The hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an autosomal dominant genetic disease characterized by amyloid formation in different tissues due to pathogenic variants in the TTR gene. Great heterogeneity in the penetrance and manifestation of ATTRv amyloidosis is observed. In Bulgaria, the most common TTR pathogenic variant is Glu89Gln. Other TTR pathogenic variants are also found – Val30Met, Ser77Phe, Gly47Glu and Ser52Pro. There is a proven founder effect for the Glu89Gln variant, thus the aim of the present study is to investigate the founder effect for the other TTR pathogenic variants in Bulgaria. Haplotype analysis was performed by using microsatellite markers close to the TTR gene. DNA samples from ATTRv amyloidosis patients and their healthy relatives were analyzed. Theoretical haplotype reconstruction was done with Arlequin v.3.01 software. The age of the most recent common ancestor (hypothetical founder) for the studied variants was calculated with the DMLE 2.2 software. In addition, DBS screening among 100 Roma newborns was done for the Gly47Glu TTR variant via direct Sanger sequencing. The reconstructed haplotypes of the patients were compared to their healthy relatives and to a control group of 40 healthy individuals. The results showed a possible founder effect for each of the studied variants. The Val30Met haplotype was compared to published haplotype data for this variant and no similarity was found. The result from the DBS screening showed no pathogenic TTR variants in exon 2 of the gene, so we considered the presence of the Gly47Glu variant in our population a sporadic event. With this study, we succeeded to gain a more complete picture of the population genetics of ATTRv amyloidosis in Bulgaria and made another step towards a more detailed understanding of the disease epidemiology.

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the extracellular deposition of amyloid fibrils. Materials and Methods: A 65-year-old female patient with suspected clinical diagnosis of ATTR was referred for genetic testing for pathogenic variants in the TTR gene after physical, neurological and cardiac testing. Results: The patient had had cardiac dysfunction, atrial fibrillation and supraventricular tachycardia for around 10 years before the suspected and confirmed cardiac amyloidosis. The molecular genetic testing showed a heterozygous pathogenic variant in exon 3 of the TTR gene NM_000371.4(TTR): c.258A>C, p.(Glu86Asp). This variant in the TTR gene is classified as pathogenic in accordance with ACMG/AMP for the interpretation of variants. Conclusions: The presented case of a very rare pathogenic variant in the TTR gene displays the valuable role of genetic testing on the way to clarifying a diagnosis.

Въведение: Хередитарната гелсолинова амилоидоза (синдром на Meretoja) е рядка системна амилоидоза с автозомно-доминантен тип унаследяване, проявяваща се с офталмологични, неврологични и дерматологични симптоми. Заболяването е описано първоначално във финландската популация, но понастоящем се съобщава и в други региони. Методи: Представяме клиничен случай на 57-годишен мъж с прогресивни неврологични, офталмологични и дерматологични прояви. Извършен бе мултимодален диагностичен подход, включващ неврологичен преглед, електроневрография, офталмологично и дерматологично изследване, образна диагностика и молекулярно-генетичен анализ. Резултати: Пациентът показа клинична изява на двустранна лицева невропатия, сензорна и автономна полиневропатия, решетъчна дегенерация на роговицата, катаракта, синдром на „сухо око“ и кожни промени тип cutis laxa. Допълнително бе установено дългогодишно рецидивиращо депресивно разстройство. Генетичното изследване идентифицира хетерозиготен missense вариант c.487G>A, p.(Asp163Asn) в гелсолиновия ген (GSN ген; NM_198252.3). Същият генетичен вариант беше установен и при неговите деца. Фамилната анамнеза допълнително подкрепи автозомно-доминантния тип на унаследяване. Заключение: Това е първият потвърден случай на гелсолинова амилоидоза в България.Докладът подчертава значението на ранната генетична верификация, мултидисциплинарния подход и внимателното проследяване на засегнатите пациенти. Въпреки липсата на етиологично лечение, правилната диагноза позволява оптимизиране на симптоматичната терапия и подобряване на качеството на живот.