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

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

HOMOCYSTINURIA (cbs def)

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

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

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…”

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.

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

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

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

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