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 comparing C...
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
In conclusion, we identified two pathogenic splice-site variants inKIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants inKIF5A in the Japanese series. (Source: Neurogenetics)
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 mother, were ...
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 causing in...
Source: Neurogenetics - July 6, 2020 Category: Genetics & Stem Cells Source Type: research
