Discrimination of heterozygotes for phenylketonuria, persistent hyperphenylalaninemia and controls by phenylalanine loading

Blitzer, Miriam G.; Bailey-Wilson, Joan E.; Shapira, Emmanuel

doi:10.1016/0009-8981(86)90020-3

Cited by 6 publications

(4 citation statements)

References 15 publications

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“…This mild elevation of glutamine may be because of technical artifacts or to a minor influence of the mutation on the biochemical values but not on the clinical presentation. Similar phenomena are observed in other metabolic disorders, such as phenylketonuria …”

Section: Discussionsupporting

confidence: 84%

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

et al. 2019

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IMPORTANCE The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. OBJECTIVE To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. DESIGN, SETTING, AND PARTICIPANTS We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. MAIN OUTCOMES AND MEASURES Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. RESULTS A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. CONCLUSIONS AND RELEVANCE We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.

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Section: Discussionsupporting

confidence: 84%

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

et al. 2019

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“…The procedure adopted in this study is simple and adapted to detecting carriers; no Phe loading or venepuncture is required since a single semifasting specimen of only 100 #I of plasma obtained by finger prick is sufficient. The spectrofluorimetric method used for the quantitation of plasma Phe and Tyr levels is much more practical, economical and time-saving than autoanalytical (Blitzer et al, 1986), highperformance liquid chromatographic (Hilton et al, 1986) or DNA analysis (Lehmann, 1989) techniques. The accuracy of the fluorimetric method for the determination of Phe and Tyr has been assessed by the stability of repeated measurements.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous carriers of classical phenylketonuria in a sample of the turkish population: Detection by a spectrofluorimetric method

Güneral

Ozalp

Tatlidil

1990

J of Inher Metab Disea

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Blood obtained by finger prick from 209 presumed normal homozygotes and 42 heterozygotes for classical PKU was analyzed for plasma phenylalanine (Phe) and tyrosine (Tyr) by a fluorimetric method. Subjects were tested near midday and 3 hours after a protein-rich breakfast. The plot of Phe/Tyr (micromolar ratio) against Phe2/Tyr, permitted the detection of 11 heterozygotes among 209 controls. The accuracy of this method was checked by computation of a stepwise multivariate discriminant analysis, using Phe and Tyr (mumol/L), Phe/Tyr micromolar ratio and Phe2/Tyr as variables. Ten of the 11 subjects were recovered with a percentage of correct classification of over 90%, while one case had a percentage of 89.45%. The PKU gene frequency was found to be 1/19. This emphasizes the importance of a screening programme for PKU gene carrier status in Turkey.

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“…A small possibility of having heterozygotes in the control group can be discarded since the frequency in the population is 1:50 to 1:70. 4,8,30 …”

Section: Discussionmentioning

confidence: 99%

Phenylalanine and Tyrosine Metabolism Analysis in Heterozygotes for Phenylketonuria and in Healthy Individuals

Andrade

Monteiro

Cruz

et al. 2015

Journal of Inborn Errors of Metabolism and Screening

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Phenylketonuria (PKU) is an inherited metabolic disorder derived from a deficiency in the enzyme phenylalanine hydroxylase, which converts the amino acid phenylalanine (Phe) into tyrosine (Tyr). Here we aimed to examine the metabolism of Phe and Tyr in heterozygotes for PKU during fasting and after oral overload of Phe (25 mg/kg). Plasma concentration of Phe and Tyr and Phe 2 -Tyr ratio were determined under fasting condition or 30, 45, 60, and 90 minutes after Phe overload. The sample consisted of 50 participants: 23 heterozygotes for PKU (10 men and 13 women) and a control group of 27 healthy individuals (13 men and 14 women). The dosage of Phe at 45 and 90 minutes and the micromolar fraction of Phe 2 /Tyr after 90 minutes of overload efficiently differentiated PKU heterozygotes. The discriminant function revealed 86% of accuracy. In fact, 94.4% of heterozygotes for PKU were correctly classified.

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Discrimination of heterozygotes for phenylketonuria, persistent hyperphenylalaninemia and controls by phenylalanine loading

Cited by 6 publications

References 15 publications

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

Heterozygous carriers of classical phenylketonuria in a sample of the turkish population: Detection by a spectrofluorimetric method

Phenylalanine and Tyrosine Metabolism Analysis in Heterozygotes for Phenylketonuria and in Healthy Individuals

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