CAUSES OF ACUTE COLLAPSE IN CHILDREN: NEW PERSPECTIVES Marta Cohen - - PowerPoint PPT Presentation

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  Rest  Sleep

According to gene involved

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

• f 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

• ffer 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 HOSPITAL CHRONIC CONDITION Number samples Significant results Number samples Significant results Number samples Significan t results Numbe r samples Signific. results

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

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

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.

Metabolic decompensation

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-

• xygenate 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

• f 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

• nly (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

LCR: Apnoea

• life- threatening event: asphyxia, brain hypoperfusion or both

Not recovery

• vulnerable infant: inability to recover from apnoea

Hypoxic coma

• progressive asphyxia leads to loss of

consciousness, areflexia

Impaired AR

• Extreme bradycardia and ineffectual gasping

Continuous Apnoea

• Death

Kinney & Thach NEJM 2009

The future

Research need to be done to understand :

 Why some young infants have apnoeic

episodes

 Why and when is the vulnerable window  Genes involved

Genome-wide association study

• f SIDS

 What is already known:

• Monogenic causes of SIDS of Mendelian

inheritance: 5-15% LQT; 2-5% MCAD

• Others: congenital central hypoventilation and

Brugada syndromes

• Studies focusing in the candidate gene

approach can only identify 15% SIDS cases.

• GWAS study compared 295 SIDS vs 823

control cases (GeSID/Sheffield)

• Identified a genome-wide significant

association between a SNP on Chr. 15 and

• SIDS. OR=8.9 (95%CI (6.3-13.1, p=4.0x10-28)
• The Chr.15 signal includes more than 20

genome-wide significant markers, has at least three statistically independent peaks and is located within the PWS/AS region known to be parentally imprinted

Manhattan plot of the pilot study GWAS results featuring 4 Mio SNPs after QC and imputation using a SNP haplotype backbone derived from the 1000 Genomes project and demonstrating a genome-wide significant association signal on Chr. 15

 Further steps

• To perform Whole exome sequencing (WES)
• r whole genome sequencing (WGS)