Generation of an iPSC line (FINi001-A) from a girl with developmental and epileptic encephalopathy due to a heterozygous gain-of-function p.R1882Q variant in the voltage-gated sodium channel Nav1.2 protein encoded by the SCN2A gene.

A range of epilepsies, including the most severe group of developmental and epileptic encephalopathies (DEEs), are caused by gain-of-function variants in voltage-gated channels. Here we report the generation and characterisation of an iPSC cell line from the fibroblasts of a girl with early infantile DEE carrying heterozygous missense gain-of-function mutation (R1882Q) in Nav1.2(SCN2A) protein, using transient transfection with a single mRNA molecule. The established iPSC line displays typical human primed pluripotent stem cell characteristics: typical colony morphology and robust expression of pluripotency-associated marker genes, ability to give rise to derivatives of all three embryonic germ layers, and normal karyotype without any SNP array-detectable copy number variations. We anticipate that this iPSC line will be useful for the development of neuronal hyperactivity-caused human stem cell-based DEE models, advancing both understanding and potential therapy development for this debilitating condition.

Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome.

BACKGROUND AND PURPOSE: Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia. MATERIALS AND METHODS: Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities. RESULTS: Pathogenic variants in SON, causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria. CONCLUSIONS: The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

MRI and pathology correlations in the medulla in sudden unexpected death in epilepsy (SUDEP): a postmortem study.

AIMS: Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. METHODS: Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. RESULTS: Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P < 0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P < 0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P < 0.05). CONCLUSIONS: Rostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

Frequency, severity and predictors of playing-related musculoskeletal pain in professional orchestral musicians in Germany.

Playing-related musculoskeletal disorders (PRMD) in professional musicians are common. Existing literature demonstrates that up to 86 % of musicians are affected. The aim of the study was to evaluate the frequency of musculoskeletal pain in professional orchestral musicians with regard to their instrument affiliation. Of special interest were pain intensity and its association with predictors such as gender, instrument group, age or stage fright. Professional orchestra players completed a self-report questionnaire to assess playing-related musculoskeletal pain and its frequency and intensity in various body regions on a numeric rating scale (NRS). Relative frequencies and prevalence ratios for different instrument groups were estimated. Out of 720 approached musicians, 408 were included in the sample (response rate 57 %); overall, 89.5 % had been affected by current or past playing-related musculoskeletal pain, 62.7 % reported pain in the previous 3 months, and 8.6 % reported current pain. Pain distribution and frequency varied between instrument groups. For all instrument groups, the neck was the most common pain region. About 43 % of musicians presented more than five pain regions, in particular violin players. Approximately 40 % of musicians indicated frequent or permanent pain. Average pain intensities increased from NRS 3.8 up to a range of 5.9 and 7.4 for frequent and permanent pain, respectively. Female gender and stage fright were proven to be predictors for musculoskeletal pain. Professional orchestral musicians are greatly affected by PRMD, often experiencing frequent or permanent pain, high pain levels and pain in various body regions. As PRMD might contribute considerably to performance disability, sick leave and the possibility of premature termination of a musicians' career, this study highlights the necessity for tailored therapeutic and preventive strategies in performing arts medicine.

Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities.

BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.

De novo SCN1A mutations in migrating partial seizures of infancy.

OBJECTIVE: To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI). METHODS: Fifteen unrelated children with MPSI were screened for mutations in genes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, STXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy number variations. RESULTS: One patient had a de novo SCN1A missense mutation p.R862G that affects the voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 females), and the 3 common European mutations of POLG (11/15) was negative. Pathogenic copy number variations were not detected in 11/12 cases. CONCLUSION: Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A phenotype described to date. While not a common cause of MPSI, SCN1A screening should now be considered in patients with this devastating epileptic encephalopathy.

Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations.

OBJECTIVE: Two unrelated families were ascertained in which sisters had infantile onset of epilepsy and developmental delay. Mutations in the protocadherin 19 (PCDH19) gene cause epilepsy and mental retardation limited to females (EFMR). Despite both sister pairs having a PCDH19 mutation, neither parent in each family was a heterozygous carrier of the mutation. The possibility of parental mosaicism of PCDH19 mutations was investigated. METHODS: Genomic DNA from peripheral blood was obtained and sequenced for PCDH19 mutations. Parentage was confirmed by markers. RESULTS: Both sister pairs have a mutation in PCDH19. Sister pair 1 has a missense mutation, c.74T>C, L25P, while sequence analysis indicates both of their parents are negative for the mutation. Diagnostic restriction enzyme analysis detected low-level mosaicism of the mutation in their mother. Sister pair 2 are half-sisters who share a mother and each has the missense PCDH19 mutation c.1019 A>G, N340S. The sequence chromatograph of their mother shows reduced signal for the same mutation. These data indicate maternal somatic and gonadal mosaicism of the PCDH19 mutation in both sister pairs. Phenotyping is suggestive of, and PCDH19 mutation detection is diagnostic for, the disorder EFMR in the affected girls. CONCLUSIONS: We show that gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of EFMR. This should be considered when providing genetic counseling for couples who have one affected daughter as they may risk recurrence of affected daughters and having sons at risk of transmitting EFMR.

Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations.

OBJECTIVES: Heterozygous mutations in STXBP1, encoding the syntaxin binding protein 1, have recently been identified in Ohtahara syndrome, an epileptic encephalopathy with very early onset. In order to explore the phenotypic spectrum associated with STXBP1 mutations, we analyzed a cohort of patients with unexplained early-onset epileptic encephalopathies. METHODS: We collected and clinically characterized 106 patients with early-onset epileptic encephalopathies. Mutation analysis of the STXBP1 gene was done using sequence analysis of the exon and intron-exon boundaries and multiplex amplification quantification to detect copy number variations. RESULTS: We identified 4 truncating mutations and 2 microdeletions partially affecting STXBP1 in 6 of the 106 patients. All mutations are predicted to abolish STXBP1 function and 5 mutations were proven to occur de novo. None of the mutation-carrying patients had Ohtahara syndrome. One patient was diagnosed with West syndrome at disease onset, while the initial phenotype of 5 further patients did not fit into a specific recognized epilepsy syndrome. Three of these patients later evolved to West syndrome. All patients had severe to profound mental retardation, and ataxia or dyskinetic movements were present in 5 patients. CONCLUSION: This study shows that mutations in STXBP1 are not limited to patients with Ohtahara syndrome, but are also present in 10% (5/49) of patients with an early-onset epileptic encephalopathy that does not fit into either Ohtahara or West syndrome and rarely in typical West syndrome. STXBP1 mutational analysis should be considered in the diagnostic evaluation of this challenging group of patients.

The core network in absence epilepsy. Differences in cortical and thalamic BOLD response.

OBJECTIVES: We used EEG-fMRI to study epileptiform activity in a cohort of untreated children with typical absence seizures (AS). Our aim was to identify cortical and subcortical regions involved in spike and wave events and to explore the timing of activity in these regions. METHODS: Eleven children with AS confirmed on video-EEG underwent EEG-fMRI. An event-related analysis of epileptiform activity was performed. Regions of interest (ROIs), identified in the event-related analysis, were used to study the time course of the blood oxygen level-dependent (BOLD) signal prior to and immediately following events of interest in these ROIs. RESULTS: Group analysis confirmed positive BOLD in the thalamus and negative BOLD in the lateral and mesial parietal lobe, caudate nuclei, and additionally the brainstem reticular formation. The event-related time course differed between the thalamus, the parietal cortex, and the pons and caudate nuclei. In the subcortical structures, BOLD signal change occurred at, or immediately after, electrographic onset. Importantly, in the parietal cortex, but not in other cortical regions, there was a subtle BOLD signal increase for 10 seconds prior to the onset of epileptiform activity. CONCLUSIONS: In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity.

Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency.

BACKGROUND: Familial glucose transporter type 1 (GLUT1) deficiency due to autosomal dominant inheritance of SLC2A1 mutations is associated with paroxysmal exertional dyskinesia; epilepsy and intellectual disability occur in some family members. We recently demonstrated that GLUT1 deficiency occurs in over 10% of patients with early-onset absence epilepsy. METHODS: This family study analyses the phenotypes in 2 kindreds segregating SLC2A1 mutations identified through probands with early-onset absence epilepsy. One comprised 9 individuals with mutations over 3 generations; the other had 6 individuals over 2 generations. RESULTS: Of 15 subjects with SLC2A1 mutations, epilepsy occurred in 12. Absence seizures were the most prevalent seizure type (10/12), with onset from 3 to 34 years of age. Epilepsy phenotypes varied widely, including idiopathic generalized epilepsies (IGE) with absence (8/12), myoclonic-astatic epilepsy (2/12), and focal epilepsy (2/12). Paroxysmal exertional dyskinesia occurred in 7, and was subtle and universally undiagnosed prior to molecular diagnosis. There were 2 unaffected mutation carriers. CONCLUSIONS: GLUT1 deficiency is an important monogenic cause of absence epilepsies with onset from early childhood to adult life. Individual cases may be phenotypically indistinguishable from common forms of IGE. Although subtle paroxysmal exertional dyskinesia is a helpful diagnostic clue, it is far from universal. The phenotypic spectrum of GLUT1 deficiency is considerably greater than previously recognized. Diagnosis of GLUT1 deficiency has important treatment and genetic counseling implications.

Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis.

Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.

The role of neuronal GABA(A) receptor subunit mutations in idiopathic generalized epilepsies.

Rare GABA(A) receptor gamma2 and alpha1 subunit mutations of pathogenic effect have been described segregating in families with "monogenic" epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABA(A) receptor subunit genes from the one patient cohort. The cohort consists of GEFS(+), FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABA(A) receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations.

Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice.

BACKGROUND: Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation and congenital abnormality. Copy number variations (CNVs) are now readily detectable using a variety of platforms and a major challenge is the distinction of pathogenic from ubiquitous, benign polymorphic CNVs. The aim of this study was to investigate replacement of time consuming, locus specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV aetiologies as well as new ones. METHODS: Genome wide copy number analysis was performed on 117 patients using Affymetrix 250K microarrays. RESULTS: 434 CNVs (195 losses and 239 gains) were found, including 18 pathogenic CNVs and 9 identified as "potentially pathogenic". Almost all pathogenic CNVs were larger than 500 kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity larger than 5 Mb were found in 5 patients. CONCLUSIONS: Genome microarray analysis has improved diagnostic success in this group of patients. Several examples of recently discovered "new syndromes" were found suggesting they are more common than previously suspected and collectively are likely to be a major cause of mental retardation. The findings have several implications for clinical practice. The study revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counselling and the consent process. The importance of contributing novel CNVs to high quality databases for genotype-phenotype analysis and review of guidelines for selection of individuals for microarray analysis is emphasised.

Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion.

BACKGROUND: Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned. METHODS: We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions. RESULTS: The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes. CONCLUSION: We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.

Reduced striatal D1 receptor binding in autosomal dominant nocturnal frontal lobe epilepsy.

BACKGROUND: Mutations of the neuronal nicotinic acetylcholine (nACh) receptor identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) lead to increased sensitivity to ACh. As activation of presynaptic nicotinic receptors augments the release of dopamine in the striatum and the prefrontal regions, we tested the hypothesis that that the alpha4-Ser248Phe mutation affects dopaminergic transmission. METHODS: We measured D(1) receptor binding using [(11)C]-SCH23390 and PET in 12 subjects with the alpha4-Ser248Phe mutation (3 men, mean age 41 +/- 16 years) and 19 controls (8 men, mean age 36 +/- 13 years) matched for gender, smoking status, and age. Parametric images were produced using the simplified reference region method. Both MRI-based regions of interest and voxel based analyses were used. RESULTS: Reduced striatal [(11)C]-SCH23390 binding occurred with the mutation (controls 1.1 +/- 0.1; ADNFLE 0.97 +/- 0.2; p < 0.01). Statistical parametric mapping confirmed a region of reduced [(11)C]-SCH23390 binding in the right putamen in alpha4-Ser248Phe subjects compared to controls (309 voxels, local maxima 20 16 -2 mm; Z(score) 3.57, p < 0.05). CONCLUSIONS: Reduced D(1) receptor binding may represent increased extracellular dopamine levels or, more likely, receptor downregulation. Alterations in mesostriatal dopaminergic circuits may contribute to nocturnal paroxysmal motor activity in autosomal dominant nocturnal frontal lobe epilepsy.