Helen K. Berry

Intellectual development and academic achievement of children treated early for phenylketonuria.

Twenty early‐treated children with classical phenylketonuria (PKU), five early‐treated children with variant PKU and seven untreated children with hyperphenylalinemia were compared with non‐PKU family members in terms of intellectual development, and 14 school‐age PKU children were also compared for academic achievement.

Organophosphates: The relationship between chronic and acute exposure effects

The relationship between chronic (nonreversing) neuropsychological effects and acute exposure effects was investigated in 77 organophosphate exposed male sheep-dippers. Acute exposure effects were assessed prospectively using a purpose-constructed symptoms questionnaire administered pre-, and 24 h postexposure. Urine was analysed for dialkylphosphate levels to confirm recent exposure. Chronic effects were assessed in a cross-sectional neuropsychological study in the absence of recent exposure using computerised neuropsychological tests, the General Health Questionnaire, and the Subjective Memory Questionnaire. Simple correlation and multiple linear regression analyses (adjusting for confounders) were used to assess relationships between the change in total symptom reporting from baseline to 24 h after exposure and chronic effect outcomes. There was no evidence of any association between reported symptom levels and chronic neuropsychological effects. This suggests that chronic effects of OP exposure appear to occur independently of symptoms that might immediately follow acute OP exposure. This has implications for exposure control: individuals may experience chronic effects without the benefit of earlier warning signs of toxic effects during acute exposures.

Tyrosinemia with acute intermittent porphyria: Aminolevulinic acid dehydratase deficiency related to elevated urinary aminolevulinic acid levels

A patient who had hereditary tyrosinemia was observed during two illnesses to have characteristics of acute intermittent porphyria with associated hypertension. Metabolic studies revealed elevated levels of urinary aminolevulinic acid but normal levels of porphyrin metabolites associated with, and possibly explained by, decreased red blood cell activity of the zinc-dependent enzyme, aminolevulinic acid dehydratase. Zinc deficiency could not be directly associated with the diminished enzyme activity. The patients hypertension appeared to be related to increased urinary excretion of catecholamines and to elevated renin activity in peripheral venous blood.

PHENYLKETONURIA AND COMPLEX SPATIAL VISUALIZATION: AN ANALYSIS OF INFORMATION PROCESSING

Recent neuropsychological studies have suggested that patients with early‐treated phenylketonuria (PKU) and normal intelligence have a specific deficiency in solving complex spatial problems. In the present study a task involving the assembly of various shapes was used to compare the performance of 16 PKU patients and 11 sibling controls. Error rates generally were higher and response times slower among the PKU patients, but greater complexity did not produce differential changes in accuracy or speed in the PKU group compared to the controls. Correlations between task performance and IQ measures were significant for the PKU patients, but when IQ was controlled for the group differences vanished. The results suggest that choice of problem‐solving strategy, attention span and accuracy of mental representation may be affected in PKU patients, despite efforts to maintain well‐controlled phenylalanine concentrations in the blood.

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

Summary: A supplement of the branched chain amino acids, valine, isoleucine, and leucine (VIL) was administered orally to patients with phenylketonuria, either together with unrestricted diet of natural protein or with a low phenylalanine diet. The VIL supplement brought about a significant reduction of the cerebrospinal fluid-serum ratio of phenylalanine from a mean value of 0.254 without VIL to 0.204 with VIL. The reduction varied from 15–40% (mean 21%). Concentrations of glycine, lysine, methionine, threonine, tryptophan, and tyrosine were within normal limits in serum and cerebrospinal fluid of infants with phenylketonuria. No amino acid imbalance was created by the supplement and no adverse effects from VIL were observed.Speculation: The branched chain amino acids and phenylalanine share a common transport system. High levels of phenylalanine in brain of children with phenylketonuria may be reduced by administration of a supplement of valine, isoleucine and leucine (VIL). Supplementation of the low-phenylalanine diet with VIL during the first 2 years of life may add a measure of protection to the developing brain beyond that which can be achieved by diet alone. In older children, VIL supplementation may permit liberalization of the diet without unfavorable behavioral consequences.

Adult psychosocial outcome in early-treated phenylketonuria

Concerns about the psychosocial risk of adults with early-treated phenylketonuria (ETPKU) are predicated on four sources of scientific data: (1) consistent documentation of increased behavioural risk in children with ETPKU; (2) recent evidence of neurocognitive impairment in adults with ETPKU; (3) reports of neuroimaging abnormalities in adults with ETPKU; and (4) preliminary evidence of increased rates of psychiatric disturbance in this population. We studied the psychosocial adjustment of 25 patients, aged 18 years and older, with ETPKU. On most pscyhosocial outcome measures, patients were indistinguishable from 15 sibling controls. However, on a self-report inventory of psychiatric symptoms, 20% of the patients demonstrated significant morbidity. Psychosocial outcome of these patients was unrelated to concurrent or historical biological dietary disease factors, unlike neurocognitive outcome. A strong relationship was demonstrated, however, between neurocognitive measures and psychosocial morbidity. These findings indicate that a significant minority of patients with ETPKU develop psychosocial difficulties with multiple clinical elevations on a psychiatric inventory. However, most adults with ETPKU cope with the challenges of young adulthood with the same degree of success as their unaffected siblings. Neuropsychological surveillance during childhood and adolescence is important in identifying patients at risk for both neurocognitive and psychosocial morbidity.

Paper chromatographic method for estimation of phenylalanine.

Summary For paper chromatographic estimation of phenylalanine, 0.5 ml samples of blood serum are deproteinized with 4 volumes of 95% ethyl alcohol and the filtrate used for preparation of the chromatogram. The method is especially useful in study of phenylketonuric infants, and in following the changes in serum phenylalanine when a low-phenylalanine diet is used for their treatment. The recovery range of phenylalanine added to serum was from 80% to 106% with an average recovery of 95%.

Progress in experimental phenylketonuria: A critical review☆

Experimental progress in the development of an accurate and useful model of phenylketonuria (PKU) during the last 15 years is reviewed in detail. From this review it is clear that the recent emergence of models using the combined administration of phenylalanine (phe) and p-chlorophenylalanine (PCPA) constitutes a major success that lays the groundwork for future research into the pathogenesis and treatment of PKU. Biochemical evidence on the pathophysiology of PKU is also briefly reviewed in the context of the behavioral and biochemical adequacy of the models used. It appears that in the past biochemical investigations into PKU have been impaired by use of inadequate models, a situation that should now change if the best of the phe-PCPA models are more widely adopted. New trends in PKU research involve the role of large neutral amino acids other than phe as potential aids in the treatment of PKU and the appearance of a new model based on the use of alpha-methylphenylalanine (AMPhe) combined with phe. It appears that PKU research may be on the brink of a new and productive era as investigations into these promising areas unfold and as new emerge through the full utilization of existing models.

A syndrome of phenylketonuria with normal intelligence and behavior disturbances

Summary 1. Two patients with biochemical characteristics of phenylketonuria have been described, one with normal and the other with nearly normal mental ability. 2. On preliminary examination a previously unreviewed psychological and psychomotor symptom complex common to both patients was recognized, which made diagnosis possible despite normal mental capacity. 3. A phenylalanine-restricted diet employed in treatment of one patient brought about alleviation of psychomotor and psychological agitation, suggesting that dietary therapy in the older phenylketonuric child may be beneficial. 4. There appears to be a definite relationship between I.Q. and serum phenylalanine concentration in these 2 children with normal and nearly normal intelligence. 5. The diagnosis of phenylketonuria in a child with normal mental ability may lead to recognition of families in which the abnormal gene might not otherwise have been discovered.

Preliminary support for the oral administration of valine, isoleucine and leucine for phenylketonuria.

Recent behavioral data have demonstrated the importance of maintaining low phenylalanine concentrations beyond early childhood in patients with phenylketonuria, which can be a difficult task, particularly during adolescence. Administration of certain large neutral amino‐acids (valine, isoleucine, leucine–VIL) appears to reduce phenylalanine concentrations in the cerebrospinal fluid of humans and in the brain of rats. The present study compared neuropsychological test‐performance of six patients with phenylketonuria during periods of VIL administration and periods when this supplement was not given. Although individual responses to VIL were variable, there was an over‐all improvement of about 1½ SD in neuropsychological test performance during VIL treatment. Abstract reasoning and tactile motor problem‐solving increased more than pure motor performance.