Iron accumulation in brain linked to higher risk of movement disorders

Overview: Those with inherited hemochromatosis who have two copies of the gene mutation that causes the condition are at an increased risk of developing movement disorders, including Parkinson’s disease.

Source: UCSD

A condition called hereditary hemochromatosis, caused by a gene mutation, causes the body to absorb too much iron, leading to tissue damage and conditions such as liver disease, heart problems, and diabetes.

Little and contradictory research, however, had suggested that the brain was spared iron build-up by the blood-brain barrier, a network of blood vessels and tissue made up of closely spaced cells that protects against invasive pathogens and toxins.

But in a new study published in the August 1, 2022 online issue of JAMA NeurologyResearchers at the University of California San Diego, with colleagues from UC San Francisco, Johns Hopkins Bloomberg School of Public Health and Laureate Institute for Brain Research, report that individuals with two copies of the gene mutation (one inherited from each parent) show evidence of significant iron accumulation in areas of the brain responsible for movement.

The findings suggest that the gene 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.

In addition, the researchers found that men of European descent who carry two of the gene mutations were most at risk; females were not.

“The sex-specific effect is consistent with other secondary disorders of hemochromatosis,” said first author Robert Loughnan, PhD, a postdoctoral researcher in the Population Neuroscience and Genetics Lab at UC San Diego. “Men show a higher disease burden than women due to natural processes, such as menstruation and childbirth, that expel excess iron build-up in women.”

The observational study involved performing MRI scans on 836 participants, 165 of whom were at high genetic risk for developing hereditary hemochromatosis, which affects about 1 in 300 non-Hispanic whites, according to the Centers for Disease Control and Prevention. The scans detected significant iron deposits located in motor circuits of the brain for these high-risk individuals.

The researchers then analyzed data representing nearly 500,000 individuals and found that men, but not women, at high genetic risk for hemochromatosis had a 1.80-fold increased risk of developing a movement disorder, with many of these individuals not being diagnosed at the same time. for hemochromatosis.

In these brain scans, blue areas indicate areas 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 can make hemochromatosis more aware, as many high-risk individuals are unaware of the abnormal amounts of iron that accumulate in their brains,” said senior corresponding author Chun Chieh Fan, MD, PhD, an assistant associate professor at UC San Diego and principal investigator at the Laureate Institute for Brain Research, located in Tulsa, OK.

“Screening individuals at high risk for early detection may be helpful in determining when to intervene to prevent more serious consequences.”

Loughnan said the findings have immediate clinical significance because safe and approved treatments already exist to reduce excess iron due to the gene mutation. In addition, the new data could 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, 60 percent of whom are men. Late-onset Parkinson’s disease (after age 60) is most common, but the number is increasing in 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 Andreassen, University of Oslo, Norway; Leo Sugrue, UC San Francisco; Mary E.T. Boyle, UC San Diego and Johns Hopkins Bloomberg School of Public Health; and Wesley K. Thompson at UC San Diego and Laureate Institute for Brain Research.

About this genetics and neurology research news

Author: Scott La Fee
Source: UCSD
Contact: Scott La Fee – UCSD
Image: The image is credited to UCSD

Original research: Closed access.
“Association of Genetic Variant Linked to Hemochromatosis with Brain Magnetic Resonance Imaging Measurements of Iron and Movement Disorders” by Robert Loughnan et al. JAMA Neurology


Association of Genetic Variant Linked to Hemochromatosis with Brain Magnetic Resonance Imaging Measures of 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 is spared the toxic effects of iron in HH.

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This is a drawing of two people.  One faces forward, the other faces the other


To test the association of the strongest genetic risk variant for HH on brain-wide measures sensitive to iron deposition and the rate of movement disorders in a significantly larger sample than previous studies of its kind.

Design, setting 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 performed from January 2021 to April 2022. Conditions 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 codes R26), and other nervous system disorders (ICD-10 code G90-G99).

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

Main results and measures

T2-weighted and T2* signal intensity from brain magnetic resonance MRI scans, 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 years, mostly Northern European ancestry), of whom 2,889 were p.C282Y homozygotes. The 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 analysis due to consent withdrawal. Neuroimaging analysis showed that p.C282Y homozygosity was associated with reduced T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus and cerebellum; Cohen d >1) consistent with significant iron deposition. Across the UK Biobank (2889 p.C282Y homozygotes, 485 399 controls) we found a significantly increased prevalence of movement disorders in male homozygotes (OR 1.80; 95% CI 1.28-2.55; p= .001) but no female individuals (OR, 1.09; 95% CI, 0.70-1.73; p= 0.69). Of the 31 p.C282Y male homozygotes with a movement disorder, only 10 had a concomitant HH diagnosis.

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 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 brain iron overload and reduce the risk of movement disorders in male individuals homozygous for this mutation.

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