Transthyretin-amyloidosis E85.9

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.11.2022

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Synonym(s)

ATTR amyloidosis; transthyretin amyloidosis; Transthyretinamyloidosis; transthyretin-type amyloidosis

Definition
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Rare, usually hereditary, early-manifested, but also acquired, late-manifested systemic amyloidosis involving multiple organ systems, characterized by deposition of transthyretin amyloid produced by hepatocytes in peripheral nerves and cardiac muscle (less commonly skin). S.a. Amyloidosis systemic.

Occurrence/Epidemiology
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Transthyretin amyloidoses include "familial amyloid polyneuropathy" (FAP) or amyloid-induced cardiomyopathy (FAC), which occurs early (from the age of 20), and "senile systemic amyloidosis" (SSA), which occurs late (from the age of 60) and is characterized by a cardiomyopathy.

Etiopathogenesis
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More than 150 mutations in the transthyretin gene(TTR gene, located on chromosome 18q12.1) have now been reported and are associated with the autosomal dominant form of the disease. Because most disease-associated mutations affect the dissociation rate of TTR tetramers, destabilization of TTR tetramers is widely considered to be a critical step in TTR amyloid formation. Recently, effective disease-modifying therapies such as TTR tetramer stabilizers and TTR gene silencing therapies have been developed for ATTR amyloidosis.

The most common mutation associated with familial amyloid polyneuropathy is the V30M mutation. The amyloid deposited in versch. The pathologically mutated amyloid of the transthyretin type deposited in various organs (and not degradable) may be associated with inflammatory or degenerative processes (carpal tunnel syndrome, intestinal chronic inflammation) but also with malignancies (bladder tumors, prostate carcinoma).

Furthermore, the mutations are involved in the development of several diseases, including:

  • amyloidotic polyneuropathy
  • euthyroid hyperthyroxinemia
  • amyloidotic vitreous opacities
  • Cardiomyopathy

Clinical features
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Diagnosis
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Diagnosis of transthyretin amyloidosis includes clinical/pathologic findings, detection of amyloid (histochemical detection with Congo red), identification of transthyretin as the major component of amyloid (immunohistochemistry), and detection or exclusion of an amyloidogenic mutation in the transthyretin gene (gene name TTR).

Left ventricular wall thickening greater than 12 mm may indicate transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Echocardiography as the most important diagnostic measure should therefore be performed early in suspected cases.

Therapy
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Newer therapeutic options to suppress transthyretin production are available using RNA interference (RNAi).

Recently, new therapeutic strategies have emerged that aim to stabilize TTR or neutralize the TTR gene. The kinetic TTR stabilizer tafamidis is the first drug approved in the EU with this indication.

Note(s)
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In systemic transthyretinamyloidoses, the amyloid can be detected bioptically by rectal biopsy or by skin biopsy (only from lesioned skin). (Note: The material obtained should contain vessels/nerves).

A mutation in transthyretin can be detected/excluded by DNA analysis of exons 2-4 (exon 1 does not contain amyloidogenic mutations).

Literature
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  1. Coelho T et al (2013) Safety and efficacy of RNAi therapy for transthyrethine amyloidosis. N Engl J Med 368: 819-829
  2. Ferreira AC et al (2012) Familial amyloidotic polineuropathy and systemic lupus. Lupus 21:1455-1458
  3. Hagenacker T et al (2014) First report of a rare mutation in a Polish patient with painful late-onset transthyretin amyloidosis. J Neurol Sci 346:331-332
  4. Harkany Tet al (2002) Cutaneous lymphatic amyloid deposits in Hungarian-type familial transthyretin amyloidosis: a case report. Br J Dermatol 146:674-679
  5. Jimenez-Zepeda VH et al (2014) A novel transthyretin variant p.H110D (H90D) as a cause of familial amyloid polyneuropathy in a large Irish kindred. amyloid 28:1-5
  6. Maia LF et al (2014) CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings. J Neurol Neurosurg Psychiatry. doi: 10.1136/jnnp-2014-308107
  7. Magy N et al (2003) A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. Amyloid 10:29-33
  8. Sikora JL et al (2014) Genetic variation of the transthyretin gene in wild-type transthyretin amyloidosis (ATTRwt). Hum Genet PubMed PMID: 25367359
  9. Yagi H et al (2014) A representative case of hereditary transthyretin amyloidosis complicated by intramyocardial hemorrhage. Amyloid 27:1-3 .

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 29.11.2022