Background

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy is a rare, progressive, and debilitating genetic disorder characterized by the accumulation of abnormal amyloid protein deposits in various tissues and organs, particularly affecting the peripheral nerves.

This condition arises from mutations in the transthyretin gene, leading to the production of misfolded TTR proteins that form amyloid fibrils, impacting nerve function and causing systemic complications. 

Initially recognized as a familial disease with a predominantly neurological impact, hATTR-PN often manifests with a broad spectrum of symptoms, including sensory, motor, and autonomic neuropathies, resulting in significant impairment in daily functioning.  

Epidemiology

Prevalence: hATTR-PN is considered a rare disease, and its prevalence varies among different populations and geographical regions. The prevalence estimates might be influenced by factors such as genetic background, ethnicity, and specific TTR mutation types, including Portuguese, Japanese, and Swedish individuals. For the current scenario, at least 29 nations worldwide have now reported hATTR on a consistent basis. 

Genetic Inheritance: hATTR-PN is inherited in an autosomal dominant pattern. Affected individuals’ offspring are 50% likely to acquire the TTR gene mutation. 

Age of Onset: The age of onset for hATTR-PN can vary widely. Symptoms may begin to manifest in adulthood, typically between the ages of 30 and 80 years, with an average onset usually occurring in the fourth or fifth decade of life. However, certain mutations might lead to earlier or later onset of symptoms. 

Disease Progression: The progression of hATTR-PN is often gradual and can lead to significant morbidity and reduced quality of life. Symptoms typically start with sensory and motor disturbances in the extremities, leading to weakness, pain, sensory loss, and autonomic dysfunction. Over time, the condition can progress to involve multiple organ systems, including the heart, gastrointestinal tract, and eyes. 

Anatomy

Pathophysiology

Genetic Mutation: hATTR-PN is caused by mutations in the TTR gene, which encodes for the transthyretin protein. Normally, transthyretin is produced by the liver and plays a role in transporting thyroxine and vitamin A in the blood. However, mutations in the TTR gene cause the production of abnormal TTR protein, which tends to misfold and aggregate into amyloid fibrils. 

Misfolding and Aggregation of TTR: The mutated transthyretin protein tends to misfold, losing its normal structure and function. These misfolded proteins tend to aggregate and form amyloid fibrils. 

Amyloid Deposition: The aggregated amyloid fibrils accumulate primarily in peripheral nerves, but they can also deposit in other organs and tissues such as the heart, kidneys, eyes, and gastrointestinal tract. In the context of hATTR-PN, the deposition of amyloid fibrils in peripheral nerves leads to nerve damage, affecting their ability to transmit signals properly. 

Nerve Damage: The deposition of amyloid fibrils in the peripheral nerves disrupts their normal structure and function. This interferes with nerve signaling, impairs the transmission of sensory and motor signals, and leads to progressive damage and dysfunction of the nerves. Over time, this results in a variety of symptoms, including sensory loss, muscle weakness, autonomic dysfunction, and organ impairment. 

Etiology

Genetic Mutation: To develop the disease, the condition is inherited in an autosomal dominant form. The TTR gene mutation leads to the production of abnormal transthyretin protein. 

Abnormal Protein Aggregation: Normally, transthyretin protein helps transport thyroid hormone and retinol-binding protein in the blood. However, in hATTR-PN, the mutated transthyretin protein tends to misfold and aggregate into amyloid fibrils instead of functioning properly. These amyloid fibrils accumulate in different tissues, including nerves, heart, kidneys, and gastrointestinal tract. 

Accumulation in Peripheral Nerves: In the case of hATTR-PN, the deposition of amyloid fibrils in the peripheral nerves, particularly in the nerve endings, disrupts nerve function.  

Genetics

Prognostic Factors

The existence and identification of a TTR variation, as well as the organ or organs implicated, determine the prognosis. Within a few years of diagnosis, patients with variant-sequence TTR that manifests early may pass away. Elderly people with gradually worsening conditions may not experience life-threatening illness for decades after symptoms first appear. 

Clinical History

• Age group 

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy is a genetic disorder caused by mutations in the transthyretin gene. The age of onset for hATTR-PN can vary widely, but symptoms typically appear in adulthood. 

The specific age group affected by hATTR-PN can therefore span from early adulthood to older age. 

Physical Examination

Neurological Examination: 

Cranial Nerves Assessment: Evaluate facial movements, visual acuity, eye movements, and sensation in the face. 

Motor Function: Assess muscle strength in upper and lower extremities, including hands, arms, legs, and feet. Look for signs of muscle wasting. 

Sensory Examination: Evaluate sensation to light touch, pinprick, vibration, and proprioception in various parts of the body. 

Autonomic Function Assessment: 

Blood Pressure Monitoring: Check for orthostatic hypotension. 

Musculoskeletal Examination: 

Joint Examination: Assess for joint pain, stiffness, and limitations in range of motion, which may occur due to peripheral neuropathy. 

Muscle Examination: Evaluate for muscle weakness, wasting, and fasciculations. 

Systemic Assessment: 

Evaluation of Eyes: Look for signs of vitreous opacities or deposits in the cornea. 

Cardiac Assessment: Assess for signs of cardiac involvement, including heart murmurs, arrhythmias, or signs of heart failure. 

Functional Assessment: 

Activities of Daily Living: Assess the patient’s ability to perform routine tasks such as dressing, grooming, eating, and walking. 

Age group

Associated comorbidity

Neuropathy-related symptoms: Patients commonly experience symptoms related to peripheral neuropathy, such as sensory disturbances, motor impairments, autonomic dysfunction, and pain. 

Cardiac involvement: Amyloid deposits can affect the heart, leading to cardiomyopathy and arrhythmias. Cardiac involvement can result in heart failure and significantly impact a patient’s health. 

Gastrointestinal complications: Digestive issues like constipation, diarrhea, and difficulties in swallowing might occur due to amyloid deposition in the gastrointestinal tract. 

Ocular manifestations: Amyloid deposits can accumulate in the eyes, leading to symptoms such as dry eyes, vision changes, and in some cases, glaucoma. 

Renal involvement: Amyloidosis can affect the kidneys, potentially leading to proteinuria, kidney dysfunction, and eventually renal failure. 

Musculoskeletal complications: Patients might experience joint pain, stiffness, and limited mobility due to amyloid deposition in joints and soft tissues. 

Associated activity

Acuity of presentation

Peripheral Neuropathy: 

Sensory disturbances: Patients may experience numbness, tingling, or loss of sensation in the extremities, starting in the feet and hands and progressing upwards. 

Motor deficits: Muscle weakness, loss of coordination, and difficulty with fine motor skills. 

Cardiac Involvement: 

Cardiomyopathy: Some individuals may develop heart abnormalities, including thickening of the heart walls and impaired cardiac function, leading to heart failure. 

Ocular Manifestations: 

Ocular deposits: Rarely, amyloid deposits can accumulate in the eyes, causing visual disturbances and, in severe cases, leading to glaucoma or other vision impairments. 

Systemic Involvement: 

Other systemic symptoms: Amyloid deposition can affect various organs such as the kidneys, leading to renal dysfunction, or the gastrointestinal tract, causing malabsorption and related complications. 

Differential Diagnoses

Chronic Inflammatory Demyelinating Polyneuropathy: It is an autoimmune disorder causing progressive weakness and sensory abnormalities in the limbs. Distinguishing between CIDP and hATTR-PN may require electrodiagnostic studies and nerve biopsy. 

Diabetic Neuropathy: Diabetes patients may experience peripheral neuropathy because of excessive blood sugar levels harming nerves. Detailed history, examination, and lab tests can help differentiate it from hATTR-PN. 

Amyloidosis (non-TTR related): There are various forms of amyloidosis caused by the deposition of different types of abnormal proteins in organs. Immunohistochemical staining or genetic testing may differentiate between TTR-related amyloidosis and other types. 

Guillain-Barre Syndrome: This is an autoimmune condition causing rapid-onset muscle weakness and, in severe cases, paralysis. Differentiation is based on the acute nature of GBS compared to the chronic progression seen in hATTR-PN. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

lifestyle-modifications-in-treating-hattr-pn

Mobility Assistance: Since hATTR-PN affects the peripheral nerves, causing numbness, tingling, and muscle weakness, assistive devices like canes, walkers, or wheelchairs may be necessary for maintaining mobility and preventing falls. 

Physical Therapy: Frequent physical therapy sessions can support the preservation of muscle flexibility and strength. A physical therapist can create a personalised training regimen based on the needs and skills of the patient. 

Nutritional Support: A balanced diet rich in nutrients, especially those that promote nerve health like vitamin B12, may be recommended. Consultation with a nutritionist or dietitian specializing in neurological conditions can be beneficial. 

Pain Management: Medications or therapies prescribed by healthcare providers can help manage neuropathic pain associated with hATTR-PN. 

Regular Medical Check-ups: Routine monitoring by healthcare professionals is essential to track disease progression and manage symptoms effectively. This may involve visits to neurologists, genetic counselors, and other specialists. 

Emotional Support: Living with a chronic condition like hATTR-PN can be emotionally challenging. Support groups, counselling, or therapy can serve as a network of support and aid in the emotional adjustment for people and their families. 

Temperature Management: Extreme temperatures can affect nerve function, so individuals need to be cautious in both hot and cold environments. 

Medication Adherence: Following the prescribed medication regimen strictly is vital. These medications might aim to stabilize or slow the progression of the disease. 

Role of siRNA agents in treating hATTR

vutrisiran (Amvuttra) 

It is recommended for the treatment of adult polyneuropathy linked to hATTR.  

The administration of the drug is through subcutaneous route every three months. 

patisiran (Onpattro) 

Patisiran works by interfering with the production of the abnormal protein transthyretin responsible for the disease.

It utilizes RNA interference RNAi technology to target and inhibit the production of the mutant transthyretin protein by interfering with the RNA that carries the genetic instructions for producing this protein. 

Effectiveness of antisense oligonucleotides in treating hATTR-PN

inotersen (Tegsedi) 

Inotersen is an antisense oligonucleotide. It works by targeting and reducing the production of the abnormal transthyretin protein, thereby slowing down the progression of hATTR-PN and its associated symptoms. 

Use of cardiovascular, other drugs in treating hATTR-PN

tafamidis (Vyndamax) 

Tafamidis is a medication classified as a transthyretin stabilizer. It works by binding to the transthyretin protein, stabilizing its structure, and preventing the formation of amyloid fibrils.

By doing so, it helps slow down the progression of nerve damage and the debilitating symptoms associated with hATTR-PN. 

role-of-liver-transplantion-surgery-in-treating-hattr-pn

In hATTR-PN, mutated transthyretin protein is mainly produced in the liver. Therefore, replacing the liver through transplantation with a healthy liver from a donor without the mutated gene could stop the production of abnormal TTR.

The purpose of this surgery is to stop the condition from getting worse by stopping the production of aberrant TTR proteins. However, this method may not be widely adopted due to the invasive nature of the surgery and the risk of complications associated with transplantation. 

role-of-management-in-treating-in-hattr-pn

Diagnosis and Assessment: Accurate diagnosis is crucial. Physicians typically perform a thorough clinical evaluation, including a detailed medical history, physical examination, and various tests. 

Symptomatic Management: Treatment focuses on managing symptoms to improve the patient’s quality of life. This may involve the use of medications to alleviate neuropathic pain like gabapentin, gastrointestinal symptoms, and medications to manage cardiac or autonomic dysfunction. 

Disease-Modifying Therapies: There are disease-modifying therapies available for hATTR-PN that aim to slow or halt disease progression by reducing the production of abnormal transthyretin protein or stabilizing TTR tetramers to prevent their dissociation into amyloid fibrils.  

TTR Stabilizers: Drugs like tafamidis stabilize TTR, reducing the dissociation into amyloid fibrils and slowing disease progression. 

RNA Interference therapies: Medications like patisiran and inotersen target the production of TTR protein in the liver, reducing its levels in the bloodstream. 

Monitoring and Follow-Up: Regular monitoring of disease progression, symptoms, and treatment response is essential. This involves periodic clinical assessments, laboratory tests, imaging studies, and nerve function evaluations to track the effectiveness of treatment and adjust as needed. 

Supportive Care and Lifestyle Modifications: Patients benefit from comprehensive supportive care measures and lifestyle adjustments. This includes physical therapy, occupational therapy, assistive devices for mobility, nutritional support, and psychological support to manage emotional well-being. 

Genetic counseling and family screening: Genetic counseling is crucial for individuals with hATTR-PN and their families. It involves discussing the genetic nature of the disease, risks of inheritance, family planning, and offering genetic testing and counseling to at-risk family members. 

Clinical Trials and Emerging Therapies: Participation in clinical trials investigating new therapies or interventions is an option for some patients. Emerging treatments or therapies under investigation might offer potential benefits and may be accessed through participation in clinical research studies. 

Medication

Future Trends

Media Gallary

References

Hereditary Transthyretin Amyloidosis with Polyneuropathy: Monitoring and Management – PMC (nih.gov)