Improved Measurement of Brain Phenylalanine and Tyrosine Related to Neuropsychological Functioning in Phenylketonuria

Abstract

Introduction: Researchers hypothesized that in phenylketonuria (PKU) high brain phenylalanine (Phe) levels and low brain tyrosine (Tyr) levels affect neuropsychological functioning. However, traditional magnetic resonance spectroscopy (MRS) yielded uncertain results of brain Phe and could not adequately measure brain Tyr. This pilot study examined the potential of correlated spectroscopy (COSY) to quantify these biomarkers and explain variability in neuropsychological functioning.Methods: Nine adults with early treated classic PKU received magnetic resonance imaging (MRI) with COSY and a battery of neuropsychological tests. Brain Phe and Tyr in parietal white matter (PWM) were compared to results in gray matter of the posterior cingulate gyrus (PCG).Results: Brain Phe ranged from 101 to 182 (mean ¼ 136.76 AE 23.77) mmol/L in PCG and 76 to 185 (mean ¼ 130.11 AE 37.88) mmol/L in PWM. Brain Tyr ranged from 4.0 to 7.4 (mean ¼ 5.44 AE 1.01) mmol/L in PCG and 4.1 to 8.4 (mean ¼ 5.90 AE 1.48) mmol/L in PWM. Correlation coefficients were largest for brain Phe PWM and measures of auditory memory (rho ¼ À0.79), anxiety (rho ¼ 0.79), and executive functioning (rho ¼ 0.69). Associations were in the expected direction, with higher brain Phe and lower brain Tyr related to poorer functioning. The two participants with severe structural MRI abnormalities had low brain Tyr levels in PCG and 3/5 of the participants with moderate to severe MRI abnormalities had higher than average brain Phe levels.Conclusion: COSY has the potential to quantify brain Phe and Tyr at low concentrations and in specific brain regions. In this pilot study, these biomarkers were associated with indices of neuropsychological functioning. Additional studies are needed to validate the COSY results.

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

“…We did not measure tyrosine concentrations, or rates of monoamine synthesis directly in nerve terminal in relevant brain tissues in the affected patients. Although a strong correlation has previously been reported between plasma levels of tyrosine and its concentration in cerebrospinal fluid in HT‐1 patients (Thimm et al, ), a recent magnetic resonance spectroscopy study on PKU patients indicated a large concentration gradient between blood and brain (posterior cingulate gyrus and perventricular white matter) levels of phenylalanine and tyrosine (Waisbren et al, ). Still, the effective subcellular concentration of amino acids in relevant compartments of monoaminergic neurons in these patients is not known.…”

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

“…Recently, two‐dimensional shift correlated spectroscopy has been applied for the unambiguous quantification of cerebral metabolites, Phe and tyrosine, that present spectral overlap via conventional spectroscopy. With this technique, brain concentrations of these metabolites were significantly associated with some indices of neuropsychological functioning (eg, auditory memory and executive functioning) …”

New protein structures provide an updated understanding of phenylketonuria

“…(14, 15)). Nevertheless, restoration of Phe regulation begins with understanding how unaffected individuals control Phe levels, and why there is extensive variation in phenotype among those who cannot regulate Phe.…”