Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Genet Metab. 2019 Dec;128(4):463-469. doi: 10.1016/j.ymgme.2019.09.002. Epub 2019 Sep 12.
Panthothenate kinase-associated neurodegeneration (PKAN, OMIM 234200), is an inborn is an autosomal recessive inborn error of metabolism caused by pathogenic variants in PANK2. PANK2 encodes the enzyme pantothenate kinase 2 (EC 2.7.1.33), an essential regulatory enzyme in CoA biosynthesis. Clinical presentation includes dystonia, rigidity, bradykinesia, dysarthria, pigmentary retinopathy and dementia with variable age of onset ranging from childhood to adulthood. In order to provide an accurate incidence estimate of PKAN, we conducted a systematic review of the literature and databases for pathogenic mutations and constructed a bioinformatic profile for pathogenic missense variants in PANK2. We then studied the gnomAD cohort of ~140,000 unrelated adults from global populations to determine the allele frequency of the variants in PANK2 reported pathogenic for PKAN and for those additional variants identified in gnomAD that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based on three different models using the allele frequencies of pathogenic PKAN variants with or without those bioinformatically determined to be potentially pathogenic. Disease incidence calculations showed PKAN incidence ranging from 1:396,006 in Europeans, 1:1,526,982 in Africans, 1:480,826 in Latino, 1:523,551 in East Asians and 1:531,118 in South Asians. These results indicate PKAN is expected to occur in approximately 2 of every 1 million live births globally outside of Africa, and has a much lower incidence 1 in 1.5 million live births in the African population.
泛酸激酶相关神经变性（PKAN，OMIM 234200）是一种常染色体隐性遗传的先天性代谢缺陷，由 PANK2 中的致病性变异引起。PANK2 编码泛酸激酶 2（EC 2.7.1.33），该酶是 CoA 生物合成的必需调节酶。临床表现包括肌张力障碍、僵硬、运动迟缓、构音障碍、色素性视网膜炎和痴呆，发病年龄从儿童到成年不等。为了提供 PKAN 的准确发病率估计，我们对文献和数据库中的致病性突变进行了系统综述，并构建了 PANK2 中致病性错义变异的生物信息学特征。然后，我们研究了来自全球人群的约 140,000 名无关成年人的 gnomAD 队列，以确定报告为 PKAN 致病性的 PANK2 变异的等位基因频率，以及在 gnomAD 中发现的符合潜在致病性生物信息学标准的其他变异的等位基因频率。发病率是基于三种不同的模型，使用致病性 PKAN 变异的等位基因频率来计算，这些变异要么是报告为致病性的，要么是根据生物信息学标准确定为潜在致病性的。疾病发病率的计算结果显示，PKAN 的发病率在欧洲人为 1:396,006，在非洲人为 1:1,526,982，在拉丁裔人为 1:480,826，在东亚人为 1:523,551，在南亚人为 1:531,118。这些结果表明，PKAN 预计在非洲以外的全球每 100 万活产儿中会出现 2 例，而在非洲人口中每 150 万活产儿中发病率较低，为 1 例。
