| Symbol
| PKU
|
| Location
| 12q23.1
|
| Name
|
phenylketonuria |
| Other name(s)
|
hyperphenylalaninemia, variant PKU
phenylalanine hydroxylase deficiency |
| Corresponding gene
|
PAH
|
| Other symbol(s)
| PKU, non-PKU, HPA
|
| Main clinical features
|
intolerance to the dietary intake of phenylalanine
dietary restriction may avoid profound and irreversible mental retardation
three group of phenotypes
Group 1 (meanąSD in vitro residual activity 53.0%) corresponds to the very mild phenotype
Group 2 (meanąSD in vitro residual activity, 41.5%) corresponds to the mild PKU phenotype
Group 3 (mean in vitro residual activity 6.9%) corresponds to severe PKU and includes the only moderate mutant (A309V), in addition to a large group of mutations unambiguously reported as "severe"
associated to bone impairment characterized by circulating osteoclast precursors and activated T cell increase (PMID: 21152388)) |
| Genetic determination
| autosomal recessive |
| Related entries
| hyperphenylalaninemia
|
| Function/system disorder
| metabolism/aminoacids |
| Type
| disease
|
| Name
| phenylalanine hydroxylase (PAH)
|
| Gene mutation | Chromosome rearrangement | Effect | Comments |
|
|---|
|
|
|
| over 400 different disease-causing mutations have been identified in the PAH gene ; Most patients are compound heterozygotes.
| | missense
|
| abnormal protein/loss of function
| result in misfolding of PAH, increased protein turnover, and a loss of enzymatic function
| | missense
|
| abnormal protein/loss of function
| (R158Q, I174T and R408W) result in the classical phenylketonuria (PMID: 19036622)
| |
| Remark(s)
|
commonly diagnosed upon routine screening of newborns (Guthrie card bloodspot). PAH genotype is the main determinant of metabolic phenotype in most cases. In compound heterozygote the less severe of the two PAH mutations determine disease severity
decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome
protein-misfolding disease in which global conformational changes hinder molecular motions essential for physiological enzyme function (PMID: 18538294)) |
| Genotype/Phenotype correlations
|
Classic PKU is associated with a high risk of mental impairment in the absence of treatment, non-PKU HPA with a much lower risk and variant PKU are intermediate. Pregnancies in women with PAH deficiency are at risk of congenital abnormalities and should be monitored from before conception |