Summary: Those with hereditary hemochromatosis who have two copies of the genetic mutation that causes the disorder have an increased risk of developing movement disorders including Parkinson’s disease.
source: University of California
A disorder called hereditary hemochromatosis, caused by a genetic mutation, causes the body to absorb too much iron, resulting in tissue damage and conditions such as liver disease, heart problems, and diabetes.
However, little and conflicting research has indicated that the brain is spared iron accumulation by the blood-brain barrier, a network of blood vessels and tissues composed of closely spaced cells that protect against invading pathogens and toxins.
But in a new study published in the August 1, 2022 online issue of Gamma Neurologyresearchers at UCSD, along with colleagues at UCSF, Johns Hopkins Bloomberg School of Public Health and the Laureate Institute for Brain Research, report that individuals with two copies of the genetic mutation (one inherited from each parent) show evidence of significant iron accumulation in The areas of the brain responsible for movement.
The findings suggest that the genetic mutation primarily responsible for hereditary hemochromatosis may be a risk factor for developing movement disorders, such as Parkinson’s disease, which result from the loss of neurons that produce the chemical dopamine.
In addition, the researchers found that males of European descent who carried two genetic mutations were at greater risk. They are not female.
“The sex-specific effect is consistent with other secondary disorders of hemochromatosis,” said first author Robert Lognan, PhD, a postdoctoral researcher in the Laboratory of Neuroscience and Genetics at UCSD. “The burden of disease for males appears higher than for females because of natural processes, such as menstruation and childbirth, that flush out the body of excess iron accumulated in women.”
The observational study involved MRI scans of 836 participants, 165 of whom were at high genetic risk for hereditary hemochromatosis, which affects about 1 in 300 non-Hispanic white people, according to the Centers for Disease Control and Prevention. Scans revealed large iron deposits localized in the motor circuits of the brain of these high-risk individuals.
The researchers then analyzed data representing nearly 500,000 individuals and found that males, rather than females, who had a high genetic risk of developing hemochromatosis were 1.80 times more likely to develop a movement disorder, as many of these people did not have a diagnosis of hemochromatosis. Simultaneous hemochromatosis.
“We hope our study will bring more awareness of hemochromatosis, as many high-risk people are not aware of the abnormal amounts of iron accumulating in their brains,” said senior corresponding author Chun Chih-Fan, MD, PhD, assistant professor of University of California, San Diego and Principal Investigator at the Laureate Institute for Brain Research, based in Tulsa, Oklahoma.
Screening individuals at high risk for early detection may be useful in determining when to intervene to avoid more severe consequences.
Lognan said the findings are of immediate clinical significance because there are already safe and approved treatments to reduce excess iron caused by the genetic mutation. In addition, the new data may lead to further discoveries about how iron builds up in the brain and increases the risk of movement disorders.
Approximately 60,000 Americans are diagnosed with Parkinson’s disease annually, 60 percent of whom are male. Late Parkinson’s disease (after age 60) is more common, but rates are higher among younger adults.
More broadly, an estimated 42 million people in the United States suffer from some form of movement disorder, such as idiopathic tremor, dystonia, and Huntington’s disease.
Co-authors are: Jonathan Ahern, Sheris Tompkins, Claire E. Palmer, John Iverson, Terry Jernigan and Anders Dale, all at UCSD; Ole Andresen, University of Oslo, Norway; Leo Sugro, University of California, San Francisco; Mary E. T. Boyle, University of California, San Diego, and Johns Hopkins Bloomberg School of Public Health; and Wesley K. Thompson at the UC San Diego and Laureate Institute for Brain Research.
About this genetics and neuroscience news
author: Scott La Vi
source: University of California
Contact: Scott La Vie – University of California
picture: Photo credited to University of California, San Francisco
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“Association of a hemochromatosis-associated gene variant with brain MRI measures of iron and movement disorders” by Robert Lognan et al. Gamma Neurology
Association of hemochromatosis-associated gene variant with brain MRI procedures for iron and movement disorders
Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that leads to iron overload. Conflicting results from previous research have led some to believe that the brain survives the toxic effects of iron in HH.
To test the association of the strongest risk genetic variant for HH on sensitive brain measures of iron deposition and rates of movement disorders in a much larger sample than previous studies of its kind.
Design, setup and participants
This retrospective cross-sectional study included participants from the UK Biobank, a population-based sample. Genotype, health history, and neuroimaging data were collected from January 2006 to May 2021. Data analysis was conducted from January 2021 to April 2022. The disorders tested included movement disorders (International Statistical Classification of Diseases and Related Health Problems, 10th Revision [ICD-10]codes G20-G26), gait and mobility abnormalities (ICD-10 codes R26), and other nervous system disorders (ICD-10 G90-G99 codes).
exposures Heterozygosity for p.C282Y, the largest known genetic risk factor for HH.
Main findings and measures
Weighting of T2 and T2 signal intensity* from brain MRI scans, sensitive measurements of iron deposition, and clinical diagnosis of neurological disorders.
The total group consisted of 488,288 individuals (264,719 female; aged 49–87 years, largely of Northern European ancestry), 2,889 of whom were from r. C282Y is homozygous. Neuroimaging analysis consisted of 836 individuals: 165 p.C282Y homozygotes (99 females) and 671 matched controls (399 females). A total of 206 individuals were excluded from the analysis due to the withdrawal of consent. Neuroimaging analysis showed that p.C282Y homozygosity was associated with decreased T2 and T2* signaling intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, cerebellum; Cohen Dr >1) Consistent with iron deposition significantly. Across the UK Biobank (2889 p.C282Y homozygous, 485399 controls), we found a significantly increased prevalence of movement disorders in homozygous males (OR, 1.80; 95% CI, 1.28–2.55; s= .001) but not female individuals (OR, 1.09; 95% CI, 0.70-1.73; s= .69). Among the 31 p. C282Y homozygous males with a movement disorder, only 10 have a diagnosis of concurrent HH.
Conclusions and relevance
These findings indicate increased iron deposition in subcortical motor circuits in p.C282Y homozygotes and confirm an increased association with movement disorders in homozygous males. Early treatment of HH effectively prevents the negative consequences of excess iron in the liver and heart. Our work indicates that screening for p.C282Y homozygosity in high-risk individuals also has the potential to reduce brain iron accumulation and reduce the risk of movement disorders among male individuals who are homozygous for this mutation.
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