{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T19:37:00Z","timestamp":1773517020495,"version":"3.50.1"},"reference-count":9,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,29]],"date-time":"2019-12-29T00:00:00Z","timestamp":1577577600000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Neurol"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the <jats:italic>ALDH4A1<\/jats:italic> gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Case presentation<\/jats:title>\n<jats:p>The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0\u2009mmol\/l (reference: 0.55\u20132.2\u2009mmol\/l) and CSF 12.01 mmol\/l (reference: 1.12\u20132.47\u2009mmol\/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20\u2009days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B<jats:sub>6<\/jats:sub> serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The <jats:italic>ALDH4A1<\/jats:italic> gene sequencing confirmed two previously unknown compound heterozygous variants (<jats:italic>ALDH4A1<\/jats:italic> gene (NM_003748.3) Intron 1: c.62\u2009+\u20091G\u2009&gt;\u2009A - heterozygous and <jats:italic>ALDH4A1<\/jats:italic> gene (NM_003748.3) Exon 5 c.349G\u2009&gt;\u2009C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B<jats:sub>6<\/jats:sub> therapy no further seizures occurred.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>We describe two novel <jats:italic>ALDH4A1<\/jats:italic>-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12883-019-1583-0","type":"journal-article","created":{"date-parts":[[2019,12,29]],"date-time":"2019-12-29T06:02:16Z","timestamp":1577599336000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel variants in a patient with late-onset hyperprolinemia type II: diagnostic key for status epilepticus and lactic acidosis"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6624-8565","authenticated-orcid":false,"given":"Jeremias","family":"Motte","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Lena","family":"Fisse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Gr\u00fcter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Breuer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"L\u00fccke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huu Phuc","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf","family":"Gold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilya","family":"Ayzenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisa","family":"Ellrichmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,12,29]]},"reference":[{"key":"1583_CR1","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1093\/hmg\/7.9.1411","volume":"7","author":"M Geraghty","year":"1998","unstructured":"Geraghty M. Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia. Hum Mol Genet. 1998;7:1411\u20135.","journal-title":"Hum Mol Genet"},{"key":"1583_CR2","doi-asserted-by":"publisher","first-page":"15107","DOI":"10.1074\/jbc.M010860200","volume":"276","author":"R Farrant","year":"2001","unstructured":"Farrant R, Walker V, Mills G, Mellor J, Langley G. Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. J Biol Chem. 2001;276:15107\u201316.","journal-title":"J Biol Chem"},{"key":"1583_CR3","first-page":"139","volume":"131","author":"S van de Ven","year":"2013","unstructured":"van de Ven S, Gardeitchik T, Kouwenberg D, Kluijtmans L, Wevers R, Morava E. Long-term clinical outcome, therapy and mild mitochondrial dysfunction in hyperprolinemia. 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Arch Dis Child. 1989;64:1699\u2013707.","journal-title":"Arch Dis Child"},{"key":"1583_CR7","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/ped.12420","volume":"56","author":"H Mitsubuchi","year":"2014","unstructured":"Mitsubuchi H, Nakamura K, Matsumoto S, Endo F. Biochemical and clinical features of hereditary hyperprolinemia. Pediatr Int. 2014;56:492\u20136.","journal-title":"Pediatr Int"},{"key":"1583_CR8","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s11011-011-9246-x","volume":"26","author":"AT Wyse","year":"2011","unstructured":"Wyse AT, Netto C. Behavioral and neurochemical effects of proline. Metab Brain Dis. 2011;26:159\u201372.","journal-title":"Metab Brain Dis"},{"key":"1583_CR9","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s11064-011-0604-1","volume":"37","author":"AG Ferreira","year":"2001","unstructured":"Ferreira AG, da Cunha AA, Scherer EB, Machado FR, da Cunha MJ, Braga A, et al. Evidence that Hyperprolinemia alters Glutamatergic homeostasis in rat brain: Neuroprotector effect of Guanosine. Neurochem Res. 2001;37:205\u201313.","journal-title":"Neurochem Res"}],"container-title":["BMC Neurology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-019-1583-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12883-019-1583-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12883-019-1583-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T00:05:01Z","timestamp":1609113901000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcneurol.biomedcentral.com\/articles\/10.1186\/s12883-019-1583-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":9,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1583"],"URL":"https:\/\/doi.org\/10.1186\/s12883-019-1583-0","relation":{},"ISSN":["1471-2377"],"issn-type":[{"value":"1471-2377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"11 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All procedures performed in studies involving humans participants were in accordance with the ethical standard of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendment or comparable ethical standards.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The patients gave spoken and written consent prior to participation to the study as well as a written consent for the publication of the results.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"345"}}