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CBS deficiency: clinical guidelines
Andrew Morris Central Manchester University Hospitals
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Methyltetrahydrofolate
Methionine Methyl group B12 Methyltetrahydrofolate Homocysteine Serine Cystathionine β-synthase Pyridoxal 5’-phosphate Cystathionine Cysteine 2
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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
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CBS deficiency: Clinical problems
Eye Lens dislocation High Myopia Brain Learning difficulties Psychiatric & behaviour disorders Seizures Clumsiness Strokes
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CBS deficiency: Skeleton
Tall Pigeon chest Knock knees Osteoporosis Scoliosis
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Classical Homocystinuria: Blood clots
Deep Venous Thromboses Pulmonary Emboli Saggital sinus thrombosis
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Presentation Paediatricians, including those working with learning disorders Paediatric & adult neurologists Ophthalmologists Orthopedic surgeons Haematologists
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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
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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
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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
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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
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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)
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CBS deficiency: Newborn screening
Blood methionine Outcomes Normal if good compliance Problem Some cases not detected
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Dietary restriction Methionine Betaine Homocysteine Pyridoxine
Folic acid B12 Betaine Homocysteine Pyridoxine Cystathionine Cysteine 14
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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
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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
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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
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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
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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
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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
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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
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Minimise risk of thromboses
During travel, surgery, infections & pregnancy Good hydration Compression stockings Early mobilisation Anticoagulants Contraceptives Avoid oestrogens (combined pill)
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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
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