Understanding Hereditary Transthyretin Amyloidosis (hATTR) With Polyneuropathy

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy is a rare genetic disorder that affects multiple organs and nerves in the body. This condition is caused by a mutation in the TTR gene, which leads to the production of abnormal transthyretin proteins that form amyloid deposits in various tissues. These deposits can cause serious complications and even death if left untreated.

Causes and Risk Factors

hATTR is an inherited condition passed down through families. If one or both of your parents have the mutated TTR gene, you may inherit the disorder. While the exact prevalence is unknown, hATTR is more common in certain regions, such as parts of Brazil, Japan, Portugal, and Sweden. In the United States, it is estimated that around 6,400 people have hATTR, with a higher incidence among Americans of European, Black, and Irish descent.

Understanding Genetic Inheritance and Carrier Status

hATTR follows an autosomal dominant inheritance pattern, meaning you only need one copy of the mutated gene from either parent to potentially develop the disease. However, having the gene mutation doesn't guarantee you will develop symptoms.

Carrier Status: A carrier is someone who has inherited one copy of the mutated TTR gene but may not develop symptoms or may develop them later in life. Carriers can still pass the mutation to their children.

What Carriers Should Do:

• Undergo genetic counseling to understand risks

• Consider regular monitoring with a specialist

• Discuss family planning options

• Stay informed about emerging treatments

• Notify family members about potential genetic risk

Symptoms and Variable Presentation

The symptoms of hATTR can vary significantly depending on the specific mutation, age of onset, and organs affected. The neuropathy can present in different ways:

Pain-Predominant: Some patients experience severe burning or stabbing pain in hands and feet Numbness-Predominant: Others have loss of sensation and difficulty detecting temperature Weakness-Predominant: Some develop muscle weakness and difficulty with fine motor tasks

Age of Onset: Different TTR mutations cause symptoms at different ages:

• Some mutations cause symptoms in the 30s-40s

• Others may not appear until the 60s-70s

• The same mutation can have different onset ages even within families

Common symptoms include:

• Numbness, tingling, and swelling in the hands and feet

• Digestive problems, such as diarrhea, constipation, and early satiety

• Urinary tract issues and sexual dysfunction

• Fatigue and weakness

• Eye problems, including cloudiness, dry eyes, and increased pressure (glaucoma)

• Heart complications, such as enlargement and irregular heartbeats

Diagnosis

Diagnosing hATTR can be challenging due to its similarity to other conditions. If you have a family history of the disorder, your doctor may recommend genetic testing to check for the mutated TTR gene. Other diagnostic tests may include:

• Blood and urine tests to check for excess protein

• Tissue biopsy to detect amyloid deposits

• Fat pad biopsy: A minimally invasive procedure to sample abdominal fat tissue for amyloid deposits

• EMG (Electromyography): Tests nerve and muscle function to assess neuropathy severity

• Bone scans (scintigraphy) to identify amyloid deposits in the heart

• Genetic testing to differentiate between hereditary and non-hereditary forms of ATTR amyloidosis

Treatment Options

Treatment for hATTR focuses on managing symptoms and slowing the progression of the disease. Some options include:

Gene Silencer Drugs:

• Inotersen, patisiran, and vutrisiran, which stop the production of TTR protein

• Amvuttra (vutrisiran): A newer RNA interference therapy given as a subcutaneous injection every 3 months

• Wainua (eplontersen): Another antisense oligonucleotide treatment option

Gene Stabilizer Drugs:

• Tafamidis, diflunisal, and doxycycline, which prevent TTR proteins from misfolding and forming amyloid deposits

Other Treatments:

• Liver transplantation, which may slow the disease progression but carries risks and requires lifelong immunosuppressive therapy

• Symptom management with medications for fluid retention, digestive issues, and other complications

Researchers are also exploring innovative treatments, such as antibodies to remove amyloid deposits and new drugs to suppress or stabilize the TTR gene.

Disease Progression and Complications

hATTR with polyneuropathy is a progressive disorder that advances through several stages:

Stage 0: No symptoms, but genetic testing reveals the TTR mutation Stage I: Mild sensory, motor, and autonomic neuropathy in the lower limbs Stage II: Moderate involvement of upper and lower limbs, as well as the trunk, with difficulty walking Stage III: Severe motor, sensory, and autonomic involvement of all limbs, often requiring a wheelchair

Complications of hATTR can include peripheral nervous system issues, autonomic dysfunction affecting internal organs, irregular heartbeat, heart failure, kidney failure, eye problems, and pain.

Coping With hATTR

Living with hATTR can be challenging, but a multidisciplinary care team can help manage the various aspects of the disorder. This team may include a genetic counselor, neurologist, cardiologist, nephrologist, ophthalmologist, and physical therapist. It is essential to maintain open communication with your healthcare providers and seek support from family, friends, and patient advocacy groups.

For more information on hATTR with polyneuropathy, consult the following resources:

• Amyloidosis Foundation: ATTR Amyloidosis

• National Organization for Rare Disorders: Hereditary ATTR Amyloidosis

• Mayo Clinic: Amyloidosis