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Abstract
Objective To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.
Methods In this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients.
Results Nineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 (p = 0.003), total tau (p < 0.001), and phosphorylated tau (p = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r = 0.64, p = 0.003), neuropsychiatric symptoms (r = 0.73, p < 001), motor evoked potential latency (r = 0.48, p = 0.030), and parietal lobe atrophy.
Conclusions Our study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.
Glossary
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- AHB=
- abductor hallucis brevis;
- BDI=
- Beck Depression Inventory;
- CMCT=
- central motor conduction time;
- CWD=
- cumulative years without diet;
- ETP=
- early-treated patients with phenylketonuria;
- HC=
- healthy control;
- MEP=
- motor evoked potential;
- MoCA=
- Montreal Cognitive Assessment;
- NMSS=
- Nonmotor Symptom Scale;
- NPI=
- Neuropsychiatric Inventory;
- p-tau=
- phosphorylated tau;
- PD=
- Parkinson disease;
- Phe=
- phenylalanine;
- PKU=
- phenylketonuria;
- t-tau=
- total tau;
- SEP=
- somatosensory evoked potential;
- TMS=
- transcranial magnetic stimulation;
- TMT-A=
- Trail-Making Test part A;
- TMT-B=
- Trial-Making Test part B;
- VBM=
- voxel-based morphometry;
- WMH=
- white matter hyperintensities
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received March 5, 2020.
- Accepted in final form September 1, 2020.
- © 2020 American Academy of Neurology
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