Case report
A 57-year-old man who had been diagnosed with mild hypertension and refractory chronic Guillain-Barre syndrome first presented himself to cardiology with an episode of syncope. The 24-h holter monitoring indicated sick sinus syndrome, which was presumptively attributed to degenerative causes. Thus, a permanent pacemaker was implanted (Fig. 1, Supplementary Fig. 1). One year later, the patient was admitted for outpatient cardiology evaluation of progressive right heart failure and limb paraesthesias. Physical examination showed orthostatic hypotension and reduced muscle strength in all extremities. The patient had no history of myocardial infarction or diabetes mellitus. The results of routine biochemical investigations were within normal limits. However, the serum levels of N-terminal prohormone brain natriuretic peptide and cardiac troponin T were elevated. Both antinuclear antibodies and Bence-Jones protein electrophoresis were negative. The electrocardiogram showed pacemaker rhythm, pseudoinfarction patterns, and normal voltage complexes (Supplementary Fig. 2). Transthoracic echocardiograms showed a thickened left ventricular wall and interventricular septum (maximal left ventricular wall thickness= 16 mm, interventricular septal thickness= 20 mm), atrial enlargement, and preserved ejection fraction (EF= 55%) (Fig. 2A and 2B). The M-mode echocardiogram of the patient further revealed a thickened interventricuar septum and non-obstructive cardiomyopathy (Supplementary Fig. 3). A restrictive transmitral flow pattern that was characterized by the ratio of E wave and A wave was observed (Fig. 2C). Tissue Doppler revealed decreased early diastolic septal mitral annular velocity (Fig. 2D).
The concurrence of independent pathologic features, including cardiomyopathy with severe conduction disorders and peripheral neuropathy, may be attributed to amyloid deposition. Subsequently, Congo red staining and immunohistochemical analysis of abdominal fat-pad biopsy confirmed transthyretin (TTR)-associated amyloid deposition (Fig. 3). Genetic testing identified the G>T mutation in exon 4 of the transthyretin (TTR) gene, which resulted in alanine-to-serine substitution at amino acid position 117 (Fig. 4). Therefore, the diagnosis of familial amyloid cardiomyopathy was proposed. This diagnosis was concealed for more than five years. Finally, the genetic analysis of all the patient’s family members revealed the same TTR mutation in his asymptomatic son and grandson but not in his daughter. These results are likely consistent with the sex-specific feature of familial amyloid cardiomyopathy. Considering the risk of surgery, the patient refused orthotopic liver transplantation.
Discussion
Familial amyloid cardiomyopathy is caused by the extracellular deposition of amyloid fibrils that consist of misfolded variant TTR. TTR amyloid deposition can impair tissue structure and organ function, such as cardiovascular tissue and the nervous system [
]. The early diagnosis of familial amyloid cardiomyopathy is challenging given its phenotypic heterogeneity, which is caused by different types of mutations and environmental factors [
]. In the presented case, familial amyloid cardiomyopathy was misdiagnosed as chronic Guillain-Barre syndrome for many years until the patient manifested heart failure. TTR cardiac amyloidosis should have been suspected when the patient was admitted for overt neurological impairment accompanied by sick sinus syndrome. In patients with TTR cardiac amyloidosis, amyloids infiltrate not only the peripheral nervous system but also the cardiac conduction system, thus causing bundle branch block and atrioventricular or sinoatrial block [
]. Unfortunately, the diagnosis of TTR cardiac amyloidosis was delayed for more than five years due to the initial ignorance of mild cardiac involvement. Thus, it is crucial for physicians to recognize the characteristic signs of TTR cardiac amyloidosis. We conclude that the concurrent dysfunctions of the neurologic and cardiac conduction systems in addition to other unexplained cardiac abnormalities are red flags for possible TTR cardiac amyloidosis.
Once the clinical picture sparks the suspicion of this disease, noninvasive tests, including electrocardiography, echocardiography, and cardiac magnetic resonance imaging, can provide considerable necessary diagnostic information. Using observational surveys, such as THAOS, Damy
et al. found that some echocardiography signs are clues for the early recognition of TTR-related cardiomyopathy [
] especially in men who are more than 55 years of age and without severe hypertension. These red flags include a thickened interventricular septum, right ventricle free wall, and valve; these characteristics were partly exhibited by our patient. Absence of the restrictive pattern on echocardiography and low QRS voltages might not rule out the TTR diagnosis [
]. Histological identification, additional immune histochemical staining, and gene analysis can further confirm TTR diagnosis. Owing to the link between phenotypic heterogeneity and TTR mutation type, genetic testing should be performed for prognosis and prevention. According to the literature, many mutations are restricted to a specific geographic area, which implies the existence of founder mutations. The mutation c.349 G>T is a hot-spot mutation in the Chinese [
]. Moreover, the clinical profile of Ala117Ser is characterized by cardiac arrhythmia, congestive heart, and neuropathy, which are also presented by our patient.
Conclusions
The early diagnosis of TTR cardiac amyloidosis remains challenging for atypical presentations even after exhausting diagnostic avenues. Therefore, the concurrence of neurological impairment and unexplained cardiac abnormalities, especially in the cardiac conduction system, facilitates the diagnosis of TTR cardiac amyloidosis.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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