title: Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement.
abstract: Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness. Recently, the first de novo mutations in KIF1A were identified in patients with an early-onset severe form of complicated hereditary spastic paraplegia. We report two additional patients with novel de novo mutations in KIF1A, hereby expanding the genetic spectrum of KIF1A-related hereditary spastic paraplegia. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential magnetic resonance images (MRIs), thus linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in patient 1 and patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199 R), respectively. Therefore, our report contributes to expanding the genotypic and phenotypic spectrum of hereditary spastic paraplegia caused by mutations in KIF1A.
authors.affiliation: National Institutes of Health, Bethesda, MD, USA Weill Cornell Medical College, New York, NY, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Hotchkiss
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.affiliation: National Institutes of Health, Bethesda, MD, USA Children's National Medical Center, Washington, DC, USA.
authors.forename: Meganne E
authors.initials: ME
authors.lastname: Leach
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Payam
authors.initials: P
authors.lastname: Mohassel
authors.affiliation: National Institutes of Health, Bethesda, MD, USA Children's National Medical Center, Washington, DC, USA.
authors.forename: Diana X
authors.initials: DX
authors.lastname: Bharucha-Goebel
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Bradley
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Universidade Federal de Minas Gerais, Belo Horizonte-MG, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Gurgel-Giannetti
authors.affiliation: National Institutes of Health, Bethesda, MD, USA carsten.bonnemann@nih.gov.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: C094065:KIF1A protein, human; D016547:Kinesins
keywords: KIF1A; genetics; hereditary spastic paraplegia; neuromuscular disorders