Joachim Pietz

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.

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.

Neurological outcome in adult patients with early-treated phenylketonuria

AbstractDue 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.

Parent based language intervention for 2-year-old children with specific expressive language delay: a randomised controlled trial

Objective: The aim of this randomised controlled trial was to evaluate the effectiveness of a short, highly structured parent based language intervention group programme for 2-year-old children with specific expressive language delay (SELD, without deficits in receptive language). Methods: 61 children with SELD (mean age 24.7 months, SD 0.9) were selected between October 2003 and February 2006 during routine developmental check-ups in general paediatric practices, using a German parent-report screening questionnaire (adapted from the MacArthur Communicative Development Inventories). Standardised instruments were used to assess the language and non-verbal cognitive abilities of these children and of 36 other children with normal language development (reference group; mean age 24.6 months, SD 0.8). 58 children with SELD were sequentially randomly assigned to an intervention group (n = 29) or a 12-month waiting group (n = 29). In the intervention group, mothers participated in the 3-month Heidelberg Parent-based Language Intervention (HPLI). All children were reassessed 6 and 12 months after pretest. Assessors were blind to allocation and previous results. Results: 47 children were included in the analysis. At the age of 3 years, 75% of the children in the intervention group showed normal expressive language abilities in contrast to 44% in the waiting group. Only 8% of the children in the intervention group versus 26% in the waiting group met the criteria for specific language impairment (t score ⩽35). Conclusions: By applying the short, highly structured HPLI in children with SELD, the rate of treatment for language impairment at the age of 3 years can be significantly reduced.

Treatment of Infantile Spasms with High‐Dosage Vitamin B6

Summary: High‐dose vitamin B6 (pyridoxine‐HCl, 300 mg/kg/day orally) was introduced as the initial treatment of recently manifested infantile spasms in 17 children (13 symptomatic cases with identified brain lesion and 4 cryptogenic cases). 5 of 17 children (2 cryptogenic, 2 with severe pre/perinatal brain damage and one with Sturge‐Weber syndrome) were classified as responders to high‐dose vitamin B6. In all 5 cases the response to vitamin B6occurred within the first 2 weeks of treatment and within 4 weeks all patients were free of seizures. Two patients’ developed other seizures (partial seizures, etiologically unclear blinking attacks), but no relapse of infantile spasms was observed among the five responders to vitamin B6. No serious adverse reactions were noted. Side effects were mainly gastrointestinal symptoms, which were reversible after reduction of the dosage. Considering the life‐threatening side effects of treatment with ACTH/corticosteroids or valproate, a controlled clinical trial with high‐dose vitamin B6 would appear justified to either prove or disprove efficacy.

Children with developmental language delay at 24 months of age: results of a diagnostic work-up.

The aim of this study was to evaluate if a diagnostic work‐up should be recommended for 2‐year‐old children with developmental language delay (LD), or if the widely chosen ‘wait and see’ strategy is adequate. Children with LD were identified in paediatric practices during routine developmental check‐ups using a German parent‐report screening questionnaire (adapted from the MacArthur Communicative Development Inventories). A standardized German instrument and the Netherlands version of Bayley Scales of Infant Development (2nd edn) were used to assess language ability and nonverbal cognitive development respectively in 100 children with LD (65 males, 35 females; mean age 24.7mo [SD 0.9]) and a control group of 53 children with normal language development (33 males, 20 females; mean age 24.6mo [SD 0.8]). Neurological and audiometric testing were also performed. Sixty‐one per cent of the LD group had specific expressive LD and 17% specific receptive‐expressive LD. In 22%, LD was associated with other neurodevelopmental problems, 6% showed significant deficits in nonverbal cognitive abilities, and in 12%, nonverbal cognitive abilities were borderline. Four per cent fulfilled the criteria of childhood autism. LD at 2 years proved to represent a sensitive marker for different developmental problems. Adequate early intervention requires a clear distinction between specific expressive or receptive‐expressive LD and LD associated with other neurodevelopmental problems. Though catch‐up development is to be expected in a substantial proportion of ‘late talkers’, our data demonstrate that a general ‘wait and see’ approach is not justified in young children with LD. A proposal for a rational diagnostic work‐up is presented.

Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging.

A multimodal MR study including relaxometry, diffusion tensor imaging (DTI), and MR spectroscopy was performed on patients with classical phenylketonuria (PKU) and matched controls, to improve our understanding of white matter (WM) lesions. Relaxometry yields information on myelin loss or malformation and may substantiate results from DTI attributed to myelin changes. Relaxometry was used to determine four brain compartments in normal‐appearing brain tissue (NABT) and in lesions: water in myelin bilayers (myelin water, MW), water in gray matter (GM), water in WM, and water with long relaxation times (cerebrospinal fluid [CSF]‐like signals). DTI yielded apparent diffusion coefficients (ADCs) and fractional anisotropies. MW and WM content were reduced in NABT and in lesions of PKU patients, while CSF‐like signals were significantly increased. ADC values were reduced in PKU lesions, but also in the corpus callosum. Diffusion anisotropy was reduced in lesions because of a stronger decrease in the longitudinal than in the transverse diffusion. WM content and CSF‐like components in lesions correlated with anisotropy and ADC. ADC values in lesions and in the corpus callosum correlated negatively with blood and brain phenylalanine (Phe) concentrations. Intramyelinic edema combined with vacuolization is a likely cause of the WM alterations. Correlations between diffusivity and Phe concentrations confirm vulnerability of WM to high Phe concentrations. Magn Reson Med 58:1145–1156, 2007.

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.

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Cognitive development in very vs. moderately to late preterm and full-term children: Can effortful control account for group differences in toddlerhood?

BACKGROUND Preterm birth is thought to have an adverse impact on cognitive development and self-regulation. AIM Examining the effect of very vs. moderately to late premature birth on cognitive development and effortful control, as well as evaluating whether effortful control explains the link between preterm birth and poorer cognitive development. SUBJECTS Fifty-eight very preterm children (<32 weeks gestation or <1500 g birth weight), 88 moderately to late preterm children (≥32 weeks gestation and ≥1500 birth weight) and 86 full-term children (≥38 weeks gestation and ≥2500 g birth weight) were examined at the corrected age of 24 months. OUTCOME MEASURES Observational and parent-report measures of effortful control as well as the Bayley Scales of Infant Development II (BSID II, Mental Scale) as a measurement of cognitive development were analyzed. RESULTS Very preterm and moderately to late preterm children showed significantly lower cognitive performance compared to full-term children. Lower effortful control scores (on observational measures, but not on parent-reports) were merely found for very preterm children compared to full-term children. Observational measures of effortful control partially mediated the effects of very preterm birth on cognitive performance, but did not explain the effects of moderately to late preterm birth on cognitive performance. CONCLUSION Preterm birth in general is related to poorer cognitive performance in toddlerhood. In addition, effortful control mediates the effects of very preterm birth on cognitive development. Findings suggest that different mechanisms link moderately to late premature birth to poor cognitive development.