Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.

Seizure outcome after extratemporal epilepsy surgery in childhood.

AIM: The aim of the study was to describe seizure outcome following surgery for focal extratemporal epilepsy and identify factors associated with prolonged postsurgical freedom from seizures. METHOD: In this retrospective cohort study, children with drug-resistant focal extratemporal epilepsy were treated surgically and followed up in a single tertiary care centre between 1997 and 2008. RESULTS: Eighty children were identified for inclusion in the study (42 males, 38 females; median age 9y 1mo, range 3mo-18y 7mo). The aetiology was identified as focal cortical dysplasia (n=37), low-grade tumour (n=22), tuberous sclerosis (n=9), or non-specific (n=12). Children were followed for a median of 3 years 1 month (range 8mo-10y 7mo) after surgery. Overall, at last follow-up, 50% of the children had been completely seizure free since surgery (Engel class Ia); of these 40 individuals, 15 had discontinued all antiepileptic drugs. Several presurgical factors were associated with a favourable outcome. However, after controlling for confounding factors, aetiology appeared to be the only determinant of long-term seizure outcome as non-specific lesion pathology was associated with seizure recurrence (hazard ratio 10.43; 95% confidence interval 3.26-33.39). INTERPRETATION: In 50% of cases, children with surgically treated drug-resistant extratemporal epilepsies have an excellent long-term outcome. The aetiology of the epileptogenic lesion appears to be the only significant determinant of surgical outcome in this population of children. It is difficult to correctly identify non-specific pathology on presurgical magnetic resonance imaging.

Psychopathology in children before and after surgery for extratemporal lobe epilepsy.

AIM: To establish the rates and types of psychiatric disorder in children before and after surgery for extratemporal epilepsy. Relationships between psychiatric morbidity and demographic/clinical variables were examined. METHOD: A retrospective case note review of 71 children undergoing extratemporal focal resection for drug resistant epilepsy in a specialist epilepsy surgery programme between 1997 and 2008. Psychiatric diagnoses were derived from pre- and postoperative assessments according to DSM-IV criteria. RESULTS: Seventy-one children (38 males, 33 females) were eligible for this study. Mean age (SD) at surgery was 9 (5) years. Frontal resections were performed in 73% of the children, parietal in 17%, and occipital in 10%. Mental health problems were present in 37 of 71 (52%) children pre- and/or postoperatively. A similar proportion of children had psychiatric diagnoses pre- and postoperatively: 31 of 71 (44%) and 32 of 71 (45%) respectively. INTERPRETATION: Psychopathology is common in children with extratemporal epilepsy. In this sample, the impact of surgery on psychiatric symptoms was not predictable: some children were unchanged, others improved, and others acquired new psychiatric diagnoses postoperatively. Given the high rates of psychiatric disorder in this group of patients, detection and treatment of mental health needs may be important.

Cognitive outcome after extratemporal epilepsy surgery in childhood.

PURPOSE: The present study aims to describe the cognitive profile of children with medically refractory extratemporal epilepsies who undergo focal surgery and to identify determinants for preoperative and postoperative cognitive level. METHODS: This is a retrospective cohort study. Children who underwent operations between 1997 and 2008 with a focal lesion in frontal, parietal, or occipital cortices and with a presurgical or postsurgical cognitive evaluation, were eligible for the study. KEY FINDINGS: Sixty-six children (53% male) with a mean age of 9.3 ± 8.8 years were enrolled. The overall full-scale IQ (FSIQ) at cognitive testing was 77.4 ± 44.4 before surgery. Children did not show any significant change in their FSIQ after surgery. Duration of presurgical epilepsy, age at epilepsy onset, etiology, and gender were found to be independently associated with lower FSIQ before surgery. Presurgical cognitive level was the only factor independently associated with postsurgical FSIQ. Overall, 51.5% of children who underwent surgery were seizure-free; however, the good postsurgical epilepsy control did not seem to influence the cognitive outcome. SIGNIFICANCE: Children with extratemporal lobe epilepsy are below the normal cognitive level range. Intellectual abilities of children undergoing surgery are determined independently by presurgical factors and surgery does not seem to affect the cognitive level in the postsurgical period, even for those who become free from clinical seizures.

Selenoprotein N-related myopathy: a retrospective natural history study to guide clinical trials.

OBJECTIVE: To describe clinical features and disease progression of Selenoprotein N-related myopathy in a large multicenter cohort of patients. METHODS: Cross-sectional multicenter data analysis of 60 patients (53 families) with Selenoprotein N-related myopathy and single-center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years. RESULTS: The majority of patients (46/60, 77%) presented before age 2 years with hypotonia, poor head/neck control, and developmental delay. At last assessment (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no ambulation. Ventilatory support was initiated in 50/60 patients at a mean Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty-five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scoliosis surgery at a median age of 13.6 years. Five children needed nasogastric feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed progressive decline of Hammersmith functional motor scores (estimated annual change -0.55 point), time to walk 10 meter, time standing from sitting, and from lying. Sixteen patients had weights < 2nd centile. The estimated change in FVC % per year was -2.04, with a 95% CI (-2.94, -1.14). CONCLUSIONS: This comprehensive analysis of patients with Selenoprotein N-related myopathy further describes the clinical course of this rare condition. The observed functional motor and respiratory data provide evidence of the slow decline patients experience over time which is useful when considering therapeutic intervention.

Two Cases of Guillain-Barré Syndrome Variants Presenting With Dysautonomia.

We describe 2 pediatric cases presenting with posterior reversible encephalopathy syndrome secondary to autonomic dysfunction preceding the onset of motor symptoms in Guillain-Barré syndrome variants. Patient 1 presented acutely with encephalopathy, cerebellar signs, hypertension, lower limb weakness, and respiratory decompensation. Magnetic resonance imaging (MRI) brain showed occipital lesions consistent with posterior reversible encephalopathy syndrome. Nerve conduction studies were consistent with Miller-Fisher syndrome. After intravenous immunoglobulin and plasmapheresis, he improved clinically with radiological resolution. Patient 2 presented with headache, leg pain, seizures, and significant hypertension. Brain MRI was normal but spine MRI revealed enhancement of the cauda equina ventral nerve roots. She was areflexic with lower limb weakness a few days after intensive care unit admission and made a significant improvement after treatment with intravenous immunoglobulin. In children presenting with posterior reversible encephalopathy syndrome in the absent of other causes of primary hypertension, Guillain-Barré syndrome variants are an important differential etiology, presenting with autonomic dysfunction, even before signs of motor weakness become evident.

ECEL1 gene related contractural syndrome: Long-term follow-up and update on clinical and pathological aspects.

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease.

Does cesarean section prevent mortality and cerebral ultrasound abnormalities in preterm newborns?

OBJECTIVE: Despite the increased use of the cesarean section (CS), the rates of cerebral palsy, a frequent consequence of brain damage, have remained stable over the last decades. Whether an actual decrease in cerebral palsy has been masked by increased survival of infants delivered by CS or not, remains undefined. To investigate the role of CS, we compared risks of mortality and brain damage, as defined by ultrasound (US) abnormalities, in preterm newborns by mode of delivery. METHODS: Information on fetal, maternal, and neonatal risk factors was collected from the paired clinical records of preterm newborns and mothers. Crude and adjusted odds ratios (OR) of mortality and ultrasound abnormalities, according to mode of delivery (i.e., vaginal, elective CS, and emergency CS) were calculated. All the analyses were controlled for possible confounding by indication. RESULTS: In newborns of gestational age <32 weeks, no effect of CS on cerebral US abnormalities was found (OR 0.71 and 0.73 for emergency CS and elective CS, respectively). None of the maternal and neonatal factors were associated with both cerebral US abnormalities and mode of delivery. Among newborns of gestational age >or=32 weeks, after controlling for known and potential confounders in a multivariate model, the adjusted ORs remained close to one for both elective CS and emergency CS. CONCLUSIONS: CS does not reduce overall mortality in preterm newborns. No protective effect of CS on US abnormalities was found after stratifying by gestational age and controlling for possible confounding. These results do not encourage the widespread use of CS in preterm labor.

Backpack palsy: A rare complication of backpack use in children and young adults - A new case report.

Backpack palsy is a well-recognised, albeit rare, complication of carrying backpacks. Although it has been mostly described in cadets during strenuous training, sporadic cases of brachial nerve impairment have been reported in children and young adults. Here we reported the case of a 15-year-old girl who presented with a left-side brachial palsy with axonal denervation of C5C7 motor roots following a school challenge for the Duke of Edinburgh Award. Her symptoms began soon after starting the challenge and included weakness of shoulder abduction and elevation, as well as forearm, wrist and fingers extension. After 6 months of physiotherapy her motor function was completely restored. Backpack palsy can sometimes present in children and young adults. This disorder should be taken in consideration when planning for daily, as well as more challenging, physical activities in these age groups.

Exanthematic diseases during pregnancy and attention-deficit/hyperactivity disorder (ADHD).

Rash causing viral diseases may be transmitted during pregnancy, causing severe congenital disease. Although neurological and psychiatric disorders are common consequences of congenital rubella, children born to women who developed a viral rash during pregnancy do not appear to be at increased risk of these disorders if they were asymptomatic at birth. In a case-control study conducted to evaluate risk factors for ADHD, we found an increased risk of this disorder among children born to women experiencing a viral rash during pregnancy. The viral rash (i.e. measles, varicella, or rubella) was reported by 4 of 71 mothers of children with ADHD and none of the 118 controls' mothers (P<0.01). The difference remained statistically significant after adjusting for potential confounders (i.e. other factors found associated with ADHD, such as gender and familiarity). Although, the viral disease reported by the mothers, in accordance with their physician's diagnosis, did not represent a homogeneous nosological group, the unexpectedly high rate found among ADHD cases' mothers suggest a role for viral diseases occurring during pregnancy in the development of ADHD.

Brain damage in preterm infants: etiological pathways.

Preterm newborns represent a high-risk population for brain damage, primarily affecting the white matter, and for related neurodevelopmental disabilities. Determinants of brain damage have been extensively investigated, but there are still many controversies on how these factors can influence the developing brain and provoke damage. The concept of etiological pathway, instead of a single determinant, appears to better explain pathogenetic mechanisms: the brain damage may represent the final outcome of exposure to several combinations of risk factors in the same pathway or in different pathways and can change according to the gestational age. The aim of this article is to review the current knowledge on the pathogenesis of brain damage in preterm infants, within the frame of two main theoretical models, the ischemic and the inflammatory pathway. The relationship between the two pathways and the contribution of genetic susceptibility to ischemic and/or inflammatory insult, in modulating the extent and severity of brain damage, is also discussed.

Adverse events occurring during invasive electroencephalogram recordings in children.

BACKGROUND: In cryptogenic epilepsy or when multifocal seizure onset is suspected, intracranial monitoring of the EEG is required. OBJECTIVE: To report on the adverse events related to electroencephalogram (EEG) intracranial recording in one of the largest pediatric series published and to discuss the avoidance of adverse events in our experience and with respect to a review of the literature. METHODS: A retrospective analysis of our department database and hospital charts of 95 children operated on between 1994 and 2009 was performed. RESULTS: Invasive recording was uneventful in 51.1% of cases. Observed frequency of infection was 14.9%, cerebrospinal fluid leak was 10.6%, brain swelling was 6.4%, and hemorrhage was 17%. Brain swelling was more frequent in older patients, whereas the length of recording, number of electrode contacts used, and presence of depth electrodes were not relevant. Cerebrospinal fluid leakage was completely prevented by the routine introduction of dural graft substitutes in 2003. CONCLUSION: Invasive recordings carry a noticeable rate of adverse events but provide invaluable information in delineating the epileptogenic zone. The low incidence of such events among younger children suggests that invasive recordings can be successfully performed with low morbidity in this age group.

Abnormal parieto-motor connectivity in Tuberous Sclerosis Complex.

Abnormal connectivity might be involved in the pathophysiology of Tuberous Sclerosis Complex (TSC). We used twin-coil Transcranial Magnetic Stimulation protocol to investigate connectivity between posterior parietal cortex (PPC) and motor cortex (M1) in TSC patients. In comparison with healthy subjects and TSC patients treated with antiepileptic drugs, non-medicated TSC patients exhibited abnormal excitability of PPC-M1 connection. Such altered connectivity might play a role in TSC epileptic phenotype.