Midterm Exam

Week 1 - 5 notes

What is the inheritance pattern of Malignant Hyperthermia Susceptibility (MHS)?

AD, mostly inherited

What is on the differential for Malignant Hyperthermia Susceptibility (MHS)?

nothing, unique condition

* can occur randomly, 1 episode -→ negative genetic test and muscle biopsy

What is Malignant Hyperthermia Susceptibility (MHS)?

inappropriate contractions of skeletal muscles that produces excessive heat and lactate

* often observed during surgery

What are the symptoms of Malignant Hyperthermia Susceptibility (MHS)?

1. Hyperthermia
2. Hypercapnia- excessive CO2 in blood
3. Acidosis-- excess CO2
4. Tachycardia- fast heartbeat
5. Muscle rigidity or spasms
6. Rhabdomyolysis
7. Compartment syndrome- increased pressure around muscles, can lead to damage
8. Hyperkalemia- high potassium, can lead to cardiac arrhythmia


1. Myoglobinuria- excess myoglobin in urine, leads to kidney injury

What triggers Malignant Hyperthermia Susceptibility (MHS)?

often triggered by volatile anesthetics during surgery

* may be induced by extreme exercise or exposure to severe heat for susceptible individuals

What is the biological mechanism of muscle contractions in Malignant Hyperthermia Susceptibility (MHS)?

1. action potential arrives at neuromuscular junction signaling muscle cells to contract
2. calcium is released from the sarcoplasmic reticulum (SR)


1. action potential finishes, calcium moves back to SR and muscle relaxes

What is the RYR1, STAC3, and CACNA1S genes in Malignant Hyperthermia Susceptibility (MHS)?

1. RYR1- encodes ryanodine receptor that releases calcium from SR
2. STAC3- may regulate activity of L-type channel or RYR1 linking with other proteins
3. CACNA1S- encodes one component of L-type calcium channels

What genes are associated with Malignant Hyperthermia Susceptibility (MHS)?

RYR1, STAC3, CACNA1S

What does molecular testing look like for Malignant Hyperthermia Susceptibility (MHS)?

up to 40% of cases are caused by unidentified variants

* negative test doesn’t mean they do not have MHS

How do you diagnosis Malignant Hyperthermia Susceptibility (MHS)?

in proband: postive diagnostic contracture OR heterozygous pathogenic variant in RYR1, STAC3, or CACNA1S

* testing is not 100% sensitive

Can you rule of Malignant Hyperthermia Susceptibility (MHS) if the patient doesn’t react to exposure?

No, they don’t have an episode with every exposure. History of anesthesia doesn’t rule out the diagnosis.

How is contracture testing performed?

few sites in the US and around the world, more sensitive than current genetic testing


1. Patient must have muscle biopsy (in larger muscle) at the site


1. Can’t be transported, must be immediate
2. Sample is exposed to caffeine and halothane which stimulate calcium release from the sarcoplasmic reticulum
3. Sample contracts abnormally = patient is diagnosed with MHS

What do you do if someone with Malignant Hyperthermia Susceptibility (MHS) needs surgery?

* use a different type of anesthetic if possible
* monitor internal body temperature
* treat with dantrolene sodium and cooling measures if an episode occurs
* quick to expire, expensive

Based on this family history of malignant hyperthermia susceptibility (MHS), how would you follow up with the family testing?

* test the father if possible -→ genetic testing
* If negative, then contracture test
* test Elisa or Manuel if dad isn’t available
* family has negative genetic testing -→ Manuel can have contracture test OR schedule surgery at facility with an MH protocol

What should patients with Malignant Hyperthermia Susceptibility (MHS) do to ensure their safety?

* avoid volatile anesthetics such as halothane
* have surgery at large medical center
* more likely to have dantrolene to treat MH
* avoid extreme heat/exercise if previous events have occurred in those circumstances
* wear medical alert bracelet

What are the psychosocial concerns associated with Malignant Hyperthermia Susceptibility (MHS)?

* Elisa may be worried about her son, guilt for him being at risk
* Doesn’t understand why she’s at risk still even though she has had prior surgery w/o anesthesia complications
* Doesn’t know much of her family history, may be estranged
* May worry about what could happen in emergency if she has MHS and needs surgery

What are multifactorial conditions?

conditions with genetic and non-genetic causes

What are some examples of multifactorial conditions?

autism, cardiac defects, diabetes, asthma, and mental illness

What are some environmental factors that affect the development of multifactorial conditions?

diet, smoking, exposure to pollutant, geographic location

What is diabetes type 1?

multifactorial condition

* Type 1: caused by autoimmune process that destroys insulin-producing cells in pancreas
* Not enough insulin is made

What is diabetes type 2?

multifactorial condition

* Type 2: cells in the body become resistant to insulin and pancreas can’t produce enough to overcome this resistance

What are some risk factors for diabetes type 1?

1. family history
2. exposure to viruses
3. higher rates in some countries
4. presence of diabetes autoantibodies

What are some risk factors for diabetes type 2?

1. family history
2. obesity
3. age
4. some racial/ethnic groups
5. low HDL or high triglycerides
6. history of heart disease or stroke


1. history of gestational diabetes

Which risk factors are genetic?

family history, racial/ethnic groups

Which risk factors are environmental?

virus exposure

Which risk factors are genetic and environmental?

higher rates of incidence in some countries, presence of diabetes autoantibodies, obesity, low HDL or high triglycerides, history of heart disease or stroke, history of gestational diabetes

What are the two rare monogenic causes of diabetes?

1. Maturity Onset Diabetes of the Young (MODY) – onset in adolescence or young adulthood, features are not typical for type 1 or type 2 diabetes, can often be treated without insulin or with very low doses
2. Some mitochondrial diseases and other syndromes can include diabetes but typically have other features

David is a 26 yr old man with a family history of diabetes. He would like to know how likely he is to develop diabetes and how to reduce his risk. How do you counsel David?

* Prevalence of diabetes in the population (8.7%)
* Identify risk factors that may apply to him
* Empirical risk is based on relatedness
* Which can he control? Make an action plan for risk reduction and surveillance

What are risk alleles?

refers to variant(s) with very low penetrance such that their effects are incomplete

* Do not manifest in a Mendelian pattern of inheritance

Thrombophilia: Nicola has a brother with a history of deep vein thrombosis at age 29 after having surgery for a torn ligament in his knee. She also had a maternal uncle who passed away from a pulmonary embolism at age 48. She is considering a second pregnancy but is concerned about her risk of developing a blood clot. What risk factors impact thrombosis?

* Genetic risk factors and environmental risk factors will increase risk
* Factor V Leiden (genetics): 8% of white Americans, 1.2% of black Americans, 1/5000 homozygous
* Factor II (prothrombin, genetics): 5% of white Americans, 2% of Hispanic Americans, 0.6% of black Americans, 1/10,000 are homozygous

What population is most likely to have venous thromboembolism?

Black Americans, 30-60% more likely to have VTE than other populations

* Don’t know of genetic risk alleles that explain this

What is the general population risk for thrombosis?

5/10,000 per year

What variant of thrombosis is highest?

prothrombin

* Factor II (prothrombin, genetics): 5% of white Americans, 2% of Hispanic Americans, 0.6% of black Americans, 1/10,000 are homozygous

How does pregnancy impact thrombosis risk?

5x higher risk

How does pregnancy and prothrombin impact thrombosis risk?

15-31x higher risk

How do you do genetic testing for thrombosis risk factors? (5 things)

Testing for factor V Leiden and factor II c.\*97G>A (prothrombin) is recommended in the following circumstances:


1. A first unprovoked VTE, especially

Why isn’t thrombophilia testing recommended for the general population?

Shouldn’t be offered to people who haven’t yet clotted since the same treatment will be given in first clot

* Variants are too common to be useful predictors of risk on their own
* Only change medical care when there is also a personal or close family history of thrombosis

Thrombophilia: Nicola has a brother with a history of deep vein thrombosis at age 29 after having surgery for a torn ligament in his knee. She also had a maternal uncle who passed away from a pulmonary embolism at age 48. She is considering a second pregnancy but is concerned about her risk of developing a blood clot. Who else qualifies for testing, if any?

30yo brother doesn’t meet criteria, but will likely be tested

Celiac disease: Avram (they/them) is 24 yrs old. Their older sister has been diagnosed with celiac disease. They have no symptoms but would like to know if they should have genetic testing. What is celiac disease?

autoimmune condition in which the body reacts to dietary gluten

What is the classic form of celiac disease?

less common form, in kids

* malabsorption (in childhood), failure to thrive, GI symptoms, weight loss, short stature
* commonly seen is fatigue, migraines

What is the non-classic form of celiac disease?

more common form

* no classic symptoms of malabsorption, but can have GI symptoms and/or iron deficiency anemia

What symptoms can be seen in either form of celiac disease? (8 things)

* osteoporosis/osteopenia
* dental enamel hypoplasia
* infertility and/or recurrent fetal loss
* vitamin deficiencies
* abnormal liver function tests
* fatigue
* psychiatric syndromes
* various neurologic conditions including peripheral neuropathy, ataxia, seizures, migraines, attention-deficit hyperactivity disorder, and poor school performance

How do you diagnose celiac disease?

1. Positive celiac serology test, blood test


1. Must be on a diet containing gluten
2. Characteristic findings on intestinal biopsy


1. Looks for inflammation, colonoscopy
3. Positive genetic test for risk-conferring HLA haplotype

What is a haplotype?

variants that travel together, historically

* presence of specific variants in 2+ genes

What does it mean to be DQ2-positive in celiac disease?

HLA-DQA1\*\*0\*501 or 0505 __AND__ HLA-DQB1\*0201 or 0202

* >90%

What does it mean to be half DQ2-positive in celiac disease?

HLA-DQA1***0501 or 0505 __OR__ HLA-DQB1\*0201 or 0202

*

What does it mean to be DQ8-positive in celiac disease?

HLA-DQA1\*03 __AND__ HLA-DQB1\*0302

* 5%-10%

What does HLA-DQ2 alleles expressed in cis look like?

celiac disease

What does HLA-DQ2 alleles expressed in trans look like?

on 2 chromosomes

* both chains are abnormal
* haplotypes remain because abnormal genes have high risk for celiac disease (different than ancestry haplotype)

Which HLA diplotype has the highest risk?

Q2+DQ8, 1:7 (14.3%)

* 2 different haplotypes per chromosome
* doesn’t mean they have celiac, are at higher risk to develop it
* incomplete penetrance -→ multifactorial

What is a diplotype?

what is on both chromosomes

Celiac disease: Avram (they/them) is 24 yrs old. Their older sister has been diagnosed with celiac disease. They have no symptoms but would like to know if they should have genetic testing. Based on their sister, do we know what Avram’s diplotype is?

No, don’t know parental alleles

* no direct math to answer
* assess risk benefit instead

Alzheimer’s disease: Gemma’s mother was recently diagnosed with Alzheimer’s disease. Her maternal aunt was diagnosed with the condition as well before she passed away from other causes. Gemma would like to know her APOE genotype to determine her risk of developing Alzheimer’s disease. What is Alzheimer’s disease?

* Progressive neurodegenerative disease typically diagnosed after age 60
* Most common cause of dementia

Do people with Alzheimer’s disease typically have family history? If they do, what is their risk?

No, but having a family history increases risk by 30%

* 65yo, 2% risk = 2.6% risk
* 75yo, 5% risk = 6.5% risk

What is the Apo-E2 genotype?

112 = Cys

158 = Cys

General allele frequency = 8.4%

AD allele frequency = 3.9%

* less than general population

What is the Apo-E3 genotype?

112 = Cys

158 = Arg

General allele frequency = 77.9%

AD allele frequency = 59.4%

What is the Apo-E4 genotype?

112 = Arg

158 = Arg

General allele frequency = 13.7%

AD allele frequency = 36.7%

* higher than general population

Should you genetic test for Alzheimer’s disease?

No, APOE genotype alone does not provide sufficient sensitivity or specificity to allow genotyping to be used as a diagnostic test

* Develops in the absence of APOE e-4 and because many with APOE e-4 seem to escape disease, genotyping is also not recommended for use as a predictive genetic test

Explain the heart rhythm and how it works.

1. SA node
2. AV node
3. Bundle of His
4. Down to bundle branches and divisions in the ventricles

What is bradycardia?

less than 60 bpm

What is tachycardia?

more than 100 bpm

What is palpitations?

fluttering sensation, irregular heartbeats such as premature ventricular contractions (PVCs)

* Often benign

What are atrial fibrillation (afib)?

arrhythmia in the atria

* can cause irregular heartbeat
* problems with coordination of heart chambers

What is supraventricular tachycardia (SVT)?

atrial, extra heartbeats

* common during exercise
* usually not dangerous

What is ventricular fibrillation (vfib)?

ventricles quiver instead of contracting, leading to no blood flow

* can lead to cardiac arrest

Describe PQRST complex in EKG.

1. P = atrial contraction
2. QRS = ventricular contraction
3. T = ventricular relaxation

What is a primary electrical disease?

arrhythmia in the absence of structural heart disease

* Hereditary arrhythmia
* Electrolyte imbalance
* Medication side effect

What is a secondary electrical disease?

arrhythmia caused by structural abnormality in heart

* Congenital heart malformation
* Anatomical differences
* Wolff-Parkinson-White syndrome
* Scarring from previous heart attack
* Arrhythmogenic right ventricular dysplasia (ARVD/ARVC) or other cardiomyopathy

What is Wolff-Parkinson-White syndrome?

aka WDW

* extra pathway from AV node to accessory pathway -→ causes extra heartbeat
* treat with radiofrequency ablation
* Catheter into heart, zap the accessory pathway to kill it, no conduction further

What are 5 examples of genetic arrhythmias?

1. Long QT syndrome (LQTS)


1. Timothy syndrome
2. Jervell and Lange-Nielsen syndrome (JLNS)
2. Brugada syndrome
3. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

When it comes to cardiac arrhythmias, what genes are causative?

phenotypes and genes overlap with other arrhythmias

* can be hard to distinguish in families

This family is from the Philippines and have had minimal access to high level healthcare. Most sudden deaths occurred during sleep. The proband has a history of syncope and his brother (D) and father (E) did as well. The family calls the condition “bangungot.” What condition is this? What does this tell us about cardiac conditions and cultural barriers?

Brugada syndrome, many cultures have legacy stories to describe health conditions commonly seen in their communities

What community is most commonly seen with Brugada syndrome?

Southeast Asian populations, 1/2000

What is the inheritance of Brugada syndrome?

autosomal dominant (most genes) or X-linked (*KCNE5* gene)

* prevalence of Brugada syndrome is higher in people AMAB

What is the penetrance for Brugada syndrome?

unknown for many genes

* SCN5A: 20-30% of people have diagnostic EKG, and up to 80% have inducible EKG pattern with sodium-channel blocker

What is Brugada syndrome?

Cardiac conduction disease with high risk for ventricular arrhythmias, recurrent syncope, and sudden death

* May cause other conduction defects including: first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome

When is the mean age for sudden death in Brugada syndrome?

Mean age of sudden death is 40 years

* Associated with sudden infant death syndrome (SIDS) or sudden unexplained nocturnal death syndrome (SUNDS)

How is Brugada syndrome diagnosed?

Diagnosis can be made clinically in a person with both:


1. Type 1 EKG pattern AND
2. At least one of the following:


1. Documented ventricular fibrillation
2. Self-terminating polymorphic ventricular tachycardia
3. A family history of sudden cardiac death
4. Coved-type EKGs in family members
5. Electrophysiologic inducibility
6. Syncope or nocturnal agonal respiration

What is the management of Brugada syndrome?

1. ICD placement
2. Surveillance with EKG
3. Careful monitoring during surgery and postsurgical period
4. Avoid precipitating factors-- high fever, some medications, cocaine, electrolyte imbalance

What is the prevalence of catecholaminergic polymorphic ventricular tachycardia (CPVT)?

less common arrhythmia, unknown prevalence (1/10,000 or less)

What is the inheritance pattern of catecholaminergic polymorphic ventricular tachycardia (CPVT)?

* autosomal dominant: RYR2, 60-70% of cases
* autosomal recessive: CASQ2, 5%
* other genes are rare
* unknown, 25% but with clear clinical manifestations

What is the penetrance of catecholaminergic polymorphic ventricular tachycardia (CPVT)?

1. RYR2 = 83%
2. Biallelic, CASQ2 variants = 100%

What is the notable relationship between RYR2 gene and malignant hyperthermia susceptibility (MHS)?

functions like RYR1, but in cardiac muscles

What triggers catecholaminergic polymorphic ventricular tachycardia (CPVT)? What do they cause?

exercise or acute emotion

* causes syncope, dizziness, or palpitations
* not every time, just increased risk

What is the age of onset for catecholaminergic polymorphic ventricular tachycardia (CPVT)?

mean age = 7-12 years old

Sometimes, what is the first manifestation of catecholaminergic polymorphic ventricular tachycardia (CPVT)?

sudden death

How do you manage catecholaminergic polymorphic ventricular tachycardia (CPVT)?

* Beta blockers, sometimes anti-arrhythmia medication
* Surveillance by cardiologist every 6-12 months
* Exercise limitations
* ICD if arrhythmias are not controlled by medication

What is Timothy syndrome?

prolonged QT interval, autism, and cardiovascular malformation w syndactyly of fingers and toes

* cardiovascular malformations are caught in infancy
* syndactyly of fingers and toes are hallmark

What is the cause of Timothy syndrome?

de novo gain of function variant of CACNA1C p.Gly406Arg

How common is Timothy syndrome?

rare, \~100 cases worldwide

Can Timothy syndrome be treated?

no, very high mortality rate even if treated

* new development in them since de novo, pass by 2yo so no reproduction

What else can variants in CACNA1C cause other than Timothy syndrome?

typically LOF, lead to non-syndromic arrhythmias such as short QT syndrome or Brugada syndrome

What is Jervell and Lange-Nielsen syndrome (JLNS)?

congenital profound sensorineural hearing loss and long QT interval, syncope during stress & exercise

* subtype of LQTS

What is the inheritance pattern of Jervell and Lange-Nielsen syndrome (JLNS)? Associated genes?

AR

* biallelic pathogenic variant in LCNQ1 or KCNE1

What does KCNE1 biallelic pathogenic variants cause? Associated condtion?

Jervell and Lange-Nielsen syndrome (JLNS), causes profound sensorineural hearing loss

What is the prevalence of Jervell and Lange-Nielsen syndrome (JLNS)?

1/200,000 in Norway, Sweden

* due to founder variants

What is the phenotype for heterzygotes of Jervell and Lange-Nielsen syndrome (JLNS)?

may have long QT phenotype, complicates family testing/counseling

* could be that both parents have variants, 50% siblings have LQTS

How do you test for arrhythmia syndromes?

panel testing, many genes have layovers

Ex: KCNQ1 in BrS, LQTS, and CPVT

* only single gene if the family variant is known

What are some psychosocial considerations for arrhythmia syndromes?

* Sudden cardiac arrest can be traumatic for patient/family
* Waiting for something bad to happen
* Negative genetic testing can be emotionally difficult
* Can’t test other members
* Some patients have trouble with treatments (medication side effects, ICD shocks)
* Waiting to be shocked/hit in the chest randomly
* Exercise limitations cause stress
* Athletes, ignoring recommendation since it reduces quality of life
* Coping mechanism for some

What is Ehlers-Danlos syndrome (EDS)?

group of rare inherited conditions that affect connective tissue

* Danish dermatologist Edvard Ehlers and French dermatologist Henri-Alexandre Danlos