1. Academic Validation
  2. Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia

Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia

  • Am J Hum Genet. 2012 Dec 7;91(6):1073-81. doi: 10.1016/j.ajhg.2012.10.017.
Janneke H M Schuurs-Hoeijmakers 1 Michael T Geraghty Erik-Jan Kamsteeg Salma Ben-Salem Susanne T de Bot Bonnie Nijhof Ilse I G M van de Vondervoort Marinette van der Graaf Anna Castells Nobau Irene Otte-Höller Sascha Vermeer Amanda C Smith Peter Humphreys Jeremy Schwartzentruber FORGE Canada Consortium Bassam R Ali Saeed A Al-Yahyaee Said Tariq Thachillath Pramathan Riad Bayoumi Hubertus P H Kremer Bart P van de Warrenburg Willem M R van den Akker Christian Gilissen Joris A Veltman Irene M Janssen Anneke T Vulto-van Silfhout Saskia van der Velde-Visser Dirk J Lefeber Adinda Diekstra Corrie E Erasmus Michèl A Willemsen Lisenka E L M Vissers Martin Lammens Hans van Bokhoven Han G Brunner Ron A Wevers Annette Schenck Lihadh Al-Gazali Bert B A de Vries Arjan P M de Brouwer
Affiliations

Affiliation

  • 1 Department of Human Genetics 855, Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB Nijmegen, The Netherlands.
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.

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