{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:14:09Z","timestamp":1785500049129,"version":"3.56.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, is a rare autosomal recessive disorder characterized by impaired ornithine transport across the inner mitochondrial membrane. HHH is caused by biallelic disease-causing variants in the <jats:italic>SLC25A15<\/jats:italic> gene. The clinical presentation of HHH is highly variable ranging from severe neonatal encephalopathy and hepatic failure to a milder form with corresponding learning difficulties.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In this study, data from thirteen patients with HHH syndrome, diagnosed between the age of 1\u00a0week\u201329\u00a0years at two tertiary care centers in Palestine, is presented. The clinical, biochemical, and molecular data are reviewed.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Analysis of the <jats:italic>SLC25A15<\/jats:italic> gene sequence revealed a novel homozygous frameshift deletion in exon 5, NM_014252.4:c.552-555delTTTC; p (Phe185SerfsTer8) in nine patients. The remaining four patients had a recurrent homozygous frameshift variant; NM_014252.4:c.446delG, (p.Ser149ThrfsTer45). The major acute clinical presentation found was encephalopathy and liver dysfunction. Nervous system involvement was common, progressive, and presented with signs of upper motor neuron disease as well as variable degrees of cognitive impairment. One patient had an initial presentation in adulthood with acute encephalopathy that responded well to treatment. There was no clear genotype-phenotype correlation.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our results confirm the marked clinical heterogeneity of HHH including severe neonatal presentation, hepatic failure, and progressive pyramidal tract dysfunction in all age groups. The disease progression was variable, even in patients with the same genetic variant, and in patients with severe neonatal-onset hepatic encephalopathy. We report a novel pathogenic variant in the <jats:italic>SLC25A15<\/jats:italic> gene, further expanding the molecular spectrum of the disease.<\/jats:p>","DOI":"10.3389\/fgene.2022.1004598","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T12:47:02Z","timestamp":1669294022000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Clinical heterogeneity of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in thirteen palestinian patients and report of a novel variant in the SLC25A15 gene"],"prefix":"10.3389","volume":"13","author":[{"given":"Imad","family":"Dweikat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham","family":"Khalaf-Nazzal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-05080-0_17","article-title":"Genetic disorders among the Palestinians","volume-title":"Genetic disorders among Arab populations","author":"Abu-Libdeh","year":"2010"},{"key":"B2","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/9658","article-title":"Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter","volume":"22","author":"Camacho","year":"1999","journal-title":"Nat. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1136\/jmg.2008.059097","article-title":"Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15","volume":"45","author":"Debray","year":"2008","journal-title":"J. Med. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"00735","DOI":"10.1016\/j.ymgme.2021.06.006","article-title":"Childhood-onset hereditary spastic paraplegia and its treatable mimics","author":"Ebrahimi-Fakhari","year":"2021","journal-title":"Mol. Genet. Metab."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1007\/s10072-012-1266-8","article-title":"Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome in adulthood: A rare recognizable condition","volume":"34","author":"Filosto","year":"2013","journal-title":"Neurol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41431-020-0609-9","article-title":"First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery","volume":"28","author":"Hengel","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1055\/s-2008-1052499","article-title":"Studies on a case of HHH-syndrome (hyperammonemia, hyperornithinemia, homocitrullinuria)","volume":"17","author":"Hommes","year":"1986","journal-title":"Neuropediatrics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/0304-4165(88)90071-2","article-title":"Biochemical analysis of decreased ornithine transport activity in the liver mitochondria from patients with hyperornithinemia, hyperammonemia and homocitrullinuria","volume":"964","author":"Inoue","year":"1988","journal-title":"Biochim. Biophys. Acta"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/j.cca.2012.03.015","article-title":"Long-term follow-up of four patients affected by HHH syndrome","volume":"413","author":"Kim","year":"2012","journal-title":"Clin. Chim. Acta."},{"key":"B10","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jns.2003.10.017","article-title":"Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family","volume":"218","author":"Korman","year":"2004","journal-title":"J. Neurol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13023-015-0242-9","article-title":"The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome","volume":"10","author":"Martinelli","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s13023-019-1181-7","article-title":"Corticospinal tract damage in HHH syndrome: A metabolic cause of hereditary spastic paraplegia","volume":"14","author":"Olivieri","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/BF01800748","article-title":"The mechanism of hyperammonaemia and hyperornithinaemia in the syndrome of hyperornithinaemia, hyperammonaemia with homocitrullinuria","volume":"6","author":"Oyanagi","year":"1983","journal-title":"J. Inherit. Metab. Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"131","DOI":"10.3389\/fneur.2019.00131","article-title":"Hereditary spastic paraplegia is a common phenotypic finding in ARG1 deficiency, P5CS deficiency and HHH syndrome: Three inborn errors of metabolism caused by alteration of an interconnected pathway of glutamate and urea cycle metabolism","volume":"10","author":"Panza","year":"2019","journal-title":"Front. Neurol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1212\/wnl.57.5.911","article-title":"Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome","volume":"57","author":"Salvi","year":"2001","journal-title":"Neurology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/nmeth0810-575","article-title":"MutationTaster evaluates disease-causing potential of sequence alterations","volume":"7","author":"Schwarz","year":"2010","journal-title":"Nat. Methods"},{"key":"B17","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/s0387-7604(12)80222-1","article-title":"Abnormal urinary excretion of polyamines in HHH syndrome (hyperornithinemia associated with hyperammonemia and homocitrullinuria)","volume":"12","author":"Shimizu","year":"1990","journal-title":"Brain Dev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1186\/s13256-018-1794-9","article-title":"Late onset hyperornithinemia-hyperammonemia-homocitrullinuria syndrome - how web searching by the family solved unexplained unconsciousness: A case report","volume":"12","author":"Silfverberg","year":"2018","journal-title":"J. Med. Case Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1097\/00005176-199211000-00011","article-title":"Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: Presentation as acute liver disease with coagulopathy","volume":"15","author":"Smith","year":"1992","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"B20","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/8904_2011_71","article-title":"Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications","volume":"3","author":"Tezcan","year":"2012","journal-title":"JIMD Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1002\/1531-8249(200005)47:5<625::aid-ana10>3.0.co;2-q","article-title":"Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome","volume":"47","author":"Tsujino","year":"2000","journal-title":"Ann. Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1007\/8904_2018_132","article-title":"Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome causing severe neonatal hyperammonemia","volume":"44","author":"Wild","year":"2019","journal-title":"JIMD Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0196849","DOI":"10.1371\/journal.pone.0196849","article-title":"ENTPRISE-X: Predicting disease-associated frameshift and nonsense mutations","volume":"13","author":"Zhou","year":"2018","journal-title":"PloS one"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1004598\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T12:47:06Z","timestamp":1669294026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1004598\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":23,"alternative-id":["10.3389\/fgene.2022.1004598"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.1004598","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,24]]},"article-number":"1004598"}}