Long-term effectiveness of eliglustat treatment: A real-world analysis from the International Collaborative Gaucher Group Gaucher Registry.

Gaucher disease type 1 (GD1) is known for phenotypic heterogeneity and varied natural history. Registrational clinical trials enrolled narrowly defined phenotypes, but greater diversity is encountered in clinical practice. We report real-world outcomes with long-term eliglustat treatment in adults with GD1 in the International Collaborative Gaucher Group Gaucher Registry. Among 5985 GD1 patients in the Registry as of January 6, 2023, 872 started eliglustat at ≥18 years old; of these, 469 met inclusion criteria. We compared clinical parameters at eliglustat initiation (i.e., baseline) and follow-up in treatment-naïve patients and used linear mixed models to estimate annual change from baseline in parameters among patients who switched to eliglustat after ≥1 year on enzyme replacement therapy. Over 4 years of follow-up in non-splenectomized treatment-naïve patients, hemoglobin and platelet count increased, liver and spleen volume decreased, and total lumbar spine bone mineral density (BMD) Z-score decreased slightly. Among non-splenectomized switch patients, on average, hemoglobin decreased -0.030 (95% CI: -0.053, -0.008) g/dL (N = 272) and platelet count increased 2.229 (95% CI: 0.751, 3.706) × 103/mm3 (N = 262) annually up to 10 years; liver volume decreased (-0.009 [95% CI: -0.015, -0.003] MN) (N = 102) and spleen volume remained stable (-0.070 [95% CI: -0.150, 0.010] MN) (N = 106) annually up to 7 years; and total lumbar spine BMD Z-score increased 0.041 (95% CI: 0.015, 0.066) (N = 183) annually up to 8 years. Among splenectomized switch patients, clinical parameters were stable over time. These long-term, real-world outcomes are consistent with the eliglustat clinical trials and emerging real-world experience across the GD phenotypic spectrum.

The Definition of Sarcomeric and Non-Sarcomeric Gene Mutations in Hypertrophic Cardiomyopathy Patients: A Multicenter Diagnostic Study Across Türkiye.

BACKGROUND: Hypertrophic cardiomyopathy is a common genetic heart disease and up to 40%-60% of patients have mutations in cardiac sarcomere protein genes. This genetic diagnosis study aimed to detect pathogenic or likely pathogenic sarcomeric and non-sarcomeric gene mutations and to confirm a final molecular diagnosis in patients diagnosed with hypertrophic cardiomyopathy. METHODS: A total of 392 patients with hypertrophic cardiomyopathy were included in this nationwide multicenter study conducted at 23 centers across Türkiye. All samples were analyzed with a 17-gene hypertrophic cardiomyopathy panel using next-generation sequencing technology. The gene panel includes ACTC1, DES, FLNC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, PTPN11, TNNC1, TNNI3, TNNT2, TPM1, and TTR genes. RESULTS: The next-generation sequencing panel identified positive genetic variants (variants of unknown significance, likely pathogenic or pathogenic) in 12 genes for 121 of 392 samples, including sarcomeric gene mutations in 30.4% (119/392) of samples tested, galactosidase alpha variants in 0.5% (2/392) of samples and TTR variant in 0.025% (1/392). The likely pathogenic or pathogenic variants identified in 69 (57.0%) of 121 positive samples yielded a confirmed molecular diagnosis. The diagnostic yield was 17.1% (15.8% for hypertrophic cardiomyopathy variants) for hypertrophic cardiomyopathy and hypertrophic cardiomyopathy phenocopies and 0.5% for Fabry disease. CONCLUSIONS: Our study showed that the distribution of genetic mutations, the prevalence of Fabry disease, and TTR amyloidosis in the Turkish population diagnosed with hypertrophic cardiomyopathy were similar to the other populations, but the percentage of sarcomeric gene mutations was slightly lower.

The Frequency of Fabry Disease in Patients with Cardiac Hypertrophy of Various Phenotypes Including Prominent Papillary Muscle: The TUCARFAB Study in Turkey.

BACKGROUND: The present study aimed to identify the frequency of Fabry disease in patients with cardiac hypertrophy of unknown etiology and to evaluate demographic and clinical characteristics, enzyme activity levels, and genetic mutations at the time of diagnosis. METHODS: This national, multicenter, cross-sectional, single-arm, observational registry study was conducted in adult patients with a clinical echocardiographic diagnosis of left ventricular hypertrophy and/or the presence of prominent papillary muscle. In both genders, genetic analysis was performed by DNA Sanger sequence analysis. RESULTS: A total of 406 patients with left ventricular hypertrophy of unknown origin were included. Of the patients, 19.5% had decreased enzyme activity (≤2.5 nmol/mL/h). Although genetic analysis revealed GLA (galactosidase alpha) gene mutation in only 2  patients (0.5%), these patients were considered to have probable but not 'definite Fabry disease' due to normal lyso Gb3 levels and gene mutations categorized as variants of unknown significance. CONCLUSION: The prevalence of Fabry disease varies according to the characteristics of the population screened and the definition of the disease used in these trials. From cardiology perspective, left ventricular hypertrophy is the major reason to consider screening for Fabry disease. Enzyme testing, genetic analysis, substrate analysis, histopathological examination, and family screening should be performed, when necessary, for a definite diagnosis of Fabry disease. The results of this study underline the importance of the comprehensive use of these diagnostic tools to reach a definite diagnosis. The diagnosis and management of Fabry disease should not be based solely on the results of the screening tests.