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Historically it has been thought that the majority of elderly cardiomyopathy patients diagnosed with amyloidosis, ATTR-CM, transthyretin amyloid cardiomyopathy, suffered from wild-type, a non-genetic version of the disease that most commonly affects but is not exclusive to men over seventy years of age. A study in the UK conducted from January 2010 through August 2022 was conducted to determine whether this was true. It is thought that this study was the first time such a large population of ATTR-CM patients was studied to consider the actual prevalence of the differing disease types. The researchers stated purpose was “ …to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM.”¹

A paper detailing the results of the study, ‘Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy’ by A. Porcari et al.¹, published January 16, 2023 in the European Journal of Heart Failure provide specifics about the methodology, statistical analysis of the results, and an analysis of the findings. An invited editorial about that article, ‘Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?’, by Osnat Itzhaki Ben Zadok and Rodney H. Falk provides comments and an assessment of the study discussed in the A. Porcari paper.² A helpful summary of the differences between wild-type and hereditary amyloidosis can be found here.³

With increased awareness of amyloidosis and the various types as well as developments in the technology used to diagnose and type ATTR amyloidosis, it has now become relatively easy to determine whether a patient is suffering from the hereditary version or the wild-type. Imaging has become preferred over the previous “gold standard” of endomyocardial biopsy. The study population was selected from those for whom ATTR-CM was established as the diagnosis using echocardiography, nuclear scintigraphy, and TTR gene sequencing at the National Amyloidosis Center (NAC) in London, the single center for diagnosing and treating amyloidosis patients in the UK. Correct diagnosis and typing of the disease could allow for appropriate treatment to begin resulting in the likelihood of an improved disease management and outcome for the patient.

A total of 2,029 patients were accepted into the study, none of whom had previously received genetic testing for the disease. Patients identified through gene sequencing as having the hereditary version of the disease, 141 total, were moved to medication as soon as it became available. Of note, all patients who had been treated with any of the then available medication for ATTR amyloidosis — tafamidis, inotersen, diflunisal, or patisiran, and all patients who were participating in clinical trials for therapies for the disease — were excluded from the study. This was to remove the possibility of the therapies skewing the results. All participants were 70 years of age or older. The patients were all followed at the NAC in London, the only center for the diagnosis and treatment of Amyloidosis in the UK. This allowed for unprecedented access to what is thought to be the majority of ATTR-CM in the country. All causes of death were tracked for the duration of the study.

The table below illustrates the number of ATTM-CM patients in the study who were thought to be suffering from wild-type amyloidosis but after testing were actually found to have a hereditary, variant, version of the disease instead. Specific data from the tests used to make this determination can be found in the article where the following table is found.

Correcting the diagnosis then allowed the patients to be moved to more appropriate therapies.

Further discussion in the Porcari article considers the study population and those currently listed in the THAOS registry⁴ by percentage of total ATTR-CM patients in the United Kingdom, the United States, and the rest of the World for both wild-type and variant disease with the more common variants also identified. It is thought that as many as 20% of ATTR-CM identified as having the wild-type disease likely have a variant version but have not had genetic testing to correctly determine that.¹

The article goes on to discuss the most commonly seen demographics and presentations of ATTRwt-CM and ATTRv-CM in the elderly, and the effects of the various therapies currently available as well as their mechanisms and limitations.

While some symptoms of wild-type amyloidosis and hereditary, variant, amyloidosis are similar, it is easy to differentiate between the two diseases. With careful testing, as noted in the article, this then allows for the proper management and treatment of the disease. The concluding paragraph of the paper really sums up the findings and sends an important message.

“In conclusion, up to 20.7% of elderly patients with ATTR-CM carry a pathogenic TTR mutation with a higher proportion still among specific ethnic groups. Among patients diagnosed with ATTR-CM, younger age at diagnosis, female gender, Afro-Caribbean ethnicity, AF, IHD, polyneuropathy and orthostatic hypotension are independently associated with ATTRv-CM. A diagnosis of ATTR-CM should prompt sequencing of the TTR gene in all patients, regardless of age, gender and ethnicity.”¹

Sources:
1. https://onlinelibrary.wiley.com/doi/full/10.1002/ejhf.2776 Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy, Aldostefano Porcari, Yousuf Razvi, Ambra Masi, Rishi Patel, Adam Ioannou, Muhammad U. Rauf, David F. Hutt, Dorota Rowczenio, Janet Gilbertson, Ana Martinez-Naharro, Lucia Venneri, Carol Whelan, Helen Lachmann, Ashutosh Wechalekar, Candida Cristina Quarta, Marco Merlo, Gianfranco Sinagra, Philip N. Hawkins, Marianna Fontana, Julian D. Gillmore, January 2023

2. https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2808 Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?
Osnat Itzhaki Ben Zadok, Rodney H. Falk, February 2023

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500251/ Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies
Haruki Koike and Masahisa Katsuno, September 2020

4. https://www.jns-journal.com/article/S0022-510X(15)00745-5/fulltext THAOS – The Transthyretin Amyloidosis Outcome Survey , F. Barroso, M. Waddinton-Cruz, et. Al., October 2015

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:

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/

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.

Amyloidosis is a “group of diseases” that have the common feature where abnormal proteins (or in some cases normal proteins) behave abnormally, and the breakdown product of these proteins fold upon themselves, creating amyloid” fibrils” which deposit in various organs throughout the body. This potentially life-threatening disease can affect the heart, kidneys, liver, spleen, nervous system and digestive tract. (Falk, R., MD, 2018) A basic illustration of the creation of amyloid “fibrils” is shown below.

(Cleveland Clinic, 2020)

There are different types of the disease including AL or Light Chain Amyloidosis, AA Amyloidosis, Transthyretin Amyloidosis (referred to as TTR amyloidosis), and Localized Amyloidosis. TTR amyloidosis includes a hereditary type and a non-hereditary type. (Falk, R, MD, 2018)

Common symptoms of amyloidosis are shown in the following figure.

(The Canadian Amyloidosis Support Network)

Light Chain (AL) Amyloidosis

AL amyloidosis is the most common type of amyloidosis in developed countries, accounting for approximately 85% of all cases. There are approximately 3,000-5,000 new AL amyloidosis cases a year in the United States. (Falk, R., MD, 2018)

The disease usually affects the heart, kidneys, liver and nerves. This type of amyloidosis is blood related, associated with the abnormality of proteins from plasma cells associated with bone marrow. Plasma cells normally create antibodies, known as immunoglobulins, that serve to combat bacteria and viruses. Antibodies are made up of “heavy chains” and “light chains.” AL amyloidosis stems from an abnormal expansion of plasma cells. The abnormal plasma cells secrete abnormal “free light chains” (FLCs) into the bloodstream. These abnormal light chain mutations become “sticky.” The sticky light chains bind together to form amyloid fibrils which can then accumulate in various body organs, as shown below. (Sherwood, A.L.)

(Cleveland Clinic, 2020)

Diagnostic testing for AL amyloidosis includes blood testing, urine tests and biopsies. Blood and/or urine tests are used to indicate the presence of amyloid protein, however bone marrow tests or other small biopsy samples of tissue or organs are needed to positively confirm the diagnosis of amyloidosis. Specific types of blood/urine testing include:

A 24-hour urine collection to look at the level of protein in your urine sample. Excess protein in the urine may be an indication of kidney involvement.
The level of ALP (an enzyme called “alkaline phosphatase”) in your regular blood workup.
Blood tests to look for stress and strain on the heart. Cardiac biomarkers that are used include troponin T or troponin I, and NT-proBNP (which stands for N-terminal pro-brain natriuretic peptide) or BNP (brain natriuretic peptide).
Tests for abnormal antibody (immunoglobulin) proteins in the blood include the Free Light Chain Assay, which shows the level of kappa and lambda light chains in a separate blood test. The Free Light Chain Assay test is often referred to as FLC, which is an abbreviation for free light chains.
Another test for abnormal immunoglobulin can be done with blood and/or urine. It is called “immunofixation electrophoresis.”

Echocardiogram and imaging are performed so that the doctor can look for amyloid deposits in the heart, while viewing the size and shape of it and the location and extent of any impact of amyloid.

Tissue biopsy are performed to identify evidence of amyloid deposits. Tissue samples are sent to a lab for microscopic examination, where the tissue is stained with a dye called “Congo-red.” After putting it under a microscope, amyloid protein is discovered if it turns an apple-green color, resulting in a diagnosis of amyloidosis. The most common tissue sample, which is almost always involved in generating an AL diagnosis, is called a fat-pad biopsy. Fat-pad biopsies are taken from the stomach. Biopsy samples may also be taken from the liver, kidney, nerves, heart, stomach, or intestines.

Bone marrow tests are also performed. These involve the removal of some liquid bone marrow and/or the removal of bone tissue. These samples can help to determine the percentage of amyloid producing plasma cells, and when tested in the lab they can assist in identifying whether the abnormal plasma cells are producing kappa or lambda light chains. (Amyloidosis Foundation, 2021)

If treatment begins during the early onset of clinical symptoms, the overall success rate is higher, so early detection is essential.

Patients with AL amyloidosis have benefited from the recent development of new drugs for myeloma, many of which work effectively on the plasma cells that cause AL amyloidosis. In addition, the FDA approved the first drug treatment specifically for AL amyloidosis in January 2021, called DARZALEX (daratumumab). Drug combinations are more effective than single drugs in attacking the abnormal plasma cells. Drugs that may be useful include traditional chemotherapy drugs (such as melphalan, and cyclophosphamide), as well as “proteasome inhibitor” and “immunomodulator” drugs. (Amyloidosis Foundation, 2021)

Stem cell transplant is also a preferred therapy, as it can provide long-term control of the underlying disease. However, only a minority of AL patients (typically less than 25%) are eligible. (Amyloidosis Foundation, 2021)

AA Amyloidosis

AA amyloidosis results from increased levels of the circulating serum “amyloid A protein.” Amyloid A protein levels normally elevate in the bloodstream as a response to infection and inflammation. If a patient has an infection or inflammatory condition for an extended period of time (six months or more) they would be at risk for developing AA amyloidosis. The amyloidosis can arise due to chronic inflammatory and infectious conditions, including rheumatic disease, inflammatory bowel disease, tuberculosis, osteomyelitis, lupus, and hereditary fever syndromes. Amyloid deposition usually begins in the kidneys, but the liver, spleen, lymphnodes, and intestines are also commonly affected.

If a patient has been diagnosed with a chronic inflammatory disease or chronic infection and they develop high levels of protein in the urine or other associated AA symptoms, then the physician should test for AA amyloid deposition. When kidney damage occurs, it can be clinically shown as protein found in the urine (nephrotic syndrome) or impairment of kidney function.

A test involving a 24-hour urine collection can be performed to look at the level of protein in the patient’s urine. If amyloidosis is suspected in most cases a biopsy of the kidney tissue performed.

In order to identify AA amyloid, the most common diagnostic test is staining the tissue sample with antibodies that are specific to AA amyloid, the “anti-AA serum.” If the anti-AA serum result is positive then AA amyloidosis is diagnosed. Once AA amyloidosis is confirmed the primary underlying inflammatory condition should then be identified.

With AA amyloidosis it is most important to treat the underlying infection or inflammation in order to reduce the level of the precursor for the AA amyloid deposits. These treatments vary depending on the underlying condition. Some treatments that exist for inflammatory diseases include surgery on the infection or tumor, drug therapies for rheumatoid arthritis, antibiotics for chronic infection, among others.

With effective treatment of the underlying inflammation amyloid deposits have been known to reduce and nephrotic syndrome can improve. If the kidney function has become significantly impaired, it rarely recovers.

Supportive treatment is very important, including nephrology, cardiology, and neurology. (Amyloidosis Foundation, 2021)

TTR (Transthyretin) Amyloidosis

As stated earlier, TTR amyloidosis includes a hereditary type and a non-hereditary type.

Hereditary (Familial) Amyloidosis, also referred to as ATTRv amyloidosis, is associated with an inherited genetic mutation. There are various subtypes of familial amyloidosis that are associated with specific demographic groups including Portuguese, Irish, Swedish, Afro-American, and Japanese lineage.

The non-hereditary type of TTR amyloidosis, known as Wild Type Amyloidosis is a disorder predominately of older men in their 70s and beyond. This form of the disease may actually be responsible for up to 10% of male patients having heart failure due to stiff heart tissue. (Falk, R., MD, 2018)

As with AL and AA Amyloidosis, TTR Amyloidosis can manifest itself with a multitude of symptoms. In a vast majority of cases the resultant symptoms are cardiological and/or neuropathic in nature. A basic illustration of the production method for TTR amyloid fibrils is shown below.

Early diagnosis if TTR amyloidosis is essential so as to help minimize the extent of bodily tissue or system damage. First, a patient is tested to determine if they have amyloid proteins in their body. The main diagnostic testing is similar to that described above for AL Amyloidosis, including blood tests, urine tests and biopsies. If amyloidosis is confirmed but the type is not initially identified, additional tests are performed to determine the existence and variation of ATTR.

Once it is determined that there is transthyretin amyloid protein (via biopsy and Congo red staining), the specific protein needs to be identified by protein sequence analysis and DNA sequencing. A blood sample is sent to a lab where the DNA chains are analyzed. Sections of the DNA chain are checked for genetic markers of the DNA defect. Hereditary amyloidosis variations affect patients differently. It is critical to establish which variation exists in order to identify a tailored treatment plan.

Treatment of TTR amyloidosis include treating the source and symptoms. Source treatment involves slowing down, or stopping, the overproduction of amyloid at the source of the disease. Historically, liver transplant has been helpful, however, the statistics vary as to who can benefit from these transplants, with the outcome dependent largely on the specific mutation that exists in the patient. In some situations, combined heart and liver transplants have helped patients with an ATTR variant that produces cardiac problems.

In 2019, two drugs were approved for treatment of ATTR polyneuropathy associated with TTR amyloidosis in adults. The first was ONPATTRO (patisiran), a first of its kind RNA interference therapeutic drug which aims to silence the gene expression for patients with the hereditary type TTR. The second drug approved is TEGSEDI (inotersen), which reduces the production of TTR protein. Also, in 2019, VYNDAQEL and VYNDAMAX (tafamidis) were approved by the FDA for ATTR cardiomyopathy. (Amyloidosis Foundation, 2021)

There is supportive treatment for the various symptoms associated with TTR Amyloidosis, possible symptoms include peripheral neuropathy, autonomic neuropathy, cardiac and kidney problems. There are medications that can be prescribed to treat the effects of peripheral neuropathy, such as tingling or burning sensations. Many patients experience autonomic neuropathy and may require treatment for blood pressure, heart rate, digestion, and perspiration, depending on the location of the damage to the nerves. Other gastrointestinal dysfunctions may require treatment for symptoms that include poor nutritional health, diarrhea or constipation, and nausea or vomiting. (Amyloidosis Foundation, 2021)

Localized Amyloidosis

Localized amyloidosis often has a better prognosis than the types that affect one or more organ systems. Typical sites for localized amyloidosis include the bladder, skin, throat or lungs. Correct diagnosis is important so that treatments that affect the entire body can be avoided. (Mayo Clinic. 2021)

Summary

Amyloidosis is a complex multi-systemic disease where no two patients are alike. Symptoms are often vague and vary from patient to patient, even within the same disease type, making diagnosis one of the biggest hurdles for the medical community. It is not uncommon to hear from patients that it took multiple years and multiple doctors to ultimately arrive at a correct diagnosis, all the while the disease continued to progress. While treatment is type-specific, it is individualized from patient to patient depending on organ involvement.

In the words of Morie A. Gertz, M.D., M.A.C.P., of the Mayo Clinic and regarded as a leading world expert on amyloidosis.

“Thanks to the Amyloidosis Speakers Bureau, providers across the country are being instructed on techniques to suspect and recognize amyloidosis and how to efficiently make the diagnosis in a timely fashion. Incorporating testing for amyloidosis into the work flow of patients with cardiomyopathy, proteinuria, peripheral neuropathy, unexplained weight loss, and smoldering multiple myeloma has been successful.

Comprehensive education remains the best strategy to save lives for this rare disorder.”

Sources

Falk, Rodney, MD, Understanding Amyloidosis. (2018).https://www.youtube.com/watch?v=bE68vvDtnyM&t=134s.

Cleveland Clinic. (2020, June 2). Amyloidosis: AL (Light Chain). https://my.clevelandclinic.org/health/diseases/15718-amyloidosis-al-amyloid-light-chain.

Sherwood, A. L. (n.d.). Understanding Freelite®, the lab test for serum free light chains. Lecture.

The Canadian Amyloidosis Support Network. (n.d.). About Amyloidosis. http://thecasn.org/home-2/what-is-amyloidosis/al-amyloidosys/al-amyloidosis-symptoms/.

Mayo Clinic. 2021. Amyloidosis – Symptoms and causes. [online] Available at: <https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178> [Accessed 14 July 2021].

Amyloidosis Foundation. 2021. AL – Amyloidosis Foundation. [online] Available at: <https://amyloidosis.org/facts/al/#diagnosis> [Accessed 14 July 2021].

Wild-type ATTR is also referred to as ATTRwt. It is not caused by any known genetic mutations, such as in the case of hereditary forms of the disease (hATTR). This disease used to be called SSA or SCA, which stood for Senile Systemic Amyloidosis and Senile Cardiac Amyloidosis, respectively, which are now outdated terminologies. The disease is not known to be directly related to dementia, but it is related to aging.

Deposits of TTR amyloid can be found throughout the body, so it is a systemic amyloidosis disease. The most common place it is found is in the heart. Wild-type ATTR is also known to cause some cases of carpal tunnel syndrome, which can be the first (early) symptom. Recent data suggests that lumbar spine involvement as well as a rupture of the biceps tendon in the forearm can precede cardiac involvement by many years.

This is a disease that has traditionally been found mostly in men, originally reported in those aged 80 and over. As awareness of the disease increases, wild-type ATTR average age at diagnosis is 75. It is often overlooked as an amyloidosis disease because so many people experience heart problems in their later years.

As with hereditary forms of the disease (hATTR), wild-type ATTR causes problems due to the breaking apart, misfolding and deposition of amyloid protein fibrils in healthy tissue. “Wild-type” refers to this form of the disease because it is the natural form of this protein, without genetic mutation. These deposits can interfere with the heart’s normal function, by causing stiffness of the heart tissue, making it more difficult for the heart to fill, leading to heart rhythm problems and heart failure.

In this special video, hear world-renowned expert Dr. Mathew S. Maurer and his patient John Basdavanos presenting to a group of medical students. Dr. Maurer provides a brief overview of ATTRwt, while John provides the patient perspective. Together, these insights offer a compelling story about battling a life threatening disease.

The Protein Folding Problem

Proteins are the building blocks of life. They are large complex molecules, made up of chains of amino acids, and what a protein does largely depends on its unique 3D structure. Figuring out what shapes proteins fold into is known as the “protein folding problem.” For decades and decades, one of biology’s biggest challenges has been finding a solution for the “protein folding problem” and is explained in the linked video below.

AI, DeepMind and Google Find Answers

Founded in 2010, DeepMind researches and builds safe AI (Artificial Intelligence) systems that learn how to solve problems and advance scientific discovery for all. They joined forces with Google in 2014 to accelerate their work. They’re a team of scientists, engineers, machine learning experts and more, working together to advance the state of the art in AI.

In a major scientific breakthrough, DeepMind’s AI system AlphaFold has been recognized as a solution to this grandest of all biological problems – the “protein folding problem.” Here is an excellent video explaining AlphaFold and the making of a scientific breakthrough.

According to Professor Venki Ramakrishman, Nobel laureate and President of the Royal Society,

This computational work represents a stunning advance on the protein-folding problem, a 50-year-old grand challenge in biology. It has occurred decades before many people in the field would have predicted. It will be exciting to see the many ways in which it will fundamentally change biological research.

Potential Impact for Amyloidosis

For diseases which originate with misfolded proteins, such as amyloidosis, “investigators have been doing this exercise by ‘brute force’ until now,” according to Dr. Angela Dispenzieri from the Mayo Clinic. This AI research is likely to open a whole new world of insight and answers, from which new and more effective treatments can be developed.

Marina Ramirez-Alvarado, Ph.D., whose research laboratory at the Mayo Clinic studies misfolding and amyloid formation in light chain amyloidosis, had this to say.

The protein folding problem, one of the most important scientific questions of the 20^th century is making headlines today with the artificial intelligence work from DeepMind. It is clear that DeepMind will provide important basic understanding of the folding process and will significantly benefit those amyloidosis diseases that involve secreted, folded proteins, such as light chain (AL), and Transthyretin (ATTR) amyloidosis.

Dr. Morie Gertz, a hematologist/oncologist from the Mayo Clinic who has decades of clinical experience with amyloidosis, weighs in on some of the possible outcomes from this ground-breaking research.

The ability to predict protein folding in three dimensions may result in the ability to predict which protein sequences are likely to form amyloid fibrils. In light chain amyloidosis this could allow for long-term monitoring of selected patients likely to develop amyloidosis. This would permit extremely early diagnosis long before symptoms developed. It would also allow for the exploration of why wild-type TTR amyloidosis forms amyloid fibrils in the heart in some patients but not in others.

However, it won’t answer all questions …

Dr. Vaishali Sanchorawala, director of Boston University’s Amyloidosis Center offers these words of perspective.

The “protein folding problem” that DeepMind’s AlphaFold is designed to solve is predicting the native, functional state of a protein from just its amino acid sequence. Amyloidosis, though, is caused by our bodies’ failure to solve that problem, resulting in misfolded and aggregated proteins. AlphaFold’s remarkable achievement can definitely help to better understand native structure of amyloidogenic light chain proteins. However, amyloid fibrils are different from the native states of their precursor proteins and therefore the adaptation of AlphaFold to study protein misfolding and aggregation, perhaps by predicting the structures of complex amyloid fibrils, might be better able to predict the effects of mutations that alter people’s risk of developing amyloidosis.

In closing …

AI is rapidly advancing the knowledge of protein misfolding, unlocking answers for amyloidosis which should lead to earlier diagnosis, improved treatment, and better patient survival.

———————————————————-

Sources:

Angela Dispenzieri, M.D.

Morie A. Gertz, M.D., M.A.C.P.

Vaishali Sanchorawala, M.D.

Marina Ramirez-Alvarado, Ph.D.

High Accuracy Protein Structure Prediction Using Deep Learning

John Jumper, Richard Evans, Alexander Pritzel, Tim Green, Michael Figurnov, Kathryn Tunyasuvunakool, Olaf Ronneberger, Russ Bates, Augustin Žídek, Alex Bridgland, Clemens Meyer, Simon A A Kohl, Anna Potapenko, Andrew J Ballard, Andrew Cowie, Bernardino Romera-Paredes, Stanislav Nikolov, Rishub Jain, Jonas Adler, Trevor Back, Stig Petersen, David Reiman, Martin Steinegger, Michalina Pacholska, David Silver, Oriol Vinyals, Andrew W Senior, Koray Kavukcuoglu, Pushmeet Kohli, Demis Hassabis.

In Fourteenth Critical Assessment of Techniques for Protein Structure Prediction (Abstract Book), 30 November – 4 December 2020. Retrieved from here.

WHAT IS SPINAL STENOSIS?

Spinal stenosis is narrowing of the spinal column that causes pressure on the spinal cord, or narrowing of the openings (called neural foramina) where spinal nerves leave the spinal column.

This can develop as you age from drying out and shrinking of the disk spaces. (The disks are 80% water.) The narrowing can cause compression on nerve roots resulting in pain or weakness of the legs. If this happens, even a minor injury can cause inflammation of the disk and put pressure on the nerve. You can feel pain anywhere along your back or leg(s) that this nerve supplies.¹

SYMPTOMS¹

Symptoms often get worse slowly over time. Most often, symptoms will be on one side of the body, but may involve both legs. Symptoms include:

Numbness, cramping, or pain in the back, buttocks, thighs, or calves, or in the neck, shoulders, or arms
Weakness of part of a leg or arm

Symptoms are more likely to be present or get worse when you stand or walk. They often lessen or disappear when you sit down or lean forward. Most people with spinal stenosis cannot walk for a long period. More serious symptoms include:

Difficulty or poor balance when walking
Problems controlling urine or bowel movements

A POTENTIAL CLUE TO AMYLOIDOSIS?

Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs.

“Another very important historical clue is spinal stenosis, and actually that’s much more commonly seen in patients with ATTR than AL, and in fact, again, almost exclusively in wild type,” according to Dr. Mazen Hanna²

WHAT IS SENILE, AKA WILD-TYPE, AMYLOIDOSIS (ATTRwt)?

Amyloidosis is a generic name for a very diverse group of protein folding disorders, all characterized by creation of cross-beta-sheet fibrils. At least 30 different human proteins have been shown to form amyloid fibrils in vivo (7). Two main groups of amyloid conditions exist: systemic and localized. In the systemic conditions, deposits occur in many organs and tissues, and the diseases are usually life-threatening; in each of these diseases one out of at least 15 plasma proteins forms amyloid fibrils far from the place of parent protein synthesis. In the localized conditions, the proteins are expressed at the site of deposition (8). In both groups, fibrils usually deposit extracellularly and can form conspicuous masses that deform a tissue and interfere with its normal functions.⁵

Senile systemic amyloidosis (SSA), derived from wild-type transthyretin (TTR), is common in association with aging, although symptom-giving disease usually is comparably rare and affects males at least 10 times more often than women. Restrictive cardiomyopathy is the main clinical expression. However, carpal tunnel syndrome is common in SSA, and widely spread wild-type ATTR amyloid deposits at other connective tissue sites have been demonstrated (25).⁵

Joint cartilage and ligaments are targets of both localized and systemic amyloid. Of the systemic forms, Aβ2-microglobulin [for nomenclature, see (7)] amyloidosis is well-known to engage skeletal and joint structures in patients under hemodialysis due to renal insufficiency (9-13). Also, immunoglobulin light chain (AL) amyloidosis is known to generate a variety of symptoms from joints and skeleton, sometimes with neural lesions. Carpal tunnel syndrome is often noted in transthyretin (ATTR) and Aβ2-microglobulin amyloidosis (15–17).⁵

CONCLUSION

From the studies referenced therein, results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected³and that lumbar spinal stenosis quite frequently may be a consequence of senile systemic amyloidosis [also known as wild-type amyloidosis; ATTRwt]⁵.

Stay suspicious.

Sources:

¹https://www.mountsinai.org/health-library/diseases-conditions/spinal-stenosis

² https://www.neurologylive.com/view/cardiac-amyloidosis-management

³ https://pubmed.ncbi.nlm.nih.gov/21334722/

Sueyoshi T, Ueda M, Jono H, Irie H, Sei A, Ide J, Ando Y, Mizuta H. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011 Sep;42(9):1259-64. doi: 10.1016/j.humpath.2010.11.017. Epub 2011 Feb 21. PMID: 21334722.

⁴ https://pubmed.ncbi.nlm.nih.gov/14640042/

Westermark P, Bergström J, Solomon A, Murphy C, Sletten K. Transthyretin-derived senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 2003 Aug;10 Suppl 1:48-54. PMID: 14640042.

⁵ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116761/

Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. doi:10.3109/03009734.2014.895786

⁶ https://en.wikipedia.org/wiki/Spinal_stenosis

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CRISPR FIXES GENES INSIDE THE BODY (3)

APPLYING THE CRISPR TECHNOLOGY (3)

CLINICAL TRIAL UPDATE — NTLA-2001 (1)

BACKGROUND

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

Light Chain (AL) Amyloidosis

AA Amyloidosis

TTR (Transthyretin) Amyloidosis

Localized Amyloidosis

Summary

Sources

Falk, Rodney, MD, Understanding Amyloidosis. (2018).https://www.youtube.com/watch?v=bE68vvDtnyM&t=134s.

Cleveland Clinic. (2020, June 2). Amyloidosis: AL (Light Chain). https://my.clevelandclinic.org/health/diseases/15718-amyloidosis-al-amyloid-light-chain.

Sherwood, A. L. (n.d.). Understanding Freelite®, the lab test for serum free light chains. Lecture.

The Canadian Amyloidosis Support Network. (n.d.). About Amyloidosis. http://thecasn.org/home-2/what-is-amyloidosis/al-amyloidosys/al-amyloidosis-symptoms/.

Mayo Clinic. 2021. Amyloidosis – Symptoms and causes. [online] Available at: <https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178> [Accessed 14 July 2021].

Amyloidosis Foundation. 2021. AL – Amyloidosis Foundation. [online] Available at: <https://amyloidosis.org/facts/al/#diagnosis> [Accessed 14 July 2021].

The Protein Folding Problem

AI, DeepMind and Google Find Answers

Potential Impact for Amyloidosis

However, it won’t answer all questions …

In closing …

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