What is primary amyloidosis with cardiomyopathy?

History: Patients often present with nonspecific symptoms such as weakness and weight loss. The presenting symptoms depend on the TTR variant present and the organ(s) involved. Amyloid deposition in a particular organ leads to similar clinical consequences, and therefore similar complaints, regardless of the type of amyloid deposited. For example, cardiac ATTR and cardiac AL cause similar symptoms. The most common sites of deposition are the following:

* Cardiovascular involvement

o Patients with cardiac deposition often present with symptoms suggesting congestive heart failure (ie, dyspnea on exertion, peripheral edema) and/or arrhythmias (ie, palpitations, lightheadedness, syncope).

o Deposition in the subendothelium of the peripheral vasculature can lead to severe postural hypotension.

Background: The amyloidoses are diseases of secondary protein structure, in which a normally soluble protein forms insoluble extracellular fibril deposits, causing organ dysfunction. All types of amyloid contain a major fibril protein that defines the type of amyloid, plus minor components. Twenty different fibril proteins have been described in human amyloidosis, each with a different clinical picture (see Amyloidosis, Overview). One of the 20 proteins that form human amyloid fibrils is transthyretin (TTR).

TTR is a serum protein that transports thyroxine and retinol-binding protein. It circulates as a tetramer of 4 identical subunits of 127 amino acids each. TTR formerly was called prealbumin because it migrates anodally to albumin on serum protein electrophoresis, but this name was misleading because TTR is not a precursor of albumin. The TTR monomer contains 8 antiparallel beta pleated sheet domains. TTR is synthesized primarily in the liver, as well as in the choroid plexus and retina. Its gene is located on chromosome 18 and contains 4 exons.

The systemic amyloidoses are designated by a capital A (for amyloid) followed by the abbreviation for the chemical identity of the fibril protein. Thus, for example, TTR amyloidosis is abbreviated ATTR, and amyloidosis of the immunoglobulin light chain type is abbreviated AL.

Pathophysiology: Both normal-sequence TTR and variant-sequence TTR form amyloidosis. Normal-sequence TTR forms cardiac amyloidosis in people who are elderly and is termed senile cardiac amyloidosis (SCA). When it was recognized that SCA often is accompanied by microscopic deposits in many other organs, the alternative name senile systemic amyloidosis (SSA) was proposed. Both terms are used now.

TTR mutations accelerate the process of TTR amyloid formation and are the most important risk factor for the development of clinically significant ATTR. More than 85 amyloidogenic TTR variants cause systemic familial amyloidosis. The age at symptom onset, pattern of organ involvement, and disease course vary, but most mutations are associated with cardiac and/or and nerve involvement. The gastrointestinal tract, vitreous, and carpal ligament are also frequently affected.

Amyloidogenic TTR mutations destabilize TTR monomers or tetramers, allowing the molecule to more easily attain an amyloidogenic intermediate conformation. Other, unknown factors also play a role in TTR amyloid formation because the clinical picture of disease varies widely among people carrying the same TTR variant.

When the peripheral nerves are affected prominently, the disease is termed familial amyloidotic polyneuropathy (FAP). When the heart is involved heavily but the nerves are not, the disease is called familial amyloid cardiomyopathy (FAC). Regardless of which organ is involved most heavily, the general term is simply amyloidosis-transthyretin type, abbreviated ATTR.

Primary amyloidosis is a disorder in which protein fibers are deposited in tissues and organs, harming them......which can lead to other conditions such as cardiomyopathy.... Cardiomyopathy is a weakening of the heart muscle or a change in heart muscle structure. It is often associated with inadequate heart pumping or other heart function abnormalities.

As an interesting note, the well-known writer of the fantasy series "The Wheel of Time" - James Rigney who also wrote under various pen names - recently passed away at age 58 of this condition, which led me to research it. The article stated only eight in 1 million contract the disease each year.