Hereditary Transthyretin Amyloidosis: Symptoms, Causes & Treatment

What Is Hereditary Transthyretin Amyloidosis?

Hereditary transthyretin amyloidosis (hATTR) is a rare inherited disorder where mutations in the TTR gene cause the transthyretin protein to misfold and accumulate as amyloid deposits in various organs, particularly nerves and heart. Approximately 50,000 people worldwide are affected, with endemic areas in Portugal, Sweden, Japan, and Brazil.

Hereditary transthyretin amyloidosis represents one of the most significant hereditary neurological conditions affecting adults worldwide. The disease occurs when a mutation in the transthyretin (TTR) gene causes the normally stable transthyretin protein to become unstable and misfold. These misfolded proteins aggregate together to form insoluble fibrils called amyloid, which progressively deposit in tissues throughout the body. The accumulation of amyloid disrupts normal organ function, leading to the diverse and often debilitating symptoms characteristic of this condition.

The transthyretin protein normally functions as a transport molecule in the blood, carrying thyroid hormone (thyroxine) and retinol-binding protein (which transports vitamin A). Produced primarily in the liver, transthyretin circulates throughout the body in its stable, tetrameric form. However, when certain mutations are present in the TTR gene, the protein becomes prone to dissociating into monomers that then misfold and aggregate into amyloid fibrils. Over 140 different mutations in the TTR gene have been identified, each associated with varying disease characteristics, age of onset, and organ involvement patterns.

The disease follows an autosomal dominant inheritance pattern, meaning that a person only needs to inherit one copy of the mutated gene to be at risk of developing the condition. This translates to a 50% chance of inheritance for each child of an affected parent. However, it is important to note that not everyone who carries a TTR mutation will necessarily develop symptoms, a phenomenon known as incomplete penetrance. The age at which symptoms begin and the severity of the disease can vary considerably even among family members carrying the same mutation.

Endemic Areas and Geographic Distribution

While hereditary transthyretin amyloidosis occurs worldwide, certain geographic regions have particularly high prevalence rates due to founder effects, where a mutation arose in a common ancestor and was passed down through generations within relatively isolated populations. Portugal has the highest known prevalence, particularly in the northern regions around Porto and Póvoa de Varzim, where the Val30Met mutation is most common. Sweden, especially the northern region around Skellefteå (where the disease is sometimes called "Skellefteå disease"), represents another major endemic area with the same Val30Met mutation. Japan, particularly the Nagano and Kumamoto prefectures, has significant clusters of affected individuals. Brazil, with its historical Portuguese colonial ties, also has notable endemic regions. Beyond these endemic areas, the condition occurs sporadically in families throughout the world, often with different mutations predominating in different populations.

The Different Types of TTR Mutations

The specific TTR mutation a person carries significantly influences the clinical presentation of their disease. The Val30Met (V30M) mutation, where valine is replaced by methionine at position 30 of the protein, is the most common worldwide and typically causes a polyneuropathy-predominant form of the disease. The Val122Ile (V122I) mutation is particularly common in people of African descent and tends to cause a cardiomyopathy-predominant form with later onset. The Thr60Ala (T60A) mutation, more common in Ireland and the United Kingdom, causes a mixed phenotype affecting both nerves and heart. Understanding which mutation is present helps healthcare providers predict disease course and tailor treatment approaches accordingly.

What Are the Symptoms of Hereditary Transthyretin Amyloidosis?

Symptoms typically begin between ages 30-70 and include progressive numbness and tingling in the feet and hands (peripheral neuropathy), carpal tunnel syndrome, heart problems including arrhythmias and heart failure, gastrointestinal issues like diarrhea and constipation, unexplained weight loss, and orthostatic hypotension causing dizziness when standing.

The symptom profile of hereditary transthyretin amyloidosis reflects the wide distribution of amyloid deposits throughout the body. Because the disease can affect multiple organ systems simultaneously, patients often experience a constellation of symptoms that may initially seem unrelated. This complexity frequently leads to delayed diagnosis, as individual symptoms may be attributed to other, more common conditions. Understanding the full spectrum of possible symptoms is crucial for both patients and healthcare providers to ensure timely recognition and treatment.

The progression of symptoms typically follows a predictable pattern, though the rate of progression varies among individuals and mutations. In the early stages, symptoms are often subtle and may be dismissed as normal aging or attributed to other causes. As the disease advances, symptoms become more pronounced and debilitating, eventually affecting daily activities and quality of life. The average time from symptom onset to diagnosis historically has been several years, though increased awareness and improved diagnostic tools are helping to shorten this delay.

Peripheral Neuropathy Symptoms

Peripheral neuropathy represents the hallmark manifestation of the polyneuropathy-predominant form of hereditary transthyretin amyloidosis. The symptoms typically begin in the feet and progress upward in a length-dependent pattern, meaning that the longest nerve fibers are affected first. Patients initially notice numbness, tingling, or burning sensations in their feet, often described as a "pins and needles" feeling or a sensation of walking on cotton. As the disease progresses, these sensory disturbances spread to involve the lower legs and eventually the hands. Pain is a common feature and can be particularly distressing, ranging from shooting pains to a constant burning sensation that may worsen at night and interfere with sleep.

Motor weakness develops as the neuropathy progresses, affecting the muscles controlled by damaged nerves. Patients may notice foot drop, difficulty walking, weakness in the hands affecting grip strength, and problems with fine motor tasks. The combination of sensory loss and motor weakness significantly impacts mobility and independence. Importantly, because patients lose the ability to feel pain and temperature, they become susceptible to injuries that go unnoticed, including burns and wounds on the feet that can become infected.

Carpal Tunnel Syndrome

Carpal tunnel syndrome frequently appears as an early manifestation of hereditary transthyretin amyloidosis, often preceding other symptoms by several years. The condition occurs when amyloid deposits in the transverse carpal ligament compress the median nerve as it passes through the wrist. Patients experience numbness, tingling, and pain in the thumb, index finger, middle finger, and part of the ring finger. Symptoms are often worse at night and may wake patients from sleep. When carpal tunnel syndrome occurs bilaterally (in both wrists) and particularly in a person with a family history of unexplained neuropathy or heart problems, it should raise suspicion for possible hereditary transthyretin amyloidosis.

Cardiac Symptoms

Cardiac involvement in hereditary transthyretin amyloidosis results from amyloid infiltration of the heart muscle, leading to a condition called infiltrative cardiomyopathy. The heart walls become thickened and stiff, impairing the heart's ability to fill with blood properly (diastolic dysfunction) and eventually affecting its pumping capacity. Patients may experience shortness of breath, particularly with exertion or when lying flat. Fatigue and reduced exercise tolerance are common. Leg swelling (edema) may develop as the heart struggles to maintain adequate circulation. Palpitations or irregular heartbeat may occur due to conduction abnormalities caused by amyloid infiltration of the heart's electrical system. Some patients develop atrial fibrillation, which increases the risk of stroke.

Autonomic Dysfunction

Autonomic neuropathy affects the nerves that control involuntary bodily functions. Orthostatic hypotension, a significant drop in blood pressure upon standing, is a particularly troublesome symptom that can cause dizziness, lightheadedness, and fainting. This increases the risk of falls and injuries. Gastrointestinal autonomic dysfunction leads to alternating diarrhea and constipation, nausea, early satiety (feeling full after eating small amounts), and delayed gastric emptying. These symptoms contribute to the significant weight loss commonly seen in affected individuals. Urinary dysfunction may include difficulty emptying the bladder or urinary incontinence. Sexual dysfunction, including erectile dysfunction in men, is common. Abnormalities in sweating patterns, either excessive sweating or decreased sweating, may also occur.

Eye Involvement

The eyes can be affected in hereditary transthyretin amyloidosis, particularly in certain mutations. Vitreous opacities occur when amyloid deposits form in the vitreous humor (the gel-like substance filling the eye), causing floaters and potentially affecting vision. Glaucoma can develop due to amyloid deposits affecting fluid drainage from the eye. Dry eyes may result from decreased tear production. Regular ophthalmologic examinations are important for patients with this condition.

How Is Hereditary Transthyretin Amyloidosis Diagnosed?

Diagnosis involves a combination of clinical evaluation, genetic testing to identify TTR gene mutations, tissue biopsy showing amyloid deposits with Congo red staining, nerve conduction studies for neuropathy assessment, and cardiac imaging including echocardiography, cardiac MRI, and nuclear scintigraphy. Early diagnosis is crucial as new treatments can slow disease progression.

Diagnosing hereditary transthyretin amyloidosis requires a systematic approach that integrates clinical findings, family history, laboratory tests, imaging studies, and genetic analysis. Given the rarity of the condition and the nonspecific nature of many early symptoms, diagnosis can be challenging. Increased awareness among healthcare providers, combined with advances in diagnostic techniques, has improved the ability to identify affected individuals earlier in their disease course, which is crucial for optimizing treatment outcomes.

The diagnostic process typically begins when a patient presents with symptoms suggestive of the disease, particularly when there is a family history of similar symptoms or when common diagnoses fail to fully explain the clinical picture. A thorough medical history and physical examination provide important clues. The presence of progressive peripheral neuropathy, unexplained cardiomyopathy, gastrointestinal symptoms, or bilateral carpal tunnel syndrome should prompt consideration of hereditary transthyretin amyloidosis, especially when multiple symptoms occur together.

Genetic Testing

Genetic testing represents a cornerstone of diagnosis and involves analyzing the TTR gene for known mutations. A simple blood test can identify whether a person carries a pathogenic TTR variant. The test is highly accurate and can definitively confirm the genetic basis for the disease. For individuals with a confirmed family history and known mutation, genetic testing can determine whether they have inherited the mutation even before symptoms develop, enabling proactive monitoring and early intervention when appropriate. Genetic counseling should accompany testing to help individuals understand the implications of results for themselves and their family members.

Tissue Biopsy

Tissue biopsy provides direct evidence of amyloid deposits and remains an important diagnostic tool, particularly when genetic testing results are inconclusive or when confirming the type of amyloid present. Various tissues can be sampled, with fat pad aspiration (taking a small sample of subcutaneous fat from the abdomen) being a relatively noninvasive first-line option. Other biopsy sites include the salivary glands, rectum, or affected organs such as the heart or nerves. The tissue is stained with Congo red dye, which causes amyloid to display a characteristic apple-green birefringence under polarized light microscopy. Additional immunohistochemical staining or mass spectrometry can identify the specific protein composing the amyloid deposits, confirming transthyretin as the source.

Nerve Conduction Studies and Electromyography

Electrodiagnostic studies, including nerve conduction studies (NCS) and electromyography (EMG), evaluate the extent and nature of peripheral nerve involvement. These tests measure how well and how quickly electrical impulses travel through nerves and how muscles respond to nerve signals. In hereditary transthyretin amyloidosis, nerve conduction studies typically show reduced amplitude of sensory and motor nerve responses, reflecting axonal loss. The pattern of findings helps characterize the neuropathy and distinguish it from other causes. Serial testing can monitor disease progression and response to treatment.

Cardiac Evaluation

Comprehensive cardiac assessment is essential given the frequency and severity of heart involvement. Echocardiography reveals characteristic findings including increased wall thickness of both ventricles, a distinctive "granular sparkling" appearance of the myocardium, diastolic dysfunction with preserved or mildly reduced ejection fraction in early stages, and small pericardial effusion. Electrocardiography (ECG) may show low voltage despite increased wall thickness, a discordance that is highly suggestive of cardiac amyloidosis. Cardiac MRI provides detailed imaging of the heart structure and can demonstrate characteristic patterns of late gadolinium enhancement. Nuclear scintigraphy using bone-avid tracers (such as technetium pyrophosphate or DPD) shows preferential uptake in the heart with ATTR amyloidosis and can help distinguish it from other forms of cardiac amyloidosis without the need for cardiac biopsy in many cases.

What Treatments Are Available for Hereditary Transthyretin Amyloidosis?

Modern treatments include gene silencing therapies (patisiran and inotersen) that reduce production of abnormal transthyretin by 80-90%, TTR stabilizers (tafamidis) that prevent protein misfolding, and liver transplantation. Supportive care addresses symptoms affecting nerves, heart, and other organs. Treatment choice depends on disease stage, affected organs, and specific mutation.

The treatment landscape for hereditary transthyretin amyloidosis has been transformed over the past decade with the development of disease-modifying therapies that target the underlying cause of the condition. These advances have shifted the paradigm from purely symptomatic management to treatments that can slow, halt, or in some cases potentially reverse disease progression. A comprehensive treatment approach combines disease-modifying therapy with symptomatic management tailored to each patient's specific manifestations.

Treatment decisions are guided by several factors, including the stage of disease, the organs primarily affected, the specific TTR mutation, overall health status, and patient preferences. Early initiation of disease-modifying therapy offers the best chance of preserving organ function and quality of life. Treatment is typically managed by a multidisciplinary team including neurologists, cardiologists, geneticists, and other specialists as needed.

Gene Silencing Therapies

Gene silencing therapies represent a revolutionary approach that reduces the production of transthyretin protein at the genetic level. By decreasing the amount of mutant transthyretin produced by the liver, these treatments reduce the supply of protein available to misfold and form amyloid. Two medications in this class have been approved for use in hereditary transthyretin amyloidosis with polyneuropathy.

Patisiran (Onpattro) uses RNA interference (RNAi) technology to degrade the messenger RNA for transthyretin before it can be translated into protein. Administered as an intravenous infusion every three weeks, patisiran has been shown in clinical trials (the APOLLO study) to reduce transthyretin levels by approximately 80% and significantly slow progression of neuropathy compared to placebo. Many patients experience stabilization or improvement in neuropathy symptoms and quality of life. Common side effects include infusion-related reactions (managed with premedication) and peripheral edema. Patients must take vitamin A supplements since reduced transthyretin affects vitamin A transport.

Inotersen (Tegsedi) is an antisense oligonucleotide that also reduces transthyretin production by blocking messenger RNA. It is administered as a weekly subcutaneous injection that patients can self-administer at home after training. The NEURO-TTR trial demonstrated significant benefits in slowing neuropathy progression. Side effects include injection site reactions, thrombocytopenia (low platelet count requiring regular monitoring), and glomerulonephritis (kidney inflammation), necessitating careful patient selection and monitoring.

TTR Stabilizers

Tafamidis (Vyndaqel, Vyndamax) works by a different mechanism, stabilizing the transthyretin tetramer to prevent it from dissociating into the monomers that misfold and form amyloid. Taken as a daily oral capsule, tafamidis has been shown in the ATTR-ACT trial to significantly reduce mortality and cardiovascular hospitalizations in patients with ATTR cardiomyopathy. It is approved for ATTR cardiomyopathy (both hereditary and wild-type forms) and for hereditary transthyretin amyloidosis with polyneuropathy in some regions. Tafamidis is generally well tolerated with few side effects.

Diflunisal, a nonsteroidal anti-inflammatory drug (NSAID), has also been shown to stabilize transthyretin and has been used off-label for hereditary transthyretin amyloidosis. However, its use is limited by the cardiovascular and gastrointestinal risks associated with NSAIDs, and it is not approved specifically for this indication.

Liver Transplantation

Liver transplantation was the first disease-modifying treatment for hereditary transthyretin amyloidosis and remains an option for selected patients. Because the liver is the primary source of circulating transthyretin, replacing the liver with one that produces normal transthyretin eliminates the supply of mutant protein. Liver transplantation has been shown to slow or halt neuropathy progression, particularly when performed early in the disease course. However, cardiac disease may continue to progress after transplantation due to wild-type transthyretin depositing on existing amyloid. The procedure carries significant risks and requires lifelong immunosuppression. With the advent of effective pharmacological therapies, liver transplantation is now typically reserved for younger patients with polyneuropathy-predominant disease or in situations where medication therapy is not suitable.

Symptomatic Management

Addressing the symptoms and complications of hereditary transthyretin amyloidosis is an essential component of comprehensive care. Neuropathic pain can be managed with medications such as gabapentin, pregabalin, duloxetine, or topical treatments. Physical therapy helps maintain strength and mobility. Orthotic devices, including ankle-foot orthoses for foot drop, can improve walking ability. Occupational therapy assists with adaptations for hand weakness. Cardiac management may include diuretics for fluid overload, rate control for atrial fibrillation, and anticoagulation when indicated. Pacemaker implantation may be necessary for conduction abnormalities. Orthostatic hypotension can be managed with compression stockings, increased salt and fluid intake, and medications like midodrine or fludrocortisone. Gastrointestinal symptoms require dietary modifications and medications to manage diarrhea, constipation, and nausea. Nutritional support may be needed for significant weight loss.

What Is It Like Living with Hereditary Transthyretin Amyloidosis?

Living with hATTR requires adapting to progressive symptoms while maintaining quality of life through medical treatment, lifestyle modifications, and support systems. Regular monitoring, medication adherence, safety precautions due to sensory loss, and emotional support are essential. Many patients continue meaningful activities with appropriate adaptations.

Living with hereditary transthyretin amyloidosis presents ongoing challenges that extend beyond the medical aspects of the disease. The progressive nature of the condition means that patients must continually adapt to changing abilities and needs. However, with modern treatments and comprehensive supportive care, many individuals with the disease are able to maintain meaningful and fulfilling lives. Understanding what to expect and developing effective coping strategies is crucial for patients and their families.

The impact of hereditary transthyretin amyloidosis on daily life varies considerably depending on the stage of disease, organs affected, response to treatment, and individual circumstances. In the early stages, symptoms may be mild and cause minimal disruption to normal activities. As the disease progresses, more significant adaptations become necessary. The availability of effective disease-modifying treatments has changed the outlook for many patients, offering hope for slowing progression and preserving function.

Regular Medical Monitoring

Ongoing medical care is essential for managing hereditary transthyretin amyloidosis effectively. Regular appointments with neurologists, cardiologists, and other specialists allow for monitoring of disease progression and treatment response. Periodic testing, including nerve conduction studies, echocardiography, blood tests, and other evaluations, helps track the status of affected organs. Medication adjustments may be needed over time. Patients on certain treatments require specific monitoring, such as platelet counts for those taking inotersen. Maintaining consistent communication with the healthcare team enables early identification and management of complications.

Safety Considerations

Sensory loss in the feet and hands necessitates special precautions to prevent injuries. Because affected individuals may not feel pain from cuts, burns, or pressure injuries, regular inspection of the feet becomes important. Appropriate footwear protects against injuries. Water temperature should be tested with an unaffected body part before bathing to prevent burns. Kitchen safety requires extra care when handling hot items. Falls represent a significant risk due to sensory loss, weakness, and orthostatic hypotension, making home safety modifications worthwhile. These might include removing tripping hazards, installing grab bars, ensuring adequate lighting, and using mobility aids when needed.

Emotional and Psychological Support

Coping with a progressive genetic disease involves significant emotional challenges. Anxiety about disease progression, grief over lost abilities, and concerns about the impact on family members are common. Psychological support through counseling, support groups, or therapy can be invaluable. Connecting with others who have the same condition provides understanding and practical advice that only those with lived experience can offer. Patient advocacy organizations offer resources, educational materials, and opportunities to connect with the broader community. Many patients find that focusing on what they can do rather than what they cannot, maintaining social connections, and finding purpose and meaning in life despite the disease contributes to better psychological well-being.

Family Considerations

The hereditary nature of transthyretin amyloidosis has implications for the entire family. First-degree relatives (parents, siblings, children) of affected individuals may be at risk and should be offered genetic counseling and testing. This enables identification of carriers who can benefit from monitoring and early treatment when appropriate. Family planning discussions may include consideration of options such as preimplantation genetic diagnosis for couples who wish to avoid passing the mutation to children. Open communication within the family about the disease, while respecting individual choices about testing, helps everyone cope with the reality of a hereditary condition.

What Is the Prognosis for Hereditary Transthyretin Amyloidosis?

Prognosis has improved significantly with new treatments. Without treatment, median survival was 7-12 years from symptom onset. With disease-modifying therapies started early, many patients experience slowed or halted progression. Factors affecting prognosis include specific mutation, age at onset, organs involved, disease stage at diagnosis, and response to treatment.

The prognosis for hereditary transthyretin amyloidosis has been transformed by the development of effective disease-modifying treatments. Historically, the disease was considered uniformly progressive and fatal, with median survival times of approximately 7 to 12 years from the onset of symptoms, depending on the mutation and predominant organ involvement. Cardiac involvement, in particular, was associated with poorer prognosis. Today, with early diagnosis and treatment, the outlook is considerably better for many patients.

Several factors influence individual prognosis. The specific TTR mutation plays a role, with some mutations associated with more aggressive disease than others. Age at symptom onset matters, as earlier onset generally correlates with faster progression. The extent of organ involvement at the time of diagnosis significantly impacts outcomes, underscoring the importance of early detection. Patients diagnosed and treated before significant cardiac or neurological damage has occurred tend to do better than those diagnosed at later stages. Response to disease-modifying therapy is a crucial determinant, with patients who achieve good reduction in transthyretin levels generally experiencing better outcomes.

The clinical trials of gene silencing therapies and TTR stabilizers have provided evidence that these treatments can significantly alter the natural history of the disease. In the APOLLO trial, patisiran-treated patients showed stabilization or improvement in neuropathy measures while placebo-treated patients continued to decline. The ATTR-ACT trial demonstrated that tafamidis reduced mortality and hospitalizations in patients with ATTR cardiomyopathy. Long-term follow-up studies continue to evaluate durability of treatment benefits, and emerging therapies under development may offer additional options in the future.

What Research Is Being Done on Hereditary Transthyretin Amyloidosis?

Active research includes development of new gene silencing therapies, CRISPR gene editing approaches, monoclonal antibodies targeting amyloid deposits, combination therapies, improved diagnostic biomarkers, and studies to understand disease mechanisms. Clinical trials are ongoing for multiple investigational treatments.

Research into hereditary transthyretin amyloidosis is advancing rapidly, driven by improved understanding of disease mechanisms and advances in therapeutic technologies. The success of first-generation disease-modifying therapies has spurred development of next-generation treatments that may offer improved efficacy, convenience, or safety. Additionally, research is exploring ways to address limitations of current treatments, such as continued cardiac progression after liver transplantation or the need for ongoing medication therapy.

Gene editing approaches, particularly using CRISPR-Cas9 technology, represent a potentially transformative area of research. Rather than suppressing transthyretin production indefinitely, gene editing aims to permanently correct or disable the mutant TTR gene, offering the possibility of a one-time treatment. Early clinical trials of CRISPR-based therapies for transthyretin amyloidosis have shown promising results with sustained reduction in transthyretin levels following a single treatment. Longer-term follow-up and larger studies are needed to fully evaluate safety and efficacy.

Other research directions include the development of monoclonal antibodies designed to target and clear existing amyloid deposits from tissues, which current treatments do not directly address. Combination approaches using multiple mechanisms may prove more effective than single-agent therapy. Improved biomarkers for early diagnosis and monitoring of treatment response are being developed and validated. Basic research continues to elucidate the molecular mechanisms of amyloid formation and toxicity, potentially revealing new therapeutic targets.