Multi-system neurological disorder associated with a CRYAB variant
We report a multiplex family with extended multisystem neurological phenotype associated with aCRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its...
Source: Neurogenetics - April 3, 2021 Category: Genetics & Stem Cells Source Type: research

Welcoming articles on genotype-dependent clinical features and diagnostics
(Source: Neurogenetics)
Source: Neurogenetics - April 1, 2021 Category: Genetics & Stem Cells Source Type: research

Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia
AbstractAtaxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of twoATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this f...
Source: Neurogenetics - March 29, 2021 Category: Genetics & Stem Cells Source Type: research

8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder
AbstractAde novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders:D...
Source: Neurogenetics - March 8, 2021 Category: Genetics & Stem Cells Source Type: research

Myoclonic dystonia phenotype related to a novel calmodulin-binding transcription activator 1 sequence variant
We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novelCAMTA1 sequence variant. Furthermore, by identifying an additional, recurrentCAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated withCAMTA1 gene mutations. (Source: Neurogenetics)
Source: Neurogenetics - March 6, 2021 Category: Genetics & Stem Cells Source Type: research

De novo homozygous variant of the SCN1A gene in a patient with severe Dravet syndrome complicated by acute encephalopathy
AbstractVariants in theSCN1A gene have been identified in epilepsy patients with widely variable phenotypes and they are generally heterozygous. Here, we report a homozygous missense variant, NM_001165963.4: c.4319C>T (p.Ala1440Val), in theSCN1A gene which seemed to occur de novo together with a gene conversion event. It ’s highly possible that this variant, although located in a critical functional domain of protein Nav1.1, depending on the nature of the amino acid substitution, may not cause the complete loss of protein function. And the accumulated effect by having this variant on both alleles results in a Drav...
Source: Neurogenetics - March 5, 2021 Category: Genetics & Stem Cells Source Type: research

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations
We report the largest published series of 21 novel patients with nine newCAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing.CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at ...
Source: Neurogenetics - January 23, 2021 Category: Genetics & Stem Cells Source Type: research

Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series
AbstractPrimary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition:SLC20A2,PDGFRB,PDGFB, andXPR1 inherited as autosomal-dominant trait, whileMYORG andJAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants inSLC20A2, two exonic and ...
Source: Neurogenetics - January 20, 2021 Category: Genetics & Stem Cells Source Type: research

X-linked partial corpus callosum agenesis with mild intellectual disability: identification of a novel L1CAM pathogenic variant
We report here a second family, including 5 patients with mild to moderate ID and partial CCA without signs usually associated withL1CAM pathogenic variations (such as hydrocephalus, pyramidal syndrome, thumb adductus, aphasia). We identified a previously unreported c.3226A> C transversion leading to a p.Thr1076Pro amino acid substitution in the fifth fibronectin type III domain (FnIII) of the protein which co-segregates with the phenotype within the family. We performed in vitro assays to assess the pathogenic status of this variation. First, the expression of the novel p.Thr1076Pro mutant in COS7 cells resulted in end...
Source: Neurogenetics - January 7, 2021 Category: Genetics & Stem Cells Source Type: research

Detection of SMN1 to SMN2 gene conversion events and partial SMN1 gene deletions using array digital PCR
In this study, we describe the development of array digital PCR (dPCR) to quantifySMN1 andSMN2 CNs in DNA samples using probes that can distinguish the single nucleotide difference betweenSMN1 andSMN2 in exon 8. This set of dPCR assays can accurately and reliably measure the number ofSMN1 andSMN2 copies in DNA samples. In a cohort of SMA patient –derived cell lines, the assay confirmed a strong inverse correlation betweenSMN2 CN and disease severity. We can detectSMN1 –SMN2 gene conversion events in DNA samples by comparing CNs at exon 7 and exon 8. Partial deletions ofSMN1 can also be detected with dPCR by com...
Source: Neurogenetics - January 7, 2021 Category: Genetics & Stem Cells Source Type: research

Selective loss of a LAP1 isoform causes a muscle-specific nuclear envelopathy
AbstractThe nuclear envelope (NE) separates the nucleus from the cytoplasm in all eukaryotic cells. A disruption of the NE structure compromises normal gene regulation and leads to severe human disorders collectively classified as nuclear envelopathies and affecting skeletal muscle, heart, brain, skin, and bones. The ubiquitous NE component LAP1B is encoded byTOR1AIP1, and the use of an alternative start codon gives rise to the shorter LAP1C isoform.TOR1AIP1 mutations have been identified in patients with diverging clinical presentations such as muscular dystrophy, progressive dystonia with cerebellar atrophy, and a severe...
Source: Neurogenetics - January 6, 2021 Category: Genetics & Stem Cells Source Type: research

SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review
AbstractC19orf12 gene biallelic mutations lead mainly to neurodegeneration with brain iron accumulation-4. A 15-year-old male and his 17-year-old sister complained of cramps and exercise intolerance. Clinical examination of the boy mainly showed distal amyotrophy and mild weakness, while the sister predominantly had a tetrapyramidal syndrome. Widespread chronic neurogenic signs and hypointense signals on the striatum were present in both patients. Clinical exome sequencing identified, on both patients, the compound heterozygous pathogenic mutations c.204_214del p.(Gly69ArgfsTer10) and c.32C>T p.(Thr11Met). The descripti...
Source: Neurogenetics - January 4, 2021 Category: Genetics & Stem Cells Source Type: research

De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females
We report the first affected females harboring de novo SNVs inARHGEF9, expanding the genotypic and phenotypic spectrum ofARHGEF9-related neurodevelopmental disorder in females. (Source: Neurogenetics)
Source: Neurogenetics - September 16, 2020 Category: Genetics & Stem Cells Source Type: research

Cerebellar dysplasia related to PIK3CA mutation: a three-case series
We present three cases withPIK3CA mutation and clinical characteristics encompassing MCAP (megalencephaly-capillary malformation) condition but lacking all criteria to a certain diagnosis, most of all showing prevalent and peculiar involvement of cerebellar structures at MRI (magnetic resonance imaging) mainly consisting in cortical rim thickening and abnormal orientation of folia axis. These cases expand the spectrum of intracranial MRI features inPIK3CA disorders. (Source: Neurogenetics)
Source: Neurogenetics - September 7, 2020 Category: Genetics & Stem Cells Source Type: research

Acknowledgement to referees 2019/2020
(Source: Neurogenetics)
Source: Neurogenetics - August 26, 2020 Category: Genetics & Stem Cells Source Type: research

Familial writer ’s cramp: a clinical clue for inherited coenzyme Q 10 deficiency
This report highlights that ARCA2 should be considered in the differential diagnosis of familial writer’s cramp. (Source: Neurogenetics)
Source: Neurogenetics - August 23, 2020 Category: Genetics & Stem Cells Source Type: research

Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25 -related: polymicrogyria as a distinctive neuroradiological finding
This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome. (Source: Neurogenetics)
Source: Neurogenetics - August 19, 2020 Category: Genetics & Stem Cells Source Type: research

Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis
AbstractOur objective was to investigate the frequency ofKIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants inKIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF  
Source: Neurogenetics - August 18, 2020 Category: Genetics & Stem Cells Source Type: research

Distal myopathy due to TCAP variants in four unrelated Chinese patients
AbstractDistal myopathies are a group of clinically and genetically heterogeneous hereditary muscle disorders characterized by progressive muscular weakness starting in the distal parts of the limbs. The most common subtype of distal myopathy is GNE myopathy, a rare muscle disease with autosomal recessive inheritance. Limb-girdle muscular dystrophy 2G (LGMD2G) is a rare autosomal recessive subtype of LGMDs caused byTCAP variant. Patients with LGMD2G can present with distal myopathy and rimmed vacuoles on muscle pathology. Thus far, the most reportedTCAP mutations related to LGMD2G were recessive frameshift or nonsense vari...
Source: Neurogenetics - August 5, 2020 Category: Genetics & Stem Cells Source Type: research

Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia
AbstractFriedreich ’s ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at theFXN locus can cause pitfalls in the molecular diagnosis of FRDA. Here we describe a family whose proband was affected by late-onset Friedreich ’s ataxia (LOFA); long-range PCR (LR-PCR) documented two small expanded GAA alleles both in the proband and in her unaffected younger sister, who therefore received a diagnosis of pre-symptomatic LOFA. Later studies, however, revealed that the proband’s unaffected sister, as well as their health y m...
Source: Neurogenetics - July 6, 2020 Category: Genetics & Stem Cells Source Type: research

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients
In this study, we identified 31 differentARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C> T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenicARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease ...
Source: Neurogenetics - July 6, 2020 Category: Genetics & Stem Cells Source Type: research

Novel familial IQSEC2 pathogenic sequence variant associated with neurodevelopmental disorders and epilepsy
We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted “next-generation” sequencing (NGS) with a gene panel ClearSeq Inherited DiseaseXT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linkedIQSEC2 gene NM_0011...
Source: Neurogenetics - June 19, 2020 Category: Genetics & Stem Cells Source Type: research

Is NIPA1-associated hereditary spastic paraplegia always ‘pure’? Further evidence of motor neurone disease and epilepsy as rare manifestations
We present a patient with childhood idiopathic generalised epilepsy (IGE) who later developed HSP. She rapidly deteriorated 27  years later with clinically definite amyotrophic lateral sclerosis (ALS). Her family history included HSP, IGE and motor neurone disease. Genetic testing identified a pathogenic variant in theNIPA1 gene associated with spastic paraplegia 6 (SPG6). This case provides the first description ofNIPA1 in a family with epilepsy, ALS and thus complex HSP. (Source: Neurogenetics)
Source: Neurogenetics - June 4, 2020 Category: Genetics & Stem Cells Source Type: research

Novel MTMR2 mutation causing severe Charcot-Marie-Tooth type 4B1 disease: a case report
We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation inMTMR2, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis ofMTMR2-related neuropathies. (Source: Neurogenetics)
Source: Neurogenetics - June 2, 2020 Category: Genetics & Stem Cells Source Type: research

A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures
AbstractDeficiency of the endoplasmic reticulum transmembrane proteinARV1 leads to epileptic encephalopathy in humans and in mice.ARV1 is highly conserved, but its function in human cells is unknown. Studies of yeastarv1 null mutants indicate that it is involved in a number of biochemical processes including the synthesis of sphingolipids and glycosylphosphatidylinositol (GPI), a glycolipid anchor that is attached to the C-termini of many membrane bound proteins. GPI anchors are post-translational modifications, enabling proteins to travel from the endoplasmic reticulum (ER) through the Golgi and to attach to plasma membra...
Source: Neurogenetics - May 26, 2020 Category: Genetics & Stem Cells Source Type: research

Genetic Creutzfeldt-Jakob disease in Sardinia: a case series linked to the PRNP R208H mutation due to a single founder effect
AbstractIn genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208HPRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our ...
Source: Neurogenetics - May 25, 2020 Category: Genetics & Stem Cells Source Type: research

Expanding the genotype-phenotype spectrum of ISCA2 -related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival
This report expands the clinical spectrum ofISCA2-related disorders to include a milder phenotype with a longer life span and better psychomotor function and cavitating leukodystrophy on MRI. We discuss the possible genetic explanation for the different presentation. (Source: Neurogenetics)
Source: Neurogenetics - May 17, 2020 Category: Genetics & Stem Cells Source Type: research

Rare copy number variations of planar cell polarity genes are associated with human neural tube defects
AbstractSelect single-nucleotide variants in planar cell polarity (PCP) genes are associated with increased risk for neural tube defects (NTDs). However, whether copy number variants (CNVs) in PCP genes contribute to NTDs is unknown. Considering that CNVs are implicated in several human developmental disorders, we hypothesized that CNVs in PCP genes may be causative factors to human NTDs. DNA from umbilical cord tissues of NTD-affected fetuses and parental venous blood samples were collected. We performed a quantitative analysis of copy numbers of all exon regions in theVANGL1,VANGL2,CELSR1,SCRIB,DVL2,DVL3, andPTK7 genes u...
Source: Neurogenetics - May 8, 2020 Category: Genetics & Stem Cells Source Type: research

Oligogenicity, C9orf72 expansion, and variant severity in ALS
Abstract“Oligogenic inheritance” is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sc lerosis (ALS). We sequenced ALS-associated genes inC9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was signific...
Source: Neurogenetics - May 7, 2020 Category: Genetics & Stem Cells Source Type: research

Polygenic risk scores indicates genetic overlap between peripheral pain syndromes and chronic postsurgical pain
In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory res ponse may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate. (Source: Neurogenetics)
Source: Neurogenetics - May 5, 2020 Category: Genetics & Stem Cells Source Type: research

Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213 , a susceptibility factor for moyamoya disease
AbstractHumanRNF213, which encodes the protein mysterin, is a known susceptibility gene for moyamoya disease (MMD), a cerebrovascular condition with occlusive lesions and compensatory angiogenesis. Mysterin mutations, together with exposure to environmental trigger factors, lead to an elevated stroke risk since childhood. Mysterin is induced during cell stress, to function as cytosolic AAA+ ATPase and ubiquitylation enzyme. Little knowledge exists, in which context mysterin is needed. Here, we found that genetic ablation of several mitochondrial matrix factors, such as the peptidaseClpP, the transcription factorTfam, as we...
Source: Neurogenetics - April 27, 2020 Category: Genetics & Stem Cells Source Type: research

Adult-onset glutaric aciduria type I: rare presentation of a treatable disorder
AbstractGlutaric aciduria type I (GA1; OMIM #231670) is an autosomal recessively inherited and treatable disorder characterized by the accumulation and irregular excretion of glutaric acid due to a defect in the glutaryl-CoA dehydrogenase enzyme involved in the catabolic pathways ofl-lysine,l-hydroxylysine, andl-tryptophan. Glutaryl-CoA dehydrogenase is encoded by theGCDH gene (OMIM #608801), and several mutations in this gene are known to result in GA1. GA1 usually presents in the first 18 –36 months of life with mild or severe acute encephalopathy, movement disorders, and striatal degeneration. Few cases of ad...
Source: Neurogenetics - April 17, 2020 Category: Genetics & Stem Cells Source Type: research

Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1
AbstractHereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by progressive spastic paraparesis.UBAP1 was recently found to induce a rare type of HSP (SPG80). We identified a family with eight inherited spastic paraplegic patients carrying a novel heterozygous mutation c.279delG (p.S94Vfs*9) ofUBAP1. We demonstrated a lack of functional UBAP1 in these patients, resulting in the neurological disorder caused by interceptions of the ESCRT pathway. Extending from the older onset-age identified from this family, we found that comparing with the European and other populations, Asian p...
Source: Neurogenetics - March 27, 2020 Category: Genetics & Stem Cells Source Type: research

Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients
AbstractEvidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of park...
Source: Neurogenetics - March 25, 2020 Category: Genetics & Stem Cells Source Type: research

Familial analysis reveals rare risk variants for migraine in regulatory regions
We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those ori...
Source: Neurogenetics - February 18, 2020 Category: Genetics & Stem Cells Source Type: research

Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype
This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts ofKCNJ10, a gene initially associated only with the EAST/SeSAME syndrome. (Source: Neurogenetics)
Source: Neurogenetics - February 14, 2020 Category: Genetics & Stem Cells Source Type: research

Reply to letter to the editor by De Michele et al
(Source: Neurogenetics)
Source: Neurogenetics - February 5, 2020 Category: Genetics & Stem Cells Source Type: research

Of cognition and cerebellum in SCA48
(Source: Neurogenetics)
Source: Neurogenetics - February 2, 2020 Category: Genetics & Stem Cells Source Type: research

POLR3A variants with striatal involvement and extrapyramidal movement disorder
AbstractBiallelic variants inPOLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants inPOLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygousPOLR3A variants and predominant striatal changes were retrospectively r...
Source: Neurogenetics - January 14, 2020 Category: Genetics & Stem Cells Source Type: research

Changes in global gene expression indicate disordered autophagy, apoptosis and inflammatory processes and downregulation of cytoskeletal signalling and neuronal development in patients with Niemann –Pick C disease
AbstractChanges in gene expression profiles were investigated in 23 patients with Niemann –Pick C1 disease (NPC). cDNA expression microarrays with subsequent validation by qRT-PCR were used. Comparison of NPC to control samples revealed upregulation of genes involved in inflammation (MMP3,THBS4), cytokine signalling (MMP3), extracellular matrix degradation (MMP3,CTSK), autophagy and apoptosis (CTSK,GPNMB,PTGIS), immune response (AKR1C3,RCAN2,PTGIS) and processes of neuronal development (RCAN2). Downregulated genes were associated with cytoskeletal signalling (ACTG2,CNN1); inflammation and oxidative stress (CNN1); inh...
Source: Neurogenetics - January 10, 2020 Category: Genetics & Stem Cells Source Type: research

Identification and characterization of novel mutations in MOGS in a Chinese patient with infantile spams
In conclusion, our study suggested whole exome sequencing, and genes associated with CDGs should be analyzed in patients with infantile spams and multiple system involvement, and mutant MOGS–impaired cell cycle progression. Our work broadens the mutation spectrum ofMOGS gene. (Source: Neurogenetics)
Source: Neurogenetics - January 9, 2020 Category: Genetics & Stem Cells Source Type: research

Mitochondrial epilepsy: a cross-sectional nationwide Italian survey
AbstractMany aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the “Nationwide Italian Collaborative Network of Mitochondrial Diseases” (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 fema...
Source: Neurogenetics - January 2, 2020 Category: Genetics & Stem Cells Source Type: research

Customized multigene panels in epilepsy: the best things come in small packages
AbstractOver the past 10  years, the increasingly important role played by next-generation sequencing panels in the genetic diagnosis of epilepsy has led to a growing list of gene variants and a plethora of new scientific data. To date, however, there is still no consensus on what constitutes the “ideal panel design,” or on the most rational criteria for selecting the best candidates for gene-panel analysis, even though both might optimize the cost-benefit ratio and the diagnostic efficiency of customized gene panels. Even though more and more laboratories are adopting whole-exome sequencing as a first-tie...
Source: Neurogenetics - December 12, 2019 Category: Genetics & Stem Cells Source Type: research

Whole exome sequencing reveals a broader variant spectrum of Charcot-Marie-Tooth disease type 2
In conclusion, our work supports that the molecular diagnostic rate of CMT2 patients can be increased via whole exome sequencing, and our data suggest that assessment of possibleHINT1 mutations should be undertaken for CMT2 patients with neuromyotonia. (Source: Neurogenetics)
Source: Neurogenetics - December 11, 2019 Category: Genetics & Stem Cells Source Type: research

Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication
AbstractMicrodeletions encompassing 14q11.2locus, involvingSUPT16H andCHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading toCHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassingCHD8 andSUPT16H, has been described, highlighting the importance of a tight control of at leastCHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severi...
Source: Neurogenetics - December 9, 2019 Category: Genetics & Stem Cells Source Type: research

Cerebellar cognitive-affective syndrome preceding ataxia associated with complex extrapyramidal features in a Turkish SCA48 family
AbstractSCA48 is a novel spinocerebellar ataxia (SCA) originally and recently characterized by prominent cerebellar cognitive-affective syndrome (CCAS) and late-onset ataxia caused by mutations on theSTUB1 gene. Here, we report the first SCA48 case from Turkey with novel clinical features and diffusion tensor imaging (DTI) findings, used for the first time to evaluate a SCA48 patient. A 65-year-old female patient with slowly progressive cerebellar ataxia, cognitive impairment, behavioral changes, and a vertical family history was evaluated. Following the exclusion of repeat expansion ataxias, whole exome sequencing (WES) w...
Source: Neurogenetics - November 18, 2019 Category: Genetics & Stem Cells Source Type: research

Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey
This study is aimed at establishing molecular classification and phenotypic correlation of childhood-onset ARAs in Southeast Anatolia of Turkey. Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015 –2018 were selected for the study. Seventeen different, clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%), 12 of which were noted to be unreported variants. Among these 33 families, 24 hadATM-related (72.72%), four hadSACS-related (12.12%), three hadCOQ8A-related (9.09%), and two hadAPTX-...
Source: Neurogenetics - November 18, 2019 Category: Genetics & Stem Cells Source Type: research

A novel cysteine-sparing G73A mutation of NOTCH3 in a Chinese CADASIL family
AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic disease leading to stroke and vascular dementia. CADASIL is an inherited small blood vessel disease caused by mutations in the gene encoding the neurogenic locus notch homolog protein 3 (NOTCH3). NOTCH3 is large type I membrane receptor mainly expressed in vascular smooth muscle cells and pericytes. Most identified mutations result in insert or deletion of a cysteine residue within the EGF-like repeats. To date, some cases with a cysteine-sparing mutant have been described. Genetic analy...
Source: Neurogenetics - November 12, 2019 Category: Genetics & Stem Cells Source Type: research

The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype
AbstractCharcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich ’s ataxia (FRDA). The identified missense mutation has been reported previously in two FRDA cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from our family indicated t...
Source: Neurogenetics - October 30, 2019 Category: Genetics & Stem Cells Source Type: research

Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion
AbstractGiant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in theGAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients withGAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2 –18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1&ndash...
Source: Neurogenetics - October 25, 2019 Category: Genetics & Stem Cells Source Type: research