hATTR-PN diagnosis

Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) diagnosis typically involves identifying hATTR-PN symptoms and performing specialized testing to confirm the disease’s presence.

Inherited mutations in the TTR gene cause hATTR-PN by destabilizing and changing the structure of the transthyretin (TTR) protein. Toxic clumps made up of misfolded TTR then accumulate and damage the peripheral nerves outside the brain and spinal cord, as well as other tissues and organs.

Early diagnosis of hATTR-PN allows for prompt treatment to potentially slow or halt nerve damage. In families with a history of the disease, genetic testing and symptom monitoring can help with the hATTR-PN diagnostic process.

What doctors look for when diagnosing hATTR-PN

Peripheral sensory-motor neuropathy, which happens when peripheral nerves responsible for controlling muscle movements and transmitting sensory information are damaged, is a key feature of hATTR-PN. Symptoms of hATTR-PN associated with peripheral sensory-motor neuropathy usually affect both sides of the body and include:

• numbness, tingling, or pain
• inability to sense temperature changes
• muscle weakness
• difficulty walking

A visit to a specialist and testing for hATTR-PN may be warranted if a person or doctor notices signs of progressive peripheral sensory-motor neuropathy in addition to:

• early signs of autonomic dysfunction, which happens when peripheral nerves responsible for controlling involuntary bodily functions become damaged (e.g., erectile dysfunction or low blood pressure when standing)
• carpal tunnel syndrome, particularly if it affects both wrists
• symptoms of heart failure, including fatigue and shortness of breath
• vision problems
• kidney failure or related symptoms
• unexplained weight loss
• chronic constipation, diarrhea, or both
• a family history of hATTR-PN or the presence of similar symptoms in family members
• rapidly worsening neuropathy symptoms

A thorough review of a person’s clinical history and a physical exam can help clinicians identify these potential red flags. Autonomic symptoms and carpal tunnel syndrome are common early in the disease course and may serve as warning signs.

Genetic testing for hATTR-PN

When symptoms are consistent with the disease, clinicians may advise patients to undergo genetic testing for hATTR-PN to confirm the presence of a TTR gene mutation, the root cause of hATTR-PN. Genetic testing is also recommended for people with a family history of TTR mutations.

Typically, amyloidosis genetic testing involves a blood sample, saliva sample, or cheek swab, which is then analyzed in a laboratory.

Before testing, genetic counseling for hATTR-PN can help a person learn more about the disease and its diagnosis. It may also help a patient understand how a positive result could affect them emotionally and logistically.

After a positive TTR gene mutation testing result, genetic counselors can explain how specific genetic mutations may affect disease progression and prognosis. They may also outline potential risks for the family and provide options for family planning.

A negative test result typically excludes hATTR-PN, pointing instead to other conditions that also cause neuropathy.

Tissue biopsy

Because carrying a TTR gene mutation doesn’t guarantee that a person has active hATTR-PN, a biopsy looking for amyloid deposits — the toxic protein clumps that accumulate and damage tissues and organs in people with the disease — is typically required to confirm the diagnosis. Biopsy samples of skin, fat, nerve, or heart tissue can be used for this purpose.

While amyloid biopsy testing is considered the gold standard for hereditary TTR amyloidosis diagnosis, it can’t distinguish hATTR-PN from non-inherited amyloidosis. A combination of a positive amyloid biopsy result, the identification of TTR mutations, and the presence of signs and symptoms of hATTR-PN is thus needed to confirm the diagnosis definitively.

Other diagnostic tests

Other hATTR-PN diagnostic tests that can be used to identify the disease and assess the extent to which it is affecting a person’s body include:

• nerve imaging tests and nerve conduction studies, which can help identify nerve damage
• heart tests, including ultrasounds or MRI scans, which can be used to identify heart-related symptoms of TTR amyloidosis
• cardiac technetium-based scintigraphy, a noninvasive test that can be used to detect amyloid deposits in the heart
• kidney function tests
• eye exams

How doctors rule out other conditions

An hATTR-PN differential diagnosis involves excluding other possible conditions to determine the most suitable treatment options. Possible misleading symptoms that can result in hATTR-PN misdiagnosis include:

• numbness, tingling, burning, or prickling sensations
• muscle weakness
• difficulty walking or maintaining balance
• difficulty speaking
• autonomic dysfunction
• weight loss

Common hATTR-PN misdiagnoses include chronic inflammatory demyelinating polyneuropathy, an autoimmune disease that affects peripheral nerves, as well as certain types of neuropathy associated with diabetes or alcohol use.

Genetic testing, tissue biopsy, and family history examination can help physicians differentiate hATTR-PN from other conditions.

Next steps after a hATTR-PN diagnosis

After a diagnosis of hATTR-PN, multidisciplinary care and monitoring can help manage symptoms and assess disease progression and response to treatment. Depending on the affected organs and genetic variants, this may warrant input from neurologists, cardiologists, ophthalmologists, kidney specialists, and general practitioners. Regular follow-up every six to 12 months is recommended.

A doctor or genetic counselor may also recommend testing family members for hATTR-PN after confirming a diagnosis. If genetic tests come back positive but symptoms aren’t present, a relative may be an asymptomatic carrier. Depending on their age and genetic variant, clinicians may want to regularly monitor them every six to 24 months.