The bifunctional homooligomeric enzyme Δ¹‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998. Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic ALDH18A1 mutations. They showed biochemical indications of decreased ornithine/proline synthesis, agreeing with the role of P5CS in the biosynthesis of these amino acids. Of 32 patients reported with this neurocutaneous syndrome, 21 familial ones hosted homozygous or compound heterozygous ALDH18A1 mutations, while 11 sporadic ones carried de novo heterozygous ALDH18A1 mutations. In 2015 to 2016, an upper motor neuron syndrome (spastic paraparesis/paraplegia SPG9) complicated with some traits of the neurocutaneous syndrome, although without report of cutis laxa, joint laxity, or herniae, was associated with monoallelic or biallelic ALDH18A1 mutations with, respectively, dominant and recessive inheritance. Of 50 SPG9 patients reported, 14 and 36 (34/2 familial/sporadic) carried, respectively, biallelic and monoallelic mutations. Thus, two neurocutaneous syndromes (recessive and dominant cutis laxa 3, abbreviated ARCL3A and ADCL3, respectively) and two SPG9 syndromes (recessive SPG9B and dominant SPG9A) are caused by essentially different spectra of ALDH18A1 mutations. On the bases of the clinical data (including our own prior patients' reports), the ALDH18A1 mutations spectra, and our knowledge on the P5CS protein, we conclude that the four syndromes share the same pathogenic mechanisms based on decreased P5CS function. Thus, these syndromes represent a continuum of increasing severity (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss‐of‐function by dominant‐negative mechanisms.

中文翻译：

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Δ1-Pyrroline-5-carboxylate synthetase 缺乏症：一种紧急的多方面尿素循环相关疾病。

双功能酶homooligomericΔ ¹吡咯啉-5-羧酸合成酶（P5CS）和它的编码基因ALDH18A1与疾病于1998年两兄妹谁提出反常高氨血症（由蛋白质减轻），精神障碍，身材矮小，白内障，皮肤松弛相关联和关节松弛，被发现携带双等位基因ALDH18A1突变。他们显示出鸟氨酸/脯氨酸合成减少的生化迹象，同意 P5CS 在这些氨基酸的生物合成中的作用。在报告有这种神经皮肤综合征的 32 名患者中，21 名家族性患者携带纯合子或复合杂合子ALDH18A1突变，而 11 名散发性患者携带新发杂合子ALDH18A1突变。2015 年至 2016 年，上运动神经元综合征（痉挛性下肢轻瘫/截瘫 SPG9）并发神经皮肤综合征的某些特征，尽管没有关于皮肤松弛、关节松弛或疝气的报告，但与单等位基因或双等位基因ALDH18A1突变相关，分别为，显性和隐性遗传。在报告的 50 名 SPG9 患者中，14 名和 36 名（34/2 家族性/散发性）分别携带双等位基因和单等位基因突变。因此，两种神经皮肤综合征（隐性和显性皮肤松弛 3，分别缩写为 ARCL3A 和 ADCL3）和两种 SPG9 综合征（隐性 SPG9B 和显性 SPG9A）是由本质上不同的ALDH18A1谱引起的突变。根据临床数据（包括我们自己之前的患者报告）、ALDH18A1突变谱以及我们对 P5CS 蛋白的了解，我们得出结论，基于 P5CS 功能下降，这四种综合征具有相同的致病机制。因此，这些综合征代表了同一疾病 P5CS 缺乏症的严重程度不断增加的连续性（SPG9A < SPG9B < ADCL3 ≤ ARCL3A），其中显性突变通过显性失活机制导致功能丧失。