Transthyretin-Related Amyloidosis - Causes, Types, Symptoms, and Treatment

Introduction:

The human body contains numerous transport mechanisms that are essential to carry the molecules from the production area to the active site. Usually, proteins serve the function of moving the molecules within the body and are termed transport proteins. Transthyretin is one such transport protein, synthesized by the liver and the choroid plexus (a network of vessels in the brain) that binds with the thyroid hormone thyroxine and retinol (vitamin A) and transports them throughout the body. This is how transthyretin acquires its name - it transports thyroxine and retinol.

What Is Transthyretin-Related Amyloidosis?

Amyloidosis is a disease with abnormal protein aggregation within the tissues. These aggregates are called the amyloid fibrils, and they are usually continuous, non-branching, and rigid. The assembly of amyloid fibrils is insoluble and resists degradation. The condition presents with a group of symptoms.

Transthyretin-related amyloidosis is a chronic disease that mainly affects the peripheral nervous system. This disease is often inherited and common in Portuguese families. The development of symptoms typically occurs between the age of 20 and 70 years.

What Are the Causes of Transthyretin-Related Amyloidosis?

• Transthyretin-related amyloidosis is caused by the mutation in the transthyretin gene. The condition is usually inherited in an autosomal dominance phenomenon (one altered gene is sufficient to cause the disease in the offspring).

• Transthyretins group together to form a four-unit protein structure called the tetramer. The tetrameric configuration of transthyretin is essential to bind with thyroxine and retinol. The mutation of the transthyretin gene alters the four-unit configuration, thus impairing its function. Thus the tetrameric unit dissociates and loses its function. These protein monomers integrate into amyloid fibrils and deposit in certain tissues.

• The hereditary form of transthyretin-related amyloidosis was first identified and described by a neurologist, Mario Corino da Costa Andrade, in 1952. Therefore the condition is also called Corino de Andrade’s disease.

What Are the Different Forms of Transthyretin-Related Amyloidosis?

Transthyretin-related amyloidosis can occur in three major forms based on the major system that is affected by the condition. They are,

• Neuropathic Form: The peripheral nervous system that controls the involuntary physiological process of the body is involved in the neuropathic form of transthyretin-related amyloidosis.

• Leptomeningeal Form: The central nervous system is affected in the leptomeningeal form of transthyretin-related amyloidosis, especially involving the thin outer lining of the brain and the spinal cord.

• Cardiac Form: The heart and the associated structures are affected in the cardiac form of transthyretin-related amyloidosis.

Other types of transthyretin-related amyloidosis are,

• Ocular Amyloidosis: The structures of the eye are involved in most patients with transthyretin-related amyloidosis.

• Nephropathic Amyloidosis: The kidneys have a significant deposition of amyloid, which may lead to severe renal system impairment during the advanced stage.

• Involving Other Systems: Amyloid fibrils can also be seen in the walls of the gastrointestinal tract, lungs, skin, and blood cells too.

What Are the Signs and Symptoms of Transthyretin-Related Amyloidosis?

The signs and symptoms of transthyretin-related amyloidosis vary according to the systems involved.

In neuropathic form,

• The control of the body's involuntary actions is lost.

• Postural hypotension (low blood pressure while standing up suddenly from a sitting or lying position).

• Weakness,tingling sensation and numbness in the hands and fingers.

In leptomeningeal form,

• Build up of protein in the brain tissue causes blood clots and internal bleeding in the brain.

• Fluid retention in the deep cavities of the brain.

• Poor postural balance.

• Muscle weakness.

• Deterioration in cognitive functions.

In cardiac form,

• Patients may have irregular heartbeat and enlargement of the heart tissue.

• Postural hypertension (abrupt increase in blood pressure while standing up).

• Progress to heart failure.

Other signs like dryness and increased pressure within the eyeball, severe kidney dysfunction, skin nodules, and breathing difficulty are also associated with transthyretin-related amyloidosis.

How to Diagnose Transthyretin-Related Amyloidosis?

• The foremost benchmark of transthyretin-related amyloidosis is that it runs in the family. Family history is in accordance with autosomal dominant manner.

• Biopsy (dissecting a sample tissue for microscopical evaluation) of the involved tissue shows the characteristic amyloid fibrils.

• Molecular genetic testing to detect changes in specific genes.

• Other systematic evaluations like basic neurologic assessment, nerve conduction test, echocardiogram (ECG), eye examination, body mass index (BMI) status, and routine blood and urine tests.

How to Treat Transthyretin-Related Amyloidosis?

Transthyretin Tetramer Stabilizers:

The tetrameric unit separation is needed for amyloid deposition, and hence by stabilizing the transthyretin structure, disease progression of amyloidosis can be halted.

• Tafamidis is an oral medication used to delay the progression of the disease. They act by binding to the specific site of transthyretin and stabilizing the tetrameric configuration, thereby limiting the rate of amyloid fibril formation. They are currently available in two strengths in capsule form.

• Capsule Tafamidis Meglumine - 20 mg.

• Capsule Tafamidis free acid - 61 mg.

The recommended dosage depends on the systemic involvement.

• Diflunisal is a salicylic acid derivative showing positive outcomes in the treatment of transthyretin-related amyloidosis.

Gene-Silencing Therapy:

The gene responsible for the development of the disease is specifically targeted and attacked in gene-silencing therapy.

• Patisiran is an RNA molecule encapsulated in fatty nanoparticles. By infusing intravenously, Patisiran specifically binds with the transthyretin messenger RNA and degrades it. Subsequently, there is a reduction in transthyretin protein level and tissue amyloid deposition.

• Inotersen also reduces the production of transthyretin in the body.

Other Treatment Strategies:

Various systemic manifestations of transthyretin-related amyloidosis are treated accordingly, like implanting cardiac pacemakers for heart block and surgical intervention for an eye problem (glaucoma - abnormal high pressure damaging the major nerve in the eye), and liver transplantation to reduce the production of transthyretin.

Conclusion:

Transthyretin-related amyloidosis is a familial disease. Each affected individual should undergo genetic counseling and be aware of the nature and mode of inheritance patterns. Prenatal testing during pregnancy can be done in persons at risk (personal history of having the disease or any of the family members are affected). Recent advancements in gene therapy have possibly slowed the disease progression and improved the quality of a patient's life. Some of the potential target-specific molecular treatments are still under investigation.