1. Defining Co-morbidities in Adults with Inborn Errors of Metabolism Farrah Rajabi, MD Clinical Genetics Fellow Boston Children’s Hospital New England Genetics Collaborative Annual Meeting April 9, 2016

2. Objectives Review Background and study aims Discuss results of pilot survey Discuss preliminary results of larger survey Discuss further research plans – Survey Study – PKU Genotype Phenotype Study 2

3. 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

4. Adult Co-morbidities of IEM Phenylketonuria (PKU, OMIM 261600) – Potential poor dietary adherence, tremor, anxiety, depression, osteopenia, and vitamin B12 deficiency. 1–3 Galactosemia (OMIM 230400) – Cataracts, low bone density, tremor, ataxia, dysarthria, depression, and anxiety. 4 Homocystinuria (OMIM 236200) – Osteoporosis, thromboembolism, psychiatric problems, and extrapyramidal signs. 8–10 4

5. Specific Aims Evaluate the natural history 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

6. 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 Erik 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

7. Since Last Year Strengthen health history questions – Age at onset for any age-related diagnosis – Family history branching Added questions about self-management Added sickle cell anemia Goal to increase power 7

8. CURRENT ADULT SURVEY RESULTS Total Number Respondents with IEM = 79 – Galactosemia = 40 – Phenylketonuria = 29 – Urea Cycle Disorder = 7 – Homocystinuria = 3 8 ControlsAdults with Metabolic Disorder Number of Respondents5679 Female4351 Average Age37 years32 years

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14. 14 ControlsAdults with IEM Average Age Onset Gray Hair34 years old26 years old Average Age Onset Hair Loss47 years old31 years old

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18. Self Care and Access to Care Following a Metabolic Diet PKU72.4% Galactosemia 90% UCD86% Homocytinuria100% Seen a doctor100% Hospital Admission21% Have Primary Care Physician89% Have Insurance100% Postponed medical Care47% Cost, Insurance, Too Busy, Thought it would get better on its own, Toughed it out, Transportation Did not fill script for medication or formula 21% Cost, Insurance, Didn’t want more meds Needed to see specialist47% Difficult to see specialist37% 18 Care in past 12 months

19. Discussion Statistical differences in – Lower incidence of Hypertension – Higher incidence of GERD, Tremor, memory difficulties, insomnia, learning disabilities Limitations – LOW STATISTICAL POWER! Need increased power to evaluate each IEM separately Variable ages limit comparison for age of onset data – Self reported results 19

20. Discussion Hypertension – In previous studies, PKU had a significantly increased triglycerides/HDL-cholesterol ratio while blood glucose and blood pressure were reduced compared to controls 14 Gastroesophageal reflux disease – No previous correlation with PKU or Galactosemia Tremor – Galactosemia 2012 study tremor was noted in 15 of 33 subjects (46%), with intention tremor in eight (24%), postural tremor in five (15%), and both kinds of tremors in two (6%) subjects. 4 Our survey reported tremor in 14 of 39 patients (36%) – PKU An action or postural tremor is estimated to occur in 5–32% of early-treated adult PKU patients. 20

21. Discussion Insomnia – No previously correlation with PKU or galactosemia – Commonly coexists with psychiatric or medical disorders, other sleep disorders, or use of certain medications or substances – A survey of primary care patients found that 69 percent had insomnia 15 – Incidence of insomnia increases with age Learning Disabilities – 2004 study of Of 177 individuals with galactosemia, 45% were described as developmentally delayed. The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age 16 – 2007 study of 33 patients with PKU compared with the control, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties 17 – 2008 study of 183 patients with UCD, Intellectual and developmental disabilities were reported in 39% with learning disabilities in 35% 18 21

22. Conclusion After all that discussion… it’s too soon to draw conclusions. 22

23. Future Studies Expand survey to increase statistical power – Correlate findings with age of onset, overall health, access to medical care, independence Genotype Phenotype correlations in phenylketonuria – Reviewing all genotypes of PKU patients following at BCH over the last 50 years – All patients will be reviewed for: Dietary phenylalanine tolerance Sapropterin responsiveness 23

24. Thank you for your time Special thank you: – Mentorship Susan Waisbren, PhD Harvey Levy, MD – Support New England and National Genetics Collaborative Health Resources and Services Administration Any Questions or Comments? 24

25. References 1.Robinson, M. et al. Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J. Pediatr. 136, 545–7 (2000). 2.Modan-Moses, D. et al. Peak bone mass in patients with phenylketonuria. J. Inherit. Metab. Dis. 30, 202–8 (2007). 3.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). 4.Waisbren, S. E. et al. The adult galactosemic phenotype. J. Inherit. Metab. Dis. 35, 279–86 (2012). 5.Muelly, E. R. et al. Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J. Clin. Invest. 123, 1809–20 (2013). 6.Carecchio, M. et al. Movement disorders in adult surviving patients with maple syrup urine disease. Mov. Disord. 26, 1324–8 (2011). 7.Stauss, K., Puffenberger, E. & Morton, D. in Gene Rev. (Pagon, R., Adam, M. & Ardinger, H.) (University of Washington, Seattle). 8.Yap, S. Classical homocystinuria: vascular risk and its prevention. J. Inherit. Metab. Dis. 26, 259–65 (2003). 9.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). 10.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). 11.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). 12.Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–47 (2000). 13.Wilson, D. M., Bohr, V. A. & McKinnon, P. J. DNA damage, DNA repair, ageing and age-related disease. Mech. Ageing Dev. 129, 349–52 (2008). 14.J.C. Rocha, F.J. van Spronsen, M.F. Almeida, G. Soares, D. Quelhas, E. Ramos, J.T. Guimaraes, N. Borges, Dietary treatment in phenylketonuria does not lead to in- creased risk of obesity or metabolic syndrome, Mol. Genet. Metab. 107 (2012) 659–663. 15.Snochat T. et al. Insomnia in primary care patients. Sleep. 1999 May 1;22 Suppl 2:S359-65. 16.Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HS, Wijburg FA, Last BF. Living with classical galactosemia: health-related quality of life consequences. Pediatrics. 2004b;113:e423–8 17.Anderson PJ. et al. Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Dev Neuropsychol. 2007;32(2):645-68. 18.Tuchmann M. et al. Cross-Sectional Multi-Center Study of Patients with Urea Cycle Disorders in the United States. Mol Genet Metab. 2008 Aug; 94(4): 397–402. 25