Hereditary transthyretin (ATTR) amyloidosis is a rare, progressive disease caused by the misfolding of a specific protein. This inherited condition leads to the accumulation of abnormal protein deposits, known as amyloid fibrils, throughout the body. These deposits can significantly impair the function of various organs and tissues, affecting multiple bodily systems. Its hereditary nature is fundamental, influencing how the disease is transmitted and progresses within families.
How Hereditary ATTR Develops
Hereditary ATTR amyloidosis involves the transthyretin (TTR) protein. Normally, TTR is produced primarily in the liver and functions as a transporter for thyroid hormone and vitamin A throughout the body. For TTR to carry out its normal functions, four individual TTR proteins must attach to each other, forming a four-unit complex.
A genetic mutation causes the TTR protein to become unstable and prone to misfolding. This instability leads to the dissociation of the four-unit complex into individual, misfolded proteins. These abnormal TTR proteins then aggregate into insoluble amyloid fibrils. These amyloid deposits accumulate in various organs and tissues, disrupting their function and leading to progressive organ damage.
The Genetic Connection
Hereditary ATTR is an autosomal dominant condition, meaning an individual only needs to inherit one copy of the mutated TTR gene to develop the disease. The TTR gene is located on chromosome 18. If one parent has hereditary ATTR, there is a 50% chance with each pregnancy that their child will inherit the mutated gene and potentially develop the condition.
While inheriting the gene means a person is at risk, the exact age of onset and symptom severity can vary, even within the same family. Over 120 different mutations in the TTR gene have been identified, each potentially leading to a different pattern of disease onset, symptoms, and progression. Genetic testing is available to confirm a TTR gene mutation, which is a key step in diagnosis and can also be considered for family planning.
Recognizing the Signs
The symptoms of hereditary ATTR are diverse and vary significantly depending on which organs are affected and the specific genetic mutation present. Symptoms can manifest at any time in adulthood, and often worsen over time due to the disease’s progressive nature.
Neurological manifestations are common, including peripheral neuropathy, which can cause numbness, tingling, pain, and weakness. Autonomic neuropathy can also occur, leading to issues such as digestive problems like constipation alternating with diarrhea, orthostatic hypotension (light-headedness upon standing), bladder dysfunction, and erectile dysfunction.
Cardiac symptoms frequently involve cardiomyopathy, where amyloid deposits stiffen and thicken the heart muscle. This can lead to heart failure, characterized by shortness of breath, fluid retention (like ankle swelling), fatigue, and an irregular heartbeat or palpitations. Other symptoms can include kidney involvement, leading to mild to severe kidney disease, and eye issues such as vitreous opacities and glaucoma. Carpal tunnel syndrome, often affecting both wrists, and other gastrointestinal problems can also be present.
Diagnosing and Managing the Condition
Diagnosing hereditary ATTR typically begins with a comprehensive medical history and physical examination, which may reveal diverse and often non-specific symptoms. Since the disease can affect multiple organ systems, a thorough assessment is necessary.
Specific diagnostic tests are then employed to confirm amyloid deposits and identify the genetic mutation. Genetic testing for TTR gene mutations is a primary diagnostic tool, confirming hereditary ATTR if a pathogenic variant is identified. Biopsies, such as from an abdominal fat pad, nerve, or affected organ, can confirm amyloid deposits. Imaging techniques like echocardiograms and cardiac MRI are used to assess the extent of organ damage, particularly in the heart, and nuclear scintigraphy can help identify cardiac amyloid deposits.
Management strategies for hereditary ATTR aim to slow disease progression, reduce amyloid production, and manage symptoms. Current treatment approaches include TTR stabilizers, which prevent the TTR protein from misfolding, and gene-silencing agents that reduce the production of the abnormal TTR protein in the liver. Liver transplantation was historically a treatment option, but newer pharmacologic therapies have significantly reduced its necessity. Given the multisystemic nature of the disease, multidisciplinary care involving neurologists, cardiologists, genetic counselors, and other specialists is important for comprehensive patient management.