Sunday, August 18, 2013

Article Review (2005) - Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen A alpha chain gene

The article being reviewed today is a 2005 report of another new fibrinogen amyloidosis mutation. This mutation is unique for two reasons. First, the patient's symptoms were first noted at the age of 7. Second, the mutation was not inherited from either parent.

Title: Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen A alpha chain gene (1)

Authors: Hee Gyung Kang, Alison Bybee,Il Soo Ha, Moon Soo Park, Janet A. Gilbertson, Hae Il Cheong, Yong Choi, and Philip N. Hawkins (Seoul National University Hospital, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea; National Amyloidosis Centre, London, UK)

Journal: Kidney International (2005)

Background. Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years.
Methods. Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen Aa chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen Aa chain genes by polymerase chain reaction (PCR) and sequencing.
Results. A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen A alpha chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo.
Conclusion. This is the first description of hereditary fibrinogen A alpha chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.

The abstract essentially tells the entire story regarding this mutation, so I will just briefly discuss some of the highlights. First, the firsts associated with this case include:
  • The first reported case of fibrinogen amyloidosis in an Asian individual.
  • The first reported case of a person under the age of 10 developing symptoms of fibrinogen amyloidosis. (The youngest reported age before this case was 12.)
  • The first reported case of a mutation causing fibrinogen amyloidosis to occur de novo, which means the mutation first occurred in this individual and was not inherited from either parent.

It is interesting that although this fibrinogen mutation is a new one, the symptoms and progression of the disease are more or less identical to those of the fibrinogen Glu526Val mutation although they occurred at least 40 years earlier in this patient's life. The renal biopsy showed enlarged glomeruli substantially replaced by amyloid deposits, and she was on peritoneal dialysis due to end-stage renal failure about two years after diagnosis. Another interesting bit of info from the article is that she had foamy urine for about a year before the proteinuria was discovered.

The mutation itself, if I understand it correctly, replaced a long section of her fibrinogen A alpha chain gene with a much shorter section. That is what the words "insertion-deletion" are referring to in the title. It is also a frameshift mutation since the remaining unchanged parts after the insertion-deletion are shifted forward in the string.

Regarding the de novo mutation, the article states that relationship testing was done to confirm that her parents were indeed her biological parents. Since neither parent had the mutation she could not have inherited it from either one, so it must have occurred first with her. She has a sister who does not have the mutation. (We would not expect the sister to have it since it was not inherited from a parent.) It would be nice to know what the status of this patient is today. This article was submitted for publication in March of 2005, and it says a combined liver-kidney transplant was being considered. One would hope that by now, eight years later, that transplant has happened and she is leading as normal a life as possible.

That's it for now . . .



(1) Kang HG, Bybee A, Ha IS, Park MS, Gilbertson JA, Cheong HI, Choi Y, Hawkins PN. Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen A alpha chain gene. Kidney Int 2005; 68: 1994-8.

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