Neurology-Genetics最新文献

{"title":"Refractory Epilepsy in Adult Patient With COQ8A Variant Improves With CoQ10 Supplementation: A Case for Exome Sequencing in the ICU.","authors":"Jonathan LoVoi,Don Q Thai,Jennifer Han,Sophia Wang,Makeda Agonafer,Baburaj Thankappan","doi":"10.1212/nxg.0000000000200184","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200184","url":null,"abstract":"ObjectivesDescribe a case of stroke-like episodes and refractory status epilepticus diagnosed with primary CoQ10 deficiency-4 (COQ10D4) using whole-exome sequencing in the intensive care unit (ICU), with treatment implications.MethodsA patient presented to the emergency department with 1 month of progressively worsening focal motor status epilepticus and stroke-like imaging abnormalities. Multiple seizure medications, ketogenic diet, and elective intubation for anesthetic drips failed to achieve sustained seizure freedom. Genetic testing was pursued for prognostic information and identified potential treatment.ResultsWhole-exome sequencing revealed compound heterozygous variants of COQ8A, including 1 allele not previously described as pathogenic. The patient's history, imaging, and genetic testing supported a diagnosis of COQ10D4. High-dose coenzyme Q10 supplementation was started with gradual clinical improvement.DiscussionWhole-exome sequencing is a fast and cost-effective means to diagnose rare neurologic disease in critically ill patients and can uncover treatment options. While primarily used in the neonatal ICU, appropriately selected adult patients may also benefit.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"13 1","pages":"e200184"},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247289","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":"Global Presence and Penetrance of CSF1R-Related Disorder.","authors":"Jaroslaw Dulski,Matthew Baker,Samantha A Banks,Michael Bayat,Rose Bruffaerts,Gabriela Ortiz Cruz,Caio C Disserol,Kristen S Fisher,Jainy N Jose,Bernadette Kalman,Orhun H Kantarci,Dmytro Maltsev,Catherine Middleton,Gabriela Novotni,Dijana Plaseska-Karanfilska,Salmo Raskin,Josiane Souza,Helio A Teive,Zbigniew K Wszolek","doi":"10.1212/nxg.0000000000200187","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200187","url":null,"abstract":"ObjectivesTo highlight the worldwide presence of CSF1R-related disorder (CSF1R-RD), discuss its penetrance, and provide the first haplotype analysis.MethodsData on patients worldwide were collected, including demographics, genotype, family history, and clinical status. For haplotype analysis, polymorphisms of short tandem repeats in 3 distinct families with CSF1R p.Ile794Thr variant were examined.ResultsNineteen new patients were included, at a mean age of 38.7 years (ranging from 11 to 74 years), from 14 families from the Americas, Asia, Australia, and Europe, including the first from Mexico, North Macedonia, and Ukraine. Fifteen CSF1R variants were found, including 8 novel. Three patients were compound heterozygotes with disease onset at 1, 4, and 22 years. Patients with heterozygous CSF1R variants developed symptoms at a mean of 39.0 years (range 8-71 years). Four patients died at a mean of 3.3 years from onset (range 2-5 years). Negative family history was noted in 7 patients. In haplotype analysis, 2 families exhibited shared haplotype encompassing ∼6-Mb region downstream of the CSF1R while the third family displayed a different haplotype.DiscussionCSF1R-RD has a global prevalence. The reasons for negative family history include de novo variants (as shown by the haplotype analysis), mosaicism, and incomplete penetrance, which are possibly modulated by environmental and genetic factors.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"110 1","pages":"e200187"},"PeriodicalIF":3.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268323","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":"Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1.","authors":"Sarah E Robinson,Andrew R Findlay,Shan Li,Feng Wang,Marianela Schiava,Jil Daw,Jordi Diaz-Manera,Tsui-Fen Chou,Conrad C Weihl","doi":"10.1212/nxg.0000000000200191","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200191","url":null,"abstract":"ObjectivesMultisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity.MethodsPatients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein.ResultsAmong the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = -0.94, p = 0.01).DiscussionPrevious studies have reported that VCP pathogenic variants are \"hyperactive.\" Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 1","pages":"e200191"},"PeriodicalIF":3.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247290","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":"Blended Phenotype of NOTCH3 and RNF213 Variants With Accelerated Large and Small Artery Crosstalk: A Case Report and Literature Review.","authors":"Satoshi Saito,Satoshi Hosoki,Eriko Yamaguchi,Hiroyuki Ishiyama,Soichiro Abe,Takeshi Yoshimoto,Tomotaka Tanaka,Yorito Hattori,Yi Chu Liao,Yi-Chung Lee,Ikuko Mizuta,Toshiki Mizuno,Masafumi Ihara","doi":"10.1212/nxg.0000000000200176","DOIUrl":"https://doi.org/10.1212/nxg.0000000000200176","url":null,"abstract":"ObjectivesRecent advancements in genome research have revealed not only the importance of variants associated with cerebrovascular diseases but also a notably high frequency of carriers harboring multiple variants, presenting with an elusive blended phenotype. In this study, we report the case of a 66-year-old man who experienced 3 stroke episodes over a 4-year period, starting at the age of 62 years. The patient presented with isolated infarcts in the left temporal pole with progressive stenosis in the ipsilateral middle cerebral artery based on large and small artery crosstalk.MethodsExons 2-24 of the NOTCH3 gene were analyzed by direct genomic DNA sequencing. The presence of the p.Arg4810Lys variant of the ring finger protein 213 (RNF213) gene was evaluated using real-time PCR.ResultsDiagnoses of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and RNF213-related vasculopathy were made based on the early-onset recurrent stroke episode, progressive intracranial artery stenosis, and presence of the heterozygous NOTCH3 p.Cys1250Arg and RNF213 p.Arg4810Lys variants.DiscussionTemporal pole infarcts could represent a blended phenotype of both variants. This case highlights the importance of large and small artery crosstalk and the pivotal role of genetic analysis in determining the pathogenesis of stroke and dementia.","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"6 1","pages":"e200176"},"PeriodicalIF":3.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179264","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":"A Novel De Novo Gain-of-Function <i>CACNA1D</i> Variant in Neurodevelopmental Disease With Congenital Tremor, Seizures, and Hypotonia.","authors":"Fabian Dannenberg, Arpad Von Moers, Petra Bittigau, Jörn Lange, Sylvia Wiegand, Ferenc Török, Gabriel Stölting, Jörg Striessnig, M Mahdi Motazacker, Marjoleine F Broekema, Markus Schuelke, Angela M Kaindl, Ute I Scholl, Nadine J Ortner","doi":"10.1212/NXG.0000000000200186","DOIUrl":"10.1212/NXG.0000000000200186","url":null,"abstract":"<p><strong>Background and objectives: </strong>De novo gain-of-function variants in the <i>CACNA1D</i> gene, encoding the L-type voltage-gated Ca²⁺ channel Ca_V1.3, cause a multifaceted syndrome. Patients show variable degrees of autism spectrum disorder, developmental delay, epilepsy, and other neurologic and endocrine abnormalities (primary aldosteronism and/or hyperinsulinemic hypoglycemia). We study here a novel variant [c.3506G>A, NM_000720.4, p.(G1169D)] in 2 children with the same <i>CACNA1D</i> mutation but different disease severity.</p><p><strong>Methods: </strong>The clinical data of the study patients were collected. After molecular analysis and cloning by site-directed mutagenesis, patch-clamp recordings of transfected tsA201 cells were conducted in whole-cell configuration. The functional effects of wild-type and mutated channels were analyzed.</p><p><strong>Results: </strong>One child is a severely affected boy with a novel de novo <i>CACNA1D</i> variant with additional clinical symptoms including prenatal-onset tremor, congenital respiratory insufficiency requiring continuous positive airway pressure ventilation, and sensorineural deafness. Despite episodes of hypoglycemia, insulin levels were normal. Aldosterone:renin ratios as a screening parameter for primary aldosteronism were variable. In the second patient, putative mosaicism of the p.(G1169D) variant was associated with a less severe phenotype. Patch-clamp electrophysiology of the p.(G1169D) variant in a heterologous expression system revealed pronounced activity-enhancing gating changes, including a shift of channel activation and inactivation to more hyperpolarized potentials, as well as impaired channel inactivation and deactivation. Despite retained sensitivity to the Ca²⁺ channel blocker isradipine in vitro, no beneficial effects of isradipine or nifedipine treatment were observed in the index case.</p><p><strong>Discussion: </strong>Through this report, we expand the knowledge about the disease presentation in patients with <i>CACNA1D</i> variants and show the novel variant's modulatory effects on Ca_V1.3 gating.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 5","pages":"e200186"},"PeriodicalIF":3.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156426","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":"Ictal and Postictal Central Apnea in <i>DEPDC5</i>-Related Epilepsy.","authors":"Stefano Meletti, Gian Marco Duma, Margherita Burani, Alberto Danieli, Giada Giovannini, Elisa Osanni, Elisa Micalizzi, Fabiana Mambretti, Matteo Pugnaghi, Anna E Vaudano, Paolo Bonanni","doi":"10.1212/NXG.0000000000200183","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200183","url":null,"abstract":"<p><strong>Objectives: </strong><i>DEPDC5</i>-related epilepsy carries an increased risk of sudden unexpected death in epilepsy. We evaluated the occurrence and features of ictal central apnea (ICA) in patients with pathogenic sequence variant in <i>DEPDC5</i>.</p><p><strong>Methods: </strong>We reviewed data of 108 patients collected in 2 independent cohorts of patients with focal epilepsy who prospectively underwent long-term video-EEG monitoring (LTVM) with cardiorespiratory polygraphy. All patients underwent (1) at least an overnight polysomnography, (2) a high-field (3T) brain MRI study, and (3) CSF analysis when clinically indicated. Genetic testing (next-generation sequencing [NGS]) was offered for diagnostic purposes to patients with focal epilepsy of unknown etiology.</p><p><strong>Results: </strong>In this cohort, NGS was finally performed in 29 patients, resulting in <i>DEPDC5</i> pathogenic mutations in 5 patients. According to the presence of ictal apnea events, 5 of 14 patients with ICA showed pathogenic <i>DEPDC5</i> variants (35%) while none of the 15 patients without ICA showed pathogenic mutation. Notably, <i>DEPDC5</i> patients showed ICA in all recorded seizures (n = 15) with apnea duration ranging from 20 seconds to more than 1 minute. All seizures were characterized by motor arrest without overt automatic behaviors during ictal apnea. Scalp EEG showed the involvement of temporal lobe leads in all events. Severe oxygen desaturation was observed in 2 cases.</p><p><strong>Discussion: </strong>In our cohort, ictal central apnea was a common finding in <i>DEPDC5</i>. These results support (1) the need for respiratory polygraphy during LTVM in <i>DEPDC5</i>-related epilepsy and (2) the potential relevance of genetic testing in patients with focal epilepsy of unknown etiology and ictal apnea.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 5","pages":"e200183"},"PeriodicalIF":3.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394353","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 Titin Truncating Variant Causing a Dominant Myopathy With Cardiac Involvement in a Large Family: The Exception That Proves the Rule.","authors":"Kristl G Claeys, Marco Savarese, Per Harald Jonson, Veerle Goosens, Ana Topf, Anna Vihola, Volker Straub, Bjarne Udd","doi":"10.1212/NXG.0000000000200185","DOIUrl":"https://doi.org/10.1212/NXG.0000000000200185","url":null,"abstract":"<p><strong>Background: </strong>Titin truncating variants (TTNtvs) have been repeatedly reported as causative of recessive but not dominant skeletal muscle disorders.</p><p><strong>Objective: </strong>To determine whether a single heterozygous nonsense variant in <i>TTN</i> can be responsible for the observed dominant myopathy in a large family.</p><p><strong>Methods: </strong>In this case series, all available family members (8 affected and 6 healthy) belonging to a single family showing autosomal dominant inheritance were thoroughly examined clinically and genetically.</p><p><strong>Results: </strong>All affected family members showed a similar clinical phenotype with a combination of cardiac and skeletal muscle involvement. Muscle imaging data revealed titin-compatible hallmarks. Genetic analysis revealed in all affected patients a nonsense <i>TTN</i> variant c.70051C>T p.(Arg23351*), in exon 327. RNA sequencing confirmed the lack of complete nonsense-mediated decay, and protein studies convincingly revealed expression of a shortened titin fragment of the expected size.</p><p><strong>Discussion: </strong>We conclude that a single heterozygous nonsense variant in titin occasionally can cause a dominant myopathy as shown in this large family. Therefore, monoallelic titin truncating variants should be considered as possible disease-causing variants in unsolved patients with a dominant myopathy. However, large segregation studies, muscle imaging, and RNA and protein assays are needed to support the clinical and genetic interpretation.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 5","pages":"e200185"},"PeriodicalIF":3.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11458131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394352","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":"Clinicopathologic Characterization of 2 Individuals With <i>TBK1</i> Variants-1 Novel Splice Variant, 2 Proteinopathies: A Case Series.","authors":"Kimiko Domoto-Reilly, B Jane Distad, Danny E Miller, Yi-Han Lin, David Ivanick, Andrew S Warren, Suman Jayadev, Caitlin S Latimer","doi":"10.1212/NXG.0000000000200173","DOIUrl":"10.1212/NXG.0000000000200173","url":null,"abstract":"<p><strong>Objectives: </strong>Here, we report detailed clinicopathologic evaluation of 2 individuals with pathogenic variants in <i>TBK1</i>, including one novel likely pathogenic splice variant. We describe the striking diversity of clinical phenotypes among family members and also the brain and spinal cord neuropathology associated with these 2 distinct <i>TBK1</i> variants.</p><p><strong>Methods: </strong>Two individuals with pathogenic variants in <i>TBK1</i> and their families were clinically characterized, and the probands subsequently underwent extensive postmortem neuropathologic examination of their brains and spinal cords.</p><p><strong>Results: </strong>Multiple affected individuals within a single family were found to carry a previously unreported c.358+3A>G variant, predicted to alter splicing. Detailed histopathologic evaluation of our 2 <i>TBK1</i> variant carriers demonstrated distinct TDP-43 pathologic subtypes, but shared argyrophilic grain disease (AGD) tau pathology.</p><p><strong>Discussion: </strong>Although all pathogenic <i>TBK1</i> variants are associated with TDP-43 pathology, the clinical and histologic features can be highly variable. Within one family, we describe distinct neurologic presentations which we propose are all caused by a novel c.358+3A>G variant. AGD is typically associated with older age, but it has been described as a copathologic finding in other <i>TBK1</i> variant carriers and may be a common feature in FTLD-TDP due to <i>TBK1</i>.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 4","pages":"e200173"},"PeriodicalIF":3.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141761811","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":"Early Peripheral Nerve Involvement at the Time of Coughing in Patients With <i>RFC1</i> Intronic Expansion.","authors":"Simon Frachet, Pauline Chazelas, Laurent Magy, Pascal Cintas, Danielle Brouquières, Pierre Girardie, Louise Espagno, Boris Melloni, Laurent Guilleminault, Anne-Sophie Lia","doi":"10.1212/NXG.0000000000200166","DOIUrl":"10.1212/NXG.0000000000200166","url":null,"abstract":"<p><strong>Objectives: </strong>Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome results from variations in <i>RFC1</i> and is mostly caused by intronic biallelic pathogenic expansions (RE-<i>RFC1</i>). Refractory chronic cough (RCC) is frequently observed for years to decades preceding ataxia onset. Whether peripheral nerves are involved in the presymptomatic phase characterized by RCC is uncertain.</p><p><strong>Methods: </strong>Here, patients previously screened for RCC and identified as having at least one RE-<i>RFC1</i> intronic expansion underwent a comprehensive clinical and neurophysiologic assessment and were screened for additional exonic variations.</p><p><strong>Results: </strong>Fourteen patients with RCC and RE-<i>RFC1</i> were investigated. Seven patients presented with biallelic RE-<i>RFC1</i> (Bi-RE-<i>RFC1</i>) while 7 presented with monoallelic RE-<i>RFC1</i> (Mono-RE-<i>RFC1</i>). In patients with Mono-RE-<i>RFC1</i>, no additional exonic variation was identified, and clinical examinations were normal. Most of the patients with Bi-RE-<i>RFC1</i> presented with subtle neurologic impairment, mainly exhibiting decreased lower limb vibration sense (85.7%). Nerve conduction studies revealed that all patients with Bi-RE-<i>RFC1</i> exhibited lower sensory sum scores than patients with Mono-RE-<i>RFC1</i> (median 20.2 µV vs 84.9 µV, <i>p</i> = 0.0012). In addition, the radial-to-sural sensory ratios were null or inverted (>0.5) in all patients but one with Bi-RE-<i>RFC1</i>, which is consistent with sensory neuronopathy.</p><p><strong>Discussion: </strong>Patients with Bi-RE-RFC1 already exhibit widespread sensory neuron involvement at the time of apparently isolated RCC.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 4","pages":"e200166"},"PeriodicalIF":3.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590889","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":"Complex <i>SMN</i> Hybrids Detected in a Cohort of 31 Patients With Spinal Muscular Atrophy.","authors":"Mar Costa-Roger, Laura Blasco-Pérez, Lorene Gerin, Marta Codina-Solà, Jordi Leno-Colorado, Marta Gómez-García De la Banda, Rocio Garcia-Uzquiano, Pascale Saugier-Veber, Séverine Drunat, Susana Quijano-Roy, Eduardo F Tizzano","doi":"10.1212/NXG.0000000000200175","DOIUrl":"10.1212/NXG.0000000000200175","url":null,"abstract":"<p><strong>Background and objectives: </strong>Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the loss or presence of point pathogenic variants in the <i>SMN1</i> gene. The main positive modifier of the SMA phenotype is the number of copies of the <i>SMN2</i> gene, a paralog of <i>SMN1</i>, which only produces around 10%-15% of functional SMN protein. The <i>SMN2</i> copy number is inversely correlated with phenotype severity; however, discrepancies between the SMA type and the <i>SMN2</i> copy number have been reported. The presence of <i>SMN2-SMN1</i> hybrids has been proposed as a possible modifier of SMA disease.</p><p><strong>Methods: </strong>We studied 31 patients with SMA, followed at a single center and molecularly diagnosed by Multiplex Ligand-Dependent Probe Amplification (MLPA), with a specific next-generation sequencing protocol to investigate their <i>SMN2</i> genes in depth. Hybrid characterization also included bioinformatics haplotype phasing and specific PCRs to resolve each <i>SMN2-SMN1</i> hybrid structure.</p><p><strong>Results: </strong>We detected <i>SMN2-SMN1</i> hybrid genes in 45.2% of the patients (14/31), the highest rate reported to date. This represents a total of 25 hybrid alleles, with 9 different structures, of which only 4 are detectable by MLPA. Of particular interest were 2 patients who presented 4 <i>SMN2-SMN1</i> hybrid copies each and no pure <i>SMN2</i> copies, an event reported here for the first time. No clear trend between the presence of hybrids and a milder phenotype was observed, although 5 of the patients with hybrid copies showed a better-than-expected phenotype. The higher hybrid detection rate in our cohort may be due to both the methodology applied, which allows an in-depth characterization of the <i>SMN</i> genes and the ethnicity of the patients, mainly of African origin.</p><p><strong>Discussion: </strong>Although hybrid genes have been proposed to be beneficial for patients with SMA, our work revealed great complexity and variability between hybrid structures; therefore, each hybrid structure should be studied independently to determine its contribution to the SMA phenotype. Large-scale studies are needed to gain a better understanding of the function and implications of <i>SMN2-SMN1</i> hybrid copies, improving genotype-phenotype correlations and prediction of the evolution of patients with SMA.</p>","PeriodicalId":48613,"journal":{"name":"Neurology-Genetics","volume":"10 4","pages":"e200175"},"PeriodicalIF":3.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735424","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}