Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity

Johanna Palmio; Panu Kiviranta; Päivi H Hartikainen; Pirjo Isohanni; Mari Auranen; Karoliina Videman; Sini Penttilä; Sara Lehtinen; Jarkko Kirjavainen; Susanna Hintikka; Katriina Paloviita; Janna Saarela; Bjarne Udd

doi:10.1212/NXG.0000000000200155

Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity

Neurol Genet. 2024 May 7;10(3):e200155. doi: 10.1212/NXG.0000000000200155. eCollection 2024 Jun.

Affiliation

¹ From the Neuromuscular Research Center (J.P., S.P., B.U.), Tampere University and University Hospital, Neurology; The Finnish Medical Society Duodecim (P.K.), Helsinki; Department of Pediatrics (P.K.), Kuopio University Hospital, and University of Eastern Finland Kuopio; Neurocenter (P.H.H.), Neurology, Kuopio University Hospital; Department of Child Neurology (P.I.), Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital; Research Programs Unit (P.I.), Stem Cells and Metabolism, University of Helsinki; Clinical Neurosciences (M.A.), Neurology, University of Helsinki and Helsinki University Hospital; Department of Pediatric Neurology (K.V.); Department of Genetics (S.L.), Fimlab Laboratories, Tampere University Hospital; Department of Pediatric Neurology (J.K.), Kuopio University Hospital; Department of Neurology (S.H., K.P.), Central Finland Central Hospital, Jyväskylä; Institute for Molecular Medicine Finland FIMM (J.S.), University Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Folkhälsan Institute of Genetics and the Department of Medical Genetics (B.U.), Haartman Institute, University of Helsinki; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland.

Abstract

Background and objectives: Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS).

Methods: Nine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations.

Results: All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth.

Discussion: The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.