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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

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.

Carpal Tunnel & Amyloidosis

Look to the Wrist for an Early Diagnostic Clue: Tissue samples from carpal tunnel surgery hold screening utility

According to the Cleveland Clinic, tenosynovial tissue biopsy at the time of carpal tunnel surgery can be a useful tool for detecting cardiac amyloidosis at an earlier stage, suggests a recent Cleveland Clinic study in the Journal of the American College of Cardiology (JACC) (2018;72:2040-2050).

“We found that 1 in 10 older patients who underwent carpal tunnel release surgery for idiopathic carpal tunnel syndrome had either ATTR [transthyretin] or AL [light chain] amyloidosis in a sample of patients who had tenosynovial tissue removed,” says Cleveland Clinic cardiologist Mazen Hanna, MD, the study’s primary investigator. “This may be an early marker or precursor of amyloid heart disease.”

An accompanying editorial in JACC (2018;72:2051-2053) calls the investigation “a well-conducted pilot study that should be seen as a justification for larger screening efforts.”

Better defining the amyloid/carpal tunnel connection

The study was prompted by recognition that, despite the classic association of amyloidosis with carpal tunnel syndrome, the frequency of cardiac involvement at the time of carpal tunnel release surgery had never been established.

“The index patient that got us thinking about this project was operated on by Cleveland Clinic orthopaedic surgeon William Seitz, MD, a key collaborator on the study, who noted thickened tenosynovial tissue and astutely asked for a Congo red stain,” Dr. Hanna explains. “In the wake of that, we decided to undertake this study to determine the prevalence and type of amyloid deposits in carpal tunnel surgery patients and assess for cardiac involvement.”

So Drs. Hanna and Seitz, together with colleagues from Cleveland Clinic’s Heart & Vascular and Orthopaedic & Rheumatologic Institutes, ended up prospectively studying consecutive men aged 50 or older and women aged 60 or older undergoing carpal tunnel release surgery at Cleveland Clinic over a one-year period. They stained samples of tenosynovial tissue from all patients; those with confirmed amyloid deposits were typed with mass spectrometry and the patients underwent cardiac evaluation consisting of electrocardiography, echocardiography with longitudinal strain, technetium pyrophosphate scintigraphy and blood tests for biomarkers.

Findings prompt therapy initiation in three patients

Of the 98 patients enrolled, 10 (10.2 percent) had a positive biopsy for amyloid — seven ATTR, two AL and one untyped. Two of these patients were diagnosed with hereditary ATTR, two were determined to have cardiac involvement (one AL, one ATTR wild-type) and three were started on pharmacologic therapy.

Notably, patients with ATTR demonstrated no difference in plasma transthyretin concentration or tetramer kinetic stability, which indicates that these measures likely cannot serve to detect cardiac amyloidosis on their own.

Low-cost method of early detection

“Amyloid cardiomyopathy is an underrecognized cause of heart failure with preserved ejection fraction,” Dr. Hanna observes. “We believe that screening patients for amyloidosis when they have carpal tunnel surgery can be an inexpensive way to diagnose cardiac involvement early and help avert progressive heart failure.”

This is particularly true, he notes, with the advent of the first effective therapies for cardiac amyloidosis, which recently have rendered the condition medically treatable for the first time.

“The early recognition made possible by tenosynovial tissue biopsy is critical, since current treatment strategies suppress the production of precursor protein or prevent protein misfolding but do not directly target current amyloid deposits,” Dr. Hanna explains. “This allows for implementation of disease-modifying therapy prior to development of cardiac symptoms.”

He adds that the detection of AL in two of the 10 patients with biopsy-diagnosed amyloidosis is especially notable since AL cardiac amyloidosis tends to progress more rapidly and has a poor prognosis once cardiac involvement advances.

Time for a screening algorithm

Dr. Hanna and his colleagues are continuing to follow up the study cohort to observe and report additional noteworthy findings. In the meantime, these initial results, together with emerging data related to soft tissue amyloidosis, have prompted implementation of a new screening algorithm at Cleveland Clinic.

The algorithm, available as a supplementary online figure to the JACC study report, guides hand surgeons on the appropriateness of tenosynovial biopsy at the time of carpal tunnel release surgery. If Congo red staining is positive, typing with mass spectrometry and referral to an amyloidosis specialist is indicated.

The authors of the accompanying JACC editorial note that while the best screening methodology remains to be determined, “a screening algorithm will likely be incorporated into everyday clinical practice in the near future.”

Source: Cleveland Clinic; Nov. 21, 2018

Learn more about other orthopedic manifestations

 

Closing Words



Cardiomyopathy & Amyloidosis

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 can lead to heart failure and even death. In this article, we’ll discuss the types of cardiomyopathy and its connection to amyloidosis. 

 

Risk Factors 

It has no ideal target, as it can affect a person of any age, race, or gender. However, there are a number of risk factors that can put one at an increased chance of developing cardiomyopathy. 

  • Genetic History → Family history of cardiomyopathy, heart failure, or sudden cardiac arrest
  • High Blood Pressure → Over a long period of time
  • Heart Conditions → Past history of heart attack, coronary artery disease, or infection of the heart
  • Obesity → Tends to make the heart work harder to perform its normal function
  • Alcohol Use → Long period of alcohol use
  • Drug Use → Use of illicit drugs, such as cocaine, amphetamines, and anabolic steroids
  • Medications → Drugs used in the treatment of cancer, such as chemotherapy and radiation

Additionally, there are a number of diseases that increase the risk of developing cardiomyopathy, including:

  • Amyloidosis
  • Connective Tissue Disorders
  • Diabetes
  • Hemochromatosis (excess iron storage)
  • Sarcoidosis
  • Thyroid Disease

 

Types of Cardiomyopathy

  • Dilated Cardiomyopathy → Dilation of the left ventricle prevents the heart from pumping effectively. It most commonly occurs in middle-aged men and is typically the result of coronary artery disease, heart attack, or genetic defects.

  • Hypertrophic Cardiomyopathy → Abnormal thickening of heart muscle, most commonly affecting the muscles surrounding the left ventricle. This type of cardiomyopathy is strongly associated with a family history of the disease. There have been genetic mutations linked specifically with this type of cardiomyopathy.

  • Restrictive Cardiomyopathy → Stiffening of the heart muscle results in an inelasticity, making it difficult for the heart to expand and fill. It is most commonly seen in the elder population. The disease can be of idiopathic origin or of disease such as amyloidosis. This is the least common type of cardiomyopathy. 
  • Arrhythmogenic Right Ventricular Dysplasia → Scar tissue replaces healthy tissue of the right ventricle. This form of cardiomyopathy is rare and often the result of genetic mutations.
  • Unclassified Cardiomyopathy → All other forms of cardiomyopathy fall within this category.

 

Amyloidosis

Cardiomyopathy is one of the hallmarks of amyloidosis, often seen in the transthyretin form of amyloidosis (ATTR). ATTR-CM, or transthyretin amyloid cardiomyopathy, is a disease where the transthyretin protein becomes unstable and misfolds. This unstable protein (“amyloid”) then deposits in the heart muscle, resulting in thickening and stiffening of the heart. 

The two types of ATTR-CM are wild-type ATTR-CM (wtATTR) or hereditary ATTR-CM (hATTR). wtATTR-CM is the most common form of ATTR-CM, affecting predominantly white males 60+ years old. hATTR-CM is genetic affecting both men and women, and presents as early as 50+ years old. Interestingly, one of the mutations causing hATTR, V122I, is seen almost exclusively in individuals of African ancestry. It is believed that approximately 3-4% of African Americans carry this mutation, regardless of whether or not they develop symptoms. 

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

 

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

https://www.yourheartsmessage.com

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

 

Amyloidosis – A Brief Clinical Overview

Dr. Sarah S. Lee, Assistant Professor, Division of Hematology, at the City of Hope, provides a brief yet comprehensive clinical overview of amyloidosis. In this video Dr. Lee discusses the breadth of amyloidosis, the wide range of symptom presentations, and which organs are typically involved. Focusing on AL (light chain) and TTR (transthyretin) types, she then goes through a diagnostic workup to arrive at a diagnosis, stressing the importance of typing once the presence of amyloid has been confirmed. Concluding her overview, Dr. Lee describes treatments available and how they impact patient prognosis and quality of life.

 

Bicep Bunching & Amyloidosis

 

 

 

 

 

 

 

 

Often called “Popeye Deformity,” bicep bunching is visible when the patient flexes their arm, giving the appearance of Popeye-like arms. While it is the result of a torn tendon, it can be a leading indicator of more serious issues.

 

WHAT IS IT?

When the bicep tendon is ruptured, patients develop a bunching of the biceps upon flexion of the arm against gentle resistance. Tendon ruptures occur largely in the dominant arm of each patient, with one-quarter of patients developing ruptures in both arms. Interestingly, of those who had a rupture, 37.8% didn’t know it.

 

 

 

 

 

 

 

 

 

Below watch a video from The Lancet showing what bicep bunching looks like.

 

WHAT DOES IT POTENTIALLY INDICATE?

Two things.

1.  Bicep bunching may be a marker for ATTRwt. According to MedPage Today, spontaneous ruptures of the distal biceps tendon may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, a single-center study found. The presentation of a tendon rupture, an easily elicited diagnostic sign, in a patient with HFpEF should raise suspicion for wild-type TTR cardiac amyloidosis.

The picture below (Source: JAMA September 12, 2017 Volume 318, Number 10) offers examples of ruptured biceps tendon in two patients with biopsy-proven ATTRwt Cardiac Amyloidosis. ATTRwt indicates wild-type transthyretin amyloidosis. Patient 1 with prior rupture of the biceps tendon and bunching of the biceps with flexion. Patient 2 with acute rupture of the biceps tendon in the left arm; the tendon rupture occurred with trivial trauma, five years after Cardiac Amyloidosis diagnosis.

2.  ATTRwt may contribute to heart failure. Wild-type transthyretin amyloidosis (ATTRwt) is increasingly recognized as an important cause of heart failure with preserved ejection fraction (HFpEF).

 

WHY IS IT IMPORTANT?

Bicep bunching may be a marker of wild-type transthyretin (TTR) cardiac amyloidosis, potentially giving physicians an easy way to determine the underlying cause of heart failure with preserved ejection fraction (HFpEF) in some patients. Those who were aware, reported that the distal biceps tendon ruptured approximately five years prior to heart failure diagnosis, thus perhaps offering a leading insight.

In addition, early diagnosis of wild-type TTR cardiac amyloidosis (ATTRwt) is important because treatments are now available to slow, if not halt, disease progression. Unfortunately, the diagnosis of ATTRwt is often not considered in bicep bunching cases due to the perceived rarity of the disease.

“The clinical importance [of this study] is that the detection of a ruptured distal biceps tendon may be a clue for the diagnosis of wild-type TTR amyloidosis as the cause for heart failure. This diagnosis is often overlooked in clinical practice, so this relatively simple evaluation could increase detection of the disease,” said Stuart Katz, MD, of NYU Langone Health. “Enhanced detection could lead to better treatment.”

 

EXPERT INSIGHTS VIDEO ON MUSCULOSKELETAL MANIFESTATIONS

Dr. Shari Liberman, a hand and upper extremities surgeon from Houston Methodist Orthopedics & Sports Medicine, discussed six orthopedic manifestations and their pathology as it relates to systemic amyloidosis. Published studies, coupled with her experience, has led to a belief that these manifestations can offer important evidence of amyloidosis. She concludes with thoughts regarding an orthopedic differential and biopsy considerations for each of these manifestations.

 

Sources ———————————————————————————————————————
https://www.healthline.com/health/popeye-deformity
https://www.medpagetoday.com/cardiology/chf/67850
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818850/
https://www.researchgate.net/publication/319657750_Association_Between_Ruptured_Distal_Biceps_Tendon_and_Wild-Type_Transthyretin_Cardiac_Amyloidosis
https://www.shoulderdoc.co.uk/article/721
https://www.thelancet.com/doi/story/10.1016/vid.2019.02.26.107679
https://www.youtube.com/watch?v=fHXu_0IZ3vU

Diagnosing AL and ATTR Cardiac Amyloidosis

Dr. Justin Grodin, a cardiologist and co-director of the UT Southwestern Multidisciplinary Amyloidosis Program, goes through the diagnostic process for AL and ATTR cardiac amyloidosis. He discusses key differences between AL and ATTR, and how typing of amyloidosis is paramount to consider in order to subsequently develop a treatment plan. He goes through a diagnostic algorithm to help clinicians arrive at an accurate diagnosis. Finally, he stresses the importance of genetic testing and counseling for ATTR to differentiate between wild-type and hereditary, as well as identifying the specific genetic variant.

Building an Index of Suspicion for Cardiac Amyloidosis

Understanding that amyloidosis exists BEFORE organs become involved is critical to developing an early diagnosis. Dr. Grodin, a cardiologist and co-director of the UT Southwestern Multidisciplinary Amyloidosis Program, discusses these early symptoms, family history, and red flags to be aware of in order to build an index of suspicion.

Raising Awareness of Cardiac Amyloidosis

Dr. Barry Trachtenberg, cardiologist at Houston Cardiovascular Associates, shares ways that physicians can raise their awareness of cardiac amyloidosis, whether AL or ATTR. He discusses multiple organ systems and how test results may present clues to consider amyloidosis. He offers a diagnostic algorithm with early red flags that can aid in the identification and typing of amyloidosis. Dr. Trachtenberg concludes with keys to remember, including questions to ask patients, which can elevate the suspicion of amyloidosis.

Patient Insights: Best kept secret

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

Have a listen to this brief clip from Ozzie on his discovery of the ‘best kept secret’ as it pertains to diagnosing amyloidosis – carpal tunnel syndrome.

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