Henry is the son of Richard Engel, NBC TV Chief Foreign Correspondent, and Mary Forrest, a freelance producer.
Henry Engel is a beautiful child—and the survivor of a rare medical condition. Now, at age two, he cannot walk or speak. When he was an infant and his parents noticed that he was falling behind, Henry underwent numerous medical exams to discover the cause.
Ultimately, a genetic test gave an answer: Henry has a mutation in his MECP2 gene. MECP2 mutations cause Rett syndrome, a disorder that typically affects girls after their first birthday, robbing them of learned skills and leaving them with cognitive deficits, loss of speech and coordination, and a variety of motor difficulties.
Distinctively, the girls lose their ability to use their hands and instead wring them constantly. They frequently develop anxiety, seizures, and breathing problems as well.
The MECP2 gene is on the X chromosome. Because females have two X chromosomes, when they have a mutation in MECP2 and get Rett syndrome, they are partially protected by the other normal copy of the gene.
Boys, on the other hand, have a single X chromosome, so when they have a MECP2 mutation, they suffer more. They typically pass away in the first year or two of life—but not Henry. Henry’s specific MECP2 mutation has never been seen before.
Researchers in Dr. Huda Zoghbi’s lab at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and Baylor College of Medicine are studying Henry’s cells. They have found that he still has functioning MeCP2 protein made from his mutant gene, just not as much of it as healthy people.
An opportunity for treatment
Dr. Zoghbi has been exploring strategies to treat patients with Rett syndrome and related disorders. Scientists have shown that, in mice with low levels of MeCP2 protein like Henry, adding an extra copy of the gene to increase the amount of MeCP2 improves their symptoms.
To find drugs that can do this for patients, the Zoghbi lab has taken a two-pronged approach. They have tested existing FDA-approved drugs to see if any of them increase MeCP2 protein levels. Reciprocally, they are testing every gene in the genome to find those that regulate MeCP2. They are looking for genes that can be targeted by drugs to increase MeCP2.
These drugs will initially be tested on Henry’s cells, to see if they can increase his MeCP2 levels. Then, the drugs will be tested in mice with Henry’s mutation to see if it improves their symptoms. Following these experiments in the Zoghbi lab, a partnering pharmaceutical company will perform clinical trials to ascertain the safety and efficacy of the drugs.
MECP2 mutations cause disease by impairing brain cells’ ability to work properly, and these impaired cells ultimately disrupt brain circuits involved in important cognitive functions such as learning and memory.
While the drugs are intended to treat the cells, Dr. Zoghbi and collaborator Dr. Jianrong Tang at the Duncan Neurological Research Institute have advanced another approach: to treat the circuits directly by neuromodulation. Their team has found that by using implantable electrodes to stimulate cells in the part of the brain responsible for memory, mice with MECP2 mutations—which typically have learning deficits—learn just as well as normal mice.
The short-term goal of these projects is to help individuals with Rett syndrome like Henry. Many of the MECP2 mutations that cause Rett syndrome affect the level of the MeCP2 protein or partially decrease its activity. Thus, finding ways to boost the levels of MeCP2 may help people with Rett who carry such mutations.
Additionally, these strategies can be used to discover treatments for numerous other diseases. Many neurological disorders, such as autism and intellectual disability, result from mutations in different genes, but in the majority of these cases, the mutations result in a change in the levels of the respective protein and, consequently, brain circuits.
The same strategies used to find therapies that boost MeCP2 levels to help Henry can be applied to develop treatments that increase the reduced proteins altered in a large number of cognitive disorders.