Amyloidosis Due to Pathogenic Variants - A Review

Introduction

Amyloidosis is a group of diseases recognized for its ability to build amyloid protein in different tissues and organs. This can result in many clinical symptoms and ultimately lead to multiple organ failure. Amyloidosis may be genetically inherited or acquired. This article intends to explore the pathogenic variant of amyloidosis, its pathophysiology, clinical features, diagnosis, and management.

What Are the Different Types of Hereditary Amyloidosis?

Hereditary Amyloidosis

1. Transthyretin Amyloidosis: This type of amyloidosis is mainly caused by genetic mutations of the gene that codes for the protein transthyretin. Numerous mutations have been identified, including more than 130 missense variants. A missense mutation means the substitution of a single base pair, leading to different amino acid formation and, ultimately, abnormal protein formation. The most common mutation is seen in the Val30Met gene.

2. Apolipoprotein A-I Amyloidosis: This type of amyloidosis is caused mainly by mutations in the APOA1 gene. This gene is important as it helps form the high-density lipoprotein component responsible for cholesterol transport. Mutant proteins are deposited in various bodily organs, such as the kidneys, liver, and heart.

3. Fibrinogen Alpha Chain Amyloidosis: This amyloidosis is caused by FGA gene mutations. This mutation results in the abnormal formation of fibrinogen A alpha chain.

4. Lysozyme Amyloidosis: This type of amyloidosis is mainly due to mutations in the LYZ gene, whose function is to form lysozyme enzymes. This enzyme is integral for bacterial cell wall degradation.

What Is the Pathophysiology of Amyloidosis?

In diseased states, the pathogenic gene variants form abnormal proteins. These proteins are known to misfold and do not disintegrate like normal proteins. They also aggregate into insoluble amyloid fibrils. In most cases, deposition is seen external to tissues, totally hampering normal tissue function.

The continuous deposition of amyloid fibrils causes the body to react, initiating an inflammatory response. Further damage leads to fibrosis and contributes to organ failure. Different mutations result in different levels of damage.

1. Transthyretin Amyloidosis: The protein transthyretin is a thyroxine transporter and also helps in binding retinol. When genetic mutations occur in the formation of this protein, the resultant abnormal mutated proteins misfold and aggregate, giving rise to amyloid fibrils.

2. Apolipoprotein A-I Amyloidosis: In this type, abnormal amyloid fibrils are formed due to mutation. This ultimately deposits fibrils in vital organs like the heart, liver, and kidneys, contributing to organ damage.

3. Fibrinogen A Alpha Chain Amyloidosis: When the FAG gene mutation occurs, it results in abnormal fibrinogen proteins. They misfold and aggregate severely.

What Are the Clinical Features of Pathogenic Variants of Amyloidosis?

Generally, amyloidosis is manifested as changes seen in the heart, kidneys, involvement of the gastrointestinal tract, and sometimes neurological involvement,

• Cardiac Involvement: Seen as heart failure, arrhythmias, restrictive cardiomyopathy.

• Kidney Involvement: Proteinuria, nephrotic syndrome, renal failure.

• Brain Involvement: Peripheral neuropathy, autonomic dysfunction, carpal tunnel syndrome.

• Gastrointestinal Involvement: Malabsorption, diarrhea, bleeding.

Transthyretin Amyloidosis:

1. Familial Amyloid Polyneuropathy: Familial amyloid polyneuropathy is a hereditary disorder caused by a mutation in the transthyretin gene, leading to the production of amyloidogenic transthyretin proteins. These proteins form amyloid fibrils that deposit in the peripheral nerve and clinically manifest as sensory and motor neuropathy, autonomic dysfunction, and, in some cases, cardiomyopathy.

2. Familial Amyloid Cardiomyopathy: Familial amyloid cardiomyopathy is a genetic disorder caused by a mutation in the transthyretin gene, leading to the production of abnormal transthyretin proteins. These aggregate into amyloid fibrils and get deposited in the heart, leading to restrictive cardiomyopathy. Patients typically have symptoms of heart failure, such as shortness of breath, fatigue, and edema.

Apolipoprotein A-I Amyloidosis

Clinically, it is seen more with

• Proteinuria: Refers to a condition where an abnormal amount of protein is seen in urine; this indicates damage to kidneys.

• Renal Insufficiency: This is also known as kidney failure. In this condition, the kidneys do not function properly in filtering waste from the blood. This ultimately leads to a condition where waste and toxins build up in the body, and the kidneys go into failure mode.

• Hepatomegaly: This condition refers to liver enlargement. This is usually accompanied by jaundice and abdominal pain.

• Cardiomyopathy: This consists of a group of diseases affecting heart muscles. It fails the heart to pump the required blood to the body, leading to failure and arrhythmias.

Fibrinogen A Alpha Chain Amyloidosis:

This alpha-chain amyloidosis commonly affects kidneys.

• Nephrotic Syndrome: In this condition, the kidneys show excessive amounts of protein loss. This is seen as progressive swelling, particularly in the leg area.

• Progressive Renal Failure: In this condition, the kidneys are unable to bear the load and gradually go into failure mode. When toxins and waste products build up in the body, the patient will be required to undergo dialysis.

Lysozyme Amyloidosis

1. Hepatomegaly: Deposition of amyloid fibrils in and around the liver leads to an enlarged liver. Patients might complain of severe abdominal pain and feel full.

2. Renal Failure: Amyloid deposition in kidneys leads to significant protein loss, edema, loss of ability to filter waste, and, over time, complete failure.

3. Gastrointestinal Disturbances: The deposition of amyloid deposits in the gastrointestinal tract leads to diarrhea, malabsorption, and bleeding from the gastrointestinal tract. Patients may show symptoms like pain in the abdominal region and inability to eat food. This significantly affects nutritional status and overall quality of life.

How Is Amyloidosis Diagnosed?

To diagnose amyloidosis, various methods are used in combination.

A Thorough History and Physical Examination: The patient must be carefully assessed and checked for symptoms within the family to suggest a diagnosis of amyloidosis. Then, the patients are referred for blood and urine tests; imaging tests may indicate the degree of organ damage. Genetic testing is the main method to confirm the mutation. Sometimes, a biopsy is indicated to look for amyloid deposition. Congo red is the most common staining employed.

What Are the Various Management Strategies Used for Amyloidosis?

Treatment aims to relieve the patient's symptoms, prevent organ damage, and decrease the production of mutated and abnormal proteins.

1. Supportive Care: Patients are asked to modify their lifestyles, adopt healthier ones, and take medications to provide pain relief.

2. Targeted therapies and chemotherapy regimens may be recommended based on the patient's condition.

3. Transplantation of organs based on the severity of the damage.

4. Transthyretin Amyloidosis: Targeted therapy using medications such as Tafamids stabilizes and prevents transthyretin misfolding. Similarly, Patisiran and Inotersen help decrease the production of transthyretin by interfering with RNA and the mutation mechanism. In severe cases, liver transplantation may be indicated.

5. Apolipoprotein A-I Amyloidosis and Lysozyme Amyloidosis: The patient is first treated to provide symptom relief. In severe deposition cases, organ transplantation may be necessary.

6. Fibrinogen Alpha Chain Amyloidosis: Since it primarily affects kidneys, they might need renal transplantation.

Conclusion

Amyloidosis due to pathogenic variants is mainly a group of genetic disorders caused by mutations of genes resulting in abnormal protein formation. The fibrils deposit in the tissues and lead to organ failure and damage. Early diagnosis must be made using a combination of clinical, biopsy, and genetic testing, and treatment must be initiated as soon as possible to relieve the patient.