Statewide Systematic Evaluation of Sudden, Unexpected Infant Death Classification: Results from a National Pilot Project

The Centers for Disease Control and Prevention funded seven states, including Kentucky, to clarify statewide death certification practices in sudden, unexpected infant death and compare state performances with national expectations. Accurate assignment of the cause and manner of death in cases of sudden, unexpected infant death is critical for accurate vital statistics data to direct limited resources to appropriate targets, and to implement optimal and safe risk reduction strategies. The primary objectives are to (1) Compare SUID death certifications recommended by the KY medical examiners with the stated cause of death text field on the hard copy death electronic death certificates and (2) Compare KY and national SUID rates. Causes of death for SUID cases recommended by the medical examiners and those appearing on the hard copy and electronic death certificates in KY were collected retrospectively for 2004 and 2005. Medical examiner recommendations were based upon a classification scheme devised by them in 2003. Coroners hard copy death certificates and the cause of death rates in KY were compared to those occurring nationally. Eleven percent of infants dying suddenly and unexpectedly did not undergo autopsy during the study interval. The KY 2003 classification scheme for SIDS is at variance with the NICHD and San Diego SIDS definitions. Significant differences in causes of death recommended by medical examiners and those appearing on the hard copy and electronic death certificates were identified. SIDS rates increased in KY in contrast to decreasing rates nationally. Nationwide adoption of a widely used SIDS definition, such as that proposed in San Diego in 2004 as well as legislation by states to ensure autopsy in all cases of sudden unexpected infant death are recommended. Medical examiners’ recommendations for cause of death should appear on death certificates. Multidisciplinary pediatric death review teams prospectively evaluating cases before death certification is recommended. Research into other jurisdictions death certification process is encouraged

Noncardiac genetic predisposition in sudden infant death syndrome.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible

Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis

Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism

Paediatricians’ Practice About SUDDEN Infant Death Syndrome in Catalonia, Spain

Background SIDS is the major cause of death among healthy born infants in developed countries. Its causes are still unclear, but its risk can be reduced by implementing some simple active interventions. In Spain, limited attention was given to SIDS by the national healthcare system, and actual data on healthcare professionals’ practice on this topic was not available. This study explored for the first time paediatricians’ knowledge and practice about SIDS. Methods A cross-sectional survey was carried out between November 2012 and April 2013 in Catalonia, and reached 1202 paediatricians. The response rate was 46%. Results 94% of respondents perceived themselves as qualified for giving advice and recommendations about SIDS to parents, but only 58% recognized the supine position as the safest position and recommended the supine position exclusively to parents. Seniority and ‘having received a specific training about SIDS’ were detrimental to paediatricians’ knowledge. Discussion Efforts should be made in order to improve paediatricians’ knowledge and practice about SIDS. Specific refresher trainings are highly recommended, and should especially target paediatricians with higher seniority. These trainings could be provided as optional modules, as we could see that the paediatricians who would most benefit from them are already aware of the need to refresh their knowledge

A perspective on SIDS pathogenesis. The hypotheses: plausibility and evidence

Several theories of the underlying mechanisms of Sudden Infant Death Syndrome (SIDS) have been proposed. These theories have born relatively narrow beach-head research programs attracting generous research funding sustained for many years at expense to the public purse. This perspective endeavors to critically examine the evidence and bases of these theories and determine their plausibility; and questions whether or not a safe and reasoned hypothesis lies at their foundation. The Opinion sets specific criteria by asking the following questions: 1. Does the hypothesis take into account the key pathological findings in SIDS? 2. Is the hypothesis congruent with the key epidemiological risk factors? 3. Does it link 1 and 2? Falling short of any one of these answers, by inference, would imply insufficient grounds for a sustainable hypothesis. Some of the hypotheses overlap, for instance, notional respiratory failure may encompass apnea, prone sleep position, and asphyxia which may be seen to be linked to co-sleeping. For the purposes of this paper, each element will be assessed on the above criteria

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD