F.J. van Spronsen

Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations

Fifty-seven 7-14-year-old early- and continuously treated phenylketonuria (PKU) patients and 65 matched controls performed a sustained attention task. PKU patients with plasma phenylalanine (phe) levels higher than 360 micromol/l at the time of testing exhibited, compared to controls, lower speed of information processing, a lower ability to inhibit task-induced cognitive interference, less consistent performance, and a stronger decrease of performance level over time. Patients with concurrent phe levels lower than 360 micromol/l did not differ from controls and were significantly better than patients with levels higher than 360 micromol/l. Strong relationships were found with task performance for phe levels during the pre-school years and between ages 5 and 7. These correlations were stronger than those between concurrent phe level and task performance. Significant multiple regression models were found with age accounting for the largest proportion of variance of tempo and tempo fluctuation, and lifetime phe levels (particularly phe level between ages 5 and 7) accounting for the largest proportion of variance of the relative number of inhibition errors and its increase over time. Phe level between ages 5 and 7 also contributed significantly to the variance of tempo and tempo fluctuation. Neuropsychological outcome was independent of IQ. The results indicate that strict dietary adherence during these periods is beneficial to attentional control later in life. We suggest that phe levels should be maintained under 360 micromol/l until approximately age 12, when development of attentional control approaches an adult level.

The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation functions of working memory

In this paper, we review neuropsychological test results of early and continuously treated Phenylketonuria (PKU) patients. To increase insight into the neuropsychological profile of this population, we have attempted to place the results within an attentional network model [Images of the mind, 1994], which proposes interacting but dissociable attentional networks for orienting, vigilance, and executive control of attention. Executive control of attention is discussed against the background of the process-specific theory of working memory (WM) [Handbook of neuropsychology, 1994], which postulates a distinction between the maintenance-function of WM and the manipulation and monitoring-function. Neuropsychological results are presented for 67 early and continuously treated PKU patients and 73 controls aged 7-14 years. Four neuropsychological tasks were employed to measure orienting, mnemonic processing, interference suppression, and top-down control in visual search. No differences were found in orienting and the maintenance-function of WM. In addition to previously reported impairments in sustained attention/vigilance and inhibition of prepotent responding, PKU patients exhibited deficits when top-down control was required in a visual search task, but showed no impairment when interference suppression was required. It is discussed how the specific neuropsychological impairments in PKU may be a consequence of mid-dorsolateral prefrontal cortex (DLPFC) dysfunctioning due to deficiencies in catecholamine modulation.

Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria

This study examined motor control in 61 early and continuously treated patients with phenylketonuria (PKU) and 69 control participants, aged 7 to 14 years. The pursuit task demanded concurrent planning and execution of unpredictable movements, whereas the tracking task required a highly automated circular movement that could be planned in advance. PKU patients showed significantly poorer motor control in both tasks compared with control participants. Deficits were particularly observed for younger patients (age < 11 years). Differences between control participants and PKU patients were significantly greater in the pursuit task compared with the tracking task, indicating more serious deficits when a higher level of controlled processing is required. Correlations with historical phenylalanine levels indicated a later maturation of the level of control required by the pursuit task compared with the tracking task.

Short-term dietary interventions in children and adolescents with treated phenylketonuria: Effects on neuropsychological outcome of a well-controlled population

This study addressed two questions: is there an effect of dietary interventions that induce relatively small changes in phenylalanine (Phe) concentration on neuropsychological outcome of early- and continuously treated phenylketonuria (PKU) patients, and are there differences in effects for PKU children and adolescents? To answer the first question, the effect of a short-term dietary intervention (1–2 weeks) was compared for patients whose Phe concentrations increased vs those whose Phe concentrations decreased. Controls were tested twice to control for learning effects. To answer the second question, the effect of dietary interventions was examined in younger patients (aged 7–10 years) and older patients (aged 11–14 years). The effect of dietary interventions was determined with three neuropsychological tasks: one requiring sustained attention; a second demanding maintenance in working memory; and a third in which complex operations were performed in working memory. Relatively small fluctuations in Phe concentration were found to influence neuropsychological task performance of PKU patients. Patients whose Phe concentrations decreased at the second assessment showed generally more improvement than controls. Patients whose Phe concentrations had increased showed minimal improvement or deterioration of task performance. The strongest effects were observed when sustained attention and manipulation of working memory content were required. There were some indications of a greater sensitivity of younger patients to fluctuations in Phe concentration.

PKU-What is daily practice in various centres in Europe?

SummaryBackground:Since the start of the European Society of Phenylketonuria and Allied Disorders Treated as Phenylketonuria (ESPKU) in 1987, an increasing number of parental organizations of member countries have joined. Treatment varies widely within Europe. A survey among professionals was done to determine goals and practice.Method:In 2005, a questionnaire was sent to professionals of member countries, addressing diagnostic and treatment procedures, numbers of patients necessary for a PKU centre, guidelines followed, numbers of patients treated and professionals involved in care, target phenylalanine concentrations, amount of protein prescribed, frequency of monitoring and clinical visits, need for follow-up of various clinical and biochemical data, the importance of various abnormalities, and definition of (non)compliance.Results:Seventeen centres of 12 countries answered. Professionals of 13 countries could not be reached or did not respond. Differences in care were observed in many issues of care including target phenylalanine concentrations. Only few issues had general consensus.Conclusion:Not all countries were really active at ESPKU level. In the active countries, a professional could not always be contacted. Responses show that PKU care varies largely between European countries. Notwithstanding the large diversity on many issues of day-to-day care and therapeutic targets, results showed increasing consensus on some issues. The most important outcome of this questionnaire might be that the Scientific Advisory Committee of the ESPKU initiated meetings for professionals of different backgrounds taking care of PKU patients besides the already existing programme for parents, patients and delegates. Discussion among these professionals may improve quality of care.

The intake of total protein, natural protein and protein substitute and growth of height and head circumference in Dutch infants with phenylketonuria.

SummaryIn a previous study, Dutch children with phenylketonuria (PKU) were found to be slightly shorter than their healthy counterparts. In the literature, it has been hypothesized that a higher protein intake is necessary to optimize growth in PKU patients. The study aimed to investigate whether protein intake (total, natural and protein substitute) in this group might be an explanatory factor for the observed growth. Growth of height and head circumference and dietary data on protein intake (total, natural and protein substitute) from 174 Dutch PKU patients born between 1974 and 1996 were analysed retrospectively for the patients first 3 years of life. Analyses were corrected for energy intake during the first year of life and for the clinical severity of the deficiency of phenylalanine hydroxylase by means of plasma phenylalanine concentration at birth. Neither protein nor energy intake correlated with height growth. A positive, statistically significant relation between head circumference growth and natural protein and total protein intake was found, but not with the intake of the protein substitute or energy. Therefore, this study suggests that improvement of the protein substitute rather than an increase of total protein intake may be important in optimizing head circumference growth in PKU patients.

A patient with lethal cardiomyopathy and a carnitine-acylcarnitine translocase deficiency

In the last few years, increasing attention has been paid to the diagnosis of defects in mitochondrial fatty acid beta-oxidation in man (Stanley 1987). Clinical diagnosis of these disorders is difficult, because affected patients are often free of symptoms between metabolic crises (Hale and Bennett 1992). A total of 13 inherited beta-oxidation defects have been described (Coates and Tanaka 1992). Among those 13 disorders there are four that affect the transport into mitochondria of long-chain fatty acids that are activated to their CoA esters. Defects have been described for the plasma-membrane carnitine transporter and carnitine palmitoyltransferase types 1 and 2 (CPT I and II). Recently three patients have been described with a carnitine- acylcarnitine translocase deficiency, a defect in the transfer of fatty acylcarnitines across the inner mitochondrial membrane in exchange for free carnitine (Pande et al 1993; Stanley et al 1992; Brivet et al 1994). In this short communication we describe what is to our knowledge the fourth case of a carnitine-acylcarnitine translocase deficiency.

Phenylalanine tolerance can already reliably be assessed at the age of 2 years in patients with PKU.

SummaryBackground:The clinical severity of phenylalanine hydroxylase deficiency is usually defined by either pre-treatment phenylalanine (Phe) concentration or Phe tolerance at 5xa0years of age. So far, little is known about the course of Phe tolerance or the ability of both pre-treatment Phe and Phe tolerance at early age to predict Phe tolerance at later age.Aim:This study was conducted to investigate the course of the individual Phe tolerance and to assess the predictive value of both the pre-treatment Phe concentration and Phe tolerance at 1 and 6xa0months and 1, 2, 3 and 5xa0years for Phe tolerance at 10xa0years of age.Method:Data on blood Phe concentration, prescribed Phe intake and weight of 213 early and continuously treated Dutch PKU patients up to 10xa0years of age were collected. Data acquired under good metabolic control were used in the study. Tolerance was expressed in mg/day and mg/kg per day.Results:Data at 1 and 6xa0months and at 1, 2, 3 and 5xa0years of 61, 58, 59, 57, 56 and 59 patients were included for comparison with the Phe tolerance at 10xa0years. Phe tolerances (mg/kg per day) at 2, 3 and 5xa0years showed a clear correlation with the tolerance at 10xa0years of age (ru2009=u20090.608, ru2009=u20090.725 and ru2009=u20090.661). Results for tolerance expressed as mg/day were comparable. Pre-treatment Phe concentrations did not correlate significantly with the tolerance.Conclusion:Pre-treatment Phe is unreliable but Phe tolerance is a reliable predictor of the tolerance at 10xa0years of age, starting at 2xa0years of age.

Phenylketonuria in The Netherlands: 93% of the mutations are detected by single-strand conformation analysis.

Single-strand conformational analysis was used to screen for genetic defects in all thirteen exons of the phenylalanine hydroxylase gene (PAH) in phenylketonuria and hyperphenylalaninemia patients in the Netherlands. Exons that showed a bandshift were sequenced directly. In this way, we were able to identify 93% of the PAH mutations in a panel of 34 patients. Twenty-one different mutations were found: 4 of these gene aberrations are novel.

Biochemical Monitoring and Management During Pregnancy in Patients with Isovaleric Acidaemia is Helpful to Prevent Metabolic Decompensation

The facilities for neonatal screening, early diagnosis, and effective treatment of isovaleric acidaemia (IVA) have improved greatly over the past decades. Accordingly, IVA patients reach adolescence and may consider having children. The maintenance of a stable metabolic condition is a challenge to both the patients and their multidisciplinary team of care providers. This report presents three women with IVA during their five single or twin pregnancies, whose clinical condition were monitored with contrasting approaches. Metabolic profiles were determined and compared in these pregnancies. In one case, two pregnancies were strictly managed and monitored by measuring plasma acylcarnitine and amino acid profiles, together with adjustment of the diet and/or supplementation of L-carnitine and/or glycine. In addition, complications were prevented by intravenous glucose and L-carnitine during labor and postpartum. In two other cases, the metabolic condition of patients was less frequently monitored and additional treatment with intravenous L-carnitine and intravenous glucose/dextrose was only prescribed during periods of hyperemesis gravidarum. With respect to the differences in management and monitoring of maternal IVA all pregnancies were without complications for mother and child. Despite the favorable outcome in uncontrolled pregnancies in IVA, careful monitoring and management during pregnancy is helpful to prevent life-threatening conditions like metabolic decompensation.