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.

Biochemical Genetics St James' University Hospital Leeds UK

CHRU de Tours Université François Rabelais Tours France

Clinical IMD Birmingham Children's Hospital Birmingham UK

Department of Internal medicine Radboud University Medical Center Nijmegen Netherlands

Department of Metabolic Medicine Great Ormond Street Hospital London UK

Department of Pediatrics Hamad Medical Corporation Doha Qatar

Department of translational medicine Federico 2 University Naples Italy

Dept of Inherited Metabolic Diseases Sheffield Children's Hospital Sheffield UK

Dept of Paediatrics Landeskrankenhaus Bregenz Bregenz Austria

Dietetic Department Alder Hey Hospital Liverpool UK

Division of Endocrinology Diabetes and Clinical Nutrition University Hospital Zürich Zurich Switzerland

Division of Genetic and Metabolism Children's National Health System Washington DC USA

Division of Metabolism and Children's Research Center University Children's Hospital Zürich Zurich Switzerland

HCU Network Baulkham Hills Australia

Institute of Human Development University of Manchester Manchester UK

Institute of Inherited Metabolic Disorders Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Laboratory of Clinical Biochemistry and Metabolism Department of General Pediatrics Adolescent Medicine and Neonatology University Medical Centre Freiburg Freiburg im Breisgau Germany

Metabolism and Genetics Group Faculty of Pharmacy at University of Lisboa Lisboa Portugal

National Centre for Inherited Metabolic Disorders Temple Street Children's University Hospital Dublin Ireland

Newborn Bloodspot Screening Laboratory Temple Street Children's University Hospital Dublin Ireland

Rare Disease Initiative Zürich University of Zürich Zurich Switzerland

Royal Belfast Hospital for Sick Children Belfast UK

Service de Neurologie Pédiatrique et des Maladies Métaboliques Hôpital Robert Debré Paris France

Willink Unit Manchester Centre for Genomic Medicine Central Manchester University Hospitals St Mary's Hospital Oxford Road Manchester M13 9WL UK

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