PAH R111X - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

PAH R111X

(PAH Arg111Stop)


Short summary

The PAH-R111X allele is found in clinical cases of phenylketonuria (PKU) identified by newborn screening among patients of Asian descent. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia.

Variant evidence
Computational 1

Nonsense allele.

Functional -
Case/Control -
Familial -
 
Clinical importance
Severity 4

If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia.

See Zurflüh MR et al. 2008 (17935162).

Treatability 5

“Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder.”

See Thompson AJ et al. 1993 (8353710).

Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • None available.

Publications
 

Wang T, Okano Y, Eisensmith R, Huang SZ, Zeng YT, Lo WH, Woo SL. Molecular genetics of phenylketonuria in Orientals: linkage disequilibrium between a termination mutation and haplotype 4 of the phenylalanine hydroxylase gene. Am J Hum Genet. 1989 Nov;45(5):675-80. PubMed PMID: 2816939; PubMed Central PMCID: PMC1683443.

“Phenylketonuria (PKU) is a common metabolic disorder among Chinese, with a prevalence of about 1 in 16,500 births. This frequency is very similar to that among Caucasians…An Arg111-to-Ter111 mutation has been identified in exon 3 of the PAH gene in a Chinese PKU patient. The mutation is in linkage disequilibrium with the mutant haplotype 4 alleles which are the most prevalent haplotype among the Orientals. The mutation accounts for about 10% of the Chinese PKU alleles and is absent from the Caucasians, demonstrating that independent mutational events have occurred in the PAH locus after racial divergence.”

Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG, Brenton DP. Brain MRI changes in phenylketonuria. Associations with dietary status. Brain. 1993 Aug;116 ( Pt 4):811-21. PubMed PMID: 8353710.

“Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder. However, there is evidence that subtle neurological impairment remains common in early treated subjects and in the last 3 years there have been a number of reports of overt neurological impairment with white matter abnormalities on MRI...These data are consistent with studies in animals showing that hyperphenylalaninaemia increases myelin turnover in a dose dependent manner. It is suggested that the effects of phenylalanine on myelin pose a lifelong hazard to the nervous system.”

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat. 2008 Jan;29(1):167-75. PubMed PMID: 17935162.

If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia.

Genomes
 

Other external references
 

Other in silico analyses
 

  • NBLOSUM100 score = 10
  • GET-Evidence autoscore = 6

Edit history
 

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