Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder.

PURPOSE: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3- import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness. METHODS: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles. RESULTS: The families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In silico analyses showed 6 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants. CONCLUSION: We provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice.

Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.

BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders".

Are children with attention-deficit/ hyperactivity disorder (ADHD) more likely to develop celiac disease? A prospective study.

Purpose: The aim of this study was to evaluate whether the prevalence of celiac among attention-deficit/hyperactivity disorder (ADHD) patients is higher than among the normal population. Methods: The present study was a prospective one investigating ADHD children referred to the Neurology Clinic and Pediatric Ward at Amir Al-Momenin Hospital of Zabol (Sistan and Baluchestan, Iran) in 2019 after their parents' signing of a consent form. All patients underwent Biocard™ Celiac and serology tests. Data were analyzed with SPSS version 21 software. Results: Of all 76 ADHD children undergoing a serum IgA antibodies concentration test, 58 (76%) were male and 18 (23.7%) were female. The mean age of the children was 6.9 ± 2.4, ranging from 2 years to 12 years. The diagnosis of IgA immunodeficiency was rejected for all children based on total serum IgA antibody results. The overall mean anti-tissue transglutaminase (TTG) level was 6.8 ± 5.3 U/ml, ranging from 0.2 to 37 U/ml. There was no significant difference regarding TTG levels between boys and girls (5.1 vs. 6.0) U/ml. Based on the anti-TTG level results, no celiac case was found among the ADHD patients. Conclusions: There is as yet no evidence suggesting a link between celiac disease and ADHD. Thus, routine celiac disease screening when evaluating for ADHD (and is not recommended). However, the possibility of untreated celiac disease predisposing an individual to ADHD-like behaviors should be considered. Hence, physicians are recommended to evaluate a broad range of physical symptoms, in addition to typical neuropsychiatric symptoms, when evaluating ADHD patients.

Protective Effect of Ursodeoxycholic Acid on Liver Function in Pediatric Patients with Seizure Treated with Phenobarbital.

BackgroundEpilepsy is a common and devastating neurological disease. Its treatment, especially when using phenobarbital, causes liver complications, and it is therefore essential to identify a way to reduce liver complications. This study aimed to investigate the protective effect of ursodeoxycholic acid on liver function in pediatric patients with seizure treated with phenobarbital. Materials and methods:Materials and methods: The present study was conducted on 80 patients (40 in the placebo group and 40 in the ursodeoxycholic acid group). To assess the effect of intervention, liver enzyme levels after five weeks of treatment were recorded. Independent t-test and ANOVA repeated measures were used to compare the means. Conclusions:The study results showed that the administration of ursodeoxycholic acid had a relative effect in improving liver function in patients with liver injury caused by phenobarbital.

PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.

OBJECTIVE: Intracellular signaling networks rely on proper membrane organization to control an array of cellular processes such as metabolism, proliferation, apoptosis, and macroautophagy in eukaryotic cells and organisms. Phosphatidylinositol 4-phosphate (PI4P) emerged as an essential regulatory lipid within organelle membranes that defines their lipid composition and signaling properties. PI4P is generated by four distinct phosphatidylinositol 4-kinases (PI4K) in mammalian cells: PI4KA, PI4KB, PI4K2A, PI4K2B. Animal models and human genetic studies suggest vital roles of PI4K enzymes in development and function of various organs, including the nervous system. Bi-allelic variants in PI4KA were recently associated with neurodevelopmental disorders (NDD), brain malformations, leukodystrophy, primary immunodeficiency, and inflammatory bowel disease. Here, we describe patients from two unrelated consanguineous families with PI4K2A deficiency and functionally explored the pathogenic mechanism. METHODS: Two patients with PI4K2A deficiency were identified by exome sequencing, presenting with developmental and epileptic-dyskinetic encephalopathy. Neuroimaging showed corpus callosum dysgenesis, diffuse white matter volume loss, and hypoplastic vermis. In addition to NDD, we observed recurrent infections and death at toddler age. We further explored identified variants with cellular assays. RESULTS: This clinical presentation overlaps with what was previously reported in two affected siblings with homozygous nonsense PI4K2A variant. Cellular studies analyzing these human variants confirmed their deleterious effect on PI4K2A activity and, together with the central role of PI4K2A in Rab7-associated vesicular trafficking, establish a link between late endosome-lysosome defects and NDD. INTERPRETATION: Our study establishes the genotype-phenotype spectrum of PI4K-associated NDD and highlights several commonalities with other innate errors of intracellular trafficking.

Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders.

BACKGROUND: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive. METHODS: We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations. RESULTS: Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration. CONCLUSIONS: This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.

Elevated serum lead levels in neonates born to mothers suffering from opiate use disorder.

BACKGROUND: This study was performed to investigate lead levels in neonates born to the mothers suffering from opiate use disorder (OUD) and the association of lead levels with the Apgar score. METHODS: The present cross-sectional study included 56 neonates who were referred to the neonatal ward of Amir-Al Momenin Hospital, Zabol. The neonates were divided into two groups: the neonates whose mothers suffered OUD and the control group. Data were collected using a researcher-prepared questionnaire, and blood lead level was determined using the atomic absorption method. Data were statistically analyzed. RESULTS: In all, 56 neonates (28 from OUD mothers and 28 from the control mothers) were included in this study. Among the women with OUD, 16 (57%) used inhaled opium, while 12 (43%) consumed opium orally. There was a significant difference regarding Apgar score (9.76 ± 2.11 versus. 7.11 ± 4.21; p = 0.02) and the neonate's blood lead level (2.33 ± 1.3 µg/dl versus 7.33 ± 5.9 µg/dl) between the control and OUD groups (p < 0.001). The odds ratio of abnormally elevated blood lead level rose with increasing duration of maternal opiate disorder for opiate usage durations of 3 to 5 years (adjusted odds ratio [OR] 42.82, 95% confidence interval [CI] 3.27-561, p = 0.004) and > 5 years (adjusted OR 45.5, 95% CI 2.97-698, p = 0.006). CONCLUSION: The results of this study suggested a significant relationship between maternal opium consumption during pregnancy and neonatal serum lead levels, as well as decreased neonatal Apgar score.

Transient positivity of anti-tissue transglutaminase IgA autoantibody in febrile children: a case-control study.

BACKGROUND: Fever is a physiological response activated by integrative interactions between the neuronal and immune systems. The association of fever with the development of autoantibodies against various self-antigens is controversial. We here evaluated if fever was associated with increased levels of anti-tissue transglutaminase (tTG) IgA autoreactive antibodies in children. METHODS: This was a case-control study performed the Amir-Al-Momenin Hospital of Zabol City from January to December 2018. Febrile children (N=135) and apparently healthy counterparts (N=135) were included. Total IgA and anti-tTG IgA were measured by ELISA. RESULTS: From 270 children evaluated, 144 (53.6%) and 126 (46.4%) were males and females, respectively. The mean age was 4.7 ± 2.6 years. The mean total IgA titer was 208 ± 100 mg/dl, and the mean anti-tTG IgA titer was 15.9 ± 68 mg/dl. There was a significant difference in the mean titer of anti-tTG IgA between apparently healthy controls (1.97 ± 1.12 mg/dl) and febrile children (30.2 ± 94.9 mg/dl, p=0.002). Positivity for anti-tTG IgA was observed in 16 (11.8%) out of 135 febrile children while no subject in the control group had positive results. One out of the 16 positive cases showed persistent elevated levels after fever disappearance. On biopsy examination, this child was confirmed to have celiac disease. CONCLUSIONS: We showed that fever can trigger the production of anti-tTG IgA autoantibody in children. It is recommended for pediatricians to be vigilant in interpreting anti-tTG IgA results during fever episodes and repeat positive cases after the cease of fever. It is also recommended to reassess anti-tTG IgA seropositivity in other clinical settings in future studies.

Seizure Induced by Defecation in a 15-Year Old Autistic Patient: A Case Report and Literature Review.

Epilepsy in autism is a relatively common phenomenon. However, reflex seizures provoked by multifactorial stimuli are rare in these patients. We here reported the first case of defecation-induced seizure in a 15-year old autistic girl. The patient had been diagnosed with epilepsy within the first year after birth; however, seizures induced by bowel movements were observed at the age of 15. Reflex seizures showed a myoclonic pattern represented with one-sided neck deflection. EEG showed an abnormal polyspike and wave pattern during defecation while the patterns were normal between the attacks. The patient was partially responsive to adrenocorticotropic hormone therapy with a reduced frequency of both reflexes and generalized seizures. Phenobarbital therapy was effective to manage recurrent seizure attacks. Although seizure is commonly encountered in autism, reflex seizures induced by defecation have not been previously reported in this condition.

Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation.

PURPOSE: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. METHODS: Retrospective case series of 20 patients. RESULTS: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. CONCLUSION: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

Neurological Complications After Renal Transplantation: A Systematic Review and Meta-Analysis.

The aim of this systematic review and meta-analysis was to evaluate the prevalence of neurological complication after renal transplantation. The searches were conducted by two independent researchers in the international (PubMed, Web of Science, Scopus, and Google Scholar) and national databases (Magiran and SID) to find the relevant studies published in English and Persian languages since the creation of the databases until January 2019 (without time limitations). The keywords used in the search strategy were: neurologic complication, central nervous system, peripheral nervous system, tremor, CVA, encephalopathy, neurological complications, renal transplantation, renal failure, kidney transplantation, immunosuppression, neurotoxicity, opportunistic infections, CNS, cerebrovascular disease, chronic kidney disease, cognitive impairment, and end-stage renal disease, which were combined using the AND, OR, and NOT operators. Finally, a meta-analysis was conducted in STATA14 statistical software. Based on the random effect model, the total prevalence of neurologic complications in 4674 patients who had undergone the renal transplantation surgery was 7.9% (95% confidence interval [CI]:7.2%,8.7%, I2 = 90.1%). The prevalence of infectious, non-infectious and treatment associated neurologic complications was 9.5% (95% CI -8.9, 10.2), 91.8% (95% CI -91.3, 92.4) and 97% (95% CI-95.7%,98.4%) of all neurologic complications in renal transplant patients, respectively. And according to the present subgroup analysis, peripheral neuropathy with a prevalence about 30% (29%) (95% CI -27.6%, 30.4%, I2 = 99.4%) was the most common neurological disorder in renal transplant patients followed by tremor with a prevalence of 19.5% (CI -17.6%, 21.3%, I2 = 97.1%), cerebrovascular events with a prevalence of 15.1% (95% CI -13.9%, 16.4%, I2 = 96.5%), encephalopathy with the prevalence of 13% (95% CI -12%, 14%, I2 = 99.3%), headache with a prevalence of 8.3% (95% CI -6.8%, 9.8%, I2 = 97.3%) and seizure with a prevalence of 7.4% (CI - 6.5%, 8.3%, I2 = 94.6%). The results of the present systematic review and meta-analysis, suggests that post-kidney transplantation neurological disorders, with a prevalence rate about 8%, are relatively common; most of them are caused by immunosuppressive drugs and can be treated by decreasing the dose or switching the immunosuppressive drugs. Neurological disorders are associated with increased mortality; thus, differential diagnosis should be conducted for each individual patient with neurological symptoms after transplantation. It is important for all health care providers to become familiar with the symptoms of neurological disorders that may occur after organ transplants. Recognizing and monitoring these symptoms can reduce the risk of death in kidney transplant recipients. Further research is needed to help the transplant community to identify these issues and problems better in order to achieve the ultimate goal of helping renal patients and sending them back into their normal lives.

Assessment of scaling and corrosion potential of drinking water resources of Iranshahr.

The aim of this study was to evaluate corrosion and scaling potential of drinking water resources Iranshahr in order to considering necessary solutions to solve possible problems including internal corrosion of pipes, deterioration of water quality and reduce of water transfer capacity of distribution network system. The data showed that Langelier index ranged between -1.53 to -0.96, Ryznar index between 9.63-10.54, Aggressive index between 12.04 and 12.91, and Puckorius index between 9.05-10.68 for drinking water resources Iranshahr. Studied indices indicated that the drinking water in Iranshahr can be considered as corrosive.