Background Mutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophy, and recently, mutations in POMT2 have also been linked to a milder limb-girdle muscular dystrophy (LGMD) phenotype, named LGMD type 2N (LGMD2N). Only four cases have been reported so far.
ClinicalTrials.gov ID: NCT02759302
Methods We report 12 new cases of LGMD2N, aged 18–63 years. Muscle involvement was assessed by MRI, muscle strength testing and muscle biopsy analysis. Other clinical features were also recorded.
Results Presenting symptoms were difficulties in walking, pain during exercise, delayed motor milestones and learning disabilities at school. All had some degree of cognitive impairment. Brain MRIs were abnormal in 3 of 10 patients, showing ventricular enlargement in one, periventricular hyperintensities in another and frontal atrophy of the left hemisphere in a third patient. Most affected muscle groups were hip and knee flexors and extensors on strength testing. On MRI, most affected muscles were hamstrings followed by paraspinal and gluteal muscles. The 12 patients in our cohort carried 11 alleles with known mutations, whereas 11 novel mutations accounted for the remaining 13 alleles.
Conclusion We describe the first cohort of patients with LGMD2N and show that unlike other LGMD types, all patients had cognitive impairment. Primary muscle involvement was found in hamstring, paraspinal and gluteal muscles on MRI, which correlated well with reduced muscle strength in hip and knee flexors and extensors. The study expands the mutational spectrum for LGMD2N, with the description of 11 novel POMT2 mutations in the association with LGMD2N.
Clinical trial registration NCT02759302.
Statistics from Altmetric.com
Contributors STØ: design of study, analysis, acquisition and interpretation of data, and drafting the manuscript. KJ, TS, PDeJ, JB, KGC, RF-T, LP, AT, JC, WDeR, SN, SJ-O, CB-S, FL, DGMacA, ML, LX, IN and VS: acquisition of data and revision of manuscript. TK: acquisition and interpretation of data, and revision of manuscript. JV: design of study, acquisition and interpretation of data, and revision of manuscript.
Funding MYO-SEQ is funded by Sanofi Genzyme, Ultragenyx Pharmaceutical, the LGMD2I Research Fund, the Kurt + Peter Foundation, the LGMD2D Foundation and the Samantha J Brazzo Foundation. Also the Myocapture project, France Génomique National infrastructure, was funded as part of the ‘Investissements d’Avenir’ for performing the whole exome sequencing of our French patients. The study was also supported by the Medical Research Council UK (reference G1002274, grant ID 98482). This work was supported by the Association Belge contre les Maladies Neuromusculaire (ABMM) – Aide à la Recherche ASBL and the EUFP7/2007-2013 under grant agreement number 2012-305121 (NEUROMICS). JB is supported by a Senior Clinical Researcher mandate of the Research Fund – Flanders (FWO).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Danish National Committee on Health Research Ethics (H-3-2012-163 withamendment #41665, #43449 and #50556) and the local Ethical Review Boards of the participating centers.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.