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Congressional Hill Briefing, Improving Care for Veterans with Rare Diseases: Establishing a National Commission

We, with other members of the amyloidosis community, were proud to join an important meeting hosted by the Center for Patient Advocacy Leaders (CPALs). They hosted a Congressional Hill Briefing, Improving Care for Veterans with Rare Diseases: Establishing a National Commission, at the U.S. Capitol Visitor Center in Washington, DC. This briefing was designed to bring together Veterans/Veterans’ advocates, rare disease advocates, patients, and congressional staff to address unmet needs of Veterans with rare diseases and explore collective action to help ensure Veterans with rare diseases get the comprehensive, patient-centered care and treatment they need and deserve.

Expert Insights: Systemic Amyloidosis: You’ve Got to Think of IT to Diagnose IT

Dr. Mat Maurer, cardiologist at Columbia University Irving Medical Center, discusses the importance of developing a broad differential in order to diagnose this rare, potentially life-threatening, yet treatable disease. He shares a typical but unfortunate case of cardiac amyloidosis, along with statistics of misdiagnosis and delayed diagnosis. He shares his view on the appropriate process for diagnosis based on Dr. David Eddy’s 1982 New England Journal of Medicine piece “The Art of Diagnosis” and the need to create a broad enough differential in order to consider less common diseases such as systemic amyloidosis. Dr. Maurer lists common reasons for missing diagnosis of cardiac amyloidosis all clinicians should be aware of, punctuated by his concluding point … “The Key to Correct Treatment is Diagnosis, Diagnosis, and Diagnosis.” It’s simple … you cannot treat what has not been diagnosed.

 

This is a MUST VIEW video for clinicians who diagnose patients, regardless of sub-specialty.

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/



Patient Insights: My survival depends on my physicians communicating

Our patient speakers at the Amyloidosis Speakers Bureau are powerful educators and offer compelling insights. Have a listen to this brief clip from Rayna. She talks about how important she felt it was for her survival that her physicians communicated.

Expert Insights: AL Amyloidosis: Symptoms, Diagnostics and Challenges

Dr. Gurbakhash Kaur, co-director of the amyloidosis program at UT Southwestern Medical Center, opens with a brief overview of the disease. Focusing on AL Amyloidosis, she shares how heterogeneously this disease presents – it can be very different from patient to patient, amplifying the diagnostic challenge. Symptoms may also be more commonly associated with other diseases. For example, proteinuria is often associated with diabetes and hypertension. However, clinicians should look at the bigger picture to be sure, as amyloidosis can also be a cause. Dr. Kaur reviews what should be in a basic workup when one has a clinical suspicion for amyloidosis. Once tested positive for amyloidosis, a second necessary step is to determine the type of amyloidosis. This is critical as it will determine the appropriate course of treatment. In closing Dr. Kaur summarizes the goals of treatment, what is available today, and what drugs are in clinical trials, giving lots of hope to the AL amyloidosis community.

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.

AL and ATTR Amyloidosis: Recognition and Diagnosis — The Key to Successful Treatment

Dr. Heather Landau, Associate Attending Physician at Memorial Sloan Kettering, provides a comprehensive clinical overview of amyloidosis. Spanning recognition and diagnosis – the key to successful treatment.

 

Mackenzie’s Mission recognized by Mayo Clinic in the Hall of Benefactors

We thank the Mayo Clinic for the recognition of our ongoing support of their Amyloidosis Research Fund. Starting in 2017, shortly after Mackenzie’s Mission was founded, our cumulative support has been meaningful, and we are now Distinguished Benefactors.

In addition, we are proud to be in the Mayo Clinic Hall of Benefactors!

Dr. Morie Gertz at the Mayo Clinic works with a multidisciplinary team of experts and helps to lead research initiatives which are widely recognized worldwide as one of the original amyloidosis centers of excellence.

While we know that funding research, bio banks, conducting clinical trials, and more requires significant funds, it is our hope that our year-to-year support helps them do more and make an even bigger difference.

We are eternally grateful to the amyloidosis team at the Mayo Clinic and all they do for our patient community to improve lives.

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.”

Learn more about other orthopedic manifestations

 

Closing Words



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/

 

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