Amyloidosis is a group of rare diseases characterized by the accumulation of abnormal protein deposits called amyloid fibrils within various organs and tissues. These deposits can disrupt the normal function of affected organs, leading to a range of health issues. Familial amyloidosis represents an inherited form of this condition, where a genetic predisposition leads to the formation of these protein aggregates.
What is Familial Amyloidosis?
Familial amyloidosis is an inherited disorder, passed down through generations due to a genetic mutation. The process involves proteins misfolding from their normal shape. These misfolded proteins then aggregate into insoluble amyloid fibrils, which are highly stable and resistant to breakdown.
Once formed, these amyloid fibrils deposit in various organs and tissues throughout the body, including the nerves, heart, kidneys, and gastrointestinal tract. This accumulation interferes with the normal function of affected organs, leading to progressive damage.
Genetic Basis and Common Types
Different gene mutations are responsible for the various types of familial amyloidosis. The most common familial type is hereditary transthyretin (hATTR) amyloidosis, which results from mutations in the TTR gene. The TTR gene provides instructions for making the transthyretin protein, primarily produced in the liver, which transports thyroid hormone and vitamin A throughout the body.
When the TTR gene mutates, the transthyretin protein becomes unstable and misfolds, forming amyloid fibrils that deposit in tissues. hATTR amyloidosis is inherited in an autosomal dominant pattern, meaning that only one copy of the mutated gene from one parent is sufficient to cause the condition. Each child of an affected parent has a 50% chance of inheriting the mutated gene. While hATTR is the most prevalent familial form, other less common familial types exist, such as gelsolin amyloidosis (AGel) or apolipoprotein AI amyloidosis.
Recognizing the Signs
Symptoms of familial amyloidosis vary widely, depending on which organs and tissues are affected. These symptoms often develop gradually and can be non-specific, making early recognition challenging.
For instance, if the nervous system is impacted, individuals might experience numbness, tingling, or weakness in their hands and feet, or even carpal tunnel syndrome. When amyloid deposits affect the heart, symptoms can include shortness of breath, irregular heartbeats, ankle swelling, or chest pain. Kidney involvement may manifest as foamy urine or swelling in the legs due to protein leakage. Digestive system issues, such as chronic diarrhea, constipation, unintended weight loss, or an enlarged tongue, can also occur if amyloid accumulates in the gastrointestinal tract.
Diagnosis and Treatment Approaches
Diagnosing familial amyloidosis often involves a multi-step process. Diagnosis begins with a clinical evaluation, reviewing symptoms and family medical history. Imaging techniques, such as an echocardiogram for heart assessment, can help identify organ involvement. A definitive diagnosis requires a tissue biopsy, often from the fat pad in the abdomen or an affected organ. The sample is stained with Congo red dye, and under polarized light, amyloid deposits appear as a distinctive apple-green birefringence.
After amyloid confirmation, mass spectrometry on the biopsy identifies the specific protein, which helps determine the type of amyloidosis. Genetic testing on a blood sample identifies the specific gene mutation, confirming the familial nature of the disease. This confirmation is important for guiding treatment and informing family members about their potential risk.
Treatment strategies for familial amyloidosis aim to slow or halt the production of the amyloid-forming protein, manage symptoms, and support organ function. For hATTR amyloidosis, specific therapies include gene silencers (e.g., patisiran, vutrisiran, inotersen) that reduce the production of the transthyretin protein in the liver. Protein stabilizers like tafamidis bind to the transthyretin protein, preventing it from misfolding and forming amyloid fibrils. In some cases, particularly when the disease is caught early, organ transplantation, such as a liver transplant, may be considered, as the liver is the primary site of mutated transthyretin production.