Genetic risk for hemochromatosis associated with abnormal iron deposition localized to motor circuits of the brain

1. This retrospective cross-sectional study found that among 836 individuals at high genetic risk for developing hemochromatosis, magnetic resource imaging scans indicated substantial iron deposition localized to motor circuits of the brain.

2. Male individuals with high genetic risk for hemochromatosis were at a 1.80-fold increased risk for developing a movement disorder compared to female individuals.

Evidence Rating Level: 2 (Good)

Study Rundown: Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder characterized by excess iron in the body. This excess iron absorbed by the body then leads to an accumulation of iron in various organs, particularly the liver, which results in an increased risk of developing liver disease and diabetes. Type I HH is associated with a mutation in the HFE gene, and 95% of cases have been recorded as homozygous for p.C282Y mutation. The objective of this study was to investigate the association of the strongest genetic risk variant for HH on brain measures sensitive to iron deposition, in addition to rates of movement disorders. A total of 488,288 individuals were included in this retrospective cohort study from the UK Biobank, with data collected between January 2006 to May 2021. The primary exposure for this study was homozygosity for p.C282Y. Main outcomes included T2-weighed and T2* signal intensity from brain magnetic resonance imaging scans, measures sensitive to iron deposition, and a clinical diagnosis of neurological disorders. More specifically, the neuroimaging data analysis consisted of 836 individuals, 154 of whom were homozygotes for the p.C282Y mutation, and 595 matched controls. Analysis of the neuroimaging demonstrated that p.C282Y homozygosity was associated with a decreased T2-weighted and T2* signal intensity in the subcortical motor structures (basal ganglia, thalamus, red nucleus, and the cerebellum) which was consistent with substantial iron deposition. A significant increase in prevalence for movement disorders among male p.C282Y homozygotes was also detected. This study suggests that screening for p.C282Y homozygosity in high-risk individuals can potentially reduce excessive iron accumulation in the brain, and subsequently reduce the incidence of movement disorders among p.C282Y homozygous males. A major strength of this study was its large sample size. A limitation to this study was that some patients with milder neurological symptoms who were diagnosed at outpatient clinics may have been missed as the study sample was ascertained through a hospital registry.

Click to read the study in JAMA Neurology

Relevant Reading: Epidemiology and diagnostic testing for hemochromatosis and iron overload

In-Depth [cross-sectional study]: This study investigated the association of the strongest genetic risk variant for hereditary hemochromatosis (HH), p.C282Y, excessive iron deposition in the body and the rates of movement disorders. A total of 488,288 individuals were included in this cohort study (264, 719 females; mean (SD) age of 69.0 (8.1) years, predominantly European ancestry), of whom, 2889 (1569 female) were homozygous for the p.C282Y mutation. The neuroimaging data analysis consisted of 836 individuals, p.C282Y homozygotes (n=154) and the matched controls (n=595). Neuroimaging analysis demonstrated that p.C282Y homozygosity was associated with a decreased T2-weighed and T2* signal intensity in the subcortical motor structures of the brain, Cohen d >1, consistent with excessive iron deposition. A significant increase in prevalence for movement disorders among male p.C282Y homozygotes was also detected across the UK Biobank (2889 pC282Y homozygotes, 485,399 controls), but not in females (OR, 1.09; 95% CI, 0.70-1.73; P = .69). A sex-stratified analysis of 223 569 male individuals found that male homozygotes had a higher chance of being diagnosed with a movement disorder, or other disorders of the nervous system (OR, 1.57; 95% CI, 1.22-2.01; P < .001). Among the 31 males identified as homozygous for the p.C282Y mutation with a movement disorder, only 10 had a concurrent diagnosis of HH. No significant associations were found for p.C282Y homozygous females for any clinical diagnosis tested. Sex-stratified analysis of T2-weighed scans revealed that p.C282Y homozygote female individuals have on average an approximately 28% smaller effect size than male individuals. Through T2* imaging, this study estimated that p.C282Y heterozygosity was associated with an average iron concentration increase of 4.93 ug/g dry compared with 30.00 ug/g dry for homozygotes.

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