M. Troncoso

The phenotypic spectrum of SCN8A encephalopathy.

Objective: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations. Methods: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data. Results: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges. Conclusion: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.

Pediatric Arterial Ischemic Stroke: Clinical Presentation, Risk Factors, and Pediatric NIH Stroke Scale in a Series of Chilean Patients

Stroke is an important cause of morbidity and mortality in children. Clinical presentation is diverse, and multiple risk factors have been described. The aim of this retrospective study is to describe the clinical presentation, risk factors, and the Pediatric National Institute of Health Stroke Scale (PedNIHSS) in a series of pediatric Chilean patients with the diagnosis of arterial ischemic stroke (AIS). Children diagnosed with AIS aged between 29 d and 18 y were enrolled (1989 to 2016). Clinical characteristics and risk factors were described. PedNIHSS severity score was estimated for patients older than 4 mo of age. Sixty-two patients were included, 66% were male, and the mean age of presentation was 3.5 y. Seventy-nine percent presented motor deficit, 45% seizures, and 15% consciousness impairment. Eighty-two percent had a unilateral stroke and 73% had anterior circulation territory affected. The main risk factors were arteriopathy (63%) and infection (43%). The PedNIHSS mean was 7.6, ranging between 0 and 17. In the categories in which it was possible to apply χ2 test, only the acute systemic conditions category was statistically significant (P = 0.03), being higher in the group of patients younger than 3 y old. We confirmed male predominance in AIS and the most frequent presenting symptom was motor deficit. We found at least 1 risk factor in all patients with complete information. We confirmed arteriopathy as the most frequent risk factor, and acute systemic conditions were higher in patients younger than 3 y old with statistical significance (P = 0.03). The majority of patients presented mild to moderate severity in the PedNIHSS score.

Risk Factors for Perinatal Arterial Ischemic Stroke: A Case–Control Study

Introduction: Arterial ischemic stroke in newborns is an important cause of neonatal morbidity and mortality. Its pathophysiology and associated risk factors are not yet clearly understood and defined. Objective: The aim of this retrospective study was to investigate possible risk factors in diagnosed cases of PAIS (perinatal arterial ischemic stroke). Materials and methods: Case–control study. Clinical data of patients with PAIS diagnosis were analyzed. Two healthy controls were selected for each PAIS case, matched for gestational age. Risk factors were explored using univariable and multivariable analysis. Outcome: 40 patients were included in the study, 24 males and 16 females; 52.5% of cases were diagnosed within the first month of birth, and 47.5% were retrospectively diagnosed. The results showed a male predominance (66.7%). The distribution of cerebral ischemic injury was predominantly medial cerebral artery (87.5%) and occurred more commonly in the left cerebral hemisphere (62.5%). Significant risk factors in the univariate analysis (P < 0.05) were primiparity, stillbirth, neonatal sepsis, asphyxia, twin pregnancy, placenta abruption, emergency cesarean section, Apgar score ≤7 after 5 min, breech presentation, and hyperbilirubinemia. In the multivariate analysis, primiparity (OR 11.74; CI 3.28–42.02), emergency cesarean section (OR 13.79; CI 3.51–54.13), birth asphyxia (OR 40.55; CI 3.08–532.94) and Apgar score ≤7 after 5 min (OR 13.75; CI 1.03–364.03) were significantly associated factors with PAIS. Only five (16.6%) patients had an abnormal thrombophilia study. Conclusion: Risk factors of primiparity, emergency cesarean section, birth asphyxia, and Apgar score ≤7 after 5 min were significantly associated with perinatal stroke. More studies with a larger number of patients and with prolonged follow up are required to establish more clearly the associated risk factors involved in this pathology.

Estudio clínico genético en pacientes con complejo de esclerosis tuberosa

Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disease caused by mutations in the tumor suppressor genes TSC1 or TSC2. OBJECTIVE To characterize clinically and genetically patients diagnosed with TSC. PATIENTS AND METHOD Descriptive study of clinical records of 42 patients from a pediatric neuropsychiatry department diagnosed with TSC and genetic study in 21 of them. The exon 15 of TSC1 gene and exons 33, 36 and 37 of TSC2 gene were amplified by polymerase chain reaction and sequenced. The relationship between the mutations found with the severity and clinical course were analyzed. RESULTS In 61.9% of the patients the symptoms began before 6 months of age. The initial most frequent manifestations of TSC were new onset of seizures (73.8%) and the detection of cardiac rhabdomyomas (16.6%). During the evolution of the disease all patients had neurological involvement; 92.9% had epilepsy. All patients presented hypomelanotic spots, 47.6% facial angiofibromas, 23.8% Shagreen patch, 47.6 heart rhabdomyomas and 35.7% retinal hamartomas. In the genetic study of 21 patients two heterozygous pathogenic mutations in TSC1 and one in TSC2 genes were identified. The latter had a more severe clinical phenotype. CONCLUSIONS Neurological and dermatological manifestations were the most frequent ones in patients with TSC. Two pathogenic mutations in TSC1 and one in TSC2 genes were identified. The patient with TSC2 mutation manifested a more severe clinical phenotype.

Lesch-Nyhan disease in two families from Chiloé Island with mutations in the HPRT1 gene

ABSTRACT Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. The authors report two independent point mutations leading to splicing errors: IVS 2 +1G>A, c.134 +1G>A, and IVS 3 +1G>A, c.318 +1G>A in the hypoxanthine-phosphoribosyltransferase1 (HPRT1) gene which result in exclusion of exon 2 and exon 3 respectively, in the HGprt enzyme protein from different members of two Chiloé Island families. Molecular analysis has revealed the heterogeneity of genetic mutation of the HPRT1 gene responsible for the HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling.