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. 2022 Sep 29:13:1011470.
doi: 10.3389/fneur.2022.1011470. eCollection 2022.

Serum glial fibrillary acidic protein and neurofilament light chain in patients with early treated phenylketonuria

Amelie S Lotz-Havla  1 , Sabrina Katzdobler  2 , Brigitte Nuscher  2 , Katharina Weiß  1 , Johannes Levin  2   3   4 , Joachim Havla  5   6 , Esther M Maier  1
Affiliations

Serum glial fibrillary acidic protein and neurofilament light chain in patients with early treated phenylketonuria

Amelie S Lotz-Havla et al. Front Neurol. .

Abstract

To pave the way for healthy aging in early treated phenylketonuria (ETPKU) patients, a better understanding of the neurological course in this population is needed, requiring easy accessible biomarkers to monitor neurological disease progression in large cohorts. The objective of this pilot study was to investigate the potential of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as blood biomarkers to indicate changes of the central nervous system in ETPKU. In this single-center cross-sectional study, GFAP and NfL concentrations in serum were quantified using the Simoa® multiplex technology in 56 ETPKU patients aged 6-36 years and 16 age matched healthy controls. Correlation analysis and hierarchical linear regression analysis were performed to investigate an association with disease-related biochemical parameters and retinal layers assessed by optical coherence tomography. ETPKU patients did not show significantly higher GFAP concentrations (mean 73 pg/ml) compared to healthy controls (mean 60 pg/ml, p = 0.140). However, individual pediatric and adult ETPKU patients had GFAP concentrations above the healthy control range. In addition, there was a significant association of GFAP concentrations with current plasma tyrosine concentrations (r = -0.482, p = 0.036), a biochemical marker in phenylketonuria, and the retinal inner nuclear layer volume (r = 0.451, p = 0.04). There was no evidence of NfL alterations in our ETPKU cohort. These pilot results encourage multicenter longitudinal studies to further investigate serum GFAP as a complementary tool to better understand and monitor neurological disease progression in ETPKU. Follow-up investigations on aging ETPKU patients are required to elucidate the potential of serum NfL as biomarker.

Keywords: Simoa assay; biomarkers brain alterations; glial alterations; glial fibrillary acidic protein (GFAP); neuroaxonal damage; neurofilament light chain (NFL); optical coherence tomography; phenylketonuria (PKU).

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Conflict of interest statement

Author AL-H has received travel reimbursement from BioMarin, Nutritia Metabolics, and Sobi and author fees from Thieme medical publishers. Authors JL and SK were funded by the Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). Author JL reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent Pharmaceutical Composition and Methods of Use (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. Author JH is (partially) funded by the German Federal Ministry of Education and Research [Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H] (DIFUTURE)]. Author JH reports a grant for OCT research from the Friedrich-Baur-Stiftung, personal fees and non-financial support from Merck, Alexion, Novartis, Roche, Santhera, Biogen, Heidelberg Engineering, Sanofi Genzyme and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. Author EM has received a research grant from Nutritia Metabolic for this work and travel reimbursement from Sobi and Dr. Schär and was paid for advisory services from Sobi, APR and Sanofi-Aventis. The remaining 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.

Figures

Figure 1
Figure 1
Serum glial fibrillary acidic protein (sGFAP) in early treated phenylketonurie (ETPKU) patients. (A) Association of sGFAP concentrations and age. The quadratic relationship between sGFAP concentrations and age is depicted by the continuous line. (B) sGFAP concentrations in ETPKU 12-17 (N = 12) and 18-36 (N = 22) years of age compared to healthy controls (HC; N = 8 / 8). (C) Association of natural log-transformed sGFAP concentrations in adult ETPKU (N = 22) and current concentrations of tyrosine (Tyr) in plasma. The relationship of the variables was linear, as depicted by the continuous line.
Figure 2
Figure 2
Serum neurofilament light chain (sNfL) in early treated phenylketonurie (ETPKU) patients. (A) Association of sNfL concentrations and age. The quadratic relationship between sNfL concentrations and age is depicted by the continuous line. (B) sNfL concentrations in ETPKU 12-17 (N = 12) and 18-36 (N = 18) years of age compared to healthy controls (HC; N = 8 / 8).
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