ISSN / EISSN : 23767839 / 23767839
Current Publisher: Ovid Technologies (Wolters Kluwer Health) (10.1212)
Total articles ≅ 431
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Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000421
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Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000422
The 26th workshop of the International Stroke Genetics Consortium (ISGC) was held at the Four Seasons Hotel on November 2–4, 2019 in St. Louis, MO, and was hosted by Jin-Moo Lee, MD, PhD and Carlos Cruchaga, PhD, and co-hosted by Stephanie Debette, MD, PhD. The ISGC is an international collaboration of physicians and scientists who have agreed to pool resources and expertise in an effort to unravel the genetic basis of stroke and its comorbidities. Founded in 2007 by a small group of stroke genetics investigators, the ISGC has grown to over 200 members representing over 50 countries in North and South America, Europe, Australia, Africa, and Asia. ISGC workshops are held semi-annually and provide a forum for ISGC investigators to report on progress of ongoing scientific projects and discuss new ideas that help advance the ISGC's research mission. The ISGC nurtures junior investigators by offering several travel awards to young investigators interested in stroke genetics. Many abstracts in these Proceedings reflect the contributions of active junior investigators. Herein, we present the Proceedings and official published abstracts of the 26th ISGC Workshop.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000440
ObjectiveWe evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America.MethodsA cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested.ResultsIn the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37).ConclusionsIn a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000436
The ataxias comprise diseases of both genetic and nongenetic origin with extreme clinical and genetic heterogeneity. They may present as a pure cerebellar form or as part of a more complex neurologic syndrome. Progressive, neurodegenerative sporadic adult-onset ataxias (SAOAs) without a known cause have a prevalence rate of 2.2–12.4 per 100,000. In several ataxia cohorts, repetitive genetic screening using high-coverage ataxia-specific gene panels in combination with next-generation sequencing (NGS) failed to identify a causative gene in 50%–90% of SAOAs.1–3 Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), first described by Brownstein et al.,4 is a slowly progressive neurodegenerative disorder with adult onset, affecting the cerebellum, sensory neurons, and the vestibular system. CANVAS is usually sporadic, but occasionally occurs in siblings. Two research groups recently identified large biallelic intronic AAGGG expansions in replication factor C subunit 1 ( RFC1 ) resulting in CANVAS, an adult-onset neurodegenerative ataxia.5–7 RFC1 normally loads proliferating cell nuclear antigen onto DNA and activates DNA polymerases δ and ε to promote the coordinated synthesis of both strands during replication or after DNA damage.8
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000428
ObjectiveTo improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.MethodsExonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.ResultsWe identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.ConclusionsOur results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000442
LAMB1 encodes laminin subunit beta 1, a constituent of the extracellular matrix glycoprotein of basement membranes.1 Mutations of LAMB1 have been reported in patients with congenital or infantile- to childhood-onset leukoencephalopathy and severe developmental retardation.2,3 We report an adulthood-onset case with mild leukoencephalopathy and a novel homozygous LAMB1 missense mutation. Our findings expand the clinical spectrum of LAMB1 -related disorder.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000430
BackgroundThe huntingtin gene (HTT) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments.ObjectiveThis prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions.MethodsAcross 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing.ResultsHeterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the mHTT allele in 61% (95% high density interval: 55%, 67%) of individuals.ConclusionsThese results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000425
ObjectiveTo expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.MethodsWe performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.ResultsEach patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.ConclusionsWe describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000434
ObjectiveThe aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient.MethodsHere, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed an extensive literature research for NOTCH3 mutations published since the identification of the gene and performed a systematic review of all published cases with NOTCH3 mutations. We evaluated the mutation pathogenicity in a great number of patients with detailed clinical and genetic evaluation and investigated the possible phenotype-genotype correlations.ResultsOur patient harbored a novel mutation in the NOTCH3 gene, the c.3084 G > C, corresponding to the aminoacidic substitution p.Trp1028Cys, presenting with seizures as the first neurologic manifestation. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age at onset of CADASIL. Significant differences were also identified between men and women regarding the phenotype severity.ConclusionsThe collection and analysis of these scarce data published since the identification of NOTCH3 qualitatively by means of a systematic review and quantitatively regarding genetic profile and pathogenicity scores, highlight the significance of the ongoing trend of investigating phenotypic genotypic correlations.
Neurology Genetics, Volume 6; doi:10.1212/nxg.0000000000000432
Heterozygous germline mutations in mammalian target of rapamycin ( MTOR ) (OMIM 601231) are known to underlie Smith-Kingsmore syndrome (SKS; OMIM 616638), an infrequent entity with autosomal dominant inheritance, also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ORPHA 457485).1 Among the clinical features of SKS, the most common features include intellectual disability, macrocephaly, epilepsy, and facial dysmorphism. The aim of this case is to raise awareness of a distinct phenotypical presentation of SKS manifesting with bilateral cataracts and no history of seizures.