{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T17:58:13Z","timestamp":1771264693054,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hypophosphatasia (HPP) is caused by pathogenic variant(s) of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Diminished enzyme activity results in elevated serum concentrations of pyridoxal 5\u2032-phosphate (PLP), the main circulating form of vitamin B6. Neuropathy has been associated with HPP, but the prevalence, pathogenesis, and symptoms remain inadequately understood. Here, we describe 5 adult HPP patients with symptoms suggestive of neuropathic pain, and speculate about potential mechanisms, related to the vitamin B6 metabolism. They reported burning pain sensations, primarily in their lower extremities. One patient was diagnosed with nociceptive pain, but he also experienced numbness and tingling sensations in his hands and feet. All patients exhibited reduced serum ALP levels along with elevated levels of serum vitamin B6 and urine phosphoethanolamine, aligning with the diagnosis of HPP. Regarding treatment, one patient received asfotase alfa which had a remarkable effect with her pain significantly decreasing already within 3\u00a0wk of starting the therapy. Another patient received nortriptyline and participated in a rehabilitation program, leading to a reduction in pain within 10\u00a0mo. Gabapentin appeared to reduce the pain in one patient, although her symptoms did not fully disappear. Mechanistically, TNSALP is essential for the transformation of PLP, the active form of vitamin B6, into pyridoxal, which is required for crossing the cell membrane and the blood-brain barrier. The deficient catalytic activity of TNSALP could lead to PLP excess extracellularly or deficiency intracellularly. Lack of PLP in the brain may result in changes to metabolites, such as adenosine, which is involved in myelin synthesis. We hypothesize that neuropathic pain could be caused by defective myelination. Alternatively, several cases of polyneuropathy linked to vitamin B6 supplementation have been reported, with a mechanism that may resemble the excess of PLP extracellularly, although the exact mechanism remains unclear.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf086","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T08:48:34Z","timestamp":1749718114000},"source":"Crossref","is-referenced-by-count":1,"title":["Hypophosphatasia and neuropathic pain: related to vitamin B6 metabolism?"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5277-6202","authenticated-orcid":false,"given":"Zografia","family":"Zervou","sequence":"first","affiliation":[{"name":"Erasmus MC Bone Center, Department of Internal Medicine, Erasmus University Medical Center , 3015 GD, Rotterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6938-065X","authenticated-orcid":false,"given":"Evert F S","family":"van Velsen","sequence":"additional","affiliation":[{"name":"Erasmus MC Bone Center, Department of Internal Medicine, Erasmus University Medical Center , 3015 GD, Rotterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9186-3423","authenticated-orcid":false,"given":"M Carola","family":"Zillikens","sequence":"additional","affiliation":[{"name":"Erasmus MC Bone Center, Department of Internal Medicine, Erasmus University Medical Center , 3015 GD, Rotterdam ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"issue":"6","key":"2025071511064735200_ref1","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1001\/archpedi.1948.02030020840003","article-title":"Hypophosphatasia: a new developmental anomaly","volume":"75","author":"Rathbun","year":"1948","journal-title":"Am J Dis Child"},{"issue":"10","key":"2025071511064735200_ref2","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1002\/jbmr.3226","article-title":"Hypophosphatasia in adults: clinical assessment and treatment considerations","volume":"32","author":"Shapiro","year":"2017","journal-title":"J Bone Miner Res"},{"key":"2025071511064735200_ref3","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.bone.2017.02.011","article-title":"Hypophosphatasia: an overview for 2017","volume":"102","author":"Whyte","year":"2017","journal-title":"Bone."},{"issue":"4","key":"2025071511064735200_ref4","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nrendo.2016.14","article-title":"Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment","volume":"12","author":"Whyte","year":"2016","journal-title":"Nat Rev Endocrinol"},{"issue":"1","key":"2025071511064735200_ref5","first-page":"1","article-title":"Neonatal vitamin-responsive epileptic encephalopathies","volume":"33","author":"Gospe","year":"2010","journal-title":"Chang Gung Med J"},{"issue":"3","key":"2025071511064735200_ref6","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3109\/10408369109106862","article-title":"Hypophosphatasia and the extracellular metabolism of inorganic pyrophosphate: clinical and laboratory aspects","volume":"28","author":"Caswell","year":"1991","journal-title":"Crit Rev Clin Lab Sci"},{"issue":"1","key":"2025071511064735200_ref7","doi-asserted-by":"publisher","first-page":"116204","DOI":"10.1016\/j.bone.2021.116204","article-title":"Hypophosphatasia: vitamin B6 status of affected children and adults","volume":"154","author":"Whyte","year":"2022","journal-title":"Bone"},{"issue":"4","key":"2025071511064735200_ref8","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1172\/JCI113440","article-title":"Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5\u2032-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase","volume":"81","author":"Whyte","year":"1988","journal-title":"J Clin Invest"},{"issue":"3","key":"2025071511064735200_ref9","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1297\/cpe.27.179","article-title":"A case of perinatal hypophosphatasia with a novel mutation in the ALPL gene: clinical course and review of the literature","volume":"27","author":"Oyachi","year":"2018","journal-title":"Clin Pediatr Endocrinol"},{"key":"2025071511064735200_ref10","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/8904_2013_217","article-title":"Infantile hypophosphatasia secondary to a novel compound heterozygous mutation presenting with pyridoxine-responsive seizures","volume":"11","author":"Belachew","year":"2013","journal-title":"JIMD Rep"},{"issue":"3","key":"2025071511064735200_ref11","doi-asserted-by":"publisher","first-page":"360","DOI":"10.4274\/jcrpe.2798","article-title":"Pyridoxine-responsive seizures in infantile hypophosphatasia and a novel homozygous mutation in ALPL gene","volume":"8","author":"G\u00fczel Nur","year":"2016","journal-title":"J Clin Res Pediatr Endocrinol"},{"issue":"6","key":"2025071511064735200_ref12","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1016\/j.bone.2007.01.020","article-title":"Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T&gt;C, p.M226T; c.1112C&gt;T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene","volume":"40","author":"Baumgartner-Sigl","year":"2007","journal-title":"Bone"},{"issue":"1\u20132","key":"2025071511064735200_ref13","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.ymgme.2018.07.006","article-title":"Pyridoxal 5\u2032-phosphate and related metabolites in hypophosphatasia: effects of enzyme replacement therapy","volume":"125","author":"Akiyama","year":"2018","journal-title":"Mol Genet Metab"},{"key":"2025071511064735200_ref14","article-title":"Neuropathy","volume-title":"StatPearls Publishing LLC","author":"Hammi","year":"2025"},{"issue":"1","key":"2025071511064735200_ref15","doi-asserted-by":"publisher","first-page":"5472","DOI":"10.1038\/ncomms6472","article-title":"Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice","volume":"5","author":"Gritsch","year":"2014","journal-title":"Nat Commun"},{"issue":"6","key":"2025071511064735200_ref16","doi-asserted-by":"publisher","first-page":"e786","DOI":"10.1097\/j.pain.0000000000002576","article-title":"Chronic nociplastic and neuropathic pain: how do they differentiate?","volume":"163","author":"Shala","year":"2022","journal-title":"Pain"},{"issue":"5","key":"2025071511064735200_ref17","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1080\/00325481.2016.1188319","article-title":"Rethinking chronic pain in a primary care setting","volume":"128","author":"Stanos","year":"2016","journal-title":"Postgrad Med"},{"issue":"15","key":"2025071511064735200_ref18","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10153203","article-title":"Nociplastic pain criteria or recognition of central sensitization? Pain phenotyping in the past, present and future","volume":"10","author":"Nijs","year":"2021","journal-title":"J Clin Med"},{"issue":"6","key":"2025071511064735200_ref19","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s00223-024-01214-3","article-title":"Neuropathic and nociplastic pain profiles are common in adult chronic nonbacterial osteitis (CNO)","volume":"114","author":"Leerling","year":"2024","journal-title":"Calcif Tissue Int"},{"issue":"2","key":"2025071511064735200_ref20","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/s00198-018-4691-6","article-title":"Neurological symptoms in Hypophosphatasia","volume":"30","author":"Colazo","year":"2019","journal-title":"Osteoporos Int"},{"issue":"6","key":"2025071511064735200_ref21","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1111\/jnc.13950","article-title":"Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis","volume":"140","author":"Cruz","year":"2017","journal-title":"J Neurochem"},{"issue":"4","key":"2025071511064735200_ref22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2024.104915","article-title":"Impressive clinical improvement and disappearance of neuropathic pain in an adult patient with hypophosphatasia treated with asfotase alfa","volume":"68","author":"Zervou","year":"2024","journal-title":"Eur J Med Genet"},{"issue":"4","key":"2025071511064735200_ref23","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1590\/1806-9282.63.04.307","article-title":"Alternative option for osteogenesis imperfecta and trigeminal neuralgia","volume":"63","author":"Ruschel","year":"2017","journal-title":"Rev Assoc Med Bras (1992)"},{"issue":"6","key":"2025071511064735200_ref24","doi-asserted-by":"publisher","first-page":"e2258","DOI":"10.1210\/clinem\/dgac120","article-title":"Neuropathic-like pain in fibrous dysplasia\/McCune-Albright syndrome","volume":"107","author":"Spencer","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"2025071511064735200_ref25","doi-asserted-by":"publisher","first-page":"104866","DOI":"10.1016\/j.ejmg.2023.104866","article-title":"Serum alkaline phosphatase can be elevated in patients with hypophosphatasia due to liver disease","volume":"66","author":"van Velsen","year":"2023","journal-title":"Eur J Med Genet"},{"issue":"5","key":"2025071511064735200_ref26","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.bone.2015.05.005","article-title":"Enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia","volume":"78","author":"Liu","year":"2015","journal-title":"Bone"},{"issue":"12","key":"2025071511064735200_ref27","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1359\/jbmr.1999.14.12.2015","article-title":"Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia","volume":"14","author":"Fedde","year":"1999","journal-title":"J Bone Miner Res"},{"issue":"12","key":"2025071511064735200_ref28","first-page":"835","article-title":"[Neonatal discovery of hypophosphatasia. Bone improvement. Fatal convulsant encephalopathy] Hypophosphatasie a r\u00e9v\u00e9lation n\u00e9o-natale. Am\u00e9lioration osseuse. Enc\u00e9phalopathie convulsivante fatale","volume":"14","author":"B\u00e9thenod","year":"1967","journal-title":"Ann Pediatr (Paris)"},{"key":"2025071511064735200_ref29","first-page":"355","article-title":"Effects of pyridoxine on neonatal hypophosphatasia","volume":"9","author":"Sia","year":"1975","journal-title":"Pediatr Res"},{"issue":"3","key":"2025071511064735200_ref30","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1177\/088307380201700314","article-title":"Pyridoxine-dependent seizures associated with hypophosphatasia in a newborn","volume":"17","author":"Lahorgue Nunes","year":"2002","journal-title":"J Child Neurol"},{"issue":"1","key":"2025071511064735200_ref31","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1023\/A:1015121414782","article-title":"Glu274Lys\/Gly309Arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions","volume":"25","author":"Litmanovitz","year":"2002","journal-title":"J Inherit Metab Dis"},{"issue":"3","key":"2025071511064735200_ref32","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.pediatrneurol.2003.08.003","article-title":"A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia","volume":"30","author":"Yamamoto","year":"2004","journal-title":"Pediatr Neurol"},{"issue":"5","key":"2025071511064735200_ref33","first-page":"319","article-title":"Neonatal hypophosphatasia and seizures. 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