Neurology-Genetics最新文献

{"title":"Toward the Definition of Patient-Reported Outcome Measurements in Hereditary Spastic Paraplegia.","authors":"Matthias Amprosi,&nbsp;Elisabetta Indelicato,&nbsp;Andreas Eigentler,&nbsp;Josef Fritz,&nbsp;Wolfgang Nachbauer,&nbsp;Sylvia Boesch","doi":"10.1212/NXG.0000000000200052","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200052","url":null,"abstract":"<p><strong>Background and objectives: </strong>Hereditary spastic paraplegias (HSPs) are a heterogeneous group of rare neurodegenerative diseases, characterized by a progressive spastic paraparesis. Currently, there is a HSP-specific clinician-reported outcome measure (CROM) called Spastic Paraplegia Rating Scale (SPRS). There are, however, no specific patient-reported outcome measures (PROMs) for HSP. In the present cohort study, we prospectively follow up a well-examined Austrian HSP cohort using validated rating scales and compared PROM with disease-specific and non-disease-specific CROM.</p><p><strong>Methods: </strong>Patients were recruited and followed up at the Center for Rare Movement Disorders, Innsbruck, Austria. CROM included the SPRS, Scale for the Assessment and Rating of Ataxia (SARA), Barthel Index (BI), and Mini-Mental State Examination (MMSE). PROM included the EQ-5D questionnaire and the Patient Health Questionnaire 9 (PHQ-9). Standardized response means (SRMs) were calculated for all scales at follow-up (FU) after 1 year.</p><p><strong>Results: </strong>A total of 55 patients (36 males) with HSP were included in the study. FU was performed for 30 patients (21 males). Apart from females reporting more problems in the EQ-5D domain of anxiety and depression (<i>p</i> = 0.008), other clinician-reported outcomes (CROs) or patient-reported outcomes (PROs) did not differ significantly across sex. SPRS showed significant correlations with SARA (<i>p</i> < 0.001), mainly driven by the gait item, as well as the BI. Although SPRS did not correlate with EQ-5D visual analogue scale and PHQ-9 scores, several EQ-5D domains correlated significantly with SPRS. At FU, SPRS showed the highest responsiveness (SRM 1.11), followed by SARA (SRM 0.47). Neither MMSE nor PRO significantly increased at FU.</p><p><strong>Discussion: </strong>In this study, we present an Austrian cohort of patients with HSP and a prospective study evaluating correlations of CRO and PRO as well as their progression. Demographics from our cohort are comparable with several other European cohort studies. Our data highlight the capabilities of the SPRS to show clinical progression and warrant consideration of ataxia rating scales such as SARA in HSP cohorts. We also show that the generic PROMs are not suitable to detect change in HSP, and thus, we propose to create a disease-specific PROM fully depicting the effect of HSP on the patients' lives.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200052"},"PeriodicalIF":3.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/74/44/NXG-2022-200055.PMC9832334.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9076432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Homozygous Variant in <i>COQ7</i> in Siblings With Hereditary Motor Neuropathy.","authors":"Ian C Smith,&nbsp;Chantal A Pileggi,&nbsp;Ying Wang,&nbsp;Kristin Kernohan,&nbsp;Taila Hartley,&nbsp;Hugh J McMillan,&nbsp;Marcos Loreto Sampaio,&nbsp;Gerd Melkus,&nbsp;John Woulfe,&nbsp;Gaganvir Parmar,&nbsp;Pierre R Bourque,&nbsp;Ari Breiner,&nbsp;Jocelyn Zwicker,&nbsp;C Elizabeth Pringle,&nbsp;Olga Jarinova,&nbsp;Hanns Lochmüller,&nbsp;David A Dyment,&nbsp;Bernard Brais,&nbsp;Kym M Boycott,&nbsp;Siegfried Hekimi,&nbsp;Mary-Ellen Harper,&nbsp;Jodi Warman-Chardon","doi":"10.1212/NXG.0000000000200048","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200048","url":null,"abstract":"<p><strong>Background and objectives: </strong>Coenzyme Q₁₀ (CoQ₁₀) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ₁₀), the second-to-last step in the CoQ₁₀ biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of <i>COQ7</i> with abnormal CoQ₁₀ biosynthesis.</p><p><strong>Methods: </strong>Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the <i>COQ7</i> variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis.</p><p><strong>Results: </strong>Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous <i>COQ7</i> c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the <i>COQ7</i> variant was demonstrated by diminished COQ7 and CoQ₁₀ levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ₁₀, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle.</p><p><strong>Discussion: </strong>This report describes a new neurologic phenotype of <i>COQ7</i>-related primary CoQ₁₀ deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of <i>COQ7</i>-related CoQ₁₀ deficiency previously reported in the literature.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200048"},"PeriodicalIF":3.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/65/19/NXG-2022-200051.PMC10108386.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9738463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Frontotemporal Dementia in Females of 5 Hispanic Families With R159H VCP Multisystem Proteinopathy.","authors":"Alyaa Shmara,&nbsp;Liliane Gibbs,&nbsp;Ryan Patrick Mahoney,&nbsp;Kyle Hurth,&nbsp;Vanessa S Goodwill,&nbsp;Alicia Cuber,&nbsp;Regina Im,&nbsp;Donald P Pizzo,&nbsp;Jerry Brown,&nbsp;Christina Laukaitis,&nbsp;Shalini Mahajan,&nbsp;Virginia Kimonis","doi":"10.1212/NXG.0000000000200037","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200037","url":null,"abstract":"<p><strong>Background and objectives: </strong>Missense variants of the valosin-containing protein (<i>VCP</i>) gene cause a progressive, autosomal dominant disease termed VCP multisystem proteinopathy (MSP1). The disease is a constellation of clinical features including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically reported at a frequency of 90%, 42%, 30%, and 9%, respectively. The Hispanic population is currently underrepresented in previous reports of VCP myopathy. We expand our genotype-phenotype studies in 5 Hispanic families with the c.476G>A, p.R159H <i>VCP</i> variant.</p><p><strong>Methods: </strong>We report detailed clinical findings of 11 patients in 5 Hispanic families with the c.476G > A, p.R159H <i>VCP</i> variant. In addition, we report frequencies of the main manifestations in 28 additional affected members of the extended family members. We also compared our findings with an existing larger cohort of patients with VCP MSP1.</p><p><strong>Results: </strong>FTD was the most prevalent feature reported, particularly frequent in females. PDB was only seen in 1 patient in contrast to the earlier reported cohorts. The overall frequency of the different manifestations: myopathy, PDB, FTD, and ALS in these 5 families was 39%, 3%, 72%, and 8%, respectively. The atypical phenotype and later onset of manifestations in these families resulted in a noticeable delay in the diagnosis of VCP disease.</p><p><strong>Discussion: </strong>Studying each <i>VCP</i> variant in the context of ethnic backgrounds is pivotal in increasing awareness of the variability of VCP-related diseases across different ethnicities, enabling early diagnosis, and understanding the mechanism for these genotype-phenotype variations.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200037"},"PeriodicalIF":3.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3e/de/NXG-2022-200040.PMC9833818.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9099861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Cerebral Small Vessel Disease Caused by the Uniallelic p.A252T Variant of <i>HTRA1</i>.","authors":"Yasufumi Kondo,&nbsp;Tsuneaki Yoshinaga,&nbsp;Katsuya Nakamura,&nbsp;Tomomi Yamaguchi,&nbsp;Masumi Ishikawa,&nbsp;Tomoki Kosho,&nbsp;Yoshiki Sekijima","doi":"10.1212/NXG.0000000000200047","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200047","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the clinical effect of a heterozygous missense variant of <i>HTRA1</i> on cerebral small vessel disease (CSVD) in a large Japanese family with a p.A252T variant.</p><p><strong>Methods: </strong>We performed clinical, laboratory, radiologic, and genetic evaluations of members of a previously reported family with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).</p><p><strong>Results: </strong>Two family members were previously reported patients with CARASIL. Among 6 uniallelic p.A252T carriers, 2 had neurologic symptoms with brain MRI abnormalities, 2 showed CSVD on the MRI only, and the other 2 were unaffected. Clinical phenotypes of 2 heterozygous patients were comparable with those of patients with CARASIL, whereas the other 3 heterozygous patients had developed milder and later-onset CSVD. One heterozygous carrier was asymptomatic.</p><p><strong>Discussion: </strong>Previous studies have suggested that uniallelic p.A252T causes disease. However, our study revealed that patients with uniallelic p.A252T can have severe and young-onset CSVD. The clinical manifestations of uniallelic variant carriers were highly variable, even within the same family. Male and atherosclerotic risk factors were considered to be additional factors in the severity of neurologic symptoms in uniallelic p.A252T carriers, suggesting that strict control of vascular risk factors can prevent vascular events in uniallelic <i>HTRA1</i> carriers.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200047"},"PeriodicalIF":3.1,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fc/bc/NXG-2022-200050.PMC9756387.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10399469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropathology-Independent Association Between <i>APOE</i> Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum.","authors":"Jing Qian, Yiding Zhang, Rebecca A Betensky, Bradley T Hyman, Alberto Serrano-Pozo","doi":"10.1212/NXG.0000000000200055","DOIUrl":"10.1212/NXG.0000000000200055","url":null,"abstract":"<p><strong>Background and objectives: </strong>We previously found that the <i>APOE</i> genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the <i>APOE</i> alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies.</p><p><strong>Methods: </strong>We analyzed <i>APOE</i> associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling.</p><p><strong>Results: </strong>Carrying the <i>APOE</i>ε4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to <i>APOE</i>ε3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which <i>APOE</i>ε4 carriers declined faster than <i>APOE</i>ε3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in <i>APOE</i>ε4 vs <i>APOE</i>ε3/ε3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in <i>APOE</i>ε4 vs <i>APOE</i>ε3/ε3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in <i>APOE</i>ε4 vs <i>APOE</i>ε3/ε3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in <i>APOE</i>ε4 vs <i>APOE</i>ε3/ε3). Compared with slow decliners, fast decliners were more likely to carry the <i>APOE</i>ε4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy.</p><p><strong>Discussion: </strong>In a large national sample selected to represent the normal aging-early AD continuum, the <i>APOE</i>ε4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200055"},"PeriodicalIF":3.0,"publicationDate":"2023-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a7/2c/NXG-2022-200058.PMC9869750.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10778118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease.","authors":"Alexander G Murley, Yu Nie, Zoe Golder, Michael John Keogh, Colin Smith, James W Ironside, Patrick F Chinnery","doi":"10.1212/NXG.0000000000200054","DOIUrl":"10.1212/NXG.0000000000200054","url":null,"abstract":"<p><strong>Background and objectives: </strong>Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene <i>PRNP</i> are increased in sCJD, potentially leading to the seeding of misfolded prion protein.</p><p><strong>Methods: </strong>High-depth amplicon-based short read sequencing of the <i>PRNP</i> coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups.</p><p><strong>Results: </strong>Two sCJD cases had somatic (variant allele frequency 0.5-1%) <i>PRNP</i> variants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somatic <i>PRNP</i> in sCJD compared with controls and a lower burden compared with Alzheimer disease.</p><p><strong>Discussion: </strong>Somatic variants in <i>PRNP</i> are unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 1","pages":"e200054"},"PeriodicalIF":3.0,"publicationDate":"2023-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9853313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9147675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Mission, New Reviews, New Word Counts, Oh My!","authors":"Stefan M Pulst","doi":"10.1212/NXG.0000000000200045","DOIUrl":"10.1212/NXG.0000000000200045","url":null,"abstract":"","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"8 6","pages":"e200045"},"PeriodicalIF":3.0,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/17/6e/NXG-2022-200048.PMC9756386.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10404442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Sex-Specific Genetic Variants Associated With Tau PET.","authors":"Xin Wang, Iris Broce, Kacie D Deters, Chun Chieh Fan, Sarah Jane Banks","doi":"10.1212/NXG.0000000000200043","DOIUrl":"10.1212/NXG.0000000000200043","url":null,"abstract":"<p><strong>Background and objectives: </strong>Important sex differences exist in tau pathology along the Alzheimer disease (AD) continuum, with women showing enhanced tau deposition compared with men, especially during the mild cognitive impairment (MCI) phase. This study aims to identify specific genetic variants associated with sex differences in regional tau aggregation, as measured with PET.</p><p><strong>Methods: </strong>Four hundred ninety-three participants (women, n = 246; men, n = 247) who self-identified as White from the AD Neuroimaging Initiative study, with genotyping data and ¹⁸F-Flortaucipir tau PET data, were included irrespective of clinical diagnosis (cognitively normal [CN], MCI, and AD). We focused on the genetic variants within 10 genes previously shown to have sex-dependent effects on AD to reduce the burden of multiple comparisons: <i>BIN1</i>, <i>MS4A6A</i>, <i>DNAJA2</i>, <i>FERMT2</i>, <i>APOC1</i>, <i>APOC1P1</i>, <i>FAM193B</i>, <i>C2orf47</i>, <i>TYW5</i>, and <i>CR1.</i> Multivariate analysis of variance was applied to identify genetic variants associated with tau PET data in 3 regions of interests (composite regions of Braak I, Braak III/IV, and Braak V/VI stages) in women and men separately. We controlled for age, scanner manufacture, amyloid status, <i>APOE</i> ε4 carriership, diagnosis (CN vs MCI vs AD), and the first 10 genetic principal components to adjust for population stratification.</p><p><strong>Results: </strong>We identified 3 genetic loci within 3 different genes associated with tau deposits specifically in women: rs79711283 within <i>DNAJA2</i>, rs113357081 within <i>FERMT2</i>, and rs74614106 within <i>TYW5</i>. In men, we also identified 3 loci within <i>CR1</i> associated with tau deposits: rs115096248, rs113698814, and rs78150633.</p><p><strong>Discussion: </strong>Our findings revealed sex-specific genetic variants associated with tau deposition independent of <i>APOE</i> ε4, amyloid status, and clinical diagnosis. These results provide potential molecular targets for understanding the mechanism of sex-specific tau aggregation and developing sex-specific gene-guided precision prevention or therapeutic interventions for AD.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"8 6","pages":"e200043"},"PeriodicalIF":3.1,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8c/9d/NXG-2022-200046.PMC9756308.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9407417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain.","authors":"Raquel Baviera-Muñoz,&nbsp;Lidón Carretero-Vilarroig,&nbsp;Juan Francisco Vázquez-Costa,&nbsp;Carlos Morata-Martínez,&nbsp;Marina Campins-Romeu,&nbsp;Nuria Muelas,&nbsp;Isabel Sastre-Bataller,&nbsp;Irene Martínez-Torres,&nbsp;Julia Pérez-García,&nbsp;Rafael Sivera,&nbsp;Teresa Sevilla,&nbsp;Juan J Vilchez,&nbsp;Teresa Jaijo,&nbsp;Carmen Espinós,&nbsp;Jose M Millán,&nbsp;Luis Bataller,&nbsp;Elena Aller","doi":"10.1212/NXG.0000000000200038","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200038","url":null,"abstract":"<p><strong>Background and objectives: </strong>To determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain.</p><p><strong>Methods: </strong>A total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered. Copy number variants were analyzed when appropriate. In undiagnosed dominant and sporadic cases, repeat primed PCR was used to screen for the presence of a repeat expansion in the <i>NOP56</i> gene.</p><p><strong>Results: </strong>CES identified pathogenic or likely pathogenic variants in 50 families (39%), including 23 novel variants. Overall, there was a high genetic heterogeneity, and the most frequent genetic diagnosis was <i>SPG7</i> (n = 15), followed by <i>SETX</i> (n = 6), <i>CACNA1A</i> (n = 5), <i>POLR3A</i> (n = 4), and <i>SYNE1</i> (n = 3). In addition, 17 families displayed likely pathogenic/pathogenic variants in 14 different genes: <i>KCND3</i> (n = 2), <i>KIF1C</i> (n = 2), <i>CYP27A1A</i> (n = 2), <i>AFG3L2</i> (n = 1), <i>ANO10</i> (n = 1), <i>CAPN1</i> (n = 1), <i>CWF19L1</i> (n = 1), <i>ITPR1</i> (n = 1), <i>KCNA1</i> (n = 1), <i>OPA1</i> (n = 1), <i>PNPLA6</i> (n = 1), <i>SPG11</i> (n = 1), <i>SPTBN2</i> (n = 1), and <i>TPP1</i> (n = 1). Twenty-two novel variants were characterized. SCA36 was diagnosed in 11 families, all with autosomal dominant (AD) presentation. SCA36 screening increased the total diagnostic rate to 47% (n = 61/130). Ultimately, undiagnosed patients showed delayed age at onset (<i>p</i> < 0.05) and were more frequently sporadic.</p><p><strong>Discussion: </strong>Our study provides insight into the genetic landscape of CA in Eastern Spain. Although CES was an effective approach to capture genetic heterogeneity, most patients remained undiagnosed. SCA36 was found to be a relatively frequent form and, therefore, should be tested prior to CES in familial AD presentations in particular geographical regions.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"8 6","pages":"e200038"},"PeriodicalIF":3.1,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6d/fd/NXG-2022-200041.PMC9749935.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10400205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic Spectrum of <i>DNM2</i>-Related Centronuclear Myopathy.","authors":"Leslie Hotchkiss Hayes,&nbsp;Morgane Perdomini,&nbsp;Asli Aykanat,&nbsp;Casie A Genetti,&nbsp;Heather L Paterson,&nbsp;Belinda S Cowling,&nbsp;Christian Freitag,&nbsp;Alan H Beggs","doi":"10.1212/NXG.0000000000200027","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200027","url":null,"abstract":"<p><strong>Background and objectives: </strong>Centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene, <i>DNM2</i>, is a rare neuromuscular disease about which little is known. The objective of this study was to describe the range of clinical presentations and subsequent natural history of <i>DNM2</i>-related CNM.</p><p><strong>Methods: </strong>Pediatric and adult patients with suspicion for a CNM diagnosis and confirmed heterozygous pathogenic variants in <i>DNM2</i> were ascertained between December 8, 2000, and May 1, 2019. Data were collected through a retrospective review of genetic testing results, clinical records, and pathology slides combined with patient-reported clinical findings via questionnaires.</p><p><strong>Results: </strong>Forty-two patients with <i>DNM2</i>-related CNM, whose ages ranged from 0.95 to 75.76 years at most recent contact, were enrolled from 34 families in North or South America and Europe. There were 8 different <i>DNM2</i> pathogenic variants within the cohort. Of the 32 biopsied patients, all had histologic features of CNM. The disease onset was in infancy or childhood in 81% of the cohort, and more than half of the patients had high arched palates, indicative of weakness in utero. Ambulation was affected in nearly all (92%) the patients, and while the rapidity of progression was variable, most (67%) reported a \"deteriorating course.\" Ptosis, ophthalmoparesis, facial weakness, dysphagia, and respiratory insufficiency were commonly reported. One-third of the patients experienced restricted jaw mobility. Certain pathogenic variants appear to correlate with a more severe phenotype.</p><p><strong>Discussion: </strong><i>DNM2</i>-related CNM has a predominantly early-onset, often congenital, myopathy resulting in progressive difficulty with ambulation and occasionally bulbar and respiratory dysfunction. This detailed characterization of the phenotype provides important information to support clinical trial readiness for future disease-modifying therapies.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"8 6","pages":"e200027"},"PeriodicalIF":3.1,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1e/98/NXG-2022-200030.PMC9621335.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9486303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}