Biomedical subjects

J Pietz

Publications and source records attributed to J Pietz.

At least 19 recordsLinked to original sources

PubMed2003

Phenylalanine can be detected in brain tissue of healthy subjects by 1H magnetic resonance spectroscopy.

Transport of phenylalanine (Phe) and the other large neutral amino acids across the blood-brain barrier plays a crucial role in the pathogenesis of phenylketonuria (PKU). Thus, investigation of Phe transport kinetics by means of proton magnetic resonance spectroscopy (1H MRS) became an important research area in the mid 1990s. As 1H MRS measurements of brain phenylalanine are restricted to tissue concentrations above 100-150 micromol/kg wet weight, this approach was possible only in PKU patients, and comparison with healthy controls was not achieved. Using standardized single-dose oral Phe loading in three healthy subjects, it was shown that Phe values increase steeply, peak at about 1 h post load, and decrease thereafter. In a single case study, repetitive Phe loading was then performed to achieve a plateau of high blood Phe concentrations for several hours. It was demonstrated that detection and monitoring of brain Phe concentrations is feasible by means of 1H MRS. This approach constitutes a prerequisite for describing carrier kinetics in health.

Adult↗

PubMed2001

Quantitation of localized (31)P magnetic resonance spectra based on the reciprocity principle.

There is a need for absolute quantitation methods in (31)P magnetic resonance spectroscopy, because none of the phosphorous-containing metabolites is necessarily constant in pathology. Here, a method for absolute quantitation of in vivo (31)P MR spectra that provides reproducible metabolite contents in institutional or standard units is described. It relies on the reciprocity principle, i.e., the proportionality between the B(1) field map and the map of reception strength for a coil with identical relative current distributions in receive and transmit mode. Cerebral tissue contents of (31)P metabolites were determined in a predominantly white matter-containing location in healthy subjects. The results are in good agreement with the literature and the interexamination coefficient of variance is better than that in most previous studies. A gender difference found for some of the (31)P metabolites may be explained by different voxel composition.

Adenosine Triphosphate↗

PubMed2001

Variability of blood-brain ratios of phenylalanine in typical patients with phenylketonuria.

Blood-brain ratios (BBR) of phenylalanine (Phe) were determined by quantitative in vivo 1H magnetic resonance spectroscopy (1H-MRS) in 17 adult patients with early-treated phenylketonuria who were randomly selected from a sample of 75 adults. Measurements were performed in all patients during steady-state conditions. The BBR showed a unimodal distribution with a mean of 4.0 (range 3.3 to 4.5). Blood-brain ratios were comparable for subgroups of patients with genotypes classified as severe, moderate, or mild and for patients on different types of diets. Brain Phe concentrations showed a strong linear correlation with blood Phe values (r = 0.93, P < 0.001). There were no saturation effects for blood Phe values up to 1.8 mmol/L, and a local regression analysis did not confirm increasing BBR for increasing blood Phe values. The intellectual outcome (Wechsler Adult Intelligence Scale) was correlated with long-term dietary control (r = -0.65, P < 0.05), fluctuation of blood Phe values during treatment (r = -0.60, P < 0.05), and concurrent blood and brain Phe concentration. The severity of white matter changes visible on magnetic resonance images (MRI) was increased with high blood and brain Phe concentrations but failed to reach statistical significance. No correlation was found between BBR values, intelligence quotient, and MRI grade. Based on the assumption that BBR show intraindividual stability, the current data do not support the hypothesis that blood-brain barrier transport of Phe is a key explanatory factor for outcome variability in the vast majority of "typical" patients with phenylketonuria.

Adolescent↗

PubMed2000

Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities.

UNLABELLED: Neurological abnormalities in phenylketonuria were described before dietary treatment became possible. These included tremor, clumsiness, epilepsy, spastic paraparesis and occasionally extrapyramidal features. Neurological deterioration after childhood was recognised. Patients with neurological deterioration described recently have been late diagnosed or intellectually impaired or both. No early diagnosed patient who was well treated and of good intellectual outcome has yet shown neurological deterioration after stopping diet but it may happen. CONCLUSION: The fascinating links between pathology, magnetic resonance imaging appearances, magnetic resonance spectroscopy results and clinical features are not yet clearly understood. Patients must understand the possible risks of stopping diet and make their choice. All patients need help, support and follow-up regardless of the choices they make over continuing diet.

Adult↗

PubMed1999

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

Adult↗

PubMed1998

Neurological outcome in adult patients with early-treated phenylketonuria.

UNLABELLED: Due to the observation of severe neurological symptoms in single patients as well as brain imaging, neuropsychological and neurophysiological abnormalities, the long-term prognosis of treated phenylketonuria is still under discussion. We investigated the neurological outcome of 57 (24 male, 33 female) patients with phenylketonuria (diet onset < 3 months) at a mean age of 23.6 (17-33) years in comparison to control subjects. Methods used were a clinical-neurological examination, tests for fine motor abilities, IQ test (WAIS-R), a neuropsychological attention task and MRI (30 patients only). Tremor was increased in the patients (28%) compared to controls (15%). Fine motor abilities were significantly reduced in three areas: hand-wrist steadiness, finger-hand dexterity and hand-wrist speed. Tremor as well as reduced fine motor skills were not associated with treatment-related variables, e.g. diet onset, strictness of biochemical control or amount of MRI white matter change. IQ was lower in patients (mean 97.6) compared to matched control subjects (mean 105.5). IQ at 12 years was correlated with biochemical control from birth up to the age of 12 and remained stable up to adult age, independent of biochemical control after 12 years of age. In contrast to the other outcome parameters, the performance in a neuropsychological attention task was influenced by the concurrent plasma phenylalanine concentration. Specific late-onset neurological impairment was not identified in this sample of early-treated adults with phenylketonuria. CONCLUSION: Careful neurological investigation revealed subtle symptoms of brain damage even after early-initiated treatment in adult patients with phenylketonuria. At present it cannot be excluded that further neurological deterioration could emerge later in life. Thus, patients with phenylketonuria - either on or off diet - should be monitored throughout life.

Adolescent↗

PubMed1998

Neurological aspects of adult phenylketonuria.

Phenylketonuria, an autosomal recessively transmitted disorder of amino acid metabolism, is caused by a deficiency of hepatic phenylalanine hydroxylase converting phenylalanine to tyrosine. Thus, phenylalanine accumulates to plasma levels exceeding 1200 mumol/l. Untreated phenylketonuria is characterized by microcephaly, epilepsy, severe mental retardation and, in some cases, progressive supranuclear motor disturbances. These symptoms can largely be prevented by the early start of a phenylalanine-restricted diet. Neurological investigations of treated patients reveal only minor neurological signs, such as tremor or brisk deep tendon reflexes. Magnetic resonance imaging shows white matter abnormalities. However, in single patients, progressive neurological symptoms occurred. Thus, the long-term prognosis of treated phenylketonuria is still under discussion.

Adult↗

PubMed1997

Psychiatric disorders in adult patients with early-treated phenylketonuria.

OBJECTIVE: To determine psychiatric disorders in patients with phenylketonuria (PKU) and to test whether biochemical control, intellectual functioning, white matter abnormalities visible on magnetic resonance imaging (MRI), and/or style of parenting influence psychopathology. DESIGN AND SUBJECTS: This cross-sectional study consisted of 35 PKU patients 17 to 33 years of age (mean: 22.2). From a total of 67 patients, 3 patients were selected because of other causes of possible brain damage. Then 35 patients were randomly drawn with comparison with a control sample (n = 181) from an epidemiologic study. METHODS: We used a standardized, highly structured, face-to-face interview; intelligence quotient (IQ) test; cranial MRI (n = 26); and monitoring of plasma phenylalanine. RESULTS: The overall rate of psychiatric disorders was 25.7% in PKU patients and 16.1% in controls. This difference was not statistically significant. The pattern of psychiatric disturbances was different for PKU patients and controls (Fisher's exact test): in PKU patients, externalizing disorders were reduced (PKU: not present, controls: 7.8%), whereas internalizing disorders (PKU: 25.7%, controls: 8.3%) were increased. International Classification of Diseases, version 10, diagnoses were predominantly those of the depressive category and more frequent in women (8 of 18 females and 1 of 17 males). A correlation between IQ and both biochemical control up to 12 years of age and school education of parents was confirmed. No correlation was found between the severity or pattern of psychiatric disturbances and school education of parents, biochemical control, IQ, or the extension of MRI-visible, white matter abnormalities. It was found that a restrictive controlling style of parenting is a risk factor for the development of psychiatric symptoms. CONCLUSIONS: Our results support a psychological perspective for the development of psychiatric symptoms in PKU. Thus, optimizing medical treatment necessary to prevent brain damage should be accompanied by psychiatric monitoring and psychological support for the families.

Adolescent↗

PubMed1996

Magnetic resonance imaging of the brain in adolescents with phenylketonuria and in one case of 6-pyruvoyl tetrahydropteridine synthase deficiency.

White matter abnormalities on MRI have been observed in phenylketonuria (PKU) patients with late onset neurological symptoms as well as in neurologically inconspicious patients. We investigated 14 early treated adolescents at an age between 12 and 17 years (mean age 14.3 years) with classical PKU as well as one retarded patient with atypical PKU by cranial MRI with spinecho T1-, T2- and proton density sequences. Clinical examination was normal. Visual evoked potential (VEP) examination showed a prolonged latency of peak P100 (mean 122.6 ms; control mean 115.9) and IQ testing showed a mean IQ of 101.1. To investigate the influence of plasma phenylalanine (Phe) levels three approaches were used: Phe was determined for the day of MRI, for a period of 6 months prior to MRI and for lifetime up to 12 years. MRI scans revealed areas of abnormally increased signal intensity on T2-weighted and proton density images in 12 (86%) patients, preferably involving the parieto-occipital lobes. MRI of the patient with atypical PKU was normal. MRI findings correlated most strongly to long-term dietary control up to 12 years. We found no correlation with the other parameters of biochemical control, IQ or VEP latency. The nature and prognosis of MRI abnormalities in neurologically normal PKU patients remain unclear although abnormalities in VEPs which were not associated with the degree of MRI abnormalities in our sample indicate a disturbance in myelination along the visual pathways.

Adolescent↗

PubMed1996

Intelligence and professional career in young adults treated early for phenylketonuria.

The intellectual status and professional careers of 51 young adults with phenylketonuria whose treatment started before 3 months of age are described. Their mean IQ was 97 (SD = 16). Of the IQs, 4% were more than 2 SD below the norm. The distribution of types of schooling of the patients was comparable to that in the German population. The professional careers of nearly all the patients were according to their educational level. Within the sample the outcome was significantly correlated with phenylalanine (Phe) control, even when the patients' social background was statistically taken into account. The main influence of Phe on intelligence seems to occur during the first decade of life since IQ data remain stable even after Phe levels increased during adolescence.

Adult↗

PubMed1996

Phenylketonuria: findings at MR imaging and localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment.

PURPOSE: To characterize white matter changes in early-treated phenylketonuria (PKU) with magnetic resonance (MR) imaging and hydrogen-1 MR spectroscopy and to correlate these findings to biochemical control and brain function. MATERIALS AND METHODS: Fifty-one patients aged 12-33 years underwent T1-, T2-, and proton-density-weighted MR imaging and testing of intelligence, visual evoked potentials (VEPs), and neuropsychologic status (29 adult patients only). H-1 MR spectroscopy was performed in eight patients to determine brain metabolite concentrations, including phenylalanine (PHE) concentration, and brain compartmentation. RESULTS: MR imaging revealed a high frequency of supra- and infratentorial abnormalities. MR imaging grade, which was based on areas of high signal intensity on T2-weighted images, showed statistically significant correlation with long-term biochemical control and neuropsychologic test results but not with intelligence quotient or VEPs. H-1 MR spectroscopy revealed normal metabolite levels, except for increased PHE levels. It also showed enlarged cerebrospinal fluid-like compartments in affected white matter, related to plasma and brain concentrations of PHE and MR imaging grades. CONCLUSION: A synergistic use of MR imaging and MR spectroscopy may help elucidate both the pathogenesis of brain dysfunction and clinical treatment policies in PKU.

Adolescent↗

PubMed1995

Identification and quantitation of phenylalanine in the brain of patients with phenylketonuria by means of localized in vivo 1H magnetic-resonance spectroscopy.

Localized proton MR spectroscopy was used to identify phenylalanine (PHE) and to quantitate its cerebral concentration in patients with type I phenylketonuria (PKU). Data acquisition was optimized for the detection of low-concentration metabolites, using a short TE (20 ms) double Hahn-echo localization sequence for large volumes within the head coil and for smaller volumes using a surface coil. Previously described methods to quantitate localized MR spectra were extended to cover the case of low-concentration metabolites, unevenly distributed in three brain compartments and measured in difference spectra only. PHE content was determined in difference spectra of four PKU patients with respect to normals and in one patient before and after an oral load of L-PHE. PHE concentrations of 0.3 to 0.6 mmol/kg brain tissue were obtained, resulting in a concentration gradient for PHE between blood and brain tissue of 2.4 to 3.0. No significant changes were found for the abundant metabolites in gray or white matter. Previously reported MRI changes were confirmed to be due to increased cerebro-spinal-fluid-like spaces.

Adult↗

PubMed1995

Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria.

OBJECTIVES: To characterize abnormalities of brain function in patients with phenylketonuria (PKU) who had relaxed or stopped the dietary regimen and to test whether oral high-dose tyrosine (Tyr) supplementation has a beneficial effect. DESIGN: Comparison with a control group; double-blind, placebo-controlled study comprising six test times; crossover treatment groups; oral high-dose Tyr therapy (100 mg/kg body weight per day) or placebo administration for 4 weeks. SUBJECTS: Twenty-four early-treated patients with PKU aged 20.8 (16 to 25) years; 24 control subjects. METHODS: Plasma concentrations of phenylalanine and Tyr were monitored. Neuropsychologic tasks, visual evoked potentials, and spectral analysis of electroencephalographic activity were used to evaluate brain function. RESULTS: When patients with PKU were compared with control subjects, deficits in certain aspects of brain function were confirmed (i.e., a decreased ability to sustain attention, prolonged latencies of visual evoked potential peaks N1 and P2, and a reduced amount of fast-wave activity on the electroencephalogram). Baseline plasma phenylalanine and Tyr concentrations were in the typical range of adult patients with PKU. The plasma Tyr concentration increased approximately 200% during Tyr supplementation, but no beneficial effects were observed. CONCLUSIONS: High-dose Tyr supplementation cannot be recommended as an "alternative" treatment for patients with PKU after relaxation or termination of strict dietary adherence.

Adolescent↗

PubMed1995

The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo 1H magnetic resonance spectroscopy.

Cerebral concentrations of phenylalanine (PHE) were measured by means of quantitative in vivo 1H MR spectroscopy in 8 adult patients treated early for phenylketonuria type I. A 1.5-Tesla routine magnetic resonance scanner, localization sequence with short echo time (20 ms), and a fully automated data processing scheme were used. Baseline plasma PHE concentrations were 1.04 (0.70-1.39) mmol/L PHE with concurrent brain PHE concentrations of 0.27 (0.13-0.41) mmol/kg of wet weight resulting in a plasma/brain ratio of 4.12. Plasma and brain concentrations correlated significantly (Kendall tau b = 0.91, p < 0.01). During an oral load with a single dose of 100 mg L-PHE per kg of body weight in four patients, plasma levels steeply increased. Concurrent brain PHE increase was less steep, was significantly delayed, and still continued up to 20 h postload. Despite the proven rise in plasma and brain concentrations of PHE, neuropsychologic examinations revealed no impairment of attentional and fine motor abilities from preload up to 20 h postload.

Adult↗

PubMed1994

Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine-blood-level.

The effect of concurrent phenylalanine levels (Phe-level) on sustained attention was tested in a group of 19 early treated adult PKU patients. Mean age was 20.5 years; WAIS IQs were in the normal range (M = 109.3). Phe-levels were manipulated in a high-low-high design by reintroduction of a strict phenylalanine-reduced diet for 4 to 5 weeks between test time 1 and 2 and returning to usual diet between test time 2 and 3. A control group of 20 healthy subjects, mean age 20.7 years was tested twice. Results of a sustained attention task are presented. In adult PKU patients with high concurrent Phe-levels, sustained attention is significantly impaired and reaction times are prolonged. In the low Phe-level condition, performance improved significantly. Nevertheless, the PKU group did not reach the level of performance of the control group. Results are not influenced by IQ and suggest a sustained attention deficit in adult PKU patients that varies according to the concurrent Phe-level. The partial reversibility of the deficits provides support for the hypothesis that biochemical mechanisms rather than structural changes of the brain underlie the relationship between concurrent Phe-level and sustained attention.

Adolescent↗

PubMed1993

EEGs in phenylketonuria. I: Follow-up to adulthood; II: Short-term diet-related changes in EEGs and cognitive function.

The authors report the results of two EEG studies on adult patients with phenylketonuria (PKU) who had been treated early. Part I: the authors followed the EEGs of 34 PKU patients from birth to age 21. The frequency of abnormal EEG findings (especially epileptiform activity) steadily increased until age 12, then decreased. IQ correlated significantly with quality of dietary control during follow-up. Part II: frequency analysis of the EEG and neuropsychological testing were performed on eight adult patients after periods of four weeks with low and high levels of phenylalanine. Only five patients followed the strict dietary regulations. With high levels of phenylalanine, the dominant peak of EEG background activity shifted to the slower frequency spectrum in all patients; in addition, neuropsychological testing revealed impairment of cognitive function. The significance of different approaches of EEG examinations is discussed with respect to the problems of monitoring PKU patients and the pathogenic mechanisms of CNS damage in phenylketonuria.

Adolescent↗

PubMed1991

High-dose intravenous gammaglobulin for neonatal alloimmune thrombocytopenia in twins.

We report the successful treatment of neonatal alloimmune thrombocytopenia with repeated infusions of high-dose immunoglobulin G (400 mg/kg/d for 5 days) in twins. Platelet counts increased within 3 days from less than 20 x 10(9)/l to more than 70 x 10(9)/l. The first twin survived without neurological or other sequelae. The second twin had probably developed intracranial hemorrhage (ICH) in utero. This infant developed long-term neurological sequelae with blindness, cerebral palsy and infantile spasms. Implications of the therapeutic approach and prevention of severe complications in pregnancies with known risk for neonatal alloimmune thrombocytopenia are discussed.

Autoimmune Diseases↗

PubMed1990

EEG development in early treated PKU patients from birth to 6 years of age.

In 126 early treated PKU patients (type I and type II) a close EEG follow up was performed from birth up to 6 years of age. A total of 1465 EEGs were performed before and after onset of dietary treatment and on 11 more subsequent occasions. The composition of the background activity was normal up to 6 years when only a small number of the children (19) showed no dominant alpha activity. The frequency of epileptiform activity of generalised as well as focal type was low in the first 2 years of life, but afterwards slightly enhanced in comparison to normal control groups. Other findings like generalised theta paroxysms or focal slow waves were rarely observed. Under a standardised protein load at 6 months (52 patients) and at 5 years of age (42 patients) a moderate generalised slowing of the background activity but no other abnormalities were noted.

Aging↗