Summary: People with hereditary hemochromatosis who have two copies of the genetic mutation causing the disease have an increased risk of developing movement disorders, including Parkinson’s disease.
A disorder called hereditary hemochromatosis, caused by a genetic mutation, causes the body to absorb too much iron, leading to tissue damage and conditions such as liver disease, heart problems and diabetes.
Scant and conflicting research had suggested, however, that the brain was spared from iron accumulation by the blood-brain barrier, a network of blood vessels and tissues made up of closely spaced cells that protects against invasive pathogens and diseases. toxins.
But in a new study published in the August 1, 2022 online issue of JAMA Neurologyresearchers from the University of California, San Diego, with colleagues from UC San Francisco, the Johns Hopkins Bloomberg School of Public Health, and the Laureate Institute for Brain Research, report that individuals who carry two copies of the mutation genes (one inherited from each parent) show signs of significant iron accumulation in the brain regions responsible for movement.
The results 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 is caused by a loss of nerve cells that produce the chemical messenger dopamine.
Additionally, the researchers found that men of European descent who carried two of the genetic mutations were most at risk; the females were not.
“The sex-specific effect is consistent with other secondary disorders of hemochromatosis,” said first author Robert Loughnan, PhD, postdoctoral researcher in the Population Neuroscience and Genetics Lab at UC San Diego. “Men have a higher burden of disease than women due to natural processes, such as menstruation and childbirth, that expel excess iron accumulated in women from the body.”
The observational study involved performing MRI scans of 836 participants, 165 of whom were at high genetic risk for developing hereditary hemochromatosis, which affects about 1 in 300 non-Hispanic white people, according to the Centers for Disease Control and Prevention. The scans detected significant localized iron deposits in the motor circuits of the brain for these high-risk individuals.
The researchers then analyzed data representing almost 500,000 people and found that men, but not women, with a high genetic risk for hemochromatosis had a 1.80 times higher risk of developing a movement disorder, good many of these people do not have a concurrent diagnosis of hemochromatosis.
“We hope our study can raise awareness about hemochromatosis, as many high-risk people are unaware of abnormal amounts of iron accumulating in their brains,” said senior corresponding author Chun Chieh Fan, MD, PhD, adjunct assistant professor at UC San Diego and principal investigator at the Laureate Institute for Brain Research, based in Tulsa, OK.
“Screening high-risk individuals for early detection can be helpful in determining when to intervene to avoid more serious consequences.”
Loughnan said the results have immediate clinical significance because there are already safe and approved treatments to reduce the excess iron resulting from the genetic mutation. Additionally, the new data could lead to new insights into how iron builds up in the brain and increases the risk of movement disorders.
About 60,000 Americans are diagnosed with Parkinson’s disease each year, 60% of whom are men. Late-onset Parkinson’s disease (after age 60) is the most common, but rates increase in young adults.
More broadly, approximately 42 million people in the United States suffer from some form of movement disorder, such as essential tremor, dystonia, and Huntington’s disease.
Co-authors include: Jonathan Ahern, Cherisse Tompkins, Clare E. Palmer, John Iversen, Terry Jernigan, and Anders Dale, all at UC San Diego; Ole Andreassen, University of Oslo, Norway; Leo Sugrue, UC San Francisco; Mary ET Boyle, UC San Diego and Johns Hopkins Bloomberg School of Public Health; and Wesley K. Thompson at UC San Diego and the Laureate Institute for Brain Research.
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Author: Scott the Fairy
Contact: Scott La Fee – UCSD
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“Association of a Gene Variant Linked to Hemochromatosis with Cerebral Magnetic Resonance Imaging Measures of Iron and Movement Disordersby Robert Loughnan et al. JAMA Neurology
Association of a Gene Variant Linked to Hemochromatosis with Cerebral Magnetic Resonance Imaging Measures of Iron and Movement Disorders
Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease that leads to iron overload. Conflicting results from previous research have led some to believe that the brain is spared the toxic effects of iron in HH.
To test the association of the strongest genetic risk variant for HH on brain measures sensitive to iron deposition and rates of movement disorders in a significantly larger sample size than previous studies of this type.
Design, framework and participants
This retrospective cross-sectional study included participants from the UK Biobank, a population-based sample. Genotype, health record, and neuroimaging data were collected from January 2006 to May 2021. Data analysis was performed from January 2021 to April 2022. Disorders tested included movement disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]codes G20-G26), gait and mobility abnormalities (ICD-10 R26 codes), and other nervous system disorders (ICD-10 code G90-G99).
Exhibitions Homozygosity for p.C282Y, the greatest known genetic risk factor for HH.
Main results and measures
T2- and T2*-weighted signal intensity from cerebral magnetic resonance imaging, measurements sensitive to iron deposition, and clinical diagnosis of neurological disorders.
The total cohort consisted of 488,288 individuals (264,719 females; ages 49-87, mostly of northern European ancestry), including 2,889 p.C282Y homozygotes. The neuroimaging analysis involved 836 individuals: 165 p.C282Y homozygotes (99 women) and 671 matched controls (399 women). A total of 206 people were excluded from the analysis due to the withdrawal of their consent. Neuroimaging analysis showed that p.C282Y homozygosity was associated with decreased T2- and T2*-weighted signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum ;Cohen D >1) compatible with a significant iron deposit. Across the UK biobank (2,889 homozygous p.C282Y, 485,399 controls), we found a significantly increased prevalence of movement disorders in homozygous men (OR, 1.80; 95% CI, 1. 28-2.55; P= 0.001) but not women (OR, 1.09; 95% CI, 0.70-1.73; P= 0.69). Among the 31 p.C282Y male homozygotes presenting with a movement disorder, only 10 had a concomitant HH diagnosis.
Conclusions and relevance
These results indicate increased iron deposition in subcortical motor circuits in p.C282Y homozygotes and support an increased association with movement disorders in male homozygotes. Early treatment of HH effectively prevents the negative consequences of iron overload in the liver and heart. Our work suggests that screening for p.C282Y homozygosity in high-risk individuals also has the potential to reduce iron accumulation in the brain and reduce the risk of movement disorders in men homozygous for this mutation.