Philippe JEAN-PIERRE

Cardiac diffusion tensor imaging (cDTI) is an emerging technique for microstructural characterization of the heart and has shown clinical potential in a range of cardiomyopathies. However, there is substantial variation reported for in vivo cDTI results across the literature, and sensitivity of cDTI to differences in imaging sites, scanners, acquisition protocols and post-processing methods remains incompletely understood.

SIGNET is a prospective multi-centre, observational study in travelling and non-travelling healthy volunteers. The study was initiated by the executive board of the SCMR Cardiac Diffusion Special Interest Group (SIG) as a follow up to a previous multi-centre study on phantom validation of cardiac DTI and a recently published SCMR consensus statement on cardiac diffusion MRI. The study has been developed by the Project Management Committee in consultation with the SCMR Cardiac Diffusion SIG, which includes international experts in cardiac diffusion MRI. To date, more than 20 international institutions have engaged with the study, including sites that are new to cardiac DTI, making this the largest collaborative effort in the field.

SIGNET will provide important information about the key sources of variation in cardiac DTI. This will help rationalise strategies for addressing and minimising such variation. Harmonisation of protocols in this and future studies will underpin efforts to translate cardiac DTI for clinical application.

Background: Autosomal recessive mutations in the SH3TC2 gene cause Charcot-Marie-Tooth type 4C (CMT4C) demyelinating peripheral neuropathy. Methods: In this nationwide observational retrospective study involving 27 French University Hospitals, we analyzed the clinical, electrophysiological, and genetic features of 103 patients from 89 families with homozygous and compound heterozygous SH3TC2 gene mutations identified between 2003 and 2023. Results: Mean age was 42 years (2-80), and 49% of patients were female. Mean age at disease onset was 14 years (0-52), 60% of patients started the disease before age 10 years, and 24% after age 20 years. Patients presented with distal motor weakness (93% of cases), sensory loss (86%), foot deformities (83%), scoliosis (73%), proximal limb weakness (40%), cranial nerve involvement (48%), hearing loss (37%), scoliosis-related respiratory insufficiency (14%), and genitourinary disorders (6%). Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound. Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases. We identified 56 different pathogenic variants in the SH3TC2 gene, including 22 previously undescribed. Patients with two SH3TC2 gene truncating variants had more severe symptoms than patients with one or zero truncating variants. Interpretation: This study shows CMT4C is a severe childhood-and adult-onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years. Genotypephenotype correlations suggest two truncating SH3TC2 gene variants cause a more severe phenotype.