Intelligence in mild atypical phenylketonuria.

In 82 children with mild phenylketonuria (PKU) (blood phenylalanine (Phe) concentrations consistently below 900 mumol/l throughout follow up) the relationship between intelligence at age 4 (IQ by Stanford-Binet) and average blood Phe concentrations from birth to 4 years was examined. Of the 82 children 24 had received no treatment. In the group as a whole, and in the 24 untreated subjects alone, mean IQs were significantly below population norms, with deficits of approximately 4.5 points and 9 points respectively. After allowing for social class IQ fell progressively by approximately 6 points for each 100 mumol/l rise in mean Phe concentrations in both the treated and untreated subjects. This relationship resembled that previously reported in early treated children with more severe forms of PKU, except that the scale of the relationship was even greater. We conclude that all children whose blood Phe concentrations reach 400 mumol/l or above should receive a low Phe diet, at least during the preschool years, and that the aim should be to control blood Phe levels below 400 mumol/l throughout early childhood in all forms of PKU.

Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971.

Intellectual status at 18 years is reported in 192 patients with phenylketonuria born in the UK between 1964 and 1971, together with their school progress. Mean IQs expressed as standard deviation scores (IQ-SDS) were significantly below estimated population norms, and showed a small decrease from 14 to 18 years of age (mean IQ-SDS -1.06 +/- 1.3 at 14 years and -1.28 +/- 1.07 at 18 years, t = 5.7, p < 0.0001). At 18 years, 27% of subjects had IQs over 2 SDs below the estimated population mean. IQ-SDS at 18 years, although significantly related to average phenylalanine control both between birth and 14 years, and between 14 and 18 years, was not independently related to either variable after allowing for IQ-SDS at 14 years. We conclude that general ability in young adults with early treated phenylketonuria, although reduced in comparison with their peers and closely related to phenylalanine control in early childhood, is not directly influenced by phenylalanine control in the four years preceding the 18th birthday. The apparent fall in IQ-SDS between 14 and 18 years may be due to methodological problems in the analysis of longitudinal IQ data without a control group, rather than providing evidence of intellectual decline.

Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria.

A total of 599 children with phenylketonuria, who had been treated early, were followed up prospectively in order to examine the association between intellectual progress from 4 to 14 years of age and control of phenylalanine concentrations. The phenylalanine rose from around 400 mumol/l during the first four years to above 900 mumol/l by 12 years. The children were divided into two cohorts: cohort I comprised 224 children born in the United Kingdom between 1964 and 1971 and cohort II 375 children born between 1972 and 1978. In a previous study it was shown that by 4 years of age these children already had a mean intelligence quotient (IQ) over half a standard deviation below general population norms, and that IQ fell linearly as average phenylalanine concentrations rose. Multiple regression was used to estimate the size of the associations between IQ at later ages and average phenylalanine concentrations in the periods between assessments, after controlling for previous IQ and phenylalanine control, social class, type of phenylketonuria, and factors relating to diagnosis and early management. For each 300 mumol/l rise in average phenylalanine concentrations for those aged 5 to 8 years IQ at 8 years fell by 4-6 points. This compared with a 7-10 point fall in IQ at 4 years for a similar rise in phenylalanine. After 8 years of age the association between IQ and phenylalanine control disappeared in cohort I but persisted in cohort II and was significant up to 10 years of age, although the association was smaller than at 8 years.

Changes in carotid artery compliance with age.

Doppler-shifted ultrasound was used to measure arterial compliance non-invasively in the internal and external carotid pathways of 270 male and 388 female asymptomatic volunteers aged 5 to 90 years. There was a significant decrease in the compliance of both arteries from 5 to 50 years of age (p less than 0.001), when it then levelled out. Arteries of women were more compliant than those of men at ages 35 to 60 years.

Intelligence and quality of dietary treatment in phenylketonuria.

The records of the Phenylketonuria Register were examined to determine the factors associated with early intellectual progress in children who had received a diet low in phenylalanine from soon after birth. A total of 1031 children were born between 1964 and 1980 and started treatment before they were 4 months of age, and 808 of them were followed up prospectively. In 263 children born between 1964 and 1971 (cohort 1), the mean intelligence quotient (IQ) at 4 years rose with year of birth from 24 points below revised IQ norms to 10 points below; in 545 born between 1972 and 1980 (cohort 2) there was no further rise in IQ and the mean remained eight points below the norms. IQ fell progressively by roughly four points for each four weeks' delay in starting treatment, for each 300 mumol/l rise in mean phenylalanine concentrations during treatment, and for each five months during the first two years during which phenylalanine concentrations were below 120 mumol/l. Forty six children in cohort 2 had the most favourable treatment characteristics. Their mean IQ, after standardising for social class, was 112.6, and similar to the mean for the same group estimated by multiple regression, and to revised population IQ norms for the period during which the children were tested. The data suggest that many children who are treated early continue to suffer a mild degree of neurological impairment because of the difficulties in fully controlling the metabolic abnormality.

Behavior disturbance in 8-year-old children with early treated phenylketonuria. Report from the MRC/DHSS Phenylketonuria Register.

Using the Rutter Behavior Questionnaire, schoolteachers assessed the frequency of common abnormal behavior in 544 8-year-old children with phenylketonuria who were born in the United Kingdom and in whom the diagnosis was made by routine testing in infancy, either during the early years of screening (cohort 1, births 1964 to 1971) or after a national reorganization of the program (cohort 2, births 1972 to 1977). All children received treatment before 4 months of age. Two matched control subjects were assessed for each patient. Compared with the controls, patients in cohorts 1 and 2 receiving a strict low-phenylalanine (phe) diet (average phe concentration less than 600 mumol/L) were 1.5 and 1.7 times, respectively, more likely to have deviant behavior; those receiving a less well controlled diet were 2.5 and 1.9 times, respectively, more likely to show such behavior. Patients more often had mannerisms, hyperactivity, and signs of anxiety and were less responsive and more solitary than were controls. On the other hand, they were not more aggressive, untruthful, or disobedient, nor absent from school more frequently. The increased frequency of deviant behavior may be the result of both psychologic stress and neurologic impairment.

Errors in computation of WISC and WISC-R intelligence quotients from raw scores.

Twenty-four per cent of 457 sequential IQ assessments contained errors in the calculation of verbal, performance or full scale IQ's from the raw scores; in 2% the errors were large enough to cause a difference in full scale IQ of more than 5 points.

Red blood cell velocity changes with age and sex in the common carotid and supra-orbital arteries.

Doppler-shifted ultrasound and spectral analysis were used to assess signals from the resting supra-orbital artery and the common carotid artery at the base of the neck of 658 (270 male, 388 female) asymptomatic subjects aged 5 to 90 years. The sonagrams obtained showed two peaks (A and B) during cardiac systole. The ratio of these peaks (A/B) decreased from 20 to 50 years and then levelled out. The male A/B ratios from both arteries were higher than those for the females between 20 and 50 years, and for the common carotid these differences were highly significant (P less than 0.001).

Erythrocyte flow velocity changes with age and sex in augmented supraorbital, superficial temporal and common carotid pulses.

Doppler-shifted ultrasound and spectral analysis were used to assess signals from augmented supraorbital and superficial temporal pulses, and the common carotid pulse 4 cm above the base of the neck of 658 (270 male, 388 female) asymptomatic subjects aged 5-90 years. The sonagrams obtained showed two peaks (A and B) during cardiac systole and the ratio of these peaks (A/B) decreased between the ages of 20 and 50 years, and then levelled out. Mean male values of common carotid sonagrams were significantly higher than female values during this age range (p less than 0.001).

Diagnosis by ultrasound of severe carotid artery disease in patients undergoing cardiopulmonary bypass operations.

A non-invasive method using continuous wave Doppler shift ultrasound and spectral analysis was used as a screening test for severe carotid artery disease in patients undergoing cardiopulmonary bypass operations. One hundred and eighty-eight patients were examined before cardiac surgery (91 for ischaemic heart disease, 17 for ischaemic heart disease and valve replacement, 66 for valve replacement alone, and 14 for congenital abnormalities). The mean age of the 108 patients suffering from ischaemic heart disease was 54 years (+/- 8) and that of the 80 patients admitted either for valve replacement alone or for congenital abnormalities was 52 years (+/- 12). Five of the 108 patients suffering from ischaemic heart disease were found to have severe occlusive disease of the internal carotid artery by the ultrasound test, while the test was normal in the other two groups. Patients with severe carotid artery disease proceeded to carotid arteriography and endarterectomy before the planned heart operation.

Detection of disease at the carotid bifurcation using ultrasound--including an imaging system.

A two-stage approach is described for the detection of occlusive arterial disease at the carotid bifurcation using continuous wave Doppler-shift ultrasound with spectral analysis of backscattered signals from erythrocytes. The first stage involves analysis of Doppler-shift signals from the supraorbital and common carotid arteries. Abnormal signals from these arteries are frequently caused by the presence of atheroma at the carotid bifurcation and are used to indicate the necessity for imaging the bifurcation. This latter technique produces a physiological image of the arteries, as it depends on detecting erythrocyte velocities beneath a transducer which is guided over the surface of the neck. The investigation has advantages over arteriography in that it is noninvasive, has no attendant risk and may be repeated as often as required.In order to evaluate the accuracy of these methods the results have been compared with x-ray findings in patients undergoing carotid arteriography. In 20 comparisons there were no false positives and one false negative in which the arteriogram showed a small lesion. These results indicate that the two noninvasive methods may be used in sequence to demonstrate operable disease around the carotid junction.

Changes in internal carotid artery flow velocities with cerebral vasodilation and constriction.

Non-invasive Doppler-shift ultrasound, together with spectral analysis, have been used to study the changes in internal carotid artery flow velocity patterns that occur with cerebral vasoconstriction and vasodilation provoked by over-breathing and breath-holding. Significantly different waveform shapes, characteristic for each vessel, were demonstrated from the internal and external carotid arteries, making identification of the internal carotid certain. In 5 healthy subjects over-breathing for 3 minutes significantly lowered the mean height of the internal carotid waveform by an average of 32% (p less than 0.001). Breath-holding for 40-60 seconds raised the mean height by an average of 31% (p less than 0.001). The pulsatility index of the waveforms varied inversely to mean height. These results show that the effects of cerebral dilation or constriction are easily detected by flow-velocity changes in the internal carotid artery.

Disease at the carotid bifurcation: diagnosis by Doppler ultrasound imaging.

A non-invasive method for visualising the carotid bifurcation using continuous-wave Doppler-shift ultrasound and spectral analysis is described. The system is directional so that arteries can be visualised without interference by signals from adjacent veins. The technique uses a transducer attached to a position-sensing arm so that the position of arterial flow-velocities can be translated onto a storage oscilloscope. A two dimensional image of the carotid bifurcation is formed by moving the transducer along the length of each vessel while repeatedly scanning across the vessel lumen. The clinical application of this technique is illustrated by some specific cases.

Imaging the carotid bifurcation using continuous-wave Doppler-shift ultrasound and spectral analysis.

A non-invasive method is described for visualizing the carotid bifurcation using a continuous-wave Doppler-shift technique simultaneously with spectral analysis of the blood velocities from all parts of the vessel lumen. The system is directional so that arteries can be visualized in the presence of signals from adjacent veins. The technique uses a transducer which is attached to a position-sensing arm so that the position of the ultrasound beam on the neck, when sensing arterial blood flow-velocities, can be translated onto a storage oscilloscope. By repeated passes of the transducer across the vessel lumen a 2 dimensional image of the carotid bifurcation is formed. As each image point is marked, the full spectrum of blood-velocities corresponding to that position is continuously displayed on a second oscilloscope beside the image scope. Ultrasound images are compared with arteriograms and both continuous-wave and pulsed Doppler ultrasound imaging systems are discussed.