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Two siblings who presented paradoxical hyperammonemia (alleviated by protein), mental disability, short stature, cataracts, cutis laxa, and joint laxity, were found to carry biallelic <jats:italic>ALDH18A1<\/jats:italic> 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 <jats:italic>ALDH18A1<\/jats:italic> mutations, while 11 sporadic ones carried de novo heterozygous <jats:italic>ALDH18A1<\/jats:italic> 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 <jats:italic>ALDH18A1<\/jats:italic> 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 <jats:italic>ALDH18A1<\/jats:italic> mutations. On the bases of the clinical data (including our own prior patients' reports), the <jats:italic>ALDH18A1<\/jats:italic> 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\u2009&lt;\u2009SPG9B\u2009&lt;\u2009ADCL3\u2009\u2264\u2009ARCL3A) of the same disease, P5CS deficiency, in which the dominant mutations cause loss\u2010of\u2010function by dominant\u2010negative mechanisms.<\/jats:p>","DOI":"10.1002\/jimd.12220","type":"journal-article","created":{"date-parts":[[2020,2,4]],"date-time":"2020-02-04T14:40:41Z","timestamp":1580827241000},"page":"657-670","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["\u0394<sup>1<\/sup>\u2010Pyrroline\u20105\u2010carboxylate synthetase deficiency: An emergent multifaceted urea cycle\u2010related disorder"],"prefix":"10.1002","volume":"43","author":[{"given":"Clara","family":"Marco\u2010Mar\u00edn","sequence":"first","affiliation":[{"name":"Instituto de Biomedicina de Valencia of the CSIC  Valencia Spain"},{"name":"Centro para Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Raras CIBERER\u2010ISCIII  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M.","family":"Escamilla\u2010Honrubia","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Valencia of the CSIC  Valencia Spain"},{"name":"Centro para Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Raras CIBERER\u2010ISCIII  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 L.","family":"Ll\u00e1cer","sequence":"additional","affiliation":[{"name":"Instituto de Biomedicina de Valencia of the CSIC  Valencia Spain"},{"name":"Centro para Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Raras CIBERER\u2010ISCIII  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Seri","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences University of Bologna  Bologna Italy"},{"name":"Medical Genetics Unit S. 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