Genetic Risk for Hemochromatosis is Associated with Movement Disorders

Abstract Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that can lead to iron overload, causing oxidative damage to affected organs. HH type 1 is predominantly associated with homozygosity for the mutation p.C282Y. Previous case studies have reported tentative links between HH and movement disorders, e.g., Parkinson’s disease, and basal ganglia abnormalities on magnetic resonance imaging. We investigated the impact of p.C282Y homozygosity: on whole brain T2 intensity differences, a measure of iron deposition, and; on measures of movement abnormalities and disorders within UK Biobank. The neuroimaging analysis (154 p.C282Y homozygotes, 595 matched controls) showed that p.C282Y homozygosity was associated with decreased T2 signal intensity in motor circuits (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen’s d > 1) consistent with substantial iron deposition. Across the whole UK Biobank (2,889 p.C282Y homozygotes, 496,968 controls), we found a significant enrichment for movement abnormalities in male homozygotes (OR (95% CI) = 1.82 (1.27-2.61), p=0.001), but not females (OR (95% CI) = 1.10 (0.69-1.78), p=0.71). Among the 31 p.C282Y homozygote males with a movement disorder only 7 had a concurrent HH diagnosis. These findings indicate susceptibility to iron overload in subcortical structures in p.C282Y homozygotes, and confirmed an increased risk of movement abnormalities and disorders in males. Given the effectiveness of early treatment in HH, screening for p.C282Y homozygosity in high risk individuals may offer a potential avenue to reduce iron accumulation in the brain and limit additional risk for the development of movement disorders among males.