Document Detail

Discordant phenylketonuria phenotypes in one family: the relationship between genotype and clinical outcome is a function of multiple effects.
MedLine Citation:
PMID:  8592329     Owner:  NLM     Status:  MEDLINE    
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.
L A Tyfield; J Zschocke; A Stephenson; F Cockburn; A Harvie; J L Bidwell; N A Wood; L P Hunt
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medical genetics     Volume:  32     ISSN:  0022-2593     ISO Abbreviation:  J. Med. Genet.     Publication Date:  1995 Nov 
Date Detail:
Created Date:  1996-04-03     Completed Date:  1996-04-03     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2985087R     Medline TA:  J Med Genet     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  867-70     Citation Subset:  IM    
Department of Clinical Chemistry, Southmead Hospital, Bristol, UK.
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MeSH Terms
Genetic Heterogeneity
Infant, Newborn
Middle Aged
Minisatellite Repeats
Phenylalanine Hydroxylase / genetics
Phenylketonurias / genetics*
Grant Support
//Wellcome Trust
Reg. No./Substance:
EC Hydroxylase

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