{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T21:43:23Z","timestamp":1771969403866,"version":"3.50.1"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"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. Neurol."],"abstract":"<jats:p>RNA polymerase III (POLR3)-related leukodystrophy is an autosomal recessive form of leukodystrophy caused by homozygous or compound heterozygous mutations of the RNA polymerase III subunit genes, including subunit A (<jats:italic>POLR3A<\/jats:italic>). With respect to the manifestation triad, hypomyelination, hypodontia, and hypogonadotropic hypogonadism, it is also known as 4H leukodystrophy. Here, we report a 41-year-old woman of POLR3-related leukodystrophy by carrying compound heterozygous pathogenic variants of c.2554A&amp;gt;G (p.M852V) and c.2668G&amp;gt;T (p.V890F) in the <jats:italic>POLR3A<\/jats:italic> gene. She was amenorrheic and became a wheelchair user from the age of 15 years and suffered from multiple episodes of pathologic fractures, starting with a subtrochanteric fracture of the right femur after a tonic seizure at age 30 years. Head magnetic resonance imaging demonstrated hypomyelination and atrophies of the cerebellum, brainstem, and corpus callosum. Laboratory examination revealed a marked decrease of gonadotropins and estrogen, low bone density, and high bone resorption markers. Administration of anti-receptor activator of nuclear factor kappa-B ligand monoclonal antibody restored bone resorption markers to a normal level and prevented further pathological bone fractures. Our case emphasizes that osteoporosis should be recognized as a potential but serious complication in POLR3-related leukodystrophy. It may be feasible to prevent pathologic fractures by intensive osteoporosis therapy after endocrinological examinations and evaluation of bone metabolism.<\/jats:p>","DOI":"10.3389\/fneur.2021.622355","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T06:02:15Z","timestamp":1614319335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Case Report: Severe Osteoporosis and Preventive Therapy in RNA Polymerase III-Related Leukodystrophy"],"prefix":"10.3389","volume":"12","author":[{"given":"Soma","family":"Furukawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misako","family":"Kunii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Doi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naohide","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya","family":"Ogura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Hirabuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Itoh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiaki","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahisa","family":"Katsuno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.ajhg.2011.07.014","article-title":"Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy","volume":"89","author":"Bernard","year":"2011","journal-title":"Am J Hum Genet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.ajhg.2011.10.003","article-title":"Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal recessive hypomyelinating leukoencephalopathy","volume":"89","author":"Saitsu","year":"2011","journal-title":"Am J Hum Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1212\/01.wnl.0000247666.28904.35","article-title":"Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia","volume":"67","author":"Timmons","year":"2006","journal-title":"Neurology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/cge.12456","article-title":"Genetic epidemiology of tooth agenesis in Japan: a population- and family-based study","volume":"88","author":"Machida","year":"2015","journal-title":"Clin Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e660","DOI":"10.1210\/clinem\/dgaa700","article-title":"Endocrine and growth abnormalities in 4H leukodystrophy caused by variants in POLR3A, POLR3B, and POLR1C","volume":"106","author":"Pelletier","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B6","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1111\/cge.13371","article-title":"Genetic analysis of adult leukoencephalopathy patients using a custom-designed gene panel","volume":"94","author":"Kunii","year":"2018","journal-title":"Clin Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1212\/WNL.0000000000001002","article-title":"Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations","volume":"83","author":"Wolf","year":"2014","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.11477\/mf.1416200603","article-title":"Case of Pol III-related leukodystrophy with homozygous mutation in POLR3A","volume":"68","author":"Shima","year":"2016","journal-title":"Brain Nerve"},{"key":"B9","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1136\/practneurol-2013-000669","article-title":"Bilateral neck of femur fractures secondary to seizure","volume":"13","author":"Brennan","year":"2013","journal-title":"Pract Neurol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"bcr2015211445","DOI":"10.1136\/bcr-2015-211445","article-title":"Seizure induced polytrauma; 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