Nöronopatik Olmayan Gaucher Hastalığı olan Erişkin Hastaların Klinik, Biyokimyasal ve Genetik Özelliklerinin Değerlendirilmesi ve Uzun Süreli Takibi

Yıl 2021, Cilt: 43 Sayı: 6, 673 - 683, 24.09.2021

Gonca Kılıç Yıldırım , Neslihan Andıc

https://doi.org/10.20515/otd.945383

Öz

Gaucher hastalığı (GH), GBA (glukozidaz beta asit) genindeki mutasyonlar sonucu β-glukoserebrosidaz enzim eksikliğinin neden olduğu ve makrofajlarda anormal glukoserebrosid birikimine yol açan bir lizozomal depolama bozukluğudur. Bu çalışmanın amacı, erişkin hastalar ile ilgili bulguları tartışarak GH'nin farkındalığını artırmaktır. Çalışmamızda, nöronopatik olmayan Gaucher hastalığı olan 18 erişkin hastanın klinik özellikleri, laboratuar parametreleri ve moleküler özelliklerinin yanı sıra enzim replasman tedavisi (ERT) gören 15 hastanın hematolojik, iskelet ve viseral organ yanıtlarını bildiriyoruz. Semptomların başlangıç yaşı 1,6 ile 63 yıl arasındaydı ve semptom başlangıcından tanının doğrulanmasına kadar ortalama 3,56 yıl (0–21 yıl) gecikme saptandı. Üç hastamız GH'yi destekleyen bir patoloji raporları olmasına rağmen tanılarının farkında değillerdi ve bir uzmana görünmeleri önerilmediği veya bulamadıkları için bakımları yıllarca ertelendiği görüldü. Hastaların çoğunda hepatosplenomegali, anemi ve trombositopeni mevcuttu ve trombositopenili 15 hastanın dokuzunda (%60) orta düzeydeydi. Osteopeni %75 ve avasküler nekroz % 16.6 oranında mevcuttu. Bu kohortta saptanan en yaygın mutant allel, N409S (önceden N370S) idi, ardından L483P (önceden L444P) ve S405T mutasyonları rapor edildi. Toplam 15 hastaya ERT uygulanabildi, özellikle ilk yılda hematolojik parametrelerini önemli ölçüde iyileştirirken, karaciğer ve dalak boyutlarını anlamlı olarak düşürdüğü saptandı. Hekimler, özellikle hematoloji ve dahili tıp alanında çalışanlar, kemik ağrısı ve açıklanamayan hematolojik disfonksiyonu olan herhangi bir erişkin hastada, özellikle organomegali varsa GH'den şüphelenmelidir. Multisistemik semptomların yönetimi için multidisipliner bir ekip yaklaşımına ihtiyaç vardır.

Anahtar Kelimeler

Erişkin, hepatosplenomegali, hemoglobin konsantrasyonu, nöronopatik olmayan Gaucher hastalığı, trombosit sayısı, ferritin

Destekleyen Kurum

YOK

Evaluation of Clinical, Biochemical, and Genetic Characteristics and Long-Term Follow up of Adult Patients with Non-Neuronopathic Gaucher’s Disease

Öz

Gaucher disease (GD) is a lysosomal storage disorder caused by deficiencies of the β-glucocerebrosidase enzyme due to mutations in the GBA (glucosidase beta acid) gene, and that leads to the abnormal accumulation of glucocerebroside in lysosomal macrophages. The aim of the present study is to increase awareness of GD by discussing findings related to adults. Here, we report on the clinical features, laboratory parameters, and molecular characteristics of 18 adult patients with non-neuronopathic GD, as well as the hematologic, skeletal, and visceral responses of 15 patients who underwent enzyme replacement therapy (ERT). The age of symptom onset was between 1.6 and 63 years, and there was a delay of mean 3.56 years (0–21 years) from the time of symptom onset to confirmation of diagnosis. Despite the fact that three of our patients had a pathology report supporting GD, they were unaware of their diagnosis, and their care was delayed for years as they were not recommended to see a specialist, or were unable to find one. Hepatosplenomegaly, anemia, and thrombocytopenia were present in most of the patients, and in nine of the 15 patients (60%) with thrombocytopenia, the condition was moderate. Osteopenia was present in 75% and avascular necrosis in 16.6%. The most common mutant allele detected in this cohort was N409S (previously N370S), followed by L483P (previously L444P), and S405T mutations were reported. Of the total,15 patients were able to undergo ERT, which significantly improved their hematologic parameters, especially in the first year, and decreased the sizes of the liver and spleen. Physicians, particularly those working in hematology and internal medicine, should suspect GD in any adult patient with bone pain and unexplained hematologic dysfunction, especially if organomegaly is present. A multidisciplinary team approach is needed for the management of multisystemic symptoms.

Anahtar Kelimeler

Adult, hepatosplenomegaly, hemoglobin concentration, non-neuronopathic Gaucher disease, platelet count, ferritin

Kaynakça

• References 1- Gary SE, Ryan E, Steward AM, Sidransky E. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev. Endocrinol. Metab. 2018; 13; 107–118.
• 2- Saudubray JM, Baumgartner MR, Walter J. Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann Pick Disease Type-C and Neuronal Ceroid-Lipofuscinoses. Gaucher Disease: In Sphingolipidoses. Inborn Metabolic Diseases Diagnosis and Treatment 6th Edition. Springer Berlin, Heidelberg 2016 Chapter 38; 556-559.
• 3- Nalysnyk L, Rotella P, Simeone JC, et al. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. Hematology 2017; 22: 65-73.
• 4- Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet 2008; 372: 1263-1271.
• 5- Carla E.M. Hollak. Gaucher Disease. In: Carla E.M. Hollak, Lachmann R.H (eds). Inherited Metabolic Disease in Adults. New York, Oxford University Press, 2016
• 6- Donald M Arnold, Adam Cuker, Approach to the adult with unexplained thrombocytopenia. UpToDate 2020
• 7- Charrow J, Andersson HC, Kaplan P, et al. The Gaucher Registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med. 2000; 160: 2835–2843.
• 8- Stirneman J, Vigan M, Hamroun D et el. The French Gaucher’s disease Registry: Clinical characteristics complications and treatment of 562 patients. Orphanet J Rare Dis 2012; 7: 77.
• 9- Neal J. Weinreb & Jack Goldblatt & Jacobo Villalobos & Joel Charrow & J. Alexander Cole & Marcelo Kerstenetzky & Stephan vom Dahl & Carla Hollak. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis 2013; 36: 543–553. 10- Pastores G.M, Weinreb N.J, Aerts H, Andria G, Cox T.M, Giralt M, Grabowski G.A, Mistry P.K, Tylki-Szymańska A. Therapeutic goals in the treatment of Gaucher disease, Semin. Hematol. 2004; 41: 4–14.
• 11- Charrow J, Scott C.R. Long-term treatment outcomes in Gaucher disease. Am. J. Hematol. 2015; 90: 19–24.
• 12- Charrow J, Dulisse B, Grabowski GA, Weinreb NJ. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease. Clin Genet 2007; 71: 205–211.
• 13- Morgan M.A, Hoffbrand A.V, Laulicht M, Luck W, Knowles S. Serum ferritin concentration in Gaucher's disease, BMJ 1983; 286: 1864.
• 14- Mekinian A, Stirnemann J, Belmatoug N, Heraoui D, Fantin B, Fain O, Charpentier A, Rose C. Ferritinemia during type 1 Gaucher disease: Mechanisms and progression under treatment. Blood Cells, Molecules, and Diseases 2010; 49: 53-57.
• 15- Dekker N, van Dussen L, Hollak C.E, Overkleeft H, Scheij S, Ghauharali K, van Breemen M.J, Ferraz M.J, Groener J.E, Maas M, Wijburg F.A, Speijer D, Tylki-Szymanska A, Mistry P.K, Boot R.G, Aerts J.M. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response, Blood 2011; 118: e118–e127.
• 16- Rolfs A, Giese A.K, Grittner U, Mascher D, Elstein D, Zimran A, Bottcher T, Lukas J, Hubner R, Golnitz U, Rohle A, Dudesek A, Meyer W, Wittstock M, Mascher H. Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients, PLoS One 2013; 8: e79732.
• 17- Ortiz-Cabrera N.V, Gallego-Merlo J, Vélez-Monsalve C, de Nicolas R, Fontao Mas S, Ayuso C, Trujillo-Tiebas M.J. Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz. Molecular Genetics and Metabolism Reports 1026; 9: 79–85.
• 18- Goker-Alpan O, Schiffmann R, LaMarca M.E, Nussbaum R.L, McInerney-Leo A, Sidransky E. Parkinsonism among Gaucher disease carriers, J. Med. Genet. 2004; 41: 937–940. 19- Li Y, Sekine T, Funayama M, Li L, Yoshino H, Nishioka K, Tomiyama H, Hattori N. Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease, Neurobiol. Aging 2014; 35: 935 e3-8.
• 20- Weinreb NJ, Goldblatt J, Villalobos J, et al. Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment. J Inherit Metab Dis 2013; 36: 543–553.
• 21- McEachern KA, Fung J, Komarnitsky S, et al. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab 2007; 91: 259–67.
• 22- Mistry PK, Sirrs S, Chan A, et al. Pulmonary hypertension in type 1 Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab 2002; 77: 91–98.