Kimberly A Chapman MD PhD Childrens National Rare Disease Institute Homocystinurias Methionine Homocysteine Cystathionine Cysteine Cystathionine beta synthase CBS Adomet AdoHcy Betaine homocystine ID: 927727
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Slide1
Discussion of the new guidelines for cystathionine-beta synthase deficiency
Kimberly A Chapman, M.D., Ph.D.Children’s National Rare Disease Institute
Slide2Homocystinurias
Methionine
Homocysteine
Cystathionine
Cysteine
Cystathionine beta synthase (CBS)
Adomet
AdoHcy
Betaine homocystine
methyltransferase
Methionine
synthase
5-Methyl
tetrafolate
Tetrahydro-
folate
5,10-Methylene
tetrahydrofolate
Methylene
Tetrahydrofolate
Reductase
(MTHFR)
Slide3CNS: Psychosis, Mental Health, Intellectual Disability, Movement disorders
Eyes: Ectopia lentis, Severe myopia
Skeleton:
Excessive height, Long limbs, Osteoporosis, Bone deformities
Vascular system:
Thromboembolism (Venous > Arterial)
Clinical Features
CBS deficiency
Slide4Pyridoxine-responsive or Not
B6 responsiveResponds to B6 Goal total homocysteine: <50 µM
Often no metabolic foods or limited metabolic foods
+/- Betaine
Not B6 responsive
Does not respond to B6Goal total homocysteine: < 100 µMMetabolic foods are often needed+Betaine
Slide5CASE
Slide6Case
Ms. S. is a 54 year old with Homocystinuria
Routine clinic visit, accompanied by her husband
Currently:
Not drinking her HCU
Metabolic foods
She is taking betaine, and ‘several vitamins’ Eats meat 3 days per weekMost recent total homocysteine was 120 µM
Past Medical History:
deep vein thromboseswhite matter changes on MRIdiabetesrheumatoid arthritis poorly healing foot ulcer
Slide7Medications (prescribed)
Betaine: 4 grams twice dailyHydroxycobalamin: 1000
µg
PO daily
Aspirin:
80 mg dailyInsulin glargine injectionInsulin lispro
Slide8Medications (as reported)
Betaine: 4 grams dailyHydroxycobalamin: sometimes
Aspirin: 81 mg daily
Insulin glargine injection: maybe
Insulin
lispro: when remembers
Slide9Goals for therapy?
LaboratoryDiet
Sanity
Slide10Slide11What is your goal/target
total homocysteine level for “Classical”?
Less then 30 µM
Less then 60 µM
Less the 10 µM
Less then 80 µM Less then 100 µM Less then 130 µM
Slide12Goal Total Homocysteine
(Statement #15)
Total homocysteine:
less than 100 µM
(some experts think should be 70-80 µM)
If pyridoxine responsive: less than 50 µM
Slide13Total homocysteine vs. free homocystine
Free homocystine
difficult in many cases to do accurately
JIMD Morris et al. 2016
Slide14How to determine goals and how to
get there?Pyridoxine responsive (B6 responsive)?
Not pyridoxine-responsive
Slide15Pyridoxine responsiveness
Determine using a 10 mg/kg/day up to 500 mg pyridoxine (off all multivitamins and pyridoxine rich foods) for up to 6 weeksCheck total homocysteine at least 2x before and 2x afterwards
Responsive = total homocysteine
<
50 µM
If there is a decrease of 20% and > 50 µM possible utility in continuing (partially responsive).
Slide16Diet and Medications
Diet (most will need some methionine restriction)---difficult if have been offMedications
Pyridoxine (previous slide)
Betaine
6 g per day (or more)
250 mg/kg/dayFolate/B12
Slide17Brain
IntellectIf 1st 4 years, total homocysteine less than 100-120 µM (free 11 µM): normal intellect
Psychiatry (anxiety, depression, psychosis)
Yes
Slide18Thrombosis
Prevention is best policy by keeping homocysteine levels downIf have one, use usual interventions
Slide19Special
SurgeryAvoid dehydration and catabolismUsual anti-thrombotic interventionsPregnancy
Start anticoagulation early and 6 week post-partum
Slide20Questions?
My Contact information: Kimberly A Chapman
Children’s National
Washington DC
KChapman@childrensnational.org
Paging operators202 476 5000Ask for geneticist on call or me specificallyApril 24, 2017