Transthyretin-related hereditary amyloidosis

Transthyretin-related hereditary amyloidosis (ATTR) is a progressive genetic disorder characterized by the accumulation of amyloid fibrils, primarily composed of the transthyretin (TTR) protein, in various bodily tissues and organs. This condition is also known as familial amyloid polyneuropathy (FAP) when it predominantly affects the peripheral nerves, leading to neuropathy, or familial amyloid cardiomyopathy (FAC) when it primarily affects the heart. ATTR can lead to a wide range of symptoms, depending on the organs involved, and can be life-threatening if not diagnosed and treated early.

Etiology

ATTR is caused by mutations in the TTR gene, which encodes the transthyretin protein. This protein is primarily produced in the liver and is responsible for the transport of thyroxine and retinol-binding protein bound to vitamin A. Mutations in the TTR gene lead to the misfolding of the transthyretin protein, which then aggregates into amyloid fibrils. These fibrils deposit in various tissues, including the peripheral nerves, heart, kidneys, and gastrointestinal tract, causing organ dysfunction.

Symptoms

The symptoms of ATTR vary widely depending on the organs affected. Common symptoms include:

• Peripheral neuropathy, characterized by numbness, tingling, and pain in the hands and feet
• Autonomic neuropathy, leading to abnormalities in blood pressure, heart rate, and digestion
• Cardiomyopathy, resulting in shortness of breath, palpitations, and edema
• Kidney dysfunction, which can lead to proteinuria and renal failure
• Gastrointestinal disturbances, such as diarrhea, constipation, and unintentional weight loss

Diagnosis

The diagnosis of ATTR involves a combination of clinical evaluation, family history, laboratory tests, and imaging studies. Genetic testing is crucial for identifying mutations in the TTR gene. Biopsy of affected tissues, showing amyloid deposits when stained with Congo red, is often required to confirm the diagnosis.

Treatment

Treatment options for ATTR include:

• Tafamidis and diflunisal, which stabilize the transthyretin tetramer and slow the progression of the disease
• Liver transplantation, which can be an option for certain patients, as the liver is the primary source of the mutant transthyretin protein
• Patisiran and inotersen, which are RNA interference (RNAi) therapies that reduce the production of transthyretin protein

Prognosis

The prognosis for patients with ATTR varies depending on the type of mutation, age of onset, and organs involved. Early diagnosis and treatment can significantly improve the quality of life and life expectancy of affected individuals.