Abstract Details

Title Investigation of 11 Patients with GFPT1-Myasthenia Reveals Clinical, Structural, and Electrophysiologic Heterogeneity

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) S45 - (-)

Poster/Presentation
Number 001

Objective

Background GFPT1 is the rate limiting enzyme for N-acetylglucosamine synthesis, an essential substrate for protein glycosylation. GFPT1-CMS was identified in 2011 by Senderek and coworkers in multiplex kinships with limb-girdle myasthenia, tubular aggregates and decreased expression of GFPT1 in muscle. Reduced AChR per endplate was documented in one case.

Design/Methods We searched for GFPT1 mutations in 11 CMS patients with limb-girdle and other phenotypes. Mutation detection in 4 was facilitated by exome sequencing. Histochemical studies were done in 9, quantitative EM analysis in 6, and microelectrode studies of endplates in 5.

Results All patients had a decremental EMG. Ten had childhood onset, slowly progressive limb-girdle weakness responsive to pyridostigmine. One (Patient 6) did not move in utero, was apneic and arthrogrypotic at birth; at age 6 years she is bedfast, fed by gastrostomy, and responds poorly to cholinergic therapy. Each patient carries two heteroallelic GFPT1 mutations of which 12 are novel. Patient 6 harbors a nonsense mutation and a splice-site mutation causing frameshift at the muscle-specific GFPT1 exon. Tubular aggregates were seen in type 2 fibers in 6 patients and rimmed vacuoles in 3. Quantitative EM studies reveal small nerve terminals and short, simplified postsynaptic membranes. In Patient 6, numerous fibers harbor dilated and degenerate vesicular profiles, autophagic vacuoles, and bizarre apoptotic nuclei. Two of 5 patients have mild endplate AChR deficiency. The synaptic response to ACh is reduced in 3 and especially in Patient 6, and quantal release is severely compromised in Patient 6.

Conclusions GFPT1 myasthenia is a progressive disease. Different parameters of neuromuscular transmission are variably affected. The endplates are poorly differentiated. Loss of the muscle-specific GFPT1 isoform abrogates muscle fiber integrity, impairs the release and response to ACh quanta, and is clinically devastating.

Authors/Disclosures
Duygu Selcen, MD, FAAN (Mayo Clinic) PRESENTER	Dr. Selcen has nothing to disclose.
Xin Ming Shen, PhD, FAAN (Mayo Clinic)	The institution of Dr. Shen has received research support from NIH. The institution of Dr. Shen has received research support from Myasthenia Gravis Foundation of American.
Margherita Milone, MD, FAAN (Mayo Clinic)	Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.
Joan M. Brengman (Mayo Clinic)	No disclosure on file
Kinji Ohno, MD, PhD (Mayo Clinic Neurology Research)	No disclosure on file
Michael P. McQuillen, MD, MA, FAAN	No disclosure on file
Feza Deymeer, MD (Memorial Sisli Hospital)	No disclosure on file
Richard S. Finkel, MD, FAAN (St. Jude Children's Research Hospital)	Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AveXis. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catabasis. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Capricor. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ReveraGen. Dr. Finkel has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Finkel has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Finkel has received research support from AveXis. The institution of Dr. Finkel has received research support from Biogen. The institution of Dr. Finkel has received research support from Capricor. The institution of Dr. Finkel has received research support from Catabasis. The institution of Dr. Finkel has received research support from ReveraGen. The institution of Dr. Finkel has received research support from Roche. The institution of Dr. Finkel has received research support from Scholar Rock. Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. An immediate family member of Dr. Finkel has received intellectual property interests from a discovery or technology relating to health care. Dr. Finkel has received personal compensation in the range of $0-$499 for serving as a Speaker in workshop with National Academy of Sciences. Dr. Finkel has a non-compensated relationship as a advisor with n-Lorem Foundation that is relevant to AAN interests or activities. Dr. Finkel has a non-compensated relationship as a Board Member with EveryLife Foundation that is relevant to AAN interests or activities.
Julie Rowin, MD, FAAN (Verde Valley Naturopathic Medicine)	No disclosure on file
Andrew G. Engel, MD, FAAN (Mayo Clinic Rochester)	The institution of Dr. Engel has received research support from NIH.
Bernard M. Uitdehaag, MD, PhD, FAAN (Amsterdam University Medical Centers)	Dr. Uitdehaag has nothing to disclose.

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