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Biomedical subjects

K Ullrich

Publications and source records attributed to K Ullrich.

At least 55 records · Page 3Linked to original sources
PubMed1998

A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.

Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.

Alleles↗
PubMed1998

Blood-brain barrier phenylalanine transport and individual vulnerability in phenylketonuria.

In vivo nuclear magnetic resonance spectroscopy can be used to measure intracerebral phenylalanine (Phe) concentrations in patients with phenylketonuria (PKU). Stationary levels, obtained under free nutrition, as well as time courses after an oral Phe load (100 mg/kg) were investigated in 11 PKU patients and were correlated with the individual clinical outcome. At blood levels around 1.2 mmol/L, brain Phe was 0.41 to 0.73 mmol/L in clinically "typical" patients, but less than 0.15 mmol/L in three untreated, normally intelligent, adult women. Kinetic investigations revealed higher transport Michaelis constants and lower ratios of the brain influx and consumption rates in these women than in the "typical" control patients (Kt,app = 0.45 to 1.10 mmol/L versus 0.10 mmol/L; T(max)/v(met) = 2.55 to 3.19 versus 7.8 to 14.0). Such variations seem to be major causative factors for the individual vulnerability to PKU.

Adolescent↗
PubMed1998

Bilateral oedema of the basal ganglia in an echovirus type 21 infection: complete clinical and radiological normalization.

A 4-year-old girl with bilateral striatal oedema in association with an echovirus type 21 infection is reported. In the course of a prolonged upper respiratory-tract infection, the patient developed muscular hypotonia, resting tremor, ataxia, sleepiness, hyperaesthesia, and indistinct speech. T2-weighted cranial MRI revealed bilateral oedema of the basal ganglia and the cerebellar peduncles. At follow-up after 3 months MRI changes and clinical symptoms had fully resolved.

Basal Ganglia↗
PubMed1997

Kinetics of phenylalanine transport at the human blood-brain barrier investigated in vivo.

In vivo proton magnetic resonance spectroscopy was used to investigate intracerebral phenylalanine (Phe) concentrations in nine patients with classical phenylketonuria (PKU). The study included serial examinations (n = 31; plasma Phe levels: 0.47-2.24 mmol/l) of patients either receiving a Phe-restricted diet (200 mg Phe per day; four patients) or a diet rich in Phe (1000 mg Phe per day; three patients). No spectrum showed metabolic abnormalities besides elevated Phe. Difference spectroscopy yielded intracerebral Phe concentrations between 0.20 and 0.76 mmol/l. Regional variations between parieto-occipital periventricular brain, frontal brain, and cerebellum were not statistically significant. Data could be fitted assuming saturable Phe transport into the brain, based on a symmetric Michaelis-Menten model (characterized by an apparent Michaelis transport constant, K(t,app), and a maximum transport velocity, Tmax) and constant Phe consumption in the brain cells (described by a velocity Vmax). Non-linear least-squares fitting of the combined data from all patients yielded K(t,app) = 0.16 +/- 0.11 mmol/l and (Tmax / Vmax) = 9.0 +/- 4.1. Carrier saturation and competitive inhibition of the influx of other large neutral amino acids can be expected at plasma Phe levels usually found in PKU patients.

Adolescent↗
PubMed1997

Progression of cerebral white matter abnormalities in early treated patients with phenylketonuria during adolescence.

In this study of cranial MRI a group of 15 adolescents with classical phenylketonuria and permanent blood phenylalanine (phe) checks from infancy was investigated twice with an interval of three years in between. Cranial MRI revealed a progression of white matter abnormalities in patients with moderate and poor control of blood phe levels, however not in well controlled patients. Nevertheless results indicate an individual vulnerability of the brain against elevated phenylalanine levels in phenylketonurics.

Adolescent↗
PubMed1997

Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria.

Based on the serum phenylalanine levels under free diet patients with hyperphenylalaninemia are classified as "classical" (>1200 micromol/L), "mild" (600-1200 micromol/L), or "non-phenylketonuria (PKU)-hyperphenylalaninemia" (<600 micromol/L). Recent studies revealed intellectual, neurologic, and neuropsychologic deficits as well as abnormalities of cerebral white matter (magnetic resonance imaging, MRI) in patients with early and adequately treated PKU. In addition deficits in IQ were reported for a group of 4-y-old patients with untreated mild PKU and non-PKU hyperphenylalaninemia (serum phenylalanine levels below 900 micromol/L). As a consequence, a lifelong diet with serum phenylalanine levels below 400 micromol/L was recommended even for those patients with serum phenylalanine levels remaining consistently between 400 and 600 micromol/L. Generally patients with non-PKU hyperphenylalaninemia were not treated, as a normal outcome was suspected, but the clinical development of patients with non-PKU hyperphenylalaninemia was not so far studied systematically. We assessed 28 untreated patients with non-PKU hyperphenylalaninemia (age: mean = 21.8, SD = 4.2 y) for IQ, school and job career, clinical-neurologic development, fine motor performances, selective and sustained attention, as well as for frontal lobe-dependent "executive functions." In addition, cranial MRI was obtained in 10 of these patients. Compared with healthy control subjects, matched for age, sex, and socioeconomic status, the patients reached normal results in all clinical and psychometric tests. Cranial MRI revealed no abnormalities. Additionally, no significant correlations between serum phenylalanine levels and test results were obtained. In the absence of any demonstrative effect, treatment is unlikely to be of significant effect in patients with non-PKU hyperphenylalaninemia.

Adolescent↗
PubMed1997

[Information sources for the physician on the internet. Library catalogs, scientific bookshops and journal articles].

The fast availability of current medical literature is of paramount importance for physicians. Especially methods of online-retrieval in specialised libraries and of journal articles as well as the possibility of lending are of significance. Also, it should be possible to purchase books in online-bookshops. Therefore, the Internet with it's constantly increasing offers plays a more and more important role in scientific research.

Catalogs as Topic↗
PubMed1996

Deficits in selective and sustained attention processes in early treated children with phenylketonuria--result of impaired frontal lobe functions?

UNLABELLED: Twenty normally intelligent children with early treated phenylketonuria (PKU) (IQ: mean = 101.4, SD = 10.0; age: mean = 10 years 11 months, SD = 1.3 years) and 20 healthy controls, matched for age, sex and IQ, were assessed for their selective (Stroop Task) and sustained attention (Test-d-2). Using positron emission tomography an activation of the frontal lobe during the Stroop task had previously been demonstrated. In addition to the Stroop Task and the Test-d-2, a short-term memory test as a "non-frontal-lobe-function-task" was administered to all subjects. Group comparisons demonstrated that PKU children had specific deficits in selective and sustained attention, which were significantly correlated with the concurrent serum phenylalanine concentration. CONCLUSION: The results give evidence that even dietary treated children with PKU were suffering from impaired attentional control mechanisms in spite of a normal IQ. The deficits might be the result of impaired frontal lobe functions.

Adolescent↗
PubMed1996

Psychosocial aspects in phenylketonuria.

Psychosocial aspects in phenylketonuric (PKU) patients are reported. In two separate studies patients with PKU differing in age (children versus adolescents), were assessed. The main message of the first prospective study on 58 10-year-old patients is that normally intelligent PKU patients who were treated early and strictly did not show a higher risk for severe emotional and behavioural maladjustment compared with healthy controls at the age of 10 years. The data were obtained in the course of the German PKU Collaborative Study by the "Personality Questionnaire for Children (PFK 9-14)". All patients received nutritional, medical, and psychological counselling every 6 months. In the second retrospective study, 34 early treated, normally intelligent adolescents with PKU (age: mean = 14.6, SD = 2.0, range = 11-18 years) and their mothers were assessed with several psychometric personality inventories and self-developed questionnaires concerning their psychosocial situation and their disease- and diet-specific knowledge. Using the Mannheimer Biographic Inventory (MBI), the Personality Questionnaire for Children (PFK 9-14), and the Freiburger Personality Inventory (FPI) the adolescent patients described their social life and their emotional development as being distinctly restricted. Their knowledge concerning disease and diet was alarmingly poor and the majority had great difficulties in satisfactory dietetic management without parental help. In addition to the burdensome diet, developmental crises like puberty may cause more frequently emotional and behavioural problems in PKU patients.

Adolescent↗
PubMed1996

German Maternal Phenylketonuria Study.

The German maternal phenylketonuria (MPKU) Study began in 1989 and since 1992 works together with the American-Canadian MPKU Study. Main goals of the study are: (1) to find women with phenylketonuria (PKU) and mild untreated hyperphenylalaninaemia (HPA); (2) to inform them about the risks of an untreated pregnancy with PKU and HPA; (3) to evaluate the efficacy of the phenylalanine (Phe) restricted dietary treatment prior to and during pregnancy by following the physical and cognitive development of offspring from treated pregnancies. An interim report of the study is presented. Until now, 43 pregnancies have been followed. They resulted in 34 live births, 24 from women with PKU and 10 form women with HPA. There are significant negative correlations between the gestational age in which the dietary control (blood Phe level < 360 mumol/l) was reached and pregnancy outcome as measured by growth parameters and early cognitive and motor developmental quotients at the age of 2 years. For minimizing risks of MPKU, preconceptional dietary control is strongly recommended. Tracking and timely information of young women about risks of MPKU is of outmost importance.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Untreated non-phenylketonuric-hyperphenylalaninaemia: intellectual and neurological outcome.

The intellectual, neurological, and neuropsychological outcome of patients with non-phenylketonuric-hyperphenylalaninaemia (PKU-HPA) (serum phenylalanine levels under free diet < 600 mumol/l) has not been systematically studied so far. We therefore tested 28 patients (mean age = 21.8, SD = 4.2 years) for IQ (WAIS-R/WISC-R), school performance, job career, clinical neurological examination, fine motor performance (motor performance task), and selective and sustained attention (stroop task, Dot Pattern Exercise from the Sonneville visual attention task). In addition, cranial MRI (1.5 T unit) was obtained in 10 of these patients. Clinical-neurological examination revealed no significant abnormalities in the non-PKU-HPA patients. They also had a normal IQ (mean = 101.9, SD = 13.6). Compared to their healthy siblings, they attended a normal school and had a normal job career. The motor performance task revealed no deficits in fine motor abilities. The patients performed normally in the stroop task and the dot pattern exercise. Their MRIs were normal. Our results indicate that patients with non-PKU-HPA are not at risk for developing intellectual, neurological, and neuropsychological impairment, as described for patients with treated mild or classical phenylketonuria. From this point of view a dietary treatment is not necessary in patients with hyperphenylalaninaemia.

Adolescent↗
PubMed1996

Studies of multimodal evoked potentials in treated phenylketonuria: the pattern of vulnerability.

We performed studies of multimodal evoked potentials and peripheral sensory and motor nerve conductions in 33 early and 6 late treated patients with phenylketonuria. The studies revealed the following picture: 1. In 27% of early treated patients latencies of visual evoked potentials were increased. The cause for these changes in unknown. 2. Nerve conduction studies showed the presence of a minor sensory neuropathy which in rare cases may also affect peripheral motor nerves. This neuropathy did not have features of a central-peripheral distal axonopathy which argues against a toxic/nutritional causation. 3. Deficits in the central sensory, motor, and auditory pathways were present, but rare in early treated patients. If the results of electrophysiological studies reported by different groups are compared, the emerging picture is very similar and the majority of the-minor-differences is likely to be explained by technical aspects.

Adolescent↗
PubMed1996

Effect of L-dopa on visual evoked potentials and neuropsychological tests in adult phenylketonuria patients.

Eight adult, untreated patients with classical phenylketonuria received L-dopa and a decarboxylase inhibitor for 2 weeks. No effect of L-dopa therapy on choice reaction time tasks, sustained attention, frontal lobal function as well as latencies of visual evoked potentials was found. The results raise the question if adult patients with phenylketonuria really suffer from functional dopamine deficiency.

Adult↗
PubMed1996

Neurotransmitter positron emission tomographic-studies in adults with phenylketonuria, a pilot study.

Patients with phenylketonuria (PKU) may suffer from cognitive and neurological deficits which are related to reduced intracerebral concentrations of catecholamines. The function of phenylalanine (Phe) as an inhibitor of the uptake of the precursor amino acid tyrosine (Tyr) through the blood-brain barrier as well as an inhibitor of the expression of dopamine receptors in the brain is under investigation. Positron emission tomography (PET) is a method for quantitatively determining biochemical and physiological processes in vivo. In the current pilot study, L-[1-11C]-Tyr and 18F-fluoro-ethyl-spiperone (FESP) have been used. The metabolic pathway of carboxylic labelled Tyr is mainly incorporation into protein. From the measured tissue and plasma activity as a function of time in combination with a compartimental model the Protein Synthesis Rate (PSR) for Tyr can be calculated. FESP is a ligand which binds irreversibly to the dopamine D2-receptor and has also a low non specific binding, although affinity to the serotonin receptor has been described. The ratio of FESP concentration in striatum and in cerebellum is a measure of the receptor status in vivo. In patients with plasma Phe levels above the maximum therapeutic concentration (> 700 mumol/l) the PSR for Tyr was decreased as compared to controls and patients with plasma Phe concentrations within the therapeutic range, indicating a decreased availability of Tyr for neurotransmitter synthesis, and hence explaining the reduced cerebral concentration of catecholamines.

Adolescent↗