Cystathionine β-Synthase Deficiency in the E-HOD Registry-Part II: Dietary and Pharmacological Treatment

Abstract

Cystathionine β-synthase (CBS) deficiency (classical homocystinuria) has a wide range of severity. Mildly affected patients typically present as adults with thromboembolism and respond to treatment with pyridoxine. Severely affected patients usually present during childhood with learning difficulties, ectopia lentis and skeletal abnormalities; they are pyridoxine non-responders (NR) or partial responders (PR) and require treatment with a low-methionine diet and/or betaine. The European network and registry for Homocystinurias and methylation Defects (E-HOD) has published management guidelines for CBS deficiency and recommended keeping plasma total homocysteine (tHcy) concentrations below 100 μmol/L. We have now analysed data from 311 patients in the registry to see how closely treatment follows the guidelines. Pyridoxine-responsive patients generally achieved tHcy concentrations below 50 μmol/L, but many NRs and PRs had a mean tHcy considerably above 100 μmol/L. Most NRs were managed with betaine and a special diet. This usually involved severe protein restriction and a methionine-free amino acid mixture, but some patients had a natural protein intake substantially above the WHO safe minimum. Work is needed on the methionine content of dietary protein as estimates vary widely. Contrary to the guidelines, most NRs were on pyridoxine, sometimes at dangerously high doses. tHcy concentrations were similar in groups prescribed high or low betaine doses and natural protein intakes. High tHcy levels were probably often due to poor compliance. Comparing time-to-event graphs for NR patients detected by newborn screening and those ascertained clinically showed that treatment could prevent thromboembolism (risk ratio 0.073) and lens dislocation (risk ratio 0.069).

Keywords: betaine; homocystinuria; methionine; newborn screening; protein restriction; pyridoxine.

FIGURE 1

Venn diagrams showing the treatment modalities used in different groups (NBS, NR, PR, FR and ER). One NR and one ER patient were on no treatment when data were entered into the registry (not included in Venn diagrams).

FIGURE 2

Pyridoxine doses for patients in different groups. For each individual the dose is expressed in mg/kg/day and is the mean of the values at different visits. In the NBS group, partial pyridoxine responders are represented by X and non‐responders by a dot.

FIGURE 3

Natural protein consumption and total protein consumption (natural + amino acid mixture) for patients in different groups, expressed as a percentage of the WHO safe protein intake. In the NBS group, partial pyridoxine responders are represented by X and non‐responders by a dot.

FIGURE 4

Estimates of the methionine content of 100 g natural protein from different centres' data. These have been calculated when centres provided data for both methionine and natural protein consumption. For each centre, the diamond is the median of the estimates for different patients, the whiskers show the interquartile range and dots show the maximum and minimum. The colour shows the geographical location of the centre.

FIGURE 5

Biochemical efficacy of therapy for patients in different groups. Plasma tHcy and methionine concentrations at diagnosis are compared with the mean values on treatment for each patient whilst enrolled in the registry.

FIGURE 6

Kaplan–Meier time‐to‐event graphs for first thromboembolic event (Panel A) and lens dislocation (Panel B) in pyridoxine non‐responsive patients. For patients detected by newborn screening, the curve shows the proportion who had not suffered an event at the time of their last visit. For clinically ascertained patients, separate curves show the proportion who had not suffered an event at the time of diagnosis and at the time of their last visit. The shaded areas show 95% confidence intervals. The numbers at risk at 5‐year spaced time points are shown in Table S6.