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Zpráva o onemocněních · Metabolic

Hereditary Transthyretin Amyloidosis (ATTR)

Whole genome sequencing identifies TTR variants, enabling early initiation of disease-modifying therapy when it matters most.

Zpráva o onemocněních hledá vzácné varianty, o nichž je známo, že způsobují onemocnění, na něž se zpráva zaměřuje.

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O tomto condition

A group of genetic diseases characterized by the abnormal deposition of amyloid proteins in various tissues, causing organ damage and dysfunction.

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disorder caused by TTR mutations, which encode transthyretin, a plasma transport protein synthesized primarily in the liver and retina. Pathogenic TTR missense variants cause protein misfolding and destabilization; mutant transthyretin molecules misfold more readily and nucleate amyloid fibril formation. Progressive amyloid deposition in peripheral nerves causes progressive sensorimotor polyneuropathy; amyloid deposition in the myocardium causes restrictive cardiomyopathy. Untreated ATTR is fatal within 7-12 years of symptom onset. Over 130 pathogenic TTR variants have been identified, with strong genotype-phenotype correlations: Val30Met causes predominantly neuropathic disease; Val122Ile causes predominantly cardiomyopathic disease.

ATTR prevalence is estimated at 1 in 100,000 overall, but the Val122Ile variant alone is carried by 3-4% of African Americans, approximately 1.5 million carriers in the United States. This variant is the most common pathogenic TTR variant in the US and is associated with predominantly cardiomyopathic disease, affecting 10-15% of African American heart failure patients over 60. Val30Met is the most common amyloidogenic variant worldwide and has founder populations in Portugal, Sweden, and Japan with predominantly neuropathic disease. The genetic variant determines the predominant phenotype: neuropathic forms (like Val30Met) cause primarily peripheral nerve symptoms; cardiac forms (like Val122Ile) cause primarily myocardial infiltration and heart failure.

A confirmed TTR pathogenic variant diagnosis is transformative. Three FDA-approved disease-modifying therapies now exist: tafamidis (Vyndaqel), a kinetic stabilizer that prevents transthyretin misfolding; patisiran (Onpattro) and vutrisiran (Alnylam/Vyr), RNA interference therapeutics that reduce hepatic transthyretin production; and inotersen (Tegsedi), an antisense oligonucleotide also reducing transthyretin. These therapies halt disease progression and can induce regression if started early. Phenotype-specific therapy selection is important: tafamidis appears most effective for neuropathic disease. Genotype also informs prognosis: Val30Met neuropathy typically progresses more slowly than other variants. Family cascade screening is critical; presymptomatic carriers can begin prophylactic therapy before symptom onset.

TTR variants predict clinical phenotype: Val30Met causes predominantly peripheral neuropathy, Val122Ile causes predominantly cardiomyopathy, with dramatic implications for surveillance and treatment strategy.

Onemocnění, které analyzujeme

Autozomálně dominantní

Hereditary amyloidosis refers to a group of inherited conditions that make up one of the subtypes of amyloidosis. Hereditary amyloidosisis characterized by the deposit of an abnormal protein called amyloid in multiple organs of the body where it should not be, which causes disruption of organ tissue structure and function. In hereditary amyloidosis, amyloid deposits most often occur in tissues of the heart, kidneys, and nervous system. While symptoms of hereditary amyloidosis may appear in childhood, most individuals do not experience symptoms until adulthood. There are many types of hereditary amyloidosis associated with different gene mutations and abnormal proteins. The most common type of hereditary amyloidosis is transthyretin amyloidosis (ATTR), a condition in which the amyloid deposits are most often made up of the transthyretin protein which is made in the liver. Other examplesof hereditary amyloidosis include, but are not limited to, apolipoprotein AI amyloidosis (A ApoAI), gelsolin amyloidosis (A Gel), lysozyme amyloidosis (A Lys), cystatin C amyloidosis (A Cys), fibrinogen Aα-chain amyloidosis (A Fib), and apolipoprotein AII amyloidosis (A ApoAII).

Co se diagnózou změní

Tafamidis (kinetic stabilizer), patisiran (RNAi), vutrisiran (RNAi), inotersen (antisense), liver transplantation

Analyzované geny

Známé také jako

familial amyloidosis; hereditary amyloidosis (disease)

Zahrnuje 33 příbuzných podtypů ↓
  • AApoAI amyloidosis
  • ABeta amyloidosis, Arctic type
  • ABeta amyloidosis, dutch type
  • ABeta amyloidosis, Iowa type
  • ABeta amyloidosis, Italian type
  • ABetaA21G amyloidosis
  • ABetaL34V amyloidosis
  • ABri amyloidosis
  • ACys amyloidosis
  • ADan amyloidosis
  • AFib amyloidosis
  • ALys amyloidosis
  • Alzheimer disease type 1
  • amyloidosis, hereditary systemic 1
  • amyloidosis, hereditary systemic 3
  • amyloidosis, hereditary systemic 5
  • amyloidosis, hereditary systemic 6
  • amyloidosis, primary localized cutaneous, 1
  • amyloidosis, primary localized cutaneous, 2
  • amyloidosis, primary localized cutaneous, 3
  • apolipoprotein A-II amyloidosis
  • APP-related brain and vascular amyloidosis
  • ATTRV122I amyloidosis
  • ATTRV30M amyloidosis
  • cerebral amyloid angiopathy
  • cerebral amyloid angiopathy, APP-related
  • familial amyloid neuropathy
  • familial primary localized cutaneous amyloidosis
  • familial visceral amyloidosis
  • Finnish type amyloidosis
  • ITM2B amyloidosis
  • pulmonary amyloidosis
  • variant ABeta2M amyloidosis
MONDO:0018634Orphanet 444116MedGen 148146

Proč sekvenování celého genomu

ATTR is not typically included in broad genetic panels. Over 130 TTR variants exist, and genotype-phenotype correlation is critical for management.

ATTR requires targeted TTR screening that most panels don't include

Hereditary transthyretin amyloidosis is rarely detected by broad genetic panels because targeted TTR testing is not standard. ATTR is increasingly integrated into cardiac and neuropathy workups in specialized centers, but many patients are initially misdiagnosed as having other cardiac or neurological conditions. The clinical phenotype correlates imperfectly with specific genotypes, complicating interpretation. Over 130 pathogenic TTR variants have been identified; genetic testing is essential for phenotype prediction and prognosis. Whole genome sequencing provides complete TTR coverage and enables simultaneous evaluation of other amyloidosis genes.

Genotype predicts phenotype and enables targeted disease-modifying therapy

A confirmed TTR pathogenic variant diagnosis is life-altering. Three FDA-approved disease-modifying therapies halt disease progression or induce regression if started early. Phenotype-specific therapies are emerging: tafamidis appears most effective for neuropathic disease; RNA interference therapies reduce transthyretin production broadly. Early treatment initiation, before irreversible peripheral nerve damage or myocardial infiltration occurs, is critical. Genotype informs prognosis: Val30Met neuropathy typically progresses more slowly than other variants. Family cascade screening identifies presymptomatic carriers who can begin prophylactic therapy before symptom onset.

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