Transthyretin (TTR) amyloidosis is a hereditary, multisystem disease caused by abnormal formation and extracellular deposit of TTR protein fibrils in various tissues. Inheritance is autosomal dominant, but family history may appear to be negative in the majority of patients.¹ Age of onset is typically in the thirties but varies by decades within and between populations. Penetrance is <100% with widely ranging estimates for the same mutation in different populations.^2,3 Genotypes do not predict the onset, severity, or specific symptoms for the 100+ mutations, but many mutations tend to associate with one of three broad phenotypes of TTR amyloidosis.⁴

The most common mutation, V30M, causes progressive autonomic and sensorimotor dysfunction called familialamyloid polyneuropathy (FAP). Symptoms include carpal tunnel syndrome, tingling followed by loss of sensation and disability in hands and feet, constipation, diarrhea, vomiting, incontinence, urinary retention, absence of sweating, and/or fainting. Cardiomyopathy and vitreous opacities are common in this type.

Patients with a cardiac-predominant form have restrictive cardiomyopathy and possibly conduction defects but neuropathy is absent or less evident. This type is also called familial amyloid cardiomyopathy (FAC). One mutation associated with this type, V122I, is carried by approximately 3% of African-Americans.⁵

The leptomeningeal form generally spares sensory and autonomic functions but amyloid deposits on CNS tissues causehydrocephalus, seizures, ataxia, dementia, psychosis, motor impairment, and/or intracranial hemorrhage.

Non-amyloid and protective TTR mutations are known.⁶ Senile systemic amyloidosis results from abnormal deposition of non-mutant TTR protein.