CAUSES OF ACUTE COLLAPSE IN CHILDREN: NEW PERSPECTIVES Marta Cohen Paediatric Histopathologist
Causes of acute collapse Cardiac arrhythmias ¤ Long QT ¤ Short QT Infections Metabolic decompensation Airway obstructions Apnoea/hypoxia
Arrhythmias caused by long QT LQTS is a genetic disorder caused by mutations in genes that encode cardiac ion channels and characterized by QT interval prolongations on the ECG and by arrhythmias during: Sympathetic activation According to gene involved Rest Sleep
Type of mutations in Sodium channels : 4 mutations and 5 rare variants identified in 13 cases in cytoplasmic domains (78%) In potassium channels : in 11 SIDS cases , 9 different mutations or rare variants were identified; 7 of the 9 mutations were novel (78%)
Results 15 variants identified in 19 patients Some capable of causing lethal arrhythmia and those who may have needed the “fatal triangle”: Vulnerable stage of development, predisposition and triggering event . Children are exposed to conditions that increase cardiac electric instability: REM sleep with vagal and sympathetic activation, minor upper resp infection that can induce hypoxemia and trigger chemoreceptive reflexes Coexistence of these events could enhance the risk of lethal arrhythmias
On going multicenter study SCH, BWH, Royal London Peter Schwartz group in Italy Funding body: Lullaby Trust Already demonstrated in anonymous tissue from Norwegian SIDS that nearly 10% of cases diagnosed as SIDS carry functionally significant genetic variants in long QT syndrome (LQTS) genes.
Aim M&M Our first goal is to molecularly investigate 300 SIDS cases, enrolled in the UK, and next to offer a genetic and cardiological assessment to the families of positive cases. Through DHPLC (denaturing high- performance liquid chromatography) and sequence analysis we screened the main LQTS genes KCNQ1, KCNH2 and SCN5A. Genetic variants were verified in a panel of internal controls and in three publicly available exome databases
Results 7 missense variants were identified in 7 (15%) SIDS cases 4 genetic variants, absent in the reference exome databases, were identified respectively in KCNH2 (3 variants) and SCN5A genes: they can be considered as putative LQTS-susceptibility mutations 3 SIDS cases carried 3 already described genetic variants in SCN5A
Conclusion We confirm the contribution of LQTS in a relevant number of SIDS cases Through the study of the families we will establish if the identified mutations have arisen de novo or whether there is a clinical risk of sudden death in the families. This study will clarify the role of prospective LQTS genetic screening in SIDS victims, and its implications for national resources
Infections SPECIMEN SIDS SUDI COD SUDI CHRONIC HOSPITAL CONDITION Number Significant Number Significant Number Significan Numbe Signific. samples results samples results samples t r results results samples Total 151 41 % 81 71% 43 69% 46 29% BC 49 14% 26 27% 14 12.5% 14 7 % CSF 36 2.8% 18 11% 11 18% 13 0% Ear swab 16 69 * 9 44 %* 2 0% 3 0% “Other” 50 30% 28 61% 16 24% 16 31% * % positive samples from middle ear
Metabolic decompensation The investigation of Inherited Metabolic Disease in post mortem samples . Olpin S, Clark S, Croft J, Downing M, John C, Ghoni F, Smith E, Allen J, Cohen M, Bonham J, Manning N, Talbot R. Department of Clinical Chemistry & Histopathology, Sheffield Children’s Hospital Sheffield, S10 2TH UK . Table 1. Post Mortem diagnoses between 1989 & 2007 Respiratory chain disorder 16 Multiple acyl-CoA dehydrogenase defect (Severe) 11 Medium-chain acyl-CoA dehydrogenase deficiency 8 Carnitine palmitoyltransferase deficiency Type II 6 Very long-chain acyl-CoA dehydrogenase deficiency 4 Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency 4 Zellweger 3 Mitochondrial trifunctional protein deficiency 2 Carnitine-acylcarnitine translocase deficiency 2 Fumarate hydratase deficiency 2 Methylmalonic aciduria 2 IVA 2 Argininosuccinic aciduria 1 Carnitine palmitoyltransferase deficiency Type I 1 Glutaric aciduria type I 1 Glutathione synthetase deficiency 1 GSD IV 1 Primary carnitine deficiency 1 Pyruvate dehydrogenase deficiency 1 X-linked adrenal leucodystrophy 1
Airway obstruction (Rohde et al. Forensic Sci Med Pathol 2005) Infants are at particular risk as: Small airway Swallowing reflexes not well developed Dentition and mastication is immature Obvious causes: micrognathia, foreign body inhalation, macroglossia, tumours
However Choanal atresia : probe to exclude; 1/8000 births, may be unilateral (babies do not breath through mouth) Nasal stenosis : functional obstruction without definitive anatomical narrowing Posterior lingual masses : thyroglossal duct, cysts: accumulation of secretions may occur and result in airway obstruction and death (Byard) Laryngeal webs Laryngomalacia Vascular rings encircling trachea or oesophagus: “dying spells”
APNOEA/HYPOXIA Common to many yet unknown aetiological factors Suggestion of genetic predisposition May involve complex interplay between ¤ Autoresuscitation reflex ¤ Laryngeal chemoreflex ¤ GOR
Autoresuscitation Young infants are prone to episodes of hypoxaemia and/or hypoperfusion (Thach) Apnoeic spells include apnoea of prematurity, laryngeal chemoreflex apnoea, obstructive sleep apnoea and “ breathholding ” apneic episodes Spontaneous gasping respiration re- oxygenate the body: Autoresuscitation Presents as ALTE (near-miss SIDS) Thach B. THE AMERICAN JOURNAL OF MEDICINE (2000); Volume 108 (4A)
Autoresuscitation (AR) Mechanism that allows mammals to survive transient periods of hypoxia When deprived of oxygen will stop breathing, exhibiting bradycardia and gasping. Normal breathing resumes if air is restored during the gasping period (AR)
AR is a protective physiologic mechanism Apnea monitor recording in SIDS demonstrates that gasping occurs, suggesting a failure of AR Experiments with injection of saline in pharynx of mice in hypoxic coma: lack of swallowing and absent AR Proposal that gastric contents in the upper airway (GORD is common in infants) can impair AR.
Thach B. THE AMERICAN JOURNAL OF MEDICINE (2000); Volume 108 (4A)
AR failure is genetically determined in SWR/J mice (Thach et al. Heredity 2009) A strain of Swiss mice (SWR/J has a developmental window (19-22 days old) during which they fail to autoresucitate Before and after this window they can AR and recover Genome mapping linked 2 loci to the number of AR trial survival, including one sex-specific locus with male expression (consistent with the 50% male excess of SIDS) Demonstrates a genetic basis for AR failure
Laryngeal chemoreflex (LCR) Reflexive central apnoea, bradycardia, and cardiovascular collapse that occurs in young, mammals in response to exposure of the laryngeal mucosa to acidic and/or organic stimuli. Leads to a complex series of responses: apnoea , bradycardia, swallowing, startle, hypotension, and regional redistribution of blood flow. Age-related and confined to the young infant only (unknown when it disappears)
LCR experiments in animals LCR-induced apnoea is only life-threatening when the animal is anaesthetised and the stimulus is applied directly to the larynx (via a tracheostomy)or has stimulated the larynx via the pharynx This suggests that after pharyngeal fluid stimulation, LCR-induced apnoea could be fatal if the mechanisms that protect the airway from fluid entry, such as swallowing, arousal and expiratory reflexes, are depressed in the infant The findings from other studies indirectly support this hypothesis. Page M, Jeffery H; Early Human Development 59 (2000) 127 – 149
Genetic link to hypoxia in infants dying Suddenly and Unexpectedly Regions in the brain stem regulate upper- airway control, respiration, temperature, autonomic function, and sympathetic nervous system. the vulnerable infant’s response to environmental factors may actually reflect aberrant intrinsic responses Kinney & Thach NEJM 2009
Genetic link to hypoxia It is now known that sudden death can be due to defects in the defence system protective against hypoxia, hypercapnia, asphyxia, thermal stress and /or cardiovascular instability which is: 1. originated in utero 2. may express as an ALTE 3. Results in hypoxic ischaemic damage Kinney & Thach NEJM 2009
Death results from one or more failures in protective mechanisms against a life-threatening event in the vulnerable infant during a critical period. Complex genetic and environmental interactions influence the pathway • life- threatening event: asphyxia, brain hypoperfusion or both LCR: Apnoea • vulnerable infant: inability to recover from apnoea Not recovery • progressive asphyxia leads to loss of consciousness, areflexia Hypoxic coma • Extreme bradycardia and ineffectual gasping Impaired AR • Death Continuous Apnoea Kinney & Thach NEJM 2009
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