Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations. (9th April 2015)

• Record Type: Journal Article
• Authors: Baker, Kate; Astle, Duncan E.; Scerif, Gaia; Barnes, Jessica; Smith, Jennie; Moffat, Georgina; Gillard, Jonathan; Baldeweg, Torsten; Raymond, F. Lucy
• Is Part Of: Annals of clinical and translational neurology. Volume 2:Number 5(2015:May)
• Page Start: 559
• Page End: 569
• Publication Date: 2015-04-09
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.196
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn3196-abs-0001"> <title>Abstract</title> <sec id="acn3196-sec-0001" sec-type="section"> <title>Objective</title> <p>Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss‐of‐function mutations in <italic>ZDHHC9</italic> (OMIM #300799).</p> </sec> <sec id="acn3196-sec-0002" sec-type="section"> <title>Methods</title> <p>All known cases of X‐linked intellectual disability (XLID) due to <italic>ZDHHC9</italic> mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes.</p> </sec> <sec id="acn3196-sec-0003" sec-type="section"> <title>Results</title> <p>Seven out of nine males with <italic>ZDHHC9</italic> mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (<italic>P</italic> = 0.01). Seizure histories and EEG features amongst <italic>ZDHHC9</italic> mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with <italic>ZDHHC9</italic> mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum.</p> </sec> <sec id="acn3196-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Mutations in <italic>ZDHHC9</italic> are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter‐hemispheric connectivity. The biochemical, cellular and network‐level mechanisms responsible for the <italic>ZDHHC9</italic>‐associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.</p> </sec> </abstract>