title: KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.
abstract: Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin "motor." These results highlight the role of expanded testing and whole-exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. Ann Neurol 2016;80:633-637.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD. jduis1@jhmi.edu.
authors.forename: Jessica
authors.initials: J
authors.lastname: Duis
authors.affiliation: Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Shannon
authors.initials: S
authors.lastname: Dean
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Applegate
authors.affiliation: Carolinas Pediatric Neurology Care, Charlotte, NC.
authors.forename: Amy
authors.initials: A
authors.lastname: Harper
authors.affiliation: Department of Molecular and Human Genetics, Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Human Genetics, Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX.
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.affiliation: Carolinas Pathology Group, Charlotte, NC.
authors.forename: James D
authors.initials: JD
authors.lastname: Dollar
authors.affiliation: Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Sun
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Marta Biderman
authors.initials: MB
authors.lastname: Waberski
authors.affiliation: Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Crawford
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ada
authors.initials: A
authors.lastname: Hamosh
authors.affiliation: Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Stafstrom
mesh_terms: D001049:Apnea / Q000235:genetics; D002675:Child, Preschool; D003680:Deglutition Disorders / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D016547:Kinesins / Q000235:genetics*; D008297:Male; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D009207:Myoclonus / Q000235:genetics*; D009900:Optic Nerve / Q000002:abnormalities
chemical_list: C500506:KIF5A protein, human; D016547:Kinesins