RESUMEN

Becker muscular dystrophy (BMD) is an X-linked recessive disorder responsible for mild skeletal muscle involvement and variable degree of cardiomyopathy. The characteristics of cardiac phenotype of BMD in childhood remain elusive. Clinical manifestations, genotype, serum biomarkers, and echocardiogram were retrospectively reviewed in BMD patients. Cardiac phenotype was classified into acute progressive (AP), chronic persistent (CP), and latent (L) groups based upon symptoms and echocardiographic findings. Twenty-five BMD patients were studied over 9.5 ± 2.5 years. Sixteen patients presented initially with variable degree of muscle weakness whereas 9 were asymptomatic. Three patients developed medically refractory heart failure by age 18 with progressive dilated cardiomyopathy (DCM) (AP). Six patients developed mild to moderate left ventricular (LV) systolic dysfunction with LV dilatation but remained asymptomatic (CP). Although 16 patients continued to show normal LV function (L), they demonstrated variable degrees of skeletal muscle involvement. The AP groups presented with significantly larger LV size and LV mass index (LVMI) at the initial encounter than groups CP or L, suggesting early myocardial remodeling predicts rapid disease progression. None presented with atrophic myocardial phenotype commonly observed in Duchenne muscular dystrophy (DMD). Wide availability of genetic testing has changed the scope of clinical presentation of BMD. Cardiomyopathy in BMD presents with a diverse clinical spectrum with variable progression of DCM where larger LV dimension and mass at the time of diagnosis may predict the progressiveness of cardiomyopathy.

RESUMEN

Congenital heart disease (CHD) is an indication which spans multiple specialties across various genetic counseling practices. This practice resource aims to provide guidance on key considerations when approaching counseling for this particular indication while recognizing the rapidly changing landscape of knowledge within this domain. This resource was developed with consensus from a diverse group of certified genetic counselors utilizing literature relevant for CHD genetic counseling practice and is aimed at supporting genetic counselors who encounter this indication in their practice both pre- and postnatally.

Asunto(s)

Consejeros , Cardiopatías Congénitas , Certificación , Consejo , Consejeros/psicología , Asesoramiento Genético/psicología , Cardiopatías Congénitas/genética , Humanos

RESUMEN

PBX1 encodes the pre-B cell leukemia homeobox transcription factor, a three amino acid loop extension (TALE) homeodomain transcription factor, which forms nuclear complexes with other TALE class homeodomain proteins that ultimately regulate target genes controlling organ patterning during embryogenesis. Heterozygous de novo pathogenic variants in PBX1 resulting in haploinsufficiency are associated with congenital anomalies of the kidneys and urinary tract, most commonly renal hypoplasia, as well as anomalies involving the external ear, branchial arch, heart, and genitalia, and they cause intellectual disability and developmental delay. Affected individuals described thus far have had de novo variants. Here, we report three related individuals with an inherited pathogenic intragenic PBX1 deletion with variable clinical features typical for this syndrome.

Asunto(s)

Coloboma/genética , Predisposición Genética a la Enfermedad , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Insuficiencia Renal/genética , Anomalías Urogenitales/genética , Reflujo Vesicoureteral/genética , Adulto , Niño , Coloboma/diagnóstico , Coloboma/patología , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Femenino , Haploinsuficiencia/genética , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Mutación/genética , Fenotipo , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/patología , Anomalías Urogenitales/patología , Reflujo Vesicoureteral/diagnóstico , Reflujo Vesicoureteral/patología

RESUMEN

We identified a potentially novel homozygous duplication involving the promoter region and exons 1-4 of the gene encoding type 2 cardiac ryanodine receptor (RYR2) that is responsible for highly penetrant, exertion-related sudden deaths/cardiac arrests in the Amish community without an overt phenotype to suggest RYR2-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca2+ handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca2+ transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in RYR2 transcript/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in RYR2-mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in RYR2 transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.

Asunto(s)

Calcio/metabolismo , Duplicación de Gen , Homocigoto , Células Madre Pluripotentes Inducidas/patología , Miocitos Cardíacos/patología , Canal Liberador de Calcio Receptor de Rianodina/genética , Taquicardia Ventricular/patología , Adolescente , Estudios de Casos y Controles , Diferenciación Celular , Niño , Preescolar , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Miocitos Cardíacos/metabolismo , Linaje , Fenotipo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Taquicardia Ventricular/etiología , Taquicardia Ventricular/metabolismo

RESUMEN

Sudden cardiac death (SCD) is a rare clinical encounter in pediatrics, but its social impact is immense because of its unpredicted and catastrophic nature in previously healthy individuals. Unlike in adults where the primary cause of SCD is related to ischemic heart disease, the etiology is diverse in young SCD victims. Although certain structural heart diseases may be identified during autopsy in some SCD victims, autopsy-negative SCD is more common in pediatrics, which warrants the diagnosis of sudden arrhythmic death syndrome (SADS) based upon the assumption that the usual heart rhythm is abruptly replaced by lethal ventricular arrhythmia. Despite current advances in molecular genetics, the causes of more than half of SADS cases remain unanswered even after postmortem genetic testing. Moreover, the majority of these deaths occur at rest or during sleep even in the young. Recently, sudden unexpected death in epilepsy (SUDEP) has emerged as another etiology of SCD in children and adults, suggesting critical involvement of the central nervous system (CNS) in SCD. Primary cardiac disorders may not be solely responsible for SCD; abnormal CNS function may also contribute to the unexpected lethal event. In this review article, we provide an overview of the complex pathogenesis of SADS and its diverse clinical presentation in the young and postulate that SADS is, in part, induced by unfortunate miscommunication between the heart and CNS via the autonomic nervous system.

Asunto(s)

Arritmias Cardíacas/etiología , Sistema Nervioso Central/fisiopatología , Muerte Súbita Cardíaca/etiología , Corazón/inervación , Muerte Súbita e Inesperada en la Epilepsia/etiología , Potenciales de Acción , Adolescente , Adulto , Factores de Edad , Animales , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Causas de Muerte , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Frecuencia Cardíaca , Humanos , Lactante , Masculino , Medición de Riesgo , Factores de Riesgo , Adulto Joven

RESUMEN

Importance: The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. Objective: To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families. Design, Setting, and Participants: Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019. Main Outcomes and Measures: The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families. Results: A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests. Conclusions and Relevance: In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.

Asunto(s)

Amish/genética , Muerte Súbita Cardíaca/etiología , Duplicación de Gen , Homocigoto , Linaje , Esfuerzo Físico , Canal Liberador de Calcio Receptor de Rianodina/genética , Niño , Preescolar , Consanguinidad , Variaciones en el Número de Copia de ADN , Electrocardiografía , Exones , Femenino , Pruebas Genéticas , Humanos , Masculino , Regiones Promotoras Genéticas , Hermanos , Taquicardia Ventricular/genética

RESUMEN

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts.

RESUMEN

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13 000 IU l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence.

Asunto(s)

Cardiomiopatía Dilatada/genética , Distrofina/genética , Exones/genética , Mutación del Sistema de Lectura , Distrofia Muscular de Duchenne/genética , Adolescente , Secuencia de Bases , Western Blotting , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Niño , Análisis Mutacional de ADN , Progresión de la Enfermedad , Distrofina/metabolismo , Salud de la Familia , Resultado Fatal , Femenino , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Humanos , Mutación INDEL , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Linaje , Hermanos , Factores de Tiempo

RESUMEN

Aneurysms-osteoarthritis syndrome (AOS) caused by haploinsufficiency of SMAD3 is a recently described cause of syndromic familial thoracic aortic aneurysm and dissection (TAAD). We identified a novel SMAD3 mutation in a patient with hypoplastic left heart syndrome (HLHS) who developed progressive aortic aneurysm requiring surgical replacement of the neoaortic root, ascending aorta, and proximal aortic arch. Family screening for the mutation revealed that his father, who has vascular and skeletal features of AOS, and his brother, who is asymptomatic, also have the pathogenic mutation. This is the first case report of a SMAD3 mutation in a patient with hypoplastic left heart syndrome. This case highlights the importance of genetic testing for known causes of aneurysm in patients with congenital heart disease who develop aneurysmal disease as it may significantly impact the management of those patients and their family members.

RESUMEN

OBJECTIVE: To determine if girls with Duarte variant galactosemia (DG) have an increased risk of developing premature ovarian insufficiency based on prepubertal anti-Müllerian hormone (AMH) levels. DESIGN: Cross-sectional study. SETTING: University research laboratory. PATIENT(S): Study volunteers included 57 girls with DG, 89 girls with classic galactosemia (GG), and 64 control girls between the ages of <1 month and 10.5 years. INTERVENTION(S): Blood sampling. MAIN OUTCOME MEASURE(S): We determined AMH and FSH levels in study volunteers with and without Duarte variant or GG. RESULT(S): FSH levels were significantly higher and AMH levels significantly lower in girls with GG than in age-stratified control girls, but there was no significant difference between FSH and AMH levels in girls with DG and control girls. CONCLUSION(S): Although >80% of girls with GG in this study demonstrated low to undetectable AMH levels consistent with diminished ovarian reserve, 100% of girls with DG in our study demonstrated no apparent decrease in AMH levels or increase in FSH levels, suggesting that these girls are not at increased risk for premature ovarian insufficiency.

Asunto(s)

Galactosemias/fisiopatología , Ovario/fisiopatología , Insuficiencia Ovárica Primaria/etiología , Hormona Antimülleriana/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Hormona Folículo Estimulante Humana/sangre , Galactosemias/sangre , Galactosemias/complicaciones , Humanos , Lactante , Recién Nacido , Modelos Lineales , Ovario/metabolismo , Insuficiencia Ovárica Primaria/sangre , Insuficiencia Ovárica Primaria/fisiopatología , Medición de Riesgo , Factores de Riesgo

RESUMEN

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

Asunto(s)

Cromosomas Humanos Par 17 , Eliminación de Gen , Proteínas/genética , Espasmos Infantiles/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras , Rotura Cromosómica , Femenino , Marcadores Genéticos , Guanilato-Quinasas , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Repeticiones de Microsatélite , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/fisiopatología