Exploring the role of neuromuscular excitability in sudden infant death
Lead Research Organisation:
St George's, University of London
Department Name: Joint Research & Enterprise Office
Abstract
Sudden infant death syndrome (SIDS) is the unexpected death of a seemingly healthy infant that remains unexplained despite a thorough investigation of the scene and circumstances of death, a comprehensive post-mortem examination, and a multi-professional review of the available information. It is the leading cause of post-neonatal infant death in high income countries. Five children in the UK die each week from SIDS. Current evidence as to the cause of death proposes convergence of "a triple risk": a vulnerable infant, a critical developmental period and an external stressor e.g. fever.
Electrical signals control a muscle's excitability i.e. it's ability to contract and relax. Multiple proteins are responsible for generating and controlling these signals. Mutations in these genes can cause clinical diseases e.g. congenital myasthenia. All of these diseases tend to produce episodic muscle symptoms but in between individuals appear healthy. As they affect a muscle's electrical circuit rather than structure they also leave no post-mortem hallmark. These diseases may impair breathing and be fatal in a manner that is indistinguishable from SIDS. The SCN4A gene codes for one of the most essential proteins for muscle excitability, an ion channel called Nav1.4. Clinical disorders due to mutations in the SCN4A gene cause breathing muscle impairment including life threatening apnoeas (cessation of breathing) in infants. Based on observations I have made in infants I collaborated with my research partner Prof Behr and obtained new genetic and functional evidence that qualitatively similar SCN4A gene variants occur in some cases of (SIDS). I now hypothesise that ion channels like Nav1.4, and other proteins critical for skeletal muscle excitability may collectively account for a larger proportion of SIDS cases (contributing to the vulnerable infant risk) and that normal muscle development may change the clinical severity of these variants in early life. A severity and risk that may get less with age i.e. a critical developmental period.
This proposal aims to:
1. Determine the frequency of rare gene variants encoding proteins that influence skeletal muscle excitability in c.700 SIDS cases and UK biobank controls
2. Determine the frequency of SIDS amongst families with neuromuscular excitability diseases caused by variants in these same genes
3. Characterise the normal developmental changes of muscle fibre types in human skeletal muscle
4. Use a computer model to determine the physiological consequences of combined genetic, developmental and exogenous variables on muscle excitability - the "triple risk"
I will use whole exome sequencing data from c.700 DNA samples of infants who have died from SIDS and screen for very rare or new variants in a candidate gene list (genes critical for muscle excitability) that are predicted to affect protein function. The frequency that these gene variants are found in the SIDS cases will be compared with the UK biobank control sequencing data to see if they are more common in SIDS cases. I will also use clinical data from families with mutations in these genes causing clinical disease to ascertain the incidence of sudden infant deaths and whether this is more common than among the general population. Muscles are made up of subtypes of fast and slow fibres. I think the more fast fibres a muscle has the more severe the effect of the gene variants will be and that infants' muscle will have more fast fibres than older children. A fully automated protocol applying different coloured antibodies to the different fibre types in a single skeletal muscle section will be used on human control biopsies from age 0 to 16years to determine the proportion of each fibre type at different ages. A computer model of a muscle fibre will be used to ascertain the individual and combined effects of developmental variables on normal and mutant (with a gene variant) muscle fibre function and performance.
Electrical signals control a muscle's excitability i.e. it's ability to contract and relax. Multiple proteins are responsible for generating and controlling these signals. Mutations in these genes can cause clinical diseases e.g. congenital myasthenia. All of these diseases tend to produce episodic muscle symptoms but in between individuals appear healthy. As they affect a muscle's electrical circuit rather than structure they also leave no post-mortem hallmark. These diseases may impair breathing and be fatal in a manner that is indistinguishable from SIDS. The SCN4A gene codes for one of the most essential proteins for muscle excitability, an ion channel called Nav1.4. Clinical disorders due to mutations in the SCN4A gene cause breathing muscle impairment including life threatening apnoeas (cessation of breathing) in infants. Based on observations I have made in infants I collaborated with my research partner Prof Behr and obtained new genetic and functional evidence that qualitatively similar SCN4A gene variants occur in some cases of (SIDS). I now hypothesise that ion channels like Nav1.4, and other proteins critical for skeletal muscle excitability may collectively account for a larger proportion of SIDS cases (contributing to the vulnerable infant risk) and that normal muscle development may change the clinical severity of these variants in early life. A severity and risk that may get less with age i.e. a critical developmental period.
This proposal aims to:
1. Determine the frequency of rare gene variants encoding proteins that influence skeletal muscle excitability in c.700 SIDS cases and UK biobank controls
2. Determine the frequency of SIDS amongst families with neuromuscular excitability diseases caused by variants in these same genes
3. Characterise the normal developmental changes of muscle fibre types in human skeletal muscle
4. Use a computer model to determine the physiological consequences of combined genetic, developmental and exogenous variables on muscle excitability - the "triple risk"
I will use whole exome sequencing data from c.700 DNA samples of infants who have died from SIDS and screen for very rare or new variants in a candidate gene list (genes critical for muscle excitability) that are predicted to affect protein function. The frequency that these gene variants are found in the SIDS cases will be compared with the UK biobank control sequencing data to see if they are more common in SIDS cases. I will also use clinical data from families with mutations in these genes causing clinical disease to ascertain the incidence of sudden infant deaths and whether this is more common than among the general population. Muscles are made up of subtypes of fast and slow fibres. I think the more fast fibres a muscle has the more severe the effect of the gene variants will be and that infants' muscle will have more fast fibres than older children. A fully automated protocol applying different coloured antibodies to the different fibre types in a single skeletal muscle section will be used on human control biopsies from age 0 to 16years to determine the proportion of each fibre type at different ages. A computer model of a muscle fibre will be used to ascertain the individual and combined effects of developmental variables on normal and mutant (with a gene variant) muscle fibre function and performance.
Technical Summary
Five children in the UK die each week from Sudden Infant Death Syndrome (SIDS). The SCN4A gene codes for an ion channel Nav1.4 that is essential for muscle membrane excitability. Clinical disorders due to mutations in the SCN4A gene cause respiratory muscle impairment including life threatening apnoeas in infants. Based on these initial observations in infants I obtained new genetic and functional evidence that qualitatively similar SCN4A gene variants occur in some cases of SIDS. I hypothesise that ion channels and other proteins critical for skeletal muscle excitability may collectively account for a larger proportion of SIDS cases and that normal muscle development may contribute to the severity of these variants in early life.
This proposal aims to:
1. Determine the frequency of rare gene variants encoding proteins that influence skeletal muscle excitability using WES data from c.700 SIDS cases and UKbiobank controls
2. Determine the frequency of SIDS amongst families with neuromuscular excitability diseases caused by variants in these genes
3. Characterise the developmental changes of muscle fibre types in human skeletal muscle
4. Develop an in silico programme to model the physiological consequences of the genetic variation identified and the effect of developmental and exogenous variables on muscle excitability
A fully automated multi-coloured chromogenic IHC protocol capable of detecting myosin heavy chain isoforms I, IIA and IIX in a single skeletal muscle section will be employed on human control biopsies (age 0 to 16years) to determine the relative proportions of fast and slow fibre types at different ages. I hypothesise that excitability gene variants have a greater detriment to fast fibres and that infant muscle has more fast fibres than adults. A linear circuit model of mammalian muscle fibre will be used to ascertain the individual and combined effects of developmental variables on wild type and mutant muscle fibre function and performance.
This proposal aims to:
1. Determine the frequency of rare gene variants encoding proteins that influence skeletal muscle excitability using WES data from c.700 SIDS cases and UKbiobank controls
2. Determine the frequency of SIDS amongst families with neuromuscular excitability diseases caused by variants in these genes
3. Characterise the developmental changes of muscle fibre types in human skeletal muscle
4. Develop an in silico programme to model the physiological consequences of the genetic variation identified and the effect of developmental and exogenous variables on muscle excitability
A fully automated multi-coloured chromogenic IHC protocol capable of detecting myosin heavy chain isoforms I, IIA and IIX in a single skeletal muscle section will be employed on human control biopsies (age 0 to 16years) to determine the relative proportions of fast and slow fibre types at different ages. I hypothesise that excitability gene variants have a greater detriment to fast fibres and that infant muscle has more fast fibres than adults. A linear circuit model of mammalian muscle fibre will be used to ascertain the individual and combined effects of developmental variables on wild type and mutant muscle fibre function and performance.
Organisations
- St George's, University of London (Lead Research Organisation)
- University College London (Collaboration)
- MANCHESTER UNIVERSITY NHS FOUNDATION TRUST (Collaboration)
- Newcastle University (Collaboration)
- European Neuromuscular Centre (Collaboration)
- University of Virginia Medical Center (Collaboration)
- University of Cambridge (Project Partner)
- University College London (Project Partner)
- John Radcliffe Hospital (Project Partner)
People |
ORCID iD |
Emma Matthews (Principal Investigator) | |
Elijah Behr (Co-Investigator) |
Publications
Brunklaus A
(2022)
Gene variant effects across sodium channelopathies predict function and guide precision therapy.
in Brain : a journal of neurology
Bugiardini E
(2022)
Integrin a7 Mutations Are Associated With Adult-Onset Cardiac Dysfunction in Humans and Mice.
in Journal of the American Heart Association
Matthews E
(2023)
Care Recommendations for the Investigation and Management of Children With Skeletal Muscle Channelopathies.
in Pediatric neurology
Matthews E
(2022)
Refocusing SIDS research: Is butylcholinesterase a predictive biomarker?
in EBioMedicine
Ribeiro A
(2022)
The long exercise test as a functional marker of periodic paralysis.
in Muscle & nerve
Silksmith B
(2022)
Accelerating the genetic diagnosis of neurological disorders presenting with episodic apnoea in infancy
in The Lancet Child & Adolescent Health
Suetterlin K
(2022)
Translating genetic and functional data into clinical practice: a series of 223 families with myotonia.
in Brain : a journal of neurology
Suetterlin KJ
(2022)
Excitability properties of mouse and human skeletal muscle fibres compared by muscle velocity recovery cycles.
in Neuromuscular disorders : NMD
Themistocleous AC
(2023)
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort.
in Brain communications
Vivekanandam V
(2022)
Andersen-Tawil syndrome: deep phenotyping reveals significant cardiac and neuromuscular morbidity.
in Brain : a journal of neurology
Description | Change to national genomic test directory |
Geographic Reach | National |
Policy Influence Type | Contribution to new or improved professional practice |
Description | Rare Disease Collaborative Network |
Geographic Reach | National |
Policy Influence Type | Contribution to new or Improved professional practice |
Description | DMCRN: Myotonic Dystrophy Clinical Research Network |
Organisation | University of Virginia Medical Center |
Country | United States |
Sector | Hospitals |
PI Contribution | In exploring different NM disorders that cause sudden death, myotonic dystrophy is a significant contributor but we are still unsure who is most at risk, how to predict who is at risk and how to best prevent death. The disorder is multi-system and patients will present to different medical departments often for years before a diagnosis is made so we are also exploring different cohorts of patients to determine if screening should be applied routinely. To answer some of these questions we have joined the DMCRN and also their END DM1 natural history study. We will enrol 50 to 60 patients and provide follow up data for up to 3 years. |
Collaborator Contribution | Financial contribution to run the study. Joining the network includes a yearly F2F meeting to network with other centres and collaborators around the world including pharma opportunities. |
Impact | We have only just joined this network. |
Start Year | 2022 |
Description | FSHD UK and Europe Clinical Trial readiness networks |
Organisation | European Neuromuscular Centre |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | I attend monthly meetings with the UK team. We have agreed in clinical assessments which we complete in clinic for data collection. We help to direct and agree research priorities and next steps to achieve these. We work with pharma to attract clinical trials to the UK. |
Collaborator Contribution | As above |
Impact | ENMC workshop held beginning of 2022 with report submitted for publication. |
Start Year | 2022 |
Description | FSHD UK and Europe Clinical Trial readiness networks |
Organisation | Manchester University NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | I attend monthly meetings with the UK team. We have agreed in clinical assessments which we complete in clinic for data collection. We help to direct and agree research priorities and next steps to achieve these. We work with pharma to attract clinical trials to the UK. |
Collaborator Contribution | As above |
Impact | ENMC workshop held beginning of 2022 with report submitted for publication. |
Start Year | 2022 |
Description | FSHD UK and Europe Clinical Trial readiness networks |
Organisation | Newcastle University |
Department | MRC Neuromuscular Translational Research Centre |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | I attend monthly meetings with the UK team. We have agreed in clinical assessments which we complete in clinic for data collection. We help to direct and agree research priorities and next steps to achieve these. We work with pharma to attract clinical trials to the UK. |
Collaborator Contribution | As above |
Impact | ENMC workshop held beginning of 2022 with report submitted for publication. |
Start Year | 2022 |
Description | FSHD UK and Europe Clinical Trial readiness networks |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I attend monthly meetings with the UK team. We have agreed in clinical assessments which we complete in clinic for data collection. We help to direct and agree research priorities and next steps to achieve these. We work with pharma to attract clinical trials to the UK. |
Collaborator Contribution | As above |
Impact | ENMC workshop held beginning of 2022 with report submitted for publication. |
Start Year | 2022 |
Description | Patient group workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Approx. 25 attendees including patients, their families, clinicians, researchers and charities attended an information workshop focusing on the neuromuscular disorder myotonic dystrophy. The event generated interaction between families and support groups. 100% of attendees said they found the day useful and would recommend the event to others. |
Year(s) Of Engagement Activity | 2021 |