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The Use of RNA Interference Science in the Treatment of Hereditary Amyloidosis

Hereditary transthyretin amyloidosis (hATTR) is a severe, adult-onset inherited systemic disease which can affect the peripheral and autonomic nervous system, heart, kidney and the eyes. (1)

TTR (transthyretin) is a protein found in blood plasma and blood serum as well as in the cerebrospinal fluid (CSF). The protein is mainly synthesized (assembled) by the liver and the choroid plexus (CP). The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. The protein is created by a process called biosynthesis. Biosynthesis is carried out in accordance with genetic instructions encoded from ones DNA. The DNA instructions create messenger RNA (mRNA), which in turn biosynthesize transthyretin proteins in the form of a tetramer. (2)

In the case of hereditary amyloidosis, a DNA mutation causes an errant mRNA signal, which results in destabilization of the tetramer and misfolding of the protein. The misfolded TTR proteins aggregate into amyloid fibrils as shown in the figure below. (3) The Amyloid then deposits throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastro-intestinal, etc. in nature.

 

 

RNA interference (RNAi) is a natural process that controls gene “expression” to messenger RNAs (mRNA), thus blocking the RNA instruction for creating a protein.

The figure shown below illustrates this process. (4) In basic terms, the interfering process begins with a long double-stranded RNA (dsRNA) being “diced” into small fragments by an enzyme called a “Dicer”. These fragments, referred to as small interfering RNAs (siRNA), bind to proteins called argonaute proteins. After binding to an argonaute protein, one strand of the double-stranded RNA is removed. The remaining strand then binds to the targeted messenger RNA. The argonaute protein then cleaves the messenger RNA, destroying it.

 

RNA interfering therapeutic medicines mimic this natural process, utilizing designed small interfering RNAs (siRNA) that ultimately bind to and destroy disease-causing RNA. As a result, the cell is no longer able to produce the misfolded Amyloid protein. One such therapeutic is the drug Vutisiran, used to treat hereditary amyloidosis with polyneuropathy. The figure shown below shows how Vutisiran carries out the same silencing process. (5)

 

 

 

For additional information on ATTR Treatments such as stabilizers and silencers, please view the short Expert Insights video below by Dr. Brett W. Sperry from our Amyloidosis Lecture Series.

 

 

 

 

Sources —————————————–

  1. Carroll, A., Dyck, P. J., Carvalho, M. de, Kennerson, M., Reilly, M. M., Kiernan, M. C., & Vucic, S. (2022, June 1). Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. Journal of Neurology, Neurosurgery & Psychiatry. https://jnnp.bmj.com/content/93/6/668
  1. “Protein Biosynthesis” https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/protein-biosynthesis
  1. Diagnostic Algorithm for Transthyretin Amyloidosis with Lower… | Download Scientific Diagram, researchgate.net/figure/Diagnostic-algorithm-for-transthyretin-amyloidosis-with-lower-gastrointestinal_fig1_348081318. Accessed 28 Oct. 2024.
  1. “What Is RNAi – RNAi Biology.” UMass Chan Medical School, 7 Jan. 2022, umassmed.edu/rti/biology/rna/how-rnai-works/.
  1. “RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai

Hereditary Amyloidosis: The V122I Variant

Hereditary Amyloidosis in 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; also called variant amyloidosis ATTRv) 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/

 

From Dr. Kevin Alexander, Stanford Amyloid Center

 

 

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

ATTR-CM (cardiomyopathy) vs ATTR-PN (peripheral neuropathy)

 

Over the course of the past few 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” (ATTRwt). 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 ATTRwt 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

Expert Insights – Cardiac Clues and Clinical Signs

In part 1 of a 2-part series, Dr. Keyur Shah, cardiologist from VCU Health’s cardiac amyloidosis care team, discusses the two most common types of transthyretin (TTR) amyloidosis: hereditary and wild-type. He details how ATTR cardiomyopathy amyloidosis presents and manifests itself to impair the heart. Dr. Shah lists clinical clues, “red flags,” and biomarkers which can raise suspicion of the presence of amyloidosis. Next, he discusses insights that can be gained from echocardiograms, electrocardiograms, and cardiac MRIs and how they offer possible indicators of the disease presence. Once amyloidosis is suspected, definitive diagnosis testing is next.

 

In part 2 of a 2-part series, Sarah Paciulli, Heart Failure Nurse Practitioner, from VCU Health’s cardiac amyloidosis care team, continues from where Dr. Keyur Shah ended in Part I and discusses here in Part II the non-cardiac clues of transthyretin (TTR) amyloidosis. She expands the list of clinical clues and “red flags” that clinicians should be alert to, including orthopedic manifestations, erectile dysfunction, and polyneuropathy.

 

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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/



Diagnosing Amyloidosis: From Cardiology to Neurology – When to Think About Amyloidosis

Dr. J. Mark Sloan, Associate Professor of Medicine, Boston University Chobanian & Avedisian School of Medicine. He is a member of the BU Amyloidosis Center, the Evans Center for Interdisciplinary Biomedical Research at BU, and the program director for the hematology/oncology fellowship at Boston University. In this video, developed exclusively for the Amyloidosis Speakers Bureau, he provides a comprehensive clinical overview of diagnosing amyloidosis, from cardiology to neurology, and when to think about amyloidosis.

Peripheral Neuropathy & Amyloidosis

Neuropathy, also known as peripheral neuropathy, is a broad term that is used to describe damage to the nerves outside of the brain and spinal cord. There are over 100 types of peripheral neuropathy that can be classified into four categories, with each type having their own symptoms and prognosis. In this article, we’ll discuss the types of peripheral neuropathy and its connection to amyloidosis.

 

Symptoms

One of the challenges with neuropathy is the fact that symptoms can vary significantly based on what nerve is damaged. Additionally, symptoms can develop over the course of months to years (chronic neuropathy) or come on suddenly (acute neuropathy). Some of the most commonly seen symptoms are listed below:

  • Muscle weakness
  • Cramps
  • Muscle twitching
  • Loss of muscle and bone
  • Changes in skin, hair, or nails
  • Numbness
  • Loss of sensation or feeling in body parts
  • Loss of balance or other functions as a side effect of the loss of feeling in the legs, arms, or other body parts
  • Emotional disturbances
  • Sleep disruptions
  • Loss of pain or sensation that can put you at risk, such as not feeling an impending heart attack or limb pain
  • Inability to sweat properly, leading to heat intolerance
  • Loss of bladder control, leading to infection or incontinence
  • Dizziness, lightheadedness, or fainting because of a loss of control over blood pressure
  • Diarrhea, constipation, or incontinence related to nerve damage in the intestines or digestive tract
  • Trouble eating or swallowing
  • Life-threatening symptoms, such as difficulty breathing or irregular heartbeat

 

Types of Neuropathy

  1. Motor Neuropathy → Damage to the motor nerves control how you move.
  2. Sensory Neuropathy → Damage to sensory nerves control what you feel.
  3. Autonomic Nerve Neuropathy → Damage to autonomic nerves that control functions that are involuntary (ie. you do not consciously control).
  4. Combination Neuropathies → Damage to a mix of 2 or 3 of these other types of neuropathies. For example, damage to both sensory and motor nerves would result in sensory-motor neuropathy.

 

Amyloidosis

Peripheral Neuropathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-PN, or transthyretin amyloid polyneuropathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the nerve tissue, resulting in damage to these nerves. While amyloid deposits primarily in the peripheral nerves, it is not uncommon for amyloid deposition in the autonomic nerves as well. 

While peripheral neuropathy is most commonly associated with ATTR amyloidosis, it should be noted that peripheral neuropathy is also seen in 15-35% of patients with AL amyloidosis.

Most importantly, these are the most common and important signs and symptoms to be aware of, in order to diagnose ATTR amyloidosis.

 

Neurological Complications of ATTR Amyloidosis

Patients with ATTR amyloidosis are commonly faced with neurological complications. In this presentation, Dr. Chafic Karam from the University of Pennsylvania goes through four areas: an overview of the neurological systems, how amyloid damages the nerves, neurological signs of ATTR amyloidosis, and how to detect amyloid and diagnose ATTR amyloid neuropathy.

 

 

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References:

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/

 

Patient Insights: Discussing a hereditary disease with relatives

With a hereditary disease, talking with relatives can be challenging. Hear Greg share ways that he has advanced discussions. Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Greg.

The Future for Patients with Transthyretin Cardiac Amyloidosis is Looking Brighter

The treatment for patients with Transthyretin Cardiac Amyloidosis has advanced significantly since 2018 when there were no FDA-approved therapies. In this presentation, Dr. Mat Maurer from Columbia University shares how diagnostic imaging techniques have significantly improved, thereby reducing the need for an invasive heart biopsy. In addition, he shares fascinating statistics on how the age and stage of diagnosis has been evolving. Based on today’s clinical trials, providers are optimistic that the expansion of options for patient care will continue.

The future is indeed looking brighter.

Diagnosing Amyloidosis: A Two-Step Process

Amyloidosis can present in many types with the three most prevalent being light chain (AL) amyloidosis, hereditary variant transthyretin (ATTRv) amyloidosis, and wild type transthyretin (ATTRwt) amyloidosis. Being a rare disease, diagnosis can be particularly challenging, given that the general medical community is not well educated on the malady and symptoms are often associated with other more common ailments.

Successfully diagnosing the disease requires a two-step process before an appropriate treatment program can be determined and implemented for each patient.

  1. First, if amyloidosis is suspected, testing must be done to confirm the presence of amyloid.
  2. Second, once the presence of amyloid is confirmed, testing must then be done to identify and confirm the type of amyloidosis.

It is crucial that the second step, where the correct type of amyloidosis is identified, as the treatment regime can be different for each type. Here we share two different patient experiences which illustrate successful execution of the two-step diagnostic process.

Patient Case #1

The first case involved a 23-year old female. In 2017 she experienced an episode of coughing up blood, after which she looked in her throat with a flashlight and discovered a sizable lump. The patient met with a local ENT, who incorrectly diagnosed allergies, and prescribed over-the-counter medicine. With no improvement, she met with a second ENT. Testing was performed on the patient’s left oral pharynx utilizing a Congo red staining biopsy process which confirmed the presence of amyloid in the tissue. Additionally, mass spectrometry was performed which successfully differentiated the type of amyloidosis as being ALH (lambda light chain and delta heavy chain). Subsequently, she was referred to a hematologist who ordered a bone marrow biopsy and blood testing. The bone marrow biopsy summary notes read “….in conjunction with the concurrent finding of monoclonal lambda light chain restricted plasma cells in the marrow by flow cytometry, the findings are consistent with involvement of the marrow by a plasma cell neoplasm.”

Additionally, the blood testing confirmed elevated light chains as shown below.

Patient Case #2

The second case involved a man in his mid-fifties. He began experiencing disease symptoms approximately 6-7 years prior to being diagnosed in early 2019. He initially experienced gradually progressing numbness in his feet, legs, hands and forearms, as well as bilateral carpal tunnel syndrome. Soon after, he began experiencing symptoms of lightheadedness and fainting. Additionally, he started experiencing progressive gastro-intestinal issues such as acid reflux, chronic coughing, and frequent bouts of constipation and diarrhea. By 2018, his physical condition was rapidly deteriorating, including a total weight loss of approximately 80 pounds. During this extended period of time he was seen by a variety of physicians including internal medicine, neurology, endocrinology, gastroenterology, oncology, and cardiology, none of who were successful in arriving at a conclusive diagnosis. His list of maladies included cardiomyopathy, peripheral neuropathy, autonomic neuropathy, bilateral carpal tunnel syndrome, and gastroparesis, all which are classic symptoms of amyloidosis.

Finally, in early 2019 his condition was successfully diagnosed by an amyloidosis specialist. An echocardiogram was performed as well as a cardiac MRI (utilizing a gadolinium tracer) to identify amyloid fibrils and related damage in the heart tissue. These tests confirmed the presence of amyloid. A free light chain serum test was performed which ruled out AL amyloidosis, and Transthyretin DNA sequencing was performed to differentiate between the hereditary variant and wild-type of ATTR, which identified the T80A (legacy T60A) variant of transthyretin (ATTRv) amyloidosis. The two tests were successful in identifying the type of amyloidosis. The associated testing results are show below.

Echocardiogram Summary Notes

Associated Cardiac MRI Interpretation

DNA Sequencing Result

 

Once Diagnosed, Next is a Treatment Plan

Once the presence of amyloid is confirmed, and the type is identified, then it is time to treat the disease. In each of these patient cases the disease was diagnosed utilizing the two-step process to identify and confirm the type of amyloidosis. In both cases, successful treatment regimens were implemented which were effective in putting the disease into remission and/or halting disease progression.

Treatment options for amyloidosis have been vastly improved over the past several years. What was previously considered to be a foregone fatal disease can now be a manageable chronic disease. To ensure the best patient outcome, a timely diagnosis utilizing the two-step process, is essential.

 

Patient Insights: Impact on a Family

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights.

Have a listen to this brief clip from Darlene with thoughts on how this disease has impacted her family.

Unraveling the Lineage: The Genetic Basis of Familial ATTR Cardiomyopathy

Dr. Witteles, a cardiologist and co-director of the Stanford Amyloid Center, discusses genetic testing, sequencing the TTR gene, and clarifies the confusing mutation nomenclature. He details the most common of the more than 145 known hereditary mutations, the prevalence of cardiomyopathy versus neuropathy, and references studies around diagnostic factors.

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