RESUMEN
Introduction: Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.
RESUMEN
The role of thrombophilia in the pathogenesis of stroke is still controversial, especially in the pediatric stroke. In order to examine the role of common thrombophilic mutations in children and adults with stroke, a case-control study was carried out in a group of 80 children and 73 younger adult patients. The control groups encompassed 100 healthy children and 120 healthy blood donors. Our results showed no significant differences in the frequency of factor V (FV) Leiden, FII G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T variants between patient groups and corresponding controls. According to our results, carriers of 677CT genotype have 3.62 higher risks to develop stroke in children than in adults (P < .001). The obtained data indicate that heterozygosity for MTHFR C677T variant represents a possible important risk factor for pediatric stroke and suggest a different role of this gene variant in etiology of stroke in pediatric and adult patients.
Asunto(s)
Factor V/genética , Predisposición Genética a la Enfermedad , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación , Protrombina/genética , Accidente Cerebrovascular/genética , Adulto , Factores de Edad , Estudios de Casos y Controles , Niño , Preescolar , Factor V/metabolismo , Femenino , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/sangre , Persona de Mediana Edad , Protrombina/metabolismo , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Trombofilia/sangre , Trombofilia/complicaciones , Trombofilia/genéticaRESUMEN
In order to investigate the influence of genetic factors in childhood stroke, we compared the distributions of mutations/ polymorphisms affecting hemostasis and/or endothelial function (factor V [FV] Leiden, factor II [FII] G20210A, methylenetetrahydrofolate reductase [MTHFR] C677T, angiotensin-converting enzyme [ACE] insertion/deletion [ID], and endothelial nitric oxide synthase [eNOS] G894T) among children with stroke and controls. A total number of 26 children with arterial ischemic stroke and a control group of 50 healthy children were included in the study. No statistically significant differences in allelic and genotypic distribution were detected in comparisons between groups. However, when combined genotypes were analyzed, statistical significance was observed for the association of MTHFR CT and eNOS TT gene variants. The results of our study suggest that this genotype combination represents a risk factor of 7.2 (P = .017) for arterial ischemic stroke in children.
Asunto(s)
Isquemia Encefálica/genética , Predisposición Genética a la Enfermedad , Enfermedades Arteriales Intracraneales/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Óxido Nítrico Sintasa de Tipo III/genética , Accidente Cerebrovascular/genética , Adolescente , Niño , Preescolar , Factor V/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación Missense , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Protrombina/genética , Factores de RiesgoRESUMEN
Genetic and acquired disorders that foster a procoagulable state represent risk factors for stroke in childhood. Although an increased incidence of thromboembolic complications has been reported in patients with thalassemia, severe cerebral thromboembolism has rarely been observed in patients with beta-thalassemia minor. This article describes a case study of a 1-year-old boy who presented with left-sided hemiparesis, seizures, microcytic anemia, and recent infection with reactive thrombocytosis. Ischemic infarction in the territory of the right middle cerebral artery was confirmed by magnetic resonance imaging and magnetic resonance angiography. Genetic tests showed that the patient was heterozygous for the beta(degrees) -thalassemia IVS-I-1 mutation and homozygous for the methylentetrahydrofolate reductase C677T mutation. Based on these findings, it was concluded that the synergistic effects of multiple, genetic, and acquired prothrombotic risk factors brought about the hypercoagulable state that resulted in overt stroke in a thalassemic patient in early childhood.
Asunto(s)
Enfermedades Arteriales Cerebrales/genética , Ataque Isquémico Transitorio/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación/genética , Talasemia beta/genética , Enfermedades Arteriales Cerebrales/complicaciones , Enfermedades Arteriales Cerebrales/patología , Humanos , Lactante , Ataque Isquémico Transitorio/complicaciones , Masculino , Talasemia beta/complicacionesRESUMEN
Myotonic dystrophy type 1 (DM1) is an autosomal dominant inheritable disease associated with an expansion of CTG repeats in the 3' UTR of the DMPK gene. The subject is an 11-year-old girl with atypical myopathy. Because the proband's family has a positive DM1 history, a molecular-genetic analysis for DM1 was performed. This study showed that proband had a small DMPK expansion (91 CTG repeats) although the observed myopathy would not normally be associated with DM1. These results show how the phenotypic manifestation of DM1 can have unusual symptoms with a completely unexpected relationship to genotype.
Asunto(s)
Distrofia Miotónica/genética , Proteínas Serina-Treonina Quinasas/genética , Expansión de Repetición de Trinucleótido , Regiones no Traducidas 3'/genética , Adulto , Anciano , Niño , Preescolar , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteína Quinasa de Distrofia Miotónica , Linaje , FenotipoRESUMEN
OBJECTIVE: To determine the risk of recurrence of ischemic stroke in children and to evaluate the influence of etiological factors and underlying mechanisms on recurrence rate. SUBJECTS AND METHODS: Thirty-six children (21 boys and 15 girls) with clinically and radiographically proven ischemic cerebral infarction were prospectively followed up over a period of 1-9 years (median 5 years 5 months). The median age of onset of stroke was 8.4 years (1-16 years). Patients with hemorrhagic stroke, neonatal infarction and sinovenous thrombosis were not included. The patients were analyzed according to the mechanisms and etiology of the initial and recurrent stroke event. RESULTS: For the initial stroke, cardioembolic (33.3%) and arteriopathic processes (36.1%) were identified as the most probable mechanisms of arterial ischemic stroke. Prothrombotic abnormalities were found in 4 children (11.1%). Underlying pathology in the remaining 7 (19.4%) was not known. Recurrent ischemic infarction was diagnosed in 5 children (13.9%) within 5 days to 18 months (median 6 months) after the first stroke manifestation. In 3 of them stroke recurrence was due to cardiac or transcardiac embolism. Cardiac abnormality prior to the first stroke was detected in 1 child. Clinically silent multiple cerebral infarcts disclosed by MRI preceded the overt stroke episode in 2 patients. CONCLUSION: Congenital and acquired heart diseases were the most common cause of repeated stroke in our study. The risk of recurrence appeared to be fivefold higher in children with cardiac disease irrespective of the coexistence of other risk factors. The risk factors of stroke in children were multiple and overlapping. Consequently, recognition of the major one and its underlying mechanism is crucial for both effective therapeutic approach and the prevention of recurrence.