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ウルバッハ・ビーテ病
別称 リポイドタンパク症、真皮・粘膜ヒアリン沈着症
HE染色によるウルバッハ・ビーテ病の皮膚生検
概要
診療科 内分泌学
分類および外部参照情報
ICD-10 E78.8
ICD-9-CM 272.8
OMIM 247100
DiseasesDB 30808
MeSH D008065
ウルバッハ・ビーテ病は潜性遺伝のため、疾患の保因者同士の子供でも4分の1の確率でしか症状が現れない。

ウルバッハ・ビーテ病 (ウルバッハ・ビーテびょう、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[1][2][3]。1908年に初めて症例が確認され[4][5][6]、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。[7][8]

症状は個人差が大きく、声のかすれ、病斑や瘢痕、皮膚の自然治癒力の低下、肌の乾燥やしわ、瞼周辺の丘疹などが確認されている[4][9][10]。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りてんかんや精神神経系の異常をきたす場合もある[11]。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[10]。

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よって引き起こされる[12]。皮膚に関する症状は主に真皮におけるヒアリン（英語版）の分泌や皮膚の基底膜の肥厚が要因となる[9]。診断は特に瞼周辺の丘疹といった臨床症状によってなされる。ECM1遺伝子内の突然変異が発見されたことで、最初の臨床診断を遺伝子診断で確認できるようになった。また、PAS染色や免疫組織化学染色(IHC)も診断に使用されることがある[4][13]。

現在この疾患に対する根本的な治療法は確立されていないが、各々の症状を対処することは可能である[2]。原因がECM1遺伝子内の突然変異だと判明したことで、遺伝子治療やECM1遺伝子の再結合などの可能性が拓けてきたが、どちらも実現には至っていない。

症状と兆候

ウルバッハ・ビーテ病の症状はおおまかに皮膚に関する症状と、神経系に関する症状に分類される[14][15]。

皮膚

症状は罹患者によって、また同じ家族内であっても大きく異なるが、一般的に症状は乳幼児期に始まり、皮膚や粘膜の肥厚などが挙げられる[2]。肥厚の程度にもよるが、これは身体の至る箇所で合併症を引き起こす可能性がある。例えば声帯の肥厚によってかすれ声になることがあり、この疾患において最も顕著な臨床症状のひとつである[9]。他にも顔面や手足には病斑や瘢痕ができ、これは加齢とともに増え続ける[4]。口唇、頬粘膜、扁桃、口蓋垂、舌小帯などにおいては、白色または黄色の浸潤が形成され[4]、これが悪化すれば上気道感染症を引き起こし、症状を緩和するために気管切開が必要になる場合がある[9]。また、舌小帯が肥厚しすぎると舌の動きが制限され、言語障害を引き起こす可能性もある[16]。眼瞼周囲には丘疹が確認され、これは非常に一般的な症状であり、しばしば本疾患の診断の一部として用いられる。皮膚は自然治癒力が低下しており、軽い外傷や怪我で簡単に損傷し、水ぶくれや傷跡を残すことがある[10]。その他の皮膚症状としては、脱毛、耳下腺炎や歯の異常、角膜潰瘍、黄斑の局所変性などが見られるが、あまり一般的ではない[17]。

神経系

ウルバッハ・ビーテ病の明らかな症状は皮膚に関する変化であるが、患者の多くは神経系にも症状が現れていることが多い。患者のうち、およそ50～75%には内側側頭葉における両側対称性の石灰化が確認されており、これはしばしば扁桃体とその周囲の脳回に影響を及ぼす[11]。扁桃体は、生物学的に関連する刺激の処理と情動的長期記憶、特に恐怖に関連するものに関与していると考えられており、PETとMRI検査の両方で、扁桃体の活性化と強く情動的な刺激に対するエピソード記憶との相関が示されている[14]。したがって、これらの領域に石灰化および病変を認める本疾患は、これらのシステムに障害を来す可能性がある。これらの石灰化は、この脳領域内の血管にカルシウムが蓄積した結果である。時間の経過とともに、これらの血管は硬化し、その一部である組織が死滅して病変を引き起こす。石灰化の量はしばしば罹病期間と関連している[10]。すべての患者が脳画像検査を受けるわけではないので、これらの石灰化の真の有病率を正確に示すことは困難である。また、てんかんや精神神経系の異常を示す患者もいる。てんかんの症状は軽い不安発作から始まり、抗てんかん薬でコントロールできる[10]。精神分裂病に似た症状を示す患者もいれば、気分障害、不安障害、精神病性障害に苦しむ患者もいる[16][18]。

ウルバッハ・ビーテ病の明らかな症状は皮膚に関する変化であるが、患者の多くは神経系にも症状が現れていることが多い。およそ50～75％の患者には側頭葉の内側にある扁桃体の石灰化が確認されている[19]。この石灰化は扁桃体の血管にカルシウムが蓄積することから始まり、時間の経過とともに血管が硬化し、その一部の組織が死滅して病変を起こすことで引き起こされる。

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 calcifications on the medial temporal lobes. These calcifications often affect the amygdala and the periamygdaloid gyri. 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 PET and MRI scans have shown a correlation between amygdala activation and episodic memory for strongly emotional stimuli. 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 vessels within this brain region. Over time, these vessels harden and the tissue they are a part of dies, causing lesions. The amount of calcification is often related to disease duration. The true prevalence of these calcifications is difficult to accurately state as not all patients undergo 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. Other patients present with symptoms similar to schizophrenia while some suffer from mood, anxiety, and psychotic disorders.

 
Chromosome 1, where the ECM1 mutation occurs at 1q21

原因

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.[12] At this point, 41 different mutations within ECM1 have been reported to lead to Urbach–Wiethe disease.[13] These were all homozygous loss-of-function mutations (i.e. nonsense, frameshift or internal deletions).[9] It is an autosomal recessive condition,[2][13] requiring two mutated copies of the ECM1 gene to cause the disease.[20]

ECM1 codes for a glycoprotein of previously unknown origin. The discovery that the loss of ECM1 expression leads to the symptoms associated with Urbach–Wiethe disease suggests that ECM1 may contribute to skin adhesion, epidermal differentiation, and wound healing and scarring.[12] It is also thought to play a role in endochondral bone formation, tumor biology, endothelial cell proliferation and blood vessel formation.[9]

The dermatological symptoms are caused by a buildup of a hyaline material in the dermis and the thickening of the basement membranes in the skin.[9] The nature of this material is unknown, but researchers have suggested that it may be a glycoprotein, a glycolipid, an acid mucopolysaccharide, altered collagen or elastic tissue.[4]

Diagnosis

Urbach–Wiethe disease is typically diagnosed by its clinical dermatological manifestations, particularly the beaded papules on the eyelids. Doctors can also test the hyaline material with a periodic acid-Schiff (PAS) staining, as the material colors strongly for this stain.[4]

Immunohistochemical skin labeling for antibodies for the ECM1 protein as labeling has been shown to be reduced in the skin of those affected by Urbach–Wiethe disease.[13] Staining with anti-type IV collagen antibodies or anti-type VII collagen antibodies reveals bright, thick bands at the dermoepidermal junction.[9]

Non-contrast 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.[要出典]

治療

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.[9][18] D-penicillamine has also shown promise, but has yet to have been used extensively.[13] There are also some reports of patients being treated with etretinate, a drug typically prescribed to treat psoriasis.[17] 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 cords and beaded eyelid papules have improved these symptoms for patients.[9] The discovery of the mutations of the ECM1 gene has opened the possibility of gene therapy or a recombinant EMC1 protein for Urbach–Wiethe disease treatment, but neither of these two options are currently available.[要出典]

Prognosis

Urbach–Wiethe disease is typically not a life-threatening condition.[2] The life expectancy of these patients is normal as long as the potential side effects of thickening mucosa, such as respiratory obstruction, are properly addressed.[10] Although this may require a tracheostomy or carbon dioxide laser surgery, such steps can help ensure that individuals with Urbach–Wiethe disease are able to live a full life. Oral dimethyl sulfoxide (DMSO) has been shown to reduce skin lesions, helping to minimize discomfort for these individuals.[9]

Incidence

Urbach–Wiethe disease is very rare; there are fewer than 300 reported cases in medical literature.[2] Although Urbach–Wiethe disease can be found worldwide, almost a quarter of reported diagnoses are in South Africa.[2] Many of these are in patients of Dutch, German, and Khoisan ancestry.[2][12] This high frequency is thought to be due to the founder effect.[13] 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.[9] 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.[要出典]

歴史

In 1908, what appears to be the first case of Urbach–Wiethe disease was reported by Friedrich Siebenmann, a professor of otolaryngology in Basel, Switzerland. In 1925, Friedrich Miescher, a Swiss dermatologist, reported on three similar patients.[4] An official report of Urbach–Wiethe disease was first described in 1929 by a Viennese dermatologist and otorhinolaryngologist, Urbach and Wiethe.[12] 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.[12] 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.[9]

参照

脚注

  1. ^ “Meet the woman who can't feel fear - The Washington Post”. The Washington Post. 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 
  2. ^ a b c d e f g h DiGiandomenico S.; Masi R.; Cassandrini D.; El-Hachem M.; DeVito R.; Bruno C.; Santorelli F.M. (2006). “Lipoid proteinosis: case report and review of the literature”. Acta Otorhinolaryngol Ital 26 (3): 162–7. PMC 2639960. PMID 17063986. https://pmc.ncbi.nlm.nih.gov/articles/PMC2639960/. 
  3. ^ James, William D.、Berger, Timothy G.『Andrews' Diseases of the Skin: clinical Dermatology』Saunders Elsevier、2006年。ISBN 978-0-7216-2921-6。 
  4. ^ a b c d e f g h Caro I (1978). “Lipoid proteinosis”. International Journal of Dermatology 17 (5): 388–93. doi:10.1111/ijd.1978.17.5.388. PMID 77850. 
  5. ^ Lever, Walter F.; Elder, David A. (2005). Lever's histopathology of the skin. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 440. ISBN 978-0-7817-3742-5 
  6. ^ Siebenmann F. (1908). “Über Mitbeteilingung der Schleimhaut bei allgemeiner Hyperkeratose der Haut”. Arch Laryngol 20: 101–109. 
  7. ^ synd/924 - Who Named It?
  8. ^ Urbach E, Wiethe C (1929). “Lipoidosis cutis et mucosae”. Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medizin 273 (2): 285–319. doi:10.1007/bf02158983. 
  9. ^ a b c d e f g h i j k l m Hamada, T. (2002). “Lipoid proteinosis”. Clinical and Experimental Dermatology 27 (8): 624–629. doi:10.1046/j.1365-2230.2002.01143.x. PMID 12472532. 
  10. ^ a b c d e f Appenzeller, S; Chaloult, E; Velho, P; De Souza, E. M.; Araújo, V. Z.; Cendes, F; Li, L. M. (2006). “Amygdalae Calcifications Associated with Disease Duration in Lipoid Proteinosis”. Journal of Neuroimaging 16 (2): 154–156. doi:10.1111/j.1552-6569.2006.00018.x. PMID 16629738. 
  11. ^ a b Staut, C. C. V.; Naidich, T. P. (1998). “Urbach-Wiethe Disease(Lipoid Proteinosis)”. Pediatric Neurosurgery 28 (4): 212–214. doi:10.1159/000028653. PMID 9732251. 
  12. ^ a b c d e f Hamada T.; McLean WHI; Ramsay M.; Ashton GHS; Nanda A. (2002). “Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1)”. Human Molecular Genetics 11 (7): 833–40. doi:10.1093/hmg/11.7.833. PMID 11929856. 
  13. ^ a b c d e f Chan I.; Liu L.; Hamada T.; Sethuraman G.; McGrath J.A. (2007). “The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1”. Experimental Dermatology 16 (11): 881–90. doi:10.1111/j.1600-0625.2007.00608.x. PMID 17927570. 
  14. ^ a b Siebert M.; Markowitsch H.J.; Bartel P. (2003). “Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease”. Brain 126 (12): 2627–37. doi:10.1093/brain/awg271. PMID 12937075. 
  15. ^ Mallory S.B.; Krafchick B.R.; Holme S.A.; Lenane P.; Krafchik B.R. (2005). “What syndrome is this? Urbach-Weithe syndrome (lipoid proteinosis)”. Pediatric Dermatology 22 (3): 266–7. doi:10.1111/j.1525-1470.2005.22321.x. PMID 15916581. 
  16. ^ a b Thornton H.B.; Nel D.; Thornton D.; van Honk J.; Baker G.A.; Stein D.J. (2008). “The neuropsychiatry and neuropsychology of lipoid proteinosis”. Journal of Neuropsychiatry and Clinical Neurosciences 20 (1): 86–92. doi:10.1176/jnp.2008.20.1.86. PMID 18305289. 
  17. ^ a b Bahadir S.; Cobanoglu U.; Kapicioglu Z.; Kandil S.T.; Cimsit G. (2006). “Lipoid proteinosis: A case with ophthalmological and psychiatric findings”. The Journal of Dermatology 33 (3): 215–8. doi:10.1111/j.1346-8138.2006.00049.x. PMID 16620230. 
  18. ^ a b Cinaz P.; Guvenir T.; Gonlusen G. (1993). “Lipoid proteinosis: Urbach-Wiethe disease”. Acta Paediatrica 82 (11): 892–3. doi:10.1111/j.1651-2227.1993.tb12590.x. PMID 8241657. 
  19. ^ Hurlemann R.; Wagner M.; Hawellek B.; Reich H.; Pieperhoff P.; Amunts K. (2007). “Amygdala control of emotion-induced forgetting and remembering: Evidence from Urbach-Wiethe disease”. Neuropsychologia 45 (5): 877–84. doi:10.1016/j.neuropsychologia.2006.08.027. hdl:21.11116/0000-0001-B8EF-3. PMID 17027866. 
  20. ^ “Mutation Analysis of ECM1 Gene in Two Related Iranian Patients Affected by Lipoid Proteinosis”. Acta Medica Iranica 56 (7): 474–477. (August 2018). https://www.researchgate.net/publication/327250566 2020年9月1日閲覧。. 

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