Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations

Abstract

Objective: 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 ZDHHC9 (OMIM #300799).

Methods: All 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.

Results: Seven 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.

Interpretation: Mutations 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.

Figure 1

Clinical EEG recordings for two males with ZDHHC9 mutations. (A) Recording at age 4 years (Case #8) to investigate suspected seizures, off anti-epileptic medication. Intermittent diphasic sharp waves, synchronous in left temporal and left central leads. (B) Recording at age 9 years (Case #7) to investigate suspected seizures, off anti-epileptic medication. Clusters of raised voltage diphasic sharp waves are maximal over the centro-parietal regions, more extensive on the left than right side.

Figure 2

Attention performance in males with ZDHHC9 mutations and ability-matched X-linked intellectual disability (XLID) controls. (A) Visual attention tasks, omission errors (one minus hit rate). (B) Visual attention tasks, commission errors (false alarms and anticipatory responses).

Figure 3

Magnetic resonance imaging for males with ZDHHC9 mutations. T1-weighted MRI (midsagittal slice) for eight males with ZDHHC9 mutations. Scans are ordered by chronological age at the time of MRI image acquisition. *Clinically acquired scans. #Case number in Table S1.

Figure 4

Voxel-based morphometry. Comparison of regional volumetric differences between males with ZDHHC9 mutations (n = 7) and age-matched male controls (n = 7). Background = mean normalized segmented image for all study participants. (A) Regional gray matter reductions; red = ZDHHC9 < controls (P < 0.05_FWE), blue = ZDHHC9 < controls (P < 0.001_uncorrected). (B) Regional white matter reductions; red = ZDHHC9 < controls (P < 0.05_FWE), blue = ZDHHC9 < controls (P < 0.001_uncorrected).

Figure 5

Region-of-interest measurements. (A) Example tracings of subcortical structures at an equivalent axial level on T1-weighted imaging for a single ZDHHC9 mutation case and their age-matched control. Structures were traced from inferior to superior slices according to predefined landmarks to capture entire volumes. Pale blue = left caudate, dark blue = right caudate, green = left putamen, red = right putamen, pink = left thalamus, yellow = right thalamus. (B) Quantification of subcortical volumes for males with ZDHHC9 mutations and healthy age-matched controls, adjusted for age and total gray matter volume.