Stories about: intellectual disability

Science Seen: Disrupted developmental genes cause ‘split brain’

split brain syndrome
The two halves of the brain on the right, from a patient with the DCC mutation, are almost completely disconnected. The mutation — first recognized in worms — prevents axons (nerve fibers) from crossing the midline of the brain by interfering with guidance cues. Image courtesy Ellen Grant, MD, director, Fetal-Neonatal Neuroimaging and Developmental Science Center.

Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.

Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically.

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“Deep sequencing” finds hidden causes of brain disorders

brain malformations sequencing mosaicism
New methods can find a mutation that strikes just 1 in 10 cells.

It’s become clear that our DNA is far from identical from cell to cell and that disease-causing mutations can happen in some of our cells and not others, arising at some point after we’re conceived. These so-called somatic mutations—affecting just a percentage of cells—are subtle and easy to overlook, even with next-generation genomic sequencing. And they could be more important in neurologic and psychiatric disorders than we thought.

“There are two kinds of somatic mutations that get missed,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital. “One is mutations that are limited to specific tissues: If we do a blood test, but the mutation is only in the brain, we won’t find it. Other mutations may be in all tissues but in only a fraction of the cells—a mosaic pattern. These could be detectable through a blood test in the clinic but aren’t common enough to be easily detectable.”

That’s where deep sequencing comes in. Reporting last month in The New England Journal of Medicine, Walsh and postdoctoral fellow Saumya Jamuar, MD, used the technique in 158 patients with brain malformations of unknown genetic cause, some from Walsh’s clinic, who had symptoms such as seizures, intellectual disability and speech and language impairments.

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When reading genes, read the instructions first: Epigenetics and developmental disorders

The genome holds the instructions for making proteins, while the epigenome holds the instructions for reading the genes. Yang Shi wants to understand how those epigenetic instructions are read, especially in cases of intellectual disabilities. (JackBet/Flickr)

While the genome’s As, Ts, Cs, and Gs hold the instructions for making proteins, how does a cell know when to read a gene? And could it relate to developmental disorders?

These gene-reading instructions are encoded in our epigenome, a set of factors that give our cells exquisite control over when and where to turn individual genes on and off. This control involves a delicate and complex dance between DNA and proteins called histones – DNA wraps itself around histones to create a complex called chromatin – as well as the many different types of epigenetic tags.

Yang Shi, of the Division of Newborn Medicine at Children’s Hospital Boston, wants to understand what happens when the genome doesn’t read the epigenome’s instructions correctly, which in the developing brain can cause intellectual disabilities.

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New opportunities for Angelman

Chromosome 15. Image: Wikimedia Commons

Angelman syndrome (AS) is a rare, neurogenetic condition characterized by severe developmental delay, movement disorder, speech impairment (often with a complete lack of speech) and an unusually happy demeanor. Nearly every individual with AS faces at least two major challenges in their daily life: cognitive or intellectual disability, and movement disorder, usually in the form of ataxic (uncoordinated) gait, unsteadiness, jerky movements or tremors. Seizures are also common, and present a daunting health challenge.

Arising in one out of every 10,000 to 20,000 children from the loss of an enzyme on chromosome 15 called Ube3A, AS falls in the category of orphan diseases: ones that affect fewer than one in 200,000 Americans.  There is no cure for AS, but there are therapies and medications that can help the symptoms. Seizures can be controlled with the right medications, physical therapy can improve ataxia, and speech therapy helps improve communication skills.

Like nearly all orphan diseases, research on AS has historically not been well-funded, but orphan diseases have lately gained growing attention, especially at Children’s Hospital Boston.

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Neurogenetic disorders: Dreaming the impossible dream

People with autism and most other disorders of brain development have never had medications to treat their core behavioral and cognitive symptoms. The best they can get are drugs targeting secondary problems, like irritability or aggression. But now, a new wave of clinical trials, such as the one we posted about yesterday for Rett syndrome, aims to change this.

In the last decade, scientists have discovered many of the molecular pathways in genetic disorders that can impair cognition and place a child on the autism spectrum—such as tuberous sclerosis complex, Rett syndrome, Fragile X syndrome and Angelman syndrome. These discoveries are suggesting targets for drug treatment, and is changing how these conditions—and perhaps neurodevelopmental disorders generally—are viewed.

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