Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency

Abstract

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.

Massive Pulmonary Embolism in a Patient with Undiagnosed Homocystinuria

“…When homocystinuria is diagnosed early, the treatments discussed can drastically improve quality and duration of life. Adhering to a methionine-restricted diet from a young age has been shown to mitigate intellectual disability [5]. Betaine and pyridoxine supplementation reduces thrombosis and other morbidities associated with untreated homocystinuria.…”

“…Encoded by the start codon AUG, methionine is the first amino acid in every polypeptide chain. It is also one of only two sulfur-containing amino acids, the other being cysteine [5].…”

Therapeutic targets in homocystinuria due to cystathionine β-synthase deficiency: new European guidelines

“…These issues have been taken up in the newly available 'Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency' [4]. This guideline is one of four developed under the umbrella of eHOD -the acronym for the European Network and Registry for Homocystinurias and Methylation Defects [5].…”

Guidelines on homocystinurias and methylation defects: a harmonized approach to diagnosis and management

“…The European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) consortium (for more information, see http://www.e-hod.org) created three excellent state-of-theart recommendation papers reviewing clinical spectrum, diagnosis, and treatment of this group of disorders (see Huemer et al, 2016, Barić et al, 2016, and Morris et al, 2016.…”

“…Finally, and very importantly, the third review and guideline paper by Morris et al (2016) (this issue) focuses on classic homocystinuria due to cystathione beta synthase (CBS) deficiency. This disorder is definitely underdiagnosed due to high clinical variability, later-onset of symptoms in pyridoxine-sensitive CBS defect, metabolic differences between pyridoxine-sensitive and nonsensitive forms, and our current NBS practices (Huemer et al, 2015).…”