Hundreds of pathogenic variants are known to affect the transthyretin gene (TTR), resulting in a variety of phenotypes. The p.Ser43Asn variant is an extremely rare one, with only a few cases being reported in the literature. It is responsible for cardiac manifestations in patients with hereditary transthyretin amyloidosis (hATTR), and may be of particular concern in people of Italian descent.
The variant was first described in a 44-year-old male of Portuguese origin in 1999. The patient was diagnosed with atrioventricular conduction disorder and had a pacemaker implanted. However, his condition deteriorated after the initial diagnosis and he eventually needed a left ventricular assist device and ultimately a heart transplantation.
In 2010, a 46-year-old female of German-Italian origin was identified with the same variant. She presented with restrictive cardiomyopathy with severe heart failure. She had no evidence of polyneuropathy or involvement of other organs. The patient was unaware of a family history of amyloidosis or cardiac disease, but the medical history of her Italian father and his ancestors could not be traced. She died of sepsis-related complications.
The case of a 41-year-old male from Peru was reported in the same year. He presented with angina and dyspnea. His mother and 2 brothers experienced sudden cardiac death due to presumed hypertrophic cardiomyopathy. The patient was diagnosed with amyloidosis limited to the heart and underwent an implantable defibrillator placement. He was also referred for liver and heart transplantation.
Another 41-year-old male, from Ecuador and of Italian–Spanish origin, was the first patient to exhibit both cardiac and neurological symptoms associated with the p.Ser43Asn variant. Family history revealed that 29 family members had died of cardiac-related causes, 24 of them before the age of 55 years. The patient underwent heart and liver transplant. His liver was used for a domino liver transplantation in a 77-year-old patient who developed cardiac amyloidosis 1 year after surgery.
In addition, the p.Ser43Asn was identified in 1 participant (out of 1286) of the Transthyretin Amyloidosis Outcome Survey (THAOS) registry from continental Western Europe and 2 unrelated patients from an Italian multicenter study that included 186 patients with hATTR.
Recently, Papathanasiou et al reported the case of 2 siblings, a 45-year-old female and a 44-year-old male of Italian origin, who suffered from p.Ser43Asn mutation-associated hATTR. Their mother died at the age of 55 years from cardiac ATTR amyloidosis with progressive heart failure.
“Considering all available information and that from our own experience, we suggest that this very rare variant may be of significance in individuals of Italian [descent], while its prevalence in other parts of the word may be still unrecognized,” the study team concluded.
Two Cases of Early Diagnosis
In contrast to the previous cases described in the literature, the siblings reported by Papathanasiou and colleagues were diagnosed early in the disease course.
The female patient, who was asymptomatic at presentation, was referred to consultation after testing heterozygous for the p.Ser43Asn variant. Detailed examination revealed systolic murmur, marked left ventricular hypertrophy (LVH), grade II diastolic dysfunction, and mitral and aortic valve leaflets with abnormal thickness, resulting in regurgitation. N-terminal pro B-type natriuretic peptide (NT-proBNP) was 438 pg/mL.
[99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]-DPD) scintigraphy including thoracic single-photon emission computed tomography/low-dose computed tomography (SPECT/CT) confirmed the diagnosis of cardiac amyloidosis (Perugini grade 3) and the patient was put on tafamidis (Vyndamax™, 61 mg daily).
Read about hATTR treatment
One of her brothers tested heterozygous for the same variant. He was also asymptomatic at presentation and showed no signs of abnormalities at physical examination. Echocardiography showed LVH and grade II diastolic dysfunction with trace mitral valve regurgitation, while electrocardiogram revealed low QRS voltage. NT-proBNP was 677 pg/ml.
[99mTc]-DPD scintigraphy including thoracic SPECT/CT was consistent with cardiac amyloidosis and suggested subclinical extracardiac amyloid infiltration. He initiated tafamidis due to the extensive subclinical disease.
Both patients remained asymptomatic for 10 months after diagnosis.
Diagnostic and Treatment Considerations
The literature reporting hATTR associated with the p.Ser43Asn variant is scarce but it allows for important considerations regarding its diagnosis. Most patients exhibit an isolated cardiac phenotype and can show signs of cardiac amyloid infiltration in their early 40s.
“Based on these findings and despite the limited population studied, genetic counseling of first-degree relatives of affected individuals and close follow-up of variant carriers should be considered on time, for example, at their early thirties to prevent delayed recognition of the disease,” recommended Papathanasiou et al.
Until the recent report by Papathanasiou et al, the p.Ser43Asn variant was associated with an aggressive clinical course that required heart transplantation. Whether these patients benefit from antiarrhythmic therapies is still unknown. Also, transthyretin stabilizers, which are currently approved in many countries for the treatment of ATTR cardiomyopathy, might be a promising therapeutic option for these patients if initiated early. Additional therapeutic strategies, such as RNA interference, are currently being evaluated.
The assessment of treatment response is another challenge. To this end, a research team from Greece has developed a novel quantification method for assessing radiotracer cardiac uptake in patients with wild-type ATTR treated with tafamidis. According to the authors of the publication in the Hellenic Journal of Nuclear Medicine, “Sequential [heart-to-thigh] ratio measurements could potentially identify patients with a favorable response to tafamidis treatment at earlier stages, compared to other imaging modalities or serological biomarkers.”
Papathanasiou M, Carpinteiro A, Kersting D, et al. Rare variant (p.Ser43Asn) of familial transthyretin amyloidosis associated with isolated cardiac phenotype: a case series with literature review. Mol Genet Genomic Med. 2021;9(12):e1581. doi:10.1002/mgg3.1581
Doumas A, Zegkos T, Parcharidou D, et al. A novel quantitative method for assessing the therapeutic response to tafamidis therapy in patients with cardiac TTR amyloidosis. A preliminary report. Hell J Nucl Med. Published online August 3, 2022. doi:10.1967/s002449912483