Signs and Symptoms of hATTR Amyloidosis

Hereditary transthyretin (hATTR) amyloidosis is a rare disease that runs in families. It is caused by the buildup of toxic proteins called amyloid fibrils throughout the body. The amyloid fibrils damage tissues and organs, causing symptoms that worsen over time.

The most common sites of amyloid buildup in hATTR amyloidosis are nerves and the heart. Other targeted areas include the stomach, intestines, eyes, kidneys, brain, and spinal cord.

This article reviews the symptoms and signs of hATTR amyloidosis. Early recognition of this incurable disease is crucial to preventing or delaying disease progression and potentially life-threatening complications.

How hATTR Amyloidosis Symptoms Affect the Body

Hereditary ATTR amyloidosis occurs when a person inherits a faulty or mutated transthyretin (TTR) gene from either of their biological parents.

The mutated TTR gene codes for unstable, misshapen proteins that clump together as amyloid fibrils in the body. The settling of amyloid fibrils within different organs prevents them from functioning normally, resulting in symptoms that develop in adulthood and worsen over time.

Over 130 TTR gene mutations linked to hATTR amyloidosis have been identified. Symptoms, the extent of amyloid buildup, age of onset, and disease progression vary depending on the inherited genetic mutation.

Unfortunately, these variations in clinical manifestations can delay the diagnosis of hATTR amyloidosis, sometimes as long as six years. Since current treatment options are most effective when taken in the early stages of the disease, a delayed diagnosis can negatively impact disease outcome (prognosis).

Neurological Symptoms

Early symptoms of hATTR amyloidosis classically stem from damage to the peripheral nervous system (PNS).

The PNS is a network of nerves that carry signals between the brain/spinal cord and the rest of the body. It consists of three types of nerves:

• Sensory nerves communicate signals to the brain about what a person touches, tastes, smells, and sees.
• Motor nerves transmit signals to the muscles about movement.
• Autonomic nerves control involuntary bodily functions like digestion, heartbeat, and sexual arousal.

In hATTR amyloidosis, sensory symptoms include tingling and numbness (paresthesia), shooting or burning pain, and reduced sensitivity to heat. These symptoms are felt on both sides of the body and usually start in the toes and feet, progressing to the upper limbs over time.

Motor symptoms, namely muscle weakness and stiffness, begin in the feet and lower legs and progress to walking difficulties. As the disease advances, a person can develop a reliance on assistive devices such as a wheelchair or they are not able to leave their beds.

Autonomic symptoms in hATTR amyloidosis include:

• Digestive tract problems like constipation, diarrhea, and early satiety (feeling full after only eating a small quantity of food)
  
• Orthostatic hypotension (light-headedness when standing up)
• Increased or decreased sweating
• Bladder dysfunction (e.g., retaining urine or incontinence)
• Erectile dysfunction

Heart-Related Symptoms

Amyloid deposition in the heart muscle in hATTR amyloidosis is called transthyretin amyloidosis cardiomyopathy. This condition causes the heart to stiffen and thicken, interfering with its ability to pump blood to the rest of the body.

Transthyretin amyloidosis cardiomyopathy often leads to heart failure, which, when advanced, carries a poor prognosis and can be fatal.

Symptoms and signs of heart failure in hATTR amyloidosis include:

• Difficulty breathing, especially when lying down or with minimal activity
• Swelling (edema) of the feet, ankles, lower legs, or belly
• Confusion or problems thinking
• Coughing or wheezing, mainly when lying down
• Unusual tiredness
• Dizziness and fainting
• Heart rhythm disorder (arrhythmia), especially heart block or atrial fibrillation
  

Stomach and Digestive System Symptoms

Stomach and bowel problems are relatively common in hATTR amyloidosis, affecting between 56% and 69% of individuals, depending on the inherited TTR gene mutation.

Unintentional weight loss is the most common digestive system symptom in hATTR amyloidosis, followed by early satiety and colon (large intestine) problems like constipation, diarrhea, or alternating constipation and diarrhea.

Other potential symptoms include:

• Bloating
• Abdominal pain
• Nausea and vomiting
• Fecal incontinence (loss of control over bowel movements)

It's unclear, but experts suspect that amyloid-related damage to specific nerves, cells, and hormones responsible for gut motility and food absorption plays a role in leading to the above symptoms.

Complications of gut involvement in hATTR amyloidosis include malnutrition, social isolation, and psychological distress for the person and their loved ones and caregivers.

Eye-Related Symptoms

Eye-related manifestations are frequent in hATTR amyloidosis, can impair vision, and tend to increase with disease duration.

Eye manifestations and symptoms include:

• Vitreous opacities: Spots ("eye floaters") within the gel-like substance that fills the eyeball
• Glaucoma: Increased pressure within the eyeball
• Dilated (widening) the blood vessels in the eye's conjunctiva (clear membrane covering the white part of the eye and inside the eyelid)
• Irregularly shaped pupils (the black, center of the eye)
• Dry eyes

Kidney Symptoms

Most people have two kidneys, located below their ribcage on either side of the spine. The kidneys perform numerous functions, such as removing waste products from the body and maintaining electrolyte and fluid balances.

Chronic kidney disease (CKD) involves the gradual loss of kidney function and affects approximately 30% of people with hATTR amyloidosis.

Symptoms and signs of kidney damage and loss of function in hATTR amyloidosis include:

• Foamy urine from increased protein (proteinuria)
• Low protein levels in the blood
• Elevated blood creatinine level
• Swelling (edema) of the feet and ankles and around the eyes

In addition, complications of CKD include weakened bones and anemia (low red blood cell count).

With hATTR amyloidosis, CKD can eventually progress to end-stage renal disease (ESRD), where the kidneys basically stop working. At this point, dialysis is required to filter a person's blood.

Head and Central Nervous System Symptoms

The presence of central nervous system (CNS) symptoms—those related to the brain and spinal cord—is increased in people with longstanding hATTR amyloidosis.

Interestingly, the accumulation of amyloid fibrils tends to appear in a distinct pattern. It usually starts in the leptomeninges (the two innermost layers of tissue covering the brain/spinal cord) and nearby blood vessels before progressing to deeper brain regions.

The most common CNS manifestation of hATTR amyloidosis is transient focal neurological events (TFNEs), which are recurrent episodes of primarily sensory or motor symptoms lasting 10 to 30 minutes.

A common TFNE symptom is paraesthesia in the hand or mouth, spreading to adjacent parts of the body. Other TFNE symptoms may be weakness of a body part, difficulty speaking, or visual disturbances.

Additional potential CNS symptoms include:

• Hemorrhagic stroke (when an artery in the brain breaks open and bleeds)
• Ischemic stroke (when an artery that supplies oxygen-rich blood to the brain is blocked)
• Cognitive decline (thinking, memory, and concentration problems)
• Headache
• Seizures

Other Associated Symptoms

Other possible manifestations/symptoms of hATTR amyloidosis include:

• Nonspecific symptoms like fatigue, fever, and a general feeling of being unwell (malaise)
• An underactive thyroid gland (hypothyroidism)
• Hearing loss
• Skin changes, especially bruising around the eye (rare)
• Lumbar spinal stenosis (narrowing of the spinal canal in the lower back)

Summary

Hereditary ATTR (hATTR) amyloidosis is caused by a mutation (change in DNA sequence) in the transthyretin (TTR) gene, resulting in the accumulation of abnormal proteins (amyloid fibrils) in various organs.

The peripheral nervous system and heart are the most commonly affected organs. Amyloid fibrils can also build up within the gut, eyes, kidneys, brain, and spinal cord, causing damage and organ dysfunction.

Examples of peripheral nervous system symptoms include burning pain, numbness, tingling, muscle weakness, lightheadedness when standing up, and sexual dysfunction.

Heart-related symptoms include trouble breathing, swelling of the ankles and lower legs, dizziness, and fainting.

Additional symptoms or manifestations of hATTR amyloidosis include unexplained weight loss, kidney failure, decreased vision, dry eyes, and stroke-like episodes, among others.

Hereditary ATTR amyloidosis is a rare, albeit disabling, life-threatening condition. That said, starting a disease-modifying therapy sooner than later can help slow or stop the buildup of amyloid protein.

If you or a loved one is experiencing symptoms associated with hATTR amyloidosis, or if you have a family history of the disease, please reach out to a healthcare provider. If the diagnosis is suspected, ask for a referral to a medical center that specializes in managing amyloidosis.