Yield of brain MRI in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition. The American Academy of Paediatrics and American Academy of Neurology do not recommend routine brain magnetic resonance imaging (MRI) in the assessment of ASD. The need for a brain MRI should be decided on atypical features in the clinical history and examination. However, many physicians continue to use brain MRI routinely in the assessment process. We performed a retrospective review of indications for requesting brain MRI in our institution over a 5-year period. The aim was to identify the yield of MRI in children with ASD and calculate the prevalence of significant neuroimaging abnormalities in children with ASD and identify clinical indications for neuroimaging. One hundred eighty-one participants were analysed. An abnormal brain MRI was identified in 7.2% (13/181). Abnormal brain MRI was more likely with an abnormal neurological examination (OR 33.1, p = 0.001) or genetic/metabolic abnormality (OR 20, p = 0.02). In contrast, abnormal MRI was not shown to be more likely in children with a variety of other indications such as behavioural issues and developmental delay.      Conclusion: Thus, our findings support that MRI should not be a routine investigation in ASD, without additional findings. The decision to arrange brain MRI should be made on a case-by-case basis following careful evaluation of potential risks and benefits. The impact of any findings on the management course of the child should be considered prior to arranging imaging. What is Known: • Incidental brain MRI findings are common in children with and without ASD. • Many children with ASD undergo brain MRI in the absence of neurological comorbidities. What is New: • Brain MRI abnormalities in ASD are more likely with an abnormal neurological examination and genetic or metabolic conditions. • Prevalence of significant brain MRI abnormalities in ASD alone is low.

Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes.

A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1, and a p (Pro222Leu) variant in PRKRA, respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in ∼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis.

Dystonia in children with acquired brain injury.

AIM: To quantify the proportion of children who develop dystonia after acquired brain injury (ABI) admitted to a tertiary paediatric intensive care unit (PICU) and analyse the trajectory of dystonia over a 6 month period. METHODS: Children's Health Ireland at Temple Street PICU electronic database was searched for key terms related to ABI from January 1, 2016 to March 14, 2021. Individuals meeting inclusion criteria were analysed, and clinical data pertinent to ABI, dystonia, treatment and outcomes were reviewed. RESULTS: Six-hundred and forty-three PICU episodes (580 patients) met search criteria for ABI, with 379 included in the final analysis. Twelve patients developed dystonia following ABI, giving an incidence of 3.2%. The incidence was higher in the hypoxia/anoxia and TBI cohort at 8.3% and 6.2%, respectively. All patients developed dystonia within the first month following ABI (50% by a week). Patients who developed dystonia compared to non-dystonia cohort had a median lower GCS on admission (4.5 versus 7.0, p value 0.032), longer median length of PICU stay (14.0 versus 3.0 days, p value < 0.001) and were older (median age 9.08 versus 4.68 years, p value 0.06). Dystonia persisted in the majority at 6 months (10/11), requiring on-going medical therapies. CONCLUSION: In our retrospective study, the estimated incidence of dystonia following ABI admitted to the PICU was 3.2%, highest in the hypoxia/anoxia (8.3%) and TBI (6.2%) cohorts. Dystonia emerged early and persisted at 6 months in the majority. This is the first review of dystonia, clinical trajectory and outcomes conducted post-PICU admission for ABI. Future prospective studies are required to determine the true prevalence and burden of disease in the PICU setting.

Clinical and genetic spectrum of SCN2A-associated episodic ataxia.

BACKGROUND: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. CONCLUSIONS: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.

Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B.

In 2016, two research groups independently identified microdeletions and pathogenic variants in the lysine-specific histone methyltransferase 2B gene, KMT2B in patients with early-onset progressive dystonia. KMT2B-dystonia (DYT28) is emerging as an important and frequent cause of childhood-onset progressive generalised dystonia and is estimated to potentially account for up to 10% of early-onset generalised dystonia. Herein, we review variants in KMT2B associated with dystonia, as well as the clinical phenotype, treatment and underlying disease mechanisms. Furthermore, in context of this newly identified condition, we summarise our approach to the genetic investigation of paediatric dystonia.

NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease-causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE.

Endogenous growth hormone secretion and clearance rates in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status, and body mass.

Mean plasma GH concentrations increase in normal boys during mid- to late-puberty. To investigate the nature of the pituitary secretory events and/or altered metabolic clearance responsible for these serum GH concentration changes, we performed multiple-parameter deconvolution analysis of 46 24-h serum GH concentration-time series obtained from normal boys at various stages of puberty and young adulthood. The subjects ranged in chronological age from 7-27 yr. The height and weight of each subject were between the 5th and 95th percentile for age. The calculated daily mass of GH secreted was greatest (P less than 0.001) in late pubertal boys (mean +/- SE, 1810 +/- 250 micrograms/24 h) and was triple the value in prepubertal boys (610 +/- 65 micrograms/24 h). When the values were normalized and expressed as mass of GH secreted per unit (m2) body surface area or per L distribution volume, GH secretion in late pubertal boys was still significantly greater than that in any other group (P less than 0.05). These values for late pubertal boys were nearly double the corresponding values for prepubertal boys (1160 +/- 160 vs. 600 +/- 58 micrograms GH/m2.24 h and 440 +/- 63 vs. 270 +/- 25 micrograms GH/L vol.24 h, respectively). When the effect of clearance mechanics on serum GH concentrations was removed mathematically, the primary change in predicted GH secretory burst parameters during pubertal development was an increase in GH mass released per burst resulting from an increase in the maximal rate of GH secretion attained within the bursts. These changes in the amplitude of GH release events were specific, in that they were largely independent of any accompanying alterations in duration or frequency of the GH secretory bursts or in serum GH half-life. Correlation analysis revealed that the 24-h GH secretion rate varied inversely with the subjects' body mass index SD score (r = -0.65; P less than 0.01), suggesting that differences in body mass, even within the normal range, contribute to the wide variability in daily GH secretion rates among normally growing children. The plasma insulin-like growth factor-I concentrations of all subjects correlated positively with the calculated 24-h GH secretion rate (r = 0.51; P less than 0.001). In summary, the primary neuroendocrine alteration responsible for the augmented serum GH concentrations characterizing mid- to late-puberty in boys is an increased mass of GH released per pituitary secretory episode resulting from an increased maximal rate of GH secretion within each burst.(ABSTRACT TRUNCATED AT 400 WORDS)

Low to moderate intensity endurance training in healthy older adults: physiological responses after four months.

OBJECTIVE: To determine the physiological adaptations in previously sedentary healthy older men and women (mean age = 68) to a 16-week low-to-moderate-intensity exercise program. DESIGN: Randomized, controlled trial. SETTING: An exercise facility and testing laboratory in a gerontological research institute. PARTICIPANTS: Two-hundred forty-seven community-dwelling older persons free of significant cardiovascular, pulmonary, or uncontrolled metabolic disease, anemia, electrolyte abnormality, resting BP of 165/90 or greater, or chronic disease affecting the ability to exercise on a bicycle. INTERVENTION: Subjects were randomly assigned to either an exercise (n = 166) or attention control group (n = 81). Exercisers trained thrice weekly for 40 minutes on a cycle ergometer (5-minute warm up, 30 minutes at training heart rate (THR), 5-minute cool down). THR was set at 70% of peak heart rate attained on a maximal exercise test (mean = 115 +/- 15). Control subjects attended weekly group talks. Testing took place before and after the program. RESULTS: Peak attained oxygen uptake (VO2max) increased 8.5% in exercisers and decreased slightly in controls (p less than .001) and oxygen uptake at ventilatory threshold (VeT VO2) increased by 3.5% in exercisers and decreased by 3% in controls (p less than .001). This pattern of a greater increase in VO2max than VeT VO2 is different from that seen in young and middle-aged subjects. CONCLUSION: This study demonstrated that a large scale training program is feasible for healthy older people, that physiologic improvements can be measured after 16 weeks of low-to-moderate-intensity training, and that mechanisms of adaptation to exercise may be different in elderly subjects from those in younger ones.

Effects of exercise training in the elderly on the occurrence and time to onset of cardiovascular diagnoses.

To examine the long-term effects of aerobic exercise on the occurrence and time to onset of cardiovascular diagnoses, 184 initially healthy older subjects were randomized into either a long-term exercise group (Group A, n = 80), a short-term exercise group (Group B, n = 42), or a contract control group (Group C, n = 62). After completion of two years in the study, data on new cardiovascular diagnoses and time to onset of these diagnoses in each of the three groups were compared. The occurrence rates for new onset diagnoses were as follows: Group A, 2.5%; Group B, 2%; and Group C, 13%; the average time to onset was greatest for the long-term exercisers and shortest for the contact control group (P less than or equal to .02). The results suggest that a regular program of exercise may have cardiovascular benefits for those over 60 years of age.

Benefits of exercise in old age.

Although exercise capacity declines with age, the decline appears to be slight when measured in healthy, physically active subjects. There is growing evidence that exercise has a positive influence on increasing healthy function and decreasing the impact of diseases common in the elderly. While the dose-response relationship between physical activity and health benefits continues to be studied, there is some evidence that even low- and moderate-intensity exercise programs in older people result in tangible improvements in many physical and psychologic parameters.

Ventilatory threshold: measurement and variation with age.

The purpose of this study is to present measurement of ventilatory threshold (VeT) and maximal oxygen uptake (VO2max) in a large group of predominantly older subjects using a bicycle ergometer and an automated measuring system. One hundred and twenty-seven healthy elderly subjects (mean age: 68) and 44 young and middle-aged subjects (mean age: 39) underwent a maximal exercise test with breath-by-breath measurement of ventilation and gas exchange variables. Ventilatory threshold was determined by visual inspection of the breakpoints in the VE/VO2 and PETO2 data curves. Additional measures were made in a subset of subjects to determine the reproducibility and interobserver variability of VeT and the relationship between VeT and the venous lactate threshold (LaT). Day-to-day reproducibility of VeT was good with a mean difference in VO2 at VeT on two occasions of 40.23 +/- 125 ml/min. Interobserver variability was low (intraclass correlation coefficient of r = 0.941) and VeT was found to correlate to LaT (r = 0.79, P less than 0.05) with LaT occurring a mean 2.3 min after VeT. VeT declined significantly with age in both males and females but less rapidly than VO2max. Both VO2max and VeT were found to vary with age, sex, height, and weight in a stepwise multiple-linear regression analysis. Age-associated changes in skeletal muscle composition may be in part responsible for the less precipitous decline in VeT with age compared with VO2max.

Exercise capacity in the elderly.

One of the primary manifestations of ageing is a reduced ability to respond to physiologic challenges. With aging, the ability to perform exercise and physical work declines and is reflected in the reduction in maximal oxygen consumption. Although this decline is influenced to some degree by the state of health and age, it seems that maintenance of regular physical activity significantly counteracts the loss of aerobic capacity. In healthy old age, the cardiovascular system is able to compensate for certain age-associated declines in cardiac function. A program of endurance training, even when begun in old age, can restore more youthful levels of physical fitness and results in tangible improvements in certain resting, submaximal and maximal indicators of exercise capacity. With comprehensive preexercise clinical screening, physical training can be conducted safely with minimal musculoskeletal problems in the aged. The long-term effects of exercise on morbidity, mortality and psychologic function in old age are unknown.

A protocol for Papanicolaou staining of cytologic specimens following flow analysis.

A protocol has been developed for restaining cytologic specimens that have been analyzed on a multidimensional slit-scan flow system. The technique involves Papanicolaou staining of cells on a membrane filter that has been previously stained with acridine orange and fixed with glutaraldehyde buffer. The specimen and staining solutions were sequentially added to a 5-micrometers pore size, 47-mm diameter Gelman "Metricel" filter while it remained in a glass filtration apparatus. The practice of retaining the filter in the filtration apparatus throughout the staining procedure minimizes cell loss and eliminates specimen cross contamination when compared with conventional filter dip staining. The availability of this postflow specimen Papanicolaou staining protocol permits accurate determination of the performance characteristics of a multidimensional slit-scan flow system and should be useful whenever staining of a limited number of cells with minimal cell loss is desired.

Multidimensional slit-scan prescreening system: preliminary results of a single blind clinical study.

A multidimensional slit-scan flow system was developed to serve as an automated prescreening instrument for gynecological cytology. A 2-year single blind clinical study was carried out to evaluate system performance. Cellular material was collected by scraping the uterine cervix and stained in suspension with acridine orange. Seven hundred and forty specimens (701 patients) including 156 abnormal specimens representing a broad spectrum of abnormality were analyzed. Approximately 50,000 cells were analyzed for each specimen. The system false-positive rate was 17.6% while the false-negative rate was 2.8%. All misclassified abnormals were specimens with cellular changes consistent with a slight dysplasia of nonkeratinizing type. The instrument in its present configuration appeared sensitive to the entire spectrum of abnormality existing in the female genital tract and it classified as abnormal any specimen containing on the order of 0.1% (or greater) abnormal cells.