Adult subjects with classical phenylketonuria (PKU) who were diagnosed and treated neonatally participated in this long-term follow-up study. Twenty-four subjects received neuropsychological (NP) assessment and a subset received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to identify: (1) pattern of cognitive dysfunction; (2) effect of high blood phenylalanine (Phe) level at time of cognitive testing; and (3) treatment variables that may be associated with cognitive difficulties in adulthood. All subjects had average IQ except one subject in the borderline range. Diet was initiated by the 15th day of life. All subjects except one were on diet until age 6 years (mean years of treatment = 15). Blood Phe levels at cognitive testing ranged from 157 to 1713 micromol/L (mean = 1038); 11 subjects had levels < 1000 micromol/L and 13 subjects had levels >1000 micromol/L. Results suggest that adults with early-treated PKU demonstrate specific cognitive deficits, a number of which are associated with the frontal and temporal area of the brain. Deficits were noted in several domains including executive functioning, attention, verbal memory, expressive naming and verbal fluency. Self-report measures of depression and anxiety were generally in the normal/mild range. The group with a Phe level > 1000 micromol/L scored lower than the group with Phe level < 1000 micromol/L on measures of focused attention, verbal fluency, reaction time, verbal recognition memory, visual memory and naming. Tests of cognitive functioning were often correlated with measures of treatment during childhood rather than with Phe level at the time of cognitive testing. Subjects with abnormal MRI scored significantly lower on two cognitive tests (Trails A and CVLT Recognition Memory). We found no significant correlation between current brain Phe level obtained through MRS (n = 10) and neuropsychological functioning. Future longitudinal investigation with a larger sample size will assist in clarifying the aetiology of neuropsychological deficits and association with treatment history.
Phenylketonuria patients harboring a subset of phenylalanine hydroxylase (PAH) mutations have recently shown normalization of blood phenylalanine levels upon oral administration of the PAH cofactor tetrahydrobiopterin [(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)]. Several hypotheses have been put forward to explain BH 4 responsiveness, but the molecular basis for the corrective effect(s) of BH4 has not been understood. We have investigated the biochemical, kinetic, and structural changes associated with BH4-responsive mutations (F39L, I65T, R68S, H170D, E178G, V190A, R261Q, A300S, L308F, A313T, A373T, V388M, E390G, P407S, and Y414C). The biochemical and kinetic characterization of the 15 mutants studied points toward a multifactorial basis for the BH4 responsiveness; the mutants show residual activity (>30% of WT) and display various kinetic defects, including increased Km (BH4) and reduced cooperativity of substrate binding, but no decoupling of cofactor (BH4) oxidation. For some, BH4 seems to function through stabilization and protection of the enzyme from inactivation and proteolytic degradation. In the crystal structures of a phenylketonuria mutant, A313T, minor changes were seen when compared with the WT PAH structures, consistent with the mild effects the mutant has upon activity of the enzyme both in vitro and in vivo. Truncations made in the A313T mutant PAH form revealed that the N and C termini of the enzyme influence active site binding. Of fundamental importance is the observation that BH4 appears to increase Phe catabolism if at least one of the two heterozygous mutations has any residual activity remaining.
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