DNA sequences were once thought to be the same in every cell, but the story is now known to be more complicated than that. The brain is a case in point: Mutations can arise at different times in brain development and affect only a percentage of neurons, forming a mosaic pattern.
Now, thanks to new technology described last week in Neuron, these subtle “somatic” brain mutations can be mapped spatially across the brain and even have their ancestry traced.
Like my family, who lived in Eastern Europe, migrated to lower Manhattan and branched off to Boston, California and elsewhere, brain mutations can be followed from the original mutant cells as they divide and migrate to their various brain destinations, carrying their altered DNA with them.
“Some mutations may occur on one side of the brain and not the other,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital and co-senior author on the paper. “Some may be ‘clumped,’ affecting just one gyrus [fold] of the brain, disrupting just a little part of the cortex at a time.” …
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. …
At first, Corrie and Adam Mendes thought their daughter Emmie had an inner ear problem. She was late with several early milestones, including walking, and when she did walk, she often lost her balance. The family pediatrician sent them to a neurologist, who ordered a brain MRI and diagnosed her with pachygyria, a rare condition in which the brain is smoother than normal, lacking its usual number of folds.
Additionally, Emmie’s ventricles, the fluid-filled cushions around the brain, looked enlarged, so the neurologist recommended brain surgery to install a shunt to drain off fluid. He advised Corrie and Adam that Emmie’s life expectancy would be greatly reduced.
The butterfly effect is defined as “the sensitive dependence on initial conditions, where a small change at one place in a deterministic nonlinear system can result in large differences to a later state.” In medicine, the identification of a rare disease or a genetic mutation may provide insights that spread well beyond the initial discovery.
And in genetics, scientists are learning just how widespread the effects are for mutations in one gene: filaminA (FLNA).
FLNA is a common cause of periventricular nodular heterotopia (PVNH), a disorder of neuronal migration during brain development. The syndrome was first described by the late Peter Huttenlocher, MD, and the gene was identified by Christopher Walsh, MD, PhD, of Boston Children’s Hospital.
In normal brain development, neurons form in the periventricular region, located around fluid-filled ventricles near the brain’s center, then migrate outward to form six onion-like layers. In PVNH, some neurons fail to migrate to their proper position and instead form clumps of gray matter around the ventricles. …
Five people with an unusual pattern of brain folds have afforded a glimpse into how the human brain may have evolved its language capabilities.
How the human brain develops its hills and valleys—expanding its surface area and computational capacity—has been difficult to study. Mice, the staple of scientific research, lack folds in their brains.
Christopher Walsh, MD, PhD, head of the Division of Genetics and Genomics at Boston Children’s Hospital, runs a brain development and genetics clinic and has spent 25 years studying people in whom the brain formation process goes awry. Some brains are too small (microcephaly). Some have folds, or gyri, that are too broad and thick (pachygyria). Some are smooth, lacking folds altogether (lissencephaly). And some have an abnormally large number of small, thin folds—known as polymicrogyria.
In 2005, studying people with polymicrogyria, Walsh and colleagues identified a mutation in a gene known as GPR56, a clue that this gene helps drive the formation of folds in the cortex of the human brain.
In a study published in today’s issue of Science, Walsh and his colleagues focused on five people whose brain MRIs showed polymicrogyria, but just in one location—near a large, deep furrow known as the Sylvian fissure, which includes the brain’s primary language area. …
(Above: In double cortex syndrome, causing epilepsy and mental retardation, an extra cortex forms just beneath the cerebral cortex [right]. The causative DCX mutation interferes with migration of neurons during the cortex’s early development. Courtesy Walsh Lab)
Key to well-tuned brain function is the migration of neurons to precise locations as the brain develops. The long journey begins deep inside the brain and ends in the outer cerebral cortex—where our highest cognitive functions lie. Christopher Walsh, MD, PhD, has shown that several genetic mutations causing neurodevelopmental disorders disrupt this neuronal migration, landing neurons in the wrong places. Each gene governs a specific sub-task: one kicks off the migration process; others stop migration when neurons have arrived in the right location. …
Autism clearly runs in some families, yet few inherited genetic causes have been found. A major reason is that these causes are so varied that it’s hard to find enough people with a given mutation to establish a clear pattern. Now, three large Middle Eastern families with autism spectrum disorders (ASDs) have led the way to a few more mutations, potentially broadening the number of genetic tests available to families.
What’s fascinating is that the mutations, described earlier this week in Neuron, affect genes known to cause severe, often lethal genetic syndromes. Milder mutations in the same genes, found through genomic sequencing, primarily cause autism.
Researchers Tim Yu, MD, PhD, Maria Chahrour, PhD, and senior investigator Christopher Walsh, MD, PhD, of Boston Children’s Hospital, started with three large families that had two or more children with an ASD, in which the parents were first cousins. Cousin marriages are a common tradition in the Middle East that greatly facilitates the identification of inherited mutations—as does large family size. …
Addison Lennon met all her early milestones: she sat up on time, crawled on time and walked on time. At about 4 months, however, she had a seizure, and her parents started to worry. By 9 months, her head appeared small for her age.
Her neurologist reassured the family that Addison could still be within the lowest 5 percent of the normal range. “We were thinking she was typical,” says Kari Lennon, “she would be in that 5 percent.”
At 15 months, however, Addison had another seizure that was a lot more severe. She had been tested for everything. No one could pinpoint the cause of her so-called microcephaly, or small head.
Kari spent countless hours online in search of answers. “How I could fix Addie? How could I make her better?” (Read on, or watch this video:)
Christopher Walsh, MD, PhD, is chief of Genetics and a Howard Hughes Medical Institute Investigator at Children’s Hospital Boston, where his research focuses on genes that regulate the development and function of the human cerebral cortex. These genes are vital to normal development of the cortex, and many appear to have been altered evolutionarily to allow the unique aspects of the brain that underlie human cognitive abilities. Mutations in these genes are known to cause autism and epilepsy, as well as intellectual disabilities and other learning disorders.
In the second century, the Greek physician Galen proposed that the fluid in the brain provided energy for the entire body, theorizing that an external spirit (pneuma) from the lungs was transported to the heart, where, combined with blood, it would give rise to the vital spirit. Carried by the blood, the vital spirit was then thought to be transformed into an animal spirit before entering the cavities of the brain, then traveling through the nerves, “as sunshine passes through the air or water,” to energize the entire physical being.
In this view, the brain itself was a mere holder of the fluid. Our neuroanatomical term “thalamus,” referring to part of the brain stem, comes from the Greek word for “chamber,” implying that the brain was mainly important as a holder for CSF. The philosopher Descartes (1596-1650) thought that the brain was a pump that moved the fluid around to do the brain’s work, such as making a muscle contract. Seventeenth century Swedish scientist Emanuel Swedenborg referred to the CSF as a “spirituous lymph” and a “highly gifted juice.”