Fabry disease phenotyping in women from the complete Romanian cohort - time for early diagnostic awareness.

Fabry disease (FD) is an X-linked rare disorder caused by mutations in the GLA gene. Women with FD have been less enrolled in studies and less treated compared with men. The aim of the present study is to describe the complete phenotype of the women cohort with FD diagnosed and evaluated in Romania and compare it to the male population. This study included all consecutive patients diagnosed with FD referred to the Expert Center for Rare Genetic Cardiovascular Diseases between 2014-2023 which included 73 consecutive Romanian FD patients: 41 women (56.2%) and 32 men (43.8%) from 33 unrelated families. Women with FD were diagnosed later and had a later symptom onset. Comparing with men, women were less often symptomatic, but with similar symptom severity. They had similar ophthalmologic and ENT involvement, but less angiokeratomas. Both women and men had similar heart failure symptoms, which were usually mild to moderate, with no difference between the age of developing of the heart failure symptoms. There were also similar rates of acroparesthesia and stroke between sexes, but women presented less renal involvement, with less requirement for renal transplant. This study demonstrates that women with Fabry disease are not just carriers of the disease, they can present symptoms as severe as men, and they have less or later access to pathogenic therapy. Further studies with more female participations are needed to better understand the burden of Fabry disease in women.

Novel FHL1 mutation variant identified in a patient with nonobstructive hypertrophic cardiomyopathy and myopathy - a case report.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disorder mostly caused by sarcomeric gene mutations, but almost 10% of cases are attributed to inherited metabolic and neuromuscular disorders. First described in 2008 in an American-Italian family with scapuloperoneal myopathy, FHL1 gene encodes four-and-a-half LIM domains 1 proteins which are involved in sarcomere formation, assembly and biomechanical stress sensing both in cardiac and skeletal muscle, and its mutations are responsible for a large spectrum of neuromuscular disorders (mostly myopathies) and cardiac disease, represented by HCM, either isolated, or in conjunction with neurologic and skeletal muscle impairment. We thereby report a novel mutation variant in FHL1 structure, associated with HCM and type 6 Emery-Dreifuss muscular dystrophy (EDMD). CASE PRESENTATION: We describe the case of a 40 year old male patient, who was referred to our department for evaluation in the setting of NYHA II heart failure symptoms and was found to have HCM. The elevated muscular enzymes raised the suspicion of a neuromuscular disease. Rigid low spine and wasting of deltoidus, supraspinatus, infraspinatus and calf muscles were described by the neurological examination. Electromyography and muscle biopsy found evidence of chronic myopathy. Diagnosis work-up was completed by next-generation sequencing genetic testing which found a likely pathogenic mutation in the FHL1 gene (c.157-1G > A, hemizygous) involved in the development of X-linked EDMD type 6. CONCLUSION: This case report highlights the importance of multimodality diagnostic approach in a patient with a neuromuscular disorder and associated hypertrophic cardiomyopathy by identifying a novel mutation variant in FHL1 gene. Raising awareness of non-sarcomeric gene mutations which can lead to HCM is fundamental, because of diagnostic and clinical risk stratification challenges.

Romanian Registry of Hypertrophic Cardiomyopathy - overview of general characteristics and therapeutic choices at a national level.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a disease with increased left ventricular (LV) wall thickness not solely explained by abnormal loading conditions, with great heterogeneity regarding clinical expression and prognosis. The aim of the present study was to collect data on HCM patients from different centres across the country, in order to assess the general characteristics and therapeutic choices in this population. METHODS: Between December 2014 and April 2017, 210 patients from 11 Romanian Cardiology centres were enrolled in the National Registry of HCM. All patients had to fulfil the diagnosis criteria for HCM according to the European Society of Cardiology guidelines. Clinical, electrocardiographic, imaging and therapeutic characteristics were included in a predesigned online file. RESULTS: Median age at enrolment was 55 ± 15 years with male predominance (60%). 43.6% of the patients had obstructive HCM, 50% non-obstructive HCM, while 6.4% had an apical pattern. Maximal wall thickness was 20.3 ± 4.8 mm (limits 15-37 mm) while LV ejection fraction was 60 ± 8%. Heart failure symptoms dominated the clinical picture, mainly NYHA functional class II (51.4%). Most frequent arrhythmias were atrial fibrillation (28.1%) and non-sustained ventricular tachycardia (19.9%). Mean sudden cardiac death risk score (SCD-RS) was 3.0 ± 2.3%, with 10.4% of the patients with high risk of SCD. However, only 5.7% received an ICD. Patients were mainly treated with beta-blockers (72.9%), diuretics (28.1%) and oral anticoagulants (28.6%). Invasive treatment of LVOT obstruction was performed in a small number of patients: 22 received myomectomy and 13 septal ablation. Cardiac magnetic resonance was reported in only 14 patients (6.6%). CONCLUSIONS: The Romanian registry of HCM illustrates patient characteristics at a national level as well as the gaps in management which need improvement - accessibility to high-end diagnostic tests and invasive methods of treatment.

Fabry disease--a primer for cardiologists.

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. It is a systemic disease mostly affecting the kidneys, the heart and the brain. Cardiac involvement often presents as concentric nonobstructive left ventricular hypertrophy and is a differential to be taken into account by cardiologists. This review describes the most important systemic features, but mostly highlights the cardiac involvement. Patients with known Fabry disease should be screened early for cardiac involvement, as treatment benefit may not be seen once cardiac fibrosis has developed. Screening for Fabry can be effective among individuals with end-stage renal disease, unexplained cardiac hypertrophy or strokes in young people with no apparent predisposing factors. Enzyme replacement therapy reverses metabolic and various pathologic abnormalities and should be initiated in all patients with symptomatic Fabry disease.