Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.

Phenotypic and genotyping spectrum of two Iranian cases with RBCK1-associated polyglucosan body myopathy.

Glycogen storage diseases (GSDs) are a group of metabolic disorders affecting glycogen metabolism, with polyglucosan body myopathy type 1 (PGBM1) being a rare variant linked to RBCK1 gene mutations. Understanding the clinical diversity of PGBM1 aids in better characterization of the disease. Two unrelated Iranian families with individuals exhibiting progressive muscle weakness underwent clinical evaluations, genetic analysis using whole exome sequencing (WES), and histopathological examinations of muscle biopsies. In one case, a novel homozygous RBCK1 variant was identified, presenting with isolated myopathy without cardiac or immune involvement. Conversely, the second case harbored a known homozygous RBCK1 variant, displaying a broader phenotype encompassing myopathy, cardiomyopathy, inflammation, and immunodeficiency. Histopathological analyses confirmed characteristic skeletal muscle abnormalities consistent with PGBM1. Our study contributes to the expanding understanding of RBCK1-related diseases, illustrating the spectrum of phenotypic variability associated with distinct RBCK1 variants. These findings underscore the importance of genotype-phenotype correlations in elucidating disease mechanisms and guiding clinical management. Furthermore, the utility of next-generation sequencing techniques in diagnosing complex neurogenetic disorders is emphasized, facilitating precise diagnosis and enabling tailored genetic counseling for affected individuals and their families.

Clinical and genetic characterization of neuronal ceroid lipofuscinoses (NCLs) in 29 Iranian patients: identification of 11 novel mutations.

Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative lysosomal storage diseases which are considered among the most frequent causes of dementia in childhood worldwide This study aimed to identify the gene variants, molecular etiologies, and clinical features in 23 unrelated Iranian families with NCL. In total, 29 patients with neuronal ceroid lipofuscinoses (NCLs), diagnosed based on clinical manifestations, MRI neuroimaging, and electroencephalography (EEG), were recruited for this study. Through whole-exome sequencing (WES), functional prediction, Sanger sequencing, and segregation analysis, we found that 12 patients (41.3%) with mutations in the CLN6 gene, 7 patients (24%) with the TPP1 (CLN2) gene variants, and 4 patients (13.7%) with mutations in the MFSD8 (CLN7) gene. Also, mutations in each of the CLN3 and CLN5 genes were detected in 2 cases and mutations of each PPT1 (CLN1) and CLN8 gene were observed in only 1 separate patient. We identified 18 different mutations, 11 (61%) of which are novel, never have been reported before, and the others have been previously described. The gene variants identified in this study expand the number of published clinical cases and the variant frequency spectrum of the neuronal ceroid lipofuscinoses (NCLs) genes; moreover, the identification of these variants supplies foundational clues for future NCL diagnosis and therapy.

The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders.

Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Excitatory amino acid transporters (EAATs) have important roles in the uptake of glutamate and termination of glutamatergic transmission. Up to now, five EAAT isoforms (EAAT1-5) have been identified in mammals. The main focus of this review is EAAT2. This protein has an important role in the pathoetiology of epilepsy. De novo dominant mutations, as well as inherited recessive mutation in this gene, have been associated with epilepsy. Moreover, dysregulation of this protein is implicated in a range of neurological diseases, namely amyotrophic lateral sclerosis, alzheimer's disease, parkinson's disease, schizophrenia, epilepsy, and autism. In this review, we summarize the role of EAAT2 in epilepsy and other neurological disorders, then provide an overview of the therapeutic modulation of this protein.

Novel BRAT1 variant associated with neurodevelopmental disorder with cerebellar atrophy and seizure: Case report and a literature review.

The BRAT1 gene plays a crucial role in RNA metabolism and brain development, and mutations in this gene have been associated with neurodevelopmental disorders. The variability in the clinical presentation of BRAT1-related disorders is highlighted, emphasizing the importance of considering this condition in the differential diagnosis of neurodevelopmental disorders. This study aimed to identify a causative variant in an Iranian patient affected by developmental delay, speech delay, seizure, and clubfoot through whole exome sequencing (WES) followed by Sanger sequencing. The WES revealed a novel biallelic variant of the BRAT1, c.398A>G (p.His133Arg), in the patient, which segregated within the family. A literature review suggests that the phenotypic variability associated with BRAT1 mutations is likely due to multiple factors, including the location and type of mutation, the specific functions of the protein, and the influence of other genetic and environmental factors. The phenotypic variability of BRAT1-related disorders underscores the importance of considering BRAT1-related disorders in the differential diagnosis of epileptic encephalopathy with rigidity. These findings provide important insights into the role of BRAT1 in neurodevelopmental disorders and highlight the potential clinical implications of identifying and characterizing novel variants in this gene.

Neurodegenerative disorder and diffuse brain calcifications due to FARSB mutation in two siblings.

Pathogenic mutations in the FARSB gene are associated with neurodevelopmental disorder involving the brain, liver, and lungs. We report genetic analysis of a family including two affected members with this disorder, which revealed a homozygous pathogenic missense variant, FARSB: NM_005687.4:c.853G > A:p.E285K in both affected patients. The parents were heterozygous for this variant.

Co-administration of the low dose of orexin and nitrergic antagonists induces an antidepressant-like effect in mice.

It is now well-established that orexins (OXs) and their receptors are involved in the pathophysiology of depression. Considering the evidence indicating the importance of nitric oxide (NO) system in the mood modulation, this study investigated the effect of intraperitoneal (i.p.) administration of orexin 1 (OX1) receptor antagonist -SB334867- alone or in combination with NO agents on depression using the forced swimming test (FST), tail suspension test (TST) and the number of crossings in open-field test (OFT) in mice. Our results indicated that administration of SB334867 at the dose of 0.5 mg/kg decreased the immobility time in the FST without effect on locomotor activity, suggesting an antidepressant-like effect of SB334867. Moreover, l-Arginine (a NO precursor; 750 mg/kg) or L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg) administration by itself decreased the immobility time in the FST. Interestingly, co-administration of a sub-threshold dose of L-NAME, but not l-Arginine, in combination with an ineffective dose of SB334867 produced an antidepressant-like effect in the FST and TST. It should be noted, none of the drugs elicited significant effects on the locomotor activity in the OFT. Altogether, the present data propose that a combination of the sub-effective dose of OX and NO antagonists can be evaluated as an option for the clinical treatment of depression in humans.