CNS and Muscle Involvement Are Unrelated in Myotonic Dystrophy Type 1 Implying Different Molecular Mechanisms (PD3.008)

OBJECTIVE: To determine CNS and skeletal muscle involvement in 25 DM1 patients and study their correlation. BACKGROUND: Myotonic Dystrophy is a [CTG]n expansion-related disease due to sequestration in foci of RNA-binding proteins such as the MBNL family. Muscle impairment and MRI changes with related CNS symptoms (daily sleepiness, behavioural abnormalities) were not studied in the same DM1 patients series. DESIGN/METHODS: We studied 25 molecularly-defined DM1 patients (14 males, 11 females; age range: 15-67 years; onset range: 0-66 years), subgrouped as: CTG 0-500; CTG 500-1000; CTG 1000-2000. We investigated in our DM1 cases biopsied muscle by morphometric analysis on serial sections stained with ATPases and brain-MRI. We focused on White Matter (WM) lesions that were graded on T2/FLAIR images, according to the Age Related White Matter Change Score. We adopted a new parameter, the TOTAL WM LESION LOAD, obtained from the average scores calculated in both hemispheres, divided in 4 increasing classes. Furthermore, CNS abnormalities: cranial hyperostosis, overdevelopment of the sinuses, ventriculomegaly were collected. RESULTS: Muscle morphometry showed increased atrophy factor (AF) for both fibre types. The AF of type 1 fibres was higher than control in 50% of DM1 patients especially with large [CTG]n expansions. Few patients had normal MRI imaging: basal ganglia were affected in two cases. T2/FLAIR showed supratentorial, bilateral, symmetrical focal or diffuse WM abnormalities in 20/25 patients (80%). Diffuse symmetrical WM changes were present in insular regions in 15 patients and 12 had peculiar subcortical symmetrical diffuse involvement of polar-temporal regions. Spearman Rho test showed no correlation between classes of muscle fiber atrophy factor and classes of the WM lesion in brain. CONCLUSIONS: Skeletal muscle and brain appear independently involved in DM1. Skeletal muscle changes might be due to toxic RNA expansion that sequestrates MBNL1 protein, while CNS lesions might be due to sequestration of MBNL2 protein in neuron RNA foci. Supported by: AFM (Association Francaise contre les Myopathies) and CARIPARO. Disclosure: Dr. Ferrati has nothing to disclose. Dr. Manara has nothing to disclose. Dr. Citton has nothing to disclose. Dr. Peterle has nothing to disclose. Dr. Cudia has nothing to disclose. Dr. Tasca has nothing to disclose. Dr. Pegoraro has received personal compensation for activiteis with BioMarin Pharmaceutical Inc. and MEDA Pharmaceuticals Inc. Dr. Angelini has received personal compensation for activities with Genzyme as a member of the Advisory Board.