Adults with Inborn Errors of Metabolism Farrah Rajabi

Adults with Inborn Errors of Metabolism Farrah Rajabi, MD Clinical Genetics Fellow Boston Children’s Hospital New England Genetics Collaborative Annual Meeting April 9, 2015

Objectives • Review Background and study aims • Discuss preliminary results • Discuss further research plans 2

Background • Inborn Errors of Metabolism (IEM) have limited information about adult long-term outcome • Transition to adult care can be optimized with increased information about ageing related co -morbidities • Identifying age-related risks in IEM population could lead to tailored preventative health care 3

Adult Co-morbidities of IEM • Phenylketonuria (PKU, OMIM 261600) – Potential poor dietary adherence, tremor, anxiety, depression, osteopenia, and vitamin B 12 deficiency. 1– 3 • Galactosemia (OMIM 230400) – Cataracts, low bone density, tremor, ataxia, dyarthria, depression, and anxiety. 4 • Homocystinuria (OMIM 236200) – Osteoporosis, thromboembolism, psychiatric problems, and extrapyramidal signs. 8– 10 4

Specific Aims • Evaluate the evolution of IEM in adulthood • Focus on age-related physical and mental health complications • Evaluate if age related health problems are occurring at younger ages compared to control population 5

Survey • • Anonymous questionnaires Individuals with IEM and unaffected controls Adult subjects, age 18 -50 years Rate themselves in terms of identity, autonomy and health – Identity and Autonomy questionnaire is based on the Erikson instrument: (Modified from Rosenthal, D. A. , Gurney, R. M. , Moore, S. M. (1981). ) – Health questionnaire was modified from the health questionnaire used in a primary care medical office – Self-management questionnaire 6

PRELIMINARY SURVEY RESULTS • Total Number Respondents = 84 – Galactosemia = 39 – Phenylketonuria = 5 – Urea Cycle Disorder = 4 Controls Adults with Metabolic Disorder Number of Respondents 37 47 Female 27 26 Average Age 39 years 28 years 7

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COMPARISON OF ADULTS WITH METABOLIC DISORDERS AND CONTROLS Series 1= controls; Series 2 = adults with metabolic disorders (galactosemia, PKU and Urea Cycle Disorders) 0. 45 0. 40 0. 35 0. 30 0. 25 Percent Affected 0. 20 Series 1 Series 2 0. 15 0. 10 0. 05 0. 00 GERD 1 Vision 2 Dep 3 4 Anxiety 5 Meds 6 Sleep 7 Memory 8 Tremor 9 Teeth 9

Next Steps • Strengthen health history questions – Age at onset for any age-related diagnosis – Family history branching • Added questions about self-management • Added sickle cell anemia • Increase power 10

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Thank you for your time • Special thank you: – Mentorship • Susan Waisbren, Ph. D • Harvey Levy, MD – Support • New England National Genetics Collaboratives • Health Resources and Services Administration • Any Questions or Comments? 14

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Robinson, M. et al. Increased risk of vitamin B 12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J. Pediatr. 136, 545– 7 (2000). Modan-Moses, D. et al. Peak bone mass in patients with phenylketonuria. J. Inherit. Metab. Dis. 30, 202– 8 (2007). Waisbren, S. E. et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol. Genet. Metab. 92, 63– 70 (2007). Waisbren, S. E. et al. The adult galactosemic phenotype. J. Inherit. Metab. Dis. 35, 279– 86 (2012). Muelly, E. R. et al. Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J. Clin. Invest. 123, 1809– 20 (2013). Carecchio, M. et al. Movement disorders in adult surviving patients with maple syrup urine disease. Mov. Disord. 26, 1324– 8 (2011). Stauss, K. , Puffenberger, E. & Morton, D. in Gene Rev. (Pagon, R. , Adam, M. & Ardinger, H. ) (University of Washington, Seattle). Yap, S. Classical homocystinuria: vascular risk and its prevention. J. Inherit. Metab. Dis. 26, 259– 65 (2003). Yap, S. & Naughten, E. Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J. Inherit. Metab. Dis. 21, 738– 47 (1998). Lim, J. S. & Lee, D. H. Changes in bone mineral density and body composition of children with well-controlled homocystinuria caused by CBS deficiency. Osteoporos. Int. 24, 2535– 8 (2013). Mc Guire, P. J. , Parikh, A. & Diaz, G. a. Profiling of oxidative stress in patients with inborn errors of metabolism. Mol. Genet. Metab. 98, 173– 80 (2009). Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239– 47 (2000). Wilson, D. M. , Bohr, V. A. & Mc. Kinnon, P. J. DNA damage, DNA repair, ageing and age-related disease. Mech. Ageing Dev. 129, 349– 52 (2008). 15