Study design and description of patients

Abstract

A West German multicentre study (eight centres) of PKU was designed in 1976. The subjects of the study are the differential diagnosis, factors influencing the therapeutic outcome, and the extension of dietary therapy into adolescence. Between 1978 and 1984, 165 patients were enrolled, of whom 38 were of non-German nationality. The educational and occupational status of the West German parents were comparable to the population of the Federal Republic of Germany. In the central data bank located at the University Childrens Hospital in Heidelberg, data from recurrent medical examinations and from biochemistry, dietetics, neurology, psychometry and demography were collected. The differential diagnosis of the elevated plasma Phe level in the newborn period resulted in the detection of 2 patients with a PTPS-deficiency, and of 163 with an apo-enzyme defect. Depending upon the magnitude of the Phe levels during the first weeks of life, preliminary treatment groups were formed. They were revised at the age of 6 months with a protein challenge. The levels of Phe during the protein challenge resulted in three types of response. Of these, type III can apparently forgo dietary restrictions resulting in plasma Phe concentrations of around 10 mg/dl. Preliminary results of the whole study are now presented.

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

“…For practical and ethical reasons, in vivo 3 H or 14 C isotope studies [30] or invasive testing such as enzyme assays from liver biopsies [31] were not appropriate. Therefore, Blaskovics [32] developed in the mid-1960s the standardized three day natural protein loading test with evaporated milk that was applied at 6 months of age in the U.S. [33] and German [34] PKU Collaborative Studies for classification of PKU and for genotype-phenotype analysis. With this test three principal types of Phe blood level response, types 1, 2 and 3, were delineated in both studies.…”

“…The Blaskovics loading tests at 6 months with their resulting 72 h Phe values [32] yield indicators of metabolic phenotypes which belong to a bimodal distribution with nadir at about 1,200 and 1,600 μmol/L, respectively [33,34], thus establishing a classification into classic and variant PKU. A more detailed separation of the metabolic phenotypes was established by Güttler and Guldberg [45] through estimating Phe tolerance at 5 years of age (see also above).…”

Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

“…These results of microenzyme assay on liver needle biopsy specimens are at the root of the German Collaborative Study on Phenylketonuria (PKU)/Hyperphenylalaninaemia (HPA) (Collaborative study of children treated for phenylketonuria (PKU) in the Federal Republic of Germany 1990) which was designed in 1976. On the whole, it consisted of studies in three fields: (i) differential diagnosis of subtypes of HPA by analysis of the clinical, metabolic and molecular phenotype as an aid to rational treatment; (ii) therapeutic outcome in terms of intellectual, behavioural and neurological development; and (iii) decisions on suspending or continuing dietary treatment at given ages (Lutz et al 1990). For defining their metabolic phenotype, at the age of 6 months of life (6ML), patients with PKU/HPA were loaded with natural protein, corresponding to 180 mg phe/kg bw/ day over a period of three consecutive days (72 h).…”

“…excluding possible cases of delayed PAH maturation, the same type of loading was repeated at the age of 5 years of life (5YL) in a subset of the 6ML patients. After description of the 6ML data (Lutz et al 1990;M€ onch et al 1990;Langenbeck et al 2009) and of preliminary results of 5YL (Schmidt et al 1989), we here present for all 5YL study patients the analytical results of phe disposal in blood and of urinary excretion of acidic phe transamination metabolites. Synopsis of the 5YL blood and urine data suggests maturation of phe transamination and/or renal metabolite transport between 6 months and 5 years as the reason for both the predictability of phe tolerance from 2 years on (van Spronsen et al 2009) and reliable classification of PKU/HPA through age 5 phe tolerance data (G€ uttler and Guldberg 1996).…”

“…Because of incomplete sampling, only 145 loads were analysed, with 14 classified as response type II (Lutz et al 1990). The detailed analysis of complete test samples included 134 study cases, and 40 more patients were tested during routine diagnostic workup in the years -1998and 2007(Langenbeck et al 2009).…”