This document discusses KCNQ2 gene mutations which can cause different epilepsy phenotypes from benign familial neonatal seizures (BFNS) to more severe early-onset epileptic encephalopathy. It describes the discovery of KCNQ2 mutations in BFNS in 1998 and more recent findings of de novo missense mutations in 10% of patients with treatment-resistant neonatal epileptic encephalopathy. These mutations have a dominant-negative effect on channel function and cause neuronal hyperexcitability. The document also reviews other ion channel mutations associated with epilepsy phenotypes along a spectrum, such as SCN1A mutations which can cause GEFS+ or more severe Dravet syndrome.
1. WHAT IS GENE THERAPY
2. PRINCIPLE OF GENE THERAPY
3. TYPES OF GENE THERAPY
4. VECTORS IN GENE DELIVERY SYSTEM
5. ROLE OF GENE THERAPY IN CNS DISORDERS
6. GENE THERAPY FOR ALZHEIMERS DISEASE
7. GENE THERAPY FOR AMYOTROPIC LATERAL SCLEROSIS
8. GENE THERAPY FOR STROKE
9. CELL THERAPY FOR CNS DISORDERS
10. CELL THERAPY STRATEGIES
11. CELL THERAPY FOR PARKINSON
12. CELL THERAPY FOR HUNTINGTONS DISEASE
13. CRISPR/CAS9
This presentation summarises the importance of genetics in epilepsy, whom to test, and the various tests available. It looks at the role of genetics in various forms of epilepsy and recent advances in precision medicine.
refsum disease its a genetical disorder which is autosomal recessive phytanoyl-CoA-hydroxylase is the enzyme location of this enzyme is chromosome 10p13
1. WHAT IS GENE THERAPY
2. PRINCIPLE OF GENE THERAPY
3. TYPES OF GENE THERAPY
4. VECTORS IN GENE DELIVERY SYSTEM
5. ROLE OF GENE THERAPY IN CNS DISORDERS
6. GENE THERAPY FOR ALZHEIMERS DISEASE
7. GENE THERAPY FOR AMYOTROPIC LATERAL SCLEROSIS
8. GENE THERAPY FOR STROKE
9. CELL THERAPY FOR CNS DISORDERS
10. CELL THERAPY STRATEGIES
11. CELL THERAPY FOR PARKINSON
12. CELL THERAPY FOR HUNTINGTONS DISEASE
13. CRISPR/CAS9
This presentation summarises the importance of genetics in epilepsy, whom to test, and the various tests available. It looks at the role of genetics in various forms of epilepsy and recent advances in precision medicine.
refsum disease its a genetical disorder which is autosomal recessive phytanoyl-CoA-hydroxylase is the enzyme location of this enzyme is chromosome 10p13
s an inherited autosomal recessive disease that is characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureter, and bladder.
s an inherited autosomal recessive disease that is characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureter, and bladder.
More than 10 million people suffer from epilepsy in India.Seizures impact the lives of people with epilepsy and their family in many ways including creating barriers to employment and education and facing a sense of discrimination and isolation from their peers who donʼt understand what happens when they see a seizure occur. In India, epilepsy is still thought of as mental illness mainly due to lack of information on the condition among the general public.
This presentation touches every aspect of epilepsy
1. Overview of Epilepsy;
2. Type of Seizures;
3. Diagnosis and Management;
4. Psychological Issues; and
5. Social Perspectives.
Dr. sarah weckhuysen kcnq2 Cure summit professional track - Lean more at kcn...scottyandjim
Dr. Sarah Weckhuysen speaking at 2014 Denver KCNQ2 Cure summit professionals track at Children's Hospital of Colorado. More information at www.kcnq2summit.org
Dr. john millichap kcnq2 Cure summit professional track learn more at kcnq2cu...scottyandjim
Dr. John Millichap speaking at 2014 Denver KCNQ2 Cure summit professionals track at Children's Hospital of Colorado. More information at www.kcnq2cure.org
Toward Precision Medicine in Neurological Disease by David GoldsteinKnome_Inc
View the webinar at http://www.knome.com/webinar-toward-precision-medicine-neurological-disease. In this presentation, Dr. Goldstein reports progress in identifying pathogenic mutations large-scale scale studies in epilepsy, in particular focusing on identifying de novo mutations as a cause of the epileptic encephalopathies. Next he discusses how sequencing is being used to diagnose rare serious unresolved genetic conditions. Finally, Dr. Goldstein describes a number of examples in which a secure genetic diagnosis has led directly to a change in clinical management.
Epileptogenesis is the process by which a brain network that was previously normal is functionally altered toward increased seizure susceptibility, thus having an enhanced probability to generate spontaneous recurrent seizures (SRSs). The process of epileptogenesis occurs in 3 phases: the occurrence of a precipitating injury; a 'latent' period of epileptogenesis and chronic, established epilepsy. Structural and molecular changes associated with epileptogenesis include selective neuronal loss,axonal and dendritic reorganisation, neurogenesis, altered expression of neurotransmitters, and changes at glial architecture. Antiepileptogenesis can be complete or partial. Complete prevention aborts the development of epilepsy while partial prevention can delay the development of epilepsy or reduce its severity. Targeting signaling pathways that alter the expression of genes involved in epileptogenesis may provide novel therapeutic approaches for preventing epileptogenesis. The mTOR and REST pathways are exciting new potential targets for intervention in the epileptogenic process.
Etude des canaux ioniques intérêts pour la physiopathologie et le traitement ...Pasteur_Tunis
Présentation de Arnaud Monteil réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Triangles of Neck and Clinical Correlation by Dr. RIG.pptx
Dr. sarah weckhuysen kcnq2 Cure summit parent track learn more at kcnq2cure.org
1. KCNQ2 gene discovery;
Epilepsy mechanism, and other ion
channel mutations in epilepsy
Dr. Sarah Weckhuysen, MD, PhD
Neurogenetics Group, VIB-Department of Molecular Genetics
University of Antwerp, Belgium
2. Sarah Weckhuysen
Financial Disclosures
No relevant financial relationships with
any commercial interests.
8. Causes of epilepsy
Figure 1 Advances in understanding the causes of epilepsy
Thomas, R. H. & Berkovic, S. F. (2014) The hidden genetics of epilepsy—a clinically important
new paradigm
Nat. Rev. Neurol. doi:10.1038/nrneurol.2014.62
14. Benign Familial Neonatal
Seizures (BFNS)
• Autosomal dominant
• Seizures onset between 2 - 8 days,
remission within first months of life
• Seizures: tonic -> autonomic and motor
changes, uni- or bilateral. Often with
episodes of apnea
• Investigations normal
• Psychomotor development normal
• Small increased risk of recurring seizures
later in life
15. 1998: KCNQ2 and KCNQ3 in
BFNS
Missense, nonsense, splicing, frameshift mutations,
intragenic insertions/deletions, whole gene
deletions described
16. Where the story starts
KCNQ2 screening offered for neonatal
seizures in diagnostic unit
◦ 2010: 1 patient: refractory seizures and
psychomotor regression
Literature
◦ 4 case reports of patients with neonatal
seizures and intellectual disability
(Dedek et al 2003, Borgatti et al 2004, Schmitt et al 2005,
Steinlein et al. 2007)
17. Methods
• KCNQ2 and KCNQ3 screening in 80
patients with unexplained neonatal or
early onset epileptic encephalopathy
• Onset < 3 months
• Slowing of psychomotor development
• Metabolic screening normal
• Imaging: no explanation
• Genetic screening for relevant genes normal
Weckhuysen et al, Ann. Neurol. 2012
18. Results
No KCNQ3 mutations
7 novel KCNQ2 missense mutations in 8/80
patients (10%)
Not present in 276 ethnically matched controls
Inheritance
6 mutations de novo
1 paternal DNA unavailable
1 mosaic father
Weckhuysen et al, Ann. Neurol. 2012
19.
20.
21. September 2014:
◦ 62 patients with KCNQ2 encephalopathy
described in literature
44 different mutations
◦ 21 additional non-reported European
patients
8 novel mutations
22. KCNQ2 encephalopathy
• 10% of patients with neonatal EE of unknown
etiology
• KCNQ2 encephalopathy mutations
All missense mutations
• Several mutations recurrent in multiple patients
• Several mutations in same codon
Novel: not reported in BFNS
• Inheritance
de novo
1 mosaic father with BNS phenotype
23. KCNQ2 encephalopathy
• Neonatal onset
1 patient onset at 5 months
• Seizure type at onset
Prominent tonic component
Often autonomic features: apnea, desaturation, bradycardia
• Dramatic onset, multiple sz daily
• EEG at onset burst-suppression pattern or multifocal
epileptic activity
• Range of cognitive outcome, mostly severe to
profound intellectual disability
32. SCN1A
1997
FEVER SENSITIVITY
Clinical description GEFS+ syndrome (Scheffer et
al.)
2000
SCN1A mutation in large GEFS+ family (Escayg
et al.)
2001
SCN1A mutation in 7/7 patients with Dravet
syndrome (Claes et al.)
Follow up studies: SCN1A
mutations/deletions in 70-80% of Dravet
patients
37. General Rule
GEFS+
◦ Missense mutations
Outside pore region
SMEI
◦ Truncating mutations, splice site mutations,
deletions
◦ Missense mutations
In pore region
More often changes in AA polarity
BUT exceptions!!
38. Ion channel spectrum
KCNQ2
Functional aspects mutation + genetic
background
encephalopathy
BFNS KCNQ2
- Mostly Inherited - Mostly de novo
- Mozaicism described in
inherited cases
GEFS+ SCN1A Dravet Syndrome
Functional aspects mutation + genetic
background
42. SCN2A in BFNIS
Benign familial neonatal-infantile
seizures
• Autosomal dominant
• Seizures onset between 2 days and 7 months,
remission by 12 months of life
• Investigations normal; Psychomotor development
normal
2002: SCN2A mutations in BFNIS. All missense
mutations
44. Genotype-phenotype
correlation
• Across all phenotypes
• Most mutations = missense mutations
• BFNIS predominantly in transmembrane domains
(TMD), “severe” mutations more outside TMD
• Both net gain vs. loss of function described
• All truncating mutations => EE/ID/autism
• No conclusive results (yet)
45. SCN2A spectrum
KCNQ2
Functional aspects mutation + genetic
background
encephalopathy
BFNS KCNQ2
- Mostly Inherited - Mostly de novo
BFNIS SCN2A SCN2A encephalopathy
- Mozaicism described in
inherited cases
GEFS+ SCN1A Dravet Syndrome
Functional aspects mutation + genetic
background
54. Dravet syndrome with SCN1A
mutation
SCN1A loss of function
Aggravation of sz by sodium channel
blockers
(carbamazepine, oxcarbazepine,
lamotrigine,…)
59. ORIGIN OF ID IN EPILEPSIES
DUE TO ION CHANNEL
MUTATIONS
60. Dravet syndrome
◦ Clinical
No strict correlation seizure severity - outcome
Treatment change later in life => improvement
cognition
◦ Functional
siRNA in basal forebrain adult rats for 4 days
61. KCNQ2 encephalopathy
◦ Clinical
No strict correlation seizure severity – outcome
◦ Functional
Normal hippocampal morphology, not hyperactive, no
overt behavioral seizures
Impaired spatial learning
Reduced M-type K+ current and neuronal
hyperexcitability
62. SCN2A
De novo mutations in patients with
ID/autism without epilepsy
63. Epilepsy and ID
Seizures do not explain everything
=> Target cause not only symptom
=> New strategies for treatment development
64. Neurogenetics group -
epilepsy
◦ Rik Hendrickx
◦ Tine Deconinck
◦ Jolien Roovers
◦ Tania Djémié
◦ Katia Hardies
◦ Arvid Suls
◦ Peter De Jonghe
SPECIAL THANKS TO:
Parents and patients with
KCNQ2 mutations
All treating physicians of
patients with KCNQ2
mutations
Contact: sarahweck@hotmail.com
Editor's Notes
1h
FIGUUR!
After 2007: silence
Mutations affecting the pore region of the Kv7.2 channels showed a striking loss-of-function. Up: when expressed in Xenopus laevis oocytes, they yielded almost no currents. Below: In these experiments the injected amont of the WT was the same when it was expressed alone (left) or together with each of these mutations (right), but in the presence of mutations the WT currents were dramatically reduced, revealing that the mutant channels exerted a strong dominant-negative effect on the WT channel. The dominant-negative effect is known only for a few Kv7.2 mutations associated with neonatal seizures and is not as pronounced.
Partly replaced by Nav1.6 (SCN8A) during maturation
6/12 patients
+ 1 OS patient (exome study)
Pooled current
PAPERS?
Impaired spatial performance was associated with a dysregulation of theta frequency in hippocampus
Doxycycline during the first 1–3 weeks of life
=> normal KCNQ channels during early development, blocked channels thereafter
