Fully percutaneous fetoscopic repair of myelomeningocele: 30-month follow-up data.

OBJECTIVE: This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. METHODS: Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. RESULTS: All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. CONCLUSION: Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Epilepsy-new diagnostic tools, old drugs? : Therapeutic consequences of epilepsy genetics]. / Epilepsie ­ neue Diagnostik, alte Medikamente? : Die Konsequenzen der Epilepsiegenetik.

BACKGROUND: Recent advances in the field of epilepsy genetics have led to an increased fraction of patients with epilepsies where the etiology of the disease could be identified. Nevertheless, there is some criticism regarding the use of epilepsy genetics because in many cases the identification of a pathogenetic mutation does not lead to an adaptation of therapy or to an improved prognosis. In addition, the interpretation of genetic results might be complicated due to the considerable numbers of variants of unclear significance. OBJECTIVE: This publication presents the arguments in favour of a broad use of genetic investigations for children with epilepsies. Several diseases where a genetic diagnosis does in fact have direct therapeutic consequences are mentioned. In addition, the indirect impact of an established etiology, encompassing the avoidance of unnecessary diagnostic measures, possibility of genetic counselling, and the easing of the psychologic burden for the caregivers, should not be underestimated. CONCLUSION: The arguments in favour of broad genetic diagnostics prevail notwithstanding the lack of relevant new developments regarding the therapy.

Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.

Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

Percutaneous minimally invasive fetoscopic surgery for spina bifida aperta. Part III: neurosurgical intervention in the first postnatal year.

OBJECTIVE: To evaluate the need for postnatal neurosurgical intervention after fetoscopic patch coverage of spina bifida aperta (SBA). METHODS: This was a retrospective analysis of a cohort of 71 fetuses which underwent minimally invasive fetoscopic patch coverage of SBA between 21 + 0 and 29 + 1 weeks of gestation. Postnatal neurosurgical procedures were classified into two types: re-coverage of the SBA within the first 3 months following birth, and shunt placement as treatment of associated hydrocephalus within the first year. RESULTS: Location of the SBA was lumbosacral in 59 cases, lumbar in seven, thoracic in three and sacral in two. In total, 20/71 (28%) patients underwent early postnatal neurosurgical intervention by means of re-coverage of the SBA. This was performed because of cerebrospinal fluid leakage in seven (35%), adhesions with functional deterioration in three (15%), incomplete coverage in five (25%) and skin defect in five (25%) cases. Ventriculoperitoneal shunt placement within 1 year was required in 32 (45%) cases and was preceded by ventriculostomy in two. Three (4%) infants needed Chiari decompression surgery in the first 12 months following birth, because of syringomyelia or gait disturbance. CONCLUSIONS: Fetoscopic patch coverage of SBA may require postnatal re-coverage in some cases. In most cases, conservative wound treatment shows good results, without requiring neurosurgical intervention. The low 1-year-shunt rate is comparable to data of the Management of Myelomeningocele Study and lower compared with published data of patients with postnatal only coverage of SBA.

MERRF-like phenotype associated with a rare mitochondrial trnaile mutation (m.4284 G>A).

Nearly all patients affected by myoclonic epilepsy with ragged-red fibres (MERRF) harbour a mutation in the mitochondrial transfer RNALys gene. We report on an 8-year-old girl with clinical and diagnostic features of MERRF. After excluding one of the common mutations associated with MERRF, a complete sequence analysis of the mitochondrial genome revealed an m.4284 G>A mutation in the mitochondrial transfer RNAIle gene. This mutation has only once been described in a family with variable clinical symptoms, but has not yet been linked to MERRF. This case extends the mutational spectrum associated with the MERRF phenotype, and demonstrates the importance of performing a comprehensive mutational analysis in patients with suspected mitochondrial disease when common mutations have been ruled out.

Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis.

Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.

Progressive biological behavior of a dysembryoplastic neuroepithelial tumor.

We present the case of a 13-month-old girl with a right occipital cortical alteration on MRI that proved to be a growing lesion. Tumor growth had been observed over a period of 15 months before total resection was performed, revealing a dysembryoplastic neuroepithelial tumor WHO grade I. This case shows that dysembryoplastic neuroepithelial tumors can present as growing neoplasias. It underlines the importance of obtaining histologic diagnosis and close follow-up examinations using MRI, even in so-called stable lesions that are only unveiling through epileptic seizures.

Treatment of gastroesophageal reflux with nissen fundoplication and gastrostomy tube insertion in infantile pompe's disease.

In infantile Pompe's disease, enzyme replacement therapy (ERT) has been shown to reverse cardiomyopathy, improve skeletal muscle strength, and prolong survival. We report on five patients in whom complications related to gastroesophageal reflux (GER) resulted in deterioration of their clinical status despite initial improvement under ERT. Surgical antireflux therapy, performed in four, yielded positive results in two. Three patients experienced severe aspirations related to GER and underwent fundoplication and gastrostomy subsequently. Two did not regain former motor functions and deceased shortly thereafter, while one slowly recuperated and is in a stable state at age 53 months. In a further patient, severe GER prompted fundoplication at age 17 months. No aspirations occurred until the girl deceased probably due to cardiac arrest 20 months later. These cases suggest that infants with Pompe's disease under ERT may benefit from timely performed fundoplication and gastric tube placement.

Neurological, cognitive, and behavioural outcome of higher order multiple births.

The purpose of this study was to assess the neurodevelopmental outcome in a larger cohort of higher order multiple births (HOM). To accomplish this, we analysed the perinatal records of 90 HOM from 28 pregnancies (69 triplets, 16 quadruplets and 5 quintuplets) born at the University Hospital Kiel during the period from 1980 to 1994. Sixty-eight out of 79 surviving children (87.2%) were re-examined at a median age of 7.8 years (range: 3 to 14.5 years). Re-examination included assessment of the neurological, psychomotor (Denver developmental scale, Columbia mental maturity scale), and behavioural (childhood behaviour checklist) status. Perinatal mortality was 12%. In 62% of subjects, neurological and cognitive status at follow-up were completely normal; 32% revealed minor and 6% major neurodevelopmental deficits. Comparison between VLBW and LBW HOM disclosed significantly more neurological deficits, lower IQs and more behaviour problems in children with VLBW. Especially social problems, attention deficit, anxiety and depression symptoms were more frequent in the VLBW HOM than in the LBW HOM group. VLBW HOM parents felt significantly more stressed and VLBW HOM mothers reported reduced coping skills. These findings suggest that the overall cognitive and neurological outcome of HOM surviving the neonatal period is good, but that minor neurocognitive deficits are frequent. LBW HOM have less neurological and behaviour problems than VLBW HOM.

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes.

OBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. RESULTS: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). CONCLUSION: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

A new type of leukoencephalopathy with metaphyseal chondrodysplasia maps to Xq25-q27.

BACKGROUND: The authors report a three-generation family with four male patients presenting with a novel type of X-chromosomal leukoencephalopathy associated with skeletal abnormalities. METHODS: The index patient and his brother reached their early motor milestones in due time and had normal language development. Between the ages of 2 and 3 years, first signs of spastic paraplegia were noticed. Furthermore, the patients developed tremor, ataxia, optic atrophy, and spastic tetraparesis. Both boys had broad wrists and knees without significant contractures. A maternal uncle and a granduncle had the same disease. RESULTS: Leukoencephalopathy (MRI, MRS) and metaphyseal chondrodysplasia (X-ray, MRI) were diagnosed. MRS showed a reduction of choline-containing compounds in the white matter. An autopsy on one of the patients, who died at age 37 years, revealed an orthochromatic type of leukoencephalopathy. In bone and cartilage tissue, unspecific signs of a mild chondrodysplasia were found. At the PLP gene locus an obligate recombination was observed, which excludes the Pelizaeus-Merzbacher locus on Xq21-22. However, affected males share a fragment of the long arm of chromosome X. CONCLUSION: The authors report a new type of leukoencephalopathy associated with metaphyseal chondrodysplasia located on Xq25-q27.

[L-2-hydroxyglutaric aciduria -- a rare cause of macrocephaly]. / L-2-Hydroxy-Glutarazidurie -- eine seltene Differenzialdiagnose der Makrozephalie.

We report on a 9-year-old girl who was referred to our department because of increasing macrocephaly and school problems. The neurological examination disclosed mild cerebellar dysfunction and positive pyramidal tract signs. An MRI of the brain revealed extensive signal alterations of the white matter. Biochemical investigations established the diagnosis of L-2-hydroxyglutaric aciduria which has to be kept in mind as a rare cause of macrocephaly.

Late-onset nephrotic syndrome and severe cerebellar atrophy in Galloway-Mowat syndrome.

Galloway-Mowat syndrome (GMS) is a rare autosomal-recessive disorder characterised by nephrotic syndrome, microcephaly, and variable brain anomalies. The prognosis is poor with death almost inevitably supervening before the age of 6 years, but atypical cases with later onset of proteinuria and a more protracted course are on record. We report a female offspring from consanguineous parents suffering from microcephaly, profound psychomotor retardation, epilepsy, hiatal hernia, and striking cerebellar atrophy in whom a nephrotic syndrome became apparent at age 16 years. Renal biopsy revealed focal segmental glomerulosclerosis and glomerular basement membrane abnormalities. We postulate that this patient had a milder form of GMS with severe and diffuse cerebellar atrophy as the leading central nervous system abnormality.

SCN1A mutation analysis in myoclonic astatic epilepsy and severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures.

Severe myoclonic epilepsy in infancy (SMEI), severe idiopathic generalized epilepsy of infancy (SIGEI) with generalized tonic clonic seizures (GTCS), and myoclonic astatic epilepsy (MAE) may show semiological overlaps. In GEFS+ families, all three phenotypes were found associated with mutations in the SCN1A gene. We analyzed the SCN1A gene in 20 patients with non-familial myoclonic astatic epilepsy -- including 12 probands of the original cohort used by Doose et al. in 1970 to delineate MAE. In addition, 18 patients with sporadic SIGEI -- mostly without myoclonic-astatic seizures -- were analyzed. Novel SCN1A mutations were found in 3 individuals. A frame shift resulting in an early premature stop codon in a now 35-year-old woman with a borderline phenotype of MAE and SIGEI (L433fsX449) was identified. A splice site variant (IVS18 + 5 G --> C) and a missense mutation in the conserved pore region (40736 C --> A; R946 S) were detected each in a child with SIGEI. We conclude that, independent of precise syndromic delineation, myoclonic-astatic seizures are not predictive of SCN1A mutations in sporadic myoclonic epilepsies of infancy and early childhood.

X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting.

X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene. We report on the clinical data of a boy with a 1-bp deletion (790 delC) resulting in a frame shift in the ARX gene and prolonged survival until age 18 months. Similar to other patients, the boy showed postnatal microcephaly, hypothalamic dysfunction, intractable neonatal seizures, and chronic diarrhoea. In addition, he suffered from exocrine pancreatic insufficiency and renal phosphate wasting became apparent from age 5 months, both of which have not been described previously in XLAG. This allows us to speculate that the phenotype of XLAG is more complex than hitherto known and may include renal phosphate wasting which might not have been observed in other patients due to early death.

Atypical "benign" partial epilepsy or pseudo-Lennox syndrome. Part I: symptomatology and long-term prognosis.

PURPOSE: Atypical benign partial epilepsy (ABPE) or pseudo-Lennox syndrome (PLS) is characterised by generalised minor seizures and focal sharp slow waves and spikes (SHW) as observed in Rolandic epilepsy (RE), but with exceptional pronounced activation during sleep. The aim of this study was to describe the full spectrum of ABPE in the hitherto largest group of patients. METHODS: We retrospectively analysed the clinical and EEG data of 43 children who fulfilled the following criteria: occurrence of generalised minor seizures as described for ABPE (i.e., atonicastatic seizures, myoclonic seizures, atypical absences) and focal SHW identical to those observed in RE, but with generalisation during sleep. RESULTS: Language development prior to onset of epilepsy was retarded in 26% of patients. In 74%, age at onset of epilepsy ranged from 2 to 6 years. Manifestation occurred earlier in boys than in girls. Generalised minor seizures constituted the predominating seizure type in 67% of patients. Twenty-eight percent of patients suffered from simple partial seizures of the oro-facial region or generalised tonic-clonic seizures originating from the oro-facial region. Additionally, generalised tonic-clonic (44%), unilateral (21%), partial motor (44%), versive (12%), focal atonic (9%), and complex-partial seizures (2%) were observed. A bioelectrical status was recorded in 56% of patients during sleep. No tonic seizures and no fast spike series (bursts of 10-20 Hz rhythms) were observed. At last follow-up, 84% of patients were in clinical remission. All subjects older than age 15 were seizure-free. However, 56% of patients attended a school for mentally handicapped children. CONCLUSIONS: ABPE or PLS broadly overlaps with RE, electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Regarding the epilepsy, the prognosis is excellent, mental deficit, however, seems to be frequent. The differentiation from Lennox-Gastaut syndrome and myoclonic astatic epilepsy is essential. Instead of ABPE, the term pseudo-Lennox syndrome is proposed.

Atypical "benign" partial epilepsy of childhood or pseudo-lennox syndrome. Part II: family study.

Atypical benign partial epilepsy of childhood (ABPE = Pseudo-Lennox syndrome) shows semiologic parallels to Lennox-Gastaut syndrome, however--besides the lack of tonic seizures--it has an entirely different etiology and prognosis. Recently Hahn et al [17] investigated the long-term evolution of 43 cases with ABPE. Symptomatology, EEG findings, and course were found to overlap with Rolandic epilepsy, Landau-Kleffner syndrome and ESES. The incidence of seizures in relatives was determined in the whole series investigated by Hahn et al [17]. Five of 56 siblings suffered from seizures (3 Rolandic seizures; one febrile convulsions; one unclassified). Three fathers reported grand mal. In 29 families of the series of Hahn et al EEG recordings were performed: 22 brothers, 19 sisters and 16 pairs of parents. In 29% of the siblings a sharp wave focus was demonstrable. The rate rose to 40% when only siblings investigated at the age of maximum expression (3 to 10 years) were considered. Sharp wave foci were mostly multifocal and indistinguishable from those observed in siblings of children with Rolandic epilepsy. Photoparoxysmal response and generalized spikes and waves during rest and hyperventilation were also found to be significantly elevated (26% and 13% respectively). We conclude that ABPE is a subgroup of idiopathic partial epilepsy of childhood (representing a less benign part of a spectrum) that has to be ranked in a continuum with Rolandic epilepsy. The different clinical phenotype might be caused by a higher expressivity of the identical genetic trait, possibly facilitated by other genetic or acquired factors. Genetic heterogeneity represents another possibility.

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy.

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.