Iron accumulation in the brain is associated with a higher risk of movement disorders

Summary: Patients with hereditary hemochromatosis have two copies of the gene mutation, which puts them at an increased risk of developing Parkinson’s disease, including movement disorders.

A source: UCSD

An inherited disease called 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 disease and diabetes.

Few and conflicting studies have suggested that the blood-brain barrier, a network of closely packed cells that protect the brain from iron accumulation, is preserved from invading pathogens and toxins.

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

Research suggests that a mutation in the gene mainly responsible for hereditary hemochromatosis may be a risk factor for the development of movement disorders such as Parkinson’s disease, which is caused by the loss of nerve cells that produce the chemical messenger dopamine.

Furthermore, the researchers found that those of European descent who carried both gene mutations were at greatest risk; There were no women.

“The sex-specific effect is consistent with other secondary disorders of hemochromatosis,” said first author Robert Loughnan, PhD, a postdoctoral researcher at the Population Neuroscience and Genetics Laboratory in San Diego. “Men show a greater burden of disease than women due to natural processes such as menstruation and childbirth, which in women remove excess iron from the body.”

The observational study included MRI scans of 836 participants, 165 of whom the Centers for Disease Control and Prevention estimated had a high genetic risk for developing hereditary hemochromatosis, which affects 1 in 300 non-Hispanic whites. Scans revealed significant iron deposits in the motor circuits of the brain for these high-risk individuals.

The researchers then analyzed data from nearly 500,000 people and found that men, but not women, with a higher genetic risk for hemochromatosis had a 1.80-fold increased risk of developing a movement disorder, many of whom had not been diagnosed with hemochromatosis.

In this brain scan, the blue areas show areas of iron accumulation in people with two copies of the hemochromatosis risk gene. These areas also play a role in movement. Credit: UCSD

“We hope our study will shed more light on hemochromatosis, as many high-risk individuals are unaware that abnormal amounts of iron are accumulating in their brains,” said senior corresponding author Chun Chie Fan, MD, PhD, assistant professor. University of San Diego and Principal Investigator of the Laureate Institute for Brain Research in Tulsa.

“Screening for early identification of high-risk individuals may be useful in determining when to intervene to avoid severe consequences.”

According to Loughnan, the findings have immediate clinical implications because there are safe and approved treatments to reduce excess iron caused by the gene mutation. Additionally, the new data may shed more light on 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 rates are increasing among younger adults.

Overall, 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: Jonathan Ahern, Cherisse Tompkins, Claire 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 La Fi
A source: UCSD
The connection: Scott Lafey – UCSD
Photo: Photo courtesy of UCSD

Original research: Closed access.
“Association of Hemochromatosis-Associated Genetic Variants with Cerebral Magnetic Resonance Imaging Measures of Iron and Movement Disorders” Robert Loughnan et al. JAMA Neurology


Association of Hemochromatosis-Associated Genetic Variants with Magnetic Resonance Imaging of the Brain and Iron and Movement Disorders

an important

Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that causes iron overload. Conflicting results from previous studies have led some to believe that the toxic effect of iron on the brain in HH persists.

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The goal

To examine the association of the strongest genetic risk variant for HH with brain-scale measures sensitive to iron accumulation and rate of movement disorders in a significantly larger sample than previous studies of its type.

Design, installation 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. Tested disorders include movement disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]codes G20-G26), gait and mobility disorders (ICD-10 codes R26) and other diseases of the nervous system (ICD-10 codes G90-G99).

exposures Homozygosity for p.C282Y is the largest known genetic risk factor for HH.

Main outcomes and measures

T2-weighted and T2* signal intensity from brain magnetic resonance imaging, sensitive measures of iron accumulation and clinical diagnosis of neurological diseases.


The total composition of the cohort consisted of 488,288 individuals (264,719 women; aged 49-87 years, mostly of Northern European origin), of whom 2889 were p.C282Y homozygotes. Neuroimaging analysis consisted of 836 individuals: 165 p.C282Y homozygotes (99 women) and 671 matched controls (399 women). A total of 206 individuals were excluded from the analysis due to withdrawal of consent. Neuroimaging analysis showed that p.C282Y homozygosity is associated with a decrease in T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus and cerebellum; Cohen). d > 1) consistent with significant iron stratification. Across the UK Biobank (2,889 p.C282Y homozygotes, 485,399 controls), we found a significantly increased risk of movement disorders in male homozygotes (OR, 1.80; 95% CI, 1.28–2.55; P= .001) but not women (OR, 1.09; 95% CI, 0.70-1.73; P= .69). Of the 31 p.C282Y male homozygotes with movement disorders, only 10 had a concurrent diagnosis of HH.

Conclusions and relevance

These findings demonstrate increased iron in the subcortical motor circuits of p.C282Y homozygotes and confirm an increased association with movement disorders in male homozygotes. Early treatment of HH can effectively prevent the negative effects of iron overload on 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 accumulation and risk of movement disorders in men homozygous for this mutation.

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