Summary: People with hereditary hemochromatosis who have two copies of the gene mutation have an increased risk of developing movement disorders, including Parkinson’s disease.

Source: UCSD

The disorder, called hereditary hemochromatosis, is caused by gene mutations that cause the body to absorb too much iron, leading to tissue damage and conditions such as liver disease, heart problems and diabetes.

Scans and conflicting studies show that the brain is spared iron deposits by the blood-brain barrier, a network of blood vessels and tissues that contain cells that defend against invading pathogens and toxins.

But according to a new study published in the August 1, 2022 online edition JEMA NeurologyResearchers at the University of California, San Diego, along with colleagues from UC San Francisco, the Johns Hopkins Bloomberg School of Public Health and the Laureate Institute for Brain Research, have shown this evidence in individuals with two copies of the gene mutation (inherited from each parent). High levels of iron in brain regions responsible for movement.

The findings suggest that mutations in the gene primarily responsible for hereditary hemochromatosis may cause movement disorders such as Parkinson’s disease, which is caused by the loss of neurons that produce the chemical messenger dopamine.

The researchers also found that men of European descent who carry the two gene mutations are at higher risk; There were no women.

“The sex-specific effect is consistent with other hemochromatosis secondary diseases,” said first author Robert Lowan, PhD, a postdoctoral fellow in the Laboratory of Population Neuroscience and Genetics at UC San Diego. “Men show a higher burden of disease than women due to natural processes such as menstruation and childbirth.

The observational study included MRI scans of 836 participants, 165 of whom had a 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 study found high iron deposits localized in the motor circuits of the brain in these high-risk individuals.

The researchers analyzed data representing nearly 500,000 individuals and found that men, but not women, with a high genetic risk for hemochromatosis had a 1.80-fold increased risk of developing mobility impairment.

This is shown by brain scans
In these brain scans, blue areas indicate regions of iron accumulation in individuals with two copies of the hemochromatosis risk gene. These regions also play a role in movement. Credit: UCSD

“We hope our study will bring more awareness to hemochromatosis, because many high-risk people are unaware of the abnormal amount of iron stored in their brains,” said senior corresponding author Chun Chih Fan, MD, PhD, assistant associate professor. UC San Diego and Principal Investigator for Brain Research at the Lorette Institute in Tulsa, OK.

“Early detection of high-risk individuals may be useful in determining when to intervene to avoid worse outcomes.”

Loughnan said the findings have immediate clinical import because there are safe and approved treatments available to reduce iron overload caused by gene mutations. Additionally, the new data may lead to further revelations about how iron accumulates in the brain and increases the risk of movement disorders.

About 60,000 Americans are diagnosed with Parkinson’s disease each year, and 60 percent are men. Late-onset Parkinson’s disease (after age 60) is more common, but rates are increasing among younger adults.

More broadly, an estimated 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 Andreasen, 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 Lorette Institute for Brain Research.

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Author: Scott la fee
Source: UCSD
Contact: Scott La Fee – UCSD
Image: Image courtesy of UCSD.

Preliminary study: Closed access.
Association of hemochromatosis-associated genetic variants with brain magnetic resonance imaging measurements of iron and movement disorders.” by Robert Lownan et al JEMA Neurology


Association of hemochromatosis-associated genetic variants with brain magnetic resonance imaging measurements of iron and movement disorders.


Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder leading to iron overload. The results conflict with previous research, suggesting that some brains are damaged by HHI.

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This shows a woman drinking coffee.


To test for the strongest genetic risk factor for HH, cognitive measures related to iron accumulation and the rate of movement disorders in a larger sample than previous studies of this type.

Design, composition and participants

This cross-sectional retrospective 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 conducted from January 2021 to April 2022. Disorders tested included movement disorders.International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]G20-G26 codes), gait and movement disorders (ICD-10 code R26) and other disorders of the nervous system (ICD-10 codes G90-G99).

Exposure Homozygosity for p.C282Y, the largest known genetic risk for HH.

Main results and measurements

T2-weighted and T2* signal intensity from brain magnetic resonance imaging scans, risk factors for iron deposition, and clinical diagnosis of neurological diseases.


The total cohort included 488 288 individuals (264 719 female; aged 49–87 years, mostly of Northern European ancestry), of whom 2889 were p.C282Y homozygotes. Neuroimaging analysis included 836 individuals: 165 p.C282Y homozygotes (99 female) and 671 matched controls (399 female). A total of 206 individuals were excluded from analysis by withdrawing consent. Neuroimaging analysis shows that p.C282Y homozygosity is associated with decreased T2-weight and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen). d >1) consistent with realistic iron concentrations. Across the UK Biobank (2889 p.C282Y homozygotes, 485 399 controls) movement disorders were significantly increased in male homozygotes (OR, 1.80; 95% CI, 1.28-2.55). P= .001) but not female individuals (OR, 1.09; 95% CI, 0.70–1.73; P= .69). Among 31 p.C282Y male homozygotes with mobility impairment, only 10 had a concurrent HH diagnosis.

Conclusions and relevance

These findings indicate increased iron accumulation in subcortical motor circuits in p.C282Y homozygotes and corroborate with increased motor deficits in male homozygotes. Early treatment in HH can effectively prevent the adverse effects of iron overload in the liver and heart. Our work suggests that screening for p.C282Y homozygosity in high-risk individuals has the potential to reduce brain iron accumulation and movement disorders among men homozygous for this mutation.

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