Abstract Details

Title CNS and Muscle Involvement Are Unrelated in Myotonic Dystrophy Type 1 Implying Different Molecular Mechanisms

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) (-)

Poster/Presentation
Number 008

Objective

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.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Elena Pegoraro, MD, PhD (University of Padova)	No disclosure on file
Corrado Angelini, MD, FAAN (Università Di Padova)	Dr. Angelini has nothing to disclose.
Antonio M. Omuro, MD, FAAN (Stanford University)	Dr. Omuro has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Therapeutics. Dr. Omuro has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Telix. Dr. Omuro has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Curevac. The institution of Dr. Omuro has received research support from NIH. The institution of Dr. Omuro has received research support from Arcus Biosciences. The institution of Dr. Omuro has received research support from Denovo Biopharma. The institution of Dr. Omuro has received research support from Ono Pharmaceutical. The institution of Dr. Omuro has received research support from Servier. The institution of Dr. Omuro has received research support from Nanopharmaceuticals. The institution of Dr. Omuro has received research support from Denovo.

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