Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency < 0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency < 0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology

TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS

TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS

Diagnostic algorithm in transthyretin amyloidosis with cardiomyopathy

Транстиретиновата сърдечна амилоидоза е рестриктивна кардиомиопатия (ATTR-КМП), резултат от извънклетъчно натрупване на неразтворими транстиретинови амилоидни фибрили в миокарда, има прогресиращ ход и е възможен летален изход в рамките на 2-6 години от поставяне на диагнозата. Бива два вида – наследствена и див тип. Данни от последните години показват, че дивият тип АТТР-КМП е относително честа причина за сърдечна недостатъчност със запазена фракция на изтласкване, особено при по-възрастни мъже. В същото време в България, наследствената транстиретинова амилоидоза не е толкова рядка. Диагностицирни са пет различни патологични мутации. Най-разпространена е р.Glu89Gln, като по данни от юни 2019 г има установени 62 несвързани семейства с 117 пациенти и 72 носители. Диагнозата АТТР-КМП често се поставя със закъснение или се пропуска, а нейното ранно диагностициране е изключително важно, тъй като има одобрен медикамент (стабилизатор на транстиретина), който е по-ефикасен приложен в начален стадий на заболяването. Други медикаменти са в клинични изпитания. Диагностицирането на АТТР-КМП е процес, който изисква мултидисциплинарен подход с участието на подготвени специалисти, мултимодална образна диагностика, добре оборудвани хистопатологична и генетична лаборатории. Изграждането на експертни центрове на функционален принцип би могло да допринесе за по-ранното откриване, своевременното лечение и проследяването на пациентите с АТТР-КМП, което съответно да подобри тяхната прогноза. Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy ((ATTR-CM), caused by an extracellular deposition of insoluble amyloid fibrils in the myocardium. It is a life threatening disease with life expectancy of 2 to 6 years after diagnosis. There are two types – hereditary and wild type. Recent data reveal that the wild type ATTR-CM is a common cause of heart failure with preserved ejection fraction, especially in elderly men. Hereditary ATTR amyloidosis is not so rare in Bulgaria. Five different mutations have been diagnosed, the most common being p.Glu89Gln, identified in 62 unrelated families with 117 patients and 72 mutation carriers. ATTR-CM diagnosis is often delayed or even missed, however its early recognition has become very important as a new drug, which is a transthyretin stabilizer is now available and other drugs are under development. Updated knowledge about the clinical presentation, diagnostic algorithm, available and future therapeutic options for ATTR-CM are a prerequisite for an early identification, timely treatment and better prognosis of the affected patients. The diagnosis requires a multidisciplinary approach with the participation of experienced specialists, multimodality imaging, well equipped histopathological and genetic laboratories. Establishing centres of expertise could improve the management of the patients with ATTR-CM

Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations*

Diagnosis in the early stages of hereditary transthyretin (ATTR) amyloidosis is imperative to support timely treatment to prevent or delay disease progression. Genetic testing in the setting of genetic counselling enables identification of carriers of a TTR gene mutation who are therefore at risk of developing TTR-associated disease. Knowledge of different genotypes and how they manifest in symptomatic disease should facilitate development of a structured and targeted approach to enable diagnosis of symptomatic disease in ATTR amyloidosis mutation carriers on the first manifestation of the earliest detectable sign or symptom. A group of experts from across Europe, Israel and Japan met to reach a consensus on such an approach. The proposed approach involves establishing a baseline for key clinical parameters, determination of the timing and frequency of follow-up in TTR mutation carriers based on a predicted age of disease onset, and recognition of the likely initial clinical signs and symptoms aligned with the phenotype of the specific TTR gene mutation and family history. Minimum criteria for diagnosis of symptomatic disease have been agreed, which it is hoped will ensure diagnosis of ATTR amyloidosis at the earliest possible stage in people with a known TTR mutation