Search

Aims: Transthyretin cardiac amyloidosis (ATTR‐CM) may be an underestimated cause of heart failure among geriatric patients and represent a unique phenotype and prognostic profile. Methods and results: This retrospective, observational, cohort study characterizes cardiac and extracardiac disorders at diagnosis and assesses prognosis among ATTR‐CM patients based on age (geriatric vs. non‐geriatric) and amyloidosis subtype (wild type, ATTRwt and hereditary, ATTRv). In total, 943 patients with ATTR‐CM were included, of which 306 had ATTRv and 637 had ATTRwt. Among these, 331 (35.1%) were non‐geriatric (<75 years), and 612 (64.9%) were geriatric (≥75 years). The population exhibited conduction abnormalities, atrial fibrillation and ischaemic heart disease that progressively deteriorated with age. Among ATTRwt patients, peripheral neuropathy, neurovegetative symptoms, and hearing loss were present across all age groups, but reports of carpal tunnel symptoms or surgery decreased with age. Conversely, among ATTRv patients, reports of extracardiac symptoms increased with age and Val122ILe mutation was highly prevalent among geriatric patients. The 3‐year survival was higher among non‐geriatric ATTR‐CM patients (76%) than geriatric patients (55%) and predictors of 3‐year mortality differed. Notably, predictors identified among geriatric patients were alkaline phosphatase (ALP) (HR = 1.004, 95% CI: [0.001–1.100)], troponin T hs (HR = 1.005, 95% CI: [1.001–1.120)] and tricuspid insufficiency (HR = 1.194, 95% CI: [1.02–1.230)]. Whereas, among non‐geriatric patients, NT‐proBNP (HR = 1.002, 95% CI: [1.02–1.04], global longitudinal strain (HR = 0.95, 95% CI: [0.922–0.989], and glomerular filtration rate (HR = 0.984, 95% CI: [0.968–1.00) were identified. We propose a 3‐stage prognostic staging system combining troponin T hs (≥44 ng/L) and ALP levels (≥119 UI/L). In the geriatric population, this model discriminated survival more precisely than the National Amyloidosis Centre staging, particularly for classifying between stage 1 (82%), stage 2 (50%) and stage 3 (32%) for ATTRv and ATTRwt. Conclusions: These diagnostic and prognostic indicators, along with ATTR subtype, highlight the distinct characteristics of this important, geriatric ATTR‐CM patient group. Recognizing these mortality markers can be valuable for geriatricians to improve the prognostic quality management of geriatric patients with ATTR‐CM. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin (ATTRv) p.Val142Ile (V122I) mutation is the most common inherited cause of cardiac amyloidosis and little is known about the phenotype and outcome of the rare homozygotic genotype. This study aimed to compare phenotypic characteristics and outcomes between heterozygous and homozygous patients with ATTRv V122I amyloidosis. Material and Methods: This monocentric, observational, retrospective study conducted at the French National Referral Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Cr-eteil), described clinical, electrocardiographic, cardiac imaging features and prognostic data for patients with ATTRv V122I amyloidosis. Results: Among 185 ATTRv V122I patients identified, 161 were heterozygous and 24 were homozygous. The homozygous frequency was 13%. Onset occured significantly earlier in the homozygotes compared to heterozygotes with earlier median age at diagnosis (67[63-71] years vs 76[70-79] years, p<.001), age at first cardiac symptom (66[61-71] years vs 74[68-78] years, p<.001) and age at first extracardiac symptom (59[52-70] years vs 69[62-75] years, p=.003). Homozygous ATTRv V122I was also associated with greater disease burden with earlier events (death, transplant or hospitalisation for acute heart failure) compared with heterozygotes (71[67-74] vs 78[76-79] years, p=.018). Conclusion: This rare, homozygous V122I cohort confirmed the earlier age of onset, death and cardiac events in this population. [ABSTRACT FROM AUTHOR]

I ANK1 i is one of the most frequently mutated genes in hereditary spherocytosis (HS) in European countries and encodes the protein Ankyrin-1 which is a major membrane erythrocyte protein linking horizontal protein network to the vertical one. Briefly, total RNA was purified from cultured cells transfected with empty plasmid, minigene containing partial wild-type (WT) or mutated I ANK1 i intron, prior natural I n i + 1 exon and partial I n i + 1 intron. Molecular analysis revealed the presence of an I ANK1 i intronic variation at heterozygous state: NM 020476 ( I ANK1 i ): c.1405-9G>A (intron 13) in patient 1 and c.5097-33G>A (intron 38) in patient 2. [Extracted from the article]

Data regarding renal involvement in patients with hereditary transthyretin (ATTRv) amyloidosis are scarce and the natural course of chronic kidney disease (CKD) in this population remains unclear. This observational study, including adult patients diagnosed with ATTRv amyloidosis at the French Reference Centre for Cardiac Amyloidosis, investigated renal function outcome and its determinants. Multivariable logistic regression models identified factors associated with CKD at baseline. Determinants of the change in estimated glomerular filtration rate (eGFR) over 24 months of follow-up were assessed with a multivariable linear mixed-effects model. In total, 232 patients (78 women [34%], mean age: 64 years) with ATTRv amyloidosis were classified on the basis of their TTR variants: ATTRV122I (37%), ATTRV30M (29%), and other variants (34%). Median baseline eGFR was 78 ml/min/1.73 m2. Seventy-two patients (31%) had an eGFR below 60 ml/min/1.73m2 and 27/137 patients (20%) had significant proteinuria (urine protein/creatinine ratio ≥30 mg/mmol). Renal biopsy, performed in four cases, found typical Congo red-positive and TTR-labelled amyloid deposits in all cases. Older age (OR 1.07, p <.001) and a prior history of hypertension (OR 2.09, p =.04) were associated with a higher prevalence of CKD at baseline, whereas higher left ventricular global longitudinal strain (LVGLS) (OR 0.83, p <.001) was associated with a lower prevalence. The estimated change in eGFR was −7.12 [−9.61, −4.63] and −8.21 [−10.81, −5.60] ml/min/1.73 m2 after 12 and 24 months of follow-up, respectively. eGFR decline was independently associated with older age ((67–74], coefficient= −14.35 mL/min/1.73 m2, p <.01, >74, coefficient = −22.93 mL/min/1.73 m2, p <.001, versus <56), ATTRV122I (coefficient = −17.17 mL/min/1.73m2, p <.01, versus ATTRV30M) and LVGLS (coefficient = 1.22, p <.01). These data suggest that CKD is a common finding in patients with ATTRv amyloidosis, and that eGFR decline is rapid during the first year of evaluation. Older age, lower LVGLS and ATTRV122I were associated with a worse renal outcome. Further studies are now needed to evaluate effects of new targeted therapies on long term renal function. [ABSTRACT FROM AUTHOR]

This study aims to describe the molecular variability in the SFTPC gene in a childhood chronic respiratory disease, asthma, in the Tunisian population and to identify the implications based on a case-control study of p.Thr138Asn (T138N) and p.Ser186Asn (S186N) variants. We used direct sequencing for the genotyping of the SFTPC gene within 101 asthmatic children. The study of T138N and S186N variants in 110 controls is conducted by the PCR-RFLP technique. The molecular study revealed 26 variants including 24 intronic variations and 2 exonic variations (T138N and S186N) with respective frequencies of 16.8% and 18.3%. We conducted a case-control study of the two identified exonic variations. A different genotypic and allelic distribution between the two groups was noted. Only the T138N polymorphism showed a significant association with asthma disease (p < 1 0 −3). Statistical analysis elaborated four haplotypes with the following frequencies in patients vs controls: 138Thr-186Ser (79.5% vs 57.6%), 138Thr-186Asn (3.7% vs 7.8%), 138Asn-186Thr (2.2% vs 20.2%) and 138Asn-186Asn (14.6% vs 14.4%). A significant difference (p < 1 0 −3) was highlighted in haplotype distribution. The 138Asn-186Ser (OR [95%CI] = 0.14[0.04-0.54], p = 0.004, R2=0.93) and 138Thr-186Asn (OR [95%CI] = 0.35[0.12-0.54], p = 0.047, R2=0.88) haplotypes showed a negative association with asthma which may constitute a protective factor against the disease. In Tunisia, this work constitutes the first report interested in the SFTPC gene and highlights the genetic variability of the SFTPC gene in asthma. Therefore, the case-controls analysis may be useful in the study of surfactant proteins dysfunction in chronic respiratory disease at an early age. [ABSTRACT FROM AUTHOR]

Childhood interstitial lung diseases (chILD) are rare and usually severe disorders. Among them, very rare cases of surfactant protein (SP)-B deficiencies have been reported so far and are usually associated with fatal forms of chILD. The RespiRare network allows the collection of precise phenotypic and genotypic information. This study that reports a series of 11 SP-B-deficient patients underscores two key observations: patients with severe loss-of-function variants associated with SP-B complete deficiency presented symptoms at birth and died at a median age of 1 month; and extremely rare cases of hypomorphic variants with partially preserved SP-B function may allow survival., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers., Methods: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers., Results: We identified 99 SRG adult variant carriers ( SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer ( SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1 / SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7)., Conclusions: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated., Competing Interests: Conflict of interest: P. Bonniaud reports grants from AstraZeneca, lecture honoraria from Sanofi and AstraZeneca, travel support from AstraZeneca, Novartis, Sanofi, Boehringer and Stallergenes, and advisory board membership with AstraZeneca, Novartis, Sanofi, GSK and Boehringer. J. Cadranel had a patent planned, received consulting fees and participated on a data safety monitoring board or advisory board for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Daichi, Lilly, Pfizer, Novartis, MSD, Roche and Takeda. A. Cazes reports lecture honoraria and travel support from Boehringer Ingelheim. B. Crestani reports grants from Boehringer Ingelheim, consulting fees from Apellis, BMS, Boehringer Ingelheim and Sanofi, lecture honoraria from Apellis, AstraZeneca, BMS, Boehringer Ingelheim, Novartis and Sanofi, support for attending meetings or travel from AstraZeneca, BMS, Boehringer Ingelheim and Sanofi, participated on a data safety monitoring board or advisory board for Apellis, BMS, Boehringer Ingelheim and Sanofi, and had a leadership role as President of the Board of Trustees of the Fondation du Souffle. R. Epaud reports consulting fees from AstraZeneca, lecture honoraria from GSK, AstraZeneca and Menarini, travel support from GSK and AstraZeneca, and advisory board membership with AstraZeneca and Novartis. M-P. Debray reports lecture honoraria and travel support from Boehringer Ingelheim. E. Manali reports lecture honoraria from Boehringer Ingelheim, CLS Behring and Hoffman-La Roche, support for attending meetings or travel from Boehringer Ingelheim, CLS Behring, Hoffman-La Roche and Elpen, and had a leadership role as a Chair in the ERS Task Force for transition of chILD to adult care. S. Papiris reports lecture honoraria from Boehringer Ingelheim and Hoffmann-La Roche, and travel support from Boehringer Ingelheim and Elpen. N. Nathan reports grants from Legs poix de la Chancellerie des Universités 2022 (number 2022000594). C. Andréjak participated on a data safety monitoring board or advisory board for the EVER-ILD2 study (rituximab in diffuse interstitial pneumonia) and received funding via a grant from the French Research Ministry. S. Jouneau reports grants from AIRB, Boehringer Ingelheim and Roche, lecture honoraria from AIRB, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chiesi, Genzyme, GSK, LVL, Novartis, Pfizer, Roche and Sanofi, travel support from Boehringer Ingelheim, Roche and AIRB, and advisory board participation for Boehringer Ingelheim, GSK and Sanofi. G. Beltramo reports lecture honoraria from Bristol Myers Squibb, and support for attending meetings or travel from Sanofi Aventis France and Boehringer Ingelheim France. S. Hirschi reports research grants from Agence de la Biomedécine, CSL Behring and Adiral medical assistance, lecture honoraria from Boehringer Ingelheim, travel support from CSL Behring, Boehringer Ingelheim and ISIS Medical, and received medical equipment from ISIS Medical. C. Picard reports lecture honoraria and consulting fees from Boehringer Ingelheim. G. Prévot reports honoraria for presentations and educational event from Boehringer Ingelheim, Sanofi, Jansen and MSD. G. Zalcman reports consulting fees from AstraZeneca, BMS, Pfizer and Sanofi, lecture honoraria from BMS, AstraZeneca and Sanofi, support for attending meetings or travel from AstraZeneca and BMS, and participated on a data safety monitoring board or advisory board for AstraZeneca and BMS. V. Cottin reports grants from Boehringer Ingelheim, consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CSL Behring, Ferrer/United Therapeutics, GSK, Pliant, Pure Tech, RedX, Roche, Sanofi and Shionogi, lecture honoraria from Boehringer Ingelheim, Ferrer/United Therapeutics and Roche, support for attending meetings or travel from Boehringer Ingelheim and Roche, participated on a data safety monitoring board or advisory board for Galapagos, Galecto and GSK, and had a leadership role in an adjudication committee for Fibrogen. R. Borie reports consulting fees from Boehringer Ingelheim, Ferrer and Sanofi, lecture honoraria from Boehringer Ingelheim and Roche, travel support from Boehringer Ingelheim, Roche and Chiesi, and advisory board participation for Savara. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)