Discordant phenylketonuria phenotypes in one family: the relationship between genotype and clinical outcome is a function of multiple effects.

Abstract

Four members spanning three generations of one family have phenylketonuria of varying degrees ofseverity. 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 (RlllX 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.

Phenylalanine hydroxylase deficiency in south Italy: Genotype–phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness

“…The genotypephenotype correlation studies confirmed the c.1066−11GNA as a severe mutation, conferring a severe phenotype in compound heterozygosity with other severe mutations. Interestingly, we found that the mutation p.L48S was associated with a severe phenotype in our study when combined with mutation p.R408W, and it is inconsistent with previously reported studies for this mutation in Europe [24,25]. The high frequency of mutations with low degree of severity, such as p.L48S or p.R261Q, can explain the relatively higher prevalence of mild and moderate phenotypes in Mediterranean patients, compared with northern European populations [26].…”

Spectrum of Mutations in the Batten Disease Gene, CLN3

“…In family L46, of two siblings who were compound heterozygotes for the 1.02-kb deletion and the missense mutation (Leul7OPro), the eldest child had classical JNCL (and died at age 22 years), whereas the younger sibling, L46Pb, now 22 years old, has visual failure, a nearly normal IQ, and easily controlled seizures. Intrafamilial variation such as this has been observed in many diseases-such as type I Gaucher disease (Amaral et al 1994), cystic fibrosis (Dean et al 1990), and phenylketonuria (Tyfield et al 1995)-but its cause is still unexplained in most cases. Both genetic and environmental factors may play a role.…”

Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997

“…the quality of dietetic therapy, as well as other factors such as the family environment. It is also conceivable that hormonal and other metabolic eects may in¯uence Phe homeostasis [78].…”