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.
Highlights
Phenylalanine hydroxylase (PAH) deficiency (OMIM #261600) is caused by autosomal recessive variants in the phenylalanine hydroxylase (PAH) gene and leads to an impaired degradation of the amino acid phenylalanine (Phe) to tyrosine and, as a consequence, to elevated concentrations of Phe in blood [1]
To test the hypothesis that optical coherence tomography (OCT) is suitable to detect neurodegeneration in PAH deficiency, the present study investigated neuroaxonal retinal degeneration in patients with PAH deficiency according to phenotype and metabolic control
All registered patients who were diagnosed with PAH deficiency during neonatal or selective screening, and who were under regular care at the metabolic center of the LMU Hospital, Ludwig-Maximilians-University in Munich, Germany were invited to participate in this study
Summary
Phenylalanine hydroxylase (PAH) deficiency (OMIM #261600) is caused by autosomal recessive variants in the phenylalanine hydroxylase (PAH) gene and leads to an impaired degradation of the amino acid phenylalanine (Phe) to tyrosine and, as a consequence, to elevated concentrations of Phe in blood [1]. The approvals of BH4 (Kuvan R ; sapropterin dihydrochloride), the natural cofactor of PAH, for BH4-responsive patients and pegvaliasepqpz (Palynziq R ), a recombinant phenylalanine ammonia lyase, for adolescent and adult patients have expanded the treatment options for PKU, and thereby reduced the burden of a strict low-Phe diet for at least some of the patients [1, 5,6,7,8,9] Despite these advances, data regarding the optimal treatment targets for PKU patients are insufficient leading to different treatment recommendations worldwide [2, 10]. Neither neurocognitive nor MRI outcome studies have yet contributed to a clear decision on these issues
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