CBS deficiency: clinical guidelines Andrew Morris Central Manchester University Hospitals

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

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

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

CBS deficiency: Skeleton Tall Pigeon chest Knock knees Osteoporosis Scoliosis

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

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

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

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

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

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

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)

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

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

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

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

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

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

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 tHcy 120 fHcy 11

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

Betaine Dimethylglycine Methionine Betaine Homocysteine 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

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

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