Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene
Diagnostic Strategies for Autosomal Dominant Acute Porphyrias: Retrospective Analysis of 467 Unrelated Patients Referred for Mutational Analysis of the HMBS, CPOX, or PPOX Gene
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DOI：
10.1373/clinchem.2008.122564
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发表时间：
2009-07-01
影响因子：
9.3
通讯作者：
Badminton, Michael N.
中科院分区：
文献类型：
--
作者：
Whatley, Sharon D.;Mason, Nicola G.;Badminton, Michael N.
背景技术背景：临床上难以区分的急性卟啉症发作发生在急性间歇性卟啉症（AIP）、遗传性粪卟啉症（HCP）和变异性卟啉症（VP）中。这些disorders.METHODS：突变检测的诊断灵敏度是通过测序和基因剂量分析来确定的，以寻找467例顺序提及的无关患者的突变。在突变阳性患者中评估血浆荧光扫描、粪便卟啉分析和胆色素原脱氨酶（PBGD）测定的诊断准确性结果：突变检测的敏感性（95%CI）为：AIP为98.1%; VP为152例; HCP为31例（95.60/6-99.2%）; HCP，96.9%（84.3%-99.5%）; VP，100%（95.7%-100%）。我们确定了HMBS基因（羟甲基胆烷合酶）和CPOX基因（粪卟啉原氧化酶）中的5个大缺失。血浆荧光扫描阳性更经常在VP（99%的患者）比所有？(68%）或HCP（29%）。荧光发射峰波长和粪卟啉异构体比值对鉴别AIP、HCP和VP具有较高的诊断特异性和敏感性。在突变阴性患者中，DNA分析后进行PBGD检测对AIP的诊断准确性高于任何一种检测。alone.CONCLUSIONS:当PBG排泄增加，2调查（血浆荧光扫描，粪卟啉异构体的比例）是足够的，很少有例外，以确定急性卟啉症的类型。当PBG、5-氨基乙酰丙酸盐和卟啉分析的结果在参考区间内，并且临床怀疑既往疾病由急性卟啉症引起的可能性仍然很高时，HMBS基因突变分析后进行PBGD测定是诊断或排除AIP的有效策略。(C)2009年美国临床化学协会
BACKGROUND: Clinically indistinguishable attacks of acute porphyria occur in acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and varieegate porphyria (VP). There are few evidence-based diagnostic strategies for these disorders.METHODS: The diagnostic sensitivity of mutation detection was determined by sequencing and gene-dosage analysis to search for mutations in 467 sequentially referred) unrelated patients. The diagnostic accuracy of plasma fluorescence scanning, fecal porphyrin analysis, and porphobilinogen deaminase (PBGD) assay was assessed in mutation-positive patients (AIP, 260 patients; VP, 152 patients; HCP, 31 patients).RESULTS: Sensitivities (95% CI) for mutation detection were as follows: AIP, 98.1% (95.60/6-99.2%); HCP, 96.9% (84.3%-99.5%); VP, 100% (95.7%-100%). We identified 5 large deletions in the HMBS gene (hydroxymethylbilane synthase) and one in the CPOX gene (coproporphyrinogen oxidase). The plasma fluorescence scan was positive more often in VP (99% of patients) than in All? (68%) or HCP (29%). The wavelength of the fluorescence emission peak and the fecal coproporphyrin isomer ratio had high diagnostic specificity and sensitivity for differentiating between AIP, HCP, and VP. DNA analysis followed by PBGD assay in mutation-negative patients had greater diagnostic accuracy for AIP than either test. alone.CONCLUSIONS: When PBG excretion is increased, 2 investigations (plasma fluorescence scanning, the coproporphyrin isomer ratio) are sufficient, with rare exceptions, to identify the type of acute porphyria. When the results of PBG, 5-aminolevulinate, and porphyrin analyses are within reference intervals and clinical suspicion that a past illness was caused by an acute porphyria remains high, mutation analysis of the HMBS gene followed by PBGD assay is an effective strategy for diagnosis or exclusion of AIP. (C) 2009 American Association for Clinical Chemistry