Background

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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5-氨基乙酰丙酸脱水酶卟啉症：肝5-氨基乙酰丙酸合酶诱导和对血红素的长期反应的最新进展

背景

5-氨基乙酰丙酸脱水酶（ALAD）卟啉症（ADP）是一种罕见的常染色体隐性疾病，只有8例病例记录在案，均为男性。尽管归类为急性肝卟啉症（AHP），但尚未证明限速肝酶5-氨基乙酰丙酸合酶-1（ALAS1）的诱导，并且骨髓也可能贡献了过量的5-氨基乙酰丙酸（ALA）。两名患者死亡并报告了其他患者的随访情况，因此对该病的自然病程了解甚少，治疗经验有限。

方法

我们报告了新的分子发现，并更新了第六位报告的ADP患者的临床病程和治疗方法，该患者现年31岁，是美洲唯一的已知病例，并审查了有关基因型-表型相关性和治疗的公开数据。

结果

与其他AHP一样，这种情况下循环肝5-氨基乙酰丙酸合酶1（ALAS1）mRNA升高。未发现类红细胞特异性ALAS2（在其他一些卟啉症中X连锁的修饰基因）的功能突变。7例报告的ADP病例具有复合杂合的ALAD突变，导致极低的残留ALAD活性和生命早期或青春期的症状。一名具有生殖系ALAD突变等位基因的成年人与克隆性骨髓增生性疾病真性红细胞增多症相关联发展了ADP。

结论

循环肝ALAS1升高和对血红素的治疗反应表明，肝脏是ADP中过量ALA的重要来源，尽管骨髓也可能起作用。静脉血红素在大多数报道的病例中可有效治疗和预防神经系统症状的急性发作。