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Original Investigation
August 1, 2022

Association of Genetic Variant Linked to Hemochromatosis With Brain Magnetic Resonance Imaging Measures of Iron and Movement Disorders

Author Affiliations
  • 1Department of Cognitive Science, University of California, San Diego, La Jolla
  • 2Population Neuroscience and Genetics, University of California, San Diego, La Jolla
  • 3Center for Human Development, University of California, San Diego, La Jolla
  • 4Division of Biostatistics, Department of Radiology, University of California, San Diego, La Jolla
  • 5NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 6Department of Radiology, University of California, San Diego School of Medicine, La Jolla
  • 7Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla
  • 8Department of Radiology and Biomedical Imaging, University of California, San Francisco
  • 9Department of Psychiatry, University of California, San Francisco
  • 10Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla
  • 11Center for Multimodal Imaging and Genetics, University of California, San Diego School of Medicine, La Jolla
  • 12Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 13Center for Population Neuroscience and Genetics, Laureate Institute for Brain Research, Tulsa, Oklahoma
JAMA Neurol. 2022;79(9):919-928. doi:10.1001/jamaneurol.2022.2030
Key Points

Question  To what extent does genetic risk for hemochromatosis affect the brain and contribute to risk for neurological disorders?

Finding  In this cross-sectional study that included 836 participants, we found that individuals at high genetic risk for developing hemochromatosis had magnetic resonance imaging scans indicating substantial iron deposition localized to motor circuits of the brain. Further analysis of data for 488 288 individuals revealed that male individuals with high genetic risk for hemochromatosis (but not female individuals) were at 1.80-fold increased risk for developing a movement disorder, with the majority of these individuals not having a concurrent diagnosis for hemochromatosis.

Meaning  Genetic risk for hemochromatosis is associated with abnormal iron deposition in motor circuits and increased risk of movement disorders, regardless of formal diagnosis of hemochromatosis, and treatment for hemochromatosis that reduces iron overload may prove beneficial for male individuals at genetic risk for hemochromatosis who have movement disorders.

Abstract

Importance  Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that leads to iron overload. Conflicting results from previous research has led some to believe the brain is spared the toxic effects of iron in HH.

Objective  To test the association of the strongest genetic risk variant for HH on brainwide measures sensitive to iron deposition and the rates of movement disorders in a substantially 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 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], codes G20-G26), abnormalities of gait and mobility (ICD-10 codes R26), and other disorders of the nervous system (ICD-10 codes G90-G99).

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

Main Outcomes and Measures  T2-weighted and T2* signal intensity from brain magnetic resonance imaging scans, measures sensitive to iron deposition, and clinical diagnosis of neurological disorders.

Results  The total cohort consisted of 488 288 individuals (264 719 female; ages 49-87 years, largely northern European ancestry), 2889 of whom were p.C282Y homozygotes. The neuroimaging analysis consisted of 836 individuals: 165 p.C282Y homozygotes (99 female) and 671 matched controls (399 female). A total of 206 individuals were excluded from analysis due to withdrawal of consent. Neuroimaging analysis showed that p.C282Y homozygosity was associated with decreased T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen d >1) consistent with substantial iron deposition. Across the whole UK Biobank (2889 p.C282Y homozygotes, 485 399 controls), we found a significantly increased prevalence for movement disorders 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 the 31 p.C282Y male homozygotes with a movement disorder, only 10 had a concurrent 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 in 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 accumulation and to reduce the risk of movement disorders among male individuals who are homozygous for this mutation.

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    1 Comment for this article
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    Saeed Taheri, M.D. | NLMJ; Lahijan
    HH is not a known risk factor for neurological/movement disorders, however, the literature suggests that Parkinson's disease with tremor predominance is associated with impaired iron metabolism [1]. Therefore, it might be a distinct syndrome and different possibilities should be considered for the observed associations between p.C282Y homozygote mutations and the movement disorders. What we know from the current study is that this association is particularly significant in males, consistent with the iron overload phenomenon, but the association has not been directly investigated. The age of the participants might be a significant predictive factor. Other associations include transferrin-saturation, ferritin levels, liver enzymes/hepatomegaly/cirrhosis, bronze skin, impotence, diabetes or other presentations of hemochromatosis. Knowing these associations helps because for example if we find that a particular constellation of the abovementioned factors associated with the neurological issues, then we might be able to predict the disorder and invent individualized prophylactic measures.
    On the other hand, there might be some additional genetic associations. For example, a concomitant heterozygotic or homozygotic variation(s) in the HFE gene or other genes associated with either iron metabolism/transport or the genes associated with the respective neurological problems with no essential associations with iron metabolism [2] or genes associated with inflammatory markers in patients with p.C282Y homozygotic mutation might be the culprit. It is a serious consideration since according to this study, the neurological problems had no associations with the diagnosis (which might be translated as the severity of the HH symptoms), so further analysis are needed to find other potential associated factors.

    references
    1. Lian TH, Guo P, Zuo LJ, Hu Y, Yu SY, Yu QJ, Jin Z, Wang RD, Li LX, Zhang W. Tremor-Dominant in Parkinson Disease: The Relevance to Iron Metabolism and Inflammation. Front Neurosci. 2019 Mar 27;13:255. doi: 10.3389/fnins.2019.00255. PMID: 30971879; PMCID: PMC6445850.
    2. Pietrangelo A. Hereditary hemochromatosis--a new look at an old disease. N Engl J Med. 2004 Jun 3;350(23):2383-97. doi: 10.1056/NEJMra031573. PMID: 15175440.
    CONFLICT OF INTEREST: None Reported
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