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Objectives: To determine: i) seizure recurrence; ii) developmental disability; iii) co-morbidities and risk factors in self-limited familial neonatal and/or infantile epilepsy (SeLFE) in a multigenerational study., Methods: Families were retrospectively recruited from epilepsy databases (2021-2022) in 2 paediatric hospitals, Sydney, Australia. Eligible families had 2 first degree relatives with seizures and underwent genetic testing. Demographics/clinical data were collected from interviews and medical records. Vineland Adaptive Behaviour Scales-Third Edition measured adaptive function., Results: Fifteen families participated. Fourteen had a genetic diagnosis (93%): 11 pathogenic; PRRT2 (n=4), KCNQ2 (n=3), SCN2A (n=4), 3 likely pathogenic; KCNQ2 (n=1), SCN8A (n=2). Seizures affected 73 individuals (ages 1-76 years); 30 children and 20 adults had in-depth phenotyping. Ten of 50 individuals (20%) had seizure recurrence, aged 8-65 years. Median time from last neonatal/infantile seizure was 11.8/12.8 years. Predictors of recurrence were high seizure number (p=0.05) and longer treatment duration (p=0.03). Seven children had global developmental delay (GDD): mild (n=4), moderate (n=1) and severe (n=2). Vineland-3 identified 3 had low-average and 3 had mild-moderately impaired functioning. The majority (82%) were average. GDD was associated with older age at last seizure (p=0.03), longer epilepsy duration (p=0.02), and higher number of anti-seizure medications (p=0.05). Four children had speech delay, 5 (10%) had Autism Spectrum Disorder. Paroxysmal kinesiogenic dyskinesia (n=5) occurred in 4 families and hemiplegic migraine (n=8) in 3 families., Conclusions: Individuals with SeLFE have a small risk of recurrent seizures (20%) and neurodevelopmental disability. Significant predictors are higher seizure number and longer epilepsy duration. Developmental surveillance is imperative., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Genetic sequencing is identifying an expanding number of variants of GABA A receptors associated with human epilepsies. We identified a new de novo variant of the β2 subunit (β2L51M) of the inhibitory GABA A receptor associated with seizures. Our analysis determined the pathogenicity of the variant and the effects of anti-seizure medications. Our data demonstrates that the variant reduced cell surface trafficking and peak GABA-gated currents. Synaptic currents mediated by variant-containing receptors decayed faster than wild-type and single receptor currents showed that the variant shortened the duration of receptor activity by decreasing receptor open times. We tested the effects of the anti-seizure medications, midazolam, carbamazepine and valproate and found that all three enhance variant receptor surface expression. Additionally, midazolam restored receptor function by increasing single receptor active periods and synaptic current decay times towards wild-type levels. By contrast, valproate increased synaptic peak currents, event frequency and promoted synaptic bursting. Our study identifies a new disease-causing variant to the GABA A receptor, profiles its pathogenic effects and demonstrates how anti-seizure drugs correct its functional deficits., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro., Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs., Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001)., Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways., Methods: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing. Sensitivity analysis was included with a range of commercial exome and multigene panels., Results: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported., Conclusion: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions., (© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We report an individual who presented with severe neurodevelopmental delay and an intractable infantile-onset seizure disorder. Exome sequencing identified a homozygous single nucleotide change that abolishes a splice donor site in the ARV1 gene (c.294 + 1G > A homozygous). This variant completely prevented splicing in minigene assays, and resulted in exon skipping and an in-frame deletion of 40 amino acids in primary human fibroblasts (NP&#95;073623.1: p.(Lys59&#95;Asn98del). The p.(Lys59&#95;Asn98del) and previously reported p.(Gly189Arg) ARV1 variants were evaluated for protein expression and function. The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature. In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells. Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood. Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This is the first case-control study to determine whether smoking is associated with cervical dysplasia, after adjustment for human papillomavirus (HPV) infection, among a group of non-Hispanic black women. Subjects were interviewed and asked questions about smoking and other risk factors for cervical cancer. HPV infection was determined by hybrid capture. Thirty-two women with histologically confirmed incident dysplasia and 113 control women with normal cytologic smears were enrolled; all women were HIV negative. Smoking was more strongly associated with dysplasia among women with high-grade lesions than among all case women combined. After adjustment, women with high-grade lesions were roughly four times more likely to be ever (odds ratio [OR]: 3.8; 95% confidence interval [CI]: 0.76-18.4) or current (OR: 4.3; 95% CI: 0.83-21.9) smokers, compared with control women. Larger studies among black women that control for HPV infection are needed to confirm these findings and to explore associations among black women with low-grade lesions.

The medical records and liver biopsies of nine sickle cell patients with chronically elevated liver function tests were retrospectively reviewed to determine the etiology of chronic liver disease. There were eight women and one man with a mean age of 30 yr. All patients had hemoglobin SS. Eight patients were referred for elevated aminotransferases and one for an elevated alkaline phosphatase. Hemosiderosis was present in all of the biopsies. Two patients had cirrhosis. Chronic hepatitis was noted in two patients, and five patients had cholestasis. Two patients had serologic markers demonstrating HBV exposure but no patients were HBsAg positive. Erythrophagocytosis, sinusoidal dilatation, and Kupffer cell hyperplasia were present in all of the liver biopsies. Transfusion-related causes were the most common significant pathologic findings in our patients, and appeared to be the etiologies of chronic liver disease in sickle cell patients.

We have identified a novel growth factor, stem cell factor (SCF), for primitive hematopoietic progenitors based on its activity on bone marrow cells derived from mice treated with 5-fluorouracil. The protein was isolated from the medium conditioned by Buffalo rat liver cells. It is heavily glycosylated, with both N-linked and O-linked carbohydrate. Amino acid sequence following removal of N-terminal pyroglutamate is presented. The protein has potent synergistic activities in semisolid bone marrow cultures in conjunction with colony-stimulating factors. It is also a growth factor for mast cells. In two companion papers, we present the sequences of partial SCF cDNAs, identify SCF as a c-kit ligand, and map the SCF gene to the Sl locus of the mouse.

Ovarian stroma contains cells with the ultrastructural features of smooth-muscle cells. The purpose of this study was to analyze normal ovaries, ovarian stromal tumors (fibroma/thecomata and granulosa cell tumors), and ovarian leiomyomata for desmin reactivity. Groups of ovarian stromal cells that expressed desmin were noted in six of six normal ovaries. Desmin was also detected in two of six fibroma/thecomata and two of two ovarian leiomyomata. The number of tumor cells with detectable desmin was much greater in the leiomyomata. Desmin was not detected in any of six granulosa cell tumors. We conclude that stromal cells with an immunohistochemical feature of smooth-muscle cells are routinely found in normal ovaries. This study demonstrates the usefulness of immunohistochemistry in corroborating the diagnosis of ovarian leiomyomata, although desmin positivity per se is not diagnostic of ovarian leiomyomata, and also raises the possibility that some ovarian leiomyomata may be derived from stromal cells.

The cytogenetic analysis of an infant with multiple congenital anomalies revealed a small deletion of the long arm of one No. 11 chromosome: 46,XX,del(11)(q23). The main clinical manifestations included: ocular colobomata, absent philtrum, severe congenital heart disease, contractures of the large joints and skin pigmentation. Both parents showed a normal chromosome constitution. In comparison to the previously reported cases of 11q-, the patient presented here had more severe congenital anomalies. The correlation of the size of the deletion, and the location of the break, with the physical findings is discussed.

A simple life-saving modification of the transnasal approach, which does not require endotracheal anesthesia or preoperative tracheostomy, is described. The use of polyethylene tubes, flanged at the distal end and split at the proximal end, is the most significant feature of this technique. In 14 of the 16 cases of choanal atresia presented, this was the definitive corrective procedure, and further revisions or a later transpalatal approach were not required. The advantages of this technique are that it is simple, it may be used in the first 24 hours of life or at any age, the patient may be released from the hospital in 1 to 2 weeks, and minimal postoperative care is required.

In 1976 a 28-year-old Ecuadoran male suffered paraparesis after a kick to his back. Iophendylate myelography was followed by thoracic laminectomy with incomplete resolution of the paraparesis. One year later, worsening of the paraparesis was managed by further thoracic laminectomy without improvement. In 1978 a spinal cord stimulator was implanted via low thoracic laminectomy as a measure to counter his spasticity. In 1984 metrizamide myelography and computed tomography scanning were performed for increasing spastic paraparesis that disclosed an intramedullary lesion at the T-4 level. Exploration and myelotomy revealed an intramedullary cysticercal cyst, which was totally removed.

A 27-year-old black male with secondary syphilis and cholestatic jaundice is presented. The liver biopsy was believed to be most consistent with large bile duct obstruction, but both the ultrasound and endoscopic retrograde cholangiography were normal. Prior to treatment with penicillin, his serum was positive for antimitochondrial antibody. After treatment, the antibody was no longer detectable and the jaundice gradually resolved. The patient's pretreatment serum was, after further analysis, found to be positive for the antibody to the M1 antimitochondrial antigen subtype, which is identical to cardiolipin, the antigen in both the VDRL and Wasserman tests. A review of hepatic involvement in secondary syphilis is presented.