The familial types of amyloidoses are rare, with an estimated incidence of less than 1 per 100,000. They are autosomal dominant inherited diseases which means that a child of an affected parent has a 50% chance of inheriting the genetic trait that causes disease. Although the abnormal gene is making the amyloid protein from birth, amyloid deposits do not begin until mid-life. The most common familial amyloidosis is caused by the transthyretin (TTR) protein, of which there are over 100 mutations known to be associated with amyloidosis. Even normal TTR protein can form fibrils, causing the disease senile systemic amyloidosis, which predominantly affects the heart in older patients. Other familial amyloidoses are caused by inherited gene mutations in apolipoprotein A-I, A-II, gelsolin, cystatin C, fibrinogen Aa, or lysozyme. Amyloidosis due to those abnormal proteins is very rare and reported in only a few families worldwide.
Familial amyloidosis must be excluded in every patient who is diagnosed with amyloidosis and does not have the AL or AA type of amyloidosis. Doctors and patients need to be aware of the fact that a family history of amyloidosis may not be apparent when the disease occurs later in life; also, some cases occur through new mutations. Genetic testing should be done in all patients who have a biopsy showing amyloid and do not have AL or AA amyloidosis.
The clinical features of ATTR amyloidosis overlap AL amyloidosis and the diseases cannot be reliably distinguished on clinical grounds alone. A family history makes ATTR more likely, but some patients appear to be the first case in their family. Within each family disease begins at nearly the same age and symptoms usually include neuropathy and/or cardiomyopathy. Peripheral neuropathy begins as a lower extremity sensory and motor neuropathy and progresses to the upper extremities. Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension. Vitreous opacities caused by amyloid deposits are only found in the ATTR type of amyloidosis.
One TTR genetic trait, Val 122 Ile, occurs in 4% of the black population and may cause cardiomyopathy late in life. It is not known how frequently these individuals will actually develop amyloidosis. The disease is likely under diagnosed due to a lack of physician awareness and the difficulty of distinguishing amyloid and hypertensive cardiomyopathy without an endomyocardial biopsy.
Without major treatment intervention, survival after ATTR disease onset is 5-15 years. A liver transplant, which removes the source of variant TTR production and replaces it with normal TTR, has been the major treatment for ATTR amyloidosis. Liver transplantation arrests disease progression of autonomic and peripheral neuropathy. Cardiomyopathy does not improved and in some patients appears to worsen after liver transplantation. Long-term outcome and the timing of transplantation are being evaluated. Supportive treatment for neuropathy and cardiomyopathy are very important for patients with TTR amyloidosis.
Recent clinical trials raise hope that newer major treatments will be coming soon. An international multicenter randomized placebo controlled clinical trial is underway to test the efficacy of the non-steroidal anti-inflammatory drug, Diflunisal, for the treatment of TTR amyloidosis (www.clinicaltrials.gov/diflunisal). Laboratory studies have suggested that Diflunisal stabilizes variant TTRs and prevents unfolding and aggregation. Pharmaceutical companies are also generating potential new treatments. A clinical trial on a drug, Tafamidis, has recently been completed by FoldRx Inc, acquired by Pfizer in the fall of 2011, and awaits FDA approval. Several other pharmaceutical companies are testing strategies that cause a decrease in the production of TTR protein. These new trials give HOPE to patients with TTR amyloidosis.
Treatment for the more rare types of familial amyloidosis has not advanced to the same degree as it has for TTR amyloidosis. Fortunately, the rare types are very slowly progressing and disease is likely to be limited to the kidney. Liver transplantation has been successful in fibrinogen amyloidosis, since all fibrinogen is made in the liver. There is no major treatment for Apo lipoprotein AI and AII amyloidosis, but kidney transplantation is appropriate for end stage renal disease that occurs in these patients.