{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:58:31Z","timestamp":1793735911537,"version":"4.6.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the\n                      <jats:italic>ADSL<\/jats:italic>\n                      gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype\u2013phenotype correlations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Data were collected through \"Our Journey with ADSL deficiency Association\" by using a dedicated web survey filled-in by parents.<\/jats:p>\n                    <jats:p>\n                      Clinical and molecular data were collected from 18 patients (12 males, median age 10.9\u00a0years\u2009\u00b1\u20097.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63\u00a0years\u2009\u00b1\u20090.84 SD), and age at diagnosis varied from 2\u00a0months to 17\u00a0years, (median age 6.4\u00a0years\u2009\u00b1\u20096.1 SD). The first sign was a psychomotor delay in 8\/18 patients, epilepsy in 3\/18, psychomotor delay and epilepsy in 3\/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7\/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and\/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire\n                      <jats:italic>ADSL<\/jats:italic>\n                      coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The study adds more details on the spectrum of ADSLD patients\u2019 phenotypes and molecular data.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-021-01731-6","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T01:03:04Z","timestamp":1614560584000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Clinical and molecular characterization of patients with adenylosuccinate lyase deficiency"],"prefix":"10.1186","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7946-6422","authenticated-orcid":false,"given":"Gerarda","family":"Mastrogiorgio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Macchiaiolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Sabrina","family":"Buonuomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Bellacchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Bordi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Vecchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari Payne","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie Karen","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Contardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cecconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bartuli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,1]]},"reference":[{"issue":"8411","key":"1731_CR1","first-page":"1058","volume":"2","author":"J Jaeken","year":"1984","unstructured":"Jaeken J, Van den Berghe G. An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids. Lancet. 1984;2(8411):1058\u201361.","journal-title":"Lancet"},{"issue":"2\u20133","key":"1731_CR2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1159\/000132358","volume":"44","author":"ML Van Keuren","year":"1987","unstructured":"Van Keuren ML, Hart IM, Kao FT, Neve RL, Bruns GA, Kurnit DM, et al. A somatic cell hybrid with a single human chromosome 22 corrects the defect in the CHO mutant (Ade-I) lacking adenylosuccinase activity. Cytogenet Cell Genet. 1987;44(2\u20133):142\u20137.","journal-title":"Cytogenet Cell Genet"},{"issue":"3\u20134","key":"1731_CR3","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1159\/000133575","volume":"64","author":"EA Fon","year":"1993","unstructured":"Fon EA, Demczuk S, Delattre O, Thomas G, Rouleau GA. Mapping of the human adenylosuccinate lyase (ADSL) gene to chromosome 22q13.1\u2013 > q13.2. Cytogenet Cell Genet. 1993;64(3\u20134):201\u20133.","journal-title":"Cytogenet Cell Genet"},{"issue":"1","key":"1731_CR4","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/ng0492-59","volume":"1","author":"RL Stone","year":"1992","unstructured":"Stone RL, Aimi J, Barshop BA, Jaeken J, Van den Berghe G, Zalkin H, et al. A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. Nat Genet. 1992;1(1):59\u201363.","journal-title":"Nat Genet"},{"issue":"3","key":"1731_CR5","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1002\/(SICI)1098-1004(1999)13:3<197::AID-HUMU3>3.0.CO;2-D","volume":"13","author":"S Marie","year":"1999","unstructured":"Marie S, Cuppens H, Heuterspreute M, Jaspers M, Tola EZ, Gu XX, et al. Mutation analysis in adenylosuccinate lyase deficiency: eight novel mutations in the re-evaluated full ADSL coding sequence. Hum Mutat. 1999;13(3):197\u2013202.","journal-title":"Hum Mutat"},{"key":"1731_CR6","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.ymgmr.2016.07.007","volume":"8","author":"TR Donti","year":"2016","unstructured":"Donti TR, Cappuccio G, Hubert L, Neira J, Atwal PS, Miller MJ, et al. diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum. Mol Genet Metab Rep. 2016;8:61\u20136.","journal-title":"Mol Genet Metab Rep"},{"key":"1731_CR7","doi-asserted-by":"publisher","first-page":"2217","DOI":"10.1021\/bi011998t","volume":"41","author":"JL Brosius","year":"2002","unstructured":"Brosius JL, Colman RF. Three subunits contribute amino acids to the active site of tetrameric adenylosuccinate lyase: Lys(268) and Glu(275) are required. Biochemistry. 2002;41:2217\u201326.","journal-title":"Biochemistry"},{"issue":"1","key":"1731_CR8","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1055\/s-2007-973536","volume":"29","author":"FA van den Bergh","year":"1998","unstructured":"van den Bergh FA, Bosschaart AN, Hageman G, Duran M, Tien P-T. Adenylosuccinase deficiency with neonatal onset severe epileptic seizures and sudden death. Neuropediatrics. 1998;29(1):51\u20133.","journal-title":"Neuropediatrics"},{"issue":"9","key":"1731_CR9","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.braindev.2007.03.005","volume":"29","author":"E Jurkiewicz","year":"2007","unstructured":"Jurkiewicz E, Mierzewska H, Kusmierska K. Adenylosuccinate lyase deficiency: the first identified polish patient. Brain Dev. 2007;29(9):600\u20132.","journal-title":"Brain Dev"},{"issue":"1","key":"1731_CR10","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.jpeds.2006.09.027","volume":"150","author":"K Mouchegh","year":"2007","unstructured":"Mouchegh K, Zikanova M, Hoffmann GF, Kretzschmar B, K\u00fchn T, Mildenberger E, et al. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of 6 patients in 4 families. J Pediatr. 2007;150(1):57\u201361.","journal-title":"J Pediatr"},{"issue":"4","key":"1731_CR11","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.ymgme.2008.04.013","volume":"94","author":"A Jurecka","year":"2008","unstructured":"Jurecka A, Zikanova M, Tylki-Szymanska A, Krijt J, Bogdanska A, Gradowska W, et al. Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency. Mol Genet Metab. 2008;94(4):435\u201342.","journal-title":"Mol Genet Metab"},{"issue":"4","key":"1731_CR12","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1055\/s-2002-34493","volume":"33","author":"M Castro","year":"2002","unstructured":"Castro M, Perez-Cerda C, Merinero B, Garc\u00eda MJ, Bernar J, Gil Nagel A, et al. Screening for adenylosuccinate lyase deficiency: clinical, biochemical and molecular findings in four patients. Neuropediatrics. 2002;33(4):186\u20139.","journal-title":"Neuropediatrics"},{"issue":"23","key":"1731_CR13","doi-asserted-by":"publisher","first-page":"100592","DOI":"10.1016\/j.ymgmr.2020.100592","volume":"6","author":"M Macchiaiolo","year":"2020","unstructured":"Macchiaiolo M, Buonuomo PS, Mastrogiorgio G, Bordi M, Testa B, Weber G, et al. Very mild isolated intellectual disability caused by adenylosuccinate lyase deficiency: a new phenotype. Mol Genet Metab Rep. 2020;6(23):100592.","journal-title":"Mol Genet Metab Rep"},{"issue":"2","key":"1731_CR14","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/BF00710293","volume":"16","author":"F Van den Bergh","year":"1993","unstructured":"Van den Bergh F, Vincent MF, Jaeken J, Van den Berghe G. Functional studies in fibroblasts of adenylosuccinase-deficient children. J Inherit Metab Dis. 1993;16(2):425\u201334.","journal-title":"J Inherit Metab Dis"},{"issue":"2","key":"1731_CR15","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/BF00710291","volume":"16","author":"F Van den Bergh","year":"1993","unstructured":"Van den Bergh F, Vincent MF, Jaeken J, Van den Berghe G. Residual adenylosuccinase activities in fibroblasts of adenylosuccinase-deficient children: parallel deficiency with adenylosuccinate and succinyl-AICAR in profoundly retarded patients and non-parallel deficiency in a mildly retarded girl. J Inherit Metab Dis. 1993;16(2):415\u201324.","journal-title":"J Inherit Metab Dis"},{"issue":"5","key":"1731_CR16","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405\u201324.","journal-title":"Genet Med"},{"issue":"1","key":"1731_CR17","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13052-017-0383-7","volume":"43","author":"M Macchiaiolo","year":"2017","unstructured":"Macchiaiolo M, Barresi S, Cecconi F, Zanni G, Niceta M, Bellacchio E, et al. A mild form of adenylosuccinate lyase deficiency in absence of typical brain MRI features diagnosed by whole exome sequencing. Ital J Pediatr. 2017;43(1):65.","journal-title":"Ital J Pediatr"},{"issue":"1","key":"1731_CR18","first-page":"50","volume":"45","author":"A Jurecka","year":"2014","unstructured":"Jurecka A, Zikanova M, Jurkiewicz E, Tylki-Szymanska A. Attenuated adenylosuccinate lyase deficiency: a report of one case and a review of the literature. Neuropediatrics. 2014;45(1):50\u20135.","journal-title":"Neuropediatrics"},{"key":"1731_CR19","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1001\/jama.2014.14601","volume":"312","author":"Y Yang","year":"2014","unstructured":"Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312:1870\u20139.","journal-title":"JAMA"},{"key":"1731_CR20","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1056\/NEJMoa1306555","volume":"369","author":"Y Yang","year":"2013","unstructured":"Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013;369:1502.","journal-title":"N Engl J Med"},{"key":"1731_CR21","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00431-011-1503-9","volume":"171","author":"A Jurecka","year":"2012","unstructured":"Jurecka A, Jurkiewicz E, Szymanska A. Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature. Eur J Pediatr. 2012;171:131\u20138.","journal-title":"Eur J Pediatr"},{"issue":"2","key":"1731_CR22","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.radcr.2018.11.001","volume":"14","author":"S Kayfan","year":"2018","unstructured":"Kayfan S, Yazdani RM, Castillo S, Wong K, Miller JH, Pfeifer CM. MRI findings of hypomyelination in adenylosuccinate lyase deficiency. Radiol Case Rep. 2018;14(2):255\u20139.","journal-title":"Radiol Case Rep"},{"issue":"5","key":"1731_CR23","first-page":"301","volume":"16","author":"F Ciardo","year":"2001","unstructured":"Ciardo F, Salerno C, Curatolo P. Neurologic aspects of adenylosuccinate lyase deficiency. J Child Neurol. 2001;16(5):301\u20138.","journal-title":"J Child Neurol"},{"key":"1731_CR24","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.pediatrneurol.2010.06.007","volume":"43","author":"CT Lundy","year":"2010","unstructured":"Lundy CT, Jungbluth H, Pohl KRE, Siddiqui A, Marinaki AM, Mundy H, et al. Adenylosuccinate lyase deficiency in the United Kingdom pediatric population: first three cases. Pediatr Neurol. 2010;43:351\u20134.","journal-title":"Pediatr Neurol"},{"issue":"14","key":"1731_CR25","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.1093\/hmg\/9.14.2159","volume":"9","author":"V Race","year":"2000","unstructured":"Race V, Marie S, Vincent MF, Van den Berghe G. Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency. Hum Mol Genet. 2000;9(14):2159\u201365.","journal-title":"Hum Mol Genet"},{"key":"1731_CR26","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1007\/978-1-4615-5381-6_34","volume":"431","author":"C Salerno","year":"1998","unstructured":"Salerno C, Celli M, Finocchiaro R, D\u2019Eufemia P, Iannetti P, Crif\u00f2 C, et al. Effect of D-ribose administration to a patient with inherited deficit of adenylosuccinase. Adv Exp Med Biol. 1998;431:177\u201380.","journal-title":"Adv Exp Med Biol"},{"key":"1731_CR27","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/0-306-46843-3_14","volume":"486","author":"C Salerno","year":"2000","unstructured":"Salerno C, Crifo C, Curatolo P, Ciardo F. Effect of uridine administration to a patient with adenylosuccinate lyase deficiency. Adv Exp Med Biol. 2000;486:75\u20137.","journal-title":"Adv Exp Med Biol"},{"key":"1731_CR28","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.ejpn.2011.08.008","volume":"16","author":"B Perez-Duenas","year":"2011","unstructured":"Perez-Duenas B, Sempere A, Campistol J, Alonso-Colmenero I, D\u00edez M, Gonz\u00e1lez V, et al. Novel features in the evolution of adenylosuccinate lyase deficiency. Eur J Paediatr Neurol. 2011;16:343.","journal-title":"Eur J Paediatr Neurol"},{"key":"1731_CR29","doi-asserted-by":"publisher","first-page":"S329","DOI":"10.1007\/s10545-008-0904-z","volume":"2","author":"A Jurecka","year":"2008","unstructured":"Jurecka A, Tylki-Szymanska A, Zikanova M, Krijt J, Kmoch S. D-Ribose therapy in four Polish patients with adenylosuccinate lyase deficiency: absence of positive effect. J Inherit Metab Dis. 2008;2:S329\u201332.","journal-title":"J Inherit Metab Dis"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01731-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13023-021-01731-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01731-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T01:06:00Z","timestamp":1614560760000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-01731-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,1]]},"references-count":29,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1731"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-01731-6","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,1]]},"assertion":[{"value":"25 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All the reported investigations and a specific permission for the publication of the results was obtained through a written informed parental consent.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"112"}}