C. Rittey

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Aicardi-Goutieres Syndrome Displays Genetic Heterogeneity with One Locus (AGS1) on Chromosome 3p21

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.

Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children

To gain insight into the long‐term impact of vagus nerve stimulation (with VNS Therapy) in children with drug‐resistant epilepsy, we conducted the largest retrospective multicenter study to date over an extended follow‐up period of up to 24 months.

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy.

Summary:  Purpose: Mutations in genes coding for the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN.

Retention rate of Levetiracetam in children with intractable epilepsy at 1 year

UNLABELLED Levetiracetam (LEV) is a novel antiepileptic drug (AED) that has recently obtained marketing authorisation for use in children. The purpose of this study was to assess the efficacy, tolerability and retention rate of LEV in children with refractory epilepsies. It is a retrospective multicentre observational study reporting the use of LEV in 200 children, aged 0.3-19 years (median 9-years-old) over a 4-year period. All of the patients included in the study had refractory epilepsy with a median age of onset of epilepsy of 3 years (range 0-13 years). The 38% had failed and withdrawn 3 or more AEDs previously and 24% were taking at least 2 other AEDs in addition to LEV. The 47% had focal, and 58% had symptomatic epilepsies. The LEV dose ranged from 8 to 100 mg/kg/day (mean 39 mg/kg). The study comprised 215 person years of LEV exposure. RESULTS LEV was well tolerated with a retention rate of 49% at 1 year. No serious adverse events were reported with possibly related adverse events reported in only 24% of patients (mainly emotional or behavioural changes). At more than 2, 6 and 12 months, worthwhile improvement (>50% seizure reduction) was noted in 60, 40 and 32%, including seizure freedom in 14, 14 and 5%, respectively. CONCLUSION Our results confirm the efficacy and tolerability of LEV in children with refractory epilepsies and demonstrate good response and retention rates at 12 months. It represents the largest cohort of paediatric patients published so far on LEV with a 1-year follow-up.

A second locus for Aicardi-Goutières syndrome at chromosome 13q14–21

Background: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon α metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). Methods: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. Results: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14–21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. Conclusions: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.

Juvenile neuronal ceroid-lipofuscinosis : developmental progress after supplementation with polyunsaturated fatty acids

Six patients with juvenile neuronal ceroid‐lipofuscinosis (NCL) who were demonstrated to have abnormally low levels of membrane phospholipids were treated by dietary supplementation with polyunsaturated fatty acids (PUFAs) for periods ranging from 4 years 10 months to 7 years 3 months. Annual evaluations of intelligence and fine motor ability were undertaken while on supplementation. Mental development remained stable in most subjects throughout this period; fine motor function and vision were stable in the two youngest subjects only. These data suggest that PUFA supplementation may arrest the natural course of juvenile NCL if treatment is started early. A larger, multicenter, controlled trial is warranted.

Movement disorders associated with complex regional pain syndrome in children.

The aim of the present study was to review the history, clinical course, treatment, and outcome of movement disorders in children and young people with complex regional pain syndrome (CRPS). Case notes were reviewed retrospectively of children and young people who presented with movement disorders in CRPS to our tertiary paediatric pain service over a period of 13 years. Ten children with CRPS presented with movement disorders (eight females, two males). The age at first presentation with symptoms of CRPS ranged from 8 to 15 years (mean 11y 2mo, median 13y). The most common movement disorder was dystonia (n=8), followed by tremors (n=3) and myoclonus (n=3); two patients had all three movement disorders. The movement disorder affected mainly the lower limb (n=9) with a predilection for the foot (n=7) and was frequently initiated by minor trauma (n=7). Follow‐up ranged from 6 months to 14 years. The outcome was variable, with good prognosis in nearly half of the cases: four children experienced complete resolution of symptoms. Two children showed a slight improvement. Four children showed no improvement. Movement disorders in CRPS are under‐recognized in children. The management has to be multidisciplinary with an expertize in paediatric pain.

Outcome of children with hyperventilation-induced high-amplitude rhythmic slow activity with altered awareness.

Hyperventilation‐induced high‐amplitude rhythmic slow activity with altered awareness (HIHARS) is increasingly being identified in children and is thought to be an age‐related non‐epileptic electrographic phenomenon. We retrospectively investigated the clinical outcome in 15 children (six males, nine females) with HIHARS (mean age 7y, SD 1y 11mo; range 4y 6mo–11y). The presenting feature in 11 cases was blank spells – two of these children also had generalized tonic–clonic seizures (GTCS) – and in one individual the main concern was deteriorating school performance. Three children had symptoms suggestive of focal motor seizures. Of the nine children presenting solely with blank spells, further follow‐up (mean duration 18mo, SD 21mo) revealed full resolution of symptoms in six, but three had persistent symptoms. In our study, the symptoms of children with HIHARS presenting with blank spells in isolation appeared to resolve spontaneously and did not evolve into convulsive seizures or other paroxysmal events considered to be clearly epileptic. Children (with HIHARS) who presented with clinical features suggestive of GTCS or focal motor seizures (with or without blank spells) and/or had epileptiform discharges on interictal electroencephalography were subsequently diagnosed with epilepsy.

Neonatal hypertonia – a diagnostic challenge

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested.