Houten Sander M, van Woerden Christiaan S, Wijburg Frits A, Wanders Ronald J A, Waterham Hans R
Laboratory Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Eur J Hum Genet. 2003 Feb;11(2):196-200. doi: 10.1038/sj.ejhg.5200933.
Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G>A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65. This predicts a disease incidence between 1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis of patients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy-Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.
高IgD血症与周期性发热综合征（HIDS）和甲羟戊酸尿症（MA）是两种常染色体隐性疾病，二者均由编码基因（MVK）突变导致甲羟戊酸激酶（MK）活性缺乏引起。最常见的MVK突变V377I（1129G>A）仅在HIDS患者中被发现。其他常见突变与HIDS和MA均有关联。为估算荷兰MK缺乏症的发病率，我们通过PCR-RFLP法测定了从匿名新生儿筛查卡片中提取的基因组DNA中V377I突变的携带频率。我们在2138份分析样本中发现了14名携带者（1:153）。基于诊断为MK缺乏症患者中V377I等位基因频率为42%，荷兰人群中任何MVK突变的携带频率可计算为1:65。这预测疾病发病率在1/5196至1/53656之间，远高于实际观察到的发病率。尽管MK缺乏症患者仍有可能存在诊断不足的情况，但这种差异可能是由于V377I纯合子的外显率降低所致。对携带MVK突变患者中V377I等位基因分布的分析表明，这不符合哈迪-温伯格平衡原则（Hardy-Weinberg equilibrium principle），很可能是因为HIDS中V377I纯合子的代表性不足。V377I纯合子可能表现出更轻微的MK缺乏症表型或根本没有疾病表型。
