Richard M. Huggins

Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X

The distributions of scores for autistic behaviours obtained from the Autism Diagnostic Observation Scale-Generic (ADOS-G) were investigated in 147 males and females affected with the full mutation in the fragile X mental retardation 1 (FMR1) gene, in 59 individuals with the premutation, and in 42 non-fragile X relatives, aged 4-70 years. The scores representing communication and social interaction were continuously distributed across the two fragile X groups, and they were significantly elevated compared with the non-fragile X controls. Strong relationships were found between both these scores and FMRP deficits, but they became insignificant for social interaction, and the sum of social interaction and communication scores, when FSIQ was included as another predictor of autism scores. Other significant predictors of these scores in both sexes were those executive skills which related to verbal fluency, and to the regulation and control of motor behaviour. Overall, our data have shown that cognitive impairment, especially of verbal skills, best explains the comorbidity of autism and fragile X. This implies some more fundamental perturbations of specific neural connections which are essential for both specific behaviours and cognition. We also emphasize that FXS offers a unique molecular model for autism since FMRP regulates the translation of many other genes involved in synaptic formation and plasticity which should be natural targets for further exploration.

Effect of the fragile X status categories and the fragile X mental retardation protein levels on executive functioning in males and females with fragile X.

The effects of a fragile X disorder on executive function impairment were assessed in 144 extended families, which included individuals with fragile X premutation and full mutation and their relatives without fragile X. A modification of the maximum-likelihood estimators for pedigree data, as well as ordinal logistic regression, were used in data analysis. The most outstanding deficit, occurring especially in males, involved impaired capacity to use an intention to regulate purposeful behavior. This deficit occurred independently of general cognitive impairment but was related to depletion of fragile X mental retardation 1 gene protein product. The other executive function deficits were accounted for by the general cognitive impairment. Possible mechanisms of the effect of fragile X premutation on impairments of executive functioning are considered.

Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients

Objectives: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. Methods: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. Results: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). Conclusions: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype.

Growth in stature and head circumference in high-functioning autism and Asperger disorder during the first 3 years of life

Little effort has been made to characterize the developmental anatomic phenotype of autism; although there is evidence of an increased head circumference and brain size, few other physical characteristics have been studied. The head circumference, body length/height, and weight measurements of infants, who were later diagnosed with high-functioning autism (HFA, n = 16) and Asperger disorder (AsD, n = 12), were extracted from health records over the first 3 years of life and compared to the measurements of a matched normal control group (n = 19). Using linear mixed-effects models, no differences were found in the average growth rate for head circumference, stature, or weight between the children with HFA and AsD. However, a significantly higher growth rate in body length/height and weight was found for the combined group of children with HFA and AsD compared to the normal control group. A trend toward higher growth rate in head circumference was also found among the former group. The results indicate that growth dysregulation in autism is not specific to the brain but also involves growth in stature.

Melatonin profiles and sleep characteristics in boys with fragile X syndrome: a preliminary study

Sleep patterns and endogenous melatonin profiles in 13 fragile X boys between the age of 4.7 and 11.0 years were compared to those of 8 age-matched, normal control boys. Parents recorded sleep patterns on a Sleep Diary Chart for 14 consecutive days. Twelve saliva samples were obtained from 8 fragile X participants and all of the controls over 48 hours for the assessment of salivary melatonin profiles. The results showed greater variability in total sleep time and difficulty in sleep maintenance in fragile X boys compared with the control participants. Nocturnal melatonin production, expressed as both peak level and area under the concentration-time curve between 20:00 h and 08:00 h, were found to be significantly larger in fragile X boys than in controls. Additionally, the mean of the minimum daytime melatonin levels recorded was significantly higher for the fragile X group. Elevated levels in some fragile X boys relative to the range seen in controls, occurring either during the day or at night, or in both segments of the secretory profile for some individuals, may be due in part to overactivity of the sympathetic nervous system. Alternative molecular mechanisms leading to changes in melatonin profiles in fragile X are also discussed.

Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats

Background: Grey zone or intermediate alleles are one of the three recognised classes of the X-linked fragile X mental retardation 1 (FMR1) gene showing intergenerational instability. These classes are defined according to the number of CGG repeats in the FMR1 5′-untranslated region. Although large CGG expansions (>200 repeats) cause a neurodevelopmental anomaly through silencing of the gene, resulting in a deficit of FMR1 specific protein, smaller expansions (approximately 55–200 repeats) are associated with an increased transcription and late-onset specific phenotypes. Those alleles with a CGG repeat number ranging between approximately 41 and 55 are relatively poorly defined with regard to both transcriptional and translational activity, and also potential phenotypic effects. Methods and results: Based on a sample of 33 males carrying FMR1 alleles within the grey zone range, defined here as 41–60 CGGs, we show an increased transcriptional activity relative to that seen in common alleles (5–40 CGGS). This is the first study to report a significant relationship between FMR1 mRNA levels and CGG repeat number within the grey zone range (p<0.001). From a piecewise linear regression model, the threshold for onset of the increase in mRNA levels as a function of CGG repeat size has been determined at approximately 39 repeats (standard error (SE) 3.24), and that for the reduction in the rate of this increase at approximately 54 repeats (SE 4.27). Conclusions: The ambiguities associated with the definition and transcription dynamics of the FMR1 gene within the grey zone range are dealt with. There may be specific phenotypes associated with the toxic “gain-of-function” effect of raised mRNA.

Effect of the deficits of fragile X mental retardation protein on cognitive status of fragile x males and females assessed by robust pedigree analysis.

ABSTRACT. The effect of the fragile X mental retardation 1 (FMR1) gene product (fragile X mental retardation protein [FMRP]) deficits on Full-Scale IQ (FSIQ) and FSIQ-adjusted Wechsler subtests and index scores in fragile X disorder were assessed using a robust modification of the maximum likelihood estimators for pedigree data. The results from 144 extended families have demonstrated a linear effect of progressively reduced levels of FMRP on the FSIQ and all subtest and summary scores in either gender. The effect of FMRP in decreasing FSIQ-adjusted subtest scores was highly significant for Digit Span, Symbol Search, Object Assembly, and Picture Arrangement, with a consistent trend in both genders. Heritability for FSIQ and unadjusted subtest scores estimated from the covariance model did not exceed 50% and varied widely from the highest for Verbal score to the lowest for Picture Completion score. Possible mechanisms by which FMRP deficit impacts on specific weaknesses in fragile X are considered on the basis of present data.

Secular trend in body height and weight of Australian children and adolescents.

Secular changes in growth and maturation have been well documented in various world populations, with secular increase especially noticeable in the developed countries. To assess the trend in both adult size and tempo of growth we compared the data on stature and body weight obtained in 1992-1993 from 1,804 Melbourne school students aged 5 to 17 with historical data collected from white Australians during the last 100 years. We illustrate the age-dependent trend in stature and body weight by means of regression surfaces. These were constructed by fitting local regression models to historical data and by simple plots showing the overall, and per decade, secular increase in both these measures at peripubertal and adult ages. Because of limited information on sample sizes and variability provided by the historical data, statistical comparisons have been performed only between the present 1992-1993 survey and two earlier independent surveys conducted in 1985 and 1970. The results have shown secular increase in adult stature over the last century, with the rate of increase varying between 0.4 and 2.1 cm/decade in males and 0.01 and 1.6 cm/decade in females. While secular increase in stature has significantly slowed down during the last two decades, the increase in body weight is still continuing at a high rate, and this increase is more pronounced in females. The period of strong secular increase, especially in the tempo of growth, coincided both with the shift toward earlier menarche and the improvement of socioeconomic conditions of the Australian population. The need for further studies to identify factors determining the continuing increase in body weight is emphasized, and caution in using the existing national growth standards for stature and weight is recommended.

Magnetic resonance imaging study in older fragile X premutation male carriers

Some carriers of a “premutation” allele of the FMR1 gene develop late‐onset tremor/ataxia. We conducted a magnetic resonance imaging volumetric study in an unselected sample of eight older male premutation carriers. Volumetric measures, including total brain volume, and the volumes of cerebrum, cerebellum, and cerebral cortex all were significantly reduced in premutation carriers compared with similar data from 21 age‐matched normal controls. Total brain and cerebral volumes were significantly related to the number of CGG repeats in the FMR1 gene. Moreover, increased hippocampal volume indicates this premutation may account for both neurodegenerative and neurodevelopmental changes. Ann Neurol 2005;58:326–330

Effect of fragile X status categories and FMRP deficits on cognitive profiles estimated by robust pedigree analysis

The effect of the fragile X pre‐mutation and full mutation categories, and FMRP deficits in these categories, on neurocognitive status, have been assessed in fragile X individuals from 144 extended families, which included fragile X individuals, as well as their non‐fragile X relatives. Neuropsychological status was assessed by the Wechsler summary and subtest test scores. A modification of the maximum likelihood estimators for pedigree data that is resistant to outliers was used to analyze the data. The results have demonstrated the effect of large expansions of CGG repeat in the FMR1 (fragile X mental retardation 1) gene (full mutation) in decreasing full scale IQ (FSIQ), as well as several FSIQ‐adjusted subtest scores in the performance domain. Moreover, the results have demonstrated significant cognitive deficits in male individuals with pre‐mutation. FMRP depletion correlates strongly with neurocognitive status in the full mutation subjects. Evidence for the effect of FMRP in smaller expansions (pre‐mutation) in reducing FSIQ, Performance and Verbal scores, as well as subtest scores in males, has also been obtained. The results are also suggestive of factors other than FMRP deficit which may determine some specific cognitive deficits in fragile X pre‐mutation carriers. Genetic variance estimated from the models accounts for less than half of the total variance in FSIQ, and it varies widely between individual Wechsler subtests.