Refining the phenotypic spectrum of CCDC88A-related PEHO-like syndrome.

Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) and PEHO-like syndromes are very rare infantile disorders characterized by profound intellectual disability, hypotonia, convulsions, optic, and progressive brain atrophy. Many causative genes for PEHO and PEHO-like syndromes have been identified including CCDC88A. So far, only five patients from two unrelated families with biallelic CCDC88A variants have been reported in the literature. Herein, we describe a new family from Egypt with a lethal epileptic encephalopathy. Our patient was the youngest child born to a highly consanguineous couple and had a family history of five deceased sibs with the same condition. She presented with postnatal microcephaly, poor visual responsiveness, and epilepsy. Her brain MRI showed abnormal cortical gyration with failure of opercularization of the insula, hypogenesis of corpus callosum, colpocephaly, reduced white matter, hypoplastic vermis, and brain stem. Whole exome sequencing identified a new homozygous frameshift variant in CCDC88A gene (c.1795_1798delACAA, p.Thr599ValfsTer4). Our study presents the third reported family with this extremely rare disorder. We also reviewed all described cases to better refine the phenotypic spectrum associated with biallelic loss of function variants in the CCDC88A gene.

First LIPA Mutational Analysis in Egyptian Patients Reveals One Novel Variant: Wolman Disease.

Lysosomal acid lipase (LAL) is a necessary enzyme for the hydrolysis of both triglycerides (TGs) and cholesteryl esters (CEs) in the lysosome. Deficiency of this enzyme encoded by the lipase A (LIPA) gene leads to LAL deficiency (LAL-D). A severe disease subtype of LAL-D is known as Wolman disease (WD), present with diarrhea, hepatosplenomegaly, and adrenal calcification. Untreated patients do not survive more than a year. The aim of this study was to assess the clinical and molecular characterizations of WD patients in Egypt. A total of seven patients (from five unrelated Egyptian families) were screened by targeted next-generation sequencing (NGS), and the co-segregation of causative variants was analyzed using Sanger sequencing. Furthermore, multiple in silico analyses were performed to assess the pathogenicity of the candidate variants. Overall, we identified three diseases causing variants harbored in the LIPA gene. One of these variants is a novel missense variant (NM_000235.4: c.1122 T > G; p. His374Gln), which was classified as a likely pathogenic variant. All variants were predicted to be disease causing using in silico analyses. Our findings expand the spectrum of variants involved in WD which may help to investigate phenotype-genotype correlation and assist genetic counseling. To the best of our knowledge, this is the first clinico-genetic study carried out on Egyptian patients affected with WD.

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10-and EMC1-related disease.

Surgical nuances in corpus callosotomy as a palliative epilepsy surgery.

Background: Corpus callosotomy is a well-established palliative procedure in selected patients with drug resistant epilepsy (DRE). It has a beneficial role in ameliorating generalized seizures mainly drop attacks. Here, we present some technical tips for performing callosotomy depending on the anatomical basis, to minimize craniotomy size and guard against inadvertently entering the lateral ventricles. Methods: This study was a retrospective review of patients who received corpus callosotomy at our institute as a palliative epilepsy surgery. We present our experience and surgical tips with the extraventricular technique of corpus callosotomy with comparison of surgery-related complications and operative time between extraventricular and conventional techniques in selected patients with DRE. Results: Our study included 34 patients. First group of patients included 14 patients who received conventional approach, while the extraventricular approach was done in 20 patients. Extraventricular approach showed significantly lower wound complications rate of 10% compared to 78% in intraventricular approach (P < 0.001). Mean operative time was significantly lower in extraventricular versus conventional technique with 52 min versus 94 min, respectively (P < 0.001). Planned extent of corpus callosotomy resection was achieved in all our patients using both approaches. Conclusion: The cleft of the septum pellucidum offers a natural pursuit to section corpus callosum strictly midline and completely extraventricular in well selected patients of DRE candidate for callosotomy. Performing corpus callosotomy in extraventricular approach provided better patients outcomes regarding surgery and wound-related complications when compared to conventional approach.

Sensorineural hearing loss imprint on fine motor skills: A pediatric and adolescent innovative study.

BACKGROUND: Sensorineural hearing loss is the most common type of permanent hearing impairment and results in balance and motor deficits in children which may affect and/or delay all developmental indicators. OBJECTIVE: The purpose of this study was to investigate the consequences of sensorineural hearing loss regarding fine motor skills in children and adolescents. METHODS: Two hundred children with an age range between 7 to 18 years and diagnosed with sensorineural hearing loss were selected from the Public School for the Deaf and Hard of Hearing in El-Minia district, Minia governorate, Egypt. The outcome was assessed by the use of Bruininks-Oseretsky Test of Motor Proficiency Second Edition scale (BOT-2) to measure fine motor skills. RESULTS: There was a statistically significant difference between the scores of Fine Motor Precision and Fine Motor Integration subtests of each study subgroup and its counterpart subgroup in the control group (normative values according to the scale) which has the same age and gender characteristics where p value equals (0.0008 or less, 0.0009 or less) respectively, with a large effect size less than -0.83. CONCLUSION: The findings of this study suggest that children with sensorineural hearing loss have a defect in their fine motor skills when compared to normal children of the same gender and age groups according to Bruininks-Oseretsky scale.

Assessment of psychological disorders in Egyptian children with hearing impairment.

Impairment of hearing is a common birth defect which may be associated with varieties of psychological abnormalities in childhood. Knowledge and research of such issue are much lacking in Egypt; so the aim of the current study was to characterize and assess various psychological co-morbidities which could occur among hearing-impaired children. This prospective study has been conducted on a total of 40 male children, with age range between 7 and 12 years, divided into two groups. Group I included 20 children with different degrees of hearing impairment (HI), and Group II included 20 age-matched, healthy children with normal hearing. The studied children have been recruited from two schools (Al Amal School for the Deaf and Dumb, and Copts School) at Minia City, Minia Governorate, Egypt. Psychometric assessment, electroencephalography (EEG), and audiological evaluation were done for all included children. EEG abnormalities and anxiety scores were significantly higher in patients group compared with controls (p < 0.05); however, intelligence quotient did not differ. The present study revealed that HI is associated with psychological and EEG abnormalities. Early management of these children is expected to improve their quality of life.

Role of Serum Level of Neurometals; Copper, Zinc and Magnesium in Neonates with Hypoxic Ischemic Encephalopathy.

BACKGROUND: Perinatal HIE is associated with high morbidity and mortality rates worldwide, despite the improvements in perinatal care. The aim of this study was to evaluate the role Cu, Zn, and Mg+2 neurometals in the development of neonatal hypoxic ischemic encephalopathy. METHODS: This study included two groups: group 1 (study group): Thirty full term, and diagnosed as having hypoxic ischemic encephalopathy. Group 2 (control group): Thirty full term healthy neonates. All the neonates included in the study were subjected to full history taking and complete clinical and neuromuscular examinations. Laboratory investigations were done in both groups and included complete blood picture, renal functions test, ESR, serum zinc, copper, magnesium, sodium, potassium, and calcium levels. RESULTS: There were high serum zinc and copper levels in the patient group compared to the control group. However, there was low serum magnesium, calcium, and sodium levels in the patient group compared to the control group. There was a significant difference regarding Apgar score at 1 minute and 5 minutes between patient and control groups. The mean ESR values in patient group at the first hour and second hour were higher in the patient than the control group. CONCLUSIONS: Neonates with perinatal asphyxia have significantly higher levels of serum zinc and copper and lower serum magnesium, calcium, and potassium levels compared to healthy non asphyxiated neonates. Copper, zinc, and magnesium may play an important role in the development of neonatal hypoxic ischemic encephalopathy; however, further studies are needed to support our findings.

Phosphorothioate di- and trinucleotides as a novel class of anti-hepatitis B virus agents.

Several nucleoside analogs are under clinical development for use against hepatitis B virus (HBV). Lamivudine (3TC), a nucleoside analog, and adefovir dipivoxil (ADV), an acyclonucleotide analog, are clinically approved. However, long-term treatment can induce viral resistance, and following the cessation of therapy, viral rebound is frequently observed. There continues to be a need for new antiviral agents with novel mechanisms of action. A library of more than 600 di- and trinucleotide compounds synthesized by parallel synthesis using a combinatorial strategy was screened for potential inhibitors of HBV replication using the chronically HBV-producing cell line 2.2.15. Through an iterative process of synthesis, lead optimization, and screening, three analogs were identified as potent inhibitors of HBV replication: dinucleotides ORI-7246 (drug concentration at which a 10-fold reduction of HBV DNA was observed [EC(90)], 1.4 microM) and ORI-9020 (EC(90), 1.2 microM) and trinucleotide ORI-7170 (EC(90), 7.2 microM). These analogs inhibited the replication of both strands of HBV DNA. No suppression of HBV protein synthesis or intracellular core particle formation by these analogs was observed. No inhibition of HBV DNA strand elongation by the analogs or their 5'-triphosphate versions was apparent in in vitro polymerase assays. Although the exact mechanism of action is not yet identified, present data are consistent with an inhibition of the HBV reverse transcriptase-directed priming step prior to elongation of the first viral DNA strand. In transient-transfection assays, these analogs inhibited the replication of 3TC-resistant HBV. Synergistic interactions in combination treatments between the analogs and either 3TC or ADV were observed. These compounds represent a novel class of anti-HBV molecules and warrant further investigation as potential therapeutic agents.

Anti-hepatitis B virus activity of ORI-9020, a novel phosphorothioate dinucleotide, in a transgenic mouse model.

ORI-9020, a novel dinucleotide, evaluated in transgenic mice expressing hepatitis B virus (HBV), significantly reduced liver HBV DNA (P

Basal replication of hepatitis C virus in nude mice harboring human tumor.

Hepatitis C virus (HCV) can infect and propagate in humans and chimpanzees. Whereas the chimpanzee has been used as an animal model for infection, ethical considerations, conservation, and the prohibitively high cost preclude progress for experimental research on the biology of the virus. The development of a small animal model for HCV infection is thus desirable to facilitate studies on the infectious cycle of the virus and for the evaluation of drugs for the treatment of HCV infections in humans. As an alternative to the chimpanzee model, we have established a model based on ex vivo infection of orthotopically-implanted human hepatocellular carcinoma cells (HCC) in athymic nude mice. The results show that up to 42 days post-infection, HCV RNA was present in the tumor cells as well as in the liver and serum of infected mice. Furthermore, a direct correlation between size of the tumor and the presence of HCV RNA in the liver was observed, which is concordant with the finding that HCV RNA was detectable only in mice harboring human tumor. Immunohistochemistry analysis of infected liver specimens showed cells expressing the HCV encoded NS5B protein. A few mice developed a humoral response against the nonstructural viral proteins, providing further evidence for expression of these proteins during viral infection. In summary, these results suggest that mice harboring orthotopic tumors support a basal level of HCV replication in vivo.

The hepatitis C virus (HCV)-Trimera mouse: a model for evaluation of agents against HCV.

The lack of small-animal models that are suitable for evaluation of agents used to treat infection with hepatitis C virus (HCV) severely hinders the assessment of potential new therapies for the disease. This study created such a model, termed the "HCV-Trimera" model. The HCV-Trimera model was developed by using lethally irradiated mice, reconstituted with SCID mouse bone marrow cells, in which human liver fragments infected ex vivo with HCV had been transplanted. Viremia (positive-strand HCV RNA levels) in HCV-Trimera mice peaked at approximately day 18 after liver transplantation, and an infection rate of 85% was reached. Viral replication in liver grafts was evidenced by the presence of specific negative-strand HCV RNA. The usefulness of this model for evaluation of anti-HCV agents was demonstrated by the ability of a small molecule (an HCV internal ribosomal entry site inhibitor) and an anti-HCV human monoclonal antibody (HCV AB(XTL)68) to reduce virus loads in HCV-Trimera mice in a dose-dependent manner.