The diagnostic yield of genetic and metabolic investigations in syndromic and nonsyndromic patients with autism spectrum disorder, global developmental delay, or intellectual disability from a dedicated neurodevelopmental disorders genetics clinic.

First-tier genetic investigations for patients with neurodevelopmental disorders (NDDs) may include chromosomal microarray, Fragile X testing, and screening for inherited metabolic diseases, but most remain undiagnosed upon completion of testing. Here, we report the diagnostic yields of genetic testing for 537 patients with at least one of autism spectrum disorder, global developmental delay, and/or intellectual disability. Patients were assessed in a single neurodevelopmental genetics clinic, and each underwent a standardized history and physical examination. Each patient was characterized as syndromic or nonsyndromic based on clinical features. Our results demonstrate that multigene sequencing (with an NDD gene panel or exome) had a higher diagnostic yield (8%; 95% confidence interval [CI]: 5%, 13%) than chromosomal microarray and Fragile X testing combined (4%; 95% CI: 3%, 7%). Biochemical screening for inherited metabolic diseases had a diagnostic yield of zero. The diagnostic yield of genetic testing was significantly higher for syndromic patients than for nonsyndromic patients (odds ratio [OR] 3.09; 95% CI: 1.46, 6.83) and higher for female patients than for male (OR 3.21; 95% CI: 1.52, 6.82). These results add to the growing evidence supporting a comprehensive genetic evaluation that includes both copy number analysis and sequencing of known NDD genes for patients with NDDs.

Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis.

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/ß, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.

Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes.

Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated patients with the same missense variant. Two infants with the same homozygous variant presented with hypotonia, weakness and lactic acidosis, and one patient with compound heterozygous p.(Arg72Gln) and p.(Arg412His) variants presented as a young adult with gastrointestinal symptoms and fatigue. Skeletal muscle biopsy from patients 1 and 3 showed abnormal mitochondrial morphology, and functional analyses demonstrated decreased activity in respiratory chain complex II and variably in complexes I and III. We found decreased mitochondrial and cytosolic aconitase activities but only mildly affected lipoylation of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase enzymes. Our studies expand the phenotypic spectrum and provide further evidence for the pathogenicity and functional sequelae of NFS1-related disorders with disturbances in both mitochondrial and cytosolic iron-sulfur cluster containing enzymes.

Variable developmental delays and characteristic facial features-A novel 7p22.3p22.2 microdeletion syndrome?

Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.

Identification of a pathogenic FTO mutation by next-generation sequencing in a newborn with growth retardation and developmental delay.

BACKGROUND: A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations. METHODS: We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents. RESULTS: We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity. CONCLUSION: Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.

The Effect of the Secret Agent Society Group Program on Parent-Teacher Agreement Regarding Children's Social Emotional Functioning.

Differences in social-emotional processing and functioning characterize children with Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Anxiety Disorders. These can contribute to difficulties forming friendships and secondary challenges such as academic underachievement, depression, and substance use in adolescence. To be optimally successful, interventions typically require parents and teachers to have a shared understanding of a child's social-emotional needs and use consistent support strategies across home and school environments. However, research is yet to examine the effect that clinic-based programs have on parent-teacher agreement regarding children's social-emotional functioning. To the authors' knowledge, this is the first published study to explore this. A sample of eighty-nine youth (aged 8 to 12 years) with ASD, ADHD, and/or an Anxiety Disorder participated in the Secret Agent Society Program. The Social Skills Questionnaire and Emotion Regulation and Social Skills Questionnaire were administered to parents and teachers at pre-program, post-program, and six-month follow-up. Parent-teacher agreement was assessed at each time point. Pearson Product Moment correlations and intraclass correlations indicated that parent-teacher agreement on the measures of children's social-emotional functioning improved over time. These findings suggest that clinic-based programs can contribute to key stakeholders developing a shared understanding of children's social-emotional needs. The implications of these findings and directions for future research are discussed.

Methylmalonic aciduria as a biochemical marker for mitochondrial DNA depletion syndrome in patients with developmental delay and movement disorders: a case series.

Background: Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile. Methods: This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews. Results: All subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient (n = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject. Conclusion: MDDS associated with SUCLG1 and SUCLA2 genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.

Peptic ulcer bleeding outcomes adversely affected by end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease (ESRD) and peptic ulcer disease (PUD) bleeding may be at high risk of bleeding complications. OBJECTIVE: To investigate the outcomes of patients with ESRD and PUD bleeding. DESIGN: ESRD patients with PUD bleeding were evaluated retrospectively. SETTING: Two tertiary, university-affiliated hospitals. PATIENTS: A total of 150 PUD bleeding patients were evaluated in 3 groups; end-stage renal disease (ESRD) patients on dialysis (ESRD group) (n = 50) were age matched with patients with chronic kidney disease (CKD) not requiring dialysis (CKD group) (n = 50) and those with normal kidney function (normal group) (n = 50). MAIN OUTCOME MEASUREMENTS: Rebleeding, transfusions, length of hospitalization, mortality. RESULTS: Multivariate analysis showed significant predictors of rebleeding to be ESRD and high-risk stigmata. The ESRD group had an odds ratio (OR) of 3.8 (95% CI, 1.4-10.5; P = .008) for rebleeding compared with the normal group, and an OR of 3.8 (95% CI, 1.4-10.3; P = .01) compared with the CKD group. The mean number of (+/- SD) transfusions was higher in the ESRD group (6.3 +/- 5.7 units) than in the normal group (3.6 +/- 3.9 units; P = .01). The mean length of hospitalization was higher in the ESRD group than in the normal group (34.0 vs 16.6 days; P = .01). A greater level of comorbidity was the only significant predictor of mortality (OR 6.0; 95% CI, 2.9-12.3; P = .001). LIMITATION: Retrospective study. CONCLUSION: ESRD dialysis patients with PUD bleeding have greater rebleeding than patients not on dialysis. ESRD patients should be managed as a high-risk group.

Clinical acuity of repeat pediatric mental health presentations to the emergency department.

OBJECTIVE: We examined whether clinical acuity changed in children and youth with repeated emergency department (ED) visits for mental illness. A secondary, exploratory objective was to examine characteristics associated with clinical acuity. METHOD: We conducted a four-year historical cohort study reviewing data from 1,033 ED presentations by 474 patients (≤17 years) for mood disorders, neurotic/stress-related disorders, and psychosis-related illnesses. We used a multivariable generalized linear mixed model to examine the relationship between clinical acuity (defined by triage level at presentation) and length of time since initial ED visit. Interactions between diagnosis group and age group, sex, and visiting timing were also examined. Explanatory variables (patient demography, diagnosis, disposition, institutional classification and location) were entered into the model to explore their relationship to clinical acuity. RESULTS: Clinical acuity did not change between ED visits for children with mood disorders, neurotic/stress-related disorders, or psychosis-related illnesses. The median time to ED return was 7 days. Several characteristics were associated with a higher likelihood of increased clinical acuity at presentation: being male, presenting to the ED with a mood disorder, and attendance to an urban-based ED. CONCLUSIONS: Repeat ED visits for several pediatric mental illnesses were not a result of destabilized conditions. Further investigation of the relationship between patient characteristics, available community services, and patterned mental health care use is needed to clarify ED utilization patterns.

A Description of Emergency Care Received by Children and Youth with Mental Health Presentations for Alcohol and Other Drug use in two Alberta Emergency Departments.

OBJECTIVE: This paper describes patient and treatment characteristics of pediatric mental health Emergency Department (ED) visits associated with alcohol and other drug (AOD) use. METHOD: A medical record and administrative database review was conducted. Proportional allocation random stratified sampling identified a representative sample of pediatric (≤18 years) mental health presentations to two tertiary care EDs between April 2004 and March 2006. Descriptive statistics were used to summarize data from 161 patients with associated AOD use. RESULTS: More females (56.5%) and youth aged 15 to 18 years (70.8%) attended the ED for mental health complaints associated with AOD use. Alcohol (48.4%) and over-the-counter or prescription medications (25.5%) were the most commonly used substances. Twenty-four percent of patients had a documented psychiatric history. The most common psychiatric assessments provided were for suicidality (31.1%) and mood (18.0%). Brief counselling was provided in 31.7% of visits. Consultation with psychiatry occurred less than 20% of the time. Most patients were discharged from the ED (65.2%). Sixty-eight percent of patient records did not have documented discharge planning. CONCLUSIONS: When youth present to the ED for mental health concerns related to AOD use, mental health assessments and follow-up care are not occurring in all cases and reasons for this oversight need to be explored.

Alfentanil dosage when inserting the classic laryngeal mask airway.

BACKGROUND: The purpose of this study was to determine an optimum dose of alfentanil, coadministered with 2.5 mg/kg propofol, when inserting a classic laryngeal mask airway. METHODS: Seventy-five adult ethnic Chinese patients with an American Society of Anesthesiologists physiologic status classification I or II and requiring anesthesia for minor surgery with a laryngeal mask were recruited. They were randomly assigned to five dosage groups: placebo or 5, 10, 15, or 20 microg/kg. The study drug plus propofol were administered, and 90 s later, insertion conditions were assessed using a six-category score. The duration of apnea was recorded. A probit analysis was performed and used to estimate the ED50 and ED95 with 95% confidence intervals for each assessment. RESULTS: Twenty-five male and 50 female patients, aged 18-59 yr, were studied. The five groups were similar. Laryngeal mask insertion was successful in all but one alfentanil patient. Duration of apnea increased with increasing dosage of alfentanil to over 5 min (P < 0.001). Dose-responses could not be predicted for categories of resistance to mouth opening and to insertion. For the other four categories, swallowing, gagging, movement, and laryngospasm, ED50 and ED95 with confidence intervals for alfentanil could be determined. CONCLUSION: The optimum dose for alfentanil, when coadministered with 2.5 mg/kg propofol, was 10 microg/kg.