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Three Cases of Hereditary Tyrosinaemia Type 1: Neuropsychiatric Outcomes and Brain Imaging Following Treatment with NTBC

  • Research Report
  • Chapter
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JIMD Reports, Volume 40

Part of the book series: JIMD Reports ((JIMD,volume 40))

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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Author information

Authors and Affiliations

  1. West London Mental Health Trust, London, UK

    Helen Walker

  2. Department of Neuropsychiatry and Memory Disorders, King’s College London, London, UK

    Mervi Pitkanen

  3. Centre for Inherited Metabolic Disorders, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK

    Yusof Rahman

  4. KCL and Guy’s and St Thomas’ PET Centre, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, UK

    Sally F. Barrington

Authors
  1. Helen Walker
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  2. Mervi Pitkanen
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  3. Yusof Rahman
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  4. Sally F. Barrington
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Corresponding author

Correspondence to Mervi Pitkanen .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  2. Division of Metabolism & Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

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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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-57879-7

  • Online ISBN: 978-3-662-57880-3

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