Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

Angela J Lee; Karra A Jones; Russell J Butterfield; Mary O Cox; Chamindra G Konersman; Carla Grosmann; Jose E Abdenur; Monica Boyer; Brent Beson; Ching Wang; James J Dowling; Melissa A Gibbons; Alison Ballard; Joanne S Janas; Robert T Leshner; Sandra Donkervoort; Carsten G Bönnemann; Denise M Malicki; Robert B Weiss; Steven A Moore; Katherine D Mathews

doi:10.1212/NXG.0000000000000315

Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

Neurol Genet. 2019 Mar 1;5(2):e315. doi: 10.1212/NXG.0000000000000315. eCollection 2019 Apr.

Authors

Angela J Lee¹, Karra A Jones¹, Russell J Butterfield¹, Mary O Cox¹, Chamindra G Konersman¹, Carla Grosmann¹, Jose E Abdenur¹, Monica Boyer¹, Brent Beson¹, Ching Wang¹, James J Dowling¹, Melissa A Gibbons¹, Alison Ballard¹, Joanne S Janas¹, Robert T Leshner¹, Sandra Donkervoort¹, Carsten G Bönnemann¹, Denise M Malicki¹, Robert B Weiss¹, Steven A Moore¹, Katherine D Mathews¹

Affiliation

¹ University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa.

Abstract

Objective: To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation.

Methods: Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.

Results: We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy.

Conclusions: The clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200-1,500 years).

Abstract

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