Slider

Hereditary Amyloidosis in Black Americans of African Descent: ATTR V122I Variant

Amyloidosis, still considered a relatively rare disease, can take several forms. Each slightly different, but most sharing similar debilitating symptoms of cardiac and/or neurological impairment, or both. It is viewed by many experts that amyloidosis has been presenting in plain sight and missed, or wildly underdiagnosed, for decades and, in some cases, generations. Thankfully, education to raise awareness within the healthcare community, along with improvements in diagnostic tools and testing, the journey to diagnosis and treatment is becoming more visible.

The hereditary transthyretin amyloidosis (hATTR) type results from a genetic mutation of a protein, transthyretin, which is produced in the liver and circulates throughout the body. The mutation causes the TTR protein to misfold, becoming unstable and depositing in organs and nerve systems causing impairment and eventual organ failure. Common symptoms for the disease include bilateral carpel tunnel syndrome, muscle weakness, cardiomyopathy, polyneuropathy, GI issues especially chronic diarrhea and constipation, and both nuisance and serious concerns and if untreated can lead to death. Early diagnosis, genetic testing to identify the exact genetic mutation, and treatment are important to slow the progression of the disease and conserve quality of life.

SIGNIFICANTLY UNDER-DIAGNOSED

Considered a rare disease, advances in diagnosis have shown that it is less rare than originally thought.

Familial amyloidosis caused by a transthyretin mutation occurs in approximately 1 in 100,000 Caucasians in the U.S, and more commonly in African Americans (approximately 4% in that population). This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 40 and 65 years of age.

https://rarediseases.org/rare-diseases/amyloidosis/

To date over one hundred variants of TTR have been identified as causing ATTR amyloidosis and they are distributed worldwide with concentrations in various ethnic populations. One variant, V122I is most commonly found in people with African and especially West African ancestry. It has been distributed worldwide but especially in North America and the Caribbean through historic slave trade and the migration of populations. This variant is most often associated with ATTR-CM (Amyloidosis with cardiomyopathy) and heart failure.

Worldwide Carrier Rates of TTR V122I in Self-Reported Countries/Regions

From Multicenter Study JAMA 2019 Dec 10;322(22):2191-2202.

doi: 10.1001/jama.2019.17935.

In an article by J. Buxdaum and F. Ruberg in the Journal Genetics in Medicine January 2017, the authors stated the following findings.

Since the identification of a valine-to-isoleucine substitution at position 122 (TTR V122I; pV142I) in the transthyretin (TTR)-derived fibrils extracted from the heart of a patient with late-onset cardiac amyloidosis, it has become clear that the amyloidogenic mutation and the disease occur almost exclusively in individuals of identifiable African descent. In the United States, the amyloidogenic allele frequency is 0.0173 and is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicates that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. At autopsy, the allele was found to be associated with cardiac TTR amyloid deposition in all the carriers after age 65 years; however, the clinical penetrance varies, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. At this time there are potential forms of therapy in clinical trials. The combination of a highly accurate genetic test and the potential for specific therapy demands a greater awareness of this autosomal dominant, age-dependent cardiac disease in the cardiology community.

Genet Med advance online publication 19 January 2017

The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa.

1:CAS:528:DC%2BC28XhsFSlsbfJ 10.1002/mgg3.231 Mol Genet Genomic Med. 2016; 4: 548-556

Dr. Martha Grogan, director of the Cardiac Amyloid Clinic of Mayo Clinic in Rochester, Minnesota commented in an interview published in the Mayo News Network (https://newsnetwork.mayoclinic.org/discussion/expert-alert-cardiac-amyloidosis-masquerades-as-other-conditions-1-type-affects-more-black-americans/) that amyloidosis can be tricky to suspect because symptoms may not be initially present and they may mimic other more common diseases. Currently there are options for free saliva or blood tests through several pharmaceutical companies. To determine the type of the disease genetic testing is important.

The University of Pennsylvania and the Icahn School of Medicine at Mount Sinai conducted a study of 52,492 participants of which 11,143 were of self-reported African ancestry. https://jamanetwork.com/journals/jama/fullarticle/2757227

An excellent discussion of the results emphasizes the conclusion that a significant association of TTR V122I and heart failure in the tested population, primarily in those of West African ancestry, exists. In addition, they confirm previous studies that have suggested a high rate of underdiagnosis of hATTR-CM in cases of cardiomyopathy and heart failure in elderly patients of African Ancestry. The discussion further suggests that this is likely due to lack of information and familiarity with the disease in the medical community.

CITATION: Damrauer SM, Chaudhary K, Cho JH, et al. Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry. JAMA. 2019;322(22):2191–2202. doi:10.1001/jama.2019.17935. https://pubmed.ncbi.nlm.nih.gov/31821430/

Discussion of a different study of 7,514 African American participants in the US considered the question of the association between genetic variation and the risk of heart failure. This study was conducted by the University of Alabama, University of Colorado, Columbia University, and Cornel University. The results are similar to those in the University of Pennsylvania study discussed above, with additional comments that more subtle symptoms and changes may be apparent well before the typical onset of significant disease, average age 65, and the need for earlier screening for early detection and treatment.

An autosomal-dominant disease, hATTR-CM has a median survival of nearly 2.5 years without treatment after receiving a diagnosis.³⁴^,³⁵ Extrapolating the hATTR-CM–associated Val122Ile variant frequency to the population level suggests that approximately 1.4 million Black individuals carry this variant implicated in the development of heart failure and reduced overall survival. Despite the possible clinical implications, the Val122Ile TTR variant, which is seen relatively more commonly among individuals of African ancestry, is not included in the list of clinically actionable deleterious variants compiled by the American College of Medical Genetics and Genomics.⁹ Thus, this potentially deleterious variant may not be reported as clinically actionable, thereby reducing physician vigilance for hATTR-CM.

Findings In this retrospective cohort study that included 7,514 Black participants in the US with a median 11.1 years of follow-up, the incidence of heart failure was 15.6 per 1000 person-years among Val122Ile variant carriers compared with 7.2 per 1000 person-years among noncarriers, with an adjusted hazard ratio of 2.43.

Meaning Being a carrier of the Val122Ile variant was significantly associated with an increased risk of heart failure among Black individuals living in the US.

CITATION: Parcha V, Malla G, Irvin MR, et al. Association of Transthyretin Val122Ile Variant With Incident Heart Failure Among Black Individuals. JAMA. 2022;327(14):1368–1378. doi:10.1001/jama.2022.2896

https://pubmed.ncbi.nlm.nih.gov/35377943/

SUMMARY

Despite the evidence that a meaningful 3-4% of the US Black population of West African ancestry likely carries the V122I genetic mutation, hereditary TTR amyloidosis remains significantly underdiagnosed and undertreated in this population.

Cardiac symptoms in elderly black patients have too often been treated for more common cardiomyopathy and heart conditions, resulting in lack of appropriate treatment and often death. Because of lack of awareness in the medical community and reduced access to expert medical care, more subtle symptoms in younger black patients generally have not caused the physicians to consider amyloidosis. Additionally, lack of genetic testing can mean that entire families are unaware of the implications of the disease.

Amyloidosis can be devastating to both patients and their families. Increased awareness of the disease, availability of testing, and FDA-approved therapies are slowly beginning to shift this dynamic. However, there is still much work to be done to close the gap between diagnosed cases and the population estimated to be affected.

Early diagnosis is key.

For additional information regarding hereditary amyloidosis:

Worldwide Hotspots of Hereditary TTR Amyloidosis (ATTRv)

Hereditary Amyloidosis: T60A Variant

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

————————————————–

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:

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

———————————————————-

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

===========================================================

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.

AN UPDATE ….. WOO HOO!!!

Well, the results of the preclinical studies were presented on June 26, 2021 and it is fantastic news for hereditary ATTR amyloidosis patients!!!

Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.

CONCLUSIONS
In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.)

The New England Journal of Medicine
https://www.nejm.org/doi/full/10.1056/NEJMoa2107454

Our original blog post ….

The scientific world is abuzz … a Nobel Prize-winning technology called CRISPR/Cas9 can now edit our DNA. This programmable gene-editing technology, which is efficient, precise, and scalable, has inspired a gold rush of countless applications in medicine, agriculture and basic science. Early areas of focus include genetic diseases such as sickle cell and hereditary ATTR amyloidosis, offering new and exciting optimism.

Ground-Breaking Science in Gene Editing

“A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome – more than three billion DNA base pairs – is contained in all cells that have a nucleus.” – Intellia Therapeutics

CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, is a microbial ‘immune system’ that prokaryotes — bacteria and archaea — use to prevent infection by viruses called phages. At its core, the CRISPR system gives prokaryotes the ability to recognize precise genetic sequences that match a phage or other invaders and target these sequences for destruction using specialized enzymes.

Previous work had identified these enzymes, known as CRISPR-associated proteins (Cas), including one called Cas9. But scientist Emmanuelle Charpentier, working first at the University of Vienna and later at the Umeå Centre for Microbial Research in Sweden, identified another key component of the CRISPR system, an RNA molecule that is involved in recognizing phage sequences, in the bacterium Streptococcus pyogenes, which can cause disease in humans.

Charpentier reported the discovery in 2011 and that year struck up a collaboration with American biochemist Jennifer Doudna. In a landmark 2012 paper in Science, the duo isolated the components of the CRISPR–Cas9 system, adapted them to function in the test tube and showed that the system could be programmed to cut specific sites in isolated DNA – an incredibly precise set of DNA-editing genetic scissors. In 2020, Doudna and Charpentier won the 2020 Nobel Prize in Chemistry for their gene-editing technology.

“The ability to cut DNA where you want has revolutionized the life sciences,” said Pernilla Wittung Stafshede, a biophysical chemist and member of the Nobel chemistry committee, at the prize announcement. “The ‘genetic scissors’ were discovered just eight years ago, but have already benefitted humankind greatly.”

How Does CRISPR/Cas9 Work? (3)

This technology acts as an incredibly precise set of molecular scissors, providing instructions to cut an identified gene in a specific position in the nucleus of DNA. There are two primary components to the CRISPR/Cas9 genome editing system:

The Cas9 protein, which initially recognizes the DNA and also acts like a pair of “molecular scissors” that precisely cleaves the targeted DNA sequence.
The guide RNA, which guides the Cas9 scissors to the desired target DNA sequence and activates the scissors so they cut.

https://www.intelliatx.com/crisprcas9/how-crisprcas9-works/

Background on Hereditary Transthyretin Amyloidosis (hATTR/ATTRv) (1)

Transthyretin amyloidosis is a slowly progressive condition characterized by the buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body’s organs and tissues. These protein deposits most frequently occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract. The age at which symptoms begin to develop varies widely among individuals with this condition, and is typically between ages 20 and 70.

There are three major forms of transthyretin amyloidosis, which are distinguished by their symptoms and the body systems they affect.

The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions.
The leptomeningeal form of transthyretin amyloidosis primarily affects the central nervous system.
The cardiac form of transthyretin amyloidosis affects the heart.

Mutations in the TTR gene causes the liver to product the TTR protein in a misfolded form. This misfolded protein can then build up in the body and lead to disease-causing nerve and other organ damage.

Clinical Trial Research (4)

According to CRISPRMedicineNews, one of the early clinical trials within gene editing is focused on hereditary transthyretin amyloidosis. In these trials, CRISPR-Cas is either used directly to treat the condition by editing an individual’s genome in vivo or indirectly through ex vivo engineering of a cell-based therapy. An update published November 17, 2020 discusses the clinical trial, which is now underway in the U.K.

CRISPR-Cas9 Trial For NTLA-2001 to Treat Hereditary Transthyretin Amyloidosis With Polyneuropathy

The second newly-added trial is sponsored by US-based Intellia Therapeutics and seeks to enroll 38 participants who are diagnosed with polyneuropathy (PN) due to transthyretin (TTR) amyloidosis (ATTR).

This open-label Phase 1 two-part trial comprises a dose escalation followed by a safety dose expansion study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of Intellia’s most advanced in vivo CRISPR-based therapy candidate, NTLA-2001.

ATTR is a hereditary progressive condition that is characterized by an accumulation of misfolded transthyretin (TTR) protein. The disease results from mutation(s) in the TTR gene, leading to mutant TRR protein that is unstable and easily forms aggregates that deposit as amyloid in various organs and tissues in the body. Organs or body parts most often affected include the nerves, heart, kidneys and eyes.

Life expectancy is typically 2-15 years from disease onset, and current treatment options include transplantation of affected organs and medications to slow progression of disease symptoms.

NTLA-2001 is the first investigative CRISPR-based therapy to be administered in vivo in humans. The new therapy comprises TTR-targeting gRNA and Cas9 mRNA, both of which are delivered in vivo via Intellia’s proprietary lipid nanoparticle technology. Pre-clinical studies support the notion that NTLA-2001 has potential as a one-time curative treatment. The first patient was dosed with NTLA-2001 last week and the study is expected to be completed in 2024.

Worldwide prevalence of spontaneous and hereditary transthyretin amyloidosis (ATTR). Source: Intellia Therapeutics. https://www.intelliatx.com/in-vivo-therapies/

Potential Game-Changer for Hereditary ATTR Amyloidosis

“Once we’ve assessed safety and established an optimal dose, we intend to rapidly initiate trials for the clinical manifestations of ATTR. NTLA-2001 may halt and reverse ATTR progression by producing a deeper, permanent TTR protein reduction for all patients – regardless of disease type – than the chronically administered treatments currently available.” said Intellia Therapeutics President and CEO, John Leonard, M.D.

Intellia’s proprietary CRISPR/Cas9 system could potentially address diseases with a single course of treatment because it permanently repairs the defective DNA. This represents a breakthrough improvement over current therapies, most of which require lifelong administration because they cannot correct underlying causes of the disease. However, this technology does not pass the genetic changes made to the patient to his or her offspring … the “fix” will not pass from generation to generation.

This is exciting news, giving new hope for families who have been ravaged by disease over generations.

———————————-

If you’d like to read more about Jennifer Doudna, here’s a book recently released by bestselling author Walter Isaacson, The Code Breaker.

Sources:

https://crisprmedicinenews.com/clinical-trial/transthyretin-amyloidosis-attr-nct04601051/
crisprmedicinenews.com
https://www.intelliatx.com
https://crisprmedicinenews.com/news/crispr-cas-clinical-trial-update/
https://www.nature.com/articles/d41586-020-02765-9
Doudna Lab, Berkeley, California
CRISPR Therapeutics, Cambridge, Massachusetts
Innovative Genomics Institute, Berkeley, California

Header

Slider

Hereditary Amyloidosis in Black Americans of African Descent: ATTR V122I Variant

SIGNIFICANTLY UNDER-DIAGNOSED

SUMMARY

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

TWO STUDIES

PERSPECTIVE FROM AN ORTHOPEDIC SURGEON

CONCLUSION

Cardiomyopathy

Types of Cardiomyopathy:

Peripheral Neuropathy

Types of Neuropathy:

ATTR Amyloidosis

ATTR-CM and ATTR-PN

Ground-Breaking Science in Gene Editing

How Does CRISPR/Cas9 Work? (3)

Background on Hereditary Transthyretin Amyloidosis (hATTR/ATTRv) (1)

Clinical Trial Research (4)

CRISPR-Cas9 Trial For NTLA-2001 to Treat Hereditary Transthyretin Amyloidosis With Polyneuropathy

Potential Game-Changer for Hereditary ATTR Amyloidosis

This website uses cookies