Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10-129 vs median tHcy: 14.5 μmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5′-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 μmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-β-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.

中文翻译：

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接受精氨酸血红素或 givosiran 的急性间歇性卟啉症患者同型半胱氨酸稳态失调

急性间歇性卟啉症（AIP）是一种罕见的代谢性疾病，由羟甲基胆烷合成酶基因突变引起。先前的研究报告了有症状的 AIP 患者血浆总同型半胱氨酸 (tHcy) 水平升高。在这项研究中，我们提供了不同临床疾病状态下 AIP 患者队列（n = 37）的 tHcy 和相关参数的长期数据。总共有 25 名患者 (68%) 在观察期间出现高同型半胱氨酸血症 (HHcy; tHcy > 15 μmol/L)。接受精氨酸血红素治疗的复发性疾病 AIP 患者的 HHcy 比非复发患者更常见（中位 tHcy：21.6 μmol/L；范围：10-129 与中位 tHcy：14.5 μmol/L；范围 6-77）。长期系列分析显示个体 tHcy 变异很大，尤其是在复发患者中（变异系数：16.4%-78.8%）。HHcy 经常与 5'-磷酸吡哆醛和叶酸的低血液浓度相关，而钴胺素浓度和亚甲基四氢叶酸还原酶基因的等位基因分布正常。引人注目的是，9 名复发患者中有 6 名后来被纳入 givosiran 方案，这是一种有效减少复发性发作的小干扰 RNA，显示 tHcy 进一步增加（9 名患者的中位 tHcy：105 μmol/L；范围 16-212 ）。通过液相色谱法筛选血浆中的氨基酸显示蛋氨酸水平共同增加（中位数 71 μmol/L；范围 23-616；正常 <40），提示获得性胱硫醚-β-合酶缺乏。然而，血浆中的犬神经氨酸/色氨酸比率是正常的，表明血红素依赖性酶对色氨酸的代谢有规律。综上所述，