Mehmet KARAKAŞ, Bilgin YÜKSEL, Ali Kemal TOPALOĞLU, Mehmet Nuri ÖZBEK, Fatih TEMİZ, Neslihan MUNGAN ÖNEMLİ, Berna Şeker YILMAZ

Fabry Disease: A Turkish Case with a Novel Mutation and Dermatological Manifestations

Fabry hastalığı lizozomal ?-galaktosidaz eksikliğine bağlı görülen, X'e bağlı kalıtılan nadir bir hastalıktır. Klinik bulgular; akroparestezi, açıklanamayan ateş, hipohidroz ve anjiyokeratomlardır. Tedavi edilmeyen vakalar erken kardiyak komplikasyonlar, renal yetmezlik veya inme nedeniyle kaybedilirler. Günümüzde Fabry hastalığı için kür bulunmamakla birlikte enzim replasman tedavisi, bu ilerleyici hastalık için tek seçenektir. 9 yaşındaki erkek olgu Dermatoloji kliniğine kırmızı papüler cilt lezyonları, eklem ağrısı ve anhidrozla başvurmuştur. Cilt biyopsisinin histolojik incelemesi anjiyokeratom ile uyumlu bulunmuştur. Renal disfonksiyon veya proteinüri saptanmadı. Fabry hastalığının biyokimyasal doğrulaması lökosit ?-galaktosidaz eksikliğinin gösterilmesiyle yapıldı. Daha sonra da, hastanın moleküler incelemesiyle GLA geninde c. 785G>T tanımlanmamış mutasyonunu saptandı. 8 yıldır enzim replasman tedavisi altında izlenen hastanın halsizlik yakınmasında ve ağrı ataklarının ciddiyeti ve sıklığında belirgin iyileşme gözlendi. Bu hastayı, enzim replasman tedavisinin mümkün olduğu günümüzde, renal ve kardiyak bulgular ortaya çıkmadan sadece cilt bulguları varlığında konulan erken Fabry hastalığı tanısının önemini vurgulamak amacıyla sunduk. Ayrıca bu hasta Türkiye'de enzim replasman tedavisi uygulanan ilk olgulardan biridir.

Fabry Hastalığı: Yeni Bir Mutasyon ve Cilt Bulgulariyla Seyreden Bir Türk Olgu

Fabry disease is a rare, X-linked disease, caused by the deficiency of lysosomal ?-galactosidase. Clinical fetaures are; acroparesthesia, unexplained fever, hypohidrosis and angiokeratomas. Untreated cases die early from cardiac complications, renal insuffiency or stroke. Currently there is no cure for Fabry disease, enzyme replacement therapy is the only choice in this progressive disease. A 9-year-old boy admitted to the Dermatology Clinic with reddish papular skin lesions, joint pain and anhydrosis. Hystological examination of the skin biopsy revealed angiokeratoma. There was no renal dysfunction or proteinuria. Biochemical confirmation of Fabry disease was made by determining the deficient leukocyte ?-galactosidase activity. Subsequently, the patient's molecular analysis was identified a novel nonsense mutation c. 785G>T in the GLA gene. Enzyme replacement therapy with agalsidase beta was started. He is on enzyme replacement therapy for 8 years, significant improvement was obtained in severity and frequency of pain crisis and fatigue. We report this case to emphasize the importance of early diagnosis of Fabry disease restricted to dermatological findings, especially before renal and cardiac involvement occurs, while enzyme replacement therapy is now available. Also this patient is one of the first Fabry patients under enzyme replacement therapy in Turkey.

PDF

___

Kint JA. The enzyme defect in Fabry's disease. Nature. 1970;227:1173.
Lidove O, Kaminsky P, Hachulla E, Leguy-Seguin V, Lavigne C, Marie I, et al. Fabry disease 'The New Great Imposter': results of the French Observatoire in Internal Medicine Departments (FIMeD). Clin Genet. 2012;81:571-7.
Desnick RJ, Ioannou YA, Eng CM. ?-Galactosidase A deficiency: Fabry disease. Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic Bases of Inherited Disease. 8th ed. New York, McGraw-Hill. 2001:3733- 74.
Ramaswami U, Whybra C, Parini R, Pintos-Morell G, Mehta A, Sunder-Plassmann G, et al. Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. Acta Paediatr 2006;95:86-92.
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. 2001;38:750-60.
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. 2001;38:769-75.
Massaccesi L, Burlina A, Baquero CJ, Goi G, Burlina AP, Tettamanti G. Whole-blood alpha-D- galactosidase A activity for the identification of Fabry's patients. Clin Biochem. 2011;44:916-21.
Weidemann F, Niemann M, Breunig F, Herrmann S, Beer M, Störk S, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a beter outcome with early treatment. Circulation. 2009;119:524-9.
Alfadhel M, Sirrs S. Enzyme replacement therapy for Fabry disease: some answers but more questions. Ther Clin Risk Manag. 2011;7:69-82.
Morrissey RP, Philip KJ, Schwarz ER. Cardiac abnormalities in Anderson-Fabry disease and Fabry's cardiomyopathy. Cardiovasc J Afr. 2011;22:38-44.
Hegemann S, Hajioff D, Conti G, Beck M, Sunder- Plassmann G, Widmer U, et al. Hearing loss in Fabry disease: data from the Fabry Outcome Survey. Eur J Clin Invest. 2006;36:654-62.
Orteu CH, Jansen T, Lidove O, Jaussaud R, Hughes DA, Pintos-Morell G, et al. Fabry disease and the skin: data from FOS, the Fabry Outcome Survey. Br J Dermatol. 2007;157:331-7.
Desnick RJ, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W. Fabry's disease: enzymatic diagnosis of hemizygotes and heterozygotes. Alpha- galactosidase activities in plasma, serum, urine, and leukocytes. J Lab Clin Med. 1973;81:157-71.
Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. Fabry Registry. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008;93:112-28.
Fauchais AL, Prey S, Outara B, Vidal E, Sparsa A. Angiokeratoma regression in a Fabry disease after treatment with agalsidase-beta: clinical effectiveness marker? J Eur Acad Dermatol Venereol. 2010;24:737-8.
Eto Y, Ohashi T, Utsunomiya Y, Fujiwara M, Mizuno A, Inui K, et al. Enzyme replacement therapy in Japanese Fabry disease patients: the results of a phase 2 bridging study. J Inherit Metab Dis. 2005;28:575-83.
Furujo M, Kubo T, Kobayashi M , Ohashi T. Enzyme replacement therapy in two Japanese siblings with Fabry disease, and its effectiveness on angiokeratoma and neuropathic pain. Mol Genet Metab 2013;110:405-10.