Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies.

Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate.

Ketogenic diet in the treatment of epilepsy in children under the age of 2 years: study protocol for a randomised controlled trial.

BACKGROUND: The incidence of epilepsy is greatest in the first 2 years of life, an age group where there is generally a poor prognosis for both seizure control and neurodevelopmental outcome. Early control of seizures can be associated with better developmental outcome but many of the epilepsies presenting in infancy are poorly responsive to antiepileptic medication. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet designed to mimic the effects of starvation on the body. Dietary fat is converted into ketones in the body and used as an energy source by the brain. The KD has been shown to be successful in controlling seizures in many observational studies, and in two randomised controlled trials (RCTs) in older children. However, little evidence is available in the very young. METHODS/DESIGN: An open-label RCT where eligible children (age 3 months to 2 years with epilepsy who have failed two antiepileptic drugs (AEDs)) undergo baseline assessment, including medical and seizure history. Participants then start an observation period (7 or 14 days) with documentation of seizure frequency. Randomisation will occur on day 8 or day 15 to receive the KD or a further AED; the allocated treatment will commence on day 15, with instruction and training. A second assessment (4 weeks after start of treatment) will include a clinical review and tolerability questionnaire (modified Hague Scale of Side Effects - for those allocated to the KD group). Assessments will be repeated at 8 weeks after the start of treatment including biochemical investigations, after which, according to patient response, KD (diet group) or AED (standard AED group) will then be continued or changed. Those in the AED group who have failed to achieve seizure control at the 8-week assessment will then be offered KD outside the context of the trial. Those in the KD arm who fail to achieve seizure control will be changed to standard clinical management. All patients will be followed up for 12 months from randomisation for retention, seizure outcome, quality of life and neurodevelopmental status. DISCUSSION: The slow rate of recruitment is an ongoing practical issue. There is a limitation to the number of eligible patients compared to what was predicted, mainly due to the nature of this patient group. After a substantial amendment to widen inclusion criteria and reduce the baseline period to 7 days for patients with a high seizure burden, the rate of recruitment steadily increased. A number of operational concerns regarding dietetic time were also highlighted impacting on the recruitment rate. However, the combination of a low dropout rate and the opening of further centres, the trial should successfully meet the final recruitment target. All nine centres are now recruiting and we hope to open further centres within the UK. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02205931 . Registered on 16 December 2013.

Targeted Treatment in Childhood Epilepsy Syndromes.

OPINION STATEMENT: The mainstay of treatment of epilepsy has been antiepileptic drugs; however, despite the emergence of new agents, a consistent proportion remain drug-resistant. Newer AEDs show promise. However, as it becomes clear that the epilepsies are a group of diseases rather than a single disorder the prospect of targeted treatment in some may become a reality.

Oral glucose in preterm neonates during oropharyngeal suctioning: a randomized controlled cross-over trial.

UNLABELLED: To investigate whether orally applied glucose reduces pain response during oropharyngeal suctioning in preterm infants with a birth weight >1500 g, we conducted a randomized, double-blind, placebo-controlled cross-over trial on 32 preterm infants undergoing oropharyngeal suctioning while on nasal continuous positive airway pressure (CPAP). The Premature Infant Pain Profile (PIPP) score was assessed and compared in a cross-over design to investigate whether there was a significant difference in the patients' pain response. The mean PIPP score during oropharyngeal suctioning after placebo was 8.6 (KI 7.8-9.4). After glucose administration, the mean PIPP score was 8.0 (KI 7.1-8.9). Comparison of the treatment effects reached no statistic significance (p = 0.23). During the oral study drug administration during nasal CPAP, we observed 47 adverse events, but none necessitated therapeutic intervention and none was classified as serious. CONCLUSION: In our study, late preterm infants in the first days of life did not benefit significantly from analgesia with glucose during oropharyngeal suctioning. The oral administration of glucose under nasal CPAP led to no serious adverse events.

Results of a prospective pilot trial on mobility after whole body vibration in children and adolescents with osteogenesis imperfecta.

OBJECTIVE: To evaluate the effect of whole body vibration on the mobility of long-term immobilized children and adolescents with a severe form of osteogenesis imperfecta. Osteogenesis imperfecta is a hereditary primary bone disorder with a prevalence from 1 in 10000 to 1 in 20000 births. Most of these children are suffering from long-term immobilization after recurrent fractures. Due to the immobilization they are affected by loss of muscle (sarcopenia) and secondary loss of bone mass. SUBJECTS: Whole body vibration was applied to eight children and adolescents (osteogenesis imperfecta type 3, N=5; osteogenesis imperfecta type 4, N=3) over a period of six months. INTERVENTIONS AND RESULTS: Whole body vibration was applied by a vibrating platform (Galileo Systems) constructed on a tilting-table. Success of treatment was assessed by measuring alterations of the tilting-angle and evaluating the mobility (Brief Assessment of Motor Function). All individuals were characterized by improved muscle force documented by an increased tilting-angle (median = 35 degrees) or by an increase in ground reaction force (median at start=30.0 [N/kg] (14.48-134.21); median after six months = 146.0 [N/kg] (42.46-245.25). CONCLUSIONS: Whole body vibration may be a promising approach to improve mobility in children and adolescents severely affected with osteogenesis imperfecta.