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Discordant phenylketonuria phenotypes in one family: the relationship between genotype and clinical outcome is a
L A Tyfield1, J Zschocke, A Stephenson
1Department of Clinical Chemistry, Southmead Hospital, Bristol, UK.
Insights
Phenylketonuria (PKU) severity varies within a family due to different mutations in the phenylalanine hydroxylase (PAH) gene. Genotype influences biochemical outcomes, but the relationship between genotype and clinical presentation is complex.
Area of Science:
- Genetics
- Biochemistry
- Metabolic Disorders
Background:
- Phenylketonuria (PKU) is a genetic disorder affecting phenylalanine metabolism.
- Family studies are crucial for understanding the genetic basis of PKU severity.
- The phenylalanine hydroxylase (PAH) gene plays a central role in PKU.
Purpose of the Study:
- To investigate the genetic mutations causing phenylketonuria (PKU) in a multi-generational family.
- To correlate specific phenylalanine hydroxylase (PAH) gene mutations with varying PKU severity and biochemical phenotypes.
- To determine the prevalence of identified PAH mutations in PKU populations in Scotland and England.
Main Methods:
- Family history collection and clinical assessment of PKU severity.
- Mutation analysis of the phenylalanine hydroxylase (PAH) gene, focusing on exons 2 and 3.
- Screening of PKU populations in Scotland and England for identified PAH mutations.
- Comparison of blood phenylalanine concentrations based on genotype.
Main Results:
- Four distinct PAH gene mutations (F39L, L48S, R111X, S67P) were identified in the family.
- Exon 2 mutations (F39L, L48S) were found to be less deleterious than exon 3 mutations.
- F39L mutations are more prevalent in Scotland, while L48S mutations are more common in England.
- Genotype partially explains biochemical phenotypes, but other factors influence clinical outcomes.
Conclusions:
- Genotype at the PAH locus contributes to the varying biochemical phenotypes observed in PKU.
- The relationship between PKU genotype and clinical outcome is complex and multifactorial.
- Specific PAH mutations have regional prevalence, impacting PKU management strategies.
Abstract:
Four members spanning three generations of one family have phenylketonuria of varying degrees of severity. Two first cousins were screened in the neonatal period and have had dietary phenylalanine restriction since diagnosis, the older patient having been classified as having more severe PKU and the younger one as having mild PKU. Their mutual grandfather and his older brother also have a significant hyperphenylalaninaemia and are of normal intelligence despite never having had restricted phenylalanine intake. Mutation analysis of the phenylalanine hydroxylase (PAH) gene has established that there are four different mutations, two in exon 2 (F39L and L48S) and two in exon 3 (R111X and S67P), which give rise to PKU in this family. In order to establish their relative severity, we screened the PKU populations of western Scotland and the south west of England for these mutations. The exon 3 mutations are rare; however, F39L is relatively common in Scotland and L48S in England. A comparison of diagnostic blood phenylalanine concentrations in subjects carrying L48S/null or F39L/null mutations with those carrying two null mutations suggest that these exon 2 mutations are less deleterious. Thus, in this family, the different biochemical phenotypes can be explained, in part, by different genotypes at the PAH locus but our results show that the relationship between genotype and clinical outcome is more complex and is a function of multiple effects.
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