Dr. Andrew Morris Guidelines for the diagnosis and management of CBS deficiency

1. Dr. Andrew Morris Guidelines for the diagnosis and management of CBS deficiency

2. Established 2014 Our vision: To be a driving force in the journey to a cure, improving quality of life along the way Our priorities are: Connect and support people impacted by homocystinuria; Improve the diagnosis path to enable appropriate treatment; Provide education and information to people impacted by homocystinuria; Encourage and support clinical research, research for novel therapies and ultimately a cure; and Raise funds to achieve our objectives.

3. Classical homocystinuria : clinical guidelines Andrew Morris Central Manchester University Hospitals

4. Who are you? • Patient • Parent or other relative • Doctor • Other healthcare professional

5. Where are you? • Australasia • Europe • North America • South America • Asia • Middle East

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

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

8. CBS deficiency: Clinical problems Brain • Learning difficulties • Psychiatric & behaviour disorders • Seizures • Clumsiness • Strokes Eye • Lens dislocation • Severe myopia

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

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

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

12. Which symptom does NOT suggest CBS deficiency? • Learning difficulties • Lens dislocation • Deafness • Excessive growth • Osteoporosis • Deep venous thrombosis

13. CBS deficiency Prevalence • Unknown, maybe 1/300,000 diagnosed globally • Approx 50% cases said to respond to pyridoxine (vitamin 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

14. 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

15. Evidence-based Guideline • EHOD: European Network and Registry for Homocystinurias and Methylation Defects • Team of paediatricians, adult physicians, biochemists, dietitians, geneticist, statistician • Key questions agreed & allocated • Answers prepared with supporting evidence (often expert opinion) & discussed with team • Guideline written, circulated to team & reviewers & revised • Published in J Inherit Metab Dis, Open Access

16. 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

17. 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)

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

19. What is the most reliable test for diagnosing CBS deficiency? • X-rays • Newborn screening • Urine homocystine • Plasma total homocysteine • Plasma total homocysteine after taking vitamin supplements for 2 weeks

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

21. Treatment with Pyridoxine (B6) • Presumed to stabilise the mutant CBS enzyme • Some patients respond to low doses • Partial response in some other patients Side effects • Peripheral neuropathy with high doses (>900 mg/d) Recommended dose • Lowest effective • Up to 10mg/kg/d, max. 500mg/d

22. Testing for B6 responsiveness We propose • Test when patient 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

23. 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

24. 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

25. 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

26. 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

27. Betaine Dimethylglycine Methionine Roles • Add to diet if unable to reach homocysteine targets • Seldom achieves adequate control alone 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

28. Minimise risk of thromboses During travel, surgery, infections & pregnancy • Good hydration • Compression stockings • Early mobilisation • Anticoagulants e.g. low molecular weight heparin Contraceptives • Avoid oestrogens (combined pill)

29. Which of these should not be used in CBS deficiency? • Pyridoxine • Low methionine diet • Betaine • Low molecular weight heparin • Contraceptives with a high oestrogen dose

30. Summary: CBS deficiency • 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

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