PIGN-Related Disease in Two Lithuanian Families: A Report of Two Novel Pathogenic Variants, Molecular and Clinical Characterisation.

Background and Objectives: Pathogenic variants of PIGN are a known cause of multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Many affected individuals have clinical features overlapping with Fryns syndrome and are mainly characterised by developmental delay, congenital anomalies, hypotonia, seizures, and specific minor facial anomalies. This study investigates the clinical and molecular data of three individuals from two unrelated families, the clinical features of which were consistent with a diagnosis of MCAHS1. Materials and Methods: Next-generation sequencing (NGS) technology was used to identify the changes in the DNA sequence. Sanger sequencing of gDNA of probands and their parents was used for validation and segregation analysis. Bioinformatics tools were used to investigate the consequences of pathogenic or likely pathogenic PIGN variants at the protein sequence and structure level. Results: The analysis of NGS data and segregation analysis revealed a compound heterozygous NM_176787.5:c.[1942G>T];[1247_1251del] PIGN genotype in family 1 and NG_033144.1(NM_176787.5):c.[932T>G];[1674+1G>C] PIGN genotype in family 2. In silico, c.1942G>T (p.(Glu648Ter)), c.1247_1251del (p.(Glu416GlyfsTer22)), and c.1674+1G>C (p.(Glu525AspfsTer68)) variants are predicted to result in a premature termination codon that leads to truncated and functionally disrupted protein causing the phenotype of MCAHS1 in the affected individuals. Conclusions: PIGN-related disease represents a wide spectrum of phenotypic features, making clinical diagnosis inaccurate and complicated. The genetic testing of every individual with this phenotype provides new insights into the origin and development of the disease.

Anti-N-methyl-D-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes-macrophages, epithelial cells, and central nervous system cells. The pathogenicity of human herpesvirus-7 is unclear. Cases of anti-N-methyl-D-aspartate receptor encephalitis with human herpesvirus-7 present in cerebrospinal fluid have been documented, but the clinical significance of this finding remains unclear. CASE PRESENTATION: An 11-year-old Caucasian boy was admitted to hospital after a generalized tonic-clonic seizure. Generalized tonic seizures repeated three more times during the day of hospitalization. Blood tests showed minor ongoing inflammation, while brain computed tomography yielded normal results. Brain magnetic resonance imaging showed hyperintense focal alterations in both temporal lobes, hippocampi, and at the base of the right frontal lobe. Positive anti-N-methyl-D-aspartate receptor antibodies were found in both serum and cerebrospinal fluid. Positive novel coronavirus 2 (severe acute respiratory syndrome coronavirus 2) immunoglobulin G antibodies were found in serum. Polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 was negative. Furthermore, positive human herpesvirus-7 deoxyribonucleic acid was found in cerebrospinal fluid. The patient was treated with acyclovir, human immunoglobulin, and methylprednisolone. The seizures did not repeat, and no psychiatric symptoms were present. The patient made a full recovery. CONCLUSIONS: We present a pediatric case of anti-N-methyl-D-aspartate receptor encephalitis with atypical clinical presentation. The role of human herpesvirus-7 in neurological disorders remains unclear in immunocompetent patients.

Behavioral problems in children with benign childhood epilepsy with centrotemporal spikes treated and untreated with antiepileptic drugs.

The aim of this study was to investigate behavioral problems in two groups of children with benign childhood epilepsy with centrotemporal spikes (BECTS), i.e., those treated with antiepileptic drugs and those not treated in order to identify the factors associated with behavioral problems. MATERIAL AND METHODS. In total, 20 newly diagnosed untreated, 23 treated patients with BECTS, and 20 patients with acute/subacute peripheral nervous system disorders as a comparison group (aged 6-11 years) were examined. The evaluation was performed using the Lithuanian version of the Child Behavior Checklist (CBCL). Schooling parameters, clinical parameters, EEG parameters, and their relation to the results of the CBCL were also investigated. RESULTS. The treated patients with BECTS had significantly higher scores in the subscales of Social Problems, Anxious/Depressed, Aggressive Behavior, and Attention Problems compared with the scores of the patients with peripheral nervous system disorders. A significant relationship was established between the scores of native language grades and Attention Problems; grades in mathematics and treatment duration; and age when the first seizure occurred and Delinquent Behavior in the group of treated patients. The duration of epilepsy was positively correlated with the scores in the subscales of Withdrawn and Delinquent Behavior. The presence of additional extrarolandic focus and spread of focal specific discharges to the centrofrontotemporal and centroparietotemporal areas were related to higher scores in Social Problems, Attention Problems, and Delinquent Behavior in the group of the treated patients with BECTS. CONCLUSIONS. Children with BECTS, especially those treated and with a longer epilepsy course, were found to be at risk of behavioral problems. Lower grades were associated with a longer disease course and medications. The presence of extrarolandic discharges was related to higher CBCL scores in the group of the treated patients with BECTS.

Multidisciplinary Care of Patients with Inherited Metabolic Diseases and Epilepsy: Current Perspectives.

More than 650 inherited metabolic diseases may present with epilepsy or seizures. These diseases are often multisystem, life-long and induce complex needs of patients and families. Multidisciplinary care involves all stages of disease management: diagnostics, specific or symptomatic, acute and chronic treatments, and integrated care that takes into account not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers. Care coordination is indispensable to ensure smooth transitions of care across life and disease stages, including management of emergencies, transition from pediatric to adult services and palliative care. Care pathways are highly diverse and have to find the right balance between highly specialized and locally provided services. While multidisciplinary teams consist of many professionals, a named supervising physician in a highly specialized healthcare setting and a care coordinator are highly important. As the greatest burden of care always falls onto the shoulders of patients and/or families, patient empowerment should be a part of every care pathway and include provision of required information, involvement into common decision-making, patient's and family's education, support for self-management, liaison with peer support groups and emotional/ psychological support. Due to the rarity and complexity of these diseases, sufficient expertise may not be available in a national healthcare system and cross-border services (virtual or physical) in the recently developed European Reference Networks should be ensured through the proper organization of referral systems in each EU and EEA country. Finally, digital technologies are particularly important in the provision of services for patients with rare diseases and can significantly increase the availability of highly specialized services and expertise.

Sodium valproate stimulates potassium and chloride urinary excretion in rats: gender differences.

BACKGROUND: The diuretic effect of valproates and its relation to urinary potassium (K+) and chloride (Cl-) excretion have not yet been investigated, so the aim of this study was to evaluate the influence of a single dose of sodium valproate (NaVPA) on 24-h urinary K+ and Cl- excretion in young adult Wistar rats of both genders. For measurement of K+ in urine, the same animals and samples as in our earlier publication were used (Pharmacology 2005 Nov, 75:111-115). The authors propose a new approach to the pathophysiological mechanisms of NaVPA effect on K+ and Cl- metabolism. Twenty six Wistar rats were examined after a single intragastric administration of 300 mg/kg NaVPA (13 NaVPA-male and 13 NaVPA-female), 28 control intact Wistar rats (14 males and 14 females) were studied as a control group. The 24-h urinary K+, Cl-, creatinine and pH levels were measured. RESULTS: Total 24-h diuresis and 24-h diuresis per 100 g of body weight were found to be significantly higher in NaVPA-rats of both genders than in rats of the control group (p < 0.05). The data showed NaVPA to enhance 24-h K+ excretion in NaVPA-males and NaVPA-females with significant gender-related differences: 24-h K+ excretion in NaVPA-male rats was significantly higher than in control males (p = 0.003) and NaVPA-female rats (p < 0.001). Regarding the 24-h K+ excretion, NaVPA-female rats did not show a statistically significant difference versus females of the control group (p > 0.05). 24-h urinary K+ excretion per 100 g of body weight in NaVPA-male rats was significantly higher than in control males (p = 0.025). NaVPA enhanced Cl- urinary excretion: 24-h Cl- urinary excretion, 24-h urinary Cl- excretion per 100 g of body weight and the Cl-/creatinine ratio were significantly higher in NaVPA-male and NaVPA-female rats than in gender-matched controls (p < 0.05). 24-h chloriduretic response to NaVPA in male rats was significantly higher than in female rats (p < 0.05). CONCLUSION: NaVPA causes kaliuretic and chloriduretic effects with gender-related differences in rats. Further investigations are necessary to elucidate the mechanism of such pharmacological effects of NaVPA.

Inflammatory myopathy in a patient with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS.

Gender differences of sodium metabolism and hyponatremia as an adverse drug effect.

Gender-related differences in sodium (Na+) metabolism, Na+ transport through cell membrane, intracellular Na+ concentration, and Na+ urinary excretion review is presented in the article. Literature data on gender-related differences in the occurrence of hyponatremia and related neurology are overviewed. Some of the drugs used in neurology (carbamazepine, oxcarbazepine, thiazides, antidepressants) are pointed out as eventual sources of hyponatremia. This disorder shows a clear-cut preference of the feminine gender. The authors present literature data on gender-related differences in the mechanisms of Na+ transport (Na+/H+ exchange, Na+/K+/2Cl- cotransport, Na+, K+-ATPase). The reasons for such differences are not yet known. Investigative tests with animals of both genders, cellular studies and clinical investigations with human males and females could help to answer question why females are more prone to hyponatremia, to select more efficient measures for prevention of hyponatremia and to differentiate specific peculiarities of treatment for patients of either sex.

Sleep and behavioral problems in rolandic epilepsy.

Although patients with benign childhood epilepsy with centrotemporal spikes exhibit a benign course of the disease, some of them display sleep and behavioral problems. Sixty-one patients with rolandic epilepsy, aged 6-11 years, were included in this study. The patients were divided into two subgroups according to the presence of seizures over the preceding 6 months. The control group comprised 25 patients without epilepsy and with similar characteristics in terms of age and sex. All patients underwent evaluation of sleep (Sleep Disturbance Scale for Children) and behavior (Lithuanian version of the Child Behaviour Checklist). Only patients who had had seizures over the preceding 6 months displayed significantly higher scores for sleep problems (disorders of excessive daytime sleepiness, disorders of sleep-wake transition, and scores for total sleep problems), worse sleep quality (longer sleep-onset latency), and behavioral problems (anxiety/depression, social problems, thought problems, attention problems, and aggressive behavior) than the patients of the control group. Our data add to evidence that active epilepsy has an impact on sleep and behavior. Clinically significant sleep problems were related to the higher risk of behavioral problems. Parents' ratings for existing sleep problems were sensitive to Sleep Disturbance Scale for Children scores above normal values.

Influence of sodium valproate on sodium and chloride urinary excretion in rats, gender differences.

Evidence exists indicating that sodium valproate (VPA) increases diuresis in rats. The chloriuretic and natriuretic effect of VPA has not previously been investigated, so the aim of the present study was to define the peculiarities of 24-hour urinary sodium (Na) and chloride (Cl) excretion in young adult Wistar rats of both genders, and to evaluate the effects of VPA. 24-hour urinary Na, Cl, creatinine and pH levels were measured in 28 control intact Wistar rats and 26 Wistar rats after a single intragastric administration of 300 mg/kg VPA. After VPA administration, 24-hour diuresis and 24-hour diuresis per 100 g of body weight were significantly higher in VPA rats of both genders. 24-hour urine Na and Cl excretion were significantly higher in VPA male and VPA female rats than in gender-matched controls. The 24-hour urinary Cl excretion was found to be significantly higher in VPA male than in VPA female rats. The study data show that VPA, alongside the diuretic effect, enhances Na and Cl excretion with urine. The 24-hour chloriuretic response to VPA in male rats was significantly higher than in female rats. The mechanism of such a gender-related effect is not yet clear.