title: Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.
abstract: We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease.
authors.affiliation: Department of Human Genetics 855, Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Salma
authors.initials: S
authors.lastname: Ben-Salem
authors.forename: Susanne T
authors.initials: ST
authors.lastname: de Bot
authors.forename: Bonnie
authors.initials: B
authors.lastname: Nijhof
authors.forename: Ilse I G M
authors.initials: II
authors.lastname: van de Vondervoort
authors.forename: Marinette
authors.initials: M
authors.lastname: van der Graaf
authors.forename: Anna Castells
authors.initials: AC
authors.lastname: Nobau
authors.forename: Irene
authors.initials: I
authors.lastname: Otte-Höller
authors.forename: Sascha
authors.initials: S
authors.lastname: Vermeer
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Humphreys
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.forename: Saeed A
authors.initials: SA
authors.lastname: Al-Yahyaee
authors.forename: Said
authors.initials: S
authors.lastname: Tariq
authors.forename: Thachillath
authors.initials: T
authors.lastname: Pramathan
authors.forename: Riad
authors.initials: R
authors.lastname: Bayoumi
authors.forename: Hubertus P H
authors.initials: HP
authors.lastname: Kremer
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: Willem M R
authors.initials: WM
authors.lastname: van den Akker
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Irene M
authors.initials: IM
authors.lastname: Janssen
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.forename: Saskia
authors.initials: S
authors.lastname: van der Velde-Visser
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Adinda
authors.initials: A
authors.lastname: Diekstra
authors.forename: Corrie E
authors.initials: CE
authors.lastname: Erasmus
authors.forename: Michèl A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002490:Central Nervous System / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019066:Facies; D005260:Female; D023061:Gene Order; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D059906:Neuroimaging; D010375:Pedigree; D010641:Phenotype; D010740:Phospholipases / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D010740:Phospholipases; C541017:DDHD2 protein, human