Rare Disease AdvisorATTR-CM with Normal Left Ventricular Wall Thickness and Absent Cardiac Uptake

Rare Genetic Mutation Challenges Standard Diagnostic Protocols in Amyloid Cardiomyopathy

In a recent study published in the European Heart Journal, researchers reported a unique case of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) in a patient with the Tyr78Phe mutation, presenting without typical diagnostic markers such as left ventricular hypertrophy and cardiac uptake on scintigraphy. This finding highlights the complexities and challenges in diagnosing ATTR-CM, particularly when genetic mutations lead to atypical manifestations.

Key Points:

• A 69-year-old male, undergoing surgery for lumbar spinal stenosis, experienced cardiorespiratory arrests caused by electromechanical dissociation, prompting extensive cardiac evaluations.
• Diagnostic tools such as electrocardiograms and transthoracic echocardiography indicated severe biventricular dysfunction without left ventricular hypertrophy, a rarity in ATTR-CM cases.
• Coronary angiography results were normal, but cardiac MRI showed elevated native T1/T2 values and extensive late gadolinium enhancement, suggesting diffuse subendocardial involvement.
• Technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy did not reveal typical cardiac uptake, commonly seen in ATTR-CM patients.
• Endomyocardial biopsies confirmed amyloid deposits despite the absence of imaging findings typical for ATTR-CM, leading to further genetic testing.
• Genetic testing uncovered a Tyr78Phe mutation in the transthyretin gene, a rare variant previously documented in only three other cases since 2003.
• The patient’s medical history included previous right carpal tunnel surgery, and his brother had polyneuropathy, both of which are potential red flags for underlying ATTR-CM associated with this mutation.
• Researchers emphasize the necessity of considering ATTR-CM in patients with orthopedic manifestations and a family history of related symptoms, especially when standard diagnostic procedures yield false-negative results.

The majority of patients with ATTR-CM do not receive a timely diagnosis. In a survey of patients with ATTR-CM, diagnosis was made within 6 months of symptom onset in only 35% of those with ATTRv (variant transthyretin amyloid cardiomyopathy) and 46% of those with ATTRwt (wild-type transthyretin amyloid cardiomyopathy). Many patients see more than 5 physicians before receiving a correct diagnosis because of the perceived disease rarity, overlap with other more “common” diseases, and the seemingly disconnected constellation of clinical findings, including musculoskeletal, neurologic, gastrointestinal (GI), and renal manifestations. (JACC)

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