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The familial types of amyloidoses are rare, with an estimated incidence of less than 1 per
100,000. They are dominantly inherited diseases which mean 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
nearly 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, 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 and awaits FDA approval. Two other
pharmaceutical companies are testing strategies that cause a decrease 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, but not all fibrinogen is made in the liver. There is no major treatment
for Apolipoprotein AI and AII amyloidosis, but kidney transplantation is appropriate for end
stage renal disease that occurs in these patients.
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