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.

Fig. 1

Pathways of methionine metabolism. SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; THF, tetrahydrofolate; MeCbl, methylcobalamin. 1, cystathionine beta-synthase; 2, methionine adenosyltransferase I/III; 3, methionine adenosyltransferase II; 4, glycine N-methyltransferase; 5, numerous methyltransferases; 6, S-adenosylhomocysteine hydrolase; 7, methionine synthase; 8, betaine-homocysteine methyltransferase; 9, Serine hydroxymethyltransferase; 10, methylenetetrahydrofolate reductase; 11, cystathionine gamma-lyase

Fig. 2

Various forms of aminothiols in plasma. Hcy-SH, free homocysteine; Cys-SH, free cysteine; Hcy-S-S-Hcy, free homocystine; Cys-S-S-Cys, free cystine; Hcy-S-S-Cys, mixed disulfide; Hcy-S-S-R and Cys-S-S-R, homocysteine and cysteine bound to other thiols

Fig. 3

Relationship between plasma total homocysteine and free homocystine. Figure 3a shows the simultaneous tHcy and fHcy measurements in 3522 plasma samples collected from 46 Irish patients with CBS deficiency. Blood samples were obtained at the time of routine clinic visits. Plasma was separated within 15 minutes after collection and a 150 μL aliquot of plasma was immediately deproteinised by addition of 15 μL of 35 % sulphosalicylic acid; fHcy was measured by ion-exchange chromatography with ninhydrin detection. tHcy was measured on the aliquot of neat plasma by ion-exchange chromatography with ninhydrin detection following incubation with 2.5 % dithiothreitol. Segmented linear regression analysis was used because fHcy could not be quantified accurately below 5 μmol/L. The black point shows the model’s estimate of the tHcy concentration at which fHcy will start to be present. The shadowing around the regression line shows the 90 % confidence band within which 90 % tHcy values lie for a given fHcy value. The section of the graph for fHcy <15 μmol/L is expanded in Fig. 3b

Fig. 4

Proposal for assessing pyridoxine responsiveness after infancy. The baseline must be stable and should be the average of at least two separate measurements