Ayşe Çiğdem AKTUĞLU ZEYBEK, İnci PINAR BİLEN, Beyza BELDE DOĞAN, Ece ÖGE ENVER, Mehmet Şerif CANSEVER, Ertugrul KIYKIM, Tanyel ZÜBARİOĞLU

Serebrotendinöz ksantomatozis hastalarında kenodeoksikolik asit tedavisinin iskelet sistemi bulguları üzerine etkisinin değerlendirilmesi

Amaç: Bu çalışmanın temel amacı serebrotendinöz ksantomatozis tanılı hastalarda kullanılan kenodeoksikolik asit tedavisinin iskelet sistemi bulguları üzerine olan etkisini tanımlamaktır. Gereç ve Yöntemler: Bu geriye dönük çalışmaya Haziran 2013 ve Aralık 2018 yılları arasında Cerrahpaşa Tıp Fakültesi Çocuk Metabolizma ve Beslenme Bilim Dalı’nda izlenen serebrotendinoz ksantomatozis tanılı yedi hasta alındı. Hastalara ait klinik, epidemiyolojik ve genotipik özellikler geriye dönük incelendi ve özellikle iskelet sistemini ilgilendiren kemik kırığı öyküsü, kenodeoksikolik asit tedavisi öncesi ve sonrasında plazma kalsiyum, fosfat, alkalen fosfataz, 25-hidroksi-vitamin D düzeyleri, posteroanterior lomber vertebra (L1-L4) ve femur boynu kemik mineral dansitelerine ait bilgiler kaydedildi. Bulgular: Kemik mineral metabolizmasının değerlendirilmesi açısından ölçülen plazma kalsiyum, fosfat, alkalen fosfataz seviyeleri tüm hastalarda normal sınırlardaydı. Tanı anında yapılan plazma 25-hidroksi-vitamin D değerlendirilmesi; üç hastada eksiklik, üç hastada yetersizlik ile uyumluydu. Kenodeoksikolik asit tedavisi sonrasında 25-hidroksi-vitamin D eksikliği bir hastada devam ederken, dört hastada yetersizlik saptandı. Kemik mineral dansitometri değerlendirmelerinde, dört hastada kemik mineral dansitesi Z-skorlarının başlangıç anında ve tedavi sonunda yaşa göre düşük olarak devam ettiği görüldü. 25-hidroksi-vitamin D ve kemik mineral dansitometrisi Z-skorları arasında tedavi öncesi ve sonrasında istatistiksel olarak anlamlı farklılık izlenmedi. Çıkarımlar: Bu çalışmada, serebrotendinöz ksantomatozis tanılı hastalarda iskelet sistemi bulgularının iyileştirilmesi amacıyla kenodeoksikolik asit tedavisine ek olarak farklı medikal tedavilerin gerekli olabileceği üzerinde durulmuştur.

Evaluation of the effect of chenodeoxycholic acid treatment on skeletal system findings in patients with cerebrotendinous xanthomatosis

Aim: The primary purpose of the present study is to evaluate the effect of chenodeoxycholic acid treatment on skeletal system findings in patients with cerebrotendinous xanthomatosis. Material and Methods: This retrospective study was conducted between June 2013 and December 2018 with seven patients with cerebrotendinous xanthomatosis in Cerrahpasa Medical Faculty Pediatric Nutrition and Metabolism Department. The clinical, epidemiologic, and genotypic features of the patients were reviewed in detail and the following items, especially related with skeletal system involvement, were recorded from medical data: history of a bone fracture, plasma calcium, phosphate, alkaline phosphatase and 25-hydroxy-vitamin D concentrations, bone mineral density values of the posteroanterior lumbar spine (L1-L4), and femoral neck before and after chenodeoxycholic acid treatment. Results: Regarding the bone mineral metabolism, plasma calcium, phosphate, alkaline phosphatase levels were found in normal ranges in all patients. Plasma 25-hydroxy-vitamin D evaluation at the time of diagnosis showed deficiency in three patients and insufficiency in three patients. Following chenodeoxycholic acid therapy, 25-hydroxy-vitamin D deficiency persisted in only one patient, but insufficiency was observed in four patients. According to the bone mineral density assessments, four patients had Z-scores below the expected range for age both at initial examination and after chenodeoxycholic acid therapy. No significant difference was observed between plasma 25-hydroxy-vitamin D levels and bone mineral density Z-scores before or after treatment. Conclusion: This study elucidates the necessity of additional medical treatment as a part of chenodeoxycholic acid therapy to improve skeletal system findings in cerebrotendinous xanthomatosis.

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1. Clayton PT. Disorders of bile acid synthesis. In: Saudubray JM, Baumgartner MR, Walter J, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 6th ed. Springer-Verlag: Heidelberg; 2016.p.465−77. [CrossRef]
2. Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9: 179. [CrossRef]
3. Wong JC, Walsh K, Hayden D, Eichler FS. Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis 2018; 41: 647−56. [CrossRef]
4. Mignarri A, Dotti MT, Federico A, et al. The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression. J Neurol 2017; 264: 862−74. [CrossRef]
5. Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inherit Metab Dis 2017; 40: 771−81. [CrossRef]
6. Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 1991; 266:7779−83.
7. Mignarri A, Gallus GN, Dotti MT, Federico A. A suspicion index for early diagnosis and treatment of cerebrotendi nous xanthomatosis. J Inherit Metab Dis 2014; 37: 421−9.
8. Stelten BML, Huidekoper HH, van de Warrenburg BPC, et al. Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start. Neurology 2019; 92: 83−95. [CrossRef]
9. Zubarioglu T, Kiykim E, Yesil G, et al. Early diagnosed cerebrotendinous xanthomatosis patients: clinical, neuroradiological characteristics and therapy results of a single center from Turkey. Acta Neurol Belg 2017 Oct 22. doi: 10.1007/s13760-017-0851-2. [Epub ahead of print] [CrossRef]
10. Lewiecki EM, Gordon CM, Baim S, et al. International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions. Bone 2008; 43: 1115−21. [CrossRef]
11. Goksen D, Darcan S, Coker M, Kose T. Bone mineral density of healthy Turkish children and adolescents. J Clin Densitom 2006; 9: 84−90. [CrossRef]
12. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266−81. [CrossRef]
13. Berginer VM, Shany S, Alkalay D, et al. Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Metabolism 1993; 42: 69−74. [CrossRef]
14. Miki H, Takeuchi H, Yamada A, et al. Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system: NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27 in livers of patientswith cerebrotendinous xanthomatosis. Clin Chim Acta 1986; 160: 255−63. [CrossRef]
15. Federico A, Dotti MT, Loré F, Nuti R. Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. J Neurol Sci 1993; 115: 67−70. [CrossRef]
16. Martini G, Mignarri A, Ruvio M, et al. Long-term bone density evaluation in cerebrotendinous xanthomatosis: evidence of improvement after chenodeoxycholic acid treatment. Calcif Tissue Int 2013; 92: 282−6. [CrossRef]
17. Berginer VM, Salen G, Shefer S. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. N Engl J Med 1984; 311: 1649−52. [CrossRef]