1. Importance of Natural History Studies and Registries in Homocystinura
Harvey L. Levy, M.D.
Boston Children’s Hospital
Harvard Medical School
Boston, Massachusetts USA

2. Facts of Life Phenotypic variability in all inborn errors
Some due to biochemical variation
Some due to partial treatment
But some not associated with defined biochemical or treatment variation
As true for homocystinuria as in any inborn error
Natural history of inborn errors is quickly obscured by introduction of treatment

3. HOMOCYSTINURIA (cbs def)

6. Different Phenotypy Sib 1 20 F Sib 2 25 F Sib 3 18 M Marfanoid
Ectopia lentis
Dystonia
Sib F
Neurological normal
Sib M
Eyes normal

7. Phenotypic Variation Case 1 Case 2
42 year old male thought to have Marfan syndrome on basis of marfanoid habitus. Has borderline intelligence. Is dog walker in very high functioning family. Found to have high homocysteine when had cardiac evaluation. After diagnosis of homocystinuria, history revealed sagittal sinus thrombosis at age 8 months with developmental delay through infancy and childhood.
Normal eyes
Plasma homocystinuria 130 umol/L
G307S/D326K
Case 2
29 year old female also thought to have Marfan syndrome on basis of marfanoid habitus and also ectopia lentis. High functioning college graduate and very responsible job as software engineer.
Plasma homocysteine 332 umol/L
T257M/C109R

9. The Natural History of Homocystinuria
“…we have conducted a worldwide questionnaire survey and collected information in a standardized format on more than 600 patients with homocystinuria due to proven or presumed deficiency of cystathionine β-synthase.”
“It is hoped that the data reported here will provide the baselines necessary for design of future studies…”

13. Natural History Study
Purpose: to determine any clinical change in those with homocystinuria over a 3-year period
Inclusion Criteria
Ages 5-65
Documented homocystinuria due to CBS deficiency
↑tHcy
↓CBS enzyme activity or
CBS biallelic mutations
Clinical signs characteristics of homocystinuria
Exclusion Criteria
Medically significant postnatal complications or congenital anomalies outside of homocystinuria
Received experimental or investigational therapy for homocystinuria 6 months prior to enrollment or expected during study.

14. Natural History Study Medical History Physical Examination
Skeletal features
Eye examination
Visual acuity
Slit lamp
Fundal photograph
DXA bone density scan
Psychological assessment
Biochemical assessment
Total homocysteine
Free amino acids
General chemistries
Genetic Assessment
CBS Genotype
3 years evaluation every 6 months

15. Natural History Study Blood Tests Metabolic Total homocysteine (tHcy)
Methionine
Cystathionine
Total cysteine
S-adenosylmethionine (SAM)
S-adenosylhomocysteine (SAH)
Therapeutic
Betaine
Dimethylglycine
Nutritional
B12
Folate B6

16. Natural History Study Cardiovascular General Bone Antithrombin III CBC
Protein C
Electrolytes
Protein S free antigen
BUN, Ca, P
Fibrinogen
Liver function (ALT, AST, ALP)
D-Dimer
Creatinine
ApoA-1
Glucose
CRP
Albumin
Bone
Total cholesterol, TG
Serum N-Terminal Crosslinks of Human-Collagen Type I
Alkaline phosphatase (bone)
Serum C-Terminal Telopeptide
Cytokine/chemokine markers

17. Conclusions
Understanding the natural history of any disorder is critical to diagnosis and determining the benefits of treatment
Family registries may be the most effective and comprehensive compilations of natural history
The current “Natural History Study” will be important in assessing the benefit of ERT in HCU in comparison to pre-ERT