Cystathionine β-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis

Abstract

Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.

Keywords: developmental delay; homocystinuria; methionine; natural history; patient registry; thromboembolism.

FIGURE 1

Geographical distribution of responsiveness groups and biochemical findings at diagnosis. A, Number of patients per country; B, mode of ascertainment; C, total homocysteine and methionine at diagnosis; and D, CBS activity in fibroblasts and plasma. Data are stratified by degree of responsiveness, NR, non‐responders; PR, partial responders; FR, full responders; ER, extreme responders. Bar graphs in Panels A and B show numbers and proportion of patients with different responsivity, respectively. Horizontal bars in Panels C and D indicate the medians. If plasma CBS activities were measured on and off pyridoxine, the results are connected with diagonal lines. Fibroblast and plasma CBS activities are shown as % of median of controls

FIGURE 2

Onset of symptoms, diagnostic delay and combination of symptoms in untreated patients. A, Age at presentation and diagnosis, and B, combination of affected systems in clinically ascertained patients. Data are stratified by the degree of responsiveness, NR, non‐responders; PR, partial responders; FR, full responders; ER, extreme responders. Horizontal bars in panel A indicate the medians. Panel B, Venn diagrams showing the combination of clinical complications; numbers indicate percentages for each responsiveness group

FIGURE 3

Time‐to‐event graphs of thromboembolism and lens dislocation in untreated clinically ascertained patients. A, Presence and/or history of thromboembolism and B, presence and/or history of lens dislocation. Curves were constructed by the method of Kaplan and Meier, patients were censored at the age of diagnosis if lens dislocation or thromboembolic event were present at diagnosis and/or were recorded in patients' histories. Data are stratified by degree of responsiveness, NR, non‐responders; PR, partial responders; FR, full responders; ER, extreme responders