Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in RBL2 , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harboring RBL2 variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila , and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2 -linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate aspects of RBL2 LOF patient symptoms.

Long-term neuropsychological trajectories in children with epilepsy: does surgery halt decline?

Neuropsychological impairments are common in children with drug-resistant epilepsy. It has been proposed that epilepsy surgery may alleviate these impairments by providing seizure freedom; however, findings from prior studies have been inconsistent. We mapped long-term neuropsychological trajectories in children before and after undergoing epilepsy surgery, to measure the impact of disease course and surgery on functioning. We performed a retrospective cohort study of 882 children who had undergone epilepsy surgery at Great Ormond Street Hospital (1990-2018). We extracted patient information and neuropsychological functioning - obtained from IQ tests (domains: Full-Scale IQ, Verbal IQ, Performance IQ, Working Memory, and Processing Speed) and tests of academic attainment (Reading, Spelling and Numeracy) - and investigated changes in functioning using regression analyses. We identified 500 children (248 females) who had undergone epilepsy surgery (median age at surgery = 11.9 years, interquartile range = [7.8,15.0]) and neuropsychology assessment. These children showed declines in all domains of neuropsychological functioning in the time leading up to surgery (all p-values ≤ 0.001; e.g., ßFSIQ = -1.9, SEFSIQ = 0.3, pFSIQ < 0.001). Children lost on average one to four points per year, depending on the domain considered; 27-43% declined by 10 or more points from their first to their last preoperative assessment. At the time of presurgical evaluation, most children (46-60%) scored one or more standard deviations below the mean (<85) on the different neuropsychological domains; 37% of these met the threshold for intellectual disability (Full-Scale IQ < 70). On a group level, there was no change in performance from pre- to postoperative assessment on any of the domains (all p-values > 0.128). However, children who became seizure-free through surgery showed higher postoperative neuropsychological performance (e.g., rrb-FSIQ = 0.37, p < 0.001). These children continued to demonstrate improvements in neuropsychological functioning over the course of their long-term follow-up (e.g., ßFSIQ = 0.9, SEFSIQ = 0.3, pFSIQ = 0.004). Children who had discontinued antiseizure medication (ASM) treatment at one-year follow-up showed an eight-to-13-point advantage in postoperative Working Memory, Processing Speed, and Numeracy, and greater improvements in Verbal IQ, Working Memory, Reading, and Spelling (all p-values < 0.034) over the postoperative period compared to children who were seizure-free and still receiving ASMs. In conclusion, by providing seizure freedom and the opportunity for ASM cessation, epilepsy surgery may not only halt but reverse the downward trajectory that children with drug-resistant epilepsy display in neuropsychological functioning. To halt this decline as soon as possible, or potentially prevent it from occurring in the first place, children with focal epilepsy should be considered for epilepsy surgery as early as possible after diagnosis.

Pediatric epilepsy surgery from 2000 to 2018: Changes in referral and surgical volumes, patient characteristics, genetic testing, and postsurgical outcomes.

OBJECTIVE: Neurosurgery is a safe and effective form of treatment for select children with drug-resistant epilepsy. Still, there is concern that it remains underutilized, and that seizure freedom rates have not improved over time. We investigated referral and surgical practices, patient characteristics, and postoperative outcomes over the past two decades. METHODS: We performed a retrospective cohort study of children referred for epilepsy surgery at a tertiary center between 2000 and 2018. We extracted information from medical records and analyzed temporal trends using regression analyses. RESULTS: A total of 1443 children were evaluated for surgery. Of these, 859 (402 females) underwent surgical resection or disconnection at a median age of 8.5 years (interquartile range [IQR] = 4.6-13.4). Excluding palliative procedures, 67% of patients were seizure-free and 15% were on no antiseizure medication (ASM) at 1-year follow-up. There was an annual increase in the number of referrals (7%, 95% confidence interval [CI] = 5.3-8.6; p < .001) and surgeries (4% [95% CI = 2.9-5.6], p < .001) over time. Duration of epilepsy and total number of different ASMs trialed from epilepsy onset to surgery were, however, unchanged, and continued to exceed guidelines. Seizure freedom rates were also unchanged overall but showed improvement (odds ratio [OR] 1.09, 95% CI = 1.01-1.18; p = .027) after adjustment for an observed increase in complex cases. Children who underwent surgery more recently were more likely to be off ASMs postoperatively (OR 1.04, 95% CI = 1.01-1.08; p = .013). There was a 17% annual increase (95% CI = 8.4-28.4, p < .001) in children identified to have a genetic cause of epilepsy, which was associated with poor outcome. SIGNIFICANCE: Children with drug-resistant epilepsy continue to be put forward for surgery late, despite national and international guidelines urging prompt referral. Seizure freedom rates have improved over the past decades, but only after adjustment for a concurrent increase in complex cases. Finally, genetic testing in epilepsy surgery patients has expanded considerably over time and shows promise in identifying patients in whom surgery is less likely to be successful.

Predicting seizure outcome after epilepsy surgery: Do we need more complex models, larger samples, or better data?

OBJECTIVE: The accurate prediction of seizure freedom after epilepsy surgery remains challenging. We investigated if (1) training more complex models, (2) recruiting larger sample sizes, or (3) using data-driven selection of clinical predictors would improve our ability to predict postoperative seizure outcome using clinical features. We also conducted the first substantial external validation of a machine learning model trained to predict postoperative seizure outcome. METHODS: We performed a retrospective cohort study of 797 children who had undergone resective or disconnective epilepsy surgery at a tertiary center. We extracted patient information from medical records and trained three models-a logistic regression, a multilayer perceptron, and an XGBoost model-to predict 1-year postoperative seizure outcome on our data set. We evaluated the performance of a recently published XGBoost model on the same patients. We further investigated the impact of sample size on model performance, using learning curve analysis to estimate performance at samples up to N = 2000. Finally, we examined the impact of predictor selection on model performance. RESULTS: Our logistic regression achieved an accuracy of 72% (95% confidence interval [CI] = 68%-75%, area under the curve [AUC] = .72), whereas our multilayer perceptron and XGBoost both achieved accuracies of 71% (95% CIMLP = 67%-74%, AUCMLP = .70; 95% CIXGBoost own = 68%-75%, AUCXGBoost own = .70). There was no significant difference in performance between our three models (all p > .4) and they all performed better than the external XGBoost, which achieved an accuracy of 63% (95% CI = 59%-67%, AUC = .62; pLR = .005, pMLP = .01, pXGBoost own = .01) on our data. All models showed improved performance with increasing sample size, but limited improvements beyond our current sample. The best model performance was achieved with data-driven feature selection. SIGNIFICANCE: We show that neither the deployment of complex machine learning models nor the assembly of thousands of patients alone is likely to generate significant improvements in our ability to predict postoperative seizure freedom. We instead propose that improved feature selection alongside collaboration, data standardization, and model sharing is required to advance the field.

Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Is it possible to implement a rare disease case-finding tool in primary care? A UK-based pilot study.

INTRODUCTION: This study implemented MendelScan, a primary care rare disease case-finding tool, into a UK National Health Service population. Rare disease diagnosis is challenging due to disease complexity and low physician awareness. The 2021 UK Rare Diseases Framework highlights as a key priority the need for faster diagnosis to improve clinical outcomes. METHODS AND RESULTS: A UK primary care locality with 68,705 patients was examined. MendelScan encodes diagnostic/screening criteria for multiple rare diseases, mapping clinical terms to appropriate SNOMED CT codes (UK primary care standardised clinical terminology) to create digital algorithms. These algorithms were applied to a pseudo-anonymised structured data extract of the electronic health records (EHR) in this locality to "flag" at-risk patients who may require further evaluation. All flagged patients then underwent internal clinical review (a doctor reviewing each EHR flagged by the algorithm, removing all cases with a clear diagnosis/diagnoses that explains the clinical features that led to the patient being flagged); for those that passed this review, a report was returned to their GP. 55 of 76 disease criteria flagged at least one patient. 227 (0.33%) of the total 68,705 of EHR were flagged; 18 EHR were already diagnosed with the disease (the highlighted EHR had a diagnostic code for the same RD it was screened for, e.g. Behcet's disease algorithm identifying an EHR with a SNOMED CT code Behcet's disease). 75/227 (33%) EHR passed our internal review. Thirty-six reports were returned to the GP. Feedback was available for 28/36 of the reports sent. GP categorised nine reports as "Reasonable possible diagnosis" (advance for investigation), six reports as "diagnosis has already been excluded", ten reports as "patient has a clear alternative aetiology", and three reports as "Other" (patient left study locality, unable to re-identify accurately). All the 9 cases considered as "reasonable possible diagnosis" had further evaluation. CONCLUSIONS: This pilot demonstrates that implementing such a tool is feasible at a population level. The case-finding tool identified credible cases which were subsequently referred for further investigation. Future work includes performance-based validation studies of diagnostic algorithms and the scalability of the tool.

L1CAM variants cause two distinct imaging phenotypes on fetal MRI.

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic-mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.

Nucleocytoplasmic transport of the RNA-binding protein CELF2 regulates neural stem cell fates.

The development of the cerebral cortex requires balanced expansion and differentiation of neural stem/progenitor cells (NPCs), which rely on precise regulation of gene expression. Because NPCs often exhibit transcriptional priming of cell-fate-determination genes, the ultimate output of these genes for fate decisions must be carefully controlled in a timely fashion at the post-transcriptional level, but how that is achieved is poorly understood. Here, we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb NPC fate decisions in mice by disrupting CELF2 nucleocytoplasmic transport. In self-renewing NPCs, CELF2 resides in the cytoplasm, where it represses mRNAs encoding cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNA for translation and thereby triggers NPC differentiation. Our results reveal that CELF2 translocation between subcellular compartments orchestrates mRNA at the translational level to instruct cell fates in cortical development.

Genotype-phenotype correlation at codon 1740 of SETD2.

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.

Intracranial vascular pathology in two further patients with Floating-Harbor syndrome: Proposals for cerebrovascular disease risk management.

Floating-Harbor syndrome (FHS) is a rare, heritable disorder caused by variants in the SRCAP gene. Most individuals with FHS have characteristic facial features, short stature, and speech and language impairment. Although FHS has been likely under-diagnosed due to a combination of lack of recognition of the clinical phenotype and limited access to genomic testing, it is a rare condition with around 100 individuals reported in the medical literature. Case series have been biased towards younger individuals (vast majority <20 years of age) meaning that it has been challenging to provide accurate medical advice for affected individuals in adulthood. We report two young adults with FHS who presented with intracranial haemorrhage likely secondary to cerebrovascular aneurysms, with devastating consequences, making a total of four FHS patients reported with significant cerebrovascular abnormalities. Three of four patients had hypertension, at least one in conjunction with normal renal structure. We consider possible relationships between hypertension, renal pathology and aneurysms in the context of FHS, and consider mechanisms through which disruption of the SRCAP protein may lead to vascular pathology. We recommend that clinicians should have a low threshold to investigate symptoms suggestive of cerebrovascular disease in FHS. We advise that patients with FHS should have annual blood pressure monitoring from adolescence, renal ultrasound at diagnosis repeated in adulthood, and timely investigation of any neurological symptoms. For patients with FHS, particularly with hypertension, we advise that clinicians should consider at least one MRA (Magnetic Resonance Imaging with Angiography) to check for cerebral aneurysms.

An evaluation of demographic factors affecting performance in a paediatric membership multiple-choice examination.

OBJECTIVE: To determine if demographic factors are associated with outcome in a multiple-choice, electronically marked paediatric postgraduate examination. METHOD: Retrospective analysis of pass rates of UK trainees sitting Membership of the Royal College of Paediatrics and Child Health (MRCPCH) part 1B from 2007 to 2011. Data collected by the RCPCH from examination candidates were analysed to assess the effects of gender, age, and country and university of medical qualification on examination outcome. RESULTS: At first attempt at MRCPCH part 1B, the overall pass rate from 2007 to 2011 was 843/2056 (41.0%). In univariate analysis, passing the examination was associated with being a UK graduate (649/1376 (47.2%)) compared with being an international medical graduate (130/520 (25.0%)) (OR 2.68 (95% CI 2.14 to 3.36), p<0.001). There was strong evidence that the proportion of candidates passing the examination differed for graduates of the 19 different UK medical schools (Fisher's exact test p<0.001). In multivariate logistic regression analysis, after adjustment for age, sex and whether the part 1A examination was taken concurrently, being a UK graduate was still strongly associated with passing the examination (OR 3.17 (95% CI 2.41 to 4.17), p<0.001). UK graduates performed best at 26-27 years of age (52.4% pass rate), whereas overseas graduates performed best at ≥38 years of age (50.8% pass rate). CONCLUSIONS: MRCPCH part 1B outcome was related to place of primary medical qualification, with a significantly lower pass rate for international medical graduates compared with UK graduates, as well as significant variation in examination outcome between graduates from different UK medical schools. These data may be used to guide new initiatives to improve support and education for these trainees and to inform development of undergraduate curricula and help trainees prepare more successfully for postgraduate examinations.

The effects of puberty on white matter development in boys.

Neuroimaging studies demonstrate considerable changes in white matter volume and microstructure during adolescence. Most studies have focused on age-related effects, whilst puberty-related changes are not well understood. Using diffusion tensor imaging and tract-based spatial statistics, we investigated the effects of pubertal status on white matter mean diffusivity (MD) and fractional anisotropy (FA) in 61 males aged 12.7-16.0 years. Participants were grouped into early-mid puberty (≤Tanner Stage 3 in pubic hair and gonadal development; n=22) and late-post puberty (≥Tanner Stage 4 in pubic hair or gonadal development; n=39). Salivary levels of pubertal hormones (testosterone, DHEA and oestradiol) were also measured. Pubertal stage was significantly related to MD in diverse white matter regions. No relationship was observed between pubertal status and FA. Regression modelling of MD in the significant regions demonstrated that an interaction model incorporating puberty, age and puberty×age best explained our findings. In addition, testosterone was correlated with MD in these pubertally significant regions. No relationship was observed between oestradiol or DHEA and MD. In conclusion, pubertal status was significantly related to MD, but not FA, and this relationship cannot be explained by changes in chronological age alone.

Reduced brain white matter integrity in trichotillomania: a diffusion tensor imaging study.

CONTEXT: Trichotillomania is an Axis I disorder characterized by repetitive, pathological hair pulling. OBJECTIVE: To assess the integrity of white matter tracts in subjects with the disorder. DESIGN: Between-group comparison using permutation cluster analysis, with stringent correction for multiple comparisons. SETTING: Academic psychiatry department. PARTICIPANTS: Eighteen volunteers meeting DSM-IV criteria for trichotillomania and 19 healthy control subjects. MAIN OUTCOME MEASURES: Fractional anisotropy (measured using diffusion tensor imaging), trichotillomania disease severity (Massachusetts General Hospital Hairpulling Scale score), and dysphoria (Montgomery-Asberg Depression Rating Scale score). RESULTS: Subjects with trichotillomania exhibited significantly reduced fractional anisotropy in anterior cingulate, presupplementary motor area, and temporal cortices. Fractional anisotropy did not correlate significantly with trichotillomania disease severity or depressive mood scores. CONCLUSIONS: These data implicate disorganization of white matter tracts involved in motor habit generation and suppression, along with affective regulation, in the pathophysiology of trichotillomania.

Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review.

Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.

Endophenotypes of obsessive-compulsive disorder: rationale, evidence and future potential.

Obsessive-compulsive disorder (OCD) is a heritable and debilitating neuropsychiatric condition. Attempts to delineate genetic contributions have met with limited success, and there is an ongoing search for intermediate trait or vulnerability markers rooted in the neurosciences. Such markers would be valuable for detecting people at risk of developing the condition, clarifying etiological factors and targeting novel treatments. This review begins with brief coverage of the epidemiology of OCD, and presents a hierarchical model of the condition. The advantages of neuropsychological assessment and neuroimaging as objective measures of brain integrity and function are discussed. We describe the concept of endophenotypes and examples of their successful use in medicine and psychiatry. Key areas of focus in the search for OCD endophenotypes are identified, such as measures of inhibitory control and probes of the integrity of orbitofrontal and posterior parietal cortices. Finally, we discuss exciting findings in unaffected first-degree relatives of patients with OCD that have led to the identification of several candidate endophenotypes of the disorder, with important implications for neurobiological understanding and treatment of this and related conditions.

Grey matter abnormalities in trichotillomania: morphometric magnetic resonance imaging study.

BACKGROUND: Trichotillomania (repetitive hair-pulling) is an Axis I psychiatric disorder whose neurobiological basis is incompletely understood. Whole-brain trichotillomania neuroimaging studies are lacking. AIMS: To investigate grey and white matter abnormalities over the whole brain in patients with trichotillomania. METHOD: Eighteen patients with DSM-IV trichotillomania and 19 healthy controls undertook structural magnetic resonance imaging after providing written informed consent. Differences in grey and white matter were investigated using computational morphometry. RESULTS: Patients with trichotillomania showed increased grey matter densities in the left striatum, left amygdalo-hippocampal formation, and multiple (including cingulate, supplementary motor, and frontal) cortical regions bilaterally. CONCLUSIONS: Trichotillomania was associated with structural grey matter changes in neural circuitry implicated in habit learning, cognition and affect regulation. These findings inform animal models of the disorder and highlight key regions of interest for future translational research.

Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives.

Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors associated with underlying dysregulation of frontostriatal circuitry. Central to neurobiological models of OCD is the orbitofrontal cortex, a neural region that facilitates behavioral flexibility after negative feedback (reversal learning). We identified abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder.

White matter abnormalities in patients with obsessive-compulsive disorder and their first-degree relatives.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a common, heritable neuropsychiatric disorder, hypothetically underpinned by dysconnectivity of large-scale brain systems. The extent of white matter abnormalities in OCD is unknown, and the genetic basis of this disorder is poorly understood. The authors used diffusion tensor imaging, a magnetic resonance imaging technique, for examining white matter abnormalities in brain structure through quantification of water diffusion, to confirm whether white matter abnormalities exist in OCD. They also explored whether such abnormalities occur in healthy first-degree relatives of patients, indicating they may be endophenotypes representing increased genetic risk for OCD. METHOD: The authors used diffusion tensor imaging to measure fractional anisotropy of white matter in 30 patients with OCD, 30 unaffected first-degree relatives, and 30 matched healthy comparison subjects. Regions of significantly abnormal fractional anisotropy in patients in relation to healthy comparison subjects were identified by permutation tests. The authors assessed whether these abnormalities were also evident in the first-degree relatives. A secondary region-of-interest analysis was undertaken to assess the extent of replication between our data and previous relevant literature. RESULTS: Patients with OCD demonstrated significantly reduced fractional anisotropy in a large region of right inferior parietal white matter and significantly increased fractional anisotropy in a right medial frontal region. Relatives also exhibited significant abnormalities of fractional anisotropy in these regions. CONCLUSIONS: These findings indicate that OCD is associated with white matter abnormalities in parietal and frontal regions. Similar abnormalities in unaffected first-degree relatives suggest these may be white matter endophenotypes for OCD.