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Amyloidosis is a group of diseases that have a common feature where proteins behave abnormally, with the breakdown products of these proteins folding upon themselves and depositing in various organs. Hereditary transthyretin amyloidosis is caused by a genetic mutation which causes misfolding of transthyretin (TTR) proteins (which originate from the liver). There are over 100 genetic variants of hereditary amyloidosis.

One such variant, called T60A, is the most common variant in Ireland (and the UK).

Symptoms of hereditary amyloidosis, specifically the T60A variant, include a variety of peripheral neuropathic, autonomic, and cardiac maladies, including:

carpal tunnel syndrome
numbness and tingling in hands, feet, arms, and legs
muscular weakness
excessive sweating
dizziness/fainting (orthostatic hypotension)
sexual disfunction
unintentional weight loss
indigestion
acid reflux
bouts of constipation and diarrhea
fatigue
shortness of breath
leg swelling
chest pain

One Patient’s Story

“Do you have an ancestor from Donegal?” is a question frequently asked by doctors who are investigating the possibility that a patient may have hereditary amyloidosis type T60A. With its origins in a short ribbon of coastline in North-West Donegal (Ireland), the condition wandered worldwide with Irish migration.”

_{(Callaghan, Donegal Amy, 2022.)}

Donegal Ireland was one of the worst affected areas of Ireland’s “Great Hunger” of the mid to late 1800’s. 123,000 emigrants left the Donegal area between 1851-1900. A great many of them migrated to the United States, many to the Appalachian region of the country. The T60A variant, as it now appears in the United States, has been traced back to those settling in Appalachia. Sean Riley is a T60A amyloidosis patient who has ancestorial connections to Appalachia and the Donegal area.

Sean’s journey to diagnosis began in the fall of 2012 when he had bilateral carpal tunnel surgery. His job required quite a bit of typing and handwriting so he assumed that the condition was related to repetitive motion, which is a common cause of carpal tunnel syndrome. Little did he or the attending hand surgeon know that bilateral carpal tunnel syndrome may be an early neurological symptom of amyloidosis.

Concurrently, Sean started experiencing numbness in his left foot and lower left leg. He previously had vascular surgery on the left leg, and incorrectly assumed that the foot and leg numbness might be associated with nerve damage from the surgery. In actuality the numbness was due to the onset of peripheral neuropathy, yet another early symptom of the disease.

Between 2014 and 2017 he was taken to the hospital by ambulance on three separate occasions. In each instance he felt extreme dizziness and discomfort in his chest and assumed that the events were due to a cardiac issue, but no obvious signs of cardiac issues could be identified in any of the events. He now knows that what he was experiencing was orthostatic hypotension due to the onset of progressive autonomic neuropathy, another signature malady associated with the disease.

In the fall of 2017 Sean started being treated for severe acid reflux and gastrointestinal issues. Over time he had an endoscopy and colonoscopy performed, each which indicated normal results. These conditions likely indicated the onset of amyloidosis impact on nerves and tissue of the gastro-intestinal system.

Over the period of time from 2012 through 2017 Sean was seen by a hand surgeon, cardiology, oncology, endocrinology, neurology, and gastroenterology, along with his primary care physician. Nobody was able to connect the dots to amyloidosis, a product of the rarity of the disease and resulting lack of disease expertise by the general medical community.

In 2018 Sean moved overseas to Abu Dhabi to pursue a career opportunity. Shortly after arriving he started experiencing more frequent hypotensive episodes as well as progressive muscle wasting and weight loss. Fortunately for Sean the Cleveland Clinic has a hospital facility in Abu Dhabi. The attending cardiologist had a working knowledge of amyloidosis and ordered a series of tests, including an echocardiogram, a cardiac MRI, and a neuropathic evaluation, all of which concluded a preliminary positive diagnosis for the disease. As a result, the cardiologist recommended that Sean travel back to the United States and be seen at the amyloidosis center at Brigham and Women’s hospital in Boston. In February of 2019 he received a definitive diagnosis of hereditary transthyretin amyloidosis, specifically the T60A mutation. Excerpts of the confirming echocardiogram, cardiac MRI, and genetic testing results are shown below.

Echocardiogram Summary Notes

Associated Cardiac MRI Interpretation

DNA Sequencing Result

Shortly after diagnosis, Sean started treatment with a state-of-the-art FDA-approved amyloidosis drug. The treatment is administered every three weeks and is designed to slow or stop disease progression. The drug is an RNA signal blocker which stops the transthyretin proteins from misfolding and creating amyloid fibrils.

Sean continues this therapy to this day, and all indications show that disease progression has stopped. There is no cure for the disease, so he must contend with and manage the damage that has been done; however, he is thrilled that the disease progression is being kept in check.

For more information on hereditary amyloidosis worldwide, visit our blog — Click Here

Bibliography

“Donegal Amy-A Rare Inherited Disease from Ireland”, Rosaline Callaghan, Roscara Books, 2022.

“Unraveling the Lineage: The Genetic Basis of Familial ATTR Cardiomyopathy Ronald Witteles”, MD Professor of Medicine (Cardiovascular Medicine).

“Cardiac Amyloidosis Part 1: Understanding Types and Risks”, Dr. Rodney Falk, Brigham and Women’s Hospital, YouTube, July 2018.

Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR Epidemiology, Genetics, and Prognostic Factors. Methodist Debakey Cardiovasc J. 2022 Mar 14;18(2):17-26. doi: 10.14797/mdcvj.1066. PMID: 35414855; PMCID: PMC8932385.

Transthyretin Amyloidosis, or ATTR, is considered a single disease, however the diversity in its clinical presentation is staggering. In this blog, we’ll discuss some of the most common hereditary variants and how the disease manifestation differs around the world in documented hotspots.

Source: Epidemiology, Genetics, and Prognostic Factors (1)

There are two distinct forms of Transthyretin Amyloidosis (ATTR), the hereditary form (ATTRv), and the non-hereditary form (ATTR-wt) commonly referred to as wild-type amyloidosis. Disease manifestation is considered a spectrum involving aspects of cardiomyopathy, neuropathy, or more frequently a mixture of both.

Below we’ll discuss the hereditary form and the various genetic variants and how they differ based on geographical location.

WHAT IS TRANSTHYRETIN (TTR)

Transthyretin, also known as prealbumin, is a protein produced primarily in the liver that is responsible for the transport of thyroxine and retinol. Interesting enough, this is how it got its name.

In steady state, the protein circulates primarily as a tetramer (i.e., monomeric form), but unfortunately, its monomeric form is inherently amyloidogenic (prone to breakdown and formation of amyloid aggregates). Couple that with mutations that increase the amyloidogenicity of the protein, these tetramers dissociate into monomers that will misfold, aggregate, and form the insoluble fibrils (“amyloid”) that are resistant to the body’s inherent protective mechanisms like proteolysis.

SPECIFIC TTR PATHOGENIC VARIANTS

As of today, there have been over 145 reported variants related to hereditary transthyretin amyloidosis. Interestingly, these genetic variants have a tendency to cluster in both geographic and ethnic groups around the world. We’ll discuss some of the most prevalent mutations below.

Val122Ile

This is the most common TTR mutation in the United States, with a prevalence of roughly 3.4% in the African American community. The disease is primarily cardiac in nature, typically present when patients are in their 60s. It is thought that this mutation arose from the region of West Africa and has worked its way to the United States over time, where it has become the predominant form.

Val30Met

This is the most commonly recognized TTR mutation worldwide and the first TTR variant discovered. It is most commonly found in the regions of Portugal, Spain, France, Japan, Sweden, and Brazil. Interestingly, between these regions where this mutation dominates, there is variability in age of onset and parent-of-origin. For example, age of onset was found to be earlier in the Swedish population in comparison to Portugal and Japan. As for the parent-of-origin, it was found that the mother was more likely than the father to pass along the mutation (153 vs. 138), whereas in the French population the father was more likely to pass on the mutation (219 vs. 216), although not by much. The one thing these populations do have in common is this form of the disease is almost exclusively neurologic in nature.

Thr60Ala

This variant is most commonly found in the UK and Irish populations, and is also seen in the Appalachian region of the United States. This variant presents as a mixture of both cardiomyopathy and neuropathy symptoms. It seems to be that in early stages of the disease the neurologic symptoms are most prevalent, but cardiac symptoms present at diagnosis seem to indicate poorer patient outcomes.

Thr119Met

This is arguably the most interesting variant that was investigated in a large study of the Danish population. The presence of this mutation actually confers a protective benefit. When this mutation occurs along with the Val30Met mutation, it has the effect of stabilizing and delaying, even preventing transthyretin amyloidosis.

PROGNOSIS

While the prognosis is by no means near perfect, it is improving. There is continued advancement in the field of transthyretin amyloidosis, whether it be improving diagnostic methods, drug development, or a potential cure on the horizon with CRISPR gene-editing technology. Having said that, there continue to be significant barriers to diagnosis. The importance of being an astute clinician to suspect and work up for amyloidosis remains at the forefront of the challenge.

CONCLUSION

The geographic nature of this disease plays an important role in identifying and diagnosing amyloidosis. Having an understanding of how the presentation of the disease is heavily related to the patient’s ancestry and location around the world. The hardest part is suspecting amyloidosis, from there don’t forget the value of the diagnostic tools at your disposal, including genetic testing. Use this knowledge to strengthen and guide your suspicions of amyloidosis!

Over the upcoming months we’ll post blogs delving deeper into some of these variants, so stay tuned.

Thanks for reading,

Mackenzie

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SOURCES

Per the National Institute of Health, “One of the most promising areas of research in recent years has been gene editing, including CRISPR/Cas9, for fixing misspellings in genes to treat or even cure many conditions.” In this piece we provide a clinical trial update for transthyretin (TTR) amyloidosis using this technology.

CRISPR FIXES GENES INSIDE THE BODY (3)

CRISPR is a highly precise gene-editing system that uses guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct disease-causing misspellings.

APPLYING THE CRISPR TECHNOLOGY (3)

Science highlights a small study reported in The New England Journal of Medicine by researchers at Intellia Therapeutics, Cambridge, MA, and Regeneron Pharmaceuticals, Tarrytown, NY, in which six people with hereditary transthyretin (TTR) amyloidosis, a condition in which TTR proteins build up and damage the heart and nerves, received an infusion of guide RNA and CRISPR RNA encased in tiny balls of fat.The goal was for the liver to take them up, allowing Cas9 to cut and disable the TTR gene. Four weeks later, blood levels of TTR had dropped by at least half.”

Facts about Transthyretin (ATTR) Amyloidosis. Source: https://ir.intelliatx.com/

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

Intellia Therapeutics and Regeneron shared a press release recently announcing initial data from the cardiomyopathy arm of the ongoing Phase 1 trial of NTLA-2001, an investigational single-dose in vivo CRISPR-Cas9 therapy for the treatment of transthyretin (ATTR) amyloidosis.

According to that press release, the interim data include 12 adult patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM) with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 were administered intravenously, and the change from baseline in serum transthyretin (TTR) protein concentration was measured for each patient. The data revealed that treatment with NTLA-2001 led to rapid and deep reductions of up to 94 % in serum TTR by day 28. In February 2022, the companies reported clinical data that revealed rapid, deep and sustained responses in a cohort of 15 patients with hereditary transthyretin (TTR) amyloidosis with polyneuropathy (ATTRv-PN).

ATTR is a rare, progressive disease, in which a protein known as TTR becomes misfolded and accumulates as plaques in tissues throughout the body. This causes serious complications that mainly involve the heart and nerves, and most patients die 2-15 years after disease onset. NTLA-2001 was the first in vivo CRISPR therapy to be administered to humans via the bloodstream. It is designed to treat ATTR by selectively reducing the levels of mutated TTR protein in the blood, through CRISPR-based inactivation of the TTRgene in liver cells.

Read more about the available clinical data for NTLA-2001 in a previous CMN clinical trial update here.

BACKGROUND

Back in May, 2021 we wrote about the breakthrough gene-editing technology CRISPR being applied to hereditary transthyretin amyloidosis (hATTR), worthy of a background read for those unfamiliar with this science or those looking for a refresher.

BLOG – CRISPR/Cas9 – Editing the Code of Life

Sources:

We would like to thank the Cleveland Clinic for this information, unless specifically noted otherwise.

WHAT IS HEART FAILURE?

Heart failure occurs when the heart muscle doesn’t pump blood as well as it should. Heart failure can occur if the heart cannot pump (systolic) or fill (diastolic) adequately.

Almost six million Americans have heart failure, and more than 870,000 people are diagnosed with heart failure each year. Heart failure (congestive heart failure) is the leading cause of hospitalization in people older than 65.

WHAT ARE THE TYPES OF HEART FAILURE?

There are many causes of heart failure, but the condition is generally broken down into these types:

Left-sided heart failure

Heart failure with reduced left ventricular function (HF-rEF)

The lower left chamber of the heart (left ventricle) gets bigger and cannot squeeze (contract) hard enough to pump the right amount of oxygen-rich blood to the rest of the body.

Heart failure with preserved left ventricular function (HF-pEF)

The heart contracts and pumps normally, but the bottom chambers of the heart (ventricles) are thicker and stiffer than normal. Because of this, the ventricles can’t relax properly and fill up all the way. Because there’s less blood in the ventricles, the heart pumps out less blood to the rest of the body when it contracts.

Right-sided heart failure

Heart failure can also affect the right side of the heart. Left-sided heart failure is the most common cause of this. Other causes include certain lung problems and issues in other organs.

WHAT ARE THE SYMPTOMS OF HEART FAILURE?

Symptoms of heart failure include:

Shortness of breath.
Feeling tired (fatigue) and having leg weakness when active.
Swelling in ankles, legs and abdomen.
Weight gain.
Need to urinate while resting at night.
Rapid or irregular heartbeats (palpitations).
A dry, hacking cough.
A full (bloated) or hard stomach, loss of appetite or upset stomach (nausea).

Symptoms of heart failure can range from mild to severe and may come and go. Unfortunately, heart failure usually gets worse over time. As it worsens, patients may have more or different signs or symptoms.

WHAT CAUSES HEART FAILURE?

Although the risk of heart failure doesn’t change with age, you’re more likely to have heart failure when older. Many medical conditions that damage the heart muscle can cause heart failure. Common conditions include:

Coronary artery disease.
Heart attack.
Cardiomyopathy.
Heart issues present at birth (congenital heart disease).
Diabetes.
High blood pressure (hypertension). This is a common cause in people assigned female at birth.
Arrhythmia (abnormal heart rhythms, including atrial fibrillation).
Kidney disease.
Having obesity.
Tobacco and recreational drug use.
Medications. Some drugs used to fight cancer (chemotherapy) can lead to heart failure.

WHAT TYPES OF TESTS ARE USED TO DIAGNOSE HEART FAILURE?

Common tests include:

WHAT IS THE IMPORTANCE OF EJECTION FRACTION?

Ejection fraction (EF) is one way to measure the severity of the condition. If it’s below normal, it can mean the patient has heart failure. The ejection fraction tells the healthcare provider how good of a job the left or right ventricle is doing at pumping blood. Usually, the EF number is talking about how much blood the left ventricle is pumping out because it’s the heart’s main pumping chamber.

Several non-invasive tests can measure the EF. A normal left ventricular ejection fraction (LVEF) is 53% to 70%. An LVEF of 65%, for example, means that 65% of the total amount of blood in the left ventricle is pumped out with each heartbeat. The EF can go up and down, based on the heart condition and how well the treatment works.

HOW IS AMYLOIDOSIS RELATED TO HEART FAILURE?

As stated by the Cleveland Clinic, cardiomyopathy is one of the medical conditions that damage the heart muscle and can cause heart failure. Cardiomyopathy refers to conditions that affect the myocardium (heart muscle). Cardiomyopathy can make your heart stiffen, enlarged or thickened and can cause scar tissue. As a result, your heart can’t pump blood effectively to the rest of your body. In time, your heart can weaken and cardiomyopathy can lead to heart failure.

One of the common types of cardiomyopathy is Transthyretin amyloid cardiomyopathy (ATTR-CM), characterized by an abnormal protein buildup (ATTR amyloidosis) in the heart’s left ventricle (primary blood-pumping chamber). ATTR-CM is a life-threatening, underrecognized, and underdiagnosed type of amyloidosis that affects the heart and is associated with heart failure. It was once considered a rare disease, but recently, improved diagnostic tools and greater attention to early manifestations of the disease are leading to an increasing number of diagnosed cases. (3)

Listen to an American Heart Association podcast (12 minutes) titled “What is ATTR-CM?”

ATTR-CM Basics (5)

Recent Research (4)

Davies et al.(2022) published an informative paper titled “A Simple Score to Identify Increased Risk of Transthyretin Amyloid Cardiomyopathy in Heart Failure with Preserved Ejection Fraction.” In conclusion, they believe their findings can increase recognition of ATTR-CM among patients with HFpEF in the community.

Key Points

Question. Which patients with heart failure and preserved ejection fraction (HFpEF) have an increased risk of transthyretin amyloid cardiomyopathy (ATTR-CM) warranting technetium Tc 99m pyrophosphate scintigraphy?

Findings. The study team developed and validated an ATTR-CM score comprising of 3 clinical (age, male sex, hypertension diagnosis) and 3 echocardiographic (ejection fraction, posterior wall thickness, relative wall thickness) variables to predict increased risk of ATTR-CM in HFpEF cohorts with variable ATTR-CM prevalence.

Meaning. Because specific and highly effective therapy for ATTR-CM exists, the ATTR-CM score can provide a simple tool to guide use of technetium Tc 99m pyrophosphate scintigraphy and increase recognition and appropriate therapy of ATTR-CM in patients with HFpEF.

Abstract

Importance. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a form of heart failure (HF) with preserved ejection fraction (HFpEF). Technetium Tc 99m pyrophosphate scintigraphy (PYP) enables ATTR-CM diagnosis. It is unclear which patients with HFpEF have sufficient risk of ATTR-CM to warrant PYP.

Objective To derive and validate a simple ATTR-CM score to predict increased risk of ATTR-CM in patients with HFpEF.

Design, Setting, and Participants. Retrospective cohort study of 666 patients with HF (ejection fraction ≥ 40%) and suspected ATTR-CM referred for PYP at Mayo Clinic, Rochester, Minnesota, from May 10, 2013, through August 31, 2020. These data were analyzed September 2020 through December 2020. A logistic regression model predictive of ATTR-CM was derived and converted to a point-based ATTR-CM risk score. The score was further validated in a community ATTR-CM epidemiology study of older patients with HFpEF with increased left ventricular wall thickness ([WT] ≥ 12 mm) and in an external (Northwestern University, Chicago, Illinois) HFpEF cohort referred for PYP. Race was self-reported by the participants. In all cohorts, both case patients and control patients were definitively ascertained by PYP scanning and specialist evaluation.

Main Outcomes and Measures. Performance of the derived ATTR-CM score in all cohorts (referral validation, community validation, and external validation) and prevalence of a high-risk ATTR-CM score in 4 multinational HFpEF clinical trials.

Results. Participant cohorts included were referral derivation (n = 416; 13 participants [3%] were Black and 380 participants [94%] were White; ATTR-CM prevalence = 45%), referral validation (n = 250; 12 participants [5%]were Black and 228 participants [93%] were White; ATTR-CM prevalence = 48% ), community validation (n = 286; 5 participants [2%] were Black and 275 participants [96%] were White; ATTR-CM prevalence = 6% ), and external validation (n = 66; 23 participants [37%] were Black and 36 participants [58%] were White; ATTR-CM prevalence = 39%). Score variables included age, male sex, hypertension diagnosis, relative WT more than 0.57, posterior WT of 12 mm or more, and ejection fraction less than 60% (score range −1 to 10). Discrimination (area under the receiver operating characteristic curve [AUC] 0.89; 95% CI, 0.86-0.92; P < .001) and calibration (Hosmer-Lemeshow; χ2 = 4.6; P = .46) were strong. Discrimination (AUC ≥ 0.84; P < .001 for all) and calibration (Hosmer-Lemeshow χ2 = 2.8; P = .84; Hosmer-Lemeshow χ2 = 4.4; P = .35; Hosmer-Lemeshow χ2 = 2.5; P = .78 in referral, community, and external validation cohorts, respectively) were maintained in all validation cohorts. Precision-recall curves and predictive value vs prevalence plots indicated clinically useful classification performance for a score of 6 or more (positive predictive value ≥25%) in clinically relevant ATTR-CM prevalence (≥10% of patients with HFpEF) scenarios. In the HFpEF clinical trials, 11% to 35% of male and 0% to 6% of female patients had a high-risk (≥6) ATTR-CM score.

Conclusions and Relevance A simple 6 variable clinical score may be used to guide use of PYP and increase recognition of ATTR-CM among patients with HFpEF in the community.

In closing … a known condition of heart failure is cardiomyopathy, of which one type – Transthyretin Amyloid Cardiomyopathy (ATTR-CM) – may be the underlying cause. In seeking answers to heart failure, keep this in mind.

Sources:

https://www.heart.org/-/media/Files/Health-Topics/Answers-by-Heart/What-Is-ATTRCM.pdf

The connection between carpal tunnel and amyloidosis is one that is already established. In fact, carpal tunnel syndrome is one of many potential symptoms of amyloidosis, but it is a symptom that tends to present early. It is not uncommon to hear patients started experiencing carpal tunnel five to ten years before they were diagnosed with amyloidosis.

TWO STUDIES

Clinicians are becoming aware of this connection and are starting to investigate the connection. Two studies have been published that investigate the connection between carpal tunnel and amyloidosis.

The first study from 2018 was a “prospective, cross-sectional, multidisciplinary study of consecutive men age ≥ 50 years and women ≥ 60 years undergoing carpal tunnel release surgery. Biopsy specimens of tenosynovial tissue were obtained and stained with Congo red.”³ Of the patients that were eligible for Congo red staining (n=98), a total of 10 came back positive for amyloidosis.³ That is a hit rate of just over 10%.

In a larger second study from 2022, a total of 185 patients underwent carpal tunnel release surgery, where 54 biopsies confirmed evidence of amyloidosis with Congo red staining.¹ That is a hit rate of 29%.

The results of these studies are powerful and provide an opportunity to change the trajectory of diagnosing amyloidosis, particularly doing so much earlier. According to the Bureau of Labor and Statistics and the National Institute for Occupational Safety and Health, carpal tunnel release surgery is the second most common type of surgery, performed over 230,000 times every year.⁴

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

“Since carpal tunnel syndrome is often one of the earliest signs of underlying amyloidosis, those with undiagnosed disease could greatly benefit from tissue biopsies at the time of surgery. A positive biopsy result could initiate the road to disease stabilization and hopefully future cures, avoiding the all-too-often rapid decline of health before final recognition. Bringing the surgeon into the arena of amyloidosis diagnosis and care broadens the net for catching this disease early and prepares the surgeon as a team-player for future medical support.”

Charles Williams Sr., MD

Retired Orthopedic Surgeon

CONCLUSION

Screening for amyloidosis in carpal tunnel release surgery can be a low-cost method of detecting amyloidosis that should be considered.²

Most importantly, identifying and diagnosing amyloidosis early has the potential to significantly improve patient outcomes and substantially alter the course of disease.

Truly life changing.

P.S. Click here to read our previous post on Carpal Tunnel & Amyloidosis

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Resources:

Over the course of the past two months, we spent time discussing two of the most common hallmark symptoms of ATTR amyloidosis: cardiomyopathy and peripheral neuropathy. In this article, we’ll briefly recap both hallmark symptoms as well as bring it all together by discussing the two most common forms of ATTR amyloidosis: ATTR cardiomyopathy (ATTR-CM) and ATTR peripheral neuropathy (ATTR-PN).

To recap …

Cardiomyopathy

Cardiomyopathy is a broad term that is used to describe disease of the heart muscle, making it difficult for the heart to provide the body with an adequate blood supply. It is a common cause of sudden cardiac arrest and sudden cardiac death, which can lead to heart failure and even death.

Types of Cardiomyopathy:

Dilated Cardiomyopathy → dilation of the left ventricle prevents the heart from pumping effectively
Hypertrophic Cardiomyopathy → abnormal thickening of the heart muscle most commonly surrounding the left ventricle
Restrictive Cardiomyopathy → stiffening of the heart muscle results in an inelasticity
Arrhythmogenic Right Ventricular Dysplasia → scar tissue replaces healthy tissue of the right ventricle
Unclassified Cardiomyopathy → all other forms of cardiomyopathy fall within this category

Peripheral Neuropathy

Peripheral neuropathy, also referred to as polyneuropathy, is a very broad term used to describe damage of the peripheral nerves. Damage to these nerves most commonly causes numbness, pain, and weakness but can affect other areas of the body including, but not limited to, circulation, digestion, and urination.

Types of Neuropathy:

Motor Neuropathy → damage to the motor nerves
Sensory Neuropathy → damage to sensory nerves
Autonomic Nerve Neuropathy → damage to autonomic nerves that control involuntary functions
Combination Neuropathies → damage to a mix of 2 or 3 of these other types of neuropathies

ATTR Amyloidosis

The origin of this disease can be genetic (hATTR) or non-genetic, or “wild-type” (wtATTR). Regardless, in ATTR amyloidosis, the transthyretin (TTR) protein is misfolded and aggregates, forming amyloid fibers that deposit into tissues and organs. The deposition of protein causes organ dysfunction and can even cause organ failure and death.

ATTR-CM and ATTR-PN

Depending on the location of protein deposition, the disease is referred to in different ways. For instance, when the primary location of amyloid deposit is in the heart, the disease is referred to as ATTR cardiomyopathy (ATTR-CM). On the other hand, when the primary location of amyloid deposit is in the nerves, the disease is referred to as ATTR peripheral neuropathy (ATTR-PN).

ATTR-CM impairs the heart’s ability to pump effectively. A major challenge surrounding this disease is that symptoms of ATTR-CM are often similar to other heart conditions like enlarged heart and heart failure. This makes diagnosing the disease increasingly more difficult. Individuals with hATTR typically present symptoms in their 50s and 60s, whereas those with wtATTR may not present symptoms until their 70s and later.

Common Symptoms of ATTR-CM:

Fatigue
Swelling of legs, ankle, or abdomen
Shortness of breath with activity
Orthostatic hypotension
Difficulty breathing when lying down
Arrhythmia

ATTR-PN impairs the function of the nervous system. While amyloid most commonly builds up in the peripheral nervous system, deposition can also occur in the autonomous system. This results in a diversity of symptoms that are specific to the site of amyloid deposition. Symptom presentation is much more diverse, occurring as early as the 20s, or as late in life as the 70s.

Common Symptoms of ATTR-PN:

Carpal tunnel syndrome
Diarrhea and/or constipation
Nausea, vomiting
Loss of appetite
Sexual dysfunction
Muscle weakness
Eye problems
Orthostatic hypotension

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References:

https://www.pfizer.com/news/articles/understanding_this_rare_disease_called_attr_amyloidosis

https://www.mayoclinic.org/diseases-conditions/cardiomyopathy/symptoms-causes/syc-20370709

https://www.yourheartsmessage.com

https://healthjade.net/familial-amyloidosis/

https://my.clevelandclinic.org/health/diseases/14737-neuropathy

https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-neuropathy

https://www.mayoclinic.org/diseases-conditions/peripheral-neuropathy/symptoms-causes/syc-20352061

https://practicalneurology.com/articles/2021-july-aug/neuromuscular-amyloidosis

https://healthjade.net/familial-amyloidosis/

Alnylam Announces FDA Approval of AMVUTTRA™ (vutrisiran), an RNAi Therapeutic for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

– First and Only FDA-approved Treatment Demonstrating Reversal in Neuropathy Impairment with Subcutaneous Administration Once Every Three Months

– AMVUTTRA Met Primary and All Secondary Endpoints, with Significant Improvement in Polyneuropathy, Quality of Life and Gait Speed Relative to External Placebo

– Company Expects to Launch in Early July, with Value-Based Agreements to Accelerate Access

The FDA approval is based on positive 9-month results from the HELIOS-A Phase 3 study, where AMVUTTRA significantly improved the signs and symptoms of polyneuropathy, with more than 50 percent of patients experiencing halting or reversal of their disease manifestations.

Following yesterday’s U.S. FDA approval, people in the U.S. prescribed AMVUTTRA (vutrisiran) and their families can now enroll in Alnylam Assist, our patient support services program, to receive help accessing this new therapy. https://bit.ly/3HjOg5Q

PRESS RELEASE

According to Alnylam Pharmaceuticals, “Americans of Portuguese descent are disproportionately impacted by hereditary ATTR (hATTR) amyloidosis, a rare, rapidly progressive, and debilitating disease affecting multiple organs and tissues. These individuals have a high prevalence of the V30M variant, which is the most common of the more than 120 gene variants known to be associated with hATTR amyloidosis. The V30M variant is associated with nerve symptoms of numbness, tingling, and burning pain in hands and feet. People of Portuguese descent who develop the disease experience earlier onset symptoms, with 87 percent experiencing symptoms before age 40.

Watch this informative news segment featuring Dr. Anthony Geraci, a neurologist who specializes in managing hATTR amyloidosis. He is joined by Julio, who was diagnosed with the disease a few years ago, and his daughter and caregiver Renee. Together they explore the experience of living with this rare, genetic disease.”

The good news is there are FDA-approved treatments and clinical trials which may be helpful; however, the key is to get diagnosed as early as possible.

Our mission is to educate future doctors about amyloidosis, with the belief that heightened awareness will lead to earlier diagnosis and ultimately improve patient survivorship. We know that the level of medical school education about amyloidosis runs the gamut, from a small mention in textbooks to classroom discussions with medical professionals, although the bias is overwhelmingly towards the “minor mention.” In addition, you’ll read below about our exciting expansion into residency programs – those new physicians now practicing and diagnosing patients. As a result, we are confident our efforts will provide a valuable enriched exposure to this disease to augment the medical school curriculum and residency didactic programs.

EXECUTIVE SUMMARY

Last year, we set our 2021 goal at 60 presentations, with hopes that the year would emerge from the 2020 pandemic onset. For the most part, it did. We gave 34 presentations in the Spring, and 27 presentations this Fall. Combined, these 61 presentations were to more than 2,400 medical students and physicians! Go us!

Of the 61 presentations, 59 were virtual and 2 were in-person. Of note, both of the in-person were to our newly launched residency program outreach. Schools, with students returning to in-person in the Fall, remained largely closed to guests. Looking ahead we anticipate seeing a few more in-person, but virtual is likely here to remain in a big way for the foreseeable future.

Our recent expansion into internal medicine residency programs (over 550 of them across the U.S.) has already resulted in 6 presentations on the calendar for 2021 and 2022. Our custom video specifically focused for this audience has been very well received and provides an excellent clinical educational complement to our patient stories.

We average around 35-40 speakers, which allows for diversity in our speaker population’s disease state and flexibility in their availability. This has served us well. (more on that below)

We are particularly delighted that our medical school student mailing list – those interested post-presentation in continuing to receive information about amyloidosis – continues to grow and is now around 350! Each month we email brief information about some aspect of amyloidosis, with the content pulled from experts and other trusted organizations. Our goal is to keep amyloidosis in their mind as they approach graduation and begin seeing patients.

In October we held our first webinar, “Discover the Power of the Patient/Physician Collaboration” with guests Dr. Rodney Falk and hereditary ATTR patient Sean Riley. We ourselves were very pleased with the discussion and insights, although the attendance fell short of expectations for medical student turnout.

With the help of one of our speakers Dr. Kathy Rowan, a professor in social science, we received approval from George Mason University’s IRB (Institutional Review Board) in August and launched a study to understand the impact and effectiveness of our educational offering to medical students. At present, we are in data collection mode and anticipate in 2022 we will transition to analysis of the data. If the conclusions are insightful, we intend to seek publication.

Each Spring and Fall we reach out to medical school deans, updating them on our activities.

THE NUMBERS

Our target universe is approximately 160 continental U.S.-based medical schools – both their curriculums and student interest groups, and over 580 internal medicine residency programs.
We gave 61 presentations in 2021, and have 13 already booked for 2022.
Since the ASB started in the Fall of 2019, we now total 153 presentations, to approximately 6,900 students and physicians. A complete list of schools and resident programs can be found below.
Of the 2021 presentations, roughly 20% of the presentations were within the curriculum; 75% to student interest groups, and 5% to residency programs.

SPEAKERS

The cornerstone of our effort is our group of wonderful patient speakers, who passionately volunteer their time to give back and share their stories of life with amyloidosis.

Our speaker group is diversified by geography across the continental U.S., by amyloidosis type, by organ involvement, by gender and age. This is a rather deep bench, but we have found it both helpful and necessary. Helpful in that we can maximize attendance if we work around the preferred dates and times suggested by the schools. Helpful in that we can match specific disease states with audience focus (e.g., a cardiac amyloidosis patient speaker to a cardiology student interest group). Also, helpful in rotating speakers and types of disease at each school, since we are regularly returning to groups which have overlapping students. And necessary in that periodically, a speaker’s personal situation may change and they need to step back either temporarily, or permanently. We are delighted that our group is fairly stable and increasingly seasoned and experienced in sharing their stories. That said, we are fortunate to have a steady pipeline of new speaker interest, which we spend time screening, qualifying and training to bring online – only if needed (so it’s rare we add new speakers these days). At present, we feel this is an appropriate number of speakers for our current and anticipated growth.

Thanks to two of our speakers who have extensive experience, we offer in-depth guidance for new speakers, and current speakers wanting a ‘refresh’ in the development of their presentation outline and rehearsal training for their delivery. In addition, prior to most virtual presentations we rehearse and test the new speakers’ audio and video technology. For those partaking, it has been an appreciated additional level of support and we believe is translating to a higher quality offering.

ADVISORS

We are proud to have an impressive group of medical experts and influencers in the world of amyloidosis, some of whom are also patients, as advisors to support our initiative. Our advisors are active in our efforts and contribute their specialized expertise in a variety of ways, such as medical school introductions, grant requests, educational development, and patient speaker assessment/development. We are extremely grateful for their assistance and believe that, thanks to their contribution, the ASB will make an even bigger difference in the diagnoses of this disease. You can see our prestigious list of advisors on our website page www.mm713.org/speakers-bureau/

TESTIMONIALS – OUR TRUE REPORT CARD

Feedback from students and medical school professors has been extraordinarily positive. It reinforces to us that candid and authentic patient stories are a valuable complement to the medical school curriculum, strengthening the learning and deepening the durability for these future doctors about this disease. This is exactly why we do what we do. Here are just a few of the testimonials.

The opportunity for second year medical students to hear the story of a patient with amyloid is invaluable. The presentation addressed aspects of pathophysiology they are learning and the human side of medicine. This presentation format offered an excellent teaching opportunity to inform doctors-in-training about this serious disease. Our students gained insight into the patient’s journey through diagnosis, treatment and the challenges ahead. We all appreciated the patient’s generosity in sharing her experiences. Having patients teaching medical students about amyloidosis will have a lasting impact on our future doctors with increasing awareness of this disease and ultimately will help future patients. Theresa Kristopaitis, M.D., Professor, Assistant Dean for Curriculum Integration, Loyola University Stritch School of Medicine

Such a powerful presentation that I will carry with me throughout my whole career, no matter what specialty I go into! I not only learned the importance of keeping amyloidosis on my differential, but also the importance of really listening to your patients and working through the hard diagnoses together. Solana Archuleta, MD Candidate, University of Colorado School of Medicine

I had several students make comments after the conclusion of the presentation that it was the best, one even said ‘exceptional,’ presentations given at our school from a patient. The materials gave all of the students, including myself, a great introduction to some of the pertinent findings in patients with amyloidosis. Co-President of the Internal Medicine Interest Group, University of Arizona College of Medicine, Phoenix

Hearing Ed talking about his journey with Amyloidosis was an incredible experience that only further inspired me to want to be a better physician for my future patients. It is one thing to learn about a condition in the classroom, but hearing the real-world struggles with it from another human being provides a whole new perspective. Ed was open about his journey and shared his feelings during each step, giving us insight into what it is like to be a patient with Amyloidosis. I will take what I learned from this presentation and apply it in order to ensure that patients I see in the future do not have to deal with the same issues that Ed had to deal with. Gurkaran Singh, MD Candidate, University of Arizona College of Medicine, Tucson

Diseases such as amyloidosis are often managed by specialists, but it is important for primary care physicians to recognize these signs and direct these patients to these specialists. Increasing awareness of these diseases among all physicians will help patients reach an answer sooner and can have a significant impact on their lives. Yue Zhang, MD Candidate, Northwestern Feinberg School of Medicine

We are saddened that we lost our co-founder Charolotte Raymond earlier this year, losing her battle with AL amyloidosis. Charolotte was our true inspiration for the Amyloidosis Speakers Bureau, and we know her passion for educating future physicians will be our guiding light. To keep our patient-led focus, we were thrilled to have one of our speakers, Lane Abernathy, join our Operating Committee. Lane, an amyloidosis patient herself, brings wonderful energy, experience and passion to help manage our efforts. We feel thankful to have her with us.

An additional word about our growing list of passionate volunteers, the majority of whom are active speakers. They help our efforts across many aspects of our operations, from management, to speaker development, to research, and video production. Their dedication to our effort is a testament of their belief in what we are doing to educate areas of the medical community, and we thank them all.

We are pleased with all we have accomplished thus far, energized by the feedback, cognizant that we have much ahead, and hope we have made you proud. After all, we can’t do any of this without you! As always, we welcome any comments you may have.

Stay safe, happy holidays to you and your family, and all the best for a new 2022!

Mackenzie, Lane, and Deb

Operating Committee of the Amyloidosis Speakers Bureau, sponsored by Mackenzie’s Mission

Our initiative is being well received by medical schools across the country. Below is a list of schools we have presented to at least once a year, whether through their curriculum or interest groups. After that, is the growing list of internal medicine residency programs where we also have presented.

MEDICAL / D.O. SCHOOLS

Albert Einstein College of Medicine
Baylor College of Medicine
California University of Science & Medicine, School of Medicine, San Bernardino
Case Western Reserve School of Medicine
Central Michigan University College of Medicine
Chicago Medical School, Rosalind Franklin University of Medicine and Science
Cleveland Clinic Lerner College of Medicine
Columbia University Vagelos College of Physicians and Surgeons
Drexel University College of Medicine
Florida Atlantic University Charles E. Schmidt College of Medicine
Florida International University Herbert Wertheim School of Medicine
Florida State University College of Medicine
Geisinger Commonwealth School of Medicine
George Washington School of Medicine
Icahn School of Medicine at Mount Sinai
Lake Erie College of Osteopathic Medicine
Lewis Katz School of Medicine at Temple University
Loyola University Chicago Stritch School of Medicine
Mayo Clinic Alix School of Medicine, Rochester
Mayo Clinic Alix School of Medicine, Scottsdale
Northeast Ohio Medical University College of Medicine
Northwestern University Feinberg School of Medicine
NYU Grossman School of Medicine
Oakland University William Beaumont School of Medicine
Quinnipiac University Frank H Netter MD School of Medicine
Stanford University School of Medicine
Touro College of Osteopathic Medicine in New York City
Tufts University School of Medicine
University of Arizona College of Medicine, Phoenix
University of Arizona College of Medicine, Tucson
University of California Irvine School of Medicine
University of California San Francisco School of Medicine
University of Central Florida College of Medicine
University of Chicago Pritzker School of Medicine
University of Cincinnati College of Medicine
University of Colorado School of Medicine
University of Connecticut School of Medicine
University of Florida College of Medicine
University of Hawaii, John A. Burns School of Medicine
University of Illinois College of Medicine, Chicago
University of Illinois College of Medicine, Peoria
University of Illinois College of Medicine, Rockford
University of Iowa Carver College of Medicine
University of Kansas School of Medicine, Wichita
University of Maryland School of Medicine
University of Massachusetts Medical School
University of Minnesota Medical School
University of Missouri Kansas City School of Medicine
University of Nevada Reno, School of Medicine
University of Pittsburgh School of Medicine
University of South Alabama College of Medicine
University of South Carolina School of Medicine, Columbia
University of Toledo College of Medicine
UNLV School of Medicine
Virginia Commonwealth University School of Medicine
Wayne State University School of Medicine
Wright State University Boonshoft School of Medicine
Yale School of Medicine

RESIDENCY PROGRAMS

Central Maine Medical Center
Meharry Medical College Program
Michigan State University Program, Sparrow Hospital
St. Francis Medical Center Program, Jersey Shore University Medical Center
Texas Institute for Graduate Medical Education and Research (TIGMER) Laredo Internal Medicine Residency Program
Western Michigan University Homer Stryker M.D. School of Medicine

In this unique webinar, you will hear Dr. Rodney H. Falk and his patient Sean Riley discuss the importance of patient/physician collaboration in diagnosis, using Sean’s personal journey to illustrate the challenges of diagnosing hereditary amyloidosis, a life-threatening rare disease that hides in plain sight.

Hear how listening, observing, and questioning are critical to getting to a diagnosis, along with the recommendation for providers to always bring an elevated suspicion and curiosity to find answers.

Header

Slider

WHAT IS TRANSTHYRETIN (TTR)

SPECIFIC TTR PATHOGENIC VARIANTS

Val122Ile

Val30Met

Thr60Ala

Thr119Met

PROGNOSIS

CONCLUSION

CRISPR FIXES GENES INSIDE THE BODY (3)

APPLYING THE CRISPR TECHNOLOGY (3)

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

BACKGROUND

WHAT IS HEART FAILURE?

WHAT ARE THE TYPES OF HEART FAILURE?

Left-sided heart failure

Right-sided heart failure

WHAT ARE THE SYMPTOMS OF HEART FAILURE?

WHAT CAUSES HEART FAILURE?

WHAT TYPES OF TESTS ARE USED TO DIAGNOSE HEART FAILURE?

WHAT IS THE IMPORTANCE OF EJECTION FRACTION?

HOW IS AMYLOIDOSIS RELATED TO HEART FAILURE?

Listen to an American Heart Association podcast (12 minutes) titled “What is ATTR-CM?”

ATTR-CM Basics (5)

Recent Research (4)

Key Points

Abstract

In closing … a known condition of heart failure is cardiomyopathy, of which one type – Transthyretin Amyloid Cardiomyopathy (ATTR-CM) – may be the underlying cause. In seeking answers to heart failure, keep this in mind.

TWO STUDIES

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

CONCLUSION

Cardiomyopathy

Types of Cardiomyopathy:

Peripheral Neuropathy

Types of Neuropathy:

ATTR Amyloidosis

ATTR-CM and ATTR-PN

EXECUTIVE SUMMARY

THE NUMBERS

SPEAKERS

ADVISORS

TESTIMONIALS – OUR TRUE REPORT CARD

MEDICAL / D.O. SCHOOLS

RESIDENCY PROGRAMS

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