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.

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.

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.