Article citationsMore >>

Fukao T, Sasai H, Aoyama Y, Otsuka H, Ago Y, Matsumoto H, Abdelkreem E. Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency. J Hum Genet. 2019 Feb; 64(2): 99-111.

has been cited by the following article:

Article

Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article)

1Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

2Department of Medical Biochemistry, Sohag Faculty of Medicine, Sohag University, Egypt

3Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt

4Department of Medical Physiology, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

5Department of Clinical and Hospital Pharmacy, College of pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.

6Division of Cardiology, Department of Medicine, Taibah College of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

7Department of Medical Pharmacology, Sohag Faculty of Medicine, Sohag University, Egypt

8Department of Pediatrics, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

9Department of Ear, Nose and Throat, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia

100Department of Medical Physiology, Kafr Elshekh Faculty of Medicine, Kafr Elshekh University, Egypt

111Department of Medical Physiology, Sohag Faculty of Medicine, Sohag University, Egypt

122Department of Pediatrics, Division of Pediatric Cardiology, Sohag Teaching Hospital, Sohag, Egypt


International Journal of Clinical and Experimental Neurology. 2020, Vol. 8 No. 1, 4-8
DOI: 10.12691/ijcen-8-1-2
Copyright © 2020 Science and Education Publishing

Cite this paper:
Salah Mohamed El Sayed, Elsayed Abdelkreem, Moutasem Salih Aboonq, Sultan S. Al Thagfan, Yaser M. Alahmadi, Osama Alhadramy, Hussam Baghdadi, Mohammed Hassan, Faten M. Omran, Hytham Mahmoud Abdel-Latif, Wafaa Abdel-ziz, Azza Mahmoud Ahmed Abouelella, Amr El-Dardear, Mohamed Abdel-haleem, Elhussainy MA Elhussainy, Hassan El-Alaf, Manal Mohamed Helmy Nabo. Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article). International Journal of Clinical and Experimental Neurology. 2020; 8(1):4-8. doi: 10.12691/ijcen-8-1-2.

Correspondence to: Salah  Mohamed El Sayed, Department of Clinical Biochemistry and Molecular Medicine, Taibah Faculty of Medicine, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia. Email: salahfazara@yahoo.com, drsalahpediatr@yahoo.com

Abstract

Beta-ketothiolase deficiency (BKTD) is an inborn error of ketone bodies and isoleucine metabolism. Patients with BKTD manifest during late infancy and early childhood with recurrent episodes of ketoacidosis (accumulated acetoacetate and β-hydroxybutyrate) that may be refractory to treatment and life-threatening. BKTD is exaggerated by fasting, starvation and catabolic conditions. Dichloroacetate (DCA) is a safe effective treatment for both lactic acidosis and non-Hodgkin’s lymphoma. DCA is non-toxic and non-carcinogenic at therapeutic doses. DCA toxic doses are hundred times (12- gram/l) more than the therapeutic doses. In experimental models of ketosis, DCA reduces ketonemia and ketonuria while significantly lowering blood glucose. Importantly, DCA was reported to divert pyruvate (amino group acceptor to form alanine in transamination reactions to regenerate α-ketoglutarate from glutamate) to oxidative pathways to form acetyl CoA that is oxidized in Krebs cycle. That inhibits first step of isoleucine catabolism (transamination step) and consequently blocks formation of acetoacetate and β-hydroxybutyrate. That alleviates ketone bodies-induced refractory metabolic acidosis. On biochemical and pharmacological bases, we suggest DCA as a novel evidence-based adjuvant and life-saving treatment for BKTD. Moreover, DCA-induced inhibition of ketone bodies uptake will be alleviated by insulin effects. Causes of refractory metabolic acidosis in BKTD are increased levels of ketone bodies (due to increased isoleucine catabolism, increased ketone bodies formation and decreased ketone bodies utilization). DCA relieves most of these. Biochemically, DCA and ketone bodies (acetoacetate and β-hydroxybutyrate) are structural analogs derived from acetic acid. In neonatology, DCA improved neonatal septicaemia-induced refractory metabolic acidosis that did not respond to conventional sodium bicarbonate. In conclusion, DCA is strongly suggested to treat BKTD.

Keywords