The mutant gene of Huntington’s disease affects brain and body growth in infancy

Growing evidence supports the hypothesis that a neurodevelopmental component to the late-onset neurodegeneration occurs in the brains of the mutant carriers of the Hunttin gene (HTT gene), and to the increased vulnerability to brain cell death begins in infancy. Experts discuss the evidence that HTT gene mutation affects brain and body growth based on a special study of children at risk for HD, the Kids-HD study, in a review paper and research article published in the Journal of Huntington’s disease.

The classic concept is that Huntington’s disease is caused by toxic mutant huntin (mHTT) acting over time on mature brain cells. However, there is growing evidence for another theory in which mHTT influences brain development and that this altered development plays a crucial role in the later degenerative process. This theory is based on the idea that the action of wild type huntin (HTT) plays a role in normal brain development.

Although the gene was discovered in 1993, we still don’t have a good understanding of what causes HD – how does the mutant gene cause ‘sick’ brain cells to then die ?. The neurodevelopmental idea is a relatively new way of thinking about the disease and can help focus research efforts in a new way. This review and the accompanying study are important in reshaping our perceptions of how we look at the nature and timing of immunosuppressive treatment for HD and the factors that contribute to disease. “

Peg C. Nopoulos, MD, Principal Investigator, Department of Psychology, Department of Pediatrics, and Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

The neurodevelopmental hypothesis of HD states that disease-causing gene mutation affects the development of a specific area or specific brain circulation. These cells are abnormal in their growth; however, they receive compensation early in life. Thus, despite extreme development, there are no open symptoms. The excessively developed cells remain in a “stable mutant state.” These cells are then vulnerable to dysfunction and degeneration later in life when subjected to pressures and rays. , either normal (programmed synaptic elimination during childhood or during the aging process) or pathological (toxic effects of mHTT). Ultimately, the pathology of the disease leads to neural degeneration with the accompanying cognitive and motor deficits.

Both papers focus on the latest findings from Kids-HD, a study of specific brain images of children ages six to 18 who are at risk for HD because they have a parent or grandparent with HD. The review considers the effects of mHTT on brain development and the study evaluates the effect of mHTT on body development.

According to the authors, there is evidence in children as young as 6 who carry a mutation in the HTT gene, that mHTT production alters the growth and development of the striatum and associated circulation. The gene contains a sequence of three DNA centers – cytosine-adenine-guanine (CAG) – repeated several times. The developmental changes appear to affect all CAG recurrences and occur long before the onset of symptoms of the disease. Deficiencies can then be compensated for by increased activity in other brain circuits, especially those involving the cerebellum, and are apparent only when compensatory systems are no longer functioning.

The body development analysis used data from the 186 children in the Kids-HD study. Researchers applied simple growth measures – height, weight, and BMI measurements combined – to compare changes in two groups – those that carried a repetitive CAG expansion mutation in the HTT gene and those that did not. do rinn.

Around consumption the study began showing an altered pathway of growth in HTT gene carriers. The rate at which their BMI rose increased more slowly over time until around 17 years of age that group had a significantly lower BMI than the group without the gene. Boys with gene mutation tended to be higher than the control group, but with lower weight; girls with the gene transfer tended to be around the same height, but lower in weight.

Importantly, although carriers of gene mutation were around 30 years from the expected time of the disease, the HTT mutant gene had already impacted their growth and development. This work is important because it suggests that the mutation changes the body even before the onset of neurological disease in mid-life.

Gene therapy trials are currently underway to evaluate the effectiveness of drugs in reducing the progression of disease in affected individuals, and future trials will aim to prevent infection with delivering gene therapy to gene carriers – those with mHTT, but without symptoms.

“Gene therapy tests are finally here. However, inhibition of a gene that is responsible for brain development early in life must be prevented with sufficient caution,” Dr. Nopoulos said. “Understanding how mHTT affects brain development is crucial in the context of the design of disease prevention therapies.”

HD is a deadly genetic neurodegenerative disease that causes progressive rupture of zero cells in the brain. An estimated 250,000 people in the United States are either infected, or at risk for the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and unbalanced judgment, restless walking, and neutral movements (chorea). Every child at HD parent has a 50% chance of getting the gene. Patients usually survive 10 – 20 years after diagnosis.