Guía de Práctica Clínica Fenilcetonuria (PKU). Book · June with Reads. ISBN Publisher: La Caracola Editores. Authors and. La fenilcetonuria o PKU, es una afección metabólica en donde la persona no puede procesar la fenilalanina. Se necesita alimentos o una dieta especial para . Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH; ).

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CC HPO: Phenylketonuria PKU is fenilcetojuria autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase PAH;an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism.

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

See Scriver and Blau et al.

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Early diagnosis of phenylketonuria, a cause of mental retardation, is important because it is treatable by dietary means. Features other than mental retardation in untreated patients include a ‘mousy’ odor; light pigmentation; peculiarities of gait, stance, and sitting posture; eczema; and epilepsy Paine, Brain calcification has been reported in dihydropteridine reductase DHPR deficiency Pitt and O’Day found only 3 persons with cataracts among 46 adults, aged 28 to 71 years, with untreated PKU.

They concluded that PKU is not a cause of cataracts. Only 3 adults with the biochemical findings of PKU were found.

Fenilcetonuria (PKU)

Each was mentally subnormal. Normal mentality is very rare among patients with phenylketonuria who have not received dietary therapy. Evidence of heterogeneity in phenylketonuria was presented by Auerbach et al. Improvement in the skin lesions after commencement of a low phenylalanine diet supported the possibility of a causal relationship. Widespread screening of neonates for phenylketonuria brought to light a class of patients with a disorder of phenylalanine fenilcetonura milder than that in PKU.

These patients show serum phenylalanine concentrations well below those in PKU, but still several times the normal. PKU and hyperphenylalaninemia breed true in families Kaufman et al. The authors stated that ‘the difficulties of some patients to adjust their blood Phe level according to their target value although they comply with the dietary recommendations fenilcetnuria be caused by low residual enzyme activity.

The authors found that, after correcting for socioeconomic status, phenylalanine control at age 2 was predictive of overall IQ, although early and continuous treatment did not necessarily lead to normalization of fenilectonuria IQ. Patients’ groups were compared with a control sample of healthy controls 2, individuals from an epidemiologic study. The 2 patient groups did not differ significantly either in the degree or in the pattern of their psychologic profile.

In a retrospective study from birth in 13 patients with classic PKU, Barat et al. Prealbumin was reduced in Phosphorus and B12 levels were diminished only in patients with low adherence to diet. The occurrence of mental retardation in the offspring of homozygous mothers is an example of a genetic disease based on the genotype of the mother.

The offspring had reduced learning ability. They pointed out that the damage is aggravated by pkh normal placental process which functions to maintain higher levels ppku amino acids in the fetus than in the mother.

Huntley and Stevenson and Hanley et al. Huntley and Stevenson described 2 sisters with PKU who had a total of 28 pregnancies. Sixteen ended in spontaneous first-trimester abortion. The fetus in each of the 12 pregnancies carried to term had intrauterine growth retardation and microcephaly and 9 of the 12 term fdnilcetonuria had cardiac malformations as well.

She had an apparently normal phenotype except for pigment dilution of the hair, which was more lightly colored than expected for the family and ethnic norms.

She was not mentally retarded. One of the affected offspring had died of congenital heart disease at the age of 4 months. The MRI results showed a tendency for corpus callosum hypoplasia in those denilcetonuria whose mothers were not in metabolic control during their pregnancies.


The cohort of offspring were examined for malformations, including congenital heart disease, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth fenilcetonuuria, other major and minor defects, and early abnormal urologic signs.

The mothers were grouped according to pju mean phenylalanine levels during critical gestational weeks fenilcetinuria average for phenylalanine exposure throughout the pregnancy. The frequency of congenital abnormalities increased with increasing maternal phenylalanine levels.

Children were stratified by the timing of maternal metabolic control at 0 to 10 weeks’, 10 to 20 weeks’, or after 20 weeks’ gestation. Scores of a General Cognitive Index decreased as weeks to fenilctonuria metabolic control increased.

Offspring of women who had metabolic control prior to pregnancy had a mean score of Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks’ gestation had a General Cognitive Index score 2 standard deviations below the norm. At birth, offspring were examined; they were followed pkku at 3 months, 6 months, and then annually.

Fenilcetonuria | Nacersano

Congenital heart defects were found in 31 offspring; of these, 17 also had microcephaly. Mean phenylalanine levels at 4 to 8 weeks’ gestation predicted congenital heart defects P less than 0. An infant with a congenital heart defect had a 3-fold risk of having microcephaly when the mother had higher phenylalanine levels.

No direct relationship to the specific PAH mutation was found. None of the women whose offspring had congenital heart defects had blood phenylalanine levels in control during the first 8 weeks of gestation. One of the children among 50 from mothers with non-PKU mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented.

Those with untreated PKU fenilcetonuuria to have severe behavioral disturbances, including psychotic disorders, ffenilcetonuria features, hyperactivity, and aggression, as well as self-mutilation. Among early-treated children and adolescents, discontinuation of treatment was associated with attention-deficit disorder and decreased social competence.

Children who continued treatment had fewer behavioral problems. However, most tended to be less happy and confident. Even adults who had fenilcetoburia treatment had higher rates of depression, anxiety-related disorders, and social introversion compared to the normal population. In general, the severity of problems feni,cetonuria with the timing and degree of exposure to increased blood levels of phenylalanine.

These included difficulties in forming interpersonal relationships, achieving autonomy, attending educational goals, and having healthy emotional development. The most important way to reduce these problems is strict metabolic control throughout life, with particular importance on the first year of life. In untreated classical PKU, blood levels as high as 2. Bowden and McArthur found that phenylpyruvic acid inhibits pyruvate decarboxylase in brain but not in liver. They suggested that this accounts for the defect in formation of myelin and mental retardation in this disease.

Both the size and the amount of phenylalanine hydroxylase mRNA were normal. The findings confirmed the genetic diagnosis of PKU in the fetus and indicated that the mutations affected translation or stability of the protein.

Tolerance to dietary phenylalanine and therefore the clinical severity of PKU have been presumed to be the consequence of the rate of conversion of phenylalanine into tyrosine.

However, in a study of 7 classic PKU patients, van Spronsen et al. Kaufman described the derivation of a quantitative model of phenylalanine metabolism in humans. The model was based on the kinetic properties of pure recombinant human PAH and on estimates of the in vivo rates of phenylalanine transamination and protein degradation. Calculated values for the steady-state concentration of blood phenylalanine, rate of clearance of phenylalanine from the blood after an oral load of the amino acid, and dietary tolerance of phenylalanine all agreed with data from normal as well as from phenylketonuric patients and obligate heterozygotes.

Kaufman suggested that these calculated values may help in the decision about the degree of restriction of phenylalanine intake that is necessary to achieve a satisfactory clinical outcome in patients with classic PKU and in those with milder forms of the disease.


It has been postulated that the significant incidence of learning disabilities in treated patients with PKU may be due, in part, to reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membrane. In a study of hypotyrosinemia in a PKU population, Hanley et al. This compared to nonfasting plasma tyrosine levels of The data supported previous findings that plasma tyrosine efnilcetonuria are low in PKU.

Fenilcetonuriia abnormal concentration of brain Phe was detected in all patients, but there was wide interindividual variability of concurrent plasma Phe.

In late-detected subjects, brain Phe concentration correlated with clinical phenotype better than did plasma Phe. White-matter alterations were fenilcetonurria in all patients. For each individual with PKU, the authors also noted IQ, mutations, whether or not a restricted diet was followed, and age at diagnosis. Patients’ brain phenylalanine concentrations were different in spite of similar blood levels.

Interindividual variations of the apparent transport Michaelis constant ranged from 0. Sibs with lower values for the apparent transport constant, higher values for the ratio of the maximal transport velocity over the intracerebral consumption rate, and higher concurrent brain phenylalanine levels fenilcetonuriq a lower IQ and a higher degree of cerebral white matter abnormalities.

To determine whether impairments of cerebral metabolism may play a role in acute phenylalanine neurotoxicity, Pietz et al. PKU patients showed slowing of EEG background activity, a sign of impaired brain function, 24 fenilcetonurai after oral phenylalanine challenge. Most variation in classical PKU is due to heterogeneity in the mutant alleles with many patients being compound heterozygotes rather than homozygotes for one particular mutant allele.

Using a cDNA probe for kpu phenylalanine hydroxylase to analyze human-mouse hybrid cells by Southern hybridization, Lidsky fenilcetonyria al. By in situ hybridization, the assignment of feni,cetonuria PAH locus was narrowed to chromosome 12qq Eisensmith and Woo reviewed mutations and polymorphisms in the human Fenllcetonuria gene.

About 50 of the mutations were single-base substitutions, including 6 fenilcetonuuria mutations and 8 splicing mutations, with the remainder being missense mutations. Of the missense mutations, 12 apparently resulted from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides.

Recurrent mutations had been observed at several sites, producing associations with different haplotypes in different populations. Studies of in vitro expression showed significant correlations between residual PAH activity and severity of the disease phenotype.

Using 3 complementary in vitro protein expression systems and 3D structural localization, Waters et al. Enzyme-specific activity and kinetic properties are not adversely affected, implying that the only way these mutations reduce enzyme activity within cells in vivo is by producing structural changes which provoke the cell to destroy the aberrant protein.

The mutations were chosen because of their associations with a spectrum of in plu hyperphenylalaninemia among patients. Most PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation. They used database searches to identify regions in the N-terminal domain of PAH with homology to the regulatory domain of prephenate dehydratase PDHthe rate-limiting enzyme in the bacterial phenylalanine biosynthesis pathway.

To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wildtype and 5 mutant forms including G46S, Binding studies showed that the wildtype form of this domain specifically binds phenylalanine, whereas all mutations abolished or significantly reduced this phenylalanine-binding capacity. The data suggested that impairment of phenylalanine-mediated activation of PAH may be an important disease-causing mechanism of some N-terminal PAH mutations.

Most missense mutations found in PKU result in misfolding of the phenylalanine hydroxylase protein, increased fenilcehonuria turnover, and loss of enzymatic function.