Neurology-Genetics最新文献

{"title":"Agenesis of Pectoralis Major Muscle in Late-Onset<i>GFPT1</i>-Related Congenital Myasthenic Syndrome","authors":"Erika K. Williams, Cristina Shea, Paloma Gonzalez-Perez","doi":"10.1212/nxg.0000000000200102","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200102","url":null,"abstract":"Objectives The objective of this study was to expand the phenotypic spectrum of glutamine-fructose-6-phosphate transaminase 1 ( GFPT1 )–related congenital myasthenia syndrome (CMS). Methods A 61-year-old man with agenesis of the left pectoralis major muscle presented with progressive muscle weakness for a decade that transiently improved after exertion. Results His examination revealed proximal and distal muscle weakness in upper extremities and proximal muscle weakness in lower extremities. Muscle enzymes were elevated. An electromyogram revealed a myopathic pattern; however, a muscle biopsy of deltoid muscle and genetic testing for limb-girdle muscular dystrophies were nondiagnostic. A 3-Hz repetitive nerve stimulation of the spinal accessory nerve recording from trapezius muscle demonstrated a &gt;20% drop in amplitude of the 5th compound motor action potential relative to 1st at both baseline and after 45-second exercise. Acetylcholine receptor binding, lipoprotein-related protein 4, muscle-specific kinase, and voltage-gated calcium channel P/Q antibodies were negative. Genetic testing targeting CMS revealed 2 likely pathogenic variants within GFPT1 : novel c.7+2T&gt;G (intron 1) that was predicted to result in a null allele and known c*22 C&gt;A (exon 19) associated with reduced GFPT1 expression. His muscle strength dramatically improved after pyridostigmine initiation. Discussion In addition to other reported neurodevelopmental abnormalities, pectoralis major muscle agenesis (or Poland syndrome) may be a clinical manifestation of GFPT1 -related CMS.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"57 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134885221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic<i>SOX8</i>Variants Associated With Novel Syndrome With Myopathy, Skeletal Deformities, Intellectual Disability, and Ovarian Dysfunction","authors":"Jodi Warman-Chardon, Taila Hartley, Aren Elizabeth Marshall, Arran McBride, Madeline Couse, William Macdonald, Mellissa R.W. Mann, Pierre R. Bourque, Ari Breiner, Hanns Lochmüller, John Woulfe, Marcos Loreto Sampaio, Gerd Melkus, Bernard Brais, David A. Dyment, Kym M. Boycott, Kristin Kernohan","doi":"10.1212/nxg.0000000000200088","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200088","url":null,"abstract":"Background and Objectives The human genome contains ∼20,000 genes, each of which has its own set of complex regulatory systems to govern precise expression in each developmental stage and cell type. Here, we report a female patient with congenital weakness, respiratory failure, skeletal dysplasia, contractures, short stature, intellectual delay, respiratory failure, and amenorrhea who presented to Medical Genetics service with no known cause for her condition. Methods Whole-exome and whole-genome sequencing were conducted, as well as investigational functional studies to assess the effect of SOX8 variant. Results The patient was found to have biallelic SOX8 variants (NM_014587.3:c.422+5G&gt;C; c.583dup p.(His195ProfsTer11)). SOX8 is a transcriptional regulator, which is predicted to be imprinted (expressed from only one parental allele), but this has not yet been confirmed. We provide evidence that while SOX8 was maternally expressed in adult-derived fibroblasts and lymphoblasts, it was biallelically expressed in other cell types and therefore suggest that biallelic variants are associated with this recessive condition. Functionally, we showed that the paternal variant had the capacity to affect mRNA splicing while the maternal variant resulted in low levels of a truncated protein, which showed decreased binding at and altered expression of SOX8 targets. Discussion Our findings associate SOX8 variants with this novel condition, highlight how complex genome regulation can complicate novel disease-gene identification, and provide insight into the molecular pathogenesis of this disease.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135059469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency of GAA-<i>FGF14</i> Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia.","authors":"Luiz Eduardo Novis, Rodrigo S Frezatti, David Pellerin, Pedro J Tomaselli, Shahryar Alavi, Marcus Vinícius Della Coleta, Mariana Spitz, Marie-Josée Dicaire, Pablo Iruzubieta, José Luiz Pedroso, Orlando Barsottini, Andrea Cortese, Matt C Danzi, Marcondes C França, Bernard Brais, Stephan Zuchner, Henry Houlden, Salmo Raskin, Wilson Marques, Helio A Teive","doi":"10.1212/NXG.0000000000200094","DOIUrl":"10.1212/NXG.0000000000200094","url":null,"abstract":"<p><strong>Objectives: </strong>Intronic <i>FGF14</i> GAA repeat expansions have recently been found to be a common cause of hereditary ataxia (GAA-<i>FGF14</i> ataxia; SCA27B). The global epidemiology and regional prevalence of this newly reported disorder remain to be established. In this study, we investigated the frequency of GAA-<i>FGF14</i> ataxia in a large cohort of Brazilian patients with unsolved adult-onset ataxia.</p><p><strong>Methods: </strong>We recruited 93 index patients with genetically unsolved adult-onset ataxia despite extensive genetic investigation and genotyped the <i>FGF14</i> repeat locus. Patients were recruited across 4 different regions of Brazil.</p><p><strong>Results: </strong>Of the 93 index patients, 8 (9%) carried an <i>FGF14</i> (GAA)_≥250 expansion. The expansion was also identified in 1 affected relative. Seven patients were of European descent, 1 was of African descent, and 1was of admixed American ancestry. One patient carrying a (GAA)₃₇₆ expansion developed ataxia at age 28 years, confirming that GAA-<i>FGF14</i> ataxia can occur before the age of 30 years. One patient displayed episodic symptoms, while none had downbeat nystagmus. Cerebellar atrophy was observed on brain MRI in 7 of 8 patients (87%).</p><p><strong>Discussion: </strong>Our results suggest that GAA-<i>FGF14</i> ataxia is a common cause of adult-onset ataxia in the Brazilian population, although larger studies are needed to fully define its epidemiology.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 5","pages":"e200094"},"PeriodicalIF":3.0,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118312","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":"Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.","authors":"Marianela Schiava, Chiseko Ikenaga, Ana Topf, Marta Caballero-Ávila, Tsui-Fen Chou, Shan Li, Feng Wang, Jil Daw, Tanya Stojkovic, Rocio Villar-Quiles, Ichizo Nishino, Michio Inoue, Yukako Nishimori, Yoshihiko Saito, Masahisa Katsuno, Seiya Noda, Chihiro Ito, Mieko Otsuka, Sruthi Nahir, Georgios Manousakis, David Walk, Colin Quinn, Lindsay Alfano, Zarife Sahenk, Giorgio Tasca, Mauro Monforte, Mario Sabatelli, Giulia Bisogni, Anders Oldfors, Anna Rydeliu, Endre Pal, Carmen Paradas, Beatriz Velez, Jan L De Bleecker, Maria Elena Farugia, Cheryl Longman, Matthew B Harms, Stuart Ralston, Edmar Zanoteli, Andre Macedo Serafim da Silva, Javier Sotoca, Raul Juntas-Morales, Jorge Bevilacqua, Mireya Balart, Stuart Talbot, Volker Straub, Michela Guglieri, Chiara Marini-Bettolo, Jordi Diaz-Manera, Conrad Chris Weihl","doi":"10.1212/NXG.0000000000200093","DOIUrl":"10.1212/NXG.0000000000200093","url":null,"abstract":"<p><strong>Background and objectives: </strong>Pathogenic variants in the valosin-containing protein (<i>VCP</i>) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel <i>VCP</i> variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized <i>VCP</i> variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study.</p><p><strong>Methods: </strong>A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis.</p><p><strong>Results: </strong>All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study.</p><p><strong>Discussion: </strong>This study provides data to support pathogenicity of 14 of 19 novel <i>VCP</i> variants and provides guidance for clinicians in the evaluation of novel variants in the <i>VCP</i> gene.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 5","pages":"e200093"},"PeriodicalIF":3.0,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d1/07/NXG-2023-000033.PMC10427110.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10020392","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":"Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A.","authors":"Andrew B Stergachis,&nbsp;Elizabeth E Blue,&nbsp;Madelyn A Gillentine,&nbsp;Lee-Kai Wang,&nbsp;Ulrike Schwarze,&nbsp;Adriana Sedeño Cortés,&nbsp;Jane Ranchalis,&nbsp;Aimee Allworth,&nbsp;Austin E Bland,&nbsp;Sirisak Chanprasert,&nbsp;Jingheng Chen,&nbsp;Daniel Doherty,&nbsp;Andrew B Folta,&nbsp;Ian Glass,&nbsp;Martha Horike-Pyne,&nbsp;Alden Y Huang,&nbsp;Alyna T Khan,&nbsp;Kathleen A Leppig,&nbsp;Danny E Miller,&nbsp;Ghayda Mirzaa,&nbsp;Azma Parhin,&nbsp;Wendy H Raskind,&nbsp;Elisabeth A Rosenthal,&nbsp;Sam Sheppeard,&nbsp;Samuel Strohbehn,&nbsp;Virginia P Sybert,&nbsp;Thao T Tran,&nbsp;Mark H Wener,&nbsp;Peter H H Byers,&nbsp;Stanley F Nelson,&nbsp;Michael J Bamshad,&nbsp;Katrina M Dipple,&nbsp;Gail P Jarvik,&nbsp;Suzanne Hoppins,&nbsp;Fuki M Hisama","doi":"10.1212/NXG.0000000000200090","DOIUrl":"10.1212/NXG.0000000000200090","url":null,"abstract":"<p><strong>Objectives: </strong>Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.</p><p><strong>Methods: </strong>We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis.</p><p><strong>Results: </strong>We identified an intronic homozygous <i>MFN2</i> c.600-31T>G variant that disrupts the branch point critical for intron 6 splicing. Full-length long-read isoform complementary DNA (cDNA) sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates 5 distinct altered splicing transcripts. All 5 altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length <i>MFN2</i> transcripts are still produced, this branch point variant results in deficient MFN2 levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A).</p><p><strong>Discussion: </strong>This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 5","pages":"e200090"},"PeriodicalIF":3.1,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f3/32/NXG-2023-000030.PMC10409571.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10002928","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":"Genome-wide Analysis of Motor Progression in Parkinson Disease.","authors":"Alejandro Martínez Carrasco, Raquel Real, Michael Lawton, Regina Hertfelder Reynolds, Manuela Tan, Lesley Wu, Nigel Williams, Camille Carroll, Jean-Christophe Corvol, Michele Hu, Donald Grosset, John Hardy, Mina Ryten, Yoav Ben-Shlomo, Maryam Shoai, Huw R Morris","doi":"10.1212/NXG.0000000000200092","DOIUrl":"10.1212/NXG.0000000000200092","url":null,"abstract":"<p><strong>Background and objectives: </strong>The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets.</p><p><strong>Methods: </strong>We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores.</p><p><strong>Results: </strong>We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the <i>GJA5</i> locus at 1q12 (β = -0.25, SE = 0.04, <i>p</i> = 3.4e^-10). Exploration of the regulation of gene expression in the region (<i>cis</i>-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of <i>ACP6</i>, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL <i>p</i>-values in blood and brain RNA expression data sets: <10^-14 in eQTLGen and 10^-7 in PsychEncode).</p><p><strong>Discussion: </strong>Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 5","pages":"e200092"},"PeriodicalIF":3.1,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/86/92/NXG-2023-000032.PMC10409573.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10026949","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":"Genomic Diagnoses for Ectopic Intracerebral Calcifications.","authors":"Changrui Xiao, Thomas Cassini, Daniel Benavides, Anusha Ebrahim, David Adams, Camilo Toro","doi":"10.1212/NXG.0000000000200083","DOIUrl":"10.1212/NXG.0000000000200083","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown.</p><p><strong>Methods: </strong>This retrospective cohort study details the clinical, imaging, and genomic findings of 44 patients with EICs who had no established diagnosis despite extensive medical workup.</p><p><strong>Results: </strong>In total, 15 of 44 patients received a diagnosis through genomic testing explaining their calcifications, and 2 more received a diagnosis that has not been previously associated with EICs. Six of the 15 were found to have one of the 4 genes (<i>PDGFB</i>, <i>PDGFRB</i>, <i>SLC20A2</i>, and <i>XPR1</i>) conventionally associated with the phenotypic term \"idiopathic basal ganglia calcifications.\"</p><p><strong>Discussion: </strong>These findings support the use of genomic testing for symptomatic patients with EICs.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 5","pages":"e200083"},"PeriodicalIF":3.0,"publicationDate":"2023-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399077/pdf/NXG-2023-000175.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10006868","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":"Clinicoradiologic Criteria for the Diagnosis of Stroke-like Episodes in MELAS.","authors":"Vadim Khasminsky,&nbsp;Eitan Auriel,&nbsp;Judith Luckman,&nbsp;Ruth Eliahou,&nbsp;Edna Inbar,&nbsp;Keshet Pardo,&nbsp;Yuval Landau,&nbsp;Rani Barnea,&nbsp;Maor Mermelstein,&nbsp;Shahar Shelly,&nbsp;Jonathan Naftali,&nbsp;Shlomi Peretz","doi":"10.1212/NXG.0000000000200082","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200082","url":null,"abstract":"<p><strong>Background and objectives: </strong>Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria.</p><p><strong>Methods: </strong>We retrospectively identified patients with MELAS admitted for SLEs between January 2012 and December 2021. Clinical features and imaging findings were compared with a cohort of patients who presented with AIS and similar lesion topography. A set of criteria was formulated and then tested by a blinded rater to evaluate diagnostic performance.</p><p><strong>Results: </strong>Eleven MELAS patients with 17 SLE and 21 AISs were included. Patients with SLEs were younger (median 45 [37-60] vs 77 [68-82] years, <i>p</i> < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, <i>p</i> < 0.01), more commonly reported hearing loss (91% vs 5%, <i>p</i> < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, <i>p</i> < 0.01). The earliest neuroimaging test performed at presentation was uniformly a noncontrast CT. Two main patterns of lesion topography with a stereotypical spatiotemporal evolution were identified-an anterior pattern (7/21, 41%) starting at the temporal operculum and spreading to the peripheral frontal cortex and a posterior pattern (10/21, 59%) starting at the cuneus/precuneus and spreading to the lateral occipital and parietal cortex. Other distinguishing features for SLEs vs AIS were cerebellar atrophy (91% vs 19%, <i>p</i> < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, <i>p</i> = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, <i>p</i> < 0.01), and no large vessel occlusion on CTA (0% vs 100%, <i>p</i> < 0.01). Based on these clinicoradiologic features, a set of diagnostic criteria were constructed for possible SLE (sensitivity 100%, specificity 81%, AUC 0.905) and probable SLE (sensitivity 88%, specificity 95%, AUC 0.917).</p><p><strong>Discussion: </strong>Clinicoradiologic criteria based on simple anamnesis and a CT scan at presentation can accurately diagnose SLE and lead to early administration of appropriate therapy.</p><p><strong>Classification of evidence: </strong>This study provides Class III evidence that an algorithm using clinical and imaging features can differentiate stroke-like episodes due to MELAS from acute ischemic strokes.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200082"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/96/NXG-2023-000024.PMC10323819.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9814123","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":"Longitudinal Analysis of Respiratory Function of Different Types of Limb Girdle Muscular Dystrophies Reveals Independent Trajectories.","authors":"Robert Muni-Lofra,&nbsp;Eduard Juanola-Mayos,&nbsp;Marianela Schiava,&nbsp;Dionne Moat,&nbsp;Maha Elseed,&nbsp;Jassi Michel-Sodhi,&nbsp;Elizabeth Harris,&nbsp;Michelle McCallum,&nbsp;Ursula Moore,&nbsp;Mark Richardson,&nbsp;Christina Trainor,&nbsp;Karen Wong,&nbsp;Monika Malinova,&nbsp;Carla Bolano-Diaz,&nbsp;Michael John Keogh,&nbsp;Elisabetta Ghimenton,&nbsp;Jose Verdu-Diaz,&nbsp;Anna Mayhew,&nbsp;Michela Guglieri,&nbsp;Volker Straub,&nbsp;Meredith K James,&nbsp;Chiara Marini-Bettolo,&nbsp;Jordi Diaz-Manera","doi":"10.1212/NXG.0000000000200084","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200084","url":null,"abstract":"<p><strong>Background and objectives: </strong>The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes.</p><p><strong>Methods: </strong>We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data. A linear mixed model was used to investigate the factors associated with the progression of respiratory dysfunction.</p><p><strong>Results: </strong>We followed up 156 patients with 5 different forms of LGMDs for a median of 8 years (range 1-25 years). Of them, 53 patients had pathogenic variants in the <i>Capn3</i> gene, 47 patients in the <i>Dysf</i> gene, 24 patients in the <i>Fkrp</i> gene, 19 in the <i>Ano5</i> gene, and 13 in one of the sarcoglycan genes (SCG). At baseline, 58 patients (37.1%) had a forced vital capacity percentage predicted (FVCpp) below 80%, while 14 patients (8.9%) had peak cough flow (PCF) values below 270 L/min. As a subgroup, <i>FKRP</i> was the group with a higher number of patients having FVC <80% and/or PCF <270 L/min at initial assessment (66%). We observed a progressive decline in FVCpp and PCF measurements over time, being age, use of wheelchair, and LGMD subtype independent factors associated with this decline. <i>Fkrp</i> and sarcoglycan patients had a quicker decline in their FVC (Kaplan-Meier curve, F test, <i>p</i> < 0.001 and <i>p</i> = 0.02, respectively). Only 7 of the 58 patients with low FVCpp values reported symptoms of respiratory dysfunction, which are commonly reported by patients with FVCpp below 50%-60%. The number of patients ventilated increased from 2 to 8 during follow-up.</p><p><strong>Discussion: </strong>Respiratory dysfunction is a frequent complication of patients with LGMDs that needs to be carefully studied and has direct implications in the care offered in daily clinics. Respiratory dysfunction is associated with disease progression because it is especially seen in patients who are full-time wheelchair users, being more frequent in patients with mutations in the <i>Fkrp</i> and sarcoglycan genes.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200084"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10174320","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 an 85-kb Heterozygous 4p Microdeletion With Full Genome Analysis in Autosomal Dominant Charcot-Marie-Tooth Disease.","authors":"Hsueh Wen Hsueh,&nbsp;Hsiao-Jung Kao,&nbsp;Chi-Chao Chao,&nbsp;Sung-Ju Hsueh,&nbsp;Yu-Ning Huang,&nbsp;Wan-Jia Lin,&nbsp;Jen-Ping Su,&nbsp;Horng-Tzer Shy,&nbsp;Ti-Yen Yeh,&nbsp;Cheng-Chen Lin,&nbsp;Pui-Yan Kwok,&nbsp;Ni-Chung Lee,&nbsp;Sung-Tsang Hsieh","doi":"10.1212/NXG.0000000000200078","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200078","url":null,"abstract":"<p><strong>Background and objectives: </strong>Charcot-Marie-Tooth disease (CMT) is a syndrome of a hereditary neurodegenerative condition affecting the peripheral nervous system and is a single gene disorder. Deep phenotyping coupled with advanced genetic techniques is critical in discovering new genetic defects of rare genetic disorders such as CMT.</p><p><strong>Methods: </strong>We applied multidisciplinary investigations to examine the neurophysiology and nerve pathology in a family that fulfilled the diagnosis of CMT2. When phenotype-guided first-tier genetic tests and whole-exome sequencing did not yield a molecular diagnosis, we conducted full genome analysis by examining phased whole-genome sequencing and whole-genome optical mapping data to search for the causal variation. We then performed a systematic review to compare the reported patients with interstitial microdeletion in the short arm of chromosome 4.</p><p><strong>Results: </strong>In this family with CMT2, we reported the discovery of a heterozygous 85-kb microdeletion in the short arm of chromosome 4 (4p16.3)[NC_000004.12:g.1733926_1819031del] spanning 3 genes [<i>TACC3</i> (intron 6-exon 16), <i>FGFR3</i> (total deletion), and <i>LETM1</i> (intron 10-exon14)] that cosegregated with disease phenotypes in family members. The clinical features of peripheral nerve degeneration in our family are distinct from the well-known 4p microdeletion syndrome of Wolf-Hirschhorn syndrome, in which brain involvement is the major phenotype.</p><p><strong>Discussion: </strong>In summary, we used the full genome analysis approach to discover a new microdeletion in a family with CMT2. The deleted segment contains 3 genes (<i>TACC3</i>, <i>FGFR3</i>, and <i>LETM1</i>) that likely play a role in the pathogenesis of nerve degeneration.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 4","pages":"e200078"},"PeriodicalIF":3.1,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d6/03/NXG-2023-000021.PMC10281236.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9709345","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}