Familial transthyretin amyloidosis

Familial transthyretin amyloidosis is a hereditary multisystem disease that most often affects the nervous system, heart, kidneys, and eyes. Along with clinical evaluation and other testing, genetic testing is necessary to establish the diagnosis. 1

PrintPrint

Familial transthyretin amyloidosis is a hereditary multisystem disease that most often affects the nervous system, heart, kidneys, and eyes. Along with clinical evaluation and other testing, genetic testing is necessary to establish the diagnosis. 1

Disease Name 
Familial transthyretin amyloidosis
Disease Information 

Familial transthyretin (TTR) amyloidosis is a progressive hereditary, multisystem disease that affects the nervous system, heart, kidneys, and eyes. Symptoms usually begin in the third to fifth decade in affected individuals from Portugal and Japan; in those from other areas, the onset is later.1 It is caused by mutations in the TTR gene, responsible for producing transthyretin protein. This protein transports vitamin A and thyroxine throughout the body. Mutations in TTR can impair the ability to bind to other TTR proteins to perform this transport function, leading to extracellular deposit of TTR protein fibrils in various tissues.1

Amyloid deposits can be found in biopsy specimens. These, in combination with identification of a pathogenic variant in TTR, are necessary to establish the diagnosis.1

Inheritance is autosomal dominant, but family history may appear to be negative in the majority of patients.2 Penetrance is <100%, with widely ranging estimates for the same mutation in different populations.3,4 Anticipation has been observed.1

Clinical Subtype by Representative TTR Mutation*

Clinical subtype Representative TTR mutation Symptoms
TTR amyloid polyneuropathy Val30Met (most common in Portuguese, Swedish, Japanese) Early:
  • Sensorimotor polyneuropathy of the legs
  • Carpal tunnel syndrome
  • Autonomic dysfunction
  • Constipation/diarrhea
  • Impotence
Late:
  • Cardiomyopathy
  • Vitreous opacities
  • Nephropathy
TTR amyloid polyneuropathy Ile84Ser Early:
  • Carpal tunnel syndrome
Late:
  • Sensorimotor polyneuropathy of extremities
  • Autonomic dysfunction
  • Constipation/diarrhea
  • Impotence
  • Cardiomyopathy
  • Vitreous opacities
  • Nephropathy
TTR cardiac amyloidosis (familial amyloid cardiomyopathy) Val1221Ile (found in 3-3.9% of African Americans5
  • Cardiomegaly
  • Conduction block
  • Arrhythmia
  • Anginal pain
  • Congestive heart failure
  • Sudden death
TTR leptomeningeal/CNS amyloidosis Asp18Gly
  • Dementia
  • Ataxia
  • Spasticity
  • Seizures
  • Hemorrhage (intracerebral and/or subarachnoid)
  • Psychosis
  • Hydrocephalus

*Adapted from Sekijima Y, et al. Familial Transthyretin Amyloidosis. November 5, 2001 (updated January 26, 2012). In Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Non-amyloid and protective TTR mutations are known.6 Senile systemic amyloidosis results from abnormal deposition of non-mutant TTR protein.

Testing Benefits & Indication 

Amyloid deposits found in biopsy specimens, in combination with identification of a pathogenic variant in TTR, are necessary to establish the diagnosis.1 Genetic testing is useful for diagnostic confirmation in symptomatic individuals and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular confirmation of a diagnosis may help avoid unnecessary testing and procedures, guide recommendations for medical treatment and screening, and offer accurate genetic counseling (including risk assessment) for a family. 

Genetic testing may be considered for any of the following:

  • Confirm a suspected diagnosis of familial TTR amyloidosis and begin treatment
  • Differentiate familial TTR amyloidosis from other amyloid disease types
  • Offer treatment/screening based on genetic subtype
  • Determine carrier status for a known familial mutation
Test Description 

Our familial TTR amyloidosis genetic testing includes next generation sequencing (NGS) and deletion/duplication analysis of the TTR gene. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS.

Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.7 This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis is performed utilizing a targeted chromosomal microarray.

Mutation Detection Rate 

Our familial TTR amyloidosis genetic testing can detect >99% of affected individuals (clinical sensitivity) and can detect >99.9% of described sequencing mutations, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Prenatal testing is available. 

Turnaround Time 
TEST CODE TEST NAME TURNAROUND TIME
1560 TTR Gene Sequence and Deletion/Duplication Analysis 2-4 weeks

 

Specialty 
Genes 
TTR
References 
  1. Sekijima Y, et al. Familial Transthyretin Amyloidosis. November 5, 2001. In Pagon RA, et al., editors. GeneReviews.® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. 
  2. Soares ML, et al. Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease. Hum Mol Genet. 2005;14:543-553. 
  3. Plante-Bordeneuve V, Lalu T, et al. Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology. 1998;51:708-714.
  4. Plante-Bordeneuve V, et al. Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families. J Med Genet. 2003;40:e120.  
  5. Yamashita T, et al. A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population. Amyloid. 2005;12:127-30.  
  6. Ando Y, et al. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol. 2005;62;1057-1062.  
  7. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.