What is Hereditary Transthyretin (TTR) Amyloidosis?

From the Guidelines

Hereditary TTR amyloidosis is a rare genetic disorder that requires early diagnosis and treatment to slow disease progression and improve quality of life. This condition is caused by mutations in the TTR gene, leading to the production of abnormal transthyretin protein that forms amyloid deposits in various organs and tissues, including the heart, nerves, and other organs 1. The symptoms of hereditary TTR amyloidosis typically begin between ages 30 and 50 and may include:

• Peripheral neuropathy (numbness, tingling, and pain in the extremities)
• Autonomic dysfunction (affecting blood pressure, digestion, and other involuntary functions)
• Cardiomyopathy (heart muscle disease)
• Other organ involvement

Diagnosis involves:

• Genetic testing to identify mutations in the TTR gene
• Tissue biopsy to detect amyloid deposits
• Various imaging studies to assess organ involvement

Treatment options for hereditary TTR amyloidosis include:

• TTR stabilizers like tafamidis (Vyndaqel, Vyndamax) which prevent protein misfolding
• Gene silencers such as patisiran (Onpattro) and inotersen (Tegsedi) that reduce TTR production
• In some cases, liver transplantation to remove the source of mutated TTR
• Supportive care for specific symptoms is also important

It is essential to note that early diagnosis and treatment are crucial as they can slow disease progression and improve quality of life, though they cannot reverse existing damage 1. If you have a family history of this condition, genetic counseling is recommended to understand inheritance risks and testing options.

From the FDA Drug Label

VYNDAQEL and VYNDAMAX are transthyretin stabilizers indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) received ONPATTRO in the placebo-controlled and open-label clinical studies, including 186 patients exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years

Heredity TTR Amyloidosis is a condition caused by mutations in the transthyretin gene, leading to the production of abnormal transthyretin protein. This abnormal protein can accumulate in various tissues, including the heart, nerves, and other organs, causing damage and dysfunction.

• Key characteristics of hereditary TTR amyloidosis include:
  • Genetic mutations: Mutations in the transthyretin gene, such as Val30Met, can cause the condition.
  • Polyneuropathy: Nerve damage and dysfunction are common symptoms of hereditary TTR amyloidosis.
  • Cardiomyopathy: The condition can cause heart damage and dysfunction, leading to cardiovascular mortality and hospitalization.
• Treatment options include medications such as tafamidis (PO) 2 and patisiran (IV) 3, which can help reduce cardiovascular mortality and hospitalization, and improve symptoms.

From the Research

Overview of Hereditary TTR Amyloidosis

• Hereditary transthyretin (TTR) amyloidosis is an autosomal dominant form of fatal hereditary amyloidosis 4
• It is caused by mutations in the TTR gene, leading to the formation of amyloid deposits in various tissues 5
• The disease is characterized by a progressive, axonal fiber-length-dependent polyneuropathy, as well as cardiovascular, gastrointestinal, renal, and ocular manifestations 5

Diagnosis and Treatment

• Diagnosis of hereditary TTR amyloidosis requires genetic and proteomic analyses to distinguish it from senile systemic amyloidosis (SSA) 4
• Liver transplantation is a well-established treatment for hereditary TTR amyloidosis, but it has several limitations, including expensive medical costs and lifelong administration of immunosuppressants 4
• Other treatment approaches include TTR tetramer stabilizers, such as tafamidis and diflunisal, which can slow the progression of the disease 6, 7
• Gene therapies, such as antisense oligonucleotides and small interfering RNAs, are also being developed and have shown promise in clinical trials 8

Clinical Manifestations

• Hereditary TTR amyloidosis can manifest as a length-dependent, small fiber dominant, axonal polyneuropathy, as well as cardiac disorders and other multisystem diseases 7
• Neuropathy may affect not only large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers 7
• Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat- and cold-detection thresholds, and measurement of the electrochemical skin conductance 7

Current Research and Developments

• Recent progress in the understanding and treatment of TTR amyloidosis has led to the development of new therapies, including TTR tetramer stabilizers and gene therapies 8
• These newly developed therapies are expected to be effective for not only familial TTR amyloidosis but also SSA, based on their mechanisms of action 8
• Further research is needed to fully understand the mechanisms of TTR amyloidosis and to develop more effective treatments for this disease 4, 5, 6, 7, 8