Abstract
Aim: To examine neuropsychiatric outcomes in adults with hereditary tyrosinaemia type I (HT-1), treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and correlate these with functional imaging as well as with tyrosine and phenylalanine-tyrosine (Phe:Tyr) ratios.
Design: We retrospectively reviewed the medical records of three adult HT-1 patients with a particular focus on their FDG PET/CT brain scans, neuropsychiatric assessment (including neurocognitive assessment and mood and anxiety ratings) as well as mean tyrosine and phenylalanine levels and Phe:Tyr ratios for 3-month period. The patients had been referred to a specialist joint inherited metabolic disorder and neuropsychiatry clinic. They were all on NTBC; two since 6 weeks of age, and one since 9 years of age.
Results: All patients performed below the expectation on the formal neurocognitive testing and had raised plasma tyrosine levels and reduced plasma Phe:Tyr ratios. FDG PET/CT-brain scans were normal in two patients and the third patient (treated with NTBC from 6 weeks) had reduced metabolism in temporal and medial frontal areas bilaterally which correlated with the neurocognitive performance.
Conclusions: All three HT-1 patients treated with NTBC had high tyrosine levels, reduced Phe:Tyr ratios and underperformed in neurocognitive testing regardless of the point when the NTBC was first started. One had imaging abnormalities which also correlated with neurocognitive performance. The patient who struggled the most in neurocognitive testing had the highest average plasma tyrosine levels and the lowest Phe:Tyr ratio. Overall, these cases appear to support the previous hypothesis that either the high tyrosine levels or abnormal phenylalanine hydroxylase (PAH) function may well be the causative factor for poor neurocognitive performance. Further systematic, multi-centre studies with a longer follow-up are required to further clarify the relationship between HT-1, NTBC treatment, tyrosine and phenylalanine levels and neurocognitive outcomes.
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Communicated by: John Christodoulou, MB BS PhD FRACP FRCPA
Appendices
Appendix
Patient 1
IQ
Predicted Full Scale IQ (National Adult Reading Test): 104.
Full Scale IQ (WAIS): 83.
Memory
Wechsler Memory Scale IV
WMS IV domain | Percentile rank |
---|---|
Auditory memory | 21 |
Visual memory | 45 |
Visual working memory | 58 |
Immediate memory | 19 |
Delayed memory | 39 |
Frontal-Executive Function
Verbal Fluency: 37th percentile.
Hayling and Brixton tests
Domain | Percentile rank |
---|---|
Hayling Part A (time) | 25 |
Hayling Part B (time) | 50 |
Hayling Part B (errors) | 50 |
Brixton test (errors) | 75 |
Trail Making Test
Part A: 10th percentile.
Part B: 40th percentile.
Manual Dexterity
Perdue pegboard
Domain | Percentile rank |
---|---|
Dominant hand | 5 |
Non-dominant hand | <0.1 |
Both hands | 5 |
Assemblies, both hands | <0.1 |
Patient 2
IQ
Predicted Full Scale IQ (National Adult Reading Test): 99.
Full Scale IQ (WAIS): 86.
Memory
Doors and People
Domain | Percentile rank |
---|---|
People (verbal recall) | 25 |
Doors (visual recognition) | 10–25 |
Shapes (visual recall) | 75 |
Names (verbal recognition) | 10–25 |
Frontal-Executive Function
Verbal Fluency: 63rd percentile.
Hayling and Brixton tests
Domain | Percentile rank |
---|---|
Hayling Part A (time) | 50 |
Hayling Part B (time) | 50 |
Hayling Part B (errors) | 50 |
Brixton test (errors) | 50 |
Trail Making Test
Part A: 25–50th Percentile.
Part B: 10–25th Percentile.
Patient 3
IQ
Predicted Full Scale IQ (National Adult Reading Test): 92.
Full Scale IQ (WAIS): Could not be measured due to lack of consistency within the Verbal Comprehension Index and clinically significant differences between the Verbal and Performance Indexes.
Verbal Comprehension Index: 5th percentile.
Perceptual Organisation Index: 18th percentile.
Working Memory Index: <1st percentile.
Processing Speed Index: 5th Percentile.
Memory
Doors and People test
Domain | Percentile rank |
---|---|
People (verbal recall) | <1st percentile |
Doors (visual recognition) | <1st percentile |
Shapes (visual recall) | 9th percentile |
Names (verbal recognition) | 16th percentile |
Frontal-Executive Function
Delis-Kaplan executive function system – trail making test
Domain | Percentile rank |
---|---|
Visual scanning | 37 |
Number sequencing | <0.1 |
Letter sequencing | <0.1 |
Number-letter switching | <0.1 |
Motor speed | 25 |
Delis-Kaplan executive function system – verbal fluency test
Domain | Percentile rank |
---|---|
Letter fluency | 9 |
Category fluency | 5 |
Category switching total | 9 |
Category switching accuracy | 9 |
Modified Wisconsin Card Sorting task
Domain | Percentile rank |
---|---|
Total errors | 60 |
% perseverative errors | 20 |
Worrington Graded Calculation test: <5th Percentile.
Manual Dexterity
Perdue pegboard
Domain | Percentile rank |
---|---|
Dominant hand | 38 |
Non-dominant hand | 8 |
Both hands | 4 |
Assemblies | <0.1 |
Details of the Contributions of Individual Authors
Dr. Helen Walker (corresponding author): Drafting of the chapter, conception and design, and analysis and interpretation of data.
Dr. Pitkanen: Critical review, conception and design, analysis and interpretation of data.
Dr. Rahman: Critical review, conception and design, analysis and interpretation of data.
Dr. Barrington: Critical review, conception and design, analysis and interpretation of data.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Conflict of Interest
The authors declare that they have no conflict of interest.
Consent
Informed consent was obtained for all participants included in the study.
Guarantor
Dr. Mervi Pitkanen.
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© 2017 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Walker, H., Pitkanen, M., Rahman, Y., Barrington, S.F. (2017). Three Cases of Hereditary Tyrosinaemia Type 1: Neuropsychiatric Outcomes and Brain Imaging Following Treatment with NTBC. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 40. JIMD Reports, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_69
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DOI: https://doi.org/10.1007/8904_2017_69
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