Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder.

We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

Cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

The aim of this study was to determine prospectively the frequency of pathogenic chromosomal microdeletions and microduplications in a large group of referred patients with developmental delay (DD), intellectual disability (ID) or autism spectrum disorders (ASD) within a genetic diagnostic service. First tier testing was applied using a standardised oligo-array comparative genomic hybridization (CGH) platform, replacing conventional cytogenetic testing that would have been used in the past. Copy number variants (CNVs) found to be responsible for the clinical condition on the request form could all be subdivided into three groups: well established pathogenic microdeletion/microduplication/aneuploidy syndromes, predicted pathogenic CNVs as interpreted by the laboratory, and recently established pathogenic disease susceptibility CNVs. Totalled from these three groups, with CNVs of uncertain significance excluded, detection rates were: DD (13.0%), ID (15.6%), ASD (2.3%), ASD with DD (8.2%), ASD with ID (12.7%) and unexplained epilepsy with DD, ID and ASD (10.9%). The greater diagnostic sensitivity arising from routine application of array CGH, compared with previously used conventional cytogenetics, outweighs the interpretative issues for the reporting laboratory and referring clinician arising from detection of CNVs of uncertain significance. Precise determination of any previously hidden molecular defect responsible for the patient's condition is translated to improved genetic counselling.

Epilepsy with cognitive deficit and autism spectrum disorders: prospective diagnosis by array CGH.

The clinical significance of chromosomal microdeletions and microduplications was predicted based on their gene content, de novo or familial inheritance and accumulated knowledge recorded on public databases. A patient group comprised of 247 cases with epilepsy and its common co-morbidities of developmental delay, intellectual disability, autism spectrum disorders, and congenital abnormalities was reviewed prospectively in a diagnostic setting using a standardized oligo-array CGH platform. Seventy-three (29.6%) had copy number variations (CNVs) and of these 73 cases, 27 (37.0%) had CNVs that were likely causative. These 27 cases comprised 10.9% of the 247 cases reviewed. The range of pathogenic CNVs associated with seizures was consistent with the existence of many genetic determinants for epilepsy.

Levetiracetam in children and adolescents with epilepsy and hemiplegic cerebral palsy.

AIM: To monitor the effect of adding levetiracetam in paediatric patients with hemiplegic cerebral palsy and uncontrolled epilepsy. METHODS: A case series of eight patients with hemiplegic cerebral palsy whose focal seizures were not adequately controlled by their current anticonvulsants were monitored after levetiracetam was added to their medications. If there was a 50% reduction in seizure frequency, then the other anticonvulsants were discontinued. Prolonged follow-up occurred for a minimum of 2 years. RESULTS: There were seven males and one female whose ages ranged from 4 years to 17 years. All had focal onset seizures, while seven also had secondarily generalised tonic clonic seizures. Levetiracetam resulted in at least a 50% reduction in seizure frequency in seven, with no change in one. Three were able to wean successfully to monotherapy and remained seizure free for over 2 years. They had a prior history of infrequent seizures, one to six per year. Those who continued to require multiple anticonvulsants had a prior history of more frequent seizures, 6-50/year. Levetiracetam was well tolerated, and none ceased this because of side effects. CONCLUSION: Levetiracetam is likely to be an effective anticonvulsant in children and adolescents with hemiplegic cerebral palsy and infrequent but persistent focal seizures.

Reflex seizures induced by defecation, with an ictal EEG focus in the left frontotemporal region.

We report a 9-year-old boy with seizures induced by defecation. The episodes occurred 1-2 min after passing a bowel action and consisted of initial staring, gagging, and drooling followed by a secondarily generalized tonic-clonic seizure. The interictal EEGs were normal, but an ictal EEG with concurrent video monitoring demonstrated a polyspike wave discharge in the left frontotemporal region. There was no evidence of syncope, and the seizures did not occur while straining to empty his bowels or immediately on standing afterward. His magnetic resonance imaging scan was normal. This is the first reported case in which ictal EEG monitoring has demonstrated reflex seizures induced by defecation.