Clinical and molecular characteristics of 16 patients with defects of ketolysis: Experience from a single center
Abstract
Aim: Beta-Ketothiolase(T2) and Succinyl-CoA:3-ketoacid CoA transferase(SCOT) enzymes are crucial in ketone body utilization. Deficiencies of these enzymes present in early childhood with recurrent ketoacidosis, triggered by fasting and catabolic states. In this study, we aim to investigate clinical and molecular findings of patients who have defects of ketolysis. Methods:15 patients with T2 and one patient with SCOT deficiency who are followed up in Çukurova University Department of Pediatric Metabolism and Nutrition were included in the study. Medical records were reviewed retrospectively. Results: Eight patients were female. 13 patients had parental consanguinity; 11 had positive family history. Patient with SCOT deficiency had his first ketoacidosis episode at second day of life. Mean age at first episode for T2-deficient patients was 8,0±6,7 months (4 days-105 months). Interestingly, between episodes, SCOT-deficient patient’s ketone levels were both positive and negative. Ketone levels were zero for T2-deficient patients between episodes. During episodes, 10 patients had hypoglycemia and six patients had hyperglycemia. Mean number of attacks were 3,8±3,1. For differential diagnosis, acylcarnitine profiles and urine organic acid analysis were studied. Molecular analyses were done for 11 patients,10 had novel mutations. Conclusion: Defects of ketolysis are rare but must be included in the differential diagnosis of organic acidemias. The differences from organic acidemias are persistent ketosis independent from nutritional status and absence of typical acylcarnitine and organic acid profiles. But, SCOT and T2 deficiencies do not require severe protein restriction and cofactor supplementation compared to organic acidemias. As a consequence, they do not interfere with life quality and growth like organic acidemias.
Keywords
Defects of ketolysis beta-ketothiolase deficiency ACAT1 Succinyl-CoA:3-ketoacid CoA transferase deficiency OXCT1
References
- 1. Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis 2014;37:541-51.
- 2. Sass JO, Fukao T, Mitchell GA. Inborn Errors of Ketone Body Metabolism and Transport: An Update for the Clinic and for Clinical Laboratories. J Inborn Errors of Metabolism and Screening 2018;6:1-7.
- 3. Hori T, Yamaguchi S, Shinkaku H, Horikawa R, Shigematsu Y, Takayanagi M, Fukao T. Inborn errors of ketone body utilization. Pediatr Int 2015;57:41-8.
- 4. Tildon JT, Cornblath M. Succinyl-CoA: 3-ketoacid CoA transferase deficiency. A cause for ketoacidosis in infancy. J Clin Invest 1972;51:493-8.
- 5. Daum RS, Lamm PH, Mamer OA, Scriver CR. A ‘’new” disorder of isoleucine catabolism. Lancet 1971;2:1289-90.
- 6. Fukao T, Shintaku H, Kusubae R, Zhang GX, Nakamura K, Kondo M, Kondo N. Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA transferase (SCOT) do not show permanent ketosis. Pediatr Res 2004;56(6):858–863.
- 7. Abdelkreem E, Harijan RK, Yamaguchi S, Wierenga RK, Fukao T. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency. Human Mutation 2019;40:1641–1663.
- 8. Nguyen KN, Abdelkreem E, Colombo R, Hasegawa Y, Can NTB, Bui TP, LE HT, Tran MTC, Nguyen HT, Trinh HT, Aoyama Y, Sasai H, Yamaguchi S, Fukao T, Vu DC. Characterization and outcome of 41 patients with beta‐ketothiolase deficiency: 10 yearsʼ experience of a medical center in northern Vietnam. J Inherit Metab Dis 2017;40(3), 395–401.
- 9. Grünert SC, Schmitt RN, Schlatter SM, Gemperle‐Britschgi C, Balcı MC, Berg V, , Çoker M, Das AM, Demirkol M, Derks TGJ, Gökçay G, Uçar SK, Konstantopoulou V, Korenke GC, Lotz-Havla AS, Schlune A, Staufner C, Tran C, Visser G, Schwab KO, Fukao T, Sass JO. Clinical presentation and outcome in a series of 32 patients with 2‐methylacetoacetyl‐coenzyme A thiolase (MAT) deficiency. Mol Genet Metab 2017;122(1‐ 2), 67–75.
- 10. Fukao T, Sass JO, Kursula P, Thimm E, Wendel U, Ficicoglu C, Monastiri K, Guffon N, Baric I, Zabot MT, Kondo N. Clinical and molecular characterization of five patients with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. Biochim Biophys Acta 2011;1812(5):619–624.
- 11. Fukao, T., Sasai, H., Aoyama, Y., Otsuka, H., Ago, Y., Matsumoto, H., Abdelkreem, E. Recent advances in understanding betaketothiolase (mitochondrial acetoacetyl‐CoA thiolase, T2) deficiency. J Hum Genet 2018;64(2), 99–111.
- 12. Fukao, T., Scriver, C. R., & Kondo, N., T2 Collaborative Working Group. The clinical phenotype and outcome of mitochondrial acetoacetyl‐CoA thiolase deficiency (beta‐ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation‐defined patients. Mol Genet Metab 2001;72(2), 109–114.
- 13. Demir Köse M, Canda E, Kağnıcı M, İşgüder R, Ünalp A, Uçar SK, Bahr L, Britschgi C, Sass JO, Çoker M. Two Siblings with Beta-Ketothiolase Deficiency: One Genetic Defect Two Different Pictures. J Pediatr Res 2016;3:113-6.
- 14. Thümmler, S., Dupont, D., Acquaviva, C., Fukao, T., & DeRicaud, D. Different clinical presentation in siblings with mitochondrial acetoacetyl‐CoA thiolase deficiency and identification of two novel mutations. Tohoku J Exp Med 2010;220(1), 27–31.
- 15. Canda E, Yazıcı H, Er E, Kalkan Uçar S, Gemperle-Brıtschgı C, Habif S, Onay H, Sass JO, Çoker M. Tekrarlayan ketoasidoz atakları: Keton metabolizma bozuklukluğu olabilir mi? (Recurrent ketoacidosis: Is it a ketone metabolism disorder?) İzmir Dr. Behçet Uz Çocuk Hast. Dergisi 2018;8(2):115-121.
- 16. Paquay S, Bourillon A, Pichard S, Benoist JF, deLonlay P, Dobbelaere D, Fouilhoux A, Guffon N, Rouvet I, Labarthe F, Mention K, Touati G, Valayannopoulos V, de Baulny HO, Elmaleh-Bergès M, Acquaviva-Bourdain C, Vianey-Saban C, Schiff, M. Mitochondrial acetoacetyl‐CoA thiolase deficiency: Basal ganglia impairment may occur independently of ketoacidosis. J Inherit Metab Dis 2017;40(3), 415–422.
- 17. Abdelkreem E, Otsuka H, Sasai H, Aoyama Y, Hori T, El Aal MA, Fukao T. Beta- Ketothiolase deficiency: resolving challenges in diagnosis. J Inborn Errors of Metabolism and Screening 2016;4: 1-9
Ketoliz defekti tanısıyla izlenen 16 hastanın klinik ve moleküler özelliklerinin incelenmesi: Tek merkez deneyimi
Abstract
Amaç: Beta-ketotiolaz (T2) ve suksinil-KoA:3-ketoasit KoA transferaz (SCOT) keton cisimlerinin yıkımında görev alan iki enzimdir. Ketolizde görevli bu iki enzimin eksikliğinde erken çocuklukta açlık veya diğer katabolik süreçlerle tetiklenen ve tekrarlayan ketoasidoz atakları görülür. Bu çalışmada, ketoliz defekti tanısıyla izlenen hastaların klinik ve moleküler özelliklerinin incelenmesi amaçlandı. Yöntem: Çukurova Üniversitesi Çocuk Metabolizma ve Beslenme Bilim Dalı’nda takipli 15 T2 eksikliği ve bir SCOT eksikliği tanılı hasta çalışmaya dahil edildi. Geriye dönük hastaların tıbbi kayıtları incelendi. Bulgular: Hastaların sekizi kız, sekizi erkekti. 13 hastada anne-baba akrabalığı, 11 hastada aile öyküsü vardı. SCOT eksikliği olan hastanın ilk ketoasidoz atağı iki günlükken olmuştu. T2 eksikliği olan hastalarda ise ilk atak yaşı ortalama 8,0±6,7 aydı (4 gün-29 ay). SCOT eksikliği olan hastanın atakları arasında hem negatif hem pozitif aseton değerleri olması ilginç özelliğiydi. T2 eksikliği tanılı hastaların tümünde atak dışında keton hep negatifti. Atak sırasında 10 hastada hipoglisemi, altısında ise hiperglisemi görüldü. Hastaların izlem süresince ortalama atak sayısı 3,8±3,1 idi. Hastalardan tanı ve ayırıcı tanı için açilkarnitin profili ve organik asit analizi çalışıldı. Mutasyon analizi yapılabilen 11 hastadan 10’unda bulunan mutasyonlar literatürde ilk kez bu çalışmayla tanımlandı. Sonuç: Ketoasidoz tablosunda gelen hastalarda organik asidemi ayırıcı tanısında daha nadir görülseler de ketoliz defektlerinin akılda tutulması gereklidir. Organik asidemilerden farklı olarak hastaların çoğunda kan şekeri ve beslenme durumundan bağımsız süreğen ketozisin olması, tipik organik asit ve açilkarnitin profili en önemli tanısal ipuçlarıdır. Bu gruptaki iki hastalığın tedavileri organik asidemiler kadar ciddi ve süreğen protein kısıtlaması ve kofaktör desteği gerektirmediğinden hem hastaların büyümelerini hem de yaşam kalitelerini daha az etkilemektedir.
Keywords
Ketoliz defektleri Beta-ketotiolaz eksikliği ACAT1 Suksinil-KoA:3-ketoasit KoA transferaz eksikliği OXCT1
References
- 1. Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis 2014;37:541-51.
- 2. Sass JO, Fukao T, Mitchell GA. Inborn Errors of Ketone Body Metabolism and Transport: An Update for the Clinic and for Clinical Laboratories. J Inborn Errors of Metabolism and Screening 2018;6:1-7.
- 3. Hori T, Yamaguchi S, Shinkaku H, Horikawa R, Shigematsu Y, Takayanagi M, Fukao T. Inborn errors of ketone body utilization. Pediatr Int 2015;57:41-8.
- 4. Tildon JT, Cornblath M. Succinyl-CoA: 3-ketoacid CoA transferase deficiency. A cause for ketoacidosis in infancy. J Clin Invest 1972;51:493-8.
- 5. Daum RS, Lamm PH, Mamer OA, Scriver CR. A ‘’new” disorder of isoleucine catabolism. Lancet 1971;2:1289-90.
- 6. Fukao T, Shintaku H, Kusubae R, Zhang GX, Nakamura K, Kondo M, Kondo N. Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA transferase (SCOT) do not show permanent ketosis. Pediatr Res 2004;56(6):858–863.
- 7. Abdelkreem E, Harijan RK, Yamaguchi S, Wierenga RK, Fukao T. Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency. Human Mutation 2019;40:1641–1663.
- 8. Nguyen KN, Abdelkreem E, Colombo R, Hasegawa Y, Can NTB, Bui TP, LE HT, Tran MTC, Nguyen HT, Trinh HT, Aoyama Y, Sasai H, Yamaguchi S, Fukao T, Vu DC. Characterization and outcome of 41 patients with beta‐ketothiolase deficiency: 10 yearsʼ experience of a medical center in northern Vietnam. J Inherit Metab Dis 2017;40(3), 395–401.
- 9. Grünert SC, Schmitt RN, Schlatter SM, Gemperle‐Britschgi C, Balcı MC, Berg V, , Çoker M, Das AM, Demirkol M, Derks TGJ, Gökçay G, Uçar SK, Konstantopoulou V, Korenke GC, Lotz-Havla AS, Schlune A, Staufner C, Tran C, Visser G, Schwab KO, Fukao T, Sass JO. Clinical presentation and outcome in a series of 32 patients with 2‐methylacetoacetyl‐coenzyme A thiolase (MAT) deficiency. Mol Genet Metab 2017;122(1‐ 2), 67–75.
- 10. Fukao T, Sass JO, Kursula P, Thimm E, Wendel U, Ficicoglu C, Monastiri K, Guffon N, Baric I, Zabot MT, Kondo N. Clinical and molecular characterization of five patients with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. Biochim Biophys Acta 2011;1812(5):619–624.
- 11. Fukao, T., Sasai, H., Aoyama, Y., Otsuka, H., Ago, Y., Matsumoto, H., Abdelkreem, E. Recent advances in understanding betaketothiolase (mitochondrial acetoacetyl‐CoA thiolase, T2) deficiency. J Hum Genet 2018;64(2), 99–111.
- 12. Fukao, T., Scriver, C. R., & Kondo, N., T2 Collaborative Working Group. The clinical phenotype and outcome of mitochondrial acetoacetyl‐CoA thiolase deficiency (beta‐ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation‐defined patients. Mol Genet Metab 2001;72(2), 109–114.
- 13. Demir Köse M, Canda E, Kağnıcı M, İşgüder R, Ünalp A, Uçar SK, Bahr L, Britschgi C, Sass JO, Çoker M. Two Siblings with Beta-Ketothiolase Deficiency: One Genetic Defect Two Different Pictures. J Pediatr Res 2016;3:113-6.
- 14. Thümmler, S., Dupont, D., Acquaviva, C., Fukao, T., & DeRicaud, D. Different clinical presentation in siblings with mitochondrial acetoacetyl‐CoA thiolase deficiency and identification of two novel mutations. Tohoku J Exp Med 2010;220(1), 27–31.
- 15. Canda E, Yazıcı H, Er E, Kalkan Uçar S, Gemperle-Brıtschgı C, Habif S, Onay H, Sass JO, Çoker M. Tekrarlayan ketoasidoz atakları: Keton metabolizma bozuklukluğu olabilir mi? (Recurrent ketoacidosis: Is it a ketone metabolism disorder?) İzmir Dr. Behçet Uz Çocuk Hast. Dergisi 2018;8(2):115-121.
- 16. Paquay S, Bourillon A, Pichard S, Benoist JF, deLonlay P, Dobbelaere D, Fouilhoux A, Guffon N, Rouvet I, Labarthe F, Mention K, Touati G, Valayannopoulos V, de Baulny HO, Elmaleh-Bergès M, Acquaviva-Bourdain C, Vianey-Saban C, Schiff, M. Mitochondrial acetoacetyl‐CoA thiolase deficiency: Basal ganglia impairment may occur independently of ketoacidosis. J Inherit Metab Dis 2017;40(3), 415–422.
- 17. Abdelkreem E, Otsuka H, Sasai H, Aoyama Y, Hori T, El Aal MA, Fukao T. Beta- Ketothiolase deficiency: resolving challenges in diagnosis. J Inborn Errors of Metabolism and Screening 2016;4: 1-9
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Health Care Administration |
| Journal Section | Articles |
| Authors | |
| Publication Date | August 26, 2020 |
| Submission Date | February 10, 2020 |
| Acceptance Date | March 19, 2020 |
| Published in Issue | Year 2020 Volume: 13 Issue: 2 |
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MEU Journal of Health Sciences Assoc was began to the publishing process in 2008 under the supervision of Assoc. Prof. Gönül Aslan, Editor-in-Chief, and affiliated to Mersin University Institute of Health Sciences. In March 2015, Prof. Dr. Caferi Tayyar Şaşmaz undertook the Editor-in Chief position and since then he has been in charge.
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