{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:53:02Z","timestamp":1787028782694,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T00:00:00Z","timestamp":1753228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japan Medical Association (JMA) Fund for Investigator-Initiated Trials","award":["CCT-A-2503"],"award-info":[{"award-number":["CCT-A-2503"]}]},{"name":"the Japan Medical Association (JMA) Fund for Investigator-Initiated Trials","award":["CCT-B-2602"],"award-info":[{"award-number":["CCT-B-2602"]}]},{"name":"the Japan Medical Association (JMA) Fund for Investigator-Initiated Trials","award":["CCT-C-2671"],"award-info":[{"award-number":["CCT-C-2671"]}]},{"name":"SBI Pharmaceuticals","award":["CCT-A-2503"],"award-info":[{"award-number":["CCT-A-2503"]}]},{"name":"SBI Pharmaceuticals","award":["CCT-B-2602"],"award-info":[{"award-number":["CCT-B-2602"]}]},{"name":"SBI Pharmaceuticals","award":["CCT-C-2671"],"award-info":[{"award-number":["CCT-C-2671"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>An explorative study was conducted to evaluate the efficacy and safety of 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (SPP-004) in 10 pediatric patients with Leigh syndrome (LS) aged 3\u201324 months in 10 institutions between December 2014 and July 2019. The patients were randomized and allocated to the SPP-004 or placebo group for a 12-week double-blind period, followed by a 12-week open-label period with SPP-004 and then a long-term study of up to 180 weeks. The efficacy and safety were evaluated using the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS) and adverse events (AEs), respectively. No significant differences were found between groups in NPMDS scores, but prolonged SPP-004 treatment stabilized or improved scores. During the initial double-blind phase, the serum lactate levels increased in the placebo group but not in the SPP-004 group. Over the period of prolonged treatment with SPP-004, the average serum lactate level gradually decreased to a normal level. One patient died due to heart failure, presumably due to an underlying disease. Overall, 7 out of 10 patients received SPP-004 without developing severe AEs until the termination of the long-term study. Given the severe symptoms and poor prognosis of pediatric LS, NPMDS scores were indicative of stabilization in pediatric LS patients treated with SPP-004.<\/jats:p>","DOI":"10.3390\/life15081168","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T14:22:44Z","timestamp":1753280564000},"page":"1168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy and Safety of 5-Aminolevulinic Acid Hydrochloride Combined with Sodium Ferrous Citrate in Pediatric Patients with Leigh Syndrome and Central Nervous System Disorders: An Initial Exploratory Trial with a Double-Blind Placebo-Controlled Period, Followed by an Open-Label Period and a Subsequent Long-Term Administration Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Yuichi","family":"Abe","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Saitama Medical University Hospital, Moroyama, Saitama 350-0495, Japan"},{"name":"Division of Neurology, National Center for Child Health and Development, Tokyo 157-8535, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4928-1160","authenticated-orcid":false,"given":"Toshimitsu","family":"Hamasaki","sequence":"additional","affiliation":[{"name":"The Biostatistics Center and Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD 20852, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2081-9449","authenticated-orcid":false,"given":"Jun","family":"Natsume","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nagoya University Hospital, Nagoya 466-8550, Japan"},{"name":"Department of Developmental Disability Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-0276","authenticated-orcid":false,"given":"Yukiko","family":"Mogami","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Osaka Women\u2019s and Children\u2019s Hospital, Osaka 594-1101, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Chiba Children\u2019s Hospital, Chiba 266-0007, Japan"},{"name":"Department of Pediatrics, Juntendo University, Tokyo 113-8431, Japan"},{"name":"Department of Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8431, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hokkaido University Hospital, Sapporo 060-8648, Japan"},{"name":"Department of Pediatrics, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Niigata City General Hospital, Niigata 950-1197, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Kumada","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu 183-0042, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1638-7882","authenticated-orcid":false,"given":"Ryuta","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ibaraki Children\u2019s Hospital, Mito 311-4145, Japan"},{"name":"Ibaraki Pediatric Education and Training Station, University of Tsukuba, Tsukuba 305-8576, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8831-1991","authenticated-orcid":false,"given":"Kenji","family":"Ihara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Oita University Hospital, Oita 879-5593, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6175-0313","authenticated-orcid":false,"given":"Takafumi","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nara Medical University Hospital, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3241-5502","authenticated-orcid":false,"given":"Yasushi","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Department of Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8431, Japan"},{"name":"Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Wako 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6568-9391","authenticated-orcid":false,"given":"Hitoshi","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Development Division, SBI Pharmaceuticals, Tokyo 106-6013, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiwamu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Development Division, SBI Pharmaceuticals, Tokyo 106-6013, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsugu","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Development Division, SBI Pharmaceuticals, Tokyo 106-6013, 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for the Future","volume":"181","author":"Russell","year":"2020","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/jimd.12104","article-title":"Recent advances in understanding the molecular genetic basis of mitochondrial disease","volume":"43","author":"Thompson","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10545-010-9081-y","article-title":"Biochemical diagnosis of mitochondrial disorders","volume":"34","author":"Rodenburg","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.mito.2008.05.003","article-title":"Neuroimaging of mitochondrial disease","volume":"8","author":"Saneto","year":"2008","journal-title":"Mitochondrion"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13023-020-1297-9","article-title":"Molecular basis of Leigh syndrome: A current look","volume":"15","author":"Vilarinho","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.nmd.2023.06.002","article-title":"258th ENMC international workshop Leigh syndrome spectrum: Genetic causes, natural history and preparing for clinical trials 25\u201327 March 2022, Hoofddorp, Amsterdam, The Netherlands","volume":"33","author":"Diodato","year":"2023","journal-title":"Neuromuscul. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1097\/MOP.0000000000000954","article-title":"Mitochondrial medicine therapies: Rationale, evidence, and dosing guidelines","volume":"32","author":"Barcelos","year":"2020","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ymgme.2020.10.002","article-title":"Clinical trials in mitochondrial disorders, an update","volume":"131","author":"Almannai","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/gim.2014.177","article-title":"Diagnosis and management of mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society","volume":"17","author":"Parikh","year":"2015","journal-title":"Genet. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1007\/s00415-018-9057-7","article-title":"Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research","volume":"265","author":"Koga","year":"2018","journal-title":"J. Neurol."},{"key":"ref_11","first-page":"17","article-title":"Arginine therapy in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes","volume":"23","author":"Ikawa","year":"2020","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.intimp.2014.02.003","article-title":"5-Aminolevulinic acid combined with ferrous iron enhances the expression of heme oxygenase-1","volume":"19","author":"Nishio","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shimura, M., Nozawa, N., Ogawa-Tominaga, M., Fushimi, T., Tajika, M., Ichimoto, K., Matsunaga, A., Tsuruoka, T., Kishita, Y., and Ishii, T. (2019). Effects of 5-aminolevulinic acid and sodium ferrous citrate on fibroblasts from individuals with mitochondrial diseases. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-46772-x"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ogura, S.-I., Maruyama, K., Hagiya, Y., Sugiyama, Y., Tsuchiya, K., Takahashi, K., Abe, F., Tabata, K., Okura, I., and Nakajima, M. (2011). The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in mouse liver. BMC Res. Notes, 4.","DOI":"10.1186\/1756-0500-4-66"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41591-018-0018-6","article-title":"Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome","volume":"24","author":"Shioda","year":"2018","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eabd9440","DOI":"10.1126\/sciadv.abd9440","article-title":"CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor\/ataxia syndrome","volume":"7","author":"Asamitsu","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Suzuki, H., Masuki, S., Morikawa, A., Ogawa, Y., Kamijo, Y.I., Takahashi, K., Nakajima, M., and Nose, H. (2018). Effects of 5-aminolevulinic acid supplementation on home-based walking training achievement in middle-aged depressive women: Randomized, double-blind, crossover pilot study. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-25452-2"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4236\/ijcm.2013.410A001","article-title":"The Role of 5-aminolevulinic acid (5-ALA) and sleep","volume":"4","author":"Perez","year":"2013","journal-title":"Int. J. Clin. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Aquino, R.K., Perez, M., Sil, P., Shintani, T., Harrigan, R., and Rodriguez, B. (2018). The Relationship of 5-Aminolevulinic Acid on Mood and Coping Ability in Prediabetic Middle Aged and Older Adults. Geriatrics, 3.","DOI":"10.3390\/geriatrics3020017"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., and Nakachi, Y. (2016). A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005679"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"L337","DOI":"10.1152\/ajplung.00482.2005","article-title":"Protoporphyrin IX generation from delta-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation","volume":"291","author":"Mingone","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.pdpdt.2010.06.003","article-title":"Reduction of cutaneous photosensitivity by application of ointment containing ferrous or cobaltous ions concomitant with the use of topical protoporphyrin IX precursors","volume":"7","author":"Juzenas","year":"2010","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hayashi, M., Fukuhara, H., Inoue, K., Shuin, T., Hagiya, Y., Nakajima, M., Tanaka, T., Ogura, S.-I., and Missirlis, F. (2015). The effect of iron ion on the specificity of photodynamic therapy with 5-aminolevulinic acid. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122351"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"797","DOI":"10.3892\/mco.2015.549","article-title":"Plasma protoporphyrin IX following administration of 5-aminolevulinic acid as a potential tumor marker","volume":"3","author":"Ota","year":"2015","journal-title":"Mol. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.nmd.2006.08.006","article-title":"A scale to monitor progression and treatment of mitochondrial disease in children","volume":"16","author":"Phoenix","year":"2006","journal-title":"Neuromuscul. Disord."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1136\/jnnp-2012-304426","article-title":"A guide to diagnosis and treatment of Leigh syndrome","volume":"85","author":"Baertling","year":"2014","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/ana.26260","article-title":"Natural History of Leigh Syndrome: A Study of Disease Burden and Progression","volume":"91","author":"Lim","year":"2022","journal-title":"Ann. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/jimd.12218","article-title":"Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis","volume":"43","author":"Ogawa","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S1474-4422(11)70155-7","article-title":"FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: A diagnostic study","volume":"10","author":"Suomalainen","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.cca.2012.09.019","article-title":"FGF21 in ataxia patients with spinocerebellar atrophy and mitochondrial disease","volume":"414","author":"Su","year":"2012","journal-title":"Clin. Chim. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1212\/WNL.0000000000003374","article-title":"FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders","volume":"87","author":"Lehtonen","year":"2016","journal-title":"Neurology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, Y., Li, S., Qiu, Y., Zhou, M., Chen, M., Hu, Y., Hong, S., Jiang, L., and Guo, Y. (2022). Circulating FGF21 and GDF15 as Biomarkers for Screening, Diagnosis, and Severity Assessment of Primary Mitochondrial Disorders in Children. Front. Pediatr., 10.","DOI":"10.3389\/fped.2022.851534"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/8\/1168\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:14:40Z","timestamp":1760033680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/8\/1168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,23]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["life15081168"],"URL":"https:\/\/doi.org\/10.3390\/life15081168","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,23]]}}}