Discussion of the new guidelines for cystathionine-beta synthase deficiency - PowerPoint Presentation

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Discussion of the new guidelines for cystathionine-beta synthase deficiency

Kimberly A Chapman, M.D., Ph.D.Children’s National Rare Disease Institute

Homocystinurias

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)

CNS: 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

Pyridoxine-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

CASE

Case

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

Medications (prescribed)

Betaine: 4 grams twice dailyHydroxycobalamin: 1000

µg

PO daily

Aspirin:

80 mg dailyInsulin glargine injectionInsulin lispro

Medications (as reported)

Betaine: 4 grams dailyHydroxycobalamin: sometimes

Aspirin: 81 mg daily

Insulin glargine injection: maybe

Insulin

lispro: when remembers

Goals for therapy?

LaboratoryDiet

Sanity

What 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

Goal 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

Total homocysteine vs. free homocystine

Free homocystine

difficult in many cases to do accurately

JIMD Morris et al. 2016

How to determine goals and how to

get there?Pyridoxine responsive (B6 responsive)?

Not pyridoxine-responsive

Pyridoxine 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).

Diet 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

Brain

IntellectIf 1st 4 years, total homocysteine less than 100-120 µM (free 11 µM): normal intellect

Psychiatry (anxiety, depression, psychosis)

Yes

Thrombosis

Prevention is best policy by keeping homocysteine levels downIf have one, use usual interventions

Special

SurgeryAvoid dehydration and catabolismUsual anti-thrombotic interventionsPregnancy

Start anticoagulation early and 6 week post-partum

Questions?

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