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Studies suggest that the hereditary disease CDKL5 deficiency may be treatable after childhood

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A catastrophic genetic disorder called CDKL5 deficiency (CDD) that develops in early childhood may be significantly curable even in adulthood, according to a new study from the University of Pennsylvania’s School of Medicine Perelman.

CDD is caused by a mutation in a gene called CDKL5. It is thought to play an important role in manipulating proper brain development in childhood.In the study, published today Clinical research journal, Researchers have found compelling evidence that genes are important in the brain even after childhood.When they turn off genes in healthy adults mouseMice have developed serious neurological problems, such as those found in mice lacking genes from the beginning of life.Then scientists tried to revive CDKL5 The genetic activity of young adult mice, which had been deprived of it from an early age, found that the animals were almost normal.

“One of the major problems with hereditary disorders concerns the curability of the disorder and the range of time frames for treatment approaches such as: Gene therapy, Can help the patient. Encouragingly, these mouse experiments provide evidence that CDD is likely to be treatable even after childhood, “said Dr. Zhaolan” Joe “Zhou, senior author of genetics at the University of Pennsylvania. Says.

CDD is found in about 1 in 40,000 babies born. This disorder usually appears within the first few weeks of life and includes many intellectual and neurological disorders, including movement disorders and seizures. Patients usually need to use a wheelchair to support all activities of daily living.

In 2012, Zhou et al. Created a “Cdkl5 knockout” mouse in which Cdkl5 had a disruptive mutation as observed in CDD patients. Researchers have found that knockout mice exhibit many of the same problems found in human CDD. Given that CDD is characterized by early severe neuropathy, to some extent CDD is treatable, and if so, the time frame for treatment remains unknown.

In a new study, a graduate student in neuroscience, Barbara Terzic, and other members of the Zhou lab investigated the role of CDKL5 in mice after brain development. They first discovered that this gene was active in the mouse brain not only in early childhood but throughout life. Then, in normal, healthy 6-week-old mice, when the genes were switched off at the beginning of the young adulthood of the mice, they had essentially the same CDD-like disorders as seen in normal CDKL5. I have found that the appearance is triggered. Knockout mouse, With corresponding brain changes.

“This suggests that CDKL5 plays an essential role in the adult brain,” Zhou said.

In other words, people with CDD can suffer from developmental disabilities due to CDKL5 deficiency in childhood, as well as ongoing CDKL5 deficiency in adulthood. This deficiency may be ameliorated in adults by a therapeutic approach. In fact, researchers silenced the mouse gene from conception, and when the animal developed a normal CDD-like disorder and turned the gene back on at 6 weeks of age, the CDD-like disorder was almost gone. I found. Marc Fuccillo, MD, Ph.D., Associate Professor of Neuroscience in Penn. And in collaboration with his student Felicia Davatolhagh, they also revealed the physiological basis of phenotypic reversal in mice. These findings suggest that CDD is not only treatable, but also susceptible to treatment after childhood.

Researchers have been at least several years old since the development of gene replacement or gene reactivation therapies for CDD. This is an effort that poses many technical challenges, including the formidable hurdles associated with providing treatment to the central nervous system. However, Zhou et al.’S experiment is a promising “proof of principle” that restoring normal levels of CDKL5 activity in adulthood can reduce the signs of illness.

Zhou et al. Conducted experiments on male mice, which allowed for easier analysis, but now Female mouse.. Nine out of ten cases of CDD occur in women, but these women’s cases are complicated by the fact that one copy of the X chromosome is randomly inactivated in the female cells. This is a “mosaic phenomenon” that is not perfect but inherently difficult. Loss of CDKL5 activity to analyze.

“We are also planning to investigate the effects of CDKL5 reactivation in mice until adulthood,” Zhou said.


The new report shows more common rare diseases than previously thought


For more information:
Temporary manipulation of Barbara Terzic et al, Cdkl5 reveals essential post-development function and reversible CDKL5 deficiency-related deficiencies. Clinical research journal (2021). DOI: 10.1172 / JCI143655

Quote: According to a study, CDKL5 deficiency was obtained from https://medicalxpress.com/news/2021-10-genetic-disease-cdkl5-deficiency-disorder.html in childhood (October 15, 2021). It may be treatable later.

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Studies suggest that the hereditary disease CDKL5 deficiency may be treatable after childhood

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