Title: Studies on the pathogenesis of a familial form of renal amyloidosis (1)
Authors: Mornaghi, Rubinstein, and Franklin (New York University Medical Center and New York Blood Center)
Journal: Transactions of the Association of American Physicians (1981)
Abstract: none
Title: Familial renal amyloidosis: Case reports and genetic studies (2)
Authors: Mornaghi, Rubinstein, and Franklin (New York University Medical Center and New York Blood Center)
Authors: Mornaghi, Rubinstein, and Franklin (New York University Medical Center and New York Blood Center)
Journal: The American Journal of Medicine (1982)
Abstract:
Rapidly progressive biopsy-proved renal amyloidosis developed in three brothers, aged 49, 52, and 55, of Irish-American origin. None had evidence of a plasma cell dyscrasia, a monoclonal serum or urine protein, or any underlying chronic disease. Immunoperoxidase staining of one pulmonary and one renal biopsy specimen was negative for Amyloid A (AA), Amyloid L (AL), and prealbumin. To investigate factors that might play a role in the disease, the subjects and 21 relatives were typed for antigens of the A, B, C, and DR loci and the linked marker genes for factor B and glyoxalase. The ability of macrophages to degrade serum amyloid A (SAA) [1] was examined. One brother yielded an intermediate AA-like produce similar to what is seen in most patients with AA or AL amyloidosis and 40 percent of normal subjects. The other two degraded SAA completely to small peptides. Analysis of the families revealed first that the disease was not linked to the major histocompatibility complex. We were unable to demonstrate a genetic relationship between processing of SAA by peripheral mononuclear cells and the human leukocyte antigen locus. Finally, the pattern of SAA degradation was not associated with the development of the disease.
Although both of these articles cover the same family and discuss the genetic testing that was done, only the 1982 article provides the medical history of the three cases of renal amyloidosis. So this review will mainly follow the 1982 article, but I will mention the 1981 article occasionally.
As stated in the abstract, this article describes three brothers who developed renal amyloidosis in their 40s and 50s.
Case 1: This patient was a 49 year old Irish-American man who presented in September of 1978 with anemia and renal failure. A 24-hour urine collection showed 3 grams of protein. He declined a kidney biopsy at that time. He was admitted to the hospital four months later (January of 1979) due to dyspnea (labored breathing) and edema. A 24-hour urine collection showed 8.3 grams of protein and his serum creatinine level was 9.3 mg/100 ml. At some point he did have kidney and bone marrow biopsies. The kidney biopsy showed amyloid deposits, whereas the bone marrow biopsy was normal. He started hemodialysis which he was still on at the time this article (published in October 1982) was written.
Case 2: This patient was a 52 year old brother of Case 1 who presented with hypertension in early 1976. He was found to have proteinuria and an elevated serum creatinine level. He had a kidney biopsy in June of 1976, which was positive for amyloid, localized in the glomeruli. A bone marrow biopsy was normal.
In June of 1978 he had a myocardial infarction (heart attack.) In September of 1979 he started on hemodialysis. In March of 1981 he was hospitalized and discharged a week later with a diagnosis of congestive heart failure, end-stage kidney disease, and renal amyloidosis. He was still on hemodialysis at the time this article (published in October 1982) was written.
Case 3: This patient, a brother of Cases 1 and 2, presented in 1974 at the age of 55 with hypertension. In December of 1978 he was hospitalized with anemia. In June of 1979 he was hospitalized due to progressing renal failure and hypertension. In November of 1979 he was hospitalized and a kidney biopsy showed amyloid. In January of 1980 his serum creatinine level was 8.4 mg/100 ml and he started on hemodialysis. In June of 1980 he was admitted to the hospital due to a persistent cough and dyspnea. A lung biopsy showed amyloid deposits consistent with pulmonary amyloidosis. He was still on hemodialysis at the time this article (published in October 1982) was written.
For the most part, these three cases share a lot in common with other cases of fibrinogen amyloidosis: hypertension, proteinuria, and elevated serum creatinine level indicating kidney failure, eventually progressing to the point where dialysis is necessary. Two significant items out of the norm were the congestive heart failure in Case 2, and what is presumed to be pulmonary amyloidosis in Case 3. This is the first time I recall hearing about pulmonary amyloidosis in a person with fibrinogen amyloidosis. On the other hand, cardiac involvement is rare with fibrinogen amyloidosis, but there is a documented case in a later article. So this patient's heart may have been affected by amyloids, or he could have simply developed congestive heart failure through the "normal" means instead of amyloidosis, since amyloidosis does not prevent or cause all of the other diseases and conditions that normally occur to the body over time. In other words, you can't always blame it on the a-a-a-a-a-amyloid (apologies to Jamie Foxx).
These three brothers had an older brother who died of pneumonia at the age of 53, and they had three sisters who did not have any symptoms to indicate renal amyloidosis. Given the large size of this family, the authors were able to conduct tests on 24 family members, including the three brothers with renal amyloidosis, in an attempt to point toward some genetic causes of the amyloidosis. Both articles go into quite a bit of detail on the testing that was done, and it is way over my head, so I will try to be brief in covering them.
HLA Typing: HLA typing is commonly referred to as tissue typing. Tissue typing is important in the field of organ transplants since it gives an indication of how the recipient's body will respond to the donated (transplanted) organ. (HLA stands for Human Leukocyte Antigen.) Anyway, by comparing the HLA typing of the six siblings (three brothers and three sisters), they concluded that the evidence strongly suggests that the renal amyloidosis is not closely linked to the HLA system.
Separation of Peripheral Blood Mononuclear Cells (PBMC) and Incubation with SAA: Here is my best attempt at explaining what I think this test is. They took a quantity of blood from each family member, separated out some components, and set up experiments so they could measure how certain components (SAA, which is Serum Amyloid A) degraded over time. The authors had done previous work were they discovered a certain degradation pattern of SAA was found in almost 100% of patients with AA or AL amyloidosis. But in this case, if you have not already guessed, there was no correlation between the degradation pattern and this type of renal amyloidosis.
So these two articles document an early attempt to determine a genetic link to this type of renal amyloidosis. Although they came up empty, this additional knowledge certainly helped to support the case that this was a new type of familial amyloidosis. In fact, the authors state just that in the 1982 article: "The exact nature of this type of amyloid is still unknown, but future immunochemical studies on fibrils isolated from involved organs should provide information regarding its properties." They were right on target with that statement, and an upcoming article will show that they did a good job of predicting the future.
While they were correct in concluding this type of amyloid was different from any others previously described, the authors did reach an incorrect conclusion in the 1981 article, albeit with some caution. Here is part of the summary of the 1981 article:
". . . the disease is transmitted in a fashion which differs from most of the familial forms in that it is not inherited as an autosomal dominant trait. However, this conclusion will have to be reevaluated in years to come when the younger descendants reach the age at which amyloidosis was clinically manifested in the three propositi. It should be emphasized that these conclusions are warranted only for this unusual type of amyloidosis whose precise immunochemical nature at this time remains to be determined."
It is easy to understand how they could reach that conclusion given the data they had at the time, and the low penetrance of fibrinogen amyloidosis. Now with genetic testing available it can be clearly shown that the inheritance mode is autosomal dominant.
On a side note, one of the references listed for these articles is a 1981 article by none other than Dr. Merrill D. Benson, whose team of course discovered the first mutations for fibrinogen amyloidosis (and many others). Since 1981 was 32 years ago I wondered if that was one of Dr. Benson's first articles. Nope. According to his publications page, the first paper he co-authored was published TWENTY years before that, in 1961 (the year he earned his bachelor's degree).
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Citations:
(1) Mornaghi, R., P. Rubinstein, and E. C. Franklin. 1981. Studies on the pathogenesis of a familial form of renal amyloidosis. Trans. Assoc. Am. Phys. 94:21 1-216.
(2) Mornaghi, R., P. Rubinstein, and E. C. Franklin. 1982. Familial renal amyloidosis: case reports and genetic studies. Am. J. Med. 73:609-614.
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