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Neuropathic Impact of Amyloidosis

Systemic amyloidosis is comprised of a group of rare disorders characterized by extracellular deposition of amyloid fibrils that can damage a body’s organs, tissues, and nerves. Below we discuss both acquired and inherited types of amyloidosis and, in particular, how it can affect the body’s nervous systems – both peripheral and autonomic.

ACQUIRED TYPES OF AMYLOIDOSIS

Acquired forms of the disease include AL or “light chain” amyloidosis, where increased levels of misfolded light chain proteins lead to amyloid formation and deposition, and “wild type” transthyretin (ATTRwt) amyloidosis where amyloid fibrils deposit slowly over time, typically becoming symptomatic in the elderly.

Acquired forms of the disease tend to predominantly impact the heart and kidneys, however less common or pronounced neuropathic manifestations of the disease may also preside. In the case of AL amyloidosis, although not a prominent symptom, peripheral neuropathy is seen in 15% of patients at disease onset and in about 35% of patients as the disease progresses. In the case of wild type transthyretin amyloidosis some degree of neuropathy is found in approximately 50% of patients.

The two graphics below illustrate the most common organs affecting AL amyloidosis and wild type amyloidosis, including the nervous system.

 

 

INHERITED TYPES OF AMYLOIDOSIS

The most prominent inherited form of the disease is hereditary transthyretin amyloidosis (hATTR or ATTRv), which includes over 120 genetic variants.  With many of the variants, neuropathic symptoms frequently accompany, or even dominate, over cardiac symptoms.  (1)

The graphic below illustrates the most common organs affecting hATTR amyloidosis, including the nervous system.

 

 

HOW AMYLOIDOSIS CLINICALLY IMPACTS THE NERVOUS SYSTEM

Amyloidosis can impact the bodies peripheral and/or the autonomic nervous system. When the disease affects both systems it is defined as polyneuropathy.

Peripheral Nervous System

The peripheral nervous system consists of nerves that branch out from the brain and spinal cord to the extremities (periphery) of the body. Sensory nerves carry electrical signals from the extremities towards the brain and motor nerves (afferent nerves) carry signals from the brain to the extremities. The figure below illustrates a basic layout of the system. (2)

 

The peripheral nervous system includes dorsal root ganglion, which functions to branch sensory and motor nerves from the spine to the periphery of the body. The figure below illustrates a dorsal root ganglion. Amyloid fibrils damage the dorsal root ganglion, often early in disease progression.

 

Additionally, amyloid deposits in and damages peripheral nerve endoneurium and Schwann cells. The endoneurium is a layer connective tissue around the protective sheath of each nerve fiber in the peripheral nervous system. Schwann cells function to produce the myelin sheath around cell axons. Schwann cell entanglement with amyloid fibrils causes axon degeneration. Both of these processes contribute to nerve damage and can result in symptoms such as numbness in ankles, feet, and hands, and in many cases muscular atrophy, particularly in the legs.

The figure shown below provides an illustrated summation of the production of amyloid fibrils and their impact on both the peripheral and autonomic nervous systems.

 

Autonomic Nervous System

The autonomic nervous system controls involuntary bodily functions such as regulation of the heart rate, blood pressure, breathing, and digestion, amongst other functions. The system contains sympathetic ganglia, which signal various organs and tissues, contributing to the “fight or flight” response. Amyloid fibrils damage the sympathetic ganglia. (3). Involvement of the autonomic nervous system can lead to symptoms such as compromised heart rate and blood pressure regulation, which can result in chronic orthostatic hypotension, and even syncope (fainting), to name a few.

HEAR FROM AN EXPERT NEUROLOGIST

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.

 

 

 

Bibliography

  1. Neuromuscular Complications of Systemic Amyloidosis, Dina Namiranian, MD, Stefanie Geisler, MD, Department of Neurology, Neuromuscular Division, Washington University School of Medicine in St. Louis, Mo, 2022 Elsevier Inc. The American Journal of Medicine (2022)
  1. Peripheral nervous system, Adrian Rad. https://www.kenhub.com/en/library/anatomy/the-peripheral-nervous-system
  1. Autonomic Ganglia. https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Anatomy_and_Physiology_(Boundless)/14%3A_Autonomic_Nervous_System/14.2%3A_Structure_of_the_Autonomic_Nervous_System/14.2B%3A_Autonomic_Ganglia#:~:text=Learning%20Objectives,fight%2Dor%2Dflight%20response.
  1. Peripheral Nerve Fibers-Endoneurium

https://www.elsevier.com/resources/anatomy/peripheral-nerve-fibers/nerve-fascicles/endoneurium/16249

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/



Clinical Signs that Suggest Transthyretin Amyloidosis: Non-cardiac Clues – Part II

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.  See Part I: “Cardiac Clues that Suggest Transthyretin Amyloidosis” for more.

 

Breaking News – FDA approves WAINUA for ATTRv-PN

The U.S. FDA has approved a new treatment for adults living with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN).

WAINUA™ (eplontersen) granted regulatory approval in the U.S. for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis.
  • U.S. FDA approval based on Phase 3 NEURO-TTRansform results showing WAINUA demonstrated consistent and sustained benefit halting neuropathy disease progression and improving neuropathy impairment and quality of life
  • Additional regulatory reviews for WAINUA underway in rest of world
  • WAINUA will be available in the U.S. in January 2024

READ PRESS RELEASE HERE

“Many people living with hereditary transthyretin-mediated amyloid polyneuropathy are unable to fully enjoy their lives because of the relentless, progressive and debilitating effects of the disease,” said Michael J. Polydefkis, M.D., professor of neurology at Johns Hopkins University School of Medicine and an investigator in the NEURO-TTRansform study. “Approval of WAINUA represents a meaningful advancement in treatment, one that gives those who are living with transthyretin-mediated amyloid polyneuropathy help managing the disease.”

FDA Approved AMVUTTRA for hATTR

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

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