Gagliardi Delia, Wade Charles, Tucci Arianna, Houlden Henry, Chataway Jeremy, Barkhof Frederik, Lynch David S
Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK.
J Neurol Neurosurg Psychiatry. 2024 Dec 6. doi: 10.1136/jnnp-2024-335089.
Alexander disease is an autosomal dominant leukodystrophy caused by heterozygous pathogenic variants in the glial fibrillar acidic protein (GFAP) gene. Although increasingly recognised, there is evidence that Alexander disease, particularly later-onset disease, is significantly underdiagnosed and its true prevalence is unknown (the only population-based prevalence was estimated at one in 2.7 million). Using the extensive UK Biobank dataset, we analysed the frequency of pathogenic and likely pathogenic variants, variants, within the UK population and identified clinical and radiological phenotypes linked to these variants.
Pathogenic, likely pathogenic and variants of uncertain significance were identified in the UK Biobank whole-exome sequencing data (n=4 70 000). Demographic information, previous medical history-including symptoms associated with Alexander disease-collected from self-reported data and hospital records, family history and various MRI metrics were compared between variant carriers and controls.
We identified 36 unique pathogenic and likely pathogenic variants in 106 carriers, yielding a carrier frequency of approximately 1 in 4435. Modelling based on the UK population estimated a prevalence of 6.8 per 100 000. Carriers of pathogenic and likely pathogenic variants had higher odds of bladder dysfunction (OR 3.17, p<0.0001), upper airway dysfunction (OR 7.82, p=0.004) and psychiatric conditions (OR 1.51, p=0.04). Additionally, carriers were more likely to report a paternal history of dementia (OR 2.79, p<0.0001). MRI data revealed significant atrophy in brainstem regions among variant carriers.
Pathogenic and likely pathogenic variants are more prevalent in the general population than previously expected and are associated with clinical and radiological characteristics of Alexander disease. This study indicates that Alexander disease may be under-reported, misdiagnosed, or exhibit reduced penetrance.
亚历山大病是一种常染色体显性白质营养不良症，由胶质纤维酸性蛋白（GFAP）基因的杂合致病变异引起。尽管越来越受到认可，但有证据表明，亚历山大病，尤其是迟发性疾病，存在严重的诊断不足，其真实患病率尚不清楚（唯一基于人群的患病率估计为270万分之一）。我们使用广泛的英国生物银行数据集，分析了英国人群中致病变异和可能的致病变异的频率，并确定了与这些变异相关的临床和放射学表型。
在英国生物银行全外显子测序数据（n = 470000）中鉴定出致病性、可能致病性和意义不确定的变异。比较了变异携带者和对照组之间的人口统计学信息、既往病史（包括从自我报告数据和医院记录中收集的与亚历山大病相关的症状）、家族史和各种MRI指标。
我们在106名携带者中鉴定出36种独特的致病性和可能致病性变异，携带者频率约为4435分之一。基于英国人群的模型估计患病率为每10万人中有6.8例。致病性和可能致病性变异的携带者出现膀胱功能障碍（OR 3.17，p < 0.0001）、上呼吸道功能障碍（OR 7.82，p = 0.004）和精神疾病（OR 1.51，p = 0.04）的几率更高。此外，携带者更有可能报告有痴呆症的父系家族史（OR 2.79，p < 0.0001）。MRI数据显示变异携带者脑干区域有明显萎缩。
致病性和可能致病性变异在普通人群中的患病率比以前预期的更高，并且与亚历山大病的临床和放射学特征相关。这项研究表明，亚历山大病可能报告不足、误诊或表现出较低的外显率。
