child's physician first with any questions related to their child's individual diabetes management plan.

First Aid: Epilepsy Scotland

Simple Partial Seizures

A simple partial seizure could affect the person's movement, smell, taste, hearing, sight, breathing, heart beat, digestion or any mixture of these. They may experience, for example, twitching of an arm and nausea. The person does not lose consciousness and is fully aware of, but cannot control, what is happening.

What to do

• Stay with the person and offer reassurance until the seizure has passed
• Sometimes a simple partial seizure can act as a warning or 'aura' that a second seizure (usually a tonic-clonic or a complex partial seizure) will soon start.
• If this is the case, the person may need help in getting to a quiet and safe place.

Complex Partial Seizures

The person may experience strange or unusual feelings, lose their sense of time and appear distant from who and what is happening around them. This type of seizure can make someone behave in an odd, random or inappropriate way, such as lip smacking, plucking at clothes, moving aimlessly or compulsively around a room. Unlike simple partial seizures, there will be some loss or alteration of consciousness.

What to do

• Gently lead them from any source of danger
• Do not restrain or interfere unnecessarily with the person
• The seizure should be allowed to run its natural course
• Speaking softly and calmly may help
• Offer reassurance afterwards

Absence Seizures (previously known as petit mal)

Absence seizures consist of a brief loss of consciousness and are easily mistaken for daydreaming. The person (usually a child) stops what they are doing, remains motionless, blinks, and stares into space. Soon, the person will recover and may not be aware that a seizure has occurred.

What to do

• Absence seizures are usually very brief and often pass unnoticed
• If you witness an absence seizure stay with the person for a while to make sure they do not suffer any injury
• Tell the person what has happened
• If a child is in the classroom, repeat any information they have missed

Tonic-clonic seizures (previously known as grand mal)

The tonic-clonic seizure is the most widely recognised seizure. The person will lose consciousness and fall to the ground.


The person will stiffen (the tonic phase) and then jerk (the clonic phase).
Breathing may become irregular and as a result the person could turn slightly blue. The person may also make grunting noises, bite their tongue or cheek, or be incontinent.
After a couple of minutes the jerking normally stops and the person will slowly regain consciousness. They may feel groggy, sleepy and confused for some time afterwards and have a headache or aching limbs. How long it takes to feel ok again varies from one person to the next.

What to do

• Keep calm and note the time the seizure starts and how long it lasts
• Clear a space around the person and prevent people from crowding round
• Cushion the person's head with whatever is available
• Loosen any tight clothing round the neck and gently remove glasses (if worn)
• Watch the seizure carefully and if possible let it run its natural course
• Turn the person into the recovery position as soon as the jerking stops
• Be reassuring during the recovery period and tell the person about the seizure
• Stay, if possible, until the person is no longer confused

What not to do

• Do not try to lift or move the person while the seizure is happening unless there is an immediate danger (e.g. they are on a busy road, at the top of stairs, at the edge of water, near a fire or hot radiator)
• Do not try to stop the jerking or restrain the person
• Do not put anything in the person's mouth or between their teeth
• Do not offer the person something to drink until they are fully conscious
• Do not fuss around the person while they are recovering from the seizure

There is no need to call an ambulance unless:

• It is the person’s first seizure
• One seizure follows another without any recovery in between
• The convulsive or jerking part of the seizure lasts more than 5 minutes or longer than is usual for the person
• The person has been badly injured

Primary symptoms of psychosis may be evident in 12-year-olds

Children normally experience flights of fancy, including imaginary friends and conversations with stuffed animals, but some of them are also having hallucinations and delusions which might be the early signs of psychosis.

A study of British 12-year-olds that asked whether they had ever seen things or heard voices that weren't really there, and then asked careful follow-up questions, has found that nearly 6 percent may be showing at least one definite symptom of psychosis.

The children who exhibited these symptoms had many of the same risk factors that are known to correlate with adult schizophrenia, including genetic, social, neurodevelopmental, home-rearing and behavioral risks.

"We don't want to be unduly alarmist, but this is also not something to dismiss," said co-author Terrie Moffitt, the Knut Schmidt Nielsen professor of psychology and neuroscience and psychiatry & behavioral sciences at Duke University. The study appears in the April issue of Archives of General Psychiatry.

The children were participants in the long-term Environmental Risk Longitudinal Twin Study in Britain, which includes 2,232 children who have been tracked since age 5 and reassessed at 7, 10 and 12.

The British study is an outgrowth of research that the same group did earlier with a long-term cohort in Dunedin, New Zealand. At age 11, those children were asked about psychotic symptoms, but the researchers waited 15 years to see how, as adults, their symptoms matched what they reported at 11. By age 26, half of the people who self-reported symptoms at age 11 were found to be psychotic as adults.

"It looks like a non-trivial minority of children report these symptoms," said co-author Avshalom Caspi, the Edward M. Arnett professor of psychology and neuroscience and psychiatry & behavioral sciences at Duke.

The findings provide more clues to the development of schizophrenia, but don't solve any questions by themselves, said co-author Richard Keefe, director of the schizophrenia research group in the department of psychiatry and behavioral sciences at Duke.

Schizophrenia often goes undetected until adolescence, when the first overt symptoms -- antisocial behavior, self-harm, delusions -- begin to manifest in an obvious way. But nobody knows whether the disease is triggered by the process of adolescence itself, or brain development or hormone changes. "It's my impression that all of those things interact," Keefe said.

Psychotic symptoms in childhood also can be a marker of impaired developmental processes, and are something caregivers should look for, Moffitt said. "There is not much you can do except monitoring and surveillance," Moffitt said. "But we feel we should be alerting clinicians that there's a minority to pay attention to."

While the incidence of psychotic symptoms in this study was around 5 or 6 percent, the adult incidence of schizophrenia is believed to be about 1 percent, Keefe added. There are some recent findings however, that many more people experience hallucinations and delusions without being diagnosed as psychotic, he said.

The research was supported by the U.S. National Institutes of Health, UK Medical Research Council, The National Alliance of Research on Schizophrenia and Depression, the Health Research Board of Ireland and the William T. Grant Foundation.

Etiological and Clinical Features of Childhood Psychotic Symptoms, Guilherme Polanczyk et al, Archives of General Psychiatry, April 2010 http://archpsyc.ama-assn.org/cgi/content/full/67/4/328

Link: http://www.duke.edu/