Understanding Hereditary Transthyretin Amyloidosis (hATTR)

Hereditary ATTR amyloidosis (hATTR amyloidosis) is an inherited, rapidly progressing and life-threatening disease. It is caused by a mutation in the transthyretin (TTR) gene that results in the accumulation of abnormal TTR proteins, such as amyloid fibers, in multiple locations, including the nerves, heart, and gastrointestinal tract.

TTR protein is mainly produced in the liver and is normally a carrier for the binding protein to retinol – one of the vehicles used to transport vitamin A in the body. hATTR amyloidosis involves many systems in the body and can result in a wide range of symptoms, including sensory and motor symptoms, autonomic (e.g., diarrhea, hypotension, erectile dysfunction) and cardiac symptoms.

The continuum of hATTR amyloidosis disease includes patients who have predominant symptoms of polyneuropathy (involving the nerves), historically known as familial amyloidotic polyneuropathy (FAP), as well as patients who present with symptoms of predominant cardiomyopathy (involving the heart), historically known as cardiomyopathy familial amyloidosis (CFA). However, many patients of hATTR can experience polyneuropathy, cardiomyopathy and gastrointestinal symptoms.

hATTR represents a major unmet medical need, affecting approximately 50,000 people worldwide. The condition has a progressive course and can lead to morbidity, disability and potentially death within two to 15 years. hATTR amyloidosis is often underdiagnosed or misdiagnosed and there remains a significant unmet medical need for therapies that can treat the underlying cause of the disease.

Cause

hATTR amyloidosis is caused by a mutation in the TTR gene. It is an autosomal dominant, hereditary disease, which means that a person needs to have only one copy of the mutated gene to manifest the disease and thus can be inherited from one parent.

The mutation causes the TTR protein to reproduce abnormally and accumulate as amyloid fibers in various organs. hATTR amyloidosis is associated with more than 120 different known mutations of the TTR gene. The most frequent mutation associated with polyneuropathy is V30M, which accounts for approximately 50% of mutations predominantly presented with polyneuropathy.

Symptoms

The degree and intensity of symptoms of hATTR amyloidosis and its onset vary from person to person, depending on the degree to which organ function is compromised.

Sensory and motor symptoms frequently reported are:

● Neuropathic pain

● Sensory change (i.e., change in sensitivity to pain and temperature)

● Numbness and tingling

● Muscle weakness

● Imbalance

● Difficulty walking

Autonomic symptoms frequently reported are:

● Nausea and vomiting

● Changes in gastrointestinal motility (i.e., diarrhea, constipation, gastroparesis, early satiety)

● Orthostatic hypotension (i.e., dizziness and fainting after getting up)

● Bladder dysfunction

● Erectile dysfunction

Cardiac symptoms frequently reported are:

● Shortness of breath

● Edema

● Palpitations and arrhythmias

Other frequently reported symptoms:

● Carpal tunnel syndrome

● Generalized fatigue

● Unintentional weight loss

● Eye changes (i.e., blurred vision, blindness)

Diagnosis

Patients with hATTR amyloidosis need an early and accurate diagnosis due to the natural rapid progression of the disease. As hATTR amyloidosis is often misdiagnosed due to its wide range of symptoms, which can overlap with many other common diseases, many specialists are often consulted before diagnosis.

As the etiology of hATTR amyloidosis is different from other diseases with polyneuropathy and cardiomyopathy, a misdiagnosis could result in ineffective and possibly harmful treatment. hATTR amyloidosis should be considered in patients with progressive neuropathy or cardiomyopathy with multisystem involvement, especially in those with a family history of amyloidosis. People of Portuguese descent with a familiar history of the disease should be especially careful here.

hATTR amyloidosis is diagnosed in several ways, however blood tests and biopsies are often used to confirm the presence of the TTR amyloid protein. Genetic testing can also be used to identify the specific TTR mutation. Other diagnostic tests for hATTR amyloidosis with polyneuropathy may include nerve conduction studies and/or renal function tests. Echocardiograms, cardiac magnetic resonance (MRI) and bone scans can also be used to help diagnose patients who have predominant symptoms of cardiomyopathy.

Treatments

Despite available treatments, some patients may experience progressive and severe disease-related morbidities. Patients can consult an amyloidosis specialist to select an individual treatment plan. Based on TTR symptoms and mutation, the patient care team may include a family physician, hematologist, oncologist, neurologist, cardiologist, nephrologist, as well as other healthcare professionals.

Current treatments for hATTR amyloidosis manage symptoms (supportive treatment) or aim to stabilize the protein. Orthotopic liver transplantation can be a treatment option in selected patients. Disease progression can occur with current treatments.

Clinical studies are ongoing to develop new treatments for hATTR amyloidosis.