ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.

Retrospective study of 111 cases of congenital diaphragmatic hernia treated with early high-frequency oscillatory ventilation and presurgical stabilization.

BACKGROUND: The prognosis of babies with congenital diaphragmatic hernia (CDH) remains unsatisfactory despite recent advances in medical and surgical treatment. Most authors agree that the best way to improve outcomes for this disease is to focus on pulmonary hypoplasia and persistent pulmonary hypertension (PPH), the 2 most unfavorable prognostic factors for patient survival. However, controversy remains regarding the best treatment of CDH. In the past decade, several institutions have developed treatment protocols that include high-frequency oscillatory ventilation (HFOV), preoperative stabilization, and no thoracic drain. This strategy is 1 of several "gentle ventilation" strategies. We describe our 10-year experience in treating a cohort of 111 infants with CDH managed with this "gentle ventilation" strategy. METHODS: From October 1994 to June 2005, 111 babies with CDH were treated at our institution with HFOV. Babies progressed to inhaled nitric oxide and extracorporeal membrane oxygenation if severe PPH persisted. After a period of preoperative stabilization, surgery was performed via an abdominal approach. In case of large defects or diaphragmatic agenesis, a prosthetic patch was used. No thoracic drain was left in place at the end of surgery. The charts of all babies were reviewed. General characteristics, respiratory management, as well as perioperative and postoperative data were analyzed and correlated with survival. Predicted and actual survival rates in high-, intermediate-, and low-risk groups were analyzed on the basis of the equation described by the Congenital Diaphragmatic Hernia Study Group in 2001. RESULTS: The overall survival rate in our group of patients with CDH was 69.4% regardless of side of the defect. Incidence of a prenatal diagnosis before the 25th gestational week, coexistence of severe congenital heart disease (overall incidence, 5.4%), or other major associated anomalies, as well as the presence of a diaphragmatic agenesis were significantly higher in nonsurvivors. Thirty-six had severe PPH, of which 26 (76.5% of nonsurviving patients) died. Survivors and nonsurvivors had significant differences in blood gas analysis and respiratory management data recorded before and after the diaphragmatic correction. Ninety-nine (89%) patients underwent correction of the diaphragmatic defect. A patch was used in 44 (44%) patients and 15 of them died (survivors, 37.7%; nonsurvivors, 68.2%; P = .0111). Six (43%) of 14 patients with a preoperative pneumothorax (survivors, 10.3%; nonsurvivors, 27.3%; P > .05) and 7 (58%) of 12 patients with a postoperative pneumothorax needing a thoracic drain (survivors, 6.5%; nonsurvivors, 31.8%; P = .0013) died. In all cases, pneumothorax was ipsilateral. Two patients required oxygen therapy at discharge. The predicted survival rate was 69%; there was no difference between predicted and actual overall survival as well as between predicted and actual survival in low-risk (predicted survival rate, >66%), intermediate-risk (predicted survival rate, 34%-66%), and high-risk (predicted survival rate, <33%) groups. CONCLUSIONS: The CDH treatment strategy that includes HFOV, preoperative stabilization and no thoracic drain ensures survival with minimal pulmonary morbidity (low rate of pulmonary infections and low rate of patients requiring oxygen at home) in most affected babies. Persistent pulmonary hypertension has been the most challenging factor that ultimately determined the final outcome, and availability of new vasoactive drugs is mandatory to ameliorate the prognosis especially in high-risk patients. Meanwhile, survival comparisons of low-, intermediate-, and high-risk groups between institutions using different protocols will allow the identification of the best strategy for CDH management.