Related Experiment Videos
Biochemical control, genetic analysis and magnetic resonance imaging in patients with phenylketonuria
J H Walter1, L A Tyfield, J B Holton
1Department of Child Health, Royal Hospital for Sick Children, Bristol, United Kingdom.
Insights
Phenylketonuria (PKU) patients on early diet showed brain abnormalities in some cases. Mutations linked to residual enzyme activity correlated with normal brain imaging, suggesting genotype influences PKU outcomes.
Area of Science:
- Medical Genetics
- Neurology
- Biochemistry
Background:
- Phenylketonuria (PKU) is an inherited metabolic disorder.
- Early detection and dietary management of PKU are crucial.
- Long-term neurological outcomes in PKU patients require further investigation.
Purpose of the Study:
- To investigate the relationship between biochemical control, genotype, and brain imaging findings in PKU patients.
- To assess white matter abnormalities in PKU patients treated from infancy.
Main Methods:
- Brain MRI was performed on 13 PKU patients aged 10-18 years.
- Biochemical control was assessed by lifetime and recent blood phenylalanine (Phe) levels.
- Phenylalanine hydroxylase (PAH) gene mutations and haplotypes were analyzed.
Main Results:
- Two patients exhibited cerebral white matter abnormalities; both had poor biochemical control, but this did not reach statistical significance.
- Genotype analysis identified mutations in 12 patients.
- A significant correlation between genotype and biochemical control was observed in 5 patients with identified mutations on both chromosomes.
- Mutations associated with residual in vitro enzyme activity correlated with normal brain imaging.
Conclusions:
- While early diet is critical, some PKU patients may still develop brain abnormalities.
- Genotype plays a significant role in predicting biochemical control and potentially neurological outcomes in PKU.
- Residual enzyme activity, indicated by specific PAH gene mutations, appears protective against white matter abnormalities in PKU.
Abstract:
Thirteen patients with phenylketonuria, detected by neonatal screening and started on diet within 16 days of age, were investigated between 10 and 18 years of age by magnetic resonance imaging (MRI) of the brain. Biochemical control was assessed from: (1) the life time blood phenylalanine (Phe) control (as determined from (a) the mean yearly exposure to Phe; (b) the accumulated time for each patient that Phe was < 120 mumol/l; (c) > 400 mumol/l; (d) > 800 mumol/l; and (e) > 1200 mumol/l); and (2) the blood Phe control over the 5 years prior to imaging (assessed for each patient by the mean yearly Phe exposure over that period). In all patients the phenylalanine hydroxylase gene locus was studied using restriction fragment length polymorphism haplotypes and mutant genes were screened for a variety of specific mutations which have been reported in other European populations or in populations of north European descent. Two patients had significant abnormalities of cerebral white matter. Although both showed poor biochemical control this did not reach statistical significance when compared to those with normal imaging. DNA haplotype patterns could be assigned to 11 patients and mutant genes were identified in 12. One patient with abnormal imaging and 4 patients without abnormalities had mutations on both chromosomes identified. In these 5 patients there was significant correlation between their genotype and biochemical control. Mutations resulting in residual in vitro enzyme activity were associated with normal imaging.