CBS deficiency: clinical guidelines

1. CBS deficiency: clinical guidelines Andrew Morris Central Manchester University Hospitals

2. Tetrahydrofolate Methionine Methyl group B12 Methyltetrahydrofolate Homocysteine Serine Cystathionine β-synthase Pyridoxal 5’-phosphate Cystathionine Cysteine

3. CBS deficiency Adverse effects • Brain • Eye • Skeleton • Blood clotting Complete deficiency causes early-onset multisystem disease B6-responsive cases may be asymptomatic or only suffer adult-onset thromboembolism

4. CBS deficiency: Clinical problems Brain • Learning difficulties • Psychiatric & behaviour disorders • Seizures • Clumsiness • Strokes Eye • Lens dislocation • High Myopia

5. CBS deficiency: Skeleton • Tall • Pigeon chest • Knock knees • Osteoporosis • Scoliosis

6. Classical Homocystinuria: Blood clots • Deep Venous Thromboses • Pulmonary Emboli • Saggital sinus thrombosis

7. Presentation • Paediatricians, including those working with learning disorders • Paediatric & adult neurologists • Ophthalmologists • Orthopedic surgeons • Haematologists

8. CBS deficiency Prevalence • Unknown, maybe 1/300,000 diagnosed globally • Approx 50% cases said to respond to vit B6 BUT based on frequency of carriers • 1/10,000 probably have a mild B6-responsive form • Many asymptomatic or only have DVTs as adults

9. CBS deficiency Problems • Rare • Awareness is low • Still many uncertainties about diagnosis & management Need evidence-based guidelines • To help doctors with limited experience • To highlight uncertainties & stimulate research

10. Evidence-based Guideline • Team of paediatricians, adult physicians, biochemists, dietitians, geneticist, statistician • Kimberly Chapman identified several hundred relevant medical articles • Key questions agreed & allocated (2 people each) • Answers prepared with supporting evidence (often expert opinion) & discussed with team • Guideline written, circulated to team & reviewers & revised – nearly finalised

11. Diagnosis of homocystinuria • Plasma total homocysteine (tHcy) • Free homocystine (in plasma or urine) unreliable • tHcy may be normal in B6-responsive patients if taking multivitamins containing B6 • Plasma should be separated promptly

12. Other causes of high homocysteine • Vitamin B12 or folate deficiencies • Renal failure • Remethylation defects • Methylation defects • CBS deficiency confirmed by mutation analysis or CBS assay (in plasma or fibroblasts)

13. CBS deficiency: Newborn screening • Blood methionine Outcomes • Normal if good compliance Problem • Some cases not detected

14. Dietary restriction Methionine Folic acid B12 Betaine Homocysteine Pyridoxine Cystathionine Cysteine

15. Treatment with Pyridoxine • Presumed to stabilise the mutant CBS enzyme • Normal homocysteine on low doses in some pts • Partial response even on high doses in other pts Side effects • Peripheral neuropathy with high doses (>900 mg/d) Recommended dose • Lowest effective • Up to 10mg/kg/d, max. 500mg/d

16. Testing for B6 responsiveness We propose • Test when pt is stable, on normal protein intake • Give folate & correct B12 if deficient • Pyridoxine 10mg/kg/d up to 500mg/d • Continue for 6 weeks with at least 2 tHcy measurements before & on pyridoxine • Response: >20% fall in tHcy If detected by newborn screening, response very rare • Pyridoxine 100mg/d for 2 weeks

17. Low methionine diet • Small, measured amounts of food containing methionine • Methionine-free amino acid mixture • Adequate energy from low protein foods • most fruit & vegetables • synthetic e.g. LP bread, biscuits, pasta • Vitamin & mineral supplements

18. Monitoring • Total Homocysteine Methionine • Frequency depends on severity, treatment, age • Blood spots can be used but most labs require liquid blood, separated promptly • Also B12, folate Nutrition Bone density

19. Homocysteine targets • Normal IQ & no complications in Irish pts with free Homocystine <11 umol/l (Yap 1998 & 2001) • We propose keeping tHcy <100 • Safety of tHcy <120 based on few pts, up to 30yr • Lower levels hard to achieve 120 tHcy fHcy 11

20. Low methionine diet Problems • Diet & supplements relatively unpalatable • Restrictions unpopular • Expert dietetians required • Introduction of diet harder after infancy • Diet needed throughout life but compliance deteriorates

21. Betaine Dimethylglycine Methionine Roles • Add to diet if homocysteine above targets • Deteriorating compliance with age • Poor compliance in late diagnosed patients Side effects • Taste, Fishy odour at high doses • Methionine rises, seldom toxic but brain swelling in few patients with methionine >1000 umol/l Betaine Homocysteine

22. Minimise risk of thromboses During travel, surgery, infections & pregnancy • Good hydration • Compression stockings • Early mobilisation • Anticoagulants Contraceptives • Avoid oestrogens (combined pill)

23. Summary: Classical homocystinuria • Childhood onset: learning difficulties lens dislocation skeletal abnormalities • Later onset: thromboembolism • Treatment: pyridoxine low methionine diet betaine • Newborn screening improves outcome but sensitivity is low