The relationship of genotype to phenotype in phenylalanine hydroxylase deficiency.

Seventy-two adults with phenylketonuria were evaluated to investigate the genotypic relationship to phenotype. Patient data were collected by chart review and medical follow-up as well as current psychological evaluation. Nineteen diagnosed neonatally had remained on a phenylalanine-restricted diet all their lives, whereas 34 who were also diagnosed on newborn screening had discontinued dietary restriction during childhood. Nineteen others who were born prior to newborn screening were diagnosed later than the newborn period on clinical grounds but have remained on dietary restriction. Comparison between intellectual ability, academic achievement, and mental illness was made with degree of diet control as defined by range of blood phenylalanine levels over time. Diet discontinuation in childhood did not significantly lower IQ per se but appeared to diminish academic achievement. The lowest IQ scores were associated with poor dietary restriction of phenylalanine in the diet during childhood. While there appears to be a strong genotypic relationship to phenotypic metabolic parameters in phenylketonuria, there does not seem to be a similar relationship to intellectual ability in adults. Mutation R408W was not strongly related to the occurrence of mental illness in this sample. We conclude that dietary restriction of phenylalanine neonatally and good control contributed to normal intellectual development. Continuation of dietary treatment into adulthood appeared to improve academic achievement in patients with severe phenylalanine hydroxylase mutations.

Summary of findings from the United States Collaborative Study of children treated for phenylketonuria.

The Collaborative Study of children treated for phenylketonuria (PKUCS) was conducted to investigate prospectively the effects of dietary restriction of phenylalanine on the growth and development of these children. Patients with classic phenylketonuria were identified by newborn screening and began treatment shortly thereafter. All were given the restricted diet until age 6 years, when half were randomly assigned to continue and half to discontinue dietary therapy. By age 10 years, 35% had deviated from randomization. The effects of diagnostic, treatment, and psychosocial factors on cognitive test scores were evaluated through 12 years of age. After controlling for parent IQ, significant correlations were noted between various measures of control of blood phenylalanine and their scores on intelligence, reading, spelling and behavior tests, but not for arithmetic or language scores. Bender Gestalt test scores were related to phenylalanine level at the time of testing, but not to early treatment history. These findings strongly support the importance of early initiation of dietary treatment and continuation of therapy throughout childhood.

Care of the adult with phenylketonuria.

Forty-three adults with classical phenylketonuria were identified by neonatal screening and treated with a phenylalanine (Phe) restricted diet. Nineteen have remained on dietary treatment with varying levels of blood Phe control and 24 have discontinued the diet at an average age of 7.8 years. Follow up at an average age of 22 years revealed that the cohort remaining on dietary treatment have achieved substantially better social and academic achievement than the 24 who discontinued dietary treatment. Another group of 19 adults who were not diagnosed until an average age of 2.5 years have also been evaluated after an average of 22 years on a Phe restricted diet. This report is based upon Wechsler Adult Intelligence Revised Test scores, attendance at college, employment and marital status.

Mental development in Down syndrome mosaicism.

Serial assessments of mental status of 30 subjects with Down syndrome mosaicism were compared with those of 30 subjects with trisomy 21 Down syndrome. The samples were matched for age, sex, and parental socioeconomic background. The mean IQ level of the mosaic Down syndrome group was significantly higher than that of the trisomy 21 group. Many subjects with mosaicism showed better verbal abilities, and some also demonstrated normal visual-perceptual skills in paper- and-pencil tasks. Children with Down syndrome with IQs over 60 at 5 years of age and with relatively normal speech can be viewed as a suspected case of mosaicism. Chromosomal analysis is mandatory to confirm or disprove this diagnosis.

Clinical trial of 'off diet' older phenylketonurics with a new phenylalanine-free product.

Ten PKU subjects were treated with Product 196 for one year. Product 196 is a special phenylalanine-free dietary supplement consisting primarily of essential amino acids, carbohydrate, Vitamin C and some minerals, made by Scientific Hospital Supplies Limited, Liverpool, England. It is intended for persons with phenylketonuria who are not consuming a phenylalanine-restricted diet. During the year that the 10 subjects were on the product, they remained asymptomatic, maintained their weight and appeared healthy. Subjective behavioural improvement was noted in six but no significant changes in intelligence were noted.

Nonphenylketonuric hyperphenylalaninemia.

Sixteen subjects with nonphenylketonuric hyperphenylalaninemia were followed up during a period of years. Dietary treatment did not seem to influence the outcome, and no relationship between blood phenylalanine and intellectual outcome was demonstrable.

School achievement in treated PKU children.

Phenylketonuric children who were treated early and maintained a pherestricted diet through age 10 were compared with those who discontinued the diet after age 6 on a standardized test of intelligence, school achievement, language and perceptual skills. Mean IQ, reading and spelling test scores improved between ages 6 and 10 for the on-diet children in comparison to those who were off-diet. However, mean scores on arithmetic, language and perceptual skills declined at a uniform rate for both groups. Children with PKU scored significantly lower than did their non-PKU siblings on tests of visual perception and visual-motor skills. Because the school years, particularly, the early teens, pose increased stress in affected PKU individuals, it is recommended that dietary restriction at least through the high school years is prudent for their optimal physical, mental, emotional and educational growth.

Psychoeducational findings among children treated for phenylketonuria.

Early treated phenylketonuric children who maintained a phe-restricted diet through age 10 were compared with those who discontinued the diet after age 6 on standardized tests of intelligence, school achievement, language, and perceptual skills. Mean IQ, reading, and spelling test scores improved between ages 6 and 10 for the on-diet children in comparison to those who were off diet. Mean scores on arithmetic, language, and perceptual skills, however, declined at a uniform rate for both groups. Children with PKU scored significantly lower than did their non-PKU siblings on tests of visual perception and visual-motor skills. We conclude that children with PKU should be maintained on a phe-restricted diet.

Successful adjustment to society by adults with phenylketonuria.

The study shows that most individuals between 16 and 25 years of age with PKU appear to function in a productive manner in society. Although they have not become professional men and women, they can acquire jobs of a skilled or semiskilled nature and perform them satisfactorily. The majority seemed content with their jobs and happy with the way their lives were progressing, although only 23% were financially independent. Of the patients interviewed, the majority had made friendships and appeared to keep them without much trouble. The majority of the patients would not tell their friends that they had PKU. The reason for this was that they felt uncomfortable acknowledging that they had this disorder.

Tyrosine supplementation during pregnancy in a woman with classical phenylketonuria. A case report.

A woman with classical phenylketonuria (PKU) adhered poorly to a phenylalanine-restricted diet but did receive tyrosine supplementation from the 14th week of gestation until delivery. At birth the infant demonstrated a head circumference more than two standard deviations below the mean but at 2 years of age had a development quotient (DQ) of 94. This case illustrates the fact that while single case reports may be of value in disproving a theory, they are not sufficient to prove an association because biologic variation may explain one's results. Thus, while tyrosine supplementation may explain the relatively normal DQ, the results are also compatible with the moderate degree of phenylalanine restriction obtained. Current evidence favors the elevated maternal phenylalanine level as the cause of defects in offspring of women with PKU, but tyrosine supplementation should be considered if the level is subnormal.

Developmental aspects of galactosemia from infancy to childhood.

The developmental status of 60 galactosemic infants, their subsequent intellectual level, school status, visual-perceptual skills, and EEG results were analyzed. In addition, the intelligence of the parents and the unaffected siblings, as well as the educational and vocational status of the parents, were also investigated. The results reveal that the highest level of mental development was in the preschool age group. The lowest level, and still within normal limits, was in the school-age children. The overall findings are consistent with earlier observations that better progress is found in those individuals whose dietary control is instituted at the youngest age level.

Comparison of mental development in individuals with mosaic and trisomy 21 Down's syndrome.

During the past 15 years about 350 children with Down's syndrome have been seen at Children's Hospital of Los Angeles for psychological evaluation along with medical visits and other laboratory tests. Among this group there were 25 mosaic Down's syndrome children identified by chromosome analyses. They were matched for sex and chronological age with 25 trisomy 21 subjects and compared on psychological tests. The mosaic group demonstrated significantly higher intellectual potential, better verbal facility, and less visual perceptual difficulties than the trisomy 21 group. Their behavioral adjustment and personality characterisitcs were similar to those observed in other types of Down's syndrome. Since present psychological assessment techniques do not permit reaching valid conclusions about the ultimate intellectual status in very young infants with Down's syndrome, physicians and other professionals need to be careful when recommending early placement outside the home based merely upon the diagnosis.