Optical Coherence Tomography to Assess Neurodegeneration in Phenylalanine Hydroxylase Deficiency

Abstract

In phenylalanine hydroxylase (PAH) deficiency, an easily feasible method to access the progression of neurodegeneration is warranted to contribute to current discussions on treatment indications and targets. The objective of the present study was to investigate whether optical coherence tomography (OCT) measures as markers of neurodegeneration differ between patients with PAH deficiency and healthy controls (HCs) according to phenotype and metabolic control. In this single-center cross-sectional study, 92 patients with different phenotypes of PAH deficiency [PAH deficiency not requiring treatment, early treated phenylketonuria (ETPKU), and late-diagnosed phenylketonuria (PKU)] compared with 76 HCs were examined using spectral-domain OCT. Indices of phenylalanine elevation and variability were correlated with OCT parameters. Late-diagnosed PKU patients showed reduced peripapillary retinal nerve fiber layer (pRNFL) thickness and combined ganglion cell and inner plexiform layer (GCIPL) volume. Adult ETPKU patients were found to have lower GCIPL volume (p = 0.016), which correlated with the indices of phenylalanine control. In pediatric ETPKU patients with poor metabolic control, pRNFL was significantly reduced (p = 0.004). Patients with PAH deficiency not requiring treatment did not exhibit retinal degeneration. Inner nuclear layer (INL) was significantly increased in the pediatric ETPKU patients, driven by those with current poor metabolic control (p = 0.006). Our data provide evidence of retinal neuroaxonal degeneration and INL swelling, depending on the phenotype, current age, and metabolic control. These findings suggest that OCT is suitable to investigate neurodegeneration in PKU and we propose OCT as a sensitive, reliable, safe, low-burden, and low-cost examination for future multicenter studies.

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

“…The patients examined in this study were part of a previously published cohort of PKU patients studied with OCT ( 35 ). The pRNFL thickness and GCIPL and INL volumes of the ETPKU patients in this study are shown in Table 1 .…”

“…Limited data were available only for patients who were treated at other metabolic centers in childhood ( N = 1), or had poor adherence in adolescence ( N = 2) or adulthood ( N = 1). Indices of Phe control based on dried blood spot measurement were calculated as described before ( 16 , 35 , 49 , 50 ). We averaged Phe control in the following age bands: childhood 0–10 years of age, adolescence 11–16 years of age, adulthood 17 years of age to present, and lifetime.…”

“…OCT examination was performed using a SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) with automatic real time (ART) function for image averaging as described before ( 35 ). Data are reported for peripapillary retinal nerve fiber layer thickness (pRNFL) to assess axonal degeneration, volume of combined ganglion cell and inner plexiform layer (GCIPL = GCL + IPL) as marker for neuronal degeneration, and for inner nuclear layer (INL).…”

“…Only recently, evidence for glial alterations and neuroaxonal degeneration was found in ETPKU patients using optical coherence tomography (OCT) ( 31 – 35 ). The hypothesis of retinal glial alterations and neuroaxonal damage associated with brain lesions in ETPKU ( 35 ) was strengthened by the finding of increased S-100B protein concentration in serum ( 36 ) and t-tau and p-tau in the cerebrospinal fluid of ETPKU patients ( 20 ).…”

Dietary Liberalization in Tetrahydrobiopterin-Treated PKU Patients: Does It Improve Outcomes?

“…Tetrahydrobiopterin (BH 4 , prescribed as sapropterin dihydrochloride) is a pharmacological treatment option that aims to further improve outcomes by increasing residual PAH activity in a subset of PKU patients. Through this mechanism, daily administration of BH 4 in BH 4 -responsive patients may result in lower blood Phe concentrations, and possibly in the increased stability of blood Phe concentrations and/or increased dietary Phe tolerance [7][8][9][10][11]. In BH 4 -responsive patients with suboptimal blood Phe concentrations, BH 4 can thus be used to improve metabolic control.…”