Social Vulnerability and COVID-19: Changes in Trauma Activations at a Safety-Net Hospital.

INTRODUCTION: Following the declaration of the COVID-19 pandemic, there were reports of decreased trauma hospitalizations, although violent crime persisted. COVID-19 has had the greatest impact on minoritized and vulnerable communities. Decreases in traumatic events may not extend to these communities, given pandemic-related socioeconomic and psychological burdens that increase the risk of exposure to trauma and violence. MATERIALS AND METHODS: This was a retrospective cohort study (n = 1634) of all trauma activations presenting to our institution January 1, 2020 to May 31, 2020, and same time periods in 2018 and 2019. Census tracts and associated Social Vulnerability Index quartiles were determined from patient addresses. Changes in trauma activations pre and post Massachusetts' state-of-emergency declaration compared to a historical control were analyzed using a difference-in-differences methodology. RESULTS: Weekly all-cause trauma activations fell from 26.44 to 8.25 (rate ratio = 0.36 [0.26, 0.50]) postdeclaration, with significant difference-in-differences compared to a historical control (P < 0.0001). Nonviolent trauma activations significantly decreased from 21.11 to 5.17 after the declaration (rate ratio = 0.27 [0.37, 0.91]; P < 0.0001), whereas there was no significant decrease in violent injury (5.33 to 3.08 rate ratio = 0.69 [0.39, 1.22]; P = 0.20). Stratified by vulnerability, the most vulnerable quartile had an increased proportion of all-cause trauma postdeclaration and had no decrease in violent trauma activations following the declaration compared to the historical control (rate ratio = 0.84 [0.38-1.86]; P = 0.67). CONCLUSIONS: The state-of-emergency declaration was associated with significant decreases in overall trauma, to a greater extent in nonviolent injuries. Among those living in the most socially vulnerable communities, there was no decrease in violent trauma. These findings highlight the need for violence and injury prevention programs in vulnerable communities, particularly in times of crisis.

COVID-19 Pandemic and the Cholecystitis Experience at a Major Urban Safety-Net Hospital.

BACKGROUND: Acute cholecystitis is a common reason for emergency general surgery admission. The declaration of the COVID-19 pandemic may have resulted in treatment delays and corresponding increases in severity of disease. This study compared cholecystitis admissions and disease severity pre- and postdeclaration of pandemic. MATERIALS AND METHODS: Retrospective review of adult acute cholecystitis admissions (January 1,2020-May 31, 2020). Corresponding time periods in 2018 and 2019 comprised the historical control. Difference-in-differences analysis compared biweekly cholecystitis admissions pre- and postdeclaration in 2020 to the historical control. Odds of increased severity of disease presentation were assessed using multivariable logistic regression. RESULTS: Cholecystitis admissions decreased 48.7% from 5.2 to 2.67 cases (RR 0.51 [0.28,0.96], P = 0.04) following pandemic declaration when comparing 2020 to historical control (P = 0.02). After stratifying by severity, only Tokyo I admissions declined significantly postdeclaration (RR 0.42 [0.18,0.97]), when compared to historical control (P = 0.02). There was no change in odds of presenting with severe disease after the pandemic declaration (aOR 1.00 [95% CI 0.30, 3.38] P < 0.99) despite significantly longer lengths of symptoms reported in mild cases. CONCLUSIONS: Postpandemic declaration we experienced a significant decrease in cholecystitis admissions without corresponding increases in disease severity. The pandemic impacted healthcare-seeking behaviors, with fewer mild presentations. Given that the pandemic did not increase odds of presenting with increased severity of disease, our data suggests that not all mild cases of cholecystitis progress to worsening disease and some may resolve without medical or surgical intervention.

Forensic evaluation of alleged wrist restraint/handcuff injuries in survivors of torture utilizing the Istanbul Protocol.

Despite being a common form of abuse, there is a paucity of literature describing shackling and wrist restraint injuries among survivors of torture. Forensic evaluation of alleged wrist restraint/handcuff injuries in survivors of torture presents challenges to the evaluator, especially if the injuries are remote and do not leave lasting marks nor neurologic deficits. Thorough history-taking and physical examination are critical to effective forensic documentation. Guidance is provided in The Manual on Effective Investigation and Documentation of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment (Istanbul Protocol), the gold standard for the medicolegal documentation of torture. This guidance relies primarily on physical findings, with less direction provided on how to interpret historical evidence or when historical evidence provided by the patient can be interpreted as highly consistent with alleged injury in the absence of current physical findings. Through a case-based review, we present diagnostic strategies for the evaluation of alleged abuse involving wrist restraints/handcuffs, focusing on skin, neurologic, and osseous injuries. We highlight key findings from both the history and physical examination that will allow the evaluator to improve the accuracy of their expert medical opinion on the degree to which medical findings correlate with the patient's allegations of wrist restraint injuries.

Firearm Policy: Physician Organizations' Role in Political Action Committee Funds, 2018.

Objectives. To compare donations to individual politicians from physician organization political action committees (PACs) and from the National Rifle Association Political Victory Fund (NRA PVF) in 2018.Methods. We identified 7 organizations with published firearm injury prevention policy. We determined the difference in funds received from physician organization PACs and the NRA PVF for each congressmember. We examined their voting records on firearm-related legislation.Results. A total of 141 congressmembers received funds from both physician organization PACs and the NRA PVF. Of these, 99.3% voted for legislation not consistent with organization recommendations. The majority (70.2%) received more funds from the combined physician organization PACs than from the NRA PVF.Conclusions. Physician organization PACs have a financial impact on NRA-backed congressmembers. They currently contribute to politicians with voting records inconsistent with their own policy recommendations. Firearm violence prevention does not currently outweigh other legislative priorities for physician organization PAC contributions.

Dual array EEG-fMRI: An approach for motion artifact suppression in EEG recorded simultaneously with fMRI.

OBJECTIVE: Although simultaneous recording of EEG and MRI has gained increasing popularity in recent years, the extent of its clinical use remains limited by various technical challenges. Motion interference is one of the major challenges in EEG-fMRI. Here we present an approach which reduces its impact with the aid of an MR compatible dual-array EEG (daEEG) in which the EEG itself is used both as a brain signal recorder and a motion sensor. METHODS: We implemented two arrays of EEG electrodes organized into two sets of nearly orthogonally intersecting wire bundles. The EEG was recorded using referential amplifiers inside a 3T MR-scanner. Virtual bipolar measurements were taken both along bundles (creating a small wire loop and therefore minimizing artifact) and across bundles (creating a large wire loop and therefore maximizing artifact). Independent component analysis (ICA) was applied. The resulting ICA components were classified into brain signal and noise using three criteria: 1) degree of two-dimensional spatial correlation between ICA coefficients along bundles and across bundles; 2) amplitude along bundles vs. across bundles; 3) correlation with ECG. The components which passed the criteria set were transformed back to the channel space. Motion artifact suppression and the ability to detect interictal epileptic spikes following daEEG and Optimal Basis Set (OBS) procedures were compared in 10 patients with epilepsy. RESULTS: The SNR achieved by daEEG was 11.05±3.10 and by OBS was 8.25±1.01 (p<0.00001). In 9 of 10 patients, more spikes were detected after daEEG than after OBS (p<0.05). SIGNIFICANCE: daEEG improves signal quality in EEG-fMRI recordings, expanding its clinical and research potential.

Historic redlining, social mobility, and firearm violence.

BACKGROUND: Much of the recorded medical literature focuses on individual-level factors that contribute to firearm violence. Recently, studies have highlighted higher incidence of firearm violence in historically redlined and marginalized areas, but few have gone on to study the downstream associations causing these differences. This study aims to understand the effects of historic redlining and current income mobility on firearm violence. METHODS: Using a retrospective cross-sectional design, shooting incidents were spatially joined with redlining vector files and linked to income mobility data (how much a child makes in adulthood). Participants included all assault and homicide incidents involving a firearm in the city of Boston, between 2016 and 2019. The exposure of interest was redlining designation as outlined by the Home Owner's Loan Corporation (HOLC) in the 1930s and income mobility, stratified by race, defined as the income of a child in their 30s compared with where they grew up (census tract level). The outcome measured was shooting rate per census block. RESULTS: We find that increases in Black income mobility (BIM) and White income mobility (WIM) are associated with significant decreases in rates of firearm incidents in all HOLC designations; however, there is a larger decrease with increasing BIM (relative risk, 0.47 per unit increase in BIM [95% confidence interval, 0.35-0.64]; relative risk, 0.81 per unit increase in WIM [95% confidence interval, 0.71-0.93]). Plotting predicted rates of firearm violence in each HOLC designation at different levels of BIM, there were no significant differences in shooting rates between historically harmful and beneficial classifications above $50,000 of BIM. Despite level of WIM, there were continued disparities between harmful and beneficial HOLC classification. CONCLUSION: These findings highlight the importance of structural racism in the form of redlining and discriminatory housing policies, and the preclusion from economic mobility therein, on the incidence of firearm violence today. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

The effect of historic redlining on firearm violence.

BACKGROUND: Firearm homicides disproportionately affect young Black men, which in turn have lasting impact of communities of color as a whole. Previous cross-sectional studies have highlighted the role of discriminatory housing policies on the incidence of urban firearm violence. We sought to estimate the effects of racist housing policies on firearm incidence. METHODS: Firearm incident data were obtained from the Boston Police Department and point locations spatially joined with vector files outlining the original 1930 Home Owner Loan Corporation (HOLC) Redlining maps. A regression discontinuity design was used to assess the increased rate of firearm violence crossing from historically "desirable" neighborhoods (Green) to historically "hazardous" neighborhoods (Red and Yellow) based on HOLC definitions. Linear regression models were fit on either side of the geographic boundaries with firearm incidents graphed at varying distances and the regression coefficient calculated at the boundary. RESULTS: Crossing from desirable to Red hazardous designation there was a significant discontinuity with an increase of 4.1 firearm incidents per 1,000 people (95% CI 0.68,7.55). Similarly, when crossing from desirable areas to the Yellow hazardous designation there was a significant discontinuity and increase of 5.9 firearm incidents per 1,000 people (95% CI 1.85,9.86). There was no significant discontinuity between the two hazardous HOLC designations (coefficient -0.93, 95% CI -5.71, 3.85). CONCLUSIONS: There is a significant increase in firearm incidents in historically redlined areas of Boston. This suggests that interventions should focus on downstream socioeconomic, demographic, and neighborhood detriments of historically discriminatory housing policies in order to address firearm homicides.

History repeats itself: Impact of mental illness on violent reinjury and hospital reencounters among female victims of interpersonal violence.

BACKGROUND: Violence-related reinjury impacts both patients and health care systems. Mental illness (MI) is prevalent among violently injured individuals. The relationship between preexisting MI and violent reinjury among women has not been fully characterized. Our objective was to determine if risk of hospital reencounter-violent reinjury and all-cause-was associated with preexisting MI at time of index injury among female victims of violence. METHODS: All females (15-100 + years) presenting to a level I trauma center with violent injury (2002-2019) surviving to discharge were included (N = 1,056). Exposure was presence of preexisting MI. The primary outcome was hospital reencounters for violent reinjury and all-cause within one year (through 2020). The secondary outcome was the development of a new MI within one year of index injury. Odds of reencounter and development of new MI for those with and without preexisting MI were compared with multivariable logistic regression, stratified for interaction when appropriate. RESULTS: There were 404 women (38%) with preexisting MI at time of index injury. Approximately 11% of patients with preexisting MI experienced violent reinjury compared to 5% of those without within 1 year ( p < 0.001). Specifically, those with MI in the absence of concomitant substance use had more than three times the odds of violent reinjury (adjusted Odds Ratio, 3.52 (1.57, 7.93); p = 0.002). Of those with preexisting MI, 64% had at least one reencounter for any reason compared to 46% of those without ( p < 0.001 ) . Odds of all-cause reencounter for those with preexisting MI were nearly twice of those without (adjusted Odds Ratio, 1.81 [1.36, 2.42]; p < 0.0001). CONCLUSION: Among female victims of violence, preexisting MI is associated with a significantly increased risk of hospital reencounter and violent reinjury within the first year after index injury. Recognition of this vulnerable population and improved efforts at addressing MI in trauma patients is critical to ongoing prevention efforts to reduce violent reinjury. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

State firearm laws and nonfatal firearm injury-related inpatient hospitalizations: A nationwide panel study.

BACKGROUND: Firearm injury remains a major cause of morbidity and mortality in the United States. Because of prior lack of comprehensive data sources, there is a paucity of literature on nonfatal firearm injury. Associations have previously been shown between state-level firearm laws and firearm fatalities, but few studies have examined the effects of these laws on nonfatal firearm hospitalization rates. Our objective was to examine the relationship between state firearm laws and firearm injury-related hospitalization rates across all 50 states over a 17-year period. METHODS: In this panel study design, we used fixed effects multivariate regression models to analyze the relationship between 12 laws and firearm state-level injury-related hospitalization rates from 2000 to 2016 using the RAND Corporation Inpatient Hospitalizations for Firearm Injury Database. We used difference-in-differences to determine the impact of law passage in a given state compared with those states without the law, controlling for state-level covariates. The main outcome measure was the change in annual firearm injury-related inpatient hospitalization rates after passage or repeal of a state-level firearm law. RESULTS: Examining each law individually, passage of violent misdemeanor, permitting, firearm removal from domestic violence offenders, and 10-round limit laws were associated with significant firearm injury-related hospitalization rate reductions. Examining multiple laws in the same model, passage of violent misdemeanor laws was associated with a 19.9% (confidence interval, 11.6%-27.4%) reduction, and removal of firearms from domestic violence offenders was associated with a 17.0% (confidence interval, 9.9%-23.6%) reduction in hospitalization rates. CONCLUSION: State laws related to preventing violent offenders from possessing firearms are associated with firearm injury-related hospitalization rate reductions. Given significant physical, mental, and social burdens of nonfatal firearm injury, determining the efficacy of firearm-related policy is critical to violence and injury prevention efforts. LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level IV.

A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Historic redlining, structural racism, and firearm violence: A structural equation modeling approach.

BACKGROUND: Firearm homicides disproportionately affect Black communities. Redlining - discriminatory lending practices of the early 20th century - are associated with current increased rates of firearm violence. Poverty and concentrated disadvantage are also associated with firearm violence. The interaction of these factors with racist redlining housing practices remains unclear. METHODS: We used generalized structural equation modeling to characterize the mediators through which redlining practices of the 1930s led to present rates of firearm violence in Boston using a negative binomial model. Principle component analysis was used to create four distinct mediating variables representing census block socioeconomic and built environment information, while reducing dimensionality. We calculated the direct effect between harmful (Red and Yellow) vs beneficial (Green) designations and firearm incident rate, indirect effect between redlining designation and firearm incident rate through each mediating variable, and the total effect. The percentage mediation of each mediator was subsequently calculated. FINDINGS: Red and Yellow areas of Boston were associated with an 11•1 (95% CI 5•5,22•4) and 11•4 (5•7,22•8) increased incident rate of shooting when compared to Green. In the pathway between Red designation and firearm incident rate, poverty and poor educational attainment mediated 20% of the interaction, share of rented housing mediated 8%, and Black share of the population 3%. In the pathway between Yellow designation and firearm incident rate, poverty and poor educational attainment mediated 16% of the association, and Black share of the population mediated 13%. INTERPRETATION: Redlining practices of the 1930s potentially contribute to increased rates of firearm violence through changes to neighborhood environments, namely through preclusion from homeownership, poverty, poor educational attainment, and concentration (i.e. segregation) of Black communities. These downstream mediating factors serve as points for policy interventions to address urban firearm violence. FUNDING: Michael Poulson and Miriam Neufeld were supported by T32 Training Grants (HP10028, GM86308).

Amplifying inequity: The compounding impact of COVID-19 and violence.

While "stay-at-home" orders for COVID-19 were in effect, many American cities witnessed a rise in community and interpersonal violence. Our own institution, the largest regional trauma facility and Boston's safety net hospital, saw a paradoxical rise in penetrating violent trauma admissions despite decreases in other hospital admissions, leading to our most violent summer in five years. It has been established that minoritized and marginalized communities have faced the harshest impacts of the pandemic. Our findings suggest that the conditions created by the COVID-19 pandemic have amplified the inequities that exist in communities of color that place them at risk for exposure to violence. The pandemic has served to potentiate the impacts of violence already plaguing the communities and patients we serve.

Where did the patients go? Changes in acute appendicitis presentation and severity of illness during the coronavirus disease 2019 pandemic: A retrospective cohort study.

BACKGROUND: The coronavirus disease 2019 pandemic restricted movement of individuals and altered provision of health care, abruptly transforming health care-use behaviors. It serves as a natural experiment to explore changes in presentations for surgical diseases including acute appendicitis. The objective was to determine if the pandemic was associated with changes in incidence of acute appendicitis compared to a historical control and to determine if there were associated changes in disease severity. METHODS: The study is a retrospective, multicenter cohort study of adults (N = 956) presenting with appendicitis in nonpandemic versus pandemic time periods (December 1, 2019-March 10, 2020 versus March 11, 2020-May 16, 2020). Corresponding time periods in 2018 and 2019 composed the historical control. Primary outcome was mean biweekly counts of all appendicitis presentations, then stratified by complicated (n = 209) and uncomplicated (n = 747) disease. Trends in presentations were compared using difference-in-differences methodology. Changes in odds of presenting with complicated disease were assessed via clustered multivariable logistic regression. RESULTS: There was a 29% decrease in mean biweekly appendicitis presentations from 5.4 to 3.8 (rate ratio = 0.71 [0.51, 0.98]) after the pandemic declaration, with a significant difference in differences compared with historical control (P = .003). Stratified by severity, the decrease was significant for uncomplicated appendicitis (rate ratio = 0.65 [95% confidence interval 0.47-0.91]) when compared with historical control (P = .03) but not for complicated appendicitis (rate ratio = 0.89 [95% confidence interval 0.52-1.52]); (P = .49). The odds of presenting with complicated disease did not change (adjusted odds ratio 1.36 [95% confidence interval 0.83-2.25]). CONCLUSION: The pandemic was associated with decreased incidence of uncomplicated appendicitis without an accompanying increase in complicated disease. Changes in individual health care-use behaviors may underlie these differences, suggesting that some cases of uncomplicated appendicitis may resolve without progression to complicated disease.

Utilization of mental health services in pediatric patients surviving penetrating trauma resulting from interpersonal violence.

BACKGROUND: Violent trauma has lasting psychological impacts. Our institution's Community Violence Response Team (CVRT) offers mental health services to trauma victims. We characterized implementation and determined factors associated with utilization by pediatric survivors of interpersonal violence-related penetrating trauma. METHODS: Analysis included survivors (0-21 years) of violent penetrating injury at our institution (2011-2017). Injury and demographic data were collected. Nonparametric regression models determined factors associated with utilization. RESULTS: There was initial rapid uptake of CVRT (2011-2013) after which it plateaued, serving >80% of eligible patients (2017). White race and higher injury severity were associated with receipt and duration of services. In post-hoc analysis, race was found to be associated with continued treatment but not with initial consultation. CONCLUSION: Successful implementation required three years, aiding >80% of patients. CVRT is a blueprint to strengthen existing violence intervention programs. Efforts should be made to ensure that barriers to providing care, including those related to race, are overcome.

Mild adolescent/adult onset epilepsy and paroxysmal exercise-induced dyskinesia due to GLUT1 deficiency.

Paroxysmal exercise-induced dyskinesia (PED) and epilepsy without intellectual disability have recently been recognized as manifestations of deficiency of the glucose transporter GLUT1, due to mutations in the gene SLC2A1. We describe a family with six definitely affected members in two generations. Two had PED, three had epilepsy, and one had both. A missense mutation in SLC2A1 (c.950A>C; p.N317T) was detected in five living affected members, but absent in three nonaffected first-degree members and in one subject believed to be a phenocopy. The clinical picture of mild epilepsy with onset in adolescence or early adulthood plus PED should raise a suspicion of GLUT1 deficiency.

The effect of patient code status on surgical resident decision making: A national survey of general surgery residents.

BACKGROUND: Multiple studies have demonstrated that, compared with their full code counterparts, patients with do-not-resuscitate or do-not-intubate status have higher in-hospital and postdischarge mortality than predicted by clinical characteristics alone. We sought to determine whether patient code status affects surgical resident decision making. METHODS: We created an online survey that consisted of 4 vignettes, followed by 10 questions regarding decisions on possible diagnostic and therapeutic interventions. All program directors of Accreditation Council for Graduate Medical Education-accredited general surgery residencies were randomized to receive 1 of 2 survey versions that differed only in the code status of the patients described, with requests to distribute the survey to their residents. Responses to each question were based on a Likert scale. RESULTS: A total of 194 residents completed the survey, 51% of whom were women, and all years of surgical residency were represented. In all vignettes, patient code status influenced perioperative medical decisions, ranging from initiation of dialysis to intensive care unit transfer. In 2 vignettes, it affected decisions to proceed with indicated emergency operations. CONCLUSION: When presented with patient scenarios pertaining to clinical decision making, surgical residents tend to assume that patients with a do-not-resuscitate or do-not-intubate code status would prefer to receive less aggressive care overall. As a result, the delivery of appropriate surgical care may be improperly limited unless a patient's goals of care are explicitly stated. It is important for surgical residents to understand that a do-not-resuscitate or do-not-intubate code status should not be interpreted as a "do-not-treat" status.

SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis.

OBJECTIVE: We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+). METHODS: Multiplex ligation-dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH). RESULTS: Novel SCN1A CNVs were found in 12.5% of DS patients where sequence-based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early-onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5-6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A. DISCUSSION: Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2-3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.

Epilepsy and mental retardation limited to females: an under-recognized disorder.

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder. We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6-36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis.

A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping.

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.