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.

中文翻译：

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血色病的遗传风险与运动障碍有关

遗传性血色素沉着症 (HH) 是一种常染色体隐性遗传疾病，可导致铁过载，从而对受影响的器官造成氧化损伤。HH 1 型主要与突变 p.C282Y 的纯合性相关。以前的案例研究报告了 HH 与运动障碍（例如帕金森病）和磁共振成像基底节异常之间的初步联系。我们研究了 p.C282Y 纯合性的影响：对全脑 T2 强度差异、铁沉积的测量以及；关于英国生物银行内运动异常和障碍的测量。神经影像学分析（154 个 p.C282Y 纯合子，595 个匹配对照）显示 p.C282Y 纯合子与运动回路（基底节、丘脑、红核和小脑；Cohen's d > 1) 与大量铁沉积一致。在整个英国生物银行（2,889 个 p.C282Y 纯合子，496,968 个对照）中，我们发现男性纯合子的运动异常显着富集（OR (95% CI) = 1.82 (1.27-2.61), p=0.001），但不是女性(OR (95% CI) = 1.10 (0.69-1.78)，p=0.71)。在 31 名患有运动障碍的 p.C282Y 纯合子男性中，只有 7 名同时被诊断为 HH。这些发现表明 p.C282Y 纯合子皮层下结构对铁过载的易感性，并证实了男性运动异常和障碍的风险增加。鉴于 HH 早期治疗的有效性，在高风险个体中筛查 p.C282Y 纯合子可能提供一种潜在途径，以减少大脑中铁的积累并限制男性发生运动障碍的额外风险。