Neuropediatrics 2017; 48(06): 442-450
DOI: 10.1055/s-0037-1607054
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Molecular Analysis Confirms that FKRP-Related Disorders are Underdiagnosed in Mexican Patients with Neuromuscular Diseases

María José Navarro-Cobos*
Maestría en Ciencias Biológicas (Biomedicina)-Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México. Ciudad de México, México
,
Ariadna González-del Angel*
Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México
,
Bernardette Estandia-Ortega
Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México
,
Adriana Ruiz-Herrera
Servicio de Genética Médica, Hospital de Especialidades Pediátrico de León, Guanajuato, México
,
Arturo Becerra
Facultad de Ciencias, Universidad Nacional Autónoma de México, Ciudad de México, México
,
Guadalupe Vargas-Ramírez
Servicio de Neurología Pediátrica, Hospital de Especialidades Pediátrico de León, Guanajuato, México
,
Cesárea Bermúdez-López
Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México
,
Miguel Angel Alcántara-Ortigoza
Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Ciudad de México, México
› Author Affiliations
Further Information

Publication History

23 June 2017

21 August 2017

Publication Date:
24 October 2017 (eFirst)

Abstract

The FKRP-related disorders include the limb-girdle muscular dystrophy type 2I (LGMD2I, MIM#607155) which has a clinical overlap with dystrophinopathies. Except for Brazil, LGMD2I has not been described in other Latin-American countries, despite that 1/64 Mexican-ancestry individuals carry the commonest European p.(Leu276Ile) pathogenic FKRP variant (rs28937900, 1000 Genomes Project Phase 3), suggesting an underdiagnosis. Sequencing of exon 4 of FKRP in 60 unrelated Mexican patients with presumptive diagnoses of dystrophinopathy without DMD gene deletions, or with a neuromuscular disorder of unknown etiology, revealed two patients (2/60, 3.3%): one of them with an unreported pathogenic genotype, p.[Leu276Ile];[Asn463Asp] and a Duchenne-like phenotype; and the other that stands as the third reported case bearing the severe genotype, p.[Asn463Asp];[Asn463Asp] leading to a congenital presentation (MIM#606612). We identified two patients heterozygous for the p.(Arg143Ser) and the novel p.(Arg48Pro) variants, respectively, which were absent in 200 control alleles. Protein modeling suggests that p.(Arg143Ser) is a tolerated change, while p.(Arg48Pro) induces a structural modification, although further molecular confirmation of dystrophinopathy was obtained in the p.(Arg48Pro) patient. Our results justify the inclusion of FKRP-related disorders in the differential diagnosis of Mexican neuromuscular patients. The commonly reported heterozygous FKRP genotypes deserve attention to avoid LGMD2I molecular misdiagnosis.

Notes

This work was performed at the Instituto Nacional de Pediatría, Ciudad de México, México. The World Wide Web resources that were consulted are provided as [Supplementary Material], available online-only.


* First authors who contributed equally to this work.


Supplementary Material