An overview of genetic mutations in Aicardi-Goutières syndrome in Iranian population.

Aicardi-Goutières syndrome (AGS) is a rare neurodevelopmental disorder that can be misdiagnosed with infectious disorders. Molecular genetics tools and subsequent counseling have an important role in the estimation of recurrence risk and prevention of additional cases in the family. The current study provides an overview of genetic mutations in AGS in Iranian population. In a time period of 3 years, we assessed nine AGS cases and identified the underlying mutations using whole exome sequencing. Mutations were located in TREX1, IFIH1, RNASEH2B, RNASEH2A and SAMHD1 genes and inherited in either autosomal dominant or autosomal recessive manner. Since both modes of inheritance have been previously reported for AGS, appropriate genetic counseling is needed for estimation of recurrence risk in families.

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.

Exome sequencing reveals neurodevelopmental genes in simplex consanguineous Iranian families with syndromic autism.

BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

Expanding genetic and clinical aspects of Schwartz-Jampel syndrome: A report of two cases with literature review.

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterized by muscle stiffness (myotonia) and chondrodysplasia. This disease is caused by biallelic loss of function mutations in the HSPG2 gene, which encodes the core protein of perlecan. This study aims to investigate causative variants in two sisters born to consanguineous Iranian parents. Both patients were presented with myotonia and a mask-like face; moreover, they showed a less common symptom, gastrointestinal bleeding, which is not typical of SJS and has only been reported in one patient. Regarding the crucial role of perlecan in vascular structure and mucosal stability, bleeding disorders could be expected in perlecan dysfunctions. In addition to the case study, a comprehensive literature review was conducted to gather information on similar genetic variants, associated clinical features, and possible disease mechanisms. Results of this study contribute to our understanding of the genetic and clinical aspects of Schwartz-Jampel syndrome, and more importantly, the manifestation of gastrointestinal bleeding in patients with Schwartz-Jampel syndrome.

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.

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.

Broadening the Phenotype and Genotype Spectrum of Glycogen Storage Disease by Unraveling Novel Variants in an Iranian Patient Cohort.

Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders.

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome.

Background and aims: The occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders. Material and methods: The selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative. Results: The first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene. Conclusions: Collectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

Broadening the phenotype and genotype spectrum of novel mutations in pontocerebellar hypoplasia with a comprehensive molecular literature review.

BACKGROUND: Pontocerebellar hypoplasia is an umbrella term describing a heterogeneous group of prenatal neurodegenerative disorders mostly affecting the pons and cerebellum, with 17 types associated with 25 genes. However, some types of PCH lack sufficient information, which highlights the importance of investigating and introducing more cases to further elucidate the clinical, radiological, and biochemical features of these disorders. The aim of this study is to provide an in-depth review of PCH and to identify disease genes and their inheritance patterns in 12 distinct Iranian families with clinically confirmed PCH. METHODS: Cases included in this study were selected based on their phenotypic and genetic information available at the Center for Comprehensive Genetic Services. Whole-exome sequencing (WES) was used to discover the underlying genetic etiology of participants' problems, and Sanger sequencing was utilized to confirm any suspected alterations. We also conducted a comprehensive molecular literature review to outline the genetic features of the various subtypes of PCH. RESULTS: This study classified and described the underlying etiology of PCH into three categories based on the genes involved. Twelve patients also were included, eleven of whom were from consanguineous parents. Ten different variations in 8 genes were found, all of which related to different types of PCH. Six novel variations were reported, including SEPSECS, TSEN2, TSEN54, AMPD2, TOE1, and CLP1. Almost all patients presented with developmental delay, hypotonia, seizure, and microcephaly being common features. Strabismus and elevation in lactate levels in MR spectroscopy were novel phenotypes for the first time in PCH types 7 and 9. CONCLUSIONS: This study merges previously documented phenotypes and genotypes with unique novel ones. Due to the diversity in PCH, we provided guidance for detecting and diagnosing these heterogeneous groups of disorders. Moreover, since certain critical conditions, such as spinal muscular atrophy, can be a differential diagnosis, providing cases with novel variations and clinical findings could further expand the genetic and clinical spectrum of these diseases and help in better diagnosis. Therefore, six novel genetic variants and novel clinical and paraclinical findings have been reported for the first time. Further studies are needed to elucidate the underlying mechanisms and potential therapeutic targets for PCH.

The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum.

BACKGROUND: The ultra-rare autosomal recessive genetic disorder, You-Hoover-Fong Syndrome (YHFS), is caused by defects in the TELO2 gene and is characterized by intellectual disability, developmental delay, and ocular impairments. This study aims to contribute to a better understanding of YHFS by reviewing previous cases and introducing a novel variant in a new case. METHODS: Whole exome sequencing (WES) was conducted on the proband to identify genetic variants, and Sanger sequencing was used to confirm variants within the family. This article presents a comprehensive collection of reported cases of YHFS, incorporating both molecular and clinical data, through an extensive literature search and analysis of English-language studies published until June 2023. RESULTS: Using WES, a novel homozygous missense variant, c.1799A > G (p. Tyr600Cys), was identified in the TELO2 gene in a 4-year-old Iranian male patient. Novel clinical features, including choanal atresia and clubfoot, were also identified. A comprehensive literature review identified 27 patients with YHFS, with 20 variants in the TELO2 gene. Missense pathogenic variants were the most common type of pathogenic variant, and the most common features were microcephaly and intellectual impairment. CONCLUSION: This study presents the first case of pathogenic variants in TELO2 gene in Iran, expands the genotypic and phenotypic spectrum of YHFS and contributes to the growing body of literature pertaining to YHFS. Furthermore, our findings highlight the importance of genetic testing for non-consanguineous carrier screening, as compound heterozygosity may be a significant factor in the development of YHFS. Further research is needed to clarify the molecular mechanisms underlying YHFS pathogenesis.

Non-coding RNAs as potential therapeutic targets for receptor tyrosine kinase signaling in solid tumors: current status and future directions.

This review article presents an in-depth analysis of the current state of research on receptor tyrosine kinase regulatory non-coding RNAs (RTK-RNAs) in solid tumors. RTK-RNAs belong to a class of non-coding RNAs (nc-RNAs) responsible for regulating the expression and activity of receptor tyrosine kinases (RTKs), which play a critical role in cancer development and progression. The article explores the molecular mechanisms through which RTK-RNAs modulate RTK signaling pathways and highlights recent advancements in the field. This include the identification of potential new RTK-RNAs and development of therapeutic strategies targeting RTK-RNAs. While the review discusses promising results from a variety of studies, encompassing in vitro, in vivo, and clinical investigations, it is important to acknowledge the challenges and limitations associated with targeting RTK-RNAs for therapeutic applications. Further studies involving various cancer cell lines, animal models, and ultimately, patients are necessary to validate the efficacy of targeting RTK-RNAs. The specificity of ncRNAs in targeting cellular pathways grants them tremendous potential, but careful consideration is required to minimize off-target effects, the article additionally discusses the potential clinical applications of RTK-RNAs as biomarkers for cancer diagnosis, prognosis, and treatment. In essence, by providing a comprehensive overview of the current understanding of RTK-RNAs in solid tumors, this review emphasizes their potential as therapeutic targets for cancer while acknowledging the associated challenges and limitations.

Comprehensive review and expanding the genetic landscape of Cornelia-de-Lange spectrum: insights from novel mutations and skin biopsy in exome-negative cases.

BACKGROUND: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by a range of physical, cognitive, and behavioral abnormalities. This study aimed to perform a comprehensive review of the literature on CdLS and investigate two cases of CdLS with distinct phenotypes that underwent WES to aid in their diagnosis. METHODS: We conducted a comprehensive review of the literature on CdLS along with performing whole-exome sequencing on two CdLS patients with distinct phenotypes, followed by Sanger sequencing validation and in-silico analysis. RESULTS: The first case exhibited a classic CdLS phenotype, but the initial WES analysis of blood-derived DNA failed to identify any mutations in CdLS-related genes. However, a subsequent WES analysis of skin-derived DNA revealed a novel heterozygous mutation in the NIPBL gene (NM_133433.4:c.6534_6535del, p.Met2178Ilefs*8). The second case was presented with a non-classic CdLS phenotype, and WES analysis of blood-derived DNA identified a heterozygous missense variant in the SMC1A gene (NM_006306.4:c.2320G>A, p.Asp774Asn). CONCLUSIONS: The study shows the importance of considering mosaicism in classic CdLS cases and the value of WES for identifying genetic defects. These findings contribute to our understanding of CdLS genetics and underscore the need for comprehensive genetic testing to enhance the diagnosis and management of CdLS patients.

Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection.

Infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) is caused by biallelic mutations in the NALCN gene, the major ion channel responsible for the background Na + conduction in neurons. Through whole-exome sequencing (WES), we report three novel homozygous variants in three families, including c.1434 + 1G > A, c.3269G > A, and c.2648G > T, which are confirmed and segregated by Sanger sequencing. Consequently, intron 12's highly conserved splice donor location is disrupted by the pathogenic c.1434 + 1G > A variation, most likely causing the protein to degrade through nonsense-mediated decay (NMD). Subsequently, a premature stop codon is thus generated at amino acid 1090 of the protein as a result of the pathogenic c.3269G > A; p.W1090* variation, resulting in NMD or truncated protein production. Lastly, the missense mutation c.2648G > T; p.G883V can play a critical role in the interplay of functional domains. This study introduces recurrent urinary tract infections for the first time, broadening the phenotypic range of IHPRF1 syndrome in addition to the genotypic spectrum. This trait may result from insufficient bladder emptying, which may be related to the NALCN channelosome's function in background Na + conduction. This work advances knowledge about the molecular genetic underpinnings of IHPRF1 and introduces a novel phenotype through the widespread use of whole exome sequencing.

Megaconial congenital muscular dystrophy due to CHKB gene variants, the first report of thirteen Iranian patients.

Megaconial congenital muscular dystrophy (OMIM: 602,541) related to CHKB gene mutation is a newly defined rare autosomal recessive disorder, with multisystem involvement presenting from the neonatal period to adolescence. Choline kinase beta, lipid transport enzyme, catalyzes the biosynthesis of phosphatidylcholine and phosphatidylethanolamine, two major components of the mitochondrial membrane, on which respiratory enzyme activities are dependent. CHKB gene variants lead to loss-of-function of choline kinase b and lipid metabolism defects and mitochondrial structural changes. To date, many megaconial congenital muscular dystrophy cases due to CHKB gene variants have been reported worldwide. We describe thirteen Iranian megaconial congenital muscular dystrophy cases related to CHKB gene variants, including clinical presentations, laboratory and muscle biopsy findings, and novel CHKB gene variants. The most common symptoms and signs included intellectual disability, delayed gross-motor developmental milestones, language skills problems, muscle weakness, as well as autistic features, and behavioral problems. Muscle biopsy examination showed the striking finding of peripheral arrangements of large mitochondria in muscle fibers and central sarcoplasmic areas devoid of mitochondria. Eleven different CHKB gene variants including six novel variants were found in our patients. Despite the rarity of this disorder, recognition of the multisystem clinical presentations combined with characteristic findings of muscle histology can properly guide to genetic evaluation of CHKB gene.

Alopecia areata-like pattern of baldness: the most recent update and the expansion of novel phenotype and genotype in the CTNNB1 gene.

Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant genetic disorder caused by genetic alterations in the CTNNB1 gene. CTNNB1 is a gene that encodes ß-catenin, an effector protein in the canonical Wnt pathway involved in stem cell differentiation and proliferation, synaptogenesis, and a wide range of essential cellular mechanisms. Mutations in this gene are also found in specific malignancies as well as exudative vitreoretinopathy. To date, only a limited number of cases of this disease have been reported, and though they share some phenotypic manifestations such as intellectual disability, developmental delay, microcephaly, behavioral abnormalities, and dystonia, the variety of phenotypic traits of these patients shows extreme heterogeneity. In this study, two cases of NEDSDV with de novo CTNNB1 mutations: c.1420C>T(p.R474X) and c.1377_1378Del(p.Ala460Serfs*29), found with whole exome sequencing (WES) have been reported and the clinical and paraclinical characteristics of these patients have been described. Due to such a wide range of clinical characteristics, the identification of new patients and novel variants is of great importance in order to establish a more complete phenotypic spectrum, as well as to conclude the genotype-phenotype correlations in these cases.

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.

Five patients with spinal muscular atrophy-progressive myoclonic epilepsy (SMA-PME): a novel pathogenic variant, treatment and review of the literature.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene, a previously reported pathogenic variant, c.125C>T (p.Thr42Met), and a novel likely pathogenic variant c.109C>A (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments.

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.