Defining Comorbidities in Adults with Inborn Errors of
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
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
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, dysarthria, depression, and anxiety. 4 • Homocystinuria (OMIM 236200) – Osteoporosis, thromboembolism, psychiatric problems, and extrapyramidal signs. 8– 10 4
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
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
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
CURRENT ADULT SURVEY RESULTS • Total Number Respondents with IEM = 79 – – Galactosemia = 40 Phenylketonuria = 29 Urea Cycle Disorder = 7 Homocystinuria = 3 Controls Adults with Metabolic Disorder Number of Respondents 56 79 Female 43 51 Average Age 37 years 32 years 8
Cardiovascular Health 25. 0% Percent Affected 20. 0% 15. 0% All controls All IEM PKU 10. 0% Galactosemia 5. 0% 0. 0% HTN High Cholesterol Heart Failure Angina MI Arrythmia 9
Pulmonary and Sleep Health 35. 0% 30. 0% Percent Affected 25. 0% 20. 0% All controls All IEM PKU 15. 0% Galactosemia 10. 0% 5. 0% 0. 0% Asthma Emphysema COPD Sleep Apnea Insomnia 10
Gastrointestinal Health 30. 0% 25. 0% Percent Affected 20. 0% All Controls All IEM 15. 0% PKU Galactosemia 10. 0% 5. 0% 0. 0% GERD Liver Failure IBD IBS 11
Endocrine Health 40. 0% 35. 0% Percent Affected 30. 0% 25. 0% All controls 20. 0% All IEM PKU 15. 0% Galactosemia 10. 0% 5. 0% 0. 0% Overweight (BMI 2529. 9) Obese (BMI >30) Diabetes Thyroid Problem 12
Dental, Vision, and Hearing 40. 0% 35. 0% Percent Affected 30. 0% 25. 0% All controls All IEM 20. 0% PKU Galactosemia 15. 0% 10. 0% 5. 0% 0. 0% Dental Problems Vision Problems Cataracts Hearing Problems 13
Dermatologic Health 30. 0% Percent Affected 25. 0% 20. 0% All controls 15. 0% All IEM PKU 10. 0% 5. 0% 0. 0% Eczema Gray Hair Loss Controls Adults with IEM Average Age Onset Gray Hair 34 years old 26 years old Average Age Onset Hair Loss 47 years old 31 years old 14
Neurologic Health 35. 0% 30. 0% Percent Affected 25. 0% 20. 0% All Controls All IEM PKU 15. 0% Galactosemia 10. 0% 5. 0% 0. 0% Chronic Headaches Tremor Memory Problems. Attention or Focus Problems Learning Disabilities 15
Psychiatric Health 45. 0% 40. 0% Percent Affected 35. 0% 30. 0% 25. 0% All Controls All IEM 20. 0% PKU Galactosemia 15. 0% 10. 0% 5. 0% 0. 0% Depression Anxiety Taking Medication for Anxiety or Depression Participating in Therapy 16
Substance Use 30. 0% 25. 0% Percent Affected 20. 0% All controls 15. 0% All IEM PKU 10. 0% 5. 0% 0. 0% Cigarette Use Marijuana Use past 12 Binge Drinking past 12 months 17
Self Care and Access to Care Following a Metabolic Diet PKU Galactosemia 72. 4% 90% Care in past 12 months Seen a doctor 100% Hospital Admission 21% Have Primary Care Physician 89% Have Insurance 100% Postponed medical Care 47% • UCD Homocytinuria 86% 100% Cost, Insurance, Too Busy, Thought it would get better on its own, Toughed it out, Transportation Did not fill script for medication or 21% formula • Cost, Insurance, Didn’t want more meds Needed to see specialist 47% Difficult to see specialist 37% 18
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
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
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
Conclusion • After all that discussion… it’s too soon to draw conclusions. 22
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
Thank you for your time • Special thank you: – Mentorship • Susan Waisbren, Ph. D • Harvey Levy, MD – Support • New England National Genetics Collaborative • Health Resources and Services Administration • Any Questions or Comments? 24
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 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). 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. Snochat T. et al. Insomnia in primary care patients. Sleep. 1999 May 1; 22 Suppl 2: S 359 -65. Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HS, Wijburg FA, Last BF. Living with classical galactosemia: health-related quality of life consequences. Pediatrics. 2004 b; 113: e 423– 8 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. 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
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