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1.
Int J Mol Sci ; 25(11)2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38892025

RESUMO

Pathogenic variants in LMNA have been associated with a wide spectrum of muscular conditions: the laminopathies. LMNA-related congenital muscular dystrophy is a laminopathy characterised by the early onset of symptoms and often leads to a fatal outcome at young ages. Children face a heightened risk of malignant arrhythmias. No established paediatric protocols for managing this condition are available. We review published cases and provide insights into disease progression in two twin sisters with LMNA-related muscular dystrophy. Our objective is to propose a cardiac surveillance and management plan tailored specifically for paediatric patients. We present a family of five members, including two twin sisters with LMNA-related muscular dystrophy. A comprehensive neuromuscular and cardiac work-up was performed in all family members. Genetic analysis using massive sequencing technology was performed in both twins. Clinical assessment showed that only the twins showed diagnoses of LMNA-related muscular dystrophy. Follow-up showed an early onset of symptoms and life-threatening arrhythmias, with differing disease progressions despite both twins passing away. Genetic analysis identified a de novo rare missense deleterious variant in the LMNA gene. Other additional rare variants were identified in genes associated with myasthenic syndrome. Early-onset neuromuscular symptoms could be related to a prognosis of worse life-threatening arrhythmias in LMNA related muscular dystrophy. Being a carrier of other rare variants may be a modifying factor in the progression of the phenotype, although further studies are needed. There is a pressing need for specific cardiac recommendations tailored to the paediatric population to mitigate the risk of malignant arrhythmias.


Assuntos
Lamina Tipo A , Distrofias Musculares , Gêmeos Monozigóticos , Humanos , Lamina Tipo A/genética , Gêmeos Monozigóticos/genética , Feminino , Distrofias Musculares/genética , Distrofias Musculares/terapia , Masculino , Criança , Linhagem , Pré-Escolar , Arritmias Cardíacas/genética , Arritmias Cardíacas/etiologia
2.
Int J Mol Sci ; 25(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38612618

RESUMO

Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada , Insuficiência Cardíaca , Humanos , Cardiomiopatia Dilatada/genética , Algoritmos , Frequência do Gene
3.
Int J Legal Med ; 137(2): 345-351, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36693943

RESUMO

Sudden death cases in the young population remain without a conclusive cause of decease in almost 40% of cases. In these situations, cardiac arrhythmia of genetic origin is suspected as the most plausible cause of death. Molecular autopsy may reveal a genetic defect in up to 20% of families. Most than 80% of rare variants remain classified with an ambiguous role, impeding a useful clinical translation. Our aim was to update rare variants originally classified as of unknown significance to clarify their role. Our cohort included fifty-one post-mortem samples of young cases who died suddenly and without a definite cause of death. Five years ago, molecular autopsy identified at least one rare genetic alteration classified then as ambiguous following the American College of Medical Genetics and Genomics' recommendations. We have reclassified the same rare variants including novel data. About 10% of ambiguous variants change to benign/likely benign mainly because of improved population frequencies. Excluding cases who died before one year of age, almost 21% of rare ambiguous variants change to benign/likely benign. This fact makes it important to discard these rare variants as a cause of sudden unexplained death, avoiding anxiety in relatives' carriers. Twenty-five percent of the remaining variants show a tendency to suspicious deleterious role, highlighting clinical follow-up of carriers. Periodical reclassification of rare variants originally classified as ambiguous is crucial, at least updating frequencies every 5 years. This action aids to increase accuracy to enable and conclude a cause of death as well as translation into the clinic.


Assuntos
Arritmias Cardíacas , Morte Súbita , Humanos , Morte Súbita/etiologia , Mutação , Frequência do Gene , Autopsia , Morte Súbita Cardíaca/etiologia
4.
Hum Genet ; 141(10): 1579-1589, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34546463

RESUMO

A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics' recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.


Assuntos
Canalopatias , Canalopatias/genética , Testes Genéticos , Genômica , Humanos , Canal de Potássio KCNQ1/genética , Mutação
5.
Clin Infect Dis ; 73(4): 586-593, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-33471090

RESUMO

BACKGROUND: We aimed to assess the postnatal pattern of cardiovascular remodeling associated with intrauterine exposure to maternal HIV and antiretroviral treatment (ART). METHODS: Prospective cohort including 34 HIV-exposed uninfected (HEU) infants and 53 non-HIV-exposed infants were evaluated from fetal life up to 6 months postnatally. A cardiovascular evaluation was performed including echocardiography, blood pressure, and carotid intima media thickness (cIMT) measurement. RESULTS: ART regimens during pregnancy included 2 nucleoside reverse transcriptase inhibitors (Abacavir + Lamivudine (32.4%), Emtricitabine + Tenofovir (41.2%), and Zidovudine + Lamivudine (20.6%)). At 6 months of age, HIV-exposed uninfected infants showed thicker myocardial walls (septal wall thickness mean 5.02 mm (SD 0.85) vs 3.98 mm (0.86); P < .001), relative systolic dysfunction with decreased mitral ring displacement (8.57 mm (2.03) vs 10.34 mm (1.84); P = .002), and decreased tricuspid S' (9.71 cm/s (1.94) vs 11.54 cm/s (2.07); P = .003) together with relative diastolic dysfunction showed by prolonged left isovolumic relaxation time (58.57 ms (13.79) vs 47.94 (7.39); P < .001). Vascular assessment showed significantly higher systolic and diastolic blood pressure (102 mmHg (16.1) vs 80 mmHg (13.9); P < .001 and 64 mmHg (14.4) vs 55 mmHg (10.2); P = .045 respectively), with 50% of HIV-exposed children meeting criteria for hypertension vs 3.77% of the non-HIV-exposed group (P < .001) and thicker mean cIMT in the HIV-exposed group (0.62 µm (0.09) vs 0.51 µm (0.09); P = .015). CONCLUSIONS: Subclinical cardiac impairment together with higher blood pressure and thicker cIMT were observed in HIV-exposed infants at 6 months of age. Half of them presented hypertension. Our findings support a possible increased cardiovascular risk in HIV uninfected infants exposed in utero to ART.


Assuntos
Infecções por HIV , Hipertensão , Complicações Infecciosas na Gravidez , Espessura Intima-Media Carotídea , Criança , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos Prospectivos , Remodelação Ventricular
6.
Int J Mol Sci ; 21(19)2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998306

RESUMO

Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome.


Assuntos
Síndrome de Brugada/genética , Morte Súbita Cardíaca/patologia , Predisposição Genética para Doença , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Fibrilação Ventricular/genética , Alelos , Síndrome de Brugada/complicações , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatologia , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Expressão Gênica , Frequência do Gene , Genes Dominantes , Testes Genéticos , Humanos , Herança Multifatorial , Canal de Sódio Disparado por Voltagem NAV1.5/deficiência , Fenótipo , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologia
7.
J Emerg Nurs ; 46(1): 105-110, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31735372

RESUMO

Sudden cardiac death in the young is devastating for the family and the community. Although it has diverse etiologies, many are inherited. Discovering the disease in 1 patient offers the chance to save otherwise asymptomatic family members. Although some diseases can be discovered during autopsy, others require electrocardiograms for diagnosis, making it difficult to estimate the prevalence of disease and cause of death. Careful assessment of the history of present illness, family history, and electrocardiogram can guide clinical teams toward sometimes rare and difficult diagnoses. The purpose of this review article is to summarize the bench to bedside diagnosis of inherited dysrhythmia syndromes, which if missed on first presentation to the emergency department, have significant implications for the patient and the entire family.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Serviço Hospitalar de Emergência , Anamnese/métodos , Adolescente , Autopsia , Criança , Pré-Escolar , Eletrocardiografia/métodos , Humanos , Lactente , Medição de Risco , Adulto Jovem
8.
Hum Mutat ; 40(6): 749-764, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30821013

RESUMO

Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.


Assuntos
Síndrome de Brugada/genética , Biologia Computacional/métodos , Redes Reguladoras de Genes , Mutação , Canais Epiteliais de Sódio/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Proteínas de Membrana/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Semaforina-3A/genética , Subunidade beta-2 do Canal de Sódio Disparado por Voltagem/genética
9.
J Electrocardiol ; 56: 85-89, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31326859

RESUMO

Supraventricular tachycardias (SVT) are the most common arrhythmias in the perinatal period. Permanent junctional reciprocating tachycardia (PJRT) is a rare form of SVT, often incessant and refractory to pharmacological treatments. Our goal was to analyze the clinical features and treatment of PJRT in patients younger than 2 months and to describe their long-term outcomes. METHODS: Retrospective descriptive observational study of patients diagnosed between 2000 and 2015 in the NICU of a referral center for the treatment of pediatric arrhythmias. History of pregnancy, neonatal period, pharmacological treatment, electrophysiological study and long-term follow-up were reviewed. RESULTS: 129 of the 10.198 (1.26%) patients admitted to the NICU had SVT, sixteen of them (12.3%) being diagnosed as PJRT. Ten cases had a prenatal diagnosis. For those six patients postnatally diagnosed, the tachycardia was detected either during a routine check-up or because of acute hemodynamic instability. The majority of patients required combinations of drugs, despite that the tachycardia was poorly controlled. Fifteen patients underwent cardiac ablation, nine patients (60%) in the neonatal period and six during childhood. The procedure was completely effective in all cases. One patient had a transient complete AV block that resolved spontaneously 24 hours after the procedure. No other complications were seen. After a mean follow-up of 10.9 years, no patient has presented recurrence, cardiac dysfunction, signs of ischemia or EKG abnormalities, they all have a normal life. CONCLUSIONS: When PJRT is refractory to multiple drugs, cardiac ablation should be taken into account at early stages even in very young patients.


Assuntos
Ablação por Cateter , Taquicardia Reciprocante , Taquicardia Supraventricular , Criança , Eletrocardiografia , Seguimentos , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , Taquicardia Reciprocante/diagnóstico , Taquicardia Reciprocante/cirurgia , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/cirurgia
10.
Int J Legal Med ; 130(2): 415-20, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26872470

RESUMO

Sudden infant death syndrome is the unexpected demise of a child younger than 1 year of age which remains unexplained after a complete autopsy investigation. Usually, it occurs during sleep, in males, and during the first 12 weeks of life. The pathophysiological mechanism underlying the death is unknown, and the lethal episode is considered multifactorial. However, in cases without a conclusive post-mortem diagnosis, suspicious of cardiac arrhythmias may also be considered as a cause of death, especially in families suffering from any cardiac disease associated with sudden cardiac death. Here, we review current understanding of sudden infant death, focusing on genetic causes leading to lethal cardiac arrhythmias, considering both genes encoding ion channels as well as structural proteins due to recent association of channelopathies and desmosomal genes. We support a comprehensive analysis of all genes associated with sudden cardiac death in families suffering of infant death. It allows the identification of the most plausible cause of death but also of family members at risk, providing cardiologists with essential data to adopt therapeutic preventive measures in families affected with this lethal entity.


Assuntos
Arritmias Cardíacas/genética , Canalopatias/genética , Morte Súbita do Lactente/genética , Variação Genética , Humanos , Lactente , Mutação , Morte Súbita do Lactente/epidemiologia
11.
Curr Opin Pediatr ; 27(6): 665-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26371946

RESUMO

PURPOSE OF REVIEW: Recent international expert consensus statements have updated the clinical and genetic diagnoses of patients suffering from arrhythmogenic diseases. However, a lack of genotype-phenotype correlations has hampered the development of a risk stratification scale for sudden cardiac death. RECENT FINDINGS: The improvement in the field of genetics has prompted the discovery of new genes associated with sudden cardiac death. Sudden cardiac death is a socially devastating event, especially when it occurs in the pediatric population. Physical activity can often trigger the arrhythmia and sudden death may be the first symptom. These inherited cardiac diseases may be difficult to diagnose, leaving family members also at risk. Thanks to the development of new high-throughput technologies, genetics may be used in the diagnosis of these diseases and even cases that remain unexplained after a comprehensive autopsy. Genetic testing cannot only identify the causative genetic variant in the index case, but it enables the detection of relatives at risk of sudden death, despite remaining clinically asymptomatic. SUMMARY: We review the recent advances in the genetics of inherited arrhythmias associated with sudden cardiac death. We focus on the pediatric population, the main group of people suffering from lethal inherited arrhythmias.


Assuntos
Síndrome de Brugada/genética , Morte Súbita Cardíaca/etiologia , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Síndrome do QT Longo/genética , Taquicardia Ventricular/genética , Adolescente , Síndrome de Brugada/complicações , Síndrome de Brugada/diagnóstico , Criança , Pré-Escolar , Morte Súbita Cardíaca/prevenção & controle , Humanos , Síndrome do QT Longo/complicações , Síndrome do QT Longo/diagnóstico , Atividade Motora , Taquicardia Ventricular/complicações , Taquicardia Ventricular/diagnóstico
13.
BMJ Open Sport Exerc Med ; 10(3): e001852, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38975025

RESUMO

Sudden cardiac death is a rare but socially devastating event, especially if occurs in young people. Usually, this unexpected lethal event occurs during or just after exercise. One of the leading causes of sudden cardiac death is inherited arrhythmogenic syndromes, a group of genetic entities characterised by incomplete penetrance and variable expressivity. Exercise can be the trigger for malignant arrhythmias and even syncope in population with a genetic predisposition, being sudden cardiac death as the first symptom. Due to genetic origin, family members must be clinically assessed and genetically analysed after diagnosis or suspected diagnosis of a cardiac channelopathy. Early identification and adoption of personalised preventive measures is crucial to reduce risk of arrhythmias and avoid new lethal episodes. Despite exercise being recommended by the global population due to its beneficial effects on health, particular recommendations for these patients should be adopted considering the sport practised, level of demand, age, gender, arrhythmogenic syndrome diagnosed but also genetic diagnosis. Our review focuses on the role of genetic background in sudden cardiac death during exercise in child and young population.

14.
Genes (Basel) ; 15(5)2024 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-38790267

RESUMO

Brugada syndrome is a rare arrhythmogenic syndrome associated mainly with pathogenic variants in the SCN5A gene. Right ventricle outflow tract fibrosis has been reported in some cases of patients diagnosed with Brugada syndrome. Pulmonary atresia with an intact ventricular septum is characterized by the lack of a functional pulmonary valve, due to the underdevelopment of the right ventricle outflow tract. We report, for the first time, a 4-year-old boy with pulmonary atresia with an intact ventricular septum who harbored a pathogenic de novo variant in SCN5A, and the ajmaline test unmasked a type-1 Brugada pattern. We suggest that deleterious variants in the SCN5A gene could be implicated in pulmonary atresia with an intact ventricular septum embryogenesis, leading to overlapping phenotypes.


Assuntos
Síndrome de Brugada , Canal de Sódio Disparado por Voltagem NAV1.5 , Atresia Pulmonar , Humanos , Atresia Pulmonar/genética , Atresia Pulmonar/patologia , Masculino , Síndrome de Brugada/genética , Síndrome de Brugada/patologia , Pré-Escolar , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Septo Interventricular/patologia
15.
Front Med (Lausanne) ; 10: 1118585, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36844202

RESUMO

In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim's relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

16.
Front Cardiovasc Med ; 10: 1164028, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37082456

RESUMO

Long QT Syndrome (LQTS) is a rare, inherited channelopathy characterized by cardiac repolarization dysfunction, leading to a prolonged rate-corrected QT interval in patients who are at risk for malignant ventricular tachyarrhythmias, syncope, and even sudden cardiac death. A complex genetic origin, variable expressivity as well as incomplete penetrance make the diagnosis a clinical challenge. In the last 10 years, there has been a continuous improvement in diagnostic and personalized treatment options. Therefore, several factors such as sex, age diagnosis, QTc interval, and genetic background may contribute to risk stratification of patients, but it still currently remains as a main challenge in LQTS. It is widely accepted that sex is a risk factor itself for some arrhythmias. Female sex has been suggested as a risk factor in the development of malignant arrhythmias associated with LQTS. The existing differences between the sexes are only manifested after puberty, being the hormones the main inducers of arrhythmias. Despite the increased risk in females, no more than 10% of the available publications on LQTS include sex-related data concerning the risk of malignant arrhythmias in females. Therein, the relevance of our review data update concerning women and LQTS.

17.
Front Cell Dev Biol ; 11: 1142937, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36968203

RESUMO

Introduction: LMNA-related muscular dystrophy is a rare entity that produce "laminopathies" such as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular management in pediatric laminopathies. The aim was to perform an exhaustive cardiologic follow-up in pediatric patients diagnosed with LMNA-related muscular dystrophy. Methods: Baseline cardiac work-up consisted of clinical assessment, transthoracic Doppler echocardiography, 12-lead electrocardiogram, electrophysiological study, and implantation of a long-term implantable cardiac loop recorder (ILR). Results: We enrolled twenty-eight pediatric patients diagnosed with EDMD (13 patients), L-CMD (11 patients), LGMD1B (2 patients), and LMNA-related mild weakness (2 patients). Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM) detected by the ILR that required implantable cardioverter defibrillator (ICD) implantation. Malignant arrhythmias were detected in 20% of our cohort and early-onset EDMD showed worse cardiac prognosis. Discussion: Patients diagnosed with early-onset EDMD are at higher risk of DCM, while potentially life-threatening arrhythmias without DCM appear earlier in L-CMD patients. Early onset neurologic symptoms could be related with worse cardiac prognosis. Specific clinical guidelines for children are needed to prevent sudden death.

18.
Front Genet ; 14: 1135438, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37035729

RESUMO

Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences. Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed. Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes. Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.

19.
J Cardiovasc Dev Dis ; 9(4)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35448085

RESUMO

We report a pediatric patient with persistent left superior vena cava and a D-transposition of great arteries, which is an uncommon relation. It is crucial to know the anatomy of the persistent left superior vena cava and the dilated coronary sinus to plan the mapping techniques in cases of posterior accessory pathways.

20.
Biomedicines ; 10(1)2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-35052786

RESUMO

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40-50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype-phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype-phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

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