Biyotinidaz Eksikliği Olan Hastaların Klinik, Biyokimyasal ve Moleküler Genetik Analizlerinin Değerlendirilmesi

Öz

ÖZ Amaç: Biyotinidaz eksikliği, biyotin döngüsünün kalıtsal bir hastalığıdır. Bu çalışmanın amacı, biotinidaz eksikliği olan hastaların klinik, biyokimyasal ve genetik analizlerini değerlendirmek ve genotip-fenotip korelasyonunu yapmaktır. Gereç ve Yöntemler: Temmuz 2018-Aralık 2023 tarihleri arasında 90 biyotinidaz eksikliği tanısıyla takip edilen hastaların klinik, laboratuvar ve moleküler genetik analizleri retrospektif olarak değerlendirildi. Bulgular: Biyotinidaz eksikliği olan 33 hastada (%36,7) BTD geninde c.1270G>C (p. Asp424His) homozigot mutasyonu tespit edildi. On iki hastada (%13,3) c.410G>A (p. Arg137His) /c.1270G>C (p. Asp424His) bileşik heterozigot mutasyon tespit edildi. [c.1270G>C (p. Asp424His) mutasyonu olan hastalarda diğer sık görülen mutasyonlara kıyasla daha yüksek biyotinidaz aktiviteleri gözlendi. Sonuç: Çalışmamızda BTD geninde saptanan mutasyonların sıklığı literatürle uyumlu bulundu. Biyotinidaz eksikliği olan hastalarda tanının kesin olarak genetik analizle doğrulanması ve diğer aile bireylerinin araştırılması gerekmektedir.

Anahtar Kelimeler

• Biyotinidaz eksikliği,
• Çocuk,
• Mutasyon,
• Tarama,

Evaluation of Clinical, Biochemical and Molecular Genetic Analyses of the Patients with Biotinidase Deficiency

Öz

ABSTRACT Objective: Biotinidase deficiency is a hereditary disorder of the biotin cycle. The aim of this study is to evaluate the clinical, biochemical, and genetic findings in patients with biotinidase deficiency and to establish a genotype–phenotype correlation. Materials and Methods: Clinical, laboratory and molecular genetic analyses of the patients with 90 biotinidase deficiency between July 2018 and December 2023 were retrospectively evaluated. Results: c.1270G>C (p. Asp424His) homozygous mutation was detected in the BTD gene in 33 (36.7%) patients with biotinidase deficiency. c.410G>A (p. Arg137His)/c.1270G>C (p. Asp424His) compound heterozygous mutation in 12 (13.3%) patients. Patients with [c.1270G>C (p. Asp424His) mutation had higher biotinidase activities compared with other frequently detected mutations. Conclusion: The frequency of mutations detected in the BTD gene in our study was consistent with the literature. The diagnosis must be definitively confirmed by genetic analysis and other family members must be investigated in patients with biotinidase deficiency.

Anahtar Kelimeler

• Biotinidase deficiency,
• Child,
• Mutation,
• Screening,

Kaynakça

1. Wolf B. Biotinidase Deficiency.2000 Mar 24 [Updated 2023 May 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.
2. Tankeu AT, Van Winckel G, Elmers J, Jaccard E, Superti-Furga A, Wolf B, Tran C. Biotinidase deficiency: What have we learned in forty years? Molecular Genetics and Metabolism 2023;138: 107560.
3. Çıkı K, Alavanda C, Ceylan EI, Tanyalçın T, Kılavuz S. Comprehensive analysis of genotypic and phenotypic characteristics of biotinidase deficiency patients in the eastern region of Türkiye. The Turkish Journal of Pediatrics 2024; 66: 608-17.
4. Canda E, Kalkan Ucar S, Coker M. Biotinidase Deficiency: Prevalence, Impact and Management Strategies. Pediatric Health Medicine and Therapeutics 2020; 11:127-33.
5. Sürücü Kara I, Köse E, Koç Yekedüz M, Eminoğlu FT. A different approach to the evaluation of the genotype-phenotype relationship in biotinidase deficiency: repeated measurement of biotinidase enzyme activity. Journal of Pediatric Endocrinology and Metabolism 2023; 36:1061-71.
6. Yılmaz B, Ceylan AC, Gündüz M, Ünal Uzun Ö, Küçükcongar Yavaş A, Bilginer Gürbüz B ,Öncül U, Güleç Ceylan G, Kasapkara CS. Evaluation of clinical, laboratory, and molecular genetic features of patients with biotinidase deficiency. European Journal of Pediatrics 2024; 183:1341-51.
7. Baykal T, Hüner G, Sarbat G, Demirkol M. Incidence of biotinidase deficiency in Turkish newborns. Acta Paediatrica 1998; 87(10): 1102–3.
8. Kalkanoğlu Sivri HS, Genç GA, Tokatli A, Dursun A, Coşkun T, Aydin HI, Sennaroğlu L, Belgin E, KevJesen K, Wolf B. Hearing loss in biotinidase deficiency: genotype-phenotype correlation. The Journal of Pediatrics 2007; 150:439-42.

9. Kannan B, Navamani HK, Jayaseelan VP, Arumugam P. A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype-Phenotype Analysis. Journal of Pediatric Genetics 2022; 12:1-15.
10. Canda E, Yazici H, Er E, Kose M, Basol G, Onay H , Kalkan Ucar S, Habif S , Ozkinay F , Coker M. Single center experience of biotinidase deficiency: 259 patients and six novel mutations. Journal of Pediatric Endocrinology and Metabolism 2018; 31:917-26.
11. Akgun A, Sen A, Onal H. Clinical, biochemical and genotypical characteristics in biotinidase deficiency. Journal of Pediatric Endocrinology and Metabolism 2021; 34:1425-33.
12. Ercan M, Akbulut ED, Oz O, Ataş N, Karaca M, Meric Yılmaz F. Evaluation of the efficiency of serum biotinidase activity as a newborn screening test in Turkey. Journal of Pediatric Endocrinology and Metabolism 2020; 34:89-94.
13. Karaca M, Özgül RK, Ünal Ö, Yücel-Yılmaz D, Kılıç M, Hişmi B, Tokatlı A, Coşkun T, Dursun A, Sivri HS. Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening. European Journal of Pediatrics 2015; 174:1077-84.
14. Kasapkara CS, Akar M, Ozbek MN, Tuzun H, Aldudak B, Baran RT and Tanyalcın T. Mutations in BTD gene causing biotinidase deficiency: a regional report. J Pediatr Endocr Met 2015; 28:421–4.
15. Seker Yilmaz B, Mungan NO, Kor D, Bulut D, Seydaoglu G, Oktem M, Ceylaner S. Twenty-seven mutations with three novel pathologenic variants causing biotinidase deficiency: a report of 203 patients from the southeastern part of Turkey. Journal of Pediatric Endocrinology and Metabolism 2018; 31:339-43.
16. Thodi G, Schulpis KH, Molou E, Georgiou V, Loukas YL, Dotsikas Y, Papadopoulos K, Biti S. High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene 2013; 524: 361–2.
17. Maguolo A, Rodella G, Dianin A, Monge I, Messina M, Rigotti E, Pellegrini F , Molinaro G, Lupi F , Pasini A ,Campostrini N , Ion Popa F, Teofoli F, Vincenzi M, Camilot M , Piacentini G , Bordugo A. Newborn Screening for Biotinidase Deficiency. The Experience of a Regional Center in Italy. Frontiers in Pediatrics 2021:9:661416.
18. Semeraro D, Verrocchio S, Di Dalmazi G, Rossi C, Pieragostino D, Cicalini I , Ferrante R, Di Michele S, Stuppia L, Rizzo C, Lepri FR, Novelli A, Dionisi-Vici C, De Laurenzi V, Bucci I. High Incidence of Partial Biotinidase Deficiency in the First 3 Years of a Regional Newborn Screening Program in Italy. International Journal of Environmental Research and Public Health 2022; 19:8141.
19. Gowda VK, Kerur C, Vamyanmane DK, Kumar P, Nagarajappa VH, Shivappa SK. Treatable Cause of Myelopathy: Biotinidase Deficiency Presenting as Acute Flaccid Paralysis. Journal of Pediatric Genetics 2020; 11:257-60.
20. Erdol Ş, Saglam H, Basarır TO, Okan M. Celiac Disease Presenting with Biotinidase Deficiency and Paraplegia. Indian Journal of Pediatrics 2016; 83:596-7.
21. Baykal T, Gokcay G, Gokdemir Y, Demir F, Seckin Y, Demirkol M, Jensen K, Wolf B. Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. Journal of Inherited Metabolic Disease 2005; 28: 903–12.