Neurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up.

BACKGROUND: The long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU. METHODS: We investigated 35 patients with early-treated classical PKU aged 29 to 51 years (mean age 41 years) and 18 healthy controls matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), attention and information-processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five-year and a ten-year follow-up. RESULTS: In the entire interval IQ, information processing and attention of patients and controls remained constant. At both follow-up assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (> 42 years) showed poorer information processing and attention at both assessment times compared to young adult patients (< 42 years) and controls. IQ, information processing and attention showed no correlation to imaging results. IQ, however, was significantly correlated to blood phenylalanine (Phe) levels in patients´ childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients. CONCLUSIONS: Cognitive performance in adult patients with early-treated PKU does not seem to deteriorate in a ten-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU.

Children and adolescents with phenylketonuria display fluctuations in their blood phenylalanine levels.

AIM: This study examined the impact of fluctuations in metabolic control on the intelligence quotient (IQ) of children and adolescents with early, continuously treated phenylketonuria (PKU). METHODS: This was a clinic-based study carried out at University Hospital Munster, Germany, from 2015 to 2017. We investigated 49 patients (28 boys) with early treated PKU, who were aged 6-18 years with a mean age of 11.2 ± 4.1 years. All the patients were on a continuous phenylalanine-restricted diet. Of the 49 patients, 29 (18 boys) had classic PKU and 21 patients (11 girls) had mild PKU. The patients' blood phenylalanine levels were assessed every week for 26 weeks and analysed for fluctuations, indicated by the standard deviation of the individual blood phenylalanine levels. We also assessed the concurrent Full Scale IQ (FSIQ) of the patients. RESULTS: In patients with classic PKU, FSIQ was negatively correlated with blood phenylalanine levels, but not with level fluctuations. In patients with mild PKU, FSIQ was not correlated with blood phenylalanine levels, but was negatively correlated with level fluctuations. CONCLUSION: The blood phenylalanine levels of patients with mild PKU showed minor interindividual differences, which may have allowed fluctuations to exert a negative effect on the FSIQ.

Neurocognitive functioning in adults with phenylketonuria: results of a long term study.

OBJECTIVES: A controlled long-term study was performed to assess the neurological and neuropsychological performance in adult patients with early-treated phenylketonuria (PKU). METHODS: We investigated 57 patients with early-treated classical PKU aged 19 to 41 years (mean age 31 years) and 46 matched healthy controls, matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), and attention and information-processing abilities. Magnetic resonance imaging (MRI) of the brain was performed in all patients. Neuropsychological assessments and MRI were repeated at a five-year-follow-up. RESULTS: In the five-year interval IQ, information processing and attention of patients and controls remained constant. At both assessment times the IQ scores were significantly lower in patients compared to controls. Older adult patients (>32 years) showed poorer information processing and attention at both assessment times compared to young adult patients (<32 years) and controls. IQ, information processing and attention showed no correlation to imaging results but were significantly correlated to blood phenylalanine (Phe) levels in patients' childhood and adolescence, and Phe levels had been higher in the adolescent years of older adult patients. CONCLUSIONS: Cognitive performance in adult patients with early-treated PKU does not seem to be subject to deterioration observable in a five-year interval. Neuropsychological assessment in adults with PKU revealed neurocognitive impairment particularly in older adult patients. This seems to refer to an early relaxation of diet that was recommended when the older patients were adolescents. Results indicate a benefit of dietary control during adolescence in PKU.

Cognitive function in patients with epidermolysis bullosa: social adjustment and emotional problems.

BACKGROUND: Children with Epidermolysis bullosa (EB) suffer from an intractable, burdensome skin disease that may result in cognitive as well as social and emotional problems. PATIENTS: To assess cognitive problems in patients with EB, we investigated 20 affected children and adolescents, 6-17 years of age (mean: 10.8 years; SD: 3.4 years), and 24 healthy controls (6-15 years, mean: 10.9 years; SD: 3.0 years) for cognitive abilities. Additionally, parents were asked to assess social and emotional problems of their children. METHODS: Patients and controls were assessed using the Wechsler Intelligence Scales. Parents completed Achenbach's Child Behaviour Checklist (CBCL), a parent-report measure on emotional and behavioural symptoms in children. RESULTS: The mean scores of the young patients tested with WISC-R and WAIS-R showed no significant left shift if compared to healthy controls. Analyzing the subtypes of EB, however, considerable cognitive deficits were associated with recessive dystrophic EB (RDEB), severe generalized. Less social competence and more social and emotional problems were reported for the entire patient group. CONCLUSIONS: Functional rehabilitation is required to increase not only the physical but the cognitive development of the severely affected children with RDEB. Children and adolescents with all subtypes of EB require therapeutic support regarding their social and emotional life.

Frontal lobe-dependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults.

Even early-treated phenylketonurics may suffer from phenylalanine-related deficits. Elevated phenylalanine concentrations can interfere with the development and function of the CNS. Outcome beyond childhood has not been extensively investigated. This long-term study was performed to determine whether adolescents and young adults with PKU show frontal lobe-dependent deficits when compared to diabetic patients. The comparative study covered 35 PKU patients, 13-21 years of age (mean 17.8 years), and 35 diabetic patients matched for sex, age and socioeconomic status. Patients were assessed for IQ (Culture Fair Intelligence Test), information processing (Trail Making Test), and selective and sustained attention (Stroop Task, Test d-2). Assessments were repeated within a 3-year follow-up. PKU patients showed no increase in blood phenylalanine concentrations at follow-up. They had significantly poorer test results than the diabetic patients at both assessment times. Within the tests, however, this was due to reduced performance speed but not to deficits in specific frontal lobe-dependent functions. Elevated phenylalanine concentrations seem to exert a global effect slowing performance speed. This effect is enduring in adolescence and early adulthood.

[Intelligence, attention, and memory in patients with myasthenia gravis]. / Intelligenz, Aufmerksamkeit und Gedächtnis bei Patienten mit Myasthenia gravis.

BACKGROUND: In patients with myasthenia gravis (MG), poor performance on cognitive tests has been found. Performance on memory tasks has been reported to correlate with disease activity, but memory in MG patients was also recently found to be unimpaired. PATIENTS AND METHODS: Cognitive functioning was examined in 23 patients with MG and 23 healthy controls. The patients were assessed for IQ, memory, attention, and motor performance. Immunoglobulin G antiacetylcholine receptor autoantibody titers were determined. Event-related potentials were generated for patients and controls. RESULTS: Mean IQs of patients were at average. Memory and attention were not more impaired in patients than controls. Event-related potentials were not delayed in either group. Patients with elevated autoantibody concentrations similarly showed unimpaired neurocognitive and motor functioning. CONCLUSION: In this study, no evidence of neuropsychological impairment was found in MG, arguing against the involvement of higher cortical functions. Sleep abnormalities rather than central mechanisms may explain the memory impairments reported by some studies.

Neurofibromatosis type 1: motor and cognitive function and T2-weighted MRI hyperintensities.

BACKGROUND: Cognitive impairment and fine motor deficits are frequent manifestations in patients with neurofibromatosis type 1 (NF1). More than 50% of patients with NF1 show focal areas of high signal intensity (T2H) on T2-weighted MRI of the brain. It has been hypothesized that T2H may be associated with the cognitive and motor problems. METHODS: The authors investigated 100 patients with NF1 and 100 healthy control subjects matched for age, sex, and socioeconomic status for their IQ (Wechsler Intelligence Scale for Children-Revised [WISC-R] and Wechsler Adult Intelligence Scale-Revised [WAIS-R]), fine motor abilities (Motorische Leistungs-Serie [motor performance task]), and T2H (MRI). RESULTS: As a group, the 100 patients performed within normal limits of WISC-R and WAIS-R scores. However, the scores for the NF1 patients with normal MRI were at the mean, whereas those for the patients who had T2H (n = 58) were significantly depressed. On measures of fine motor skills, patients with T2H performed poorer than patients with normal MRI. CONCLUSION: Hyperintensities on T2-weighted MRI represent a biological marker for impaired cognitive and fine motor performance in patients with NF1.

Investigation of the cerebral energy status in patients with glutaric aciduria type I by 31P magnetic resonance spectroscopy.

In vivo phosphorus magnetic resonance spectroscopy (MRS) was used to investigate markers of the cerebral energy status in two patients with glutaric aciduria type I (GA-I). Besides an increased concentration of phosphomonoesters in one patient, no other significant alterations from controls were found. This might indicate increased resynthesis of dendritic processes secondary to preceding metabolic crises. In contrast to previous cell-culture studies, no cerebral depletion of phosphocreatine (PCr) was observed. In conclusion, a severe global and permanent depletion of cerebral energy supplies must be ruled out. The benefit of a permanent creatine substitution to stabilize mitochondrial energy metabolism seems thus questionable. However, as MRS was performed during stable clinical conditions, the possibility of a PCr decrease during acute metabolic crises cannot be assessed.

Tetrahydrobiopterin responsiveness in a large series of phenylketonuria patients.

In a group of 87 consecutive patients with hyperphenylalaninaemia born since 1990, only 3 patients showed a (temporary) decrease of serum phenylalanine levels after tetrahydrobiopterin (BH4) loading in usual doses (20 mg/kg body weight).

Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria.

Recent studies indicate that individual blood-brain transport characteristics of phenylalanine may lead to different clinical outcomes in phenylketonuria (PKU) patients in spite of comparable dietary control. To check these preliminary data, we investigated four pairs of siblings with classical PKU (and identical genotype) using in vivo nuclear magnetic resonance spectroscopy in the course of an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were different in spite of similar blood levels. Interindividual variations of the apparent transport Michaelis constant, Kt,app, ranged from 0.10 to 0.84 mmol/L. The ratio of the maximal transport velocity, Tmax, over the intracerebral consumption rate, Vmet, varied between 2.61 and 14.0. Siblings with lower values for Kt,app, higher values for Tmax/Vmet, and higher concurrent brain phenylalanine levels showed a lower IQ and a higher degree of cerebral white matter abnormalities. The results indicate that blood-brain barrier transport characteristics and the resultant brain phenylalanine levels are causative factors for the individual clinical outcome in PKU.

Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria.

Different clinical outcomes in spite of comparable dietary controls are well known in patients with phenylketonuria. Currently, reasons for this phenomenon are unknown. Kinetic investigations in 15 patients with classic phenylketonuria were performed using in vivo nuclear magnetic resonance spectroscopy before and after an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were quite different in spite of similar blood phenylalanine levels. Interindividual variations of the apparent transport Michaelis constant, K(t,app), covered a range from 0.10 to 1.03 mmol/L. The ratio of the maximal transport velocity, Tmax, over the intracerebral consumption rate, Vmet, varied between 2.61 and 14.0. Both parameters as well as the preload brain phenylalanine levels correlated significantly with the degree of cerebral white matter abnormalities on magnetic resonance images. Correlations of K(t,app), Tmax/Vmet, and the preload brain phenylalanine levels with patients' intelligence scores approached significance. In conclusion, blood-brain barrier phenylalanine transport characteristics and the resultant brain phenylalanine levels seem to be causative factors for the individual clinical outcome in phenylketonuria. This observation may lead to individual dietary recommendations in the future.

Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia.

ABSTRACT There is international consensus that patients with phenylalanine (Phe) levels <360 microM on a free diet do not need Phe-lowering dietary treatment whereas patients with levels >600 microM do. Clinical outcome of patients showing Phe levels between 360 and 600 microM in serum on a free nutrition has so far only been assessed in a small number of cases. Therefore, different recommendations exist for patients with mild hyperphenylalaninemia. We investigated in a nationwide study 31 adolescent and adult patients who persistently displayed serum Phe levels between 360 and 600 microM on a normal nutrition with a corresponding genotype. Because of limited accuracy of measurements, Phe levels should be looked on as an approximation, but not as an absolute limit in every instance. In addition to serum Phe levels, the assessment program consisted of comprehensive psychological testing, magnetic resonance imaging of the head, (1)H magnetic resonance spectroscopy, and genotyping. We found a normal intellectual (intelligence quotient, 103 +/- 15; range, 79-138) and educational (school performance and job career) outcome in these subjects as compared with healthy control subjects (intelligence quotient, 104 +/- 11; range, 80-135). Magnetic resonance imaging revealed no changes of cerebral white matter in any patient, and (1)H magnetic resonance spectroscopy revealed brain Phe levels below the limit of detection (<200 microM). In the absence of any demonstrable effect, dietary treatment is unlikely to be of value in patients with mild hyperphenylalaninemia and serum Phe levels <600 microM on a free nutrition, and should no longer be recommended. Because of a possible late-onset phenylketonuria, Phe levels of untreated patients should be monitored carefully at least during the first year of life. Nevertheless, problems of maternal phenylketonuria should still be taken into account.

In vivo proton magnetic resonance spectroscopy in phenylketonuria.

UNLABELLED: In vivo nuclear magnetic resonance spectroscopy permits the non-invasive examination of metabolic characteristics of the human brain in a clinical environment. Methods to detect elevated phenylalanine (Phe) in patients with phenylketonuria (PKU) using difference spectroscopy and to estimate absolute brain Phe concentrations, [Phe]brain, have been developed. In patients with classical PKU, [Phe]brain typically varied between 0.14 and 0.78 mmol/l depending upon actual blood Phe concentrations, [Phe]blood, between 0.47 and 2.30 mmol/l. Dynamic investigations can be used to extract information about Phe transport at the human blood-brain barrier, which may be described by a symmetric Michaelis-Menten model. Carrier saturation and competitive inhibition of the influx of other large neutral amino acids can be expected at blood levels usually found in PKU patients. In single cases of untreated, normal intelligent patients, abnormally low [Phe]brain < or = 0.15 mmol/l were observed despite high stationary Phe levels ([Phe]blood = 1.15 +/- 0.10 mmol/l). CONCLUSION: Significant variations in phenylalanine transport parameters in untreated, normal intelligent patients indicated that blood-brain barrier transport or intracerebral phenylalanine consumption are causative factors for the individual vulnerability to phenylketonuria.

Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls.

Even early-treated patients with phenylketonuria (PKU) have a higher risk of psychosocial maladjustment. This study was performed to determine whether emotional and behavioural problems are specific in phenylketonurics and whether they depend on the quality of biochemical control. This comparative study covered 42 PKU patients aged 10-18 years (mean 14.7 years) and 42 diabetic patients matched for sex, age and socioeconomic status. Patients' groups were compared with a control sample of healthy controls (n = 2900) from an epidemiological study. We used the Child Behavior Check List (CBCL) according to Achenbach, intelligence quotient (IQ) test according to Weiss, and monitoring of blood phenylalanine concentrations and HBA1 concentrations. Internalizing problems such as depressive mood, anxiety, physical complaints or social isolation were significantly elevated in both phenylketonuric and diabetic patients, whereas externalizing problems were not. The two patient groups did not differ significantly either in the degree or in the pattern of their psychological profile. In both groups no significant correlations could be computed between the psychological characteristics and the biochemical control, the IQ, and the socioeconomic status. No patient was undergoing psychiatric treatment or psychotherapy. Our results strongly support a psychological perspective for the development of behavioural and emotional problems in both phenylketonuric and diabetic patients. Thus, medical treatment should be accompanied by psychological support for the families.

Regression of neuropsychological deficits in early-treated phenylketonurics during adolescence.

Even early-treated phenylketonuric patients suffer from phenylalanine-associated (mild) neuropsychological impairment. To date it is still unclear whether patients' deficits show a progression on ageing. This unsolved question seems to be an important aspect in the still ongoing debate about how long and how strictly the patients should be maintained on diet. Twenty early-treated (20 +/- 10, 9-30 days) adolescent phenylketonurics (10 boys, 10 girls) and 20 healthy controls, matched for age, sex and IQ, were investigated twice at a mean ages of 11 and 14 years for their IQ (Culture Fair Intelligence Test-Scale 2; CFT-20), fine motor abilities (Motor Performance Task), sustained (Test d2) and selective attention (Stroop-Task). At the first test, examinations revealed significant blood phenylalanine-correlated neuropsychological deficits in PKU patients. In spite of raised blood phenylalanine concentrations during the following 3 years and significantly elevated concurrent blood phenylalanine concentrations, the repeated measurements revealed a significant decrease of patients' deficits compared to controls. Clinical-neurological status of patients and controls was normal at both test times. The results indicate a decreased vulnerability of PKU-patients with respect to their neuropsychological functioning against elevated blood phenylalanine levels on ageing.

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.