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Neurological and imaging phenotypes of adults with untreated phenylketonuria: new cases and literature review

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Abstract

Objectives

Phenylketonuria (PKU) is the most prevalent congenital disease of amino acid metabolism. Neurological manifestations usually complicate PKU in untreated adult patients. This study describes neurological and imaging phenotypes of adult patients with untreated PKU.

Methods

We investigated a cohort of 320 unrelated adult patients with suspected genetic leukoencephalopathies using whole-exome sequencing (WES). We analyzed the phenotypic features of adult PKU patients in our cohort and summarized cases reported in the literature.

Results

We identified 10 patients in our cohort and 12 patients in the literature, who presented with neurological manifestations and were diagnosed with PKU in adulthood. Approximately 60% of these patients had onset of clinical features in adulthood. The most common neurological symptoms of patients presenting in adulthood were cognitive disturbance and spastic paralysis, followed by vision loss, cerebellar ataxia, weakness of limbs, and seizure. This differed from that of patients presenting with PKU features in childhood, who consistently had mental retardation with various neurological complications emerging during a broad age range. Imaging findings were similar between patients presenting with clinical features in childhood compared with adulthood, comprising symmetric periventricular white matter hyperintense on T2-weighted imaging and diffusion-weighted imaging predominantly in the parietal and occipital lobes. Also, normal brain imaging and diffuse leukoencephalopathies were observed in both patient groups.

Conclusion

PKU with clinical features presenting in adulthood is an atypical subtype and should be considered during diagnosis of adults with neurological symptoms and leukoencephalopathy. DWI seems to be most helpful to distinguish patients with PKU. Additionally, we demonstrate that PKU constitutes a part (3.1%) of adult genetic leukoencephalopathies.

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Data availability

Any data not published within this article are available from the corresponding author on reasonable request.

References

  1. Hillert A, Anikster Y, Belanger-Quintana A et al (2020) The genetic landscape and epidemiology of phenylketonuria. Am J Hum Genet 107(2):234–250. https://doi.org/10.1016/j.ajhg.2020.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM (2021) Phenylketonuria. Nat Rev Dis Primers 7(1):36. https://doi.org/10.1038/s41572-021-00267-0

    Article  PubMed  PubMed Central  Google Scholar 

  3. Weglage J, Oberwittler C, Marquardt T, Schellscheidt J, von Teeffelen-Heithoff A, Koch G, Gerding H (2000) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 23(1):83–4. https://doi.org/10.1023/a:1005607115309

    Article  CAS  PubMed  Google Scholar 

  4. Kasim S, Moo LR, Zschocke J, Jinnah HA (2001) Phenylketonuria presenting in adulthood as progressive spastic paraparesis with dementia. J Neurol Neurosurg Psychiatry 71(6):795–797. https://doi.org/10.1136/jnnp.71.6.795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jousserand G, Antoine JC, Camdessanché JP (2010) Musty odour, mental retardation, and spastic paraplegia revealing phenylketonuria in adulthood. J Neurol 257(2):302–304. https://doi.org/10.1007/s00415-009-5358-1

    Article  PubMed  Google Scholar 

  6. Rosini F, Rufa A, Monti L, Tirelli L, Federico A (2014) Adult-onset phenylketonuria revealed by acute reversible dementia, prosopagnosia and parkinsonism. J Neurol 261(12):2446–2448. https://doi.org/10.1007/s00415-014-7492-7

    Article  PubMed  Google Scholar 

  7. Holtzman C, Slazyk WE, Cordero JF, Hannon WH (1986) Descriptive epidemiology of missed cases of phenylketonuria and congenital hypothyroidism. Pediatrics 78(4):553–558

    Article  CAS  PubMed  Google Scholar 

  8. van Wegberg AMJ, Trefz F, Gizewska M, Study Group on Missed PKU and Missed to Follow-Up et al (2021) Undiagnosed phenylketonuria can exist everywhere: results from an international survey. J Pediatr 239:231-234e2. https://doi.org/10.1016/j.jpeds.2021.08.070

    Article  CAS  PubMed  Google Scholar 

  9. van Vliet D, van Wegberg AMJ, Ahring K et al (2019) Untreated PKU patients without intellectual disability: what do they teach us? Nutrients 11(11):2572. https://doi.org/10.3390/nu11112572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Anderson PJ, Leuzzi V (2010) White matter pathology in phenylketonuria. Mol Genet Metab 99(Suppl 1):S3-9. https://doi.org/10.1016/j.ymgme.2009.10.005

    Article  CAS  PubMed  Google Scholar 

  11. Koch R, Moseley K, Ning J, Romstad A, Guldberg P, Guttler F (1999) Long-term beneficial effects of the phenylalanine-restricted diet in late-diagnosed individuals with phenylketonuria. Mol Genet Metab 67(2):148–155. https://doi.org/10.1006/mgme.1999.2863

    Article  CAS  PubMed  Google Scholar 

  12. Coker SB (1991) The diagnosis of childhood neurodegenerative disorders presenting as dementia in adults. Neurology 41(6):794–798. https://doi.org/10.1212/wnl.41.6.794

    Article  CAS  PubMed  Google Scholar 

  13. Gray RGF, Preece MA, Green SH et al (2000) Inborn errors of metabolism as a cause of neurological disease in adults: approach to investigation. J Neurol Neurosurg Psychiatry 69:5–12. https://doi.org/10.1136/jnnp.69.1.5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mak CM, Lee HC, Chan AY, Lam CW (2013) Inborn errors of metabolism and expanded newborn screening: review and update. Crit Rev Clin Lab Sci 50(6):142–162. https://doi.org/10.3109/10408363.2013.847896

    Article  CAS  PubMed  Google Scholar 

  15. Wang C, Li J (2018) Subacute onset leukodystrophy and visual-spatial disorders revealing phenylketonuria combined with homocysteinmia in adulthood: a case report. Medicine 97(8):e9801. https://doi.org/10.1097/MD.0000000000009801

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liu Y, Dong Z, Yu S (2018) Late-diagnosed phenylketonuria mimicking x-linked adrenoleukodystrophy with heterozygous mutations of the PAH Gene: a case report and literature review. Clin Neurol Neurosurg 171:151–155. https://doi.org/10.1016/j.clineuro.2018.06.009

    Article  PubMed  Google Scholar 

  17. Lynch DS, Wade C, Paiva ARB et al (2019) Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era. J Neurol Neurosurg Psychiatry 90(5):543–554. https://doi.org/10.1136/jnnp-2018-319481

    Article  PubMed  Google Scholar 

  18. Li H (2014) Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics 30(20):2843–2851. https://doi.org/10.1093/bioinformatics/btu356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. McKenna A, Hanna M, Banks E et al (2010) The genome analysis toolkit: a mapreduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303. https://doi.org/10.1101/gr.107524.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164. https://doi.org/10.1093/nar/gkq603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Plagnol V, Curtis J, Epstein M et al (2012) A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics 28(21):2747–2754. https://doi.org/10.1093/bioinformatics/bts526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ishimaru K, Tamasawa N, Baba M, Matsunaga M, Takebe K (1993) Phenylketonuria with adult-onset neurological manifestation. Rinsho Shinkeigaku 33(9):961–5 (Abstract)

    CAS  PubMed  Google Scholar 

  24. Daelman L, Sedel F, Tourbah A (2014) Progressive neuropsychiatric manifestations of phenylketonuria in adulthood. Rev Neurol (Paris) 170(4):280–287. https://doi.org/10.1016/j.neurol.2013.09.012

    Article  CAS  PubMed  Google Scholar 

  25. Narayanan D, Barski R, Henderson MJ et al (2014) Delayed diagnosis of phenylketonuria—a case report of two siblings. Ann Clin Biochem 51(Pt 3):406–408. https://doi.org/10.1177/0004563213503818

    Article  PubMed  Google Scholar 

  26. Chen S, Zhu M, Hao Y, Feng J, Zhang Y (2019) Effect of delayed diagnosis of phenylketonuria with imaging findings of bilateral diffuse symmetric white matter lesions: a case report and literature review. Front Neurol 4(10):1040. https://doi.org/10.3389/fneur.2019.01040

    Article  Google Scholar 

  27. Tufekcioglu Z, Cakar A, Bilgic B, Hanagasi H, Gurvit H, Emre M (2016) Adult-onset phenylketonuria with rapidly progressive dementia and Parkinsonism. Neurocase 22(3):273–275. https://doi.org/10.1080/13554794.2016.1142567

    Article  PubMed  Google Scholar 

  28. Guida M, Pesaresi I, Fabbri S, Sartucci F, Cosottini M, Giorgi FS (2014) Epilepsy and phenylketonuria: a case description and EEG-fMRI findings. Funct Neurol 29(1):75–9

    PubMed  PubMed Central  Google Scholar 

  29. Jaulent P, Charriere S, Feillet F, Douillard C, Fouilhoux A, Thobois S (2020) Neurological manifestations in adults with phenylketonuria: new cases and review of the literature. J Neurol 267(2):531–542. https://doi.org/10.1007/s00415-019-09608-2

    Article  PubMed  Google Scholar 

  30. Younger DS (1993) Differential diagnosis of progressive spastic paraparesis. Semin Neurol 13(4):319–321. https://doi.org/10.1055/s-2008-1041141

    Article  CAS  PubMed  Google Scholar 

  31. Zhovtis Ryerson L, Herbert J, Howard J, Kister I (2014) Adult-onset spastic paraparesis: an approach to diagnostic work-up. J Neurol Sci 346(1–2):43–50. https://doi.org/10.1016/j.jns.2014.09.015

    Article  PubMed  Google Scholar 

  32. Cleary MA, Walter JH, Wraith JE, Jenkins JP, Alani SM, Tyler K, Whittle D (1994) Magnetic resonance imaging of the brain in phenylketonuria. Lancet 344(8915):87–90. https://doi.org/10.1016/s0140-6736(94)91281-5

    Article  CAS  PubMed  Google Scholar 

  33. Manara R, Burlina AP, Citton V, Ermani M, Vespignani F, Carollo C, Burlina AB (2009) Brain MRI diffusion-weighted imaging in patients with classical phenylketonuria. Neuroradiology 51(12):803–812. https://doi.org/10.1007/s00234-009-0574-z

    Article  PubMed  Google Scholar 

  34. Scarabino T, Popolizio T, Tosetti M et al (2009) Phenylketonuria: white-matter changes assessed by 3.0-T magnetic resonance (MR) imaging, MR spectroscopy and MR diffusion. Radiol Med 114(3):461–74. https://doi.org/10.1007/s11547-009-0365-y

    Article  CAS  PubMed  Google Scholar 

  35. Hawks Z, Hood AM, Lerman-Sinkoff DB et al (2019) White and gray matter brain development in children and young adults with phenylketonuria. Neuroimage Clin 23:101916. https://doi.org/10.1016/j.nicl.2019.101916

    Article  PubMed  PubMed Central  Google Scholar 

  36. Pearsen KD, Gean-Marton AD, Levy HL, Davis KR (1990) Phenylketonuria: MR imaging of the brain with clinical correlation. Radiology 177(2):437–440. https://doi.org/10.1148/radiology.177.2.2217781

    Article  CAS  PubMed  Google Scholar 

  37. Leuzzi V, Tosetti M, Montanaro D et al (2007) The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study. J Inherit Metab Dis 30(2):209–16. https://doi.org/10.1007/s10545-006-0399-4

    Article  CAS  PubMed  Google Scholar 

  38. van Vliet D, van Wegberg AMJ, Ahring K et al (2018) Can untreated PKU patients escape from intellectual disability? A systematic review. Orphanet J Rare Dis 13(1):149. https://doi.org/10.1186/s13023-018-0890-7

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bouchlariotou S, Tsikouras P, Maroulis G (2009) Undiagnosed maternal phenylketonuria: own clinical experience and literature review. J Matern Fetal Neonatal Med 22(10):943–948. https://doi.org/10.1080/14767050902994697

    Article  PubMed  Google Scholar 

  40. Hanley WB (2008) Finding the fertile woman with phenylketonuria. Eur J Obstet Gynecol Reprod Biol 137(2):131–135. https://doi.org/10.1016/j.ejogrb.2007.12.011

    Article  PubMed  Google Scholar 

  41. Moats RA, Koch R, Moseley K, Guldberg P, Guttler F, Boles RG, Nelson MD Jr (2000) Brain phenylalanine concentration in the management of adults with phenylketonuria. J Inherit Metab Dis 23(1):7–14. https://doi.org/10.1023/a:1005638627604

    Article  CAS  PubMed  Google Scholar 

  42. Möller HE, Weglage J, Wiedermann D, Ullrich K (1998) Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria. J Cereb Blood Flow Metab 18(11):1184–1191. https://doi.org/10.1097/00004647-199811000-00004

    Article  PubMed  Google Scholar 

  43. Leuzzi V, Bianchi MC, Tosetti M, Carducci CL, Carducci CA, Antonozzi I (2000) Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria. J Inherit Metab Dis 23(6):563–570. https://doi.org/10.1023/a:1005621727560

    Article  CAS  PubMed  Google Scholar 

  44. van Spronsen FJ, Hoeksma M, Reijngoud DJ (2009) Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause? J Inherit Metab Dis 32(1):46–51. https://doi.org/10.1007/s10545-008-0946-2

    Article  CAS  PubMed  Google Scholar 

  45. Ferreira BK, Rodrigues MT, Streck EL, Ferreira GC, Schuck PF (2021) White matter disturbances in phenylketonuria: possible underlying mechanisms. J Neurosci Res 99(1):349–360. https://doi.org/10.1002/jnr.24598

    Article  CAS  PubMed  Google Scholar 

  46. Reynolds R, Burri R, Herschkowitz N (1993) Retarded development of neurons and oligodendroglia in rat forebrain produced by hyperphenylalaninemia results in permanent deficits in myelin despite long recovery periods. Exp Neurol 124(2):357–367. https://doi.org/10.1006/exnr.1993.1206

    Article  CAS  PubMed  Google Scholar 

  47. Dyer CA, Kendler A, Philibotte T, Gardiner P, Cruz J, Levy HL (1996) Evidence for central nervous system glial cell plasticity in phenylketonuria. J Neuropathol Exp Neurol 55(7):795–814. https://doi.org/10.1097/00005072-199607000-00005

    Article  CAS  PubMed  Google Scholar 

  48. Koch R, Verma S, Gilles FH (2008) Neuropathology of a 4-month-old infant born to a woman with phenylketonuria. Dev Med Child Neurol 50(3):230–233. https://doi.org/10.1111/j.1469-8749.2008.02028.x

    Article  PubMed  Google Scholar 

  49. Schoemans R, Aigrot MS, Wu C et al (2010) Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites. J Inherit Metab Dis 33(2):113–120. https://doi.org/10.1007/s10545-010-9052-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. van der Knaap MS, Bugiani M (2017) Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 134(3):351–382. https://doi.org/10.1007/s00401-017-1739-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Malamud N (1966) Neuropathology of phenylketonuria. J Neuropathol Exp Neurol 25(2):254–268. https://doi.org/10.1097/00005072-196604000-00006

    Article  CAS  PubMed  Google Scholar 

  52. Huttenlocher PR (2000) The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 159(Suppl 2):S102–S106. https://doi.org/10.1007/pl00014371

    Article  PubMed  Google Scholar 

  53. Vermathen P, Robert-Tissot L, Pietz J, Lutz T, Boesch C, Kreis R (2007) Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging. Magn Reson Med 58(6):1145–1156. https://doi.org/10.1002/mrm.21422

    Article  PubMed  Google Scholar 

  54. Sirrs SM, Laule C, Mädler B, Brief EE, Tahir SA, Bishop C, MacKay AL (2007) Normal-appearing white matter in patients with phenylketonuria: water content, myelin water fraction, and metabolite concentrations. Radiology 242(1):236–243. https://doi.org/10.1148/radiol.2421051758

    Article  PubMed  Google Scholar 

  55. Schiffmann R, van der Knaap MS (2009) Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 72:750–759. https://doi.org/10.1212/01.wnl.0000343049.00540.c8

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wolf NI, Ffrench-Constant C, van der Knaap MS (2021) Hypomyelinating leukodystrophies - unravelling myelin biology. Nat Rev Neurol 17(2):88–103. https://doi.org/10.1038/s41582-020-00432-1

    Article  CAS  PubMed  Google Scholar 

  57. van Wegberg AMJ, MacDonald A, Ahring K et al (2017) The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12(1):162. https://doi.org/10.1186/s13023-017-0685-2

    Article  PubMed  PubMed Central  Google Scholar 

  58. van Spronsen FJ, van Wegberg AM, Ahring K et al (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 5(9):743–756. https://doi.org/10.1016/S2213-8587(16)30320-5

    Article  PubMed  Google Scholar 

  59. González MJ, Gutiérrez AP, Gassió R, Fusté ME, Vilaseca MA, Campistol J (2011) Neurological complications and behavioral problems in patients with phenylketonuria in a follow-up unit. Mol Genet Metab 104(Suppl):S73–S79. https://doi.org/10.1016/j.ymgme.2011.07.015

    Article  CAS  PubMed  Google Scholar 

  60. Xiang L, Tao J, Deng K et al (2019) Phenylketonuria incidence in China between 2013 and 2017 based on data from the Chinese newborn screening information system: a descriptive study. BMJ Open 9(8):e031474. https://doi.org/10.1136/bmjopen-2019-031474

    Article  PubMed  PubMed Central  Google Scholar 

  61. Mei L, Song P, Xu L (2013) Newborn screening and related policy against Phenylketonuria in China. Intractable Rare Dis Res 2(3):72–76. https://doi.org/10.5582/irdr.2013.v2.3.72

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zhan JY, Qin YF, Zhao ZY (2009) Neonatal screening for congenital hypothyroidism and phenylketonuria in China. World J Pediatr 5(2):136–139. https://doi.org/10.1007/s12519-009-0027-0

    Article  PubMed  Google Scholar 

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Acknowledgements

We sincerely thank the participants for their cooperation and willingness to participate in this study.

Funding

This work was funded by National Natural Science Foundation of China grant 82271903 (Z.-Q.Z.)

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Author notes

  1. Meng-Wen Wang and Chu-Jun Wu have contributed equally to the study.

Authors and Affiliations

  1. Department of Neurology, Beijing Tiantan Hospital, National Clinical Research Center for Neurological Diseases, Capital Medical University, No.119 South 4Th Ring West Road, Fengtai District, Beijing, 100070, China

    Chu-Jun Wu & Zai-Qiang Zhang

  2. China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China

    Chu-Jun Wu & Zai-Qiang Zhang

  3. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China

    Meng-Wen Wang

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Contributions

Conception and drafting of the work were performed by MWW and CJW. Data acquisition and data interpretation were performed by MWW and CJW. Revision of the manuscript for intellectual content was conducted by ZQZ. All authors have read and approved the final manuscript.

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Correspondence to Zai-Qiang Zhang.

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The authors declare that they have no conflict of interest. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

This study was approved by the Ethics Committees of Beijing Tiantan Hospital (ID of the ethics approval: KY2020-105-02).

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Wang, MW., Wu, CJ. & Zhang, ZQ. Neurological and imaging phenotypes of adults with untreated phenylketonuria: new cases and literature review. J Neurol 270, 4060–4079 (2023). https://doi.org/10.1007/s00415-023-11760-9

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