RESUMEN
Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.
Asunto(s)
Epilepsia Generalizada , Epilepsia , Niño , Humanos , Egipto/epidemiología , Estudios Retrospectivos , Epilepsia/diagnóstico , Convulsiones/genética , Convulsiones/complicaciones , FenotipoRESUMEN
Acid ceramidase deficiency is an orphan lysosomal disorder caused by ASAH1 pathogenic variants and presenting with either Farber disease or spinal muscle atrophy with progressive myoclonic epilepsy (SMA-PME). Phenotypic and genotypic features are rarely explored beyond the scope of case reports. Furthermore, the new biomarker C26-Ceramide requires validation in a clinical setting. We evaluated the clinical, biomarker and genetic spectrum of 15 Egyptian children from 14 unrelated families with biallelic pathogenic variants in ASAH1 (12 Farber and 3 SMA-PME). Recruited children were nine females/six males ranging in age at diagnosis from 13 to 118 months. We detected ASAH1 pathogenic variants in all 30 alleles including three novel variants (c.1126A>G (p.Thr376Ala), c.1205G>A (p.Arg402Gln), exon-5-deletion). Both total C26-Ceramide and its trans- isomer showed 100% sensitivity for the detection of ASAH1-related disorders in tested patients. A 10-year-old girl with the novel variant c.1205G>A (p.Arg402Gln) presented with a new peculiar phenotype of PME without muscle atrophy. We expanded the phenotypic spectrum of ASAH1-related disorders and validated the biomarker C26-Ceramide for supporting diagnosis in symptomatic patients.
Asunto(s)
Ceramidasa Ácida/genética , Miopatías Distales/genética , Lipogranulomatosis de Farber/complicaciones , Epilepsias Mioclónicas Progresivas/genética , Mioclonía/congénito , Preescolar , Miopatías Distales/complicaciones , Miopatías Distales/patología , Exones/genética , Lipogranulomatosis de Farber/genética , Lipogranulomatosis de Farber/patología , Femenino , Humanos , Lactante , Masculino , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Mutación/genética , Epilepsias Mioclónicas Progresivas/complicaciones , Epilepsias Mioclónicas Progresivas/patología , Mioclonía/complicaciones , Mioclonía/genética , Mioclonía/patología , FenotipoAsunto(s)
Biomarcadores , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Enfermedad de Niemann-Pick Tipo C/genética , Fenotipo , Egipto , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad , Humanos , Proteína Niemann-Pick C1 , Secuenciación del ExomaRESUMEN
BACKGROUND: Dyslipidemia is a major health problem among children and adolescents worldwide due to its significant association with cardiovascular disease. Primary dyslipidemias are commonly familial syndromes that can be completely asymptomatic. PURPOSE: Apart from the risk of coronary artery disease (CAD), limited data are currently available on the direct effects of dyslipidemia on myocardial function in children. METHODS: We recruited 25 children with primary dyslipidemia (14 with isolated hypercholesterolemia, 4 with isolated hypertriglyceridemia, and 7 with combined dyslipidemia). Relevant clinical manifestations and laboratory and radiological investigations were evaluated. Pulsed-wave Doppler and tissue Doppler imaging echocardiography were performed for all recruited patients and the results were compared with those of 15 age- and sex-matched healthy children. RESULTS: The median age of the dyslipidemic children was 8 years (range, 1.5-16 years). A family history was documented in 13 cases (52%), while 18 (72%) had consanguineous parents. None of the dyslipidemic children had a personal history or clinical manifestations of CAD. In contrast, echocardiographic findings differed in several diastolic function parameters of both right and left ventricles in dyslipidemic children compared to controls. Based on normalized z scores, aortic valve narrowing was detected in 7 patients (28%), while narrowing of the aortic sinus (sinus of Valsalva) was detected in 15 patients (60%). CONCLUSION: Different types of primary dyslipidemia produce functional myocardial abnormalities early in childhood. Biochemical and echocardiographic screening of high-risk children is advised to minimize the incidence of serious cardiovascular complications.