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 psychosocial 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.

Early-treated phenylketonuria: adult neuropsychologic outcome.

Twenty-five adults with phenylketonuria that was treated early were compared with 15 unaffected control siblings with respect to intellectual and neuropsychologic measures. Patients were found to have normal intelligence but were significantly lower than their control siblings on measures of intelligence, attention, and complex visuoconstructional ability. Stepwise multiple regression analyses found the patients' intellectual outcome to be best predicted by indexes reflecting early insult to the brain, whereas performance on a measure of novel problem solving was best predicted by concurrent serum phenylalanine level. Different pathophysiologic mechanisms may thus account for cognitive deficits in this population. These results provide further evidence of continuing benefits of dietary adherence into adulthood.

Branched chain amino acids improve radial-arm maze acquisition and water maze forced-choice learning in rat offspring exposed in utero to hyperphenylalaninemia.

Maternal phenylketonuria results in a high incidence of children born mentally retarded. We showed that the large neutral amino acids valine, isoleucine, and leucine (VIL) ameliorate the effects of intrauterine hyperphenylalaninemia in rats on a test of complex maze learning. To further test the ameliorative effects of VIL on intrauterine CNS development during hyperphenylalaninemia, gravid rats were administered a phenylalanine/p-chlorophenylalanine (index group) supplemented diet with or without VIL added. Controls were given standard diet with or without VIL. All groups were pair-fed to the index group. As adults, the progeny exposed in utero to hyperphenylalaninemia showed characteristic learning impairments in a complex water (Cincinnati) maze on forced and elective-choice phases of the task and deficits in radial-arm maze and Morris maze acquisition, whereas those exposed to hyperphenylalaninemia combined with VIL showed no deficits in the forced-choice phase of Cincinnati maze learning and no evidence of radial-arm maze deficits. However, the improvement was not complete, with no ameliorative effects obtained on the elective-choice phase of the Cincinnati maze or on the Morris hidden platform test. No deficits were seen on phases containing test trials for memory function (Olton and Morris mazes). The acquisition differences occurred in the absence of any effects of VIL on maternal weight gain during gestation, maternal serum amino acid concentrations of phenylalanine or tyrosine, or effects on offspring growth. VIL alone produced no adverse or enhancing effects on learning or memory. Based on these data it was concluded that the VIL supplement continues to show promise as a potential treatment for intrauterinely acquired mental deficiency associated with maternal phenylketonuria.

Valine, isoleucine, and leucine. A new treatment for phenylketonuria.

Early treatment of phenylketonuria by dietary phenylalanine restriction prevents brain damage. Behavioral and cognitive deficits occur when serum phenylalanine levels increase. Administration of valine, isoleucine, and leucine to patients with phenylketonuria may inhibit entry of phenylalanine into the brain and reduce its toxic effects on the central nervous system. Sixteen adolescents and young adults with phenylketonuria participated in double-blind trials in which a valine, isoleucine, and leucine mixture or a control mixture was given for four 3-month periods. Biochemical and neuropsychologic tests were carried out before and at the end of each period. Time to completion of a test that required substantial attention with mental processing (Attention Diagnostic Method) was faster during the valine, isoleucine, and leucine periods than during the control mixture periods. Improvement with valine, isoleucine, and leucine on a less demanding task (Continuous Performance Test) approached significance. These data lent support to the hypothesis that a regimen of valine, isoleucine, and leucine may help individuals unable to maintain low serum phenylalanine levels.

Branched chain amino acids improve complex maze learning in rat offspring prenatally exposed to hyperphenylalaninemia: implications for maternal phenylketonuria.

Maternal phenylketonuria results in a high incidence of children born who are mentally retarded. It has been suggested that blood-brain-barrier transport of phenylalanine may be reduced by competitive inhibition of transporter uptake by supplemental administration of other large neutral amino acids. We hypothesized that large neutral amino acids might also be effective at improving the outcome of fetuses exposed to hyperphenylalaninemia in utero. If correct, sparing of embryonic CNS development might be possible. Pregnant rats were given a hyperphenylalaninemic diet alone or the same diet supplemented with a combination of valine, isoleucine, and leucine. As adults, the progeny exposed in utero to hyperphenylalaninemia showed characteristic learning deficits in a complex maze, while those exposed in utero to hyperphenylalaninemia combined with valine, isoleucine, and leucine showed no deficits in maze acquisition. The valine, isoleucine, and leucine supplement may show promise as a treatment for intrauterinely acquired mental deficiency associated with maternal phenylketonuria.

Protease inhibitor and defective proteolysis in cystic fibrosis.

Meconium specimens from 18 infants with cystic fibrosis (CF) had strong trypsin inhibitory activity (TIA). The same specimen, which contained increased quantities of undigested proteins, had normal concentrations of immunoreactive trypsin (IRT), but deficient trypsin catalytic activity (TCA). TIA was not detected in any specimen from non-CF infants who had high concentration of proteins comparable to that of CF infants. Subjecting meconium supernatant of CF infants to Sephadex G-75 gel filtration revealed that TCA was greatly enhanced in effluents after fractions were activated by porcine trypsin. TCA was present in the same fractions with IRT. The findings suggested that proteases were secreted into the intestinal lumen in CF infants prior to birth. Deficient proteolysis in the disease might be due to the presence of a trypsin inhibitor.

Screening for mucopolysaccharide disorders with the Berry spot test.

The Berry spot test, based on metachromatic straining of urinary acid mucopolysaccharides (MPS), is widely used to screen for inherited MPS disorders. During a 5-year period over 6000 specimens from a variety of patients were tested as part of routine metabolic screening. Urine was applied to filter paper, stained with toluidine blue, and destained by washing in acetic acid. Over 90% of specimens showed no metachromasia. Quantitative measurements of hexuronic acid were carried out on all specimens with positive tests using the borate modification of the Dische carbazole reaction. Molecular species were identified following electrophoresis on cellulose acetate and staining with alcian blue. Mean concentration of hexuronic acid in specimens with + reaction was 113 +/- 67 mumol/L. Only chondroitin sulfate A/C was identified by electrophoresis. Hexuronic acid concentration in strongly positive + + + specimens ranged from 335-1546 mumol/L, and heparan sulfate, dermatan sulfate or both were identified. Additional specimens were obtained from patients with + + + reactions and from 15 control children with negative spot tests. Excretion of hexuronic acid by + + + patients was 175-258 mumol/day (84-181 mmol/mol creatinine) compared to 41 +/- 36 mumol/day (10 +/- 5 mmol/mol creatinine) by control subjects. Urine testing simplifies the differential diagnosis by demonstrating the biochemical defect and pointing to the probable enzyme defect. The screening test has been highly effective in identifying patients with MPS disorders.

Phenylketonuria revisited: treatment of adults with behavioural manifestations.

Dietary treatment of three PKU patients with irreversible changes is described and elevated.

Phenylketonuria, adolescence, and diet.

The decision to continue treatment for phenylketonuria (PKU) patients into adolescence and adulthood presents a challenge to nutritionists and other professionals who must motivate patients to maintain the diet and give them support. Nutrition needs must be assessed and then met by commercial low-phenylalanine formula and low-protein foods, while at the same time the amount of phenylalanine in the diet is severely limited. Combinations of products can be used to tailor the diet to individual needs, e.g., weight reduction. The objective is to allow the intellectually normal PKU patient to develop as socially normal a life-style as possible.

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 1 1/2 SD in neuropsychological test performance during VIL treatment. Abstract reasoning and tactile motor problem-solving increased more than pure motor performance.

Rapid gas chromatographic--mass spectrometric quantitation of gamma-aminobutyric acid in biological specimens.

A mass fragmentographic method for gamma-aminobutyric acid (GABA) quantitation using the heptafluorobutyryl-cyclohexyl-GABA derivative is described. Both capillary and packed column gas chromatography were used. This procedure employs 2,2[2H2]GABA as an internal standard and allows the rapid, sensitive, and specific measurement of GABA with a minimum of sample clean-up. Application of the method is demonstrated in mouse embryonic brain, body, and palate and human platelets, plasma, cerebrospinal fluid, and urine.

Comparative diagnostic value of phenylalanine challenge and phenylalanine hydroxylase activity in phenylketonuria.

Serum phenylalanine (phe) concentrations during and following phe challenges and liver phenylalanine hydroxylase (PH) activity were compared in 13 phenylketonuric (PKU) patients. These patients were separated into two groups: eight patients with no detectable PH activity (PH degrees) and five patients with residual PH activity (PH-) ranging from 9 to 24% of the activity obtained in 10 non-PKU subjects. The rise in serum phe concentration during 3 days of oral loading did not differentiate the two groups. However, the difference in serum phe concentration of the PH degrees and PH- groups reached statistical significance at 24 h postloading (p less than 0.01). We concluded that combined results from multiple measurements during the oral challenge, namely serum phe concentration after termination of loading, serum phe clearance rate, post-loading phe tolerance index and urinary metabolite excretion, make a better indicator for predicting residual PH activity for the majority of PKU subjects than peak phe concentrations during phe challenge.

Early-treated phenylketonuria: neuropsychologic consequences.

Twenty-seven children with phenylketonuria who had undergone dietary restriction of phenylalanine since infancy were administered a battery of neuropsychologic tests in childhood. Children without PKU were also assessed. Discriminant function analysis of the neuropsychologic measures resulted in correct diagnostic classification for 94% of the total sample. Measured intelligence, school achievement, concept formation, and tactile-motor problem solving were the most powerful discriminators. In general, motor speed and coordination were not significantly different in patients compared with nonpatients. Serum phenylalanine concentration on the day of neuropsychologic testing was negatively correlated with performance. Correlation coefficients between infant serum phenylalanine concentrations and later neuropsychologic performance did not reach statistical significance. We suggest that concurrent serum phenylalanine concentrations affect neuropsychologic performance and that therefore the practice of terminating dietary restriction requires further scrutiny.