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Understanding Hereditary Transthyretin Amyloidosis

WHAT IS hATTR AMYLOIDOSIS?

Hereditary transthyretin amyloidosis (hATTR amyloidosis)* is a type of amyloidosis caused by a mutation in the transthyretin (TTR) gene leading to deposition of amyloid fibrils in organs and tissues throughout the body, such as the heart and the nervous system.1,2 The clinical spectrum of hATTR amyloidosis varies widely and may range from primary progressive sensorimotor and autonomic neuropathy, known as transthyretin amyloid polyneuropathy (ATTR-PN), to primary infiltrative cardiomyopathy, known as hereditary ATTR cardiomyopathy (hATTR-CM), or a mixed neurologic and cardiomyopathic phenotype.3-5

*Also known as variant ATTR (ATTRv), ATTRm, mutant ATTR, and hereditary amyloidosis.1,2,6

CLINICAL CHARACTERISTICS HETEROGENEITY IN hATTR AMYLOIDOSIS

Because hATTR amyloidosis is a multisystemic disorder that may have a heterogeneous clinical presentation, it is important to note7:

  • About 75% of patients, regardless of primary phenotype, exhibit cardiomyopathic features of the disease3
  • Carpal tunnel syndrome may often be the initial symptom in nearly one-third of hATTR-CM patients, with cardiomyopathy symptoms following as the disease progresses8

RECOGNITION OF CARDIAC INVOLVEMENT (SUCH AS CONDUCTION BLOCK, CARDIOMYOPATHY, OR ARRHYTHMIA) IS CRUCIAL IN PATIENTS WITH hATTR AMYLOIDOSIS. CARDIAC INVOLVEMENT IS ASSOCIATED WITH ADVERSE OUTCOMES AND WORSE OVERALL SURVIVAL.9

Selected genotype-phenotype
associations in hATTR amyloidosis5*

In hATTR amyloidosis, the clinical manifestation depends on mutation type, geographic origin of the patient, patient ethnicity, and other factors.2

 

Select each individual mutation type for more information on clinical manifestations, age of onset, and patient heritage.

V30M Early Onset
Clinical
Manifestations
Predominant neurological manifestations10
Approximate
Age of Onset
30-4011
Typical
Patient Heritage
Portuguese10
Japanese10
V30M Late Onset
Clinical
Manifestations
Cardiac and neurological manifestations12
Approximate
Age of Onset
50-6011
Typical
Patient Heritage
Swedish10
T60A
Clinical
Manifestations
Cardiac and neurological manifestations10
Approximate
Age of Onset
50-6011
Typical
Patient Heritage
Irish13
English10
L111M
Clinical
Manifestations
Predominant cardiac manifestations14
Approximate
Age of Onset
30-4011
Typical
Patient Heritage
Danish11
I68L
Clinical
Manifestations
Predominant cardiac manifestations14
Approximate
Age of Onset
5515
Typical
Patient Heritage
Italian13
V122I
Clinical
Manifestations
Predominant cardiac manifestations10
Approximate
Age of Onset
30-4011
Typical
Patient Heritage
African American10
African13
Afro-Caribbean13
"Neurologic"
PHENOTYPE
"Cardiac"

*This spectrum of genotype-phenotype associations is not comprehensive.

AN OVERVIEW OF hATTR-CM

Hereditary ATTR (hATTR)* occurs due to a mutation in the TTR gene.1 In the United States, the most common mutation causing the cardiac form of the disease (hATTR-CM) is the valine-to-isoleucine substitution at position 122 (V122I).5 This mutation affects almost exclusively the African American population, with a prevalence of about 3%-4%.13,16 The second most common mutation is T60A, which occurs predominantly in people of Irish descent.13 Not all patients who carry a TTR mutation will go on to have clinical signs and symptoms of this disease.

*Also known as variant ATTR.1

Also known as

  • Variant ATTR (ATTRv) amyloidosis1
  • ATTRm amyloidosis1
  • Mutant ATTR amyloidosis2
  • Hereditary amyloidosis6
  • Familial amyloid cardiomyopathy17

Patient Considerations

  • African American, African, or Afro-Caribbean descent (V122I)5,13
  • Irish descent (T60A)13
  • Men and women5

Symptoms

  • Symptom onset may occur as early as ~50 years of age18
  • Heart failure5
  • Neurological symptoms (peripheral and autonomic)5
  • Gastrointestinal symptoms5
  • History of bilateral carpal tunnel syndrome5

COMMON SIGNS AND SYMPTOMS OF
hATTR-CM2,5,19-24

Attr bodies
Attrwt

CTS, carpal tunnel syndrome; GI, gastrointestinal; HFpEF, heart failure
with preserved ejection fraction.

Cardiac

  • Fatigue
  • Shortness of breath
  • Edema
  • Arrhythmias
  • HFpEF
  • Aortic stenosis

Soft Tissue

  • Lumbar spinal stenosis
  • Biceps tendon rupture

GI

  • Diarrhea
  • Constipation
  • Nausea
  • Early satiety
  • Unintended weight loss

Neurologic

  • Carpal tunnel syndrome
  • Peripheral neuropathy
  • Orthostasis
  • Weakness

LIFE EXPECTANCY FOR PATIENTS WITH hATTR-CM

For patients with ATTR-PN, the overall life expectancy averages 10 years from symptom onset.25 However, for those with hATTR-CM, survival depends on the mutation,26 and can range from 2 to 5 years from initial presentation in untreated patients.18,27

DIAGNOSTIC URGENCY AND PROGNOSIS

ADVANCED hATTR-CM IN UNTREATED PATIENTS IS ASSOCIATED WITH RAPID PROGRESSION, SERIOUS CARDIAC COMPLICATIONS, AND A WORSE MEDIAN SURVIVAL.5,13,28 THEREFORE, EARLY DETECTION IS CRUCIAL. SURVIVAL WORSENS AS hATTR-CM ADVANCES.28

Inheritance Patterns

hATTR-CM is inherited in an autosomal dominant pattern, meaning only 1 affected parent is required to pass on the mutation. In some cases, the disease may occur in people with no family history. Not all people with a TTR gene mutation will develop hATTR-CM.29

Heterozygous Affected Individual29

Each child of an affected individual who is heterozygous for 1 TTR pathogenic variant has a 50% chance of inheriting the TTR variant.

Homozygous Affected Individual29

Each child of an affected individual who is homozygous for TTR pathogenic variants will inherit a TTR mutation.

Each sibling of an affected individual who is homozygous for TTR pathogenic variants has a 50% risk of having inherited 1 TTR mutation and a 25% risk of having inherited 2 TTR mutations.

FACTORS TO CONSIDER WHEN MONITORING CARRIERS OF TTR GENE MUTATIONS15

phenotype Group Genotype ESTIMATED PENETRANCE Typical age of onset Rate of progression
Neurologic V30M early onset >90% <40 years ++++++
Neurologic/mixed V30M late onset >60% >50 years ++++++
Cardiac V122l Unknown 55 years ++
  L111M >90% 35-40 years ++
  T60A >90% 55 years ++
  I68L >90% 55 years ++
Mixed S77Y >90% 55 years ++++
  E89Q >90% 50 years ++++
  G47E >90% 30 years ++++++

The number of “+” provides an indication of how fast the disease progresses.

Follow-Up and FREQUENCY OF
MONITORING USING PADO15

The PADO should be established once a TTR mutation has been identified

The baseline for tests used in monitoring should be established and an annual follow-up should begin 10 years before the PADO

The carrier should be educated to understand the early clinical signs associated with the mutation

Follow-up should increase in frequency as carriers approach their PADO,
particularly for genotypes associated with rapid progression

LIFE-THREATENING, UNDERRECOGNIZED, AND UNDERDIAGNOSED, IT IS VITAL TO RECOGNIZE THE CLUES OF hATTR-CM SO YOU CAN IDENTIFY THIS DISEASE.13,30,31

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