Article Review (1991) - Inherited Amyloidosis

Today's post reviews an article from 1991. Articles from the previous two decades included a few case reports of what appeared to be a hereditary form of amyloidosis that affects the kidneys, but the search for the underlying genetic cause was still in its infancy. This article was written before the first published findings on a fibrinogen mutation, so the word "fibrinogen" does not appear in this article either.

Title: Inherited Amyloidosis

Author: Dr. Merrill D. Benson (Indiana University School of Medicine, Indianapolis, IN, USA)

Journal: Journal of Medical of Genetics (1991, February)

Here's a link to the PDF of this article, if you'd like to follow along: http://jmg.bmj.com/content/28/2/73.full.pdf+html

The author of this article, Dr. Merrill D. Benson, is very well-known in the amyloidosis community, having discovered the origin of many forms of hereditary amyloidosis. He was one of the doctors at the familial meeting in Chicago in 2011. (He reminds me of Orville Redenbacher.) His lab does genetic testing on a research basis, and it's where one of my sisters sent her blood for testing in May of last year.

This article (no abstract) discusses the various types of hereditary amyloidosis that were known in 1991. It begins with a simple two-sentence definition of amyloidosis that you can memorize to amaze and impress your friends and family. Whenever someone asks you what amyloidosis is you can reply with this: "The amyloidoses are a group of deposition diseases in which the tissue deposits are composed of protein fibrils. These fibrils are the result of aggregation of specific precursor proteins into ordered structures which are resistant to proteolytic digestion and solubilisation." If that's not simple enough for your audience you can use my explanation, which is to think of amyloidosis as teeny tiny pieces of plastic floating around that your body can't get rid of, so they end up collecting in various organs and gumming things up. Ok, back to the article . . .

After a short discussion of localized vs. systemic amyloidosis, the article gives an overview of some different types of hereditary amyloidosis. It starts with familial amyloidotic polyneuropathy (FAP), the most common form of hereditary amyloidosis. FAP is primarily due to a mutation in transthyretin (hence the current designation of ATTR), although at the time this article was published a variant of apolipoprotein A1 had recently been discovered to cause FAP. Then a paragraph is spent listing a few other rare types of hereditary amyloidosis but oddly enough, hereditary renal amyloidosis is not mentioned.

The article then goes into detail on some different types of FAP. They are:

• Type I: Starts in the lower extremities.
• Type II: Typically starts with carpal tunnel syndrome and progresses to a more generalized, slowly progressing peripheral neuropathy.
• Type III: This type of FAP does not present with significant neuropathy early in the course of the disease, but instead will initially affect the heart or the gastrointestinal tract, depending on the mutation.
• Type IV: A rare Finnish type affecting the cornea and also causing cranial neuropathy.

The article then discusses the various genetic mutations that were known at the time to cause hereditary amyloidosis. As previously mentioned, transthyretin mutations (of which there are many) are the most common cause of hereditary amyloidosis, with the symptoms varying with the mutation. Other mutations covered are apolipoprotein A1, gelsolin, and cystatin C. Again, no mention of fibrinogen since that mutation was yet to be discovered.

The next two sections of the article have the headings Detection of gene carriers and Genetic counselling. This part of the article discusses the impact the current knowledge of molecular genetics has on the study and management of these diseases. I'll list these in bullet form:

• Allows more in depth studies into the pathogenesis of these diseases (how they develop and progress)
• Expands the scope of the clinical approach to these diseases
• Improves diagnosis of these diseases, especially given late onset, incomplete penetrance (not everyone with the genetic mutation will develop symptoms), and opportunities for misdiagnosis due to clinical similarities with other conditions
• Allows analysis of clinical syndromes among different ethnic groups with identical mutations
• Genetic testing can be used to determine whether or not someone at risk of having a mutation actually did inherit it.

The final section is Therapy and future prospects. It states up front that there are no specific therapies for any form of hereditary amyloidosis. Preventing the disease at the genetic level would require some mechanism of altering gene expression, but as more is understood about how the fibrils themselves are formed there may be ways of altering the biochemistry to prevent fibril formation in the future. (I believe that is indeed what is happening now with some of the drugs that have been developed for ATTR.) It is particularly important to understand why some subjects develop symptoms so much later than others with the same mutation. (Based on some discussion of that question at the 2011 familial amyloidosis meeting in Chicago, I don't think they are any closer to figuring that out yet.)

The article closes with a paragraph that starts with "although there are no specific therapies for inherited amyloidoses, modern medicine has much to offer to the person afflicted with these diseases." It then lists some medicines and other treatments available for treating peripheral neuropathy, end stage renal disease, and cardiac disease.

So that's the state of familial amyloidosis in 1991, although there is no specific mention of hereditary renal amyloidosis. Perhaps Dr. Benson was considering hereditary renal amyloidosis to be in the category of FAP Type III, which does not present with neuropathy. In any case, we don't have to wait much longer before we see the word "fibrinogen" in an article about amyloidosis.

[Minor update, 11-5-13: typo]

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Citation: Benson MD. Inherited amyloidosis. J Med Genet 1991;28: 73-8.