BRAIN and NERVE－神経研究の進歩60巻11号

2008年11月発行

特集 脳卒中と遺伝子

Fabry病

著者： 宇山英一郎¹

所属機関： ¹熊本託麻台病院神経内科

ページ範囲：P.1235 - P.1244

文献概要

はじめに

　Fabry病は，X染色体のXq22.1に位置するα-galactosidase A遺伝子（GLA）の変異により，lysosome内加水分解酵素α-galactosidase Aの活性が低下し，これで分解されるべきglobotriaosylceramide（GL-3）などのスフィンゴ糖脂質が，血管内皮細胞をはじめ諸組織細胞や体液に蓄積して，脳梗塞や心・腎障害などを呈する難病である^1－3）（Fig.1）。

　本症は1898年に英国の外科・皮膚科医Anderson博士が英文誌に^4），ドイツの皮膚科医Fabry博士が独文誌に初めて報告しているため^5），欧米では公平にAnderson-Fabry病とも呼ばれる^6－13）。また，本症の欠損酵素であるα-galactosidaseに関して，1976年まではAとBの2つのアイソザイムが存在すると解釈されていたが，翌年にα-galactosidase Bの実体はα-N-acetylgalacto- saminidaseであり，酵素蛋白質や遺伝子支配もα-galactosidase Aとは異なることが明らかにされた^14，15）。さらに，このα-N-acetylgalactosaminidase遺伝子の異常で生じる疾患は，Schindler病とされ，1型：乳児期発症の神経軸索ジストロフィー，2型（神崎病)：成人期発症のび漫性被角血管腫と軽度知能障害，3型：1型と2型の中間的病像に分類されている^16－20）。したがって最近，本邦ではFabry病の欠損酵素をα-galaclosidaseと表記する傾向にあるが^21），欧米では従来通りα-galaclosidase Aが用いられている^1－6）。

　Fabry病はこれまでX染色体連鎖劣性遺伝の形式をとり，ヘミ接合体の男性患者は古典的病像を呈し，保因者の女性にはLyonの仮説が適応されてきた。しかし，本遺伝形式をとるほかの疾患に比べ，ヘテロ接合体の女性も高頻度に発病するため，本症ではこれを保因者と呼ぶべきではない^22）との意見や，遺伝形式は単にX染色体連鎖性と呼ぶのが正しいとの見解も出ている^23，24）。したがって，特定疾患の公費申請時や酵素補充療法^25，26）の選択の際には，女性患者も対象になることを再認識すべきである。

　本症は従来，神経内科や脳神経外科領域では，若年性の脳梗塞をきたす単一遺伝子病の1つで，稀な疾患として知られてきたが，近年では酵素補充療法^25，26）や亜型“心型Fabry病”^27－29）の確立により，循環器領域で関心が高まっている。また“腎型Fabry病”^30）の存在や，慢性腎臓病（CKD）の治療可能な原因の1つとして，腎臓内科・泌尿器科の分野でも啓蒙されている^{3，31－34）}。発症頻度は人口4万人に1人とされ，世界で5,000例以上，本邦で1,000例以上の存在が推計されている^21）。最近の調査では，成人発症の特発性肥大型心筋症の6.3％，18～55歳の全潜在性脳卒中患者の1.2％，腎不全の全透析患者の0.16～1.2％がFabry病とされている^35）。

参考文献

1) Desnick RJ, Ioannou YA, Eng CM: α-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AL, Sly WS, Valle D, (eds.) McGraw-Hill, New York, 2001, pp3733-3774

2) Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 301500: March 21 in 2008, World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/, 2008

3) Breunig F, Wanner C: Update on Fabry disease: kidney involvement, renal progression and enzyme replacement therapy. N Nephrol 21: 32-37, 2008

4) Anderson W: A case of angio-keratoma. Brit J Dermatol 10: 113-117, 1898

5) Fabry J: Ein Beitrag zur Kennetnis der Purpura haemorragica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch Dermatol Syph Band 43: 187-200, 1898

6) Pierides A, Holti G, Crombie AL, Roberts DF, Gardiner SE, et al: Study on a family with Anderson-Fabry's disease and associated familial spastic paraplegia. J Med Genet 13: 455-461, 1976

7) Clement M, McGonigle RJS, Monkhouse PM, Keogh AM, Marten RH, et al: Renal transplantation in Anderson-Fabry disease. J Roy Soc Med 75: 557-560, 1980

8) Davies JP, Winchester BG, Malcolm S: Mutation analysis in patients with the typical form of Anderson-Fabry disease. Hum Mol Genet 2: 1051-1053, 1993

9) MacDermot KD, Holmes A, Miners AH: Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 38: 750-760, 2001

10) Shah JS, Hughes DA, Sachdev B, Tome M, Ward D, et al: Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease. Am J Cardiol 96: 842-846, 2005

11) Shah JS, Lee P, Hughes D, Thaman R, Sachdev B, et al: The natural history of left ventricular systolic function in Anderson-Fabry disease. Heart 91: 533-534, 2005

12) Kampmann C, Wiethoff CM, Whybra C, Baehner FA, Mengel E, et al: Cardiac manifestations of Anderson-Fabry disease in children and adolescents. Acta Paediatr 97: 463-469, 2008

13) MacDermot KD, Holmes A, Miners AH: Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 38: 769-775, 2001

14) Beutler E, Kuhl W: Fabry's disease: structural or regulatory mutation? J Lab Clin Med 78: 987, 1971

15) Kint JA: On the existence and enzymic interconversion of the isozymes of α-galactosidase in human organs. Arch Int Physiol Biochim 79: 633-634, 1971

16) van Diggelen OP, Schindler D, Kleijer WJ, Huijmans JGM, Galjaard H, et al: Lysosomal alpha-N-acetylgalactosaminidase deficiency: a new inherited metabolic disease. (Letter) Lancet II: 804 only, 1987

17) van Diggelen OP, Schindler D, Willemsen R, Boer M, Kleijer WJ, et al: Alpha-N-acetylgalactosaminidase deficiency, a new lysosomal storage disorder. J Inherit Metab Dis 11: 349-357, 1988

18) Schindler D, Bishop DF, Wallace S, Wolfe DE, Desnick RJ: Characterization of alpha-N-acetylgalactosaminidase deficiency: a new neurodegenerative lysosomal disease. (Abstract) Pediat Res 23: 333A only, 1988

19) Schindler D, Bishop DF, Wolfe DE, Wang AM, Egge H, et al: Neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. N Engl J Med 320: 1735-1740, 1989

20) Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 609241: March 21 in 2005, World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/, 2008

21) 衛藤義勝（総監修): ファブリー病―基礎から臨床までの最近の知見. ブレーン出版, 東京, 2004

22) Wang RY, Lelis A, Mirocha J, Wilcox WR: Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 9: 34-45, 2007

23) Deegan PB, Baehner AF, Barba Romero M-A, Hughes DA, Kampmann C, et al: Natural history of Fabry disease in females in the Fabry outcome survey. J Med Genet 43: 347-352, 2006

24) Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, et al: Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A 129: 136-143, 2004

25) Schiffmann R, Murray GJ, Treco D, Daniel P, Sellos-Moura M, et al: Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci U S A 97: 365-370, 2000

26) Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, et al: A phase 1/2 clinical trial of enzyme replacement in Fabry diease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 68: 711-722, 2001

27) Ogawa K, Sugamata K, Funamoto N, Abe T, Sato T, et al: Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry's disease. Hum Path 21: 1067-1073, 1990

28) Nagao Y, Nakashima H, Fukuhara Y, Shimmoto M, Oshima A, Okari Y, et al: Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of α-galactosidase A. Clin Genet 39: 233-237, 1991

29) Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, et al: An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 333: 288-293, 1995

30) Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, et al: Fabry disease: detection of undiagnosed hemodialysis patients and identification of a ‘renal variant' phenotype. Kidney Int 64: 801-807, 2003

31) Thurberg BL, Rennke H, Colvin RB, Dickman S, Gordon RE, et al: Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int 62: 1933-1946, 2002

32) Warnock DG, West ML: Diagnosis and management of kidney involvement in Fabry disease. Adv Chonic Kidnet Dis 13: 138-147, 2006

33) Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, et al: Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Int Med 146: 77-86, 2007

34) Ortiz A, Oliveira JP, Wanner C, Brenner BM, Waldek S, et al: Recommendations and guidelines for the diagnosis and treatment of Fabry nephropathy in adults. Nat Clin Pract Nephrol 4: 327-336, 2008

35) Schiffmann R, Ries M: Fabry's disease-an important risk factor for stroke. Lancet 366: 1754-1756, 2005

36) Uyama E, Ueno N, Uchino M, Narahara T, Owada M, et al: Headache associated with aseptic meningeal reaction as clinical onset of Fabry's disease. Headache 35: 498-501, 1995

37) Lao LM, Kumakiri M, Mima H, Kuwahara H, Ishida H, et al: The ultrastructural characteristics of eccrine sweat glands in a Fabry disease patient with hypohidrosis. J Dermatol Sci 18: 109-117, 1998

38) Wise D, Wallance HJ, Jellinek EH: Angiokeratoma corporis diffusum: a clinical study of eight affected families. Q J Med 31: 177-206, 1962

39) Franois J, Hanssens M, Teuchy H: Corneal ultrastructual changes in Fabry's disease. Bull Soc Belge Ophthalmol 179: 7-23, 1977

40) Orssaud C, Dufier J, Germain D: Ocular manifestations in Fabry disease: a survey of 32 hemyzygous male patients. Ophthalmic Genet 24: 129-139, 2003

41) Senechal M, Germain DP: Fabry disease: a functional and anatomical study of cardiac manifestations in 20 hemizygous male patients. Clin Genet 63: 46-52, 2003

42) Sakuraba H, Yanagawa Y, Igarashi T, Suzuki Y, Suzuki T, et al: Cardiovascular manifestations in Fabry's disease: a high incidence of mitral valve prolapse in hemizygotes and heterozygotes. Clin Genet 29: 276-283, 1986

43) Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, et al: Natural history of Fabry renal disease: influence of α-galactosidase A activity and genetic mutations on clinical course. Medicine 81: 122-138, 2002

44) Sheth KJ, Werlin S, Freeman ME, Hodach AE: Gastrointestinal structure and function in Fabry's disease. Am J Gastroenterol 76: 246-251, 1981

45) Rosenberg DM, Ferrans VJ, Fulmer JD, Line BR, Barranger JA, et al: Chronic airflow obstruction in Fabry's disease. Am J Med 68: 898-905, 1980

46) Brown LK, Miller A, Bhuptani A, Sloane MJ, Zimmerman MI, et al: Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med 155: 1004-1010, 1997

47) Sakuraba H, Oshima A, Fukuhara Y, Shimmoto M, Nagao Y, et al: Identification of point mutations in the α-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am J Hum Genet 47: 784-789, 1990

48) Elleder M, Bradova V, Smd F, Budesnsky M, Harzer K, et al: Cardiocyte storage and hypertrophy as a sole manifestation of Fabry's disease: report on a case simulating hypertrophic non-obstructive cardiomyopathy. Virchows Arch A Pathol Anat Histopathol 417: 449-455, 1990

49) von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, et al: An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 324: 395-399, 1991

50) Chimenti C, Hamdani N, Boontje NM, DeCobelli F, Esposito A, et al: Myofilament degradation and dysfunction of human cardiomyocytes in Fabry disease. Am J Pathol 172: 1482-1490, 2008

51) Monserrat L, Gimeno-Blanes JR, Marin F, Hermida-Prieto M, Garcia-Honrubia A, et al: Prevalence of Fabry disease in a cohort of 508 Unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 50: 2399-2403, 2007

52) 児玉千早: 慢性透析男性患者におけるFabry病の臨床像と遺伝子異常について. 鹿児島大学医学雑誌48: 297-308, 1996

53) Rosenthal D, Lien YH, Lager D, Lai LW, Shang S, et al: A novel α-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease. Am J Kidney Dis 44: 85-89, 2004

54) Meehan SM, Junsanto T, Rvdel JJ, Desnick RJ: Fabry disease: renal involvement limited to podocyte pathology and proteinuria in a septuagenarian cardiac variant. Pathologic and therapeutic implications. Am J Kidney Dis 43: 164-171, 2004

55) Nance CS, Klein CJ, Banikazemi M, Dikman SH, Phelps RG, et al: Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol 63: 453-457, 2006

56) Uchino M, Uyama E, Kawano H, Hokamaki J, Kugiyama K, et al: A histochemical and electron microscopic study of skeletal and cardiac muscle from a Fabry disease patient and carrier. Acta Neuropathol 90: 334-338, 1995

57) Mitsias P, Levine SR: Cerebrovascular complications of Fabry's disease. Ann Neurol 40: 8-17, 1996

58) Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, et al: Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 50: 1746-1749, 1998

59) Utsumi K, Yamamoto N, Kase R, Takata T, Okumiya T, et al: High incidence of thrombosis in Fabry's disease. Intern Med 36: 327-329, 1997

60) Garzuly F, Marodi L, Erdos M, Grubits J, Varga Z, et al: Megadolichobasilar anomaly with Fabry's disease and a novel mutation in the α-galactosidase A gene. Brain 128: 2078-2083, 2005

61) Moore DF, Ye F, Schiffmann, Butman JA: Increased signal intensity in the pulvinar on T1-weighted images. AJNR Am J Neuroradiol 24: 1096-1101, 2003

62) Ries M, Kim HJ, Zalewski CK, Mastroianni MA, Moore DF, et al: Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease. Brain 130: 143-150, 2007

63) Uyama E, Kutsukake Y, Hara A, Uemura K, Uchino M, et al: Abnormal excretion of urinary phospholipids and sulfatide in patients with mitochondrial encephalomyopathies. Biochem Biophy Res Commun 194: 266-273, 1993

64) Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, et al: Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation 108: 1299-1301, 2003

65) Germain DP, Waldek S, Banikazemi M, Bushinsky DA, Charrow J, et al: Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 18: 1547-1557, 2007