What are the signs of hereditary amyloidosis (Familial Amyloid Polyneuropathy)?

From the Guidelines

Familial amyloidosis typically presents with a combination of peripheral neuropathy, autonomic dysfunction, cardiomyopathy, nephropathy, and ocular manifestations, with the most common mutation affecting the transthyretin (TTR) gene 1. The signs of familial amyloidosis can vary depending on the specific type and which organs are affected. Some common signs include:

• Peripheral neuropathy, characterized by numbness, tingling, and pain in the extremities
• Autonomic dysfunction, which can cause orthostatic hypotension, digestive issues, and sexual dysfunction
• Cardiomyopathy, leading to heart failure, arrhythmias, and shortness of breath
• Nephropathy, resulting in proteinuria and kidney failure
• Ocular manifestations, such as vitreous opacities and glaucoma Gastrointestinal symptoms like chronic diarrhea, constipation, and unintentional weight loss are also frequent, and carpal tunnel syndrome may appear as an early sign, sometimes years before other symptoms 1. The disease typically manifests in adulthood, with onset usually between ages 30-70 depending on the genetic variant, and family history is crucial for diagnosis, as the condition follows autosomal dominant inheritance in most cases, meaning each child of an affected person has a 50% chance of inheriting the mutation 1. Early recognition of these signs is vital, as newer treatments like tafamidis, patisiran, and inotersen can slow disease progression if started before extensive organ damage occurs 1. It is essential to note that the presence and severity of these signs can vary depending on the specific mutation and the individual patient, and a comprehensive diagnosis and treatment plan should be developed in consultation with a healthcare professional 1.

From the Research

Signs and Symptoms of Familial Amyloidosis

• Peripheral neuropathy is a common sign, affecting 83% of patients at the time of diagnosis 2
• Autonomic neuropathy is also prevalent, affecting 33% of patients at the time of diagnosis 2
• Cardiomyopathy is present in 27% of patients at the time of diagnosis 2
• Renal disease and liver involvement are less common, affecting fewer than 10% and being rare, respectively 2
• Gastrointestinal symptoms and orthostatic hypotension are often present earlier than urogenital complications 3
• Autonomic dysfunction can be a hallmark feature of hereditary ATTR amyloidosis, with patients with early-onset disease displaying it more distinctively than those with late-onset disease 3

Organ Involvement

• The heart is often involved, with cardiomyopathy being a powerful predictor of survival 2
• The peripheral nerves are commonly affected, with progressive peripheral sensorimotor polyneuropathy being a characteristic feature of hereditary transthyretin amyloidosis (hATTR) 4, 5
• The autonomic nervous system is also frequently involved, with autonomic neuropathy being a common feature of hATTR amyloidosis 6, 3
• The gastrointestinal tract and kidneys can also be affected, although less commonly 2, 3

Diagnostic Considerations

• Biopsy-proven familial amyloidosis can be diagnosed through various methods, including subcutaneous fat aspirates, rectal biopsy specimens, and bone marrow specimens 2
• Immunohistochemical studies and genetic testing can be used to identify transthyretin mutations and confirm the diagnosis of hATTR amyloidosis 2, 4