Δ1-pyrroline-5-carboxylate synthase deficiency:: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline
Δ1-pyrroline-5-carboxylate synthase deficiency:: neurodegeneration, cataracts and connective tissue manifestations combined with hyperammonaemia and reduced ornithine, citrulline, arginine and proline
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DOI：
10.1007/s00431-004-1545-3
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发表时间：
2005-01-01
影响因子：
3.6
通讯作者：
Saudubray, JM
中科院分区：
文献类型：
--
作者：
Baumgartner, MR;Rabier, D;Saudubray, JM
Delta(1)-吡咯啉-5-羧酸合酶 (P5CS) 催化谷氨酸还原为 Delta(1)-吡咯啉-5-羧酸，这是脯氨酸、鸟氨酸和精氨酸生物合成的关键步骤。最近，我们报道了一种新发现的先天性缺陷，该缺陷是由于两名同胞中 P5CS 缺乏所致，其中一名出生时出现肌张力低下、畸形体征、扁平足和阵挛性癫痫发作。两人均出现进行性神经变性和周围神经病变、关节松弛、皮肤弹性过度和双侧囊下白内障。他们的代谢表型包括轻度高氨血症、低鸟氨酸血症、低瓜氨酸血症、低精氨酸血症和低脯氨酸血症。在与 H-3-谷氨酸一起孵育的成纤维细胞中，H-3-脯氨酸掺入蛋白质的能力不足。两名患者的 P5CS 错义突变 R84Q 均为纯合子。在这里，我们详细描述了同胞的临床表型，并表明禁食期间尿素循环中间体（鸟氨酸、瓜氨酸和精氨酸）的相对缺乏会导致反常的高氨血症。此外，我们还展示了鸟氨酸负载测试和间接酶研究的结果，证实了体内 P5CS 缺陷的生物学意义。结论：Delta(1)-吡咯啉-5-羧酸合酶缺乏症的代谢表型很容易被忽视。低水平的鸟氨酸、瓜氨酸、精氨酸和脯氨酸加上高氨血症倾向或上述情况之一，再加上伴有周围神经病变和/或白内障和结缔组织表现的神经变性临床表型，应提示存在这种疾病。早期识别将允许使用瓜氨酸和脯氨酸进行治疗试验。
Delta(1)-pyrroline-5-carboxylate synthase (P5CS) catalyses the reduction of glutamate to Delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine. Recently, we reported a newly recognised inborn error due to deficiency of P5CS in two sibs, one presenting at birth with hypotonia, dysmorphic signs, pes planus and clonic seizures. Both developed progressive neurodegeneration and peripheral neuropathy, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes mild hyperammonaemia, hypo-ornithinaemia, hypocitrullinaemia, hypo-argininaemia and hypoprolinaemia. Incorporation of H-3-proline into protein was deficient in fibroblasts incubated with H-3-glutamate. Both patients are homozygous for the missense mutation R84Q in P5CS. Here, we describe the clinical phenotype of the sibs in detail and show that a relative deficiency of urea cycle intermediates ( ornithine, citrulline and arginine) during fasting periods results in a paradoxical hyperammonaemia. Furthermore, we show the results of ornithine loading tests and indirect enzyme studies corroborating the biological significance of the defect in P5CS in vivo. Conclusion: The metabolic phenotype of Delta(1)-pyrroline-5-carboxylate synthase deficiency is easily missed. The combination of low levels of ornithine, citrulline, arginine and proline plus a tendency to hyperammonaemia or one of the above together with a clinical phenotype of neurodegeneration with peripheral neuropathy and/or cataracts and connective tissue manifestations should suggest this disorder. Early recognition would allow a therapeutic trial with citrulline and proline.