Tuesday, August 6, 2013

Article Reviews (2003 and 2005) - Two reviews of hereditary renal amyloidosis

It's hard to believe it has been over two months since my last article review. I suppose two emergency room visits (including one on a cruise ship), three surgeries (one of which was an emergency), two nights in the hospital, two funerals, two weeks tethered to a portable wound vacuum, and a diagnosis of skin cancer gave me something else to write about during that time. It's hard enough just writing about all that, so I can't imagine what it must be like for Mom to live through it. Once again, hopefully things will calm down for awhile.

Today's post will review two very similar articles, with the always exciting monthly blog stats at the end. Since I do not have either one of these articles, I will list their titles and abstracts first, then briefly discuss them together.

Title: Hereditary systemic amyloidosis with renal involvement (1)

Author: Philip Hawkins, National Amyloidosis Centre, London, UK

Journal: Journal of Nephrology (2003)

Hereditary systemic amyloidosis is caused by deposition of genetically variant proteins as amyloid fibrils. The types that present with renal disease are usually associated with mutations in the genes for either apolipoprotein AI, apolipoprotein AII, lysozyme or fibrinogen A alpha-chain. These diseases are inherited in an autosomal dominant manner with variable penetrance, and can present clinically at any time from the teen years to old age, though usually in mid-adult life. Hereditary amyloidosis is uncommon, but its precise characterization has major implications for patient management and genetic counseling, and it has been an extremely valuable model for elucidating the pathogenesis of amyloid deposition generally. The amyloidogenic variant proteins associated with hereditary amyloidosis are less stable than their normal wild type counterparts and even under physiological conditions can populate partly unfolded states, involving loss of tertiary or higher order structure, which readily aggregate with retention of beta-sheet secondary structure into protofilaments and fibrils. The clinical phenotype of hereditary renal amyloid is non-specific and is readily misdiagnosed as acquired AL amyloidosis. Indeed, we have lately demonstrated that five percent of patients with apparent sporadic amyloid have hereditary fibrinogen A alpha-chain amyloidosis associated with the valine 526 variant. Penetrance of this particular mutation is extremely low in most families obscuring the genetic etiology, but the renal histology is very characteristic showing substantial accumulation of amyloid within enlarged glomeruli, but none in blood vessels or the interstitium. DNA analysis is now performed routinely in UK National Amyloidosis Centre in patients with systemic amyloidosis in whom AA or AL fibril type cannot be definitively verified.

Title: Ostertag revisited: The inherited systemic amyloidoses without neuropathy (2)

Author: Merrill Benson, Indiana University School of Medicine, Indiana, USA

Journal: Amyloid (2005)

Mutations in a number of plasma proteins, including transthyretin, apolipoprotein AI, fibrinogen A alpha-chain, lysozyme, and apolipoprotein AII, are associated with hereditary systemic amyloidosis. Transthyretin amyloidosis is the most common and is usually associated with peripheral neuropathy. Mutations in the other proteins usually have no neuropathic consequences and, instead, cause principally renal and cardiac amyloidosis. Only the apolipoprotein AI glycine 26 arginine mutation may cause peripheral neuropathy and then in only some of the kindreds with this disease. This review is concerned with the non-neuropathic hereditary systemic amyloidoses. It strives to present a synopsis of the present day knowledge of these diseases including each feature of each precursor protein and its mutations; the clinical phenotype of the disease; and suggestions for treatment when feasible. The main objective is to increase awareness of these autosomal dominant diseases, enhance the chances of early diagnosis, enhance the physician's and subsequently the patient's knowledge of each disease, and finally emphasize the need for more research to find ways to treat or prevent these diseases.

These two articles, published two years apart, appear to be very similar based on the abstracts alone. They both focus on the most common familial amyloidosis types other than transthyretin (ATTR), which are apolipoprotein, fibrinogen and lysozyme, and they were published about 10 years after the first article describing the fibrinogen mutation was published. There is not much in terms of new information that we have not already covered in previous articles, but here are the highlights:

  • The inheritance mode is autosomal dominant, and penetrance (how likely a person with the mutation is to develop symptoms) is variable.
  • Hereditary renal amyloidosis is frequently misdiagnosed as AL amyloidosis because the clinical symptoms are so similar. (That article was reviewed in the May 12, 2013 blog post.)
  • A defining characteristic of the fibrinogen Glu526Val variant is the accumulation of amyloid deposits in the glomeruli of the kidneys.
The last sentence of the second abstract does a good job of summarizing the objective of these articles, which is to increase awareness of these diseases and enhance the chances of early diagnosis. A current online resource that provides a general overview, although probably not as detailed as these two published articles, is the article on familial renal amyloidosis at emedicine.com.

That is all I have to say about these two articles since I do not have the full articles to review. The next article up for review will document yet another fibrinogen mutation, with an especially unique characteristic.

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(1) Hawkins PN. Hereditary systemic amyloidosis with renal involvement. J Nephrol. 2003;16:443–448.

(2) Benson MD. Ostertag revisited: The inherited systemic amyloidoses without neuropathy. Amyloid 2005; 12: 75-87.

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