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PURPOSE: Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood. METHODS: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA). RESULTS: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis. CONCLUSION: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
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Enfermedades Fetales/genética , Factores de Intercambio de Guanina Nucleótido/genética , Proteínas de Unión al ARN/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Transactivadores/genética , Adolescente , Adulto , Artrogriposis/genética , Artrogriposis/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Femenino , Enfermedades Fetales/patología , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Adulto JovenRESUMEN
Congenital myotonic dystrophy type 1 (CDM1) is a rare neuromuscular disease. The aim of our study was to evaluate clinical variability of CDM1 and factors that may influence survival in CDM1. Research included 24 pediatric patients with CDM1. Most of our patients had some form of hypoxic ischemic encephalopathy (HIE) (74 %), from mild to severe. Prolonged and complicated deliveries (75 %), high percentage of children resuscitated at birth (57 %) and respiratory insufficiency (46 %) with consequent hypoxia were the main reasons that could explain high percentage of HIE. Therapeutic hypothermia was applied in three children with poor outcome. Median survival of all CDM1 was 14.2 ± 1.5 years. Six patients had a fatal outcome (25 %). Their mean age of death was 3.0 ± 2.8 years. Poor prognostic factors for the survival of our CDM1 patients were: preterm delivery, resuscitation at birth, severe HIE, hypothermia treatment and permanent mechanical ventilation. Respiratory insufficiency was the main life-threatening factor. Our data clearly indicates the need to develop natural history studies in CDM1 in order to enhance the standards of care and to develop clinical trials investigating causative therapies in pediatric patients with CDM1.
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Hipoxia-Isquemia Encefálica , Distrofia Miotónica , Humanos , Distrofia Miotónica/terapia , Distrofia Miotónica/complicaciones , Femenino , Masculino , Preescolar , Niño , Lactante , Hipoxia-Isquemia Encefálica/terapia , Adolescente , Hipotermia Inducida/métodos , Insuficiencia Respiratoria/terapia , Insuficiencia Respiratoria/etiología , Pronóstico , Resultado del Tratamiento , Centros de Atención Terciaria , Recién NacidoRESUMEN
This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics.
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Discapacidades del Desarrollo , Secuenciación del Exoma , Discapacidad Intelectual , Fenotipo , Humanos , Secuenciación del Exoma/métodos , Discapacidades del Desarrollo/genética , Niño , Masculino , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Femenino , Preescolar , Lactante , Adolescente , Pruebas Genéticas/métodosRESUMEN
BACKGROUND: Clinical course variability in Duchenne muscular dystrophy (DMD) is partially explained by the mutation location in the DMD gene and variants in modifier genes. We assessed the effect of the SPP1, CD40, and LTBP4 genes and DMD mutation location on loss of ambulation (LoA). METHODS: SNPs in SPP1-rs28357094, LTBP4-rs2303729, rs1131620, rs1051303, rs10880, and CD40-rs1883832 were genotyped, and their effect was assessed by survival and hierarchical cluster analysis. RESULTS: Patients on glucocorticoid corticosteroid (GC) therapy experienced LoA one year later (p = 0.04). The modifying effect of SPP1 and CD40 variants, as well as LTBP4 haplotypes, was not observed using a log-rank test and multivariant Cox regression analysis. Cluster analysis revealed two subgroups with statistical trends in differences in age at LoA. Almost all patients in the cluster with later LoA had the protective IAAM LTBP4 haplotype and statistically significantly fewer CD40 genotypes with harmful T allele and "distal" DMD mutations. CONCLUSIONS: The modifying effect of SPP1, CD40, and LTBP4 was not replicated in Serbian patients, although our cohort was comparable in terms of its DMD mutation type distribution, SNP allele frequencies, and GC-positive effect with other European cohorts. Cluster analysis may be able to identify patient subgroups carrying a combination of the genetic variants that modify LoA.
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Distrofia Muscular de Duchenne , Antígenos CD40/genética , Genes Modificadores , Glucocorticoides/uso terapéutico , Humanos , Proteínas de Unión a TGF-beta Latente/genética , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Osteopontina/genética , Polimorfismo de Nucleótido Simple , SerbiaRESUMEN
Ostojic S, Vukovic R, Milenkovic T, Mitrovic K, Djuric M, Nikolic L. Alpha coma in an adolescent with diabetic ketoacidosis. Turk J Pediatr 2017; 59: 318-321. This is the first report of alpha coma (AC) caused by brain edema in a patient with diabetic ketoacidosis (DKA). A previously healthy 15-year-old girl was admitted to the intensive care unit due to altered state of consciousness during the course of treatment for DKA. Patient was in a coma, intubated and had tachycardia with poor peripheral perfusion. Results of laboratory analyses indicated severe DKA and computed tomography scan indicated diffuse brain edema. The EEG pattern showed uniform alpha activity. Treatment with intravenous fluids, insulin and mannitol was started. Patient`s state of consciousness gradually improved and on the third day she was extubated. On the fifth day, her neurologic status and EEG findings were completely normal with no residual neurological deficits. In conclusion, although AC is associated with a high fatality rate, favorable outcome can be achieved with prompt recognition and treatment of cerebral edema in pediatric patients with DKA.
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Edema Encefálico/complicaciones , Coma/etiología , Cetoacidosis Diabética/complicaciones , Adolescente , Edema Encefálico/diagnóstico , Edema Encefálico/terapia , Coma/terapia , Cetoacidosis Diabética/terapia , Electroencefalografía , Femenino , Fluidoterapia/métodos , Humanos , Insulina/uso terapéutico , Unidades de Cuidados Intensivos , Manitol/uso terapéutico , Tomografía Computarizada por Rayos XRESUMEN
Magnesium is frequently used for pediatric migraine prophylaxis. The aim of this study was to evaluate to which extent the disability levels, quality of life (QOL), and anxiety and depressive symptoms change after 6-month magnesium prophylaxis in pediatric migraine. This is a follow-up study of 34 children aged 7-17 years with migraine treated with oral magnesium. Disability due to migraine was assessed by the Pediatric Migraine Disability Assessment tool (PedMIDAS), QOL was assessed by the KIDSCREEN-27, and anxiety and depressive symptoms were assessed by the Revised Child Anxiety and Depression Scale (RCADS). PedMIDAS scores significantly decreased from baseline to end-point (F(df, dferror) = 11.10 (1.63, 50.49), p<0.001), as well as anxiety (F(df, dferror) = 8.95 (1.64, 50.67), p = 0.001) and depressive symptoms (F(df, dferror) = 8.91 (1.59, 49.29), p = 0.001). Considering the KIDSCREEN-27, scores for physical and psychological well-being and social support domain significantly increased from baseline to end-point (p≤0.01). After 6 months of magnesium prophylaxis, disability due to migraine significantly decreased, whereas physical and psychosocial well-being improved. Children also reported fewer anxiety and depressive symptoms. More follow-up and randomized controlled clinical trials are needed to propose clinical recommendations for magnesium prophylaxis in pediatric migraine.
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Ansiedad/complicaciones , Ansiedad/tratamiento farmacológico , Depresión/complicaciones , Depresión/tratamiento farmacológico , Magnesio/uso terapéutico , Trastornos Migrañosos/complicaciones , Trastornos Migrañosos/tratamiento farmacológico , Calidad de Vida , Niño , Estudios de Seguimiento , HumanosRESUMEN
INTRODUCTION: Measures of health-related quality of life (HRQOL) are considered to be more comprehensive in health outcome assessments than scales assessing only the degree of neurological deficit. OBJECTIVE: The aim of the study was to evaluate HRQOL and its correlates among adolescents with multiple sclerosis (MS) in Serbia. METHODS: Demographic, clinical, and patient-reported outcome data were collected for 21 adolescents with MS, aged 14-18 years. The KIDSCREEN measure was used for HRQOL assessment. Anxiety and depressive symptoms were identified by the Revised Child Anxiety and Depression Scale (RCADS), while fatigue was assessed by the Paediatric - Functional Assessment of Chronic Illness Therapy-Fatigue (PedsFACIT-F). RESULTS: Compared to the national data for healthy adolescents, the scores for a domain assessing physical well-being were significantly lower among adolescents with MS. Five (23.8%) adolescents had the RCADS scores within the clinical range. The age of the disease onset significantly correlated with the social and school domain. Neurological impairment correlated negatively with self-perception, school environment, and social acceptance domain. Fatigue significantly correlated with physical and psychological domains. The RCADS scores and the disease duration correlated negatively with the majority of the KIDSCREEN scores. CONCLUSION: In adolescents with MS physical HRQOL domain is most likely to be compromised, whilst functioning and well-being in other domains are relatively preserved. Severity of the disease, its duration, and fatigue, with increased anxiety and depressive symptoms, are significant HRQOL correlates.
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Esclerosis Múltiple/psicología , Calidad de Vida , Adolescente , Ansiedad , Estudios Transversales , Depresión , Evaluación de la Discapacidad , Fatiga/psicología , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To describe 10 years of experience of prenatal analysis of spinal muscular atrophy (SMA). METHODS: Data were retrospectively evaluated from prenatal analysis and carrier screening among parents and close relatives between January 2003 and December 2012. Screening was done before the parents were offered prenatal diagnosis. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to detect the most frequent homozygous deletions in the SMN1 gene in fetal samples. A commercial MLPA kit (SALSA P060) was used to analyze SMN1 copy number for carrier status determination among healthy individuals. Bayesian calculation was used to accurately assess the risk of having a child affected with SMA. RESULTS: During the study period, 66 fetal samples from 44 Serbian families were analyzed, and 13 (19.7%) showed a homozygous deletion in the SMN1 gene. Among 28 healthy individuals, carrier status was confirmed for 16 (57.1%). For 7 couples, quantitative analyses and Bayesian calculation reduced the final risk of having a child with SMA from 1 in 200 to 1 in 2448. CONCLUSION: Owing to disease severity and lack of a curative treatment, prenatal diagnosis of SMA is the best way to prevent recurrence. Carrier detection allows accurate risk assessment and appropriate genetic counseling for all family members.