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[[File:Autosomal recessive - en.svg|thumb|Urbach–Wiethe disease is inherited in an autosomal recessive manner.]]
'''ウルバッハ・ビーテ病'''(ウルバッハ・ビーテびょう、[[英語|英]]: Urbach–Wiethe diseases)は非常に稀な[[潜性]][[遺伝疾患]]で、症例はこの疾患が初めて報告されてから現在に至るまでおよそ400件程度である<ref>{{cite news| url = https://www.washingtonpost.com/news/speaking-of-science/wp/2015/01/20/meet-the-woman-who-cant-feel-fear/?tid=hpModule_9d3add6c-8a79-11e2-98d9-3012c1cd8d1e&hpid=z11| title = Meet the woman who can't feel fear - The Washington Post| newspaper = [[The Washington Post]]}}</ref><ref name=DiGiandomenico-etal-2006>{{cite journal |author1=DiGiandomenico S. |author2=Masi R. |author3=Cassandrini D. |author4=El-Hachem M. |author5=DeVito R. |author6=Bruno C. |author7=Santorelli F.M. | year = 2006 | title = Lipoid proteinosis: case report and review of the literature | journal = Acta Otorhinolaryngol Ital | volume = 26 | issue = 3 | pages = 162–7 | pmid = 17063986 | pmc = 2639960 }}</ref><ref name="Andrews">{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |year=2006 |isbn=978-0-7216-2921-6 |display-authors=etal}}</ref>。1929年にオーストリアのエーリヒ・ウルバッハとカミーロ・ビーテによって正式に報告されたが<ref>{{WhoNamedIt|synd|924}}</ref><ref>{{cite journal | author = Urbach E, Wiethe C | year = 1929 | title = Lipoidosis cutis et mucosae | journal = Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medizin | volume = 273 | issue = 2 | pages = 285–319 | doi = 10.1007/bf02158983 | s2cid = 42016927 | doi-access = free }}</ref>、実際の症例が確認されているのは1908年のことである<ref name="Caro-1978">{{cite journal | author = Caro I | year = 1978 | title = Lipoid proteinosis | journal = International Journal of Dermatology | volume = 17 | issue = 5 | pages = 388–93 | doi = 10.1111/ijd.1978.17.5.388 | pmid = 77850 | s2cid = 43544386 }}</ref><ref name="isbn0-7817-3742-7">{{cite book |author1=Lever, Walter F. |author2=Elder, David A. |title=Lever's histopathology of the skin |publisher=[[Lippincott Williams & Wilkins]] |___location=Hagerstwon, MD |year=2005 |pages=440 |isbn=978-0-7817-3742-5 }}</ref><ref>{{cite journal | author =Siebenmann F. | year = 1908 | title = Über Mitbeteilingung der Schleimhaut bei allgemeiner Hyperkeratose der Haut | journal = Arch Laryngol | volume = 20 | pages = 101–109 }}</ref>。
症状は個人差が大きく、声のかすれ、病斑や瘢痕、easily damaged skin with poor wound healing、肌の乾燥やしわ、瞼周辺の[[丘疹]]などが確認されている<ref name=Caro-1978/><ref name=Hamada-2002-C&ED>{{Cite journal | last1 = Hamada | first1 = T. | title = Lipoid proteinosis | journal = Clinical and Experimental Dermatology | volume = 27 | issue = 8 | pages = 624–629 | year = 2002 | doi = 10.1046/j.1365-2230.2002.01143.x| pmid = 12472532 | s2cid = 28344373 }}</ref><ref name=Appenzeller-etal-2006-Neuroimaging16/>。これらは肌や粘膜の肥厚によって引き起こされる。他にも[[側頭葉]]の脳組織の硬化によって[[てんかん]]や精神神経系の異常をきたす場合もある<ref name = Staut-1998>{{Cite journal | last1 = Staut | first1 = C. C. V. | last2 = Naidich | first2 = T. P. | title = Urbach-Wiethe Disease(Lipoid Proteinosis) | journal = Pediatric Neurosurgery | volume = 28 | issue = 4 | pages = 212–214 | year = 1998 | pmid = 9732251 | doi = 10.1159/000028653| s2cid = 46862405 }}</ref>。一般的には、命に関わったり、余命が短くなるようなことはないとされている<ref name=Appenzeller-etal-2006-Neuroimaging16>{{Cite journal | title = Amygdalae Calcifications Associated with Disease Duration in Lipoid Proteinosis | journal = Journal of Neuroimaging | volume = 16 | issue = 2 | pages = 154–156 | year = 2006 | pmid = 16629738 | doi = 10.1111/j.1552-6569.2006.00018.x| last1 = Appenzeller | first1 = S | last2 = Chaloult | first2 = E | last3 = Velho | first3 = P | last4 = De Souza | first4 = E. M. | last5 = Araújo | first5 = V. Z. | last6 = Cendes | first6 = F | last7 = Li | first7 = L. M. | s2cid = 30567332 }}</ref>。
ウルバッハ・ビーテ病は常染色体潜性であるため、疾患の保因者であっても症状が現れないことがある。この病気は[[1番染色体 (ヒト)|1番染色体]]の1q21に位置する[[細胞外マトリックス]]タンパク質1(ECM1)遺伝子の機能喪失型[[突然変異]]に起因する機能不全によって引き起こされる
Currently, there is no cure for Urbach–Wiethe disease although there are ways to individually treat many of its symptoms.<ref name=DiGiandomenico-etal-2006/> The discovery of the mutations of the ECM1 gene has opened the possibility of gene therapy or a recombinant ECM1 protein for Urbach–Wiethe disease treatment, but neither of these options are currently available. Some researchers are examining patients with Urbach–Wiethe disease to learn more about other conditions that exhibit similar neurological symptoms, such as [[autism]].
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Urbach–Wiethe disease is characterized by both [[neurological]] and dermatological symptoms.<ref name = Siebert-etal-2003>{{cite journal |author1=Siebert M. |author2=Markowitsch H.J. |author3=Bartel P. | year = 2003 | title = Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease | journal = Brain | volume = 126 | issue = 12 | pages = 2627–37 | doi = 10.1093/brain/awg271 | pmid = 12937075 | doi-access = free }}</ref><ref>{{cite journal |author1=Mallory S.B. |author2=Krafchick B.R. |author3=Holme S.A. |author4=Lenane P. |author5=Krafchik B.R. | year = 2005 | title = What syndrome is this? Urbach-Weithe syndrome (lipoid proteinosis) | journal = Pediatric Dermatology | volume = 22 | issue = 3 | pages = 266–7 | doi = 10.1111/j.1525-1470.2005.22321.x | pmid = 15916581 | s2cid = 44925736 }}</ref>
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Although [[symptom]]s can vary greatly between affected individuals, even those within the same family, symptoms normally begin in [[infancy]] and are typically a result of thickening skin and mucous membranes.<ref name=DiGiandomenico-etal-2006/> The first symptom is often a weak cry or a hoarse voice due to a thickening of the vocal cords. The [[hoarse]] voice can be one of the most striking clinical manifestations of the disease.<ref name=Hamada-2002-C&ED/> Lesions and scars also appear on the [[skin]], usually the [[face]] and the [[Anatomical terms of ___location#Proximal and distal|distal]] parts of the limbs.<ref name=Caro-1978/> This is often the result of poor wound healing and the scarring continues to increase as the patient ages, leaving the skin with a waxy appearance. Skin may be easily damaged as a result of only a minor trauma or injury, leaving many blisters and additional scars.<ref name=Appenzeller-etal-2006-Neuroimaging16/> The skin is also usually very dry and wrinkly. White or yellow [[Infiltration (medical)|infiltrates]] form on the lips, [[buccal mucosa]], [[tonsils]], [[uvula]], [[epiglottis]] and [[frenulum]] of the tongue.<ref name=Caro-1978/> This can lead to [[upper respiratory tract infection]] and sometimes requires [[tracheostomy]] to relieve the symptom.<ref name=Hamada-2002-C&ED/> Too much thickening of the frenulum can restrict tongue movement and may result in [[speech impediment]]s.<ref name=Thornton-etal-2008>{{cite journal |author1=Thornton H.B. |author2=Nel D. |author3=Thornton D. |author4=van Honk J. |author5=Baker G.A. |author6=Stein D.J. | year = 2008 | title = The neuropsychiatry and neuropsychology of lipoid proteinosis | journal = Journal of Neuropsychiatry and Clinical Neurosciences | volume = 20 | issue = 1 | pages = 86–92 | doi = 10.1176/jnp.2008.20.1.86 | pmid = 18305289 | doi-access = free }}</ref> Beading of the papules around the [[eyelid]]s is a very common symptom and is often used as part of a [[diagnosis]] of the [[disease]]. Some other [[dermatological]] symptoms that are sometimes seen but less common include [[hair loss]], [[parotitis]] and other [[Dentistry|dental]] abnormalities, [[corneal]] ulceration, and focal degeneration of the [[macula]].<ref name=Bahadir-etal-2006>{{cite journal |author1=Bahadir S. |author2=Cobanoglu U. |author3=Kapicioglu Z. |author4=Kandil S.T. |author5=Cimsit G. | display-authors = etal | year = 2006 | title = Lipoid proteinosis: A case with ophthalmological and psychiatric findings | journal = The Journal of Dermatology | volume = 33 | issue = 3 | pages = 215–8 | doi = 10.1111/j.1346-8138.2006.00049.x | pmid = 16620230 | s2cid = 34699559 }}</ref>
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Although the dermatological changes are the most obvious symptoms of Urbach–Wiethe disease, many patients also have neurological symptoms. About 50–75% of the diagnosed cases of Urbach–Wiethe disease also show bilateral symmetrical [[calcification]]s on the medial [[temporal lobe]]s.<ref>{{cite journal |author1=Hurlemann R. |author2=Wagner M. |author3=Hawellek B. |author4=Reich H. |author5=Pieperhoff P. |author6=Amunts K. | display-authors = etal | year = 2007 | title = Amygdala control of emotion-induced forgetting and remembering: Evidence from Urbach-Wiethe disease | journal = Neuropsychologia | volume = 45 | issue = 5 | pages = 877–84 | doi = 10.1016/j.neuropsychologia.2006.08.027 | pmid = 17027866 | hdl = 21.11116/0000-0001-B8EF-3 | s2cid = 4101263 | hdl-access = free }}</ref> These calcifications often affect the [[amygdala]] and the periamygdaloid [[gyrus|gyri]].<ref name = Staut-1998/> The amygdala is thought to be involved in processing biologically relevant stimuli and in emotional long-term memory, particularly those associated with [[fear]], and both [[Positron emission tomography|PET]] and [[Magnetic resonance imaging|MRI]] scans have shown a correlation between amygdala activation and episodic memory for strongly emotional stimuli.<ref name=Siebert-etal-2003/> Therefore, Urbach–Wiethe disease patients with calcifications and [[lesions]] in these regions may suffer impairments in these systems. These calcifications are the result of a buildup of [[calcium]] deposits in the [[blood vessel]]s within this brain region. Over time, these vessels [[Atherosclerosis|harden]] and the tissue they are a part of dies, causing lesions. The amount of calcification is often related to disease duration.<ref name=Appenzeller-etal-2006-Neuroimaging16/> The true prevalence of these calcifications is difficult to accurately state as not all patients undergo [[neuroimaging|brain imaging]]. Some patients also exhibit [[epilepsy]] and neuropsychiatric abnormalities. Epilepsy symptoms could begin with light anxiety attacks and can be controlled with anti-epileptic medications.<ref name=Appenzeller-etal-2006-Neuroimaging16/> Other patients present with symptoms similar to schizophrenia while some suffer from mood, [[anxiety]], and psychotic disorders.<ref name = Thornton-etal-2008/><ref name = Cinaz-1993>{{cite journal |author1=Cinaz P. |author2=Guvenir T. |author3=Gonlusen G. | year = 1993 | title = Lipoid proteinosis: Urbach-Wiethe disease | journal = Acta Paediatrica | volume = 82 | issue = 11 | pages = 892–3 | doi = 10.1111/j.1651-2227.1993.tb12590.x | pmid = 8241657 | s2cid = 31104438 }}</ref> [[File:Chromosome 1.svg|frame|Chromosome 1, where the ECM1 mutation occurs at 1[[Centromere#Position|q]]21]]
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Researchers have mapped Urbach–Wiethe disease to [[chromosome 1]] at 1q21 and specifically identified the extracellular matrix protein 1 ([[ECM1]]) gene as the gene containing mutations that can lead to the development of the condition.<ref name = Hamada-etal-2002/> At this point, 41 different mutations within ECM1 have been reported to lead to Urbach–Wiethe disease.<ref name = Chan-etal-2007/> These were all [[zygosity|homozygous]] loss-of-function mutations (i.e. [[Nonsense mutation|nonsense]], [[Frameshift mutation|frameshift]] or internal [[Deletion mutation|deletions]]).<ref name=Hamada-2002-C&ED/> It is an [[autosomal recessive]] condition,<ref name=DiGiandomenico-etal-2006/><ref name=Chan-etal-2007/> requiring two mutated copies of the ECM1 gene to cause the disease.<ref>{{cite journal |vauthors = Morovvati S, Farshadyeganeh P, Hamidizadeh M, Morovvati Z, Mohammadi SD|date=August 2018 |title = Mutation Analysis of ECM1 Gene in Two Related Iranian Patients Affected by Lipoid Proteinosis|url= https://www.researchgate.net/publication/327250566|journal= Acta Medica Iranica |volume=56 |issue=7 |pages=474–477 |access-date= 1 September 2020}}</ref>
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Non-contrast [[computed tomography|CT scans]] can image calcifications, but this is not typically used as a means of diagnosing the disease. This is partly due to the fact that not all Urbach-Wiethe patients exhibit calcifications, but also because similar lesions can be formed from other diseases such as [[herpes simplex]] and [[encephalitis]]. The discovery of mutations within the ECM1 gene has allowed the use of genetic testing to confirm initial clinical diagnoses of Urbach–Wiethe disease. It also allows doctors to better distinguish between Urbach–Wiethe disease and other similar diseases not caused by mutations in ECM1.{{cn|date=October 2021}}
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Currently, there is no cure for Urbach–Wiethe disease although there are some ways to individually treat many of its symptoms. There has been some success with oral [[dimethyl sulfoxide]] (DMSO) and intralesional [[heparin]], but this is not true in all cases.<ref name=Hamada-2002-C&ED/><ref name = Cinaz-1993/> D-[[penicillamine]] has also shown promise, but has yet to have been used extensively.<ref name = Chan-etal-2007/> There are also some reports of patients being treated with [[etretinate]], a drug typically prescribed to treat [[psoriasis]].<ref name=Bahadir-etal-2006/> In some cases, calcifications in the brain can lead to abnormal electrical activity among neurons. Some patients are given anti-seizure medication to help deal with these abnormalities. [[Tracheostomy]] is often used to relieve upper respiratory tract infections. [[Carbon dioxide]] laser surgery of thickened [[vocal folds|vocal cords]] and beaded eyelid papules have improved these symptoms for patients.<ref name=Hamada-2002-C&ED/> The discovery of the mutations of the ECM1 gene has opened the possibility of gene therapy or a [[Recombinant DNA|recombinant]] EMC1 protein for Urbach–Wiethe disease treatment, but neither of these two options are currently available.{{cn|date=October 2021}}
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Urbach–Wiethe disease is very rare; there are fewer than 300 reported cases in [[medical literature]].<ref name=DiGiandomenico-etal-2006/> Although Urbach–Wiethe disease can be found worldwide, almost a quarter of reported diagnoses are in [[South Africa]].<ref name=DiGiandomenico-etal-2006/> Many of these are in patients of [[Dutch people|Dutch]], [[German people|German]], and [[Khoisan]] ancestry.<ref name=DiGiandomenico-etal-2006/><ref name=Hamada-etal-2002/> This high frequency is thought to be due to the [[founder effect]].<ref name = Chan-etal-2007/> Due to its recessive genetic cause and the ability to be a carrier of the disease without symptoms, Urbach–Wiethe disease often runs in families. In some regions of South Africa, up to one in 12 individuals may be carriers of the disease.<ref name=Hamada-2002-C&ED/> Most of the case studies involving Urbach–Wiethe disease patients involve only one to three cases and these cases are often in the same family. Due to its low incidence, it is difficult to find a large enough number of cases to adequately study the disease.{{cn|date=October 2021}}
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In 1908, what appears to be the first case of Urbach–Wiethe disease was reported by [[Friedrich Siebenmann (otolaryngologist)|Friedrich Siebenmann]], a professor of [[otolaryngology]] in [[Basel]], [[Switzerland]]. In 1925, [[Friedrich Miescher]], a Swiss dermatologist, reported on three similar patients.<ref name=Caro-1978/> An official report of Urbach–Wiethe disease was first described in 1929 by a Viennese dermatologist and otorhinolaryngologist, Urbach and Wiethe.<ref name = Hamada-etal-2002/> Its original name of 'lipoidosis cutis et mucosae' was changed to 'lipoid proteinosis cutis et mucosae' due to Urbach's belief that the condition was due to abnormal [[lipid]] and [[protein]] deposits within the tissues.<ref name = Hamada-etal-2002/> Some have debated as to whether or not the disease is actually a form of [[mucopolysaccharidosis]], [[amyloidosis]], or even [[porphyria]]. The discovery of the Urbach–Wiethe disease causing mutation to the ECM1 gene has now provided a definitive way to differentiate Urbach–Wiethe disease from these other conditions.<ref name=Hamada-2002-C&ED/>
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* [[Klüver–Bucy syndrome]]
* [[S.M. (patient)]]
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* [[List of radiographic findings associated with cutaneous conditions]]
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{{Reflist}}
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{{Medical resources
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