Hereditary

UNDERSTANDING HEREDITARY
ATTR-CM (hATTR-CM)

WHAT IS hATTR-CM?

hATTR-CM is a type of amyloidosis caused by a mutation in the TTR gene.¹hATTR-CM is inherited in an autosomal dominant pattern, meaning only 1 affected parent is required to pass on the mutation.² Though a mutation in the TTR gene is associated with an increased risk for hATTR-CM, not all people who carry this mutation will go on to develop the disease.¹

hATTR-CM is primarily associated with infiltrative cardiomyopathy, though the clinical spectrum of hereditary ATTR (hATTR) amyloidosis varies widely and can include progressive sensorimotor and autonomic neuropathy.^3-5

~75^%About 75% of patients with hATTR amyloidosis exhibited cardiomyopathic features of the disease.³

>30^%Carpal tunnel syndrome is also common and can often be the initial symptom in more than 30% of hATTR-CM patients, with cardiomyopathy symptoms following as the disease progresses.⁶

AN OVERVIEW OF hATTR-CM

RECOGNITION OF CARDIAC INVOLVEMENT IN HEREDITARY AMYLOIDOSIS (VIA NT-proBNP MEASUREMENTS) IS CRITICAL, AS CARDIAC INVOLVEMENT IS ASSOCIATED WITH ADVERSE OUTCOMES AND WORSE OVERALL SURVIVAL, REGARDLESS OF PHENOTYPE.¹⁰

NT-proBNP, N-terminal pro-B-type natriuretic peptide.

PATIENT CONSIDERATIONS

African American, African, or Afro-Caribbean descent (V122I)^5,7,8
Irish descent (T60A)⁸
Men and women⁵
Symptom onset may occur as early as 50-60 years of age⁹*

PROGNOSIS

Once diagnosed, untreated patients have a median survival of ~2 to 3 years⁸

COMMON CHARACTERISTICS THAT MAY PRESENT IN hATTR-CM PATIENTS:

Heart failure⁵
Peripheral dysfunction (eg, peripheral sensorimotor dysfunction, peripheral neuropathy)⁵
Autonomic dysfunction (eg, autonomic neuropathy, gastrointestinal complaints, unexplained weight loss, orthostatic hypotension, sexual impotence)^5,9
History of bilateral carpal tunnel syndrome⁵

*Age of onset varies depending on the causative mutation.

Selected genotype-phenotype
associations in hATTR amyloidosis*

In hATTR amyloidosis, the clinical manifestation depends on mutation type, geographic origin of the patient, patient ethnicity, and other factors.¹¹

Select each individual mutation type

for more information on clinical manifestations, age of onset, and patient heritage.

V30M Early Onset

V30M Late Onset

T60A

L111M

I68L

V122I

"Neurologic"

PHENOTYPE

"Cardiac"

About 75% of patients with hATTR amyloidosis exhibited cardiomyopathic features of the disease.³

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

DIAGNOSTIC URGENCY

In patients with hATTR-CM, survival depends on the mutation and can range from 2 to 5 years from initial presentation in untreated patients.^16-18

ADVANCED hATTR-CM IN UNTREATED PATIENTS IS ASSOCIATED WITH RAPID PROGRESSION, SERIOUS CARDIAC COMPLICATIONS, AND A WORSE MEDIAN SURVIVAL.^5,8,19 THEREFORE, EARLY DETECTION IS CRITICAL, AS SURVIVAL WORSENS AS hATTR-CM ADVANCES.¹⁹

COULD HEART FAILURE IN YOUR AFRICAN AMERICAN PATIENTS BE A CAUSE OF hATTR-CM?

In the United States, the most common mutation causing the cardiac form of the disease (hATTR-CM) is the V122I mutation. This mutation affects almost exclusively the African American population.^5,7,8

hATTR-CM due to the V122I mutation is an underdiagnosed cause of heart failure in individuals of African ancestry.²⁰

THAOS, Transthyretin Amyloid Outcome Survey.

V122I PRIMARILY PRESENTS WITH CARDIAC MANIFESTATIONS

In 1 study, the most common clinical presentation with hATTR-CM due to the V122I mutation was heart failure. The second most frequent symptom was carpal tunnel syndrome.²¹

hATTR-CM IS OFTEN UNDERRECOGNIZED, AND INDIVIDUALS OF AFRICAN DESCENT WITH hATTR-CM DUE TO V122I CAN BE ESPECIALLY OVERLOOKED.^20,22 IT IS IMPORTANT TO DISTINGUISH THESE PATIENTS FROM THOSE WITH OTHER FORMS OF CARDIOMYOPATHY AND HEART FAILURE.²²

V122I PATIENT PROFILE

A CLINICAL PROFILE FOR A 67-YEAR-OLD MAN DISPLAYING THE CLINICAL SIGNS OF hATTR-CM

*Hypothetical profile. Not an actual patient.

^†^99mTc-PYP is not FDA approved for the diagnosis of ATTR-CM. Please consult individual labeling for risks.

^99mTc-PYP, ^99mtechnetium-labeled pyrophosphate.

JOE’S MEDICAL AND FAMILY HISTORY SHOULD RAISE SUSPICION OF hATTR-CM—A PROGRESSIVE, LIFE-THREATENING DISEASE²²

Meet Joe*—A 67-Year-Old Retired High School Teacher

Family history

Mother died due to complications from heart failure at age 63
Brother suffered a stroke

Presentation and medical history

Currently experiencing shortness of breath and fatigue
History of hypertension, although blood pressure is controlled with appropriate medication
Echocardiographic evidence of increased left ventricular wall thickness
History of carpal tunnel syndrome with bilateral surgical repair

Diagnosis

AL amyloidosis was ruled out
Cardiac imaging using ^99mTc-PYP was consistent with ATTR-CM^†
Genetic testing identified the V122I mutation of the TTR gene, consistent with the hereditary form of ATTR-CM

UNDERSTANDING GENETIC RISK

DIAGNOSIS OF hATTR-CM IN AN INDEX PATIENT SHOULD PROMPT GENETIC COUNSELING AND TESTING OF FAMILY MEMBERS¹⁵

Early identification of hATTR-CM is important to enable timely treatment¹⁵
Genetic counseling and testing can be especially beneficial in at-risk family members, such as siblings or children of an index patient¹⁵

TIMING OF GENETIC TESTING¹⁵

A targeted approach may enable diagnosis of disease upon the first detectable sign or symptom

*Percentage of individuals with a mutation who exhibit clinical symptoms.

LIFE-THREATENING, UNDERRECOGNIZED, AND UNDERDIAGNOSED, IT IS VITAL TO RECOGNIZE THE CLUE OF CLUES OF hATTR-CM SO YOU CAN IDENTIFY THIS DISEASE.^8,23,24

Next section

Suspect the clues of ATTR-CM