High Prevalence of Transthyretin-Related Amyloidosis in Crete, Greece is Due to Three TTR Pathogenic Variants with Markedly Differing Phenotypic Presentations

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Objective: To describe occurrence and clinical features of hereditary Transthyretin-Related Amyloidosis (hATTR) in Crete, Greece.

Background: Over the past 27 years, we have diagnosed several hATTR patients presenting with heterogeneous clinical manifestations.

Design/Methods: Since 1993, we evaluated 33 subjects, members of 12 unrelated families, for various reasons including polyneuropathy, cardiac involvement, visual symptoms and family history suggestive of hATTR. All patients underwent genetic testing and were positive for a pathogenic TTR variant.

Results: Nineteen subjects (12 women) with the predominantly polyneuropathic phenotype were heterozygous for the p.Val50Met TTR mutation. The median age of symptom onset was 31 years (range 25 to 43 years). Common presenting manifestations were paresthesias, temperature sensory loss and weakness of the lower extremities, urinary difficulties, postural dizziness, diarrhea, and weight loss. Heart failure developed in 4 patients late in the disease course. Fourteen patients underwent orthotopic liver transplantation. Ten patients (4 females) with the predominantly cardiopathic phenotype harbored the p.Val114Ala TTR mutation. Their median age at onset was 69.8 years (range 54–78 years). These patients presented with congestive heart failure due to restrictive cardiomyopathy and showed cardiac amyloid deposition on 99mTc scintigraphy or biopsy. All patients had peripheral neuropathy, autonomic system involvement and carpal tunnel syndrome. By screening their offspring, 3 asymptomatic carriers of the p.Val114Ala TTR mutation were found. Finally, one 50-year old male with predominantly ocular involvement and positive family history of progressive visual loss harbored the p.Arg54Gly TTR change. Based on patients surviving in Crete in January 2019, we estimated the prevalence of hATTR on the island to be 35.3 per 1 million.

Conclusions: Hereditary amyloidosis is common in Crete, Greece, placing the region among those with the highest hATTR frequency world-wide. The disease is caused by three different TTR pathogenic variants with markedly differing ages of onset and phenotypic expressions.





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