Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations.

Kate Baker,Duncan E Astle,Torsten Baldeweg,Jonathan Gillard,Jessica Barnes,F Lucy Raymond,Jennie Smith,Georgina Moffat,Gaia Scerif

doi:10.1002/acn3.196

Abstract

ObjectiveSystematic 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 ZDHHC9 (OMIM #300799).MethodsAll known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes.ResultsSeven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 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.InterpretationMutations in ZDHHC9 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 ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.

Highlights

Genetic diagnosis is possible for an increasing proportion of individuals with neurodevelopmental disorders, including intellectual disability and childhood epilepsies
This study demonstrates that genetic diagnosis in neurodevelopmental disorders, including intellectual disability a 2015 The Authors
Ascertainment of ZDHHC9 cases was via genetic screening of an X-linked intellectual disability (XLID) cohort, a strategy with inherent benefits and limitations

Summary

Introduction

Genetic diagnosis is possible for an increasing proportion of individuals with neurodevelopmental disorders, including intellectual disability and childhood epilepsies. In common with many gene discovery studies, detailed neurological histories, cognitive evaluations and neuroimaging were not available at the time of the initial ZDHHC9 mutations report. To address this limitation, we carried out a neurocognitive phenotyping study of all UK-based cases diagnosed with mutations in ZDHHC9, the results of which are reported in the current paper. We assessed speech and language functions known to be impaired in a significant proportion of individuals with RE and to persist after seizure remission.[10,11,12] We assessed aspects of nonlinguistic attention, because impairments in attention have been consistently reported in RE and may reflect altered network maturation relevant to long-term cognitive outcomes.[13,14] Second, we predicted that ZDHHC9 mutations might be associated with consistent structural brain abnormalities, in contrast to heterogeneous findings in the idiopathic (mixed etiology) RE population.[15]

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