Faculty Bibliography

Purpose: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability (ID). Related female carriers were unaffected (Van Maldergem L et al. Hum Mol Genet 2013;22:3306-3314). Here, we report 12 female patients who carry a heterozygous de novo mutation of KIAA2022 and share a phenotype characterized by ID and epilepsy. Method: The 12 reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation-And expression studies were performed when possible. Clinical data were collected from medical records. Results: All mutations were predicted to result in a frameshift or premature stop. Ten out of 12 patients had intractable epilepsy with myoclonic and/or absence seizures, generalized in 9. Eleven patients had mild to severe ID. This female phenotype partially overlaps with the reported male phenotype, which consists of more severe ID, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation (XCI), complete absence of RNA expression in blood, and a phenotype similar to male patients. In five other tested patients XCI was random, confirmed by a non-significant two-To threefold decrease of RNA expression in blood, and consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles. Conclusion: De novo truncating mutations in the KIAA2022 gene can lead to a phenotype not only in males, but also in females. While males have more pronounced ID and dysmorphic features, females affected by KIAA2022 mutations show variable symptoms seemingly related to XCI skewing. Females with 100% XCI skewing and absent KIAA2022 expression show a phenotype similar to affected males. Females with random XCI tend to have a more prominent epilepsy phenotype, with predominant generalized myoclonic and/or absence seizures. Mechanisms underlying the female phenotype may be both cellular mosaicism and reduced protein expression

BACKGROUND: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy. METHODS: Reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible. RESULTS: All mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles. CONCLUSIONS: Heterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data.

OBJECTIVE: To characterize the frequency of and risk factors for out-of-hospital sudden neurologic deaths. METHODS: During the initial 25 months (February 1, 2011-March 1, 2013) of the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death Study, we captured incident WHO criteria sudden cardiac deaths (SCDs) through active surveillance of consecutive out-of-hospital deaths, which must be reported to the medical examiner by law. All cases were referred for full autopsy with detailed examination of the heart and cranial vault, toxicology, and histology. A multidisciplinary committee adjudicated a final cause of death. RESULTS: Of 352 incident SCDs, 335 (95%) underwent systematic evaluation including full autopsy. Of these 335 cases, 18 (5.4%) were sudden neurologic deaths (mean age 60.6 years [SD 17.6, range 27-87]; 67.7% female), which accounted for 14.9% of the 121 noncardiac sudden deaths. The risk of sudden neurologic death compared to non-neurologic SCD was lower in male and white participants (p < 0.01). Neurologic causes included intracranial hemorrhage (8), sudden unexpected death in epilepsy (6, including 2 with juvenile myoclonic epilepsy), aneurysmal subarachnoid hemorrhage (2), acute ischemic stroke (1), and aspiration from Huntington disease (1). Most deaths were unwitnessed (16; 89%) with asystole at presentation (17; 94%). Prior stroke/TIA was not associated with risk of stroke (odds ratio [OR] 1.4 [95% confidence interval (CI) 0.18-11.8], p = 0.73), but antithrombotic medication use was (OR 3.9 [95% 1.01-15.5], p = 0.05). CONCLUSIONS: Sudden neurologic death is an important cause of out-of-hospital apparent SCDs. Low prevailing autopsy rates may result in systematic misclassification of apparent SCDs and underestimation of the incidence of sudden neurologic death.

The two most common types of temporal lobe epilepsy are medial temporal sclerosis epilepsy (TLE-MTS) and MRI-normal temporal lobe epilepsy (TLE-no). TLE-MTS is specified by its stereotyped focus and spread pattern of neuronal damage, with pronounced neuronal loss in the hippocampus. TLE-no exhibits normal-appearing hippocampus and more widepsread neuronal loss. In both cases neuronal loss spread appears to be constrained by the white matter connections. Both varieties of epilepsy reveal pathological abnormalities in increased mean diffusivity (MD). We model MD distribution as a simple consequence of the propagation of neuronal damage. By applying this model on the structural brain connectivity network of healthy subjects we can predict at group level the mean diffusivity gray matter change in the epilepsy cohorts relative to a control group. DTI images were acquired from 10 patients with TLE-MTS, 11 patients with TLE-no, and 35 healthy subjects. Statistical validation at the group level suggests high correlation with measured neuronal loss (R = 0.56 for the TLE-MTS group and R = 0.364 for the TLE-no group). The results of this exploratory work pave the way for potential future clinical application of the proposed model on individual patients, including predicting neuronal loss spread, identification of seizure onset zones, and helping in surgical planning.

The neural mechanisms that support working memory (WM) depend on persistent neural activity. Within topographically organized maps of space in dorsal parietal cortex, spatially selective neural activity persists during WM for location. However, to date the necessity of these topographic subregions of human parietal cortex for WM remain unknown. To test the causal relationship of these areas to WM, we compared the performance of patients with lesions to topographically organized parietal cortex to controls on a memory-guided saccade (MGS) task as well as a visually-guided saccade (VGS) task. The MGS task allowed us to measure WM precision continuously with great sensitivity, while the VGS task allowed us to control for any deficits in general spatial or visuomotor processing. Compared to controls, patients generated memory-guided saccades that were significantly slower and less accurate, while visually-guided saccades were unaffected. These results provide key missing evidence for the causal role of topographic areas in human parietal cortex for WM, as well as the neural mechanisms supporting WM.

Sudden unexpected death in epilepsy (SUDEP) can affect individuals of any age, but is most common in younger adults (aged 20-45 years). Generalised tonic-clonic seizures are the greatest risk factor for SUDEP; most often, SUDEP occurs after this type of seizure in bed during sleep hours and the person is found in a prone position. SUDEP excludes other forms of seizure-related sudden death that might be mechanistically related (eg, death after single febrile, unprovoked seizures, or status epilepticus). Typically, postictal apnoea and bradycardia progress to asystole and death. A crucial element of SUDEP is brainstem dysfunction, for which postictal generalised EEG suppression might be a biomarker. Dysfunction in serotonin and adenosine signalling systems, as well as genetic disorders affecting cardiac conduction and neuronal excitability, might also contribute. Because generalised tonic-clonic seizures precede most cases of SUDEP, patients must be better educated about prevention. The value of nocturnal monitoring to detect seizures and postictal stimulation is unproven but warrants further study.