Betaine anhydrous in homocystinuria: results from the RoCH registry

Abstract

BackgroundThe Registry of Adult and Paediatric Patients Treated with Cystadane® – Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year.ResultsA total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine β-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns.ConclusionsData from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.Electronic supplementary materialThe online version of this article (10.1186/s13023-019-1036-2) contains supplementary material, which is available to authorized users.

Betaine in ameliorating alcohol-induced hepatic steatosis

“…Also, when betaine was administrated in partially hepatectomized rats, it promoted liver regeneration whereby the liver regained its original weight in 7 days after surgery [ 14 ]. Alongside, it has exhibited great therapeutic potential in clinical trials for non-alcoholic steatohepatitis [ 15 ] and homocystinuria [ 16 ]. Generally, betaine has shown hepatoprotective properties against liver injury by enhancing antioxidant mechanisms and adipose tissue function, while reducing oxidative stress, endoplasmic stress, liver fibrosis and necrosis [ 17 ].…”

“…Exposure of 4 g/day for 6 months showed no adverse effects on platelet counts in human. Exposure of 0.4 g/day betaine in addition to the endogenous exposure is considered safe for human [ 50 ] Clinical trials Oral, 1,3,6 g single doses mixed with orange juice after overnight fast [ 51 ] Oral, 3 g/day for 1 month [ 9 ] Oral, 10 g, twice a day, probably for 12 months [ 13 ] Oral, 20 g/day for 12 months [ 52 ] 3–9 g/day for different conditions for a mean of 7.4 ± 4.3 years [ 16 ] Oral, betaine glucoronate in combination with diethanolamine glucuronate and nicotinamide ascorbate for 8 weeks [ 53 ] Oral, 20 g/day in 2 divided doses for 12 months [ 54 ] Oral, 10 g (anhydrous betaine) twice a day for 12 months [ 55 ] Animal experiments Piglets: 20 g/kg feed (2% betaine in diet) for 6 weeks [ 50 ] Rats: ethanol with 1% betaine for 6 months [ 7 ] Rats: 10 and 50 mg/kg i.p for three consecutive days [ 17 ] Rats: ethanol containing water with betaine (1% w/v) for 6 months [ 18 ] Rats: betaine 0.4 g/kg/day intragastrically post 12 weeks of high-fat diet from weeks 13–16 [ 19 ] Rats: ethanol with betaine (1% w/v; 10 mg/mL) for 4–5 weeks [ 23 ] Rats: ethanol with 1% betaine for 4 weeks [ 28 ] ...…”

Interplay of Enzyme Therapy and Dietary Management of Murine Homocystinuria

“…The efficacy of Bet in lowering tHcy diminished significantly over time in HO mice [ 26 ], which was later found to be alleviated by taurine treatment, which induced Bet-repressed expression of BHMT [ 27 ]. However, the long-term efficacy of Bet in HCU patients does not seem to be compromised [ 28 ]. Our studies showed that OT-58 provided additional benefit in correcting metabolic balance in HO mice over Bet supplementation alone and successfully competed with Bet for Hcy substrate.…”

Cystathionine beta synthase deficiency and brain edema associated with methionine excess under betaine supplementation: Four new cases and a review of the evidence

“…In addition, we approached clinical metabolic specialists who participate in a large international email‐based discussion forum (Metab‐L, A mailing‐list on Inborn Errors of Metabolism, http://www.metab-l.de) and the sponsor of the European post‐authorization safety study for betaine to identify potential further unpublished cases. This project was endorsed by the European network for Homocystinurias and Remethylation Disorders (E‐HOD).…”