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WRKY transcription factors play a central role in controlling plant organ senescence; however, it is unclear whether and how they regulate petal senescence in the widely grown ornamental plant tulip (Tulipa gesneriana). In this study, we report that TgWRKY75 promotes petal senescence by enhancing the synthesis of both abscisic acid (ABA) and salicylic acid (SA) in tulip and in transgenic Arabidopsis. The expression level of TgWRKY75 was up-regulated in senescent petals, and exogenous ABA or SA treatment induced its expression. The endogenous contents of ABA and SA significantly increased during petal senescence and in response to TgWRKY75 overexpression. Two SA synthesis-related genes, TgICS1 and TgPAL1, were identified as direct targets of TgWRKY75, which binds to their promoters. In parallel, TgWRKY75 activated the expression of the ABA biosynthesis-related gene TgNCED3 via directly binding to its promoter region. Site mutation of the W-box core motif located in the promoters of TgICS1, TgPAL1, and TgNCED3 eliminated their interactions with TgWRKY75. In summary, our study demonstrates a dual regulation of ABA and SA biosynthesis by TgWRKY75, revealing a synergistic process of tulip petal senescence through feedback regulation between TgWRKY75 and the accumulation of ABA and SA.
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Arabidopsis , Tulipa , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ácido Abscísico/metabolismo , Tulipa/metabolismo , Ácido Salicílico/metabolismo , Regulación de la Expresión Génica de las Plantas , Arabidopsis/genética , Arabidopsis/metabolismoRESUMEN
Petal senescence is a crucial determinant for ornamental quality and economic value of floral crops. Salicylic acid (SA) and reactive oxygen species (ROS) are two prominent factors involved in plant senescence regulation. In this study, tulip TgNAP (NAC-like, activated by APETALA3/PISTILLATA) was characterized as positively regulating tulip petal senescence through dually regulating SA biosynthesis and ROS detoxification pathways. TgNAP was upregulated in senescing petals of tulip while exogenous SA and H2O2 treatments substantially promoted petal senescence in tulip. Silencing of TgNAP by VIGS assay delayed SA and H2O2-induced petal senescence in tulip, whereas overexpression of TgNAP promoted the senescence process in Arabidopsis (Arabidopsis thaliana) plants. Additionally, inhibition of SA biosynthesis prolonged the lifespan of TgNAP-silenced petal discs. Further evidence indicated that TgNAP activates the transcriptions of two key SA biosynthetic genes ISOCHORISMATE SYNTHASE 1 (TgICS1) and PHENYLALANINE AMMONIA-LYASE 1 (TgPAL1) through directly binding to their promoter regions. Meanwhile, TgNAP repressed ROS scavenging by directly inhibiting PEROXIDASE 12 (POD12) and POD17 expression. Taken together, these results indicate that TgNAP enhances SA biosynthesis and ROS accumulation to positively regulate petal senescence in tulip.
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Arabidopsis , Tulipa , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica de las Plantas , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Ácido Salicílico/farmacología , Ácido Salicílico/metabolismoRESUMEN
BACKGROUND: LMNA-related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation. METHODS: The clinical presentations of patients with LMNA-related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism. RESULTS: Eighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known LMNA mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology. CONCLUSIONS: Our detailed clinical and genetic analysis of 84 patients with LMNA-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.
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Lamina Tipo A/genética , Laminopatías/genética , Distrofias Musculares/genética , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Pueblo Asiatico , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Laminopatías/tratamiento farmacológico , Laminopatías/patología , Masculino , Distrofias Musculares/tratamiento farmacológico , Distrofias Musculares/patología , Adulto JovenRESUMEN
Dystroglycanopathy is a group of muscular dystrophies with deficient glycosylation of alpha-dystroglycan (α-DG). We recruited patients from 36 tertiary academic hospitals in China. In total, 143 patients with genetically diagnosed dystroglycanopathy were enrolled. Of these, limb girdle muscular dystrophy was the most common initial diagnosis (83 patients) and Walker-Warburg syndrome was the least common (1 patient). In 143 patients, mutations in FKRP gene were the most prevalent (62 patients), followed by POMT2, POMT1 (16), POMGNT1, ISPD (14), FKTN, GMPPB, B3GALNT2, DPM3, and DAG1. Several frequent mutations were identified in FKRP, POMT1, POMGNT1, ISPD, and FKTN genes. Many of these were founder mutations. Patients with FKRP mutations tended to have milder phenotypes, while those with mutations in POMGNT1 genes had more severe phenotypes. Mental retardation was a clinical feature associated with mutations of POMT1 gene. Detailed clinical data of 83 patients followed up in Peking University First Hospital were further analyzed. Our clinical and genetic analysis of a large cohort of Chinese patients with dystroglycanopathy expanded the genotype variation and clinical spectrum of congenital muscular dystrophies.
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Variación Genética , Discapacidad Intelectual/genética , Distrofias Musculares/genética , Adolescente , Edad de Inicio , Pueblo Asiatico/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Glicosilación , Humanos , Lactante , Recién Nacido , Masculino , Manosiltransferasas/genética , Distrofias Musculares/diagnóstico , Mutación , N-Acetilglucosaminiltransferasas/genética , Pentosiltransferasa/genéticaRESUMEN
The predicted synonymous mutation c.1251G>A of ISPD (NM_001101426.3) is a hot spot causing exon 9 skipping in five patients.
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Predisposición Genética a la Enfermedad , Distrofias Musculares/genética , Nucleotidiltransferasas/genética , Exones/genética , Femenino , Humanos , Masculino , Distrofias Musculares/patología , Mutación/genética , Isoformas de Proteínas/genéticaRESUMEN
LMNA-related muscular dystrophies are caused by mutations of the LMNA gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of LMNA-related muscular dystrophies. Muscle specimen of a patient with LMNA gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in LMNA mutant cells which promoted the expression of downstream inflammatory factors. The LMNA mutation also activated the molecular pathway of apoptosis in LMNA mutant cells. These are important molecular mechanisms underlying the pathogenesis of LMNA-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for LMNA-related muscular dystrophies.
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Lamina Tipo A/metabolismo , Laminopatías/metabolismo , Distrofias Musculares/metabolismo , Mutación Missense , FN-kappa B/metabolismo , Transducción de Señal , Sustitución de Aminoácidos , Células HEK293 , Humanos , Lamina Tipo A/genética , Laminopatías/genética , Laminopatías/patología , Distrofias Musculares/genética , FN-kappa B/genéticaRESUMEN
Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.
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Distrofias Musculares/epidemiología , Distrofias Musculares/genética , Alelos , China/epidemiología , Diagnóstico Diferencial , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Masculino , Distrofias Musculares/diagnóstico , Mutación , Fenotipo , Vigilancia de la Población , PrevalenciaRESUMEN
Mutations in the fukutin-related protein (FKRP) gene have been associated with dystroglycanopathies, which are common in Europe but rare in Asia. Our study aimed to retrospectively analyze and characterize the clinical, myopathological and genetic features of 12 Chinese patients with FKRP mutations. Three patients were diagnosed with congenital muscular dystrophy type 1C (MDC1C) and nine patients were diagnosed with limb girdle muscular dystrophy type 2I (LGMD2I). Three muscle biopsy specimens had dystrophic changes and reduced glycosylated α-dystroglycan staining, and two showed reduced expression of laminin α2. Two known and 13 novel mutations were identified in our single center cohort. Interestingly, the c.545A>G mutation was found in eight of the nine LGMD2I patients as a founder mutation and this founder mutation in Chinese patients differs from the one seen in European patients. Moreover, patients homozygous for the c.545A>G mutation were clinically asymptomatic, a less severe phenotype than in compound heterozygous patients with the c.545A>G mutation. The 13 novel mutations of FKRP significantly expanded the mutation spectrum of MDC1C and LGMD2I, and the different founder mutations indicate the ethnic difference in FKRP mutations.
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Efecto Fundador , Estudios de Asociación Genética , Mutación , Fenotipo , Proteínas/genética , Adolescente , Biopsia , Encéfalo/patología , Niño , Preescolar , Femenino , Genotipo , Haplotipos , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , PentosiltransferasaRESUMEN
Protein O-mannosyltransferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan glycosylation. POMT1 mutations cause a wide spectrum of clinical conditions from Walker-Warburg syndrome (WWS), which involves muscle, eye and brain abnormalities, to mild forms of limb-girdle muscular dystrophy with mental retardation. We aimed to elucidate the impact of different POMT1 mutations on the clinical phenotype. We report five Chinese patients with POMT1 mutations: one had a typical clinical manifestation of WWS, and the other four were diagnosed with congenital muscular dystrophy with mental retardation of varying severity. We analyzed the influence of the POMT1 mutations on POMT activity by assaying the patients' muscles and cultured skin fibroblasts. We demonstrated different levels of decreased POMT activity that correlated highly with decreased α-dystroglycan glycosylation. Our results suggest that POMT activity is inversely proportional to clinical severity, and demonstrate that skin fibroblasts can be used for differential diagnosis of patients with α-dystroglycanopathies. We have provided clinical, histological, enzymatic and genetic evidence of POMT1 involvement in five unrelated Chinese patients.
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Estudios de Asociación Genética , Genotipo , Manosiltransferasas/genética , Manosiltransferasas/metabolismo , Mutación , Fenotipo , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Ecocardiografía , Activación Enzimática , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofias Musculares/diagnóstico , Distrofias Musculares/enzimología , Distrofias Musculares/genética , Embarazo , Diagnóstico PrenatalRESUMEN
Background: LAMA2-related limb girdle muscular dystrophy (LGMD R23) is rare. The detailed clinical phenotypes and genetic information associated with LGMD R23 are unknown. Methods: We conducted a retrospective cross-sectional and longitudinal study on 19 LGMD R23 patients. Results: Normal early motor development was observed in 84.2% patients. Mild orthopedic complications were observed in 42.1% patients. 36.8% patients had seizures, which is unusually frequent in LGMD. Epilepsy was eventually diagnosed in 26.3% patients. 46.7% patients presented with motor neuropathy. Genetic analysis identified 29 pathogenic variants, with missense and frameshift variants being the most common. The mutant sites were mainly distributed in the N-terminal and G-like domains of laminin. The missense variants are distributed near the N-terminus (exons 3-11), whereas frameshift variants are distributed in exons 12-65. Five patients were diagnosed with epilepsy and all of them harbor at least one missense variants in exon 4. 71.4% variants of patients with motor neuropathy located in the LN domain. Conclusions: Missense variants in exon 4 maybe correlated with epilepsy and variants in the LN domain maybe correlated with motor neuropathy in Chinese patients. Our study expands the clinical and genetic spectrum caused by LAMA2 variations and provides novel genotype-phenotype correlations of LGMD R23.
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OBJECTIVE: To explore the clinical features and gene mutation of a Chinese family with Bethlem myopathy in three generations. METHODS: The clinical data of proband and his family members was collected. Genomic DNA from the patient and his family members was extracted routinely from peripheral blood leukocytes. Polymerase chain reaction and DNA direct sequencing were employed to analyze COL6A1, A2 and A3 genes to determine the mutation. And the relationship between genotype and phenotype was analyzed. Furthermore, the patient's skin fibroblast was cultured and immunofluorescent staining was performed with anti-collagen VI antibody. And the expression pattern of type VI collagen in extracellular matrix between the control and the patient's fibroblast was compared. RESULTS: In this family, 9 patients conformed to the clinical diagnosis of Bethlem myopathy. The features included motor development delay after late infantile period, generalized muscle weakness, walking unstability, distal hyper laxity, proximal joint contractures, skin changes (including hypertrophic scars) and normal intellectual development. Serum creatine kinase (CK) level became mildly elevated and electromyography showed myogenic injury. Disease progressed slowly but the lifespan was not affected. Mutation in exon 2 of COL6A1 gene with c.111-129 deletion was detected in 7 patients in this family. Immunofluorescent staining of type VI collagen in cultured skin fibroblast showed reduced expression of collagen VI in extracellular matrix in the patient compared with the control. CONCLUSIONS: Our study has defined the clinical features of Bethlem myopathy. According to molecular genetic analysis, 7 patients in this family have in-frame deletion mutations of COL6A1 and they conform to autosomal dominant inheritance. And genetic counseling and prenatal diagnosis are available. This is the first Chinese report of Bethlem myopathy family.
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Contractura/genética , Distrofias Musculares/congénito , Eliminación de Secuencia , Adolescente , Pueblo Asiatico/genética , Colágeno Tipo VI/genética , Análisis Mutacional de ADN , Genoma Humano , Humanos , Masculino , Distrofias Musculares/genética , LinajeRESUMEN
PURPOSE: To delineate the seizure type, phenotype and V-EEG patterns of dystroglycanopathy (DGP) and correlate them with the neuroradiological and genetic results. METHODS: Patients with seizures were screened from our dystroglycanopathy database from January 2010 to March 2021. Detailed clinical information, including seizure type, brain magnetic resonance imaging (MRI), EEG and genetic analysis, was collected. RESULTS: Thirteen patients (15.1%, 13/86) had seizures. Most patients had a severe phenotype. The mean age at first seizure onset was 2 years and 8 months. The most common seizure type was generalized tonic-clonic seizure (GTCS), with 92.3% (12/13) induced by fever. Three patients were diagnosed with epilepsy. Most patients did not take any medicine. A few patients had irregular use of antiseizure medications (ASMs). Of the 13 patients, seven patients were diagnosed with MEB, four patients with POMGNT1 mutations, two with ISPD mutations, and one with POMT1 mutation. Three patients were diagnosed with FCMD with FKTN mutations. Two patients were diagnosed with CMD-MR, one patient with ISPD mutation, and one with POMT1 mutation. One patient was diagnosed with LGMD with FKRP mutation. Nine patients underwent EEG examination, and eight patients had abnormal EEG results, including abnormal background activities in three patients, abnormal background activities combined with paroxysmal discharges in three patients, pure paroxysmal discharges in one patient and positive phase sharp waves in the occipital region in one patient. For radiology, brain MRI was available for 12 patients. The brain MRI of nine patients showed type II lissencephaly. Two patients showed cerebellar hypoplasia and brainstem hypoplasia. One patient had a normal brain MRI result. Patients with type II lissencephaly usually had abnormal background activities and paroxysmal discharges. CONCLUSION: The seizure phenotype of dystroglycanopathy (DGP) is characterized by GTCS, which was the most common seizure type, while focal seizures and epileptic spasms could also occur in DGP patients. Most seizures were induced by fever. Seizures were relatively more frequent in severe phenotypes of DGP, such as FCMD and MEB. Abnormal background activities were the most common EEG patterns, which were closely related to type II lissencephaly.
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Epilepsia , Lisencefalia , Convulsiones , Electroencefalografía , Epilepsia/diagnóstico , Epilepsia/genética , Humanos , Pentosiltransferasa , Convulsiones/genéticaRESUMEN
The study aimed to review the clinical, radiological, and pathological findings and electroencephalogram (EEG) of pediatric epilepsy patients with temporal onset focal seizures induced by intermittent photic stimulation (IPS). Four patients with temporal onset photosensitivity focal seizures were analyzed. Three (75%) of the four patients were female. The average age of seizure-onset was 4.4 years. The interictal EEG showed both generalized and focal spike and waves in one patient and focal or multifocal spike and waves alone in three patients. Photoparoxysmal response (PPR) was evoked in all patients and showed generalized discharges (patients 2-4), both generalized and posterior discharges (patient 1). Both generalized and focal discharges could coexist in interictal discharges and PPR. The sensitive frequencies of PPR and photoconvulsive response (PCR) were 12-30 and 10-16 Hz, respectively, which were close to the occipital rhythm. In all patients, the onset of PCR was recorded, namely, the left anterior and mesial temporal lobe (TL), the left posterior TL, and the whole left TL, which showed two forms: the seizure of two patients was the onset of slow waves in the temporal area without spreading generalized discharges (patients 1 and 4), and the other one was fast rhythmic activities in the temporal area, spreading to the occipital area or gradually evolving into the generalized discharges (patients 2 and 3). During follow-up, except for patient 3 who had occasional seizures, the seizures of the remaining patients were under control. Temporal onset focal seizures could be induced by IPS. Temporal onset photosensitivity seizures were mostly easy to control with antiseizure drugs.
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Objective: The DYNC1H1 gene is related to a variety of diseases, including spinal muscular atrophy with lower extremity-predominant 1, Charcot-Marie-Tooth disease type 2O, and mental retardation, autosomal dominant13 (MRD13). Some patients with DYNC1H1 variant also had epilepsy. This study aimed to detect DYNC1H1 variants in Chinese patients with infantile spasms (ISs). Methods: We reviewed clinical information, video electroencephalogram (V-EEG), and neuroimaging of a newly identified cohort of five patients with de novo DYNC1H1gene variants. Results: Five patients with four DYNC1H1variants from four families were included. All patients had epileptic spasms (ESs), the median age at seizure onset was 7.5 months (range from 5 months to 2 years 7 months), and the interictal V-EEG results were hypsarrhythmia. Four of five patients had brain magnetic resonance imaging (MRI) abnormalities. Four de novo DYNC1H1 variants were identified, including two novel variants (p.N1117K, p.M3405L) and two reported variants (p.R1962C, p.F1093S). As for the variant site, two variants are located in the tail domain, one variant is located in the motor domain, and one variant is located in the stalk domain. All patients had tried more than five kinds of antiepileptic drugs. One patient has been controlled well by vigabatrin (VGB) for 4 years, and another patient by VGB and steroids for 1.5 years. The other three patients still had frequent ESs. All patients had severe intellectual disability and development delays. Significance: IS was one of the phenotypes of DYNC1H1 variants. Most patients had non-specific brain MRI abnormality. Two of four DYNC1H1 variants were novel, expanding the variant spectrum. The IS phenotype was related to the variant's domains of DYNC1H1 variant sites. All patients were drug-refractory and showed development delays.
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To analyze the relationship between the characteristics of burst suppression (BS) pattern and different etiologies in epilepsy. Patients with a BS pattern who were younger than 6 months old were screened from our electroencephalogram (EEG) database. The synchronized and symmetric BS patterns under different etiologies in epilepsy were analyzed. A total of 32 patients had a BS pattern on EEG. The etiologies included genetic disorders (37.5%), cortical malformations (28.1%), inborn errors of metabolism (12.5%), and unknown (21.9%). Twenty-five patients were diagnosed with Ohtahara syndrome, one as early myoclonic encephalopathy, and one as epilepsy of infancy with migrating focal seizure. Five cases could not be classified into any epileptic syndrome. Asynchronous BS pattern was identified in 18 cases, of which 13 (72%) patients had genetic and/or metabolic etiologies. Synchronous BS pattern was identified in 14 cases, of which 8 (57%) patients had structural etiologies. Twenty-three patients had symmetric BS patterns, of which 15 (65%) patients had genetic etiologies. Nine patients had asymmetric BS patterns, of which 8 (89%) patients had structural etiologies. Patients with genetic epilepsies tended to have asynchronous and symmetric BS patterns, whereas those with structural epilepsies were more likely to have synchronous and asymmetric BS patterns.
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Ondas Encefálicas/fisiología , Epilepsia/etiología , Epilepsia/fisiopatología , China , Bases de Datos Factuales , Electroencefalografía/métodos , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/etiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Convulsiones/diagnóstico , Convulsiones/etiología , Espasmos Infantiles/diagnósticoRESUMEN
LAMA2-related muscular dystrophy (LAMA2-MD) is classified into congenital muscular dystrophy type 1A (MDC1A) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23). The purpose of this study was to identify the involvement pattern of thigh muscles of LAMA2-MD patients on magnetic resonance imaging. Fourteen MDC1A and 3 LGMDR23 patients were included, with 21 known and 8 novel LAMA2 disease-causing variants. In LAMA2-MD, the gluteus maximus, anterior (quadriceps femoris) and posterior (adductor magnus and biceps femoris) thigh muscles were extensively and severely affected with fatty infiltration, with relatively sparing of the adductor longus. The pattern of muscle involvement was similar between MDC1A and LGMDR23, but more severe in MDC1A, as well as in LAMA2-MD patients without ambulation. The rather peculiar pattern of the adductor magnus and long head of the biceps femoris first and severely affected in the mid-thigh level was found in LGMDR23. Strong correlation between fatty infiltration and age as well as disease duration was observed for the adductor longus in MDC1A. Edema and atrophy selectively involved in some muscles. The pattern of fatty infiltration on thigh muscle MRI of LAMA2-MD could provide important information for the diagnosis, differential diagnosis and assessment of clinical severity.
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Imagen por Resonancia Magnética/métodos , Músculo Esquelético/diagnóstico por imagen , Distrofia Muscular de Cinturas/diagnóstico por imagen , Adolescente , Niño , Preescolar , Femenino , Músculos Isquiosurales/diagnóstico por imagen , Humanos , Extremidad Inferior , Masculino , Músculo Cuádriceps/diagnóstico por imagen , Muslo/diagnóstico por imagenRESUMEN
BACKGROUND: LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype-phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy. METHODS: Clinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed. RESULTS: One hundred and thirty patients (116 LAMA2-CMD and 14 LGMDR23) were included. LAMA2-CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of LAMA2-CMD patients at median ages of 6.0 months (range 2.0-36.0 months), 11.0 months (range 6.0-36.0 months), and 27.0 months (range 18.0-84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0-20.0 months). Motor regression in LAMA2-CMD mainly occurred concurrently with rapid progression of contractures during 6-9 years old. Twenty-four LAMA2-related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of LAMA2-CMD patients. Forty-six novel and 97 known LAMA2 disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In LAMA2-CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in LAMA2-CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in LAMA2-CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival (p = 0.029). CONCLUSIONS: This study provides better understandings of natural history and genotype-phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.
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Distrofia Muscular de Cinturas , Distrofias Musculares , Niño , Preescolar , China , Variaciones en el Número de Copia de ADN , Humanos , Lactante , Laminina/genética , Distrofias Musculares/genéticaRESUMEN
OBJECTIVE: To investigate high-frequency oscillations (HFOs) in epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) with different etiologies. METHODS: Twenty-one CSWS patients treated with methylprednisolone were divided into structural group and genetic/unknown group. Comparisons were made between the two etiological groups: selected clinical variables including gender, age parameters, seizure frequencies and antiepileptic drugs; distribution of HFOs in pre-methylprednisolone electroencephalography (EEG) and percentage changes of HFOs and spikes after methylprednisolone treatment. RESULTS: There were 7 patients (33%) in structural group and 14 patients (68%) in genetic/unknown group. No significant difference was found between the two groups regarding selected clinical variables. HFOs were found in 12 patients in pre-methylprednisolone EEG. The distribution of HFOs was focal and accordant with lesions in 5 of structural group, and it was also focal but in different brain regions in 7 of genetic/unknown group. The percentage reduction of total HFOs and spikes was 81% (158/195) and 19% (1956/10,037) in structural group, while 98% (315/323) and 55% (6658/12,258) in genetic/unknown group after methylprednisolone treatment. CONCLUSION: The etiologies had no distinct correlation with some clinical characteristics in CSWS. HFOs recorded on scalp EEG might not only be used as makers of seizure-onset zone (SOZ), but also have association with functional disruption of brain networks. Both HFOs and spikes reduced more in genetic/unknown patients than that in structural patients after methylprednisolone treatment and HFOs were more sensitive to treatment than spikes.
Asunto(s)
Encéfalo/fisiopatología , Electroencefalografía , Epilepsia/etiología , Epilepsia/fisiopatología , Sueño/fisiología , Adolescente , Anticonvulsivantes/uso terapéutico , Encéfalo/efectos de los fármacos , Niño , Preescolar , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Metilprednisolona/uso terapéutico , Cuero Cabelludo , Sueño/efectos de los fármacos , Resultado del TratamientoRESUMEN
Clinically, some patients having genetic (idiopathic) epilepsy with photosensitive seizures were difficult to be diagnosed. We aimed to discuss whether the genetic (idiopathic) epilepsy with photosensitive seizures is a focal entity, a generalized entity or a continuum. Twenty-two patients with idiopathic epilepsies and photoconvulsive response (PCR) were retrospectively recruited. In the medical records, the seizure types included "generalized tonic-clonic seizures (GTCS)" in 15, "partial secondarily GTCS (PGTCS)" in 3, partial seizures (PS) in 3, myoclonic seizures in 2, eyelid myoclonus in one, and only febrile seizures in one. Seizure types of PCR included GTCS (1/22), PGTCS (6/22), PS (9/22), electrical seizures (ES) (3/22) and GTCS/PGTCS (3/22). Combined the medical history with PCR results, they were diagnosed as: idiopathic (photosensitive) occipital lobe epilepsy (I(P)OE) in 12, genetic (idiopathic) generalized epilepsy (GGE) in one, GGE/I(P)OE in 5, pure photosensitive seizure in one, and epilepsy with undetermined generalized or focal seizure in 3. So, the dichotomy between generalized and focal seizures might have been out of date regarding to pathophysiological advances in epileptology. To some extent, it would be better to recognize the idiopathic epilepsy with photosensitive seizures as a continuum between focal and generalized seizures.
Asunto(s)
Epilepsia Generalizada/patología , Convulsiones/clasificación , Convulsiones/patología , Adolescente , Niño , Preescolar , Electroencefalografía , Epilepsias Mioclónicas , Epilepsias Parciales , Epilepsia Generalizada/etiología , Femenino , Humanos , Lactante , Masculino , Mioclonía , Trastornos por Fotosensibilidad/etiología , Trastornos por Fotosensibilidad/patología , Estudios Retrospectivos , Convulsiones/etiología , Convulsiones FebrilesRESUMEN
Although recessive mutations in LAMA2 are already known to cause laminin α2-related muscular dystrophy, a rare neuromuscular disorder, large deletions or duplications within this gene are not well-characterized. In this study, we applied next-generation sequencing-based copy number variation profiling in 114 individuals clinically diagnosed with laminin α2-related muscular dystrophy, including 96 who harboured LAMA2 mutations and 34 who harboured intragenic rearrangements. In total, we detected 18 distinct LAMA2 copy number variations that have been reported only among Chinese, 10 of which are novel. The frequency of CNVs in the cohort was 19.3%. Deletion of exon 4 was detected in 10 alleles of eight patients, accounting for 27% of all copy number variations. These patients are Han Chinese and were found to have the same haplotype and sequence at the breakpoint junction, suggesting that exon 4 deletion is a founder mutation in Chinese Han and a mutation hotspot. Moreover, the data highlight our approach, a modified next-generation sequencing assay, as a robust and sensitive tool to detect LAMA2 variants; the assay identifies 85.7% of breakpoint junctions directly alongside sequence information. The method can be applied to clinical samples to determine causal variants underlying various Mendelian disorders.