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

Abstract

CBS deficient individuals undergoing betaine supplementation without sufficient dietary methionine restriction can develop severe hypermethioninemia and brain edema. Brain edema has also been observed in individuals with severe hypermethioninemia without concomitant betaine supplementation. We systematically evaluated reports from 11 published and 4 unpublished patients with CBS deficiency and from additional four cases of encephalopathy in association with elevated methionine. We conclude that, while betaine supplementation does greatly exacerbate methionine accumulation, the primary agent causing brain edema is methionine rather than betaine. Clinical signs of increased intracranial pressure have not been seen in patients with plasma methionine levels below 559 μmol/L but occurred in one patient whose levels did not knowingly exceed 972 μmol/L at the time of manifestation. While levels below 500 μmol/L can be deemed safe it appears that brain edema can develop with plasma methionine levels close to 1000 μmol/L. Patients with CBS deficiency on betaine supplementation need to be regularly monitored for concordance with their dietary plan and for plasma methionine concentrations. Recurrent methionine levels above 500 μmol/L should alert clinicians to check for clinical signs and symptoms of brain edema and review dietary methionine intake. Levels approaching 1000 μmol/L do increase the risk of complications and levels exceeding 1000 μmol/L, despite best dietetic efforts, should be acutely addressed by reducing the prescribed betaine dose.

Paracetamol toxicity in classic homocystinuria: Effect of N‐acetylcysteine on total homocysteine

“…8,21 Cerebral oedema and hypermethioninaemia encephalopathy with reversible neuroimaging abnormalities have been reported in patients on betaine therapy with plasma methionine levels close or exceeding 1000 μmol/L. [21][22][23] Plasma methionine levels have been reported to range from normal to extremely high in patients with fulminant hepatic failure, due to disturbed methionine metabolism. 24,25 We report elevated concentrations of methionine (>1000 μmol/L) during ICU admission in our patient, despite betaine having been stopped on admission.…”

“…It is used in treatment of HCU, yet it does not fully correct the level of tHcy in HCU patients and increases plasma methionine level 8,21 . Cerebral oedema and hypermethioninaemia encephalopathy with reversible neuroimaging abnormalities have been reported in patients on betaine therapy with plasma methionine levels close or exceeding 1000 μmol/L 21–23 . Plasma methionine levels have been reported to range from normal to extremely high in patients with fulminant hepatic failure, due to disturbed methionine metabolism 24,25 …”

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial

“…Betaine supplementation without sufficient dietary methionine restriction can induce severe hypermethioninemia in CBS patients. Clinical signs of increased intracranial pressure and brain edema can be observed in patients with plasma Met concentrations close to 1000 µmol/L [ 25 ].…”

Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants

“…Of note, MARS1‐04 (Table S1) was also reported to improve his clinical condition after methionine supplementation, but no details on dosage or methionine levels were given, nor was follow‐up data available 12 . However, methionine supplementation should be handled carefully with monitoring of methionine plasma concentrations (suggested target range 80‐150 µmol/L), as high levels (>600 µmol/L) are neurotoxic leading to severe brain edema 22 . The index patient showed a considerable fluctuation of methionine concentrations despite standardized measurement regimens.…”