Departments of Preventive Medicine and Population Health, and Internal Medicine (Division of Gastroenterology and Hepatology), University of Texas Medical Branch, Galveston, Texas, USA.
Departments of Preventive Medicine and Population Health, and Internal Medicine (Division of Gastroenterology and Hepatology), University of Texas Medical Branch, Galveston, Texas, USA.
Mol Genet Metab. 2020 Dec;131(4):418-423. doi: 10.1016/j.ymgme.2020.10.011. Epub 2020 Oct 26.
5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited.
We report new molecular findings and update the clinical course and treatment of the sixth reported ADP patient, now 31 years old and the only known case in the Americas, and review published data regarding genotype-phenotype correlation and treatment.
Circulating hepatic 5-aminolevulinic acid synthase-1 (ALAS1) mRNA was elevated in this case, as in other AHPs. Gain of function mutation of erythroid specific ALAS2 - an X-linked modifying gene in some other porphyrias - was not found. Seven reported ADP cases had compound heterozygous ALAD mutations resulting in very low residual ALAD activity and symptoms early in life or adolescence. One adult with a germline ALAD mutant allele developed ADP in association with a clonal myeloproliferative disorder, polycythemia vera.
Elevation in circulating hepatic ALAS1 and response to treatment with hemin indicate that the liver is an important source of excess ALA in ADP, although the marrow may also contribute. Intravenous hemin was effective in most reported cases for treatment and prevention of acute attacks of neurological symptoms.
5-氨基酮戊酸脱水酶（ALAD）卟啉症（ADP）是一种极为罕见的常染色体隐性遗传病，仅有 8 例确诊病例，且均为男性。尽管被归类为急性肝卟啉症（AHP），但限速肝酶 5-氨基酮戊酸合酶-1（ALAS1）的诱导尚未得到证实，骨髓也可能产生过量的 5-氨基酮戊酸（ALA）。已有两名患者死亡，其余患者的随访报告有限，因此该疾病的自然病史知之甚少，治疗经验也有限。
我们报告了新的分子发现，并更新了第六例 ADP 患者的临床病程和治疗情况，该患者现年 31 岁，是美洲唯一已知的病例，同时回顾了已发表的关于基因型-表型相关性和治疗的相关数据。
本例患者循环中的肝 5-氨基酮戊酸合酶-1（ALAS1）mRNA 升高，如同其他 AHP 一样。未发现某些其他卟啉症中红细胞特异性 ALAS2 的功能获得性突变——一种 X 连锁修饰基因。报告的 7 例 ADP 病例存在复合杂合 ALAD 突变，导致 ALAD 活性非常低，且在生命早期或青春期出现症状。一名携带 ALAD 突变等位基因的成年患者在与克隆性骨髓增生性疾病、真性红细胞增多症相关联的情况下发生 ADP。
循环中肝 ALAS1 的升高和血红素治疗的反应表明，肝脏是 ADP 中过量 ALA 的重要来源，尽管骨髓也可能有贡献。大多数报告病例中，静脉内血红素治疗对预防神经症状急性发作有效。
