Pamela Joy

Specific learning disability in children with neurofibromatosis type 1: Significance of MRI abnormalities

To determine whether previously reported areas of increased T2 signal intensity on MRI examination in children with neurofibromatosis type 1 (NF 1) are associated with deficits in development and learning common in this population, we evaluated 51 children with NF 1 (aged 8 to 16 years). Forty children completed the full assessment protocol (MRI, medical, psychometric, speech therapy, and occupational therapy assessments). The mean Full Scale IQ scores for the entire study population showed a left shift compared with the normal population, and the distribution of IQ scores was bimodal, suggesting that there are two populations of patients with NF 1–those with and those without a variable degree of cognitive impairment. There was no association between lower IQ scores and any clinical variable. Areas of increased T2 signal intensity unidentified bright objects (UBO+) were present in 62.5% of the study population, and their presence was not related to clinical severity, sex, age, socioeconomic status, macrocephaly, or family history of NF 1. However, compared with children without areas of increased T2 signal intensity (UBO-), the UBO+ group had significantly lower mean values for IQ and language scores and significantly impaired visuomotor integration and coordination. Children with areas of increased T2 signal intensity were at a much higher risk for impaired academic achievement. Children without increased T2 signal on MRI (UBO-) did not significantly differ from the general population in any measure of ability or performance. Areas of increased T2 signal on MRI represent dysplastic glial proliferation and aberrant myelination in the developing brain and are associated with deficits in higher cognitive function. The presence of these abnormal signals on MRI divides the NF 1 population into two distinct groups anatomically and developmentally (UBO+ and UBO-). These two groups should be considered separately in the assessment and management of learning disability in children with NF 1.

Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study

BACKGROUND Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the disorder thought most to justify neonatal screening by tandem-mass spectrometry because, without screening, there seems to be substantial morbidity and mortality. Our aim was to assess the overall effectiveness of neonatal screening for MCAD deficiency in Australia. METHODS We identified MCAD-deficient patients from a total population of 2,495,000 Australian neonates (810,000 screened) born between April 1, 1994, and March 31, 2004. Those from a cohort of 1,995,000 (460,000 screened) were followed up for at least 4 years, and we recorded number of deaths and severe episodes, medical and neuropsychological outcome, and hospital admissions within the screened and unscreened groups. FINDINGS In cohorts aged at least 4 years there were 35 MCAD-deficient patients in those not screened (2.28 per 100,000 total population) and 24 in the screened population (5.2 per 100,000). We estimated that patients with this disorder in the unscreened cohort remained undiagnosed. Before 4 years of age, three screened patients had an episode of severe decompensation (including one neonatal death) versus 23 unscreened patients (including five deaths). At the most conservative estimate, relative risk of an adverse event was 0.44 (95% CI 0.13-1.45). In the larger cohort the relative risk (screened vs unscreened) of an adverse event by age 2 years was 0.26 (95% CI 0.07-0.97), also a conservative estimate. 38 of 52 living patients had neuropsychological testing, with no suggestions of significant differences in general cognitive outcome between the groups. INTERPRETATION Screening is effective in patients with MCAD deficiency since early diagnosis reduces deaths and severe adverse events in children up to the age of 4 years.

Cognitive function and academic performance in children with neurofibromatosis type 1

The authors evaluated 51 consecutive children with NF1 (aged eight to 16 years) to determine the frequency of intelectual impairment and learning disability due to NF1 alone, the profile of learning disabilities and the effect of clinical variables. 40 children completed the full assessment protocol. There was no support for a profile of predominantly visuoperceptual deficits in the NH population. There was no discrepancy between verbal and performance 1Q, and the deficits in function were wide ranging. Clinical variables such as age, sex. socio‐economic status, disease severity, macrocephaly and family history of NF1 were not associated with cognitive deficits. These results emphasise the need for developmental evaluation to be included in the routine assessment of children with NFT.

Expanded newborn screening: Outcome in screened and unscreened patients at age 6 years

OBJECTIVE: Tandem mass spectrometry is widely applied to routine newborn screening but there are no long-term studies of outcome. We studied the clinical outcome at six years of age in Australia. METHODS: In a cohort study, we analyzed the outcome at 6 years for patients detected by screening or by clinical diagnosis among >2 million infants born from 1994 to 1998 (1 017 800, all unscreened) and 1998 to 2002 (461 500 screened, 533 400 unscreened) recording intellectual and physical condition, school placement, other medical problems, growth, treatment, diet, and hospital admissions. Results were analyzed separately for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and other disorders, and grouped patients as those who presented clinically or died in the first 5 days of life; patients presented later or diagnosed by screening, and those with substantially benign disorders. RESULTS: Inborn errors, excluding phenylketonuria, were diagnosed in 116 of 1 551 200 unscreened infants (7.5/100 000 births) and 70 of 461 500 screened infants (15.2/100 000 births). Excluding MCADD, 21 unscreened patients with metabolic disorders diagnosed after 5 days of life died or had a significant intellectual or physical handicap (1.35/100 000 population) compared with 2 of the screened cohort (0.43/100 000; odds ratio: 3.1 [95% CI: 0.73–13.32]). Considering the likely morbidity or mortality among the expected number of never-diagnosed unscreened patients, there would be a significant difference. Growth distribution was normal in all cohorts. CONCLUSION: Screening by tandem mass spectrometry provides a better outcome for patients at 6 years of age, with fewer deaths and fewer clinically significant disabilities.

Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1

Background: Cognitive impairment is the most common complication of neurofibromatosis type 1 (NF1) in childhood. Current research suggests a strong relationship between cognitive deficits and brain T2-hyperintensities. The majority of these lesions disappear as the child ages. Cross-sectional data suggest that there also are improvements in intellect. Objective: To determine the natural history of cognitive functioning and MRI T2-hyperintensities from childhood into adulthood, and whether changes in MRI T2-hyperintensities over time are predictive of changes in cognitive functioning. Methods: The authors conducted a prospective longitudinal study of a cohort of 32 patients with NF1 and 11 unaffected sibling controls. All patients underwent neuropsychological assessments and 27 children underwent MRI examinations. The patients were then reassessed after an 8-year period. Results and Conclusions: There was no improvement in cognitive ability as the children with NF1 developed into adulthood compared with controls. Despite significant decreases in the number, size, and intensity of the T2-hyperintensities over the 8-year period, these changes were not associated with changes in cognitive ability. T2-hyperintensities in the cortex or subcortical or deep white matter are more frequent with age and these lesions are likely to have a different pathology than basal ganglia lesions. The best predictor of cognitive dysfunction in adulthood was the presence of T2-hyperintensities in childhood, rather than current lesion status. There is a limited time window (<18 years) in which the presence of T2-hyperintensities can be used as biologic markers of cognitive dysfunction.

NEUROPSYCHOLOGICAL FUNCTION AND MRI ABNORMALITIES IN NEUROFIBROMATOSIS TYPE 1

This study investigated the relationship between MRI abnormalities and cognitive function in neurofibromatosis type 1. 40 children aged eight to 16 years underwent comprehensive neuropsychological, medical and ncuroradiological assessments. MRI scans revealed a characteristic pattern of T2‐weighted signals (‘UBOs’) located primarily in the basal ganglia, brainstem and cerebellum in 25 of the children. Reductions in global 1Q, attention, and visuopatial and executive functions were shown to occur in association with the presence of UBOs. These findings establish a link between changes in neuropsychological functions and MRI abnormalities in NF‐1, and further support neuropathological findings which sugest that UBOs may be a manifestation of delayed or disordered myelination.

Economic Evaluation of Tandem Mass Spectrometry Newborn Screening in Australia

OBJECTIVE. The goal was to investigate the cost-effectiveness of tandem mass spectrometry screening for the detection of inborn metabolic errors in an Australian setting. METHODS. Cost-effectiveness analysis from the health service perspective was undertaken on the basis of registry data for affected individuals. The intervention group was contrasted with both a contemporaneous group in nonscreening states and a historical cohort. The registry covers all individuals identified in Australia between 1994 and 2002. Main outcome measures were the total net cost of screening, the cost of treatment, life-years saved, and deaths averted. RESULTS. The total net cost of testing was estimated to be A

Developmental prosopagnosia : A case analysis and treatment study

218 000 per 100 000 infants. Medical costs incurred by the intervention group exceeded those for the control group by A

Visual agnosia and prosopagnosia in childhood: a prospective case study.

131 000 per 100 000 infants. The number of life-years saved per 100 000 infants screened was 32.378 life-years per 100 000 infants through an expected mortality rate reduction of 0.738 deaths per 100 000 infants. The cost per death averted was estimated to be A

Idiopathic macrocephaly in the infant: long-term neurological and neuropsychological outcome

472 913 and the cost per life-year saved was estimated to be A