Neurology-Genetics最新文献

{"title":"Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis.","authors":"Julie Barberio, Cathy Lally, Varant Kupelian, Orla Hardiman, W Dana Flanders","doi":"10.1212/NXG.0000000000200109","DOIUrl":"10.1212/NXG.0000000000200109","url":null,"abstract":"<p><strong>Background and objectives: </strong>Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%-10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as \"proportion fALS\") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess the effect of study characteristics on the estimates.</p><p><strong>Methods: </strong>A comprehensive literature review was performed to identify all original studies reporting the number of fALS cases in an ALS cohort. The results were stratified by geographic region, study design (case series or population-based), and decade of study publication. Subgroup analyses were conducted according to family history criteria used to define fALS. We report pooled estimates of the proportion fALS from random-effects meta-analyses when >2 studies are available and I² is < 90%; weighted averages and ranges are otherwise presented.</p><p><strong>Results: </strong>The overall pooled proportion fALS based on a total 165 studies was 8% (0%, 71%). The proportion fALS was 9% (0%, 71%) among 107 case series and 5% (4%, 6%) among 58 population-based studies. Among population-based studies, proportion fALS by geographic region was 6% (5%, 7%; N = 37) for Europe, 5% (3%, 7%; N = 5) for Latin America, and 5% (4%, 7%; N = 12) for North America. Criteria used to define fALS were reported by 21 population-based studies (36%), and proportion fALS was 5% (4%, 5%; N = 9) for first-degree relative, 7% (4%, 11%; N = 4) for first or second-degree relative, and 11% (N = 1) for more distant ALS family history. Population-based studies published in the 2000s or earlier generated a lower pooled proportion fALS than studies published in the 2010s or later.</p><p><strong>Discussion: </strong>The results suggest that variability in the reported proportion fALS in the literature may be, in part, due to the differences in geography, study design, fALS definition, and decade of case ascertainment. Few studies outside of European ancestral populations were available. The proportion fALS was marginally higher among case series compared with population-based studies, likely because of referral bias. Criteria used to define fALS were largely unreported. Consensus criteria for fALS and additional population-based studies in non-European ancestral populations are needed.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200109"},"PeriodicalIF":3.1,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10689005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479003","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":"A Phenotypic Atlas for Huntington Disease Based on Data From the Enroll-HD Cohort Study.","authors":"Douglas R Langbehn, Swati S Sathe, Clement Loy, Cristina Sampaio, Elizabeth A Mccusker","doi":"10.1212/NXG.0000000000200111","DOIUrl":"10.1212/NXG.0000000000200111","url":null,"abstract":"<p><strong>Background and objectives: </strong>The variable CAG repeat expansion in the huntingtin gene and its inverse relationship to motor dysfunction onset are fundamental features of Huntington disease (HD). However, the wider phenotype (including non-motor features) at particular CAG lengths, ages, and functional levels is less well-characterized. The large number of participants in the Enroll-HD observational study enables the development of a phenotype atlas that summarizes the range and distribution of HD phenotypes, including outliers and possible clusters, with respect to various CAG repeat lengths, age ranges, and declining functional levels.</p><p><strong>Methods: </strong>Enroll-HD is an ongoing prospective longitudinal observational study that collects natural history data, releasing periodic data sets, in people with HD (PwHD) and controls. Core assessments at annual visits focus on behavioral, cognitive, motor, and functional status. Periodic data set 5, used for the development of the first iteration of the Enroll-HD Phenotype Atlas (EHDPA), included all eligible data collected through October 31, 2020. The atlas is based on subsets (cells) of descriptive data for all motor, cognitive, psychiatric, and functional measures that are routinely collected at most Enroll-HD sites, analyzed by single CAG lengths and 5-year age blocks.</p><p><strong>Results: </strong>Data from 42,840 visits from 15,982 unique PwHD were available for analysis. At baseline, participants had a mean ± SD age of 48.9 ± 13.9 years and CAG repeat length of 43.4 ± 3.6 and 54.1% were female. The EHDPA includes 223 age-by-CAG subsets for CAG repeats between 36 and 69 with five-year age brackets starting from 20-24 years up to 85-89 years. The atlas can be browsed at enroll-hd.org/for-researchers/atlas-of-hd-phenotype/.</p><p><strong>Discussion: </strong>The EHDPA summarizes the spectrum and distribution of HD phenotypes, including outliers and possible clusters, in all domains of disease involvement for the range of CAG repeat lengths, ages, and functional levels. Its availability in an easy-to-use online format will assist clinicians in tracking disease progression in PwHD by identifying phenotypic features most associated with loss of function and enabling conversations related to prognosis. The observable patterns in the EHDPA should also catalyze more formal multidomain characterization of motor, cognitive, and psychiatric progression and their relationships to functional decline and disease modifiers.</p><p><strong>Trial registration information: </strong>Enroll-HD is registered with clinicaltrials.gov: NCT01574053.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200111"},"PeriodicalIF":3.0,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463770","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":"Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in <i>XPNPEP3</i>.","authors":"Ilan Ben-Shabat, Malin Kvarnung, Wolfgang Sperker, Helene Bruhn, Anna Wredenberg, Rolf Wibom, Inger Nennesmo, Martin Engvall, Martin Paucar","doi":"10.1212/NXG.0000000000200100","DOIUrl":"10.1212/NXG.0000000000200100","url":null,"abstract":"<p><strong>Objectives: </strong>Biallelic variants in <i>XPNPEP3</i> are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in <i>XPNPEP3</i>.</p><p><strong>Methods: </strong>Clinical evaluation, neuroimaging studies, a kidney biopsy, and whole genome sequencing (WGS) were applied. Since the phenotype was compatible with a mitochondrial disease, a muscle biopsy with morphological and mitochondrial biochemical investigations was performed.</p><p><strong>Results: </strong>Axial ataxia, cerebellar atrophy, hearing loss, myopathy, ptosis, supranuclear palsy, and kidney failure because of nephronophthisis were the prominent features in this case. WGS revealed the novel biallelic variant c.766C>T (p.Gln256*) in <i>XPNPEP3</i>. A muscle biopsy revealed COX negative fibers, a few ragged red fibers, and ultrastructural mitochondrial changes. Enzyme activity in respiratory chain complex IV was reduced in muscle and fibroblasts.</p><p><strong>Discussion: </strong>This is the first report of a slowly progressive cerebellar ataxia associated with a novel biallelic variant in <i>XPNPEP3</i>. Abnormalities typical for mitochondrial disease and the slow progression of kidney disease are also striking. Our report expands the spectrum of <i>XPNPEP3</i>-related diseases.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200100"},"PeriodicalIF":3.1,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463771","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":"Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy in Patients Clinically Suspected of FSHD Using Optical Genome Mapping.","authors":"Naga M Guruju, Vanessa Jump, Richard Lemmers, Silvere Van Der Maarel, Ruby Liu, Babi R Nallamilli, Suresh Shenoy, Alka Chaubey, Pratik Koppikar, Rajiv Rose, Satish Khadilkar, Madhuri Hegde","doi":"10.1212/NXG.0000000000200107","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200107","url":null,"abstract":"<p><strong>Background and objectives: </strong>Facioscapulohumeral muscular dystrophy (FSHD) represents the third most common muscular dystrophy in the general population and is characterized by progressive and often asymmetric muscle weakness of the face, upper extremities, arms, lower leg, and hip girdle. In FSHD type 1, contraction of the number of D4Z4 repeats to 1-10 on the chromosome 4-permissive allele (4qA) results in abnormal epigenetic derepression of the <i>DUX4</i> gene in skeletal muscle. In FSHD type 2, epigenetic derepression of the <i>DUX4</i> gene on the permissive allele (4qA) with normal-sized D4Z4 repeats (mostly 8-20) is caused by heterozygous pathogenic variants in chromatin modifier genes such as <i>SMCHD1</i>, <i>DNMT3B</i>, or <i>LRIF1</i>. We present validation of the optical genome mapping (OGM) platform for accurate mapping of the D4Z4 repeat size, followed by diagnostic testing of 547 cases with a suspected clinical diagnosis of FSHD and next-generation sequencing (NGS) of the <i>SMCHD1</i> gene to identify cases with FSHD2.</p><p><strong>Methods: </strong>OGM with Bionano Genomics Saphyr and EnFocus FSHD analysis software was used to identify FSHD haplotypes and D4Z4 repeat number and compared with the gold standard of Southern blot-based diagnosis. A custom Agilent SureSelect enrichment kit was used to enrich <i>SMCHD1</i>, followed by NGS on an Illumina system with 100-bp paired-end reads. Copy number variants were assessed using NxClinical software.</p><p><strong>Results: </strong>We performed OGM for the diagnosis of FSHD in 547 patients suspected of FSHD between December 2019 and December 2022, including 301 male (55%) and 246 female patients (45%). Overall, 308 of the referred patients were positive for D4Z4 contraction on a permissive haplotype, resulting in a diagnosis of FSHD1. A total of 252 of 547 patients were referred for concurrent testing for FSHD1 and FSHD2. This resulted in the identification of FSHD2 in 9/252 (3.6%) patients. In our FSHD2 cohort, the 4qA allele size ranged from 8 to 18 repeats. Among FSHD1-positive cases, 2 patients had biallelic contraction and 4 patients had homozygous contraction and showed early onset of clinical features. Nine of the 308 patients (3%) positive for 4qA contraction had mosaic 4q alleles with contraction on at least one 4qA allele. The overall diagnostic yield in our cohort was 58%.</p><p><strong>Discussion: </strong>A combination of OGM to identify the FSHD haplotype and D4Z4 repeat number and NGS to identify sequence and copy number variants in the <i>SMCHD1</i> gene is a practical and cost-effective option with increased precision for accurate diagnosis of FSHD types 1 and 2.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200107"},"PeriodicalIF":3.1,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463772","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":"Adult Phenotype of <i>SYNGAP1</i>-DEE.","authors":"Marlene Rong, Tim Benke, Quratulain Zulfiqar Ali, Ángel Aledo-Serrano, Allan Bayat, Alessandra Rossi, Orrin Devinsky, Farah Qaiser, Anum S Ali, Alfonso Fasano, Anne S Bassett, Danielle M Andrade","doi":"10.1212/NXG.0000000000200105","DOIUrl":"10.1212/NXG.0000000000200105","url":null,"abstract":"Background and Objectives SYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy. Methods Patients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) SYNGAP1 variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden. Results Fourteen unrelated adult patients (median: 21 years, range: 18–65 years) with SYNGAP1-DEE were identified, 11 with novel and 3 with known LP/P SYNGAP1 de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger. Discussion Seventy-one percent of patients with SYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults with SYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200105"},"PeriodicalIF":3.1,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10692795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479002","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":"Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network.","authors":"Peter B Kang, Magali Jorand-Fletcher, Wanfang Zhang, Suzanne W McDermott, Reba Berry, Chelsea Chambers, Kristen N Wong, Yara Mohamed, Shiny Thomas, Y Swamy Venkatesh, Christina Westfield, Nedra Whitehead, Nicholas E Johnson","doi":"10.1212/NXG.0000000000200113","DOIUrl":"10.1212/NXG.0000000000200113","url":null,"abstract":"<p><strong>Background and objectives: </strong>To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States.</p><p><strong>Methods: </strong>This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STAR<i>net</i>). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation.</p><p><strong>Results: </strong>Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (<i>EMD</i>) and autosomal genes reported to have skewed gender ratios (<i>ANO5</i>, <i>CAV3</i>, and <i>LMNA</i>). The most common associated genes were <i>FKRP</i>, <i>CAPN3</i>, <i>ANO5</i>, and <i>DYSF</i>. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive.</p><p><strong>Discussion: </strong>This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200113"},"PeriodicalIF":3.0,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10692796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479004","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":"Expanding the Clinical Spectrum of <i>UBTF</i>-Related Neurodevelopmental Disorder.","authors":"Andrea Pietra, Flavia Palombo, Melania Giannotta, Monica Maffei, Claudio Fiorini, Roberta Costa, Giovanna Cenacchi, Valerio Carelli, Duccio Maria Cordelli, Antonella Pini, Caterina Garone","doi":"10.1212/NXG.0000000000200098","DOIUrl":"10.1212/NXG.0000000000200098","url":null,"abstract":"<p><strong>Objectives: </strong><i>UBTF1</i> gene encodes for Upstream Binding Transcription Factor, an essential protein for RNA metabolism. A recurrent de novo variant (c.628G>A; p.Glu210Lys) has recently been associated with a childhood-onset neurodegenerative disorder characterized by motor and language regression, ataxia, dystonia, and acquired microcephaly. In this study, we report the clinical, metabolic, molecular genetics and neuroimaging findings and histologic, histochemical, and electron microscopy studies in muscle samples of 2 patients from unrelated families with a neurodevelopmental disorder.</p><p><strong>Methods: </strong>Data were retrospectively analyzed by medical charts revision.</p><p><strong>Results: </strong>Patient 1, a 16-year-old boy, presented a childhood-onset slowly progressive neurodegenerative disorder mainly affecting language skills, behavior, and motor coordination. Patient 2, a 22-year-old woman, presented with a severe and rapidly progressive disease with dystonic tetra paresis, acquired microcephaly, and severe cognitive deficit complicated by pseudobulbar syndrome characterized by involuntary and uncontrollable outbursts of laughing, dysphagia requiring tube feeding, and nocturnal hypoventilation treated with noninvasive ventilation. Both patients carried the recurrent previously described <i>UBTF1</i> de novo variant and had signs of mitochondrial dysfunction at muscle biopsy. The metabolic profile of patient 2 also revealed a decrease in CSF biopterin.</p><p><strong>Discussion: </strong>These case reports add new insights to the <i>UBTF1</i> disease spectrum instrumental to improving the diagnostic rate in neurodevelopmental disorders.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"9 6","pages":"e200098"},"PeriodicalIF":3.1,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10683853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139486337","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":"<i>FOLR1</i>Gene Variation With Adult-Onset Cerebral Folate Deficiency and Stable Clinical and MRI Features up to 2 Years","authors":"Carlo Manco, Rosa Cortese, Manfredi Alberti, Silvia Bianchi, Lucia Monti, Nicola De Stefano, Carla Battisti","doi":"10.1212/nxg.0000000000200104","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200104","url":null,"abstract":"Objectives The objective of this case report was to describe the first report of FOLR1 variants associated with adult-onset paucisymptomatic leukoencephalopathy associated with cerebral folate deficiency (CFD). Methods Considering the patient's symptoms, a nonprogressive leukoencephalopathy was suspected. CSF 5-methyltetrahydrofolate levels were low (10 nmol/L, normal range 41–117). With no other identifiable causes, a genetic analysis was conducted, revealing a compound heterozygous FOLR1 variation (c.45G&gt;T and c. 493+2T&gt;C). Results A 47-year-old man with a history of drug and alcohol abuse was admitted to the hospital for double vision and postural instability. MRI of the brain was performed, which showed bilateral leukoencephalopathy. Diffusion tensor imaging revealed a diffuse reduction in fractional anisotropy, suggesting microstructural changes. MRI of the brain and overall clinical picture were stable on subsequent serial examinations. Discussion Scientific evidence supports the deleterious effect of c.45G&gt;T and c.493+2T&gt;C variations on the folate receptor-α (FRα) protein structure and function. The weakness of the expression and function of FRα without elimination of its function caused by specific compound heterozygous variations may explain the atypical features observed in our patient. Although rare, CFD should be considered in paucisymptomatic adult patients with stable diffuse MRI white matter changes.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135217076","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":"<i>IRF2BPL</i>Causes Mild Intellectual Disability Followed by Late-Onset Ataxia","authors":"Solveig Heide, Claire-Sophie Davoine, Paulina Cunha, Clarisse Scherer-Gagou, Boris Keren, Giovanni Stevanin, Perrine Charles, Delphine Heron, Alexis Brice, Alexandra Durr","doi":"10.1212/nxg.0000000000200096","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200096","url":null,"abstract":"Background and Objectives Neurodevelopmental and neurodegenerative disorders have long been considered as different clinical and molecular entities, and only a few genes are known to be involved in both processes. The IRF2BPL (interferon regulatory factor 2 binding protein like) gene was implicated in a severe pediatric phenotype characterized by developmental and epileptic encephalopathy and early regression. In parallel, inherited IRF2BPL variants have been reported in cohorts of patients with late-onset progressive dystonic and ataxic syndrome with few information about the neurodevelopment of these patients. This study aimed to describe both neurodevelopmental and neurodegenerative aspects of the phenotype in adults with IRF2BPL pathogenic variant. Methods We report here the clinical and molecular data of 18 individuals carrying truncating IRF2BPL variants (identified by either exome or genome sequencing), including a large pedigree of 16 patients presenting with a neurodevelopmental disorder (NDD) associated with late-onset cerebellar ataxia and atrophy. Results Genome sequencing identified the p.(Gln117*) variant in a large family first assessed for familial ataxia, with multiple individuals presenting with NDD. The p.(Ser313*) variant was identified by exome sequencing in a second family with a young adult patient with NDD without ataxia which was inherited from her asymptomatic mother, suggesting incomplete penetrance of IRF2BPL -linked disorders. Discussion This study illustrates the importance of neurologic evaluation of adult patients initially diagnosed with NDD to detect a late-onset neurodegenerative condition. Two different disorders may be clinically diagnosed in the same family, when not considering that NDD and late cerebellar changes may be part of the same molecular spectrum such as for IRF2BPL .","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135729231","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":"Novel<i>SLC13A3</i>Variants and Cases of Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation and Literature Review","authors":"Kristen N. Wong, Lorenzo D. Botto, Miao He, Peter R. Baker, Adeline L. Vanderver, Joshua L. Bonkowsky","doi":"10.1212/nxg.0000000000200101","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200101","url":null,"abstract":"Objectives Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the SLC13A3 gene. ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported in the literature to date. Our objective is to report newly identified patients and their genetic variants and phenotypes and review published literature on ARLIAK. Methods This report contributes 4 additional patients to the literature; describes novel variants in SLC13A3 ; and reviews genetic, biochemical, clinical, and radiologic features of all published patients with ARLIAK. Results We provide additional genetic, imaging, and laboratory insights into ARLIAK, an atypical leukodystrophy with clinical and radiologic findings that can normalize. Discussion Our case series highlights the importance of reanalysis of next-generation sequencing in the diagnostic workup.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"8 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":"134885229","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}