Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) α1 subunit (GLRA1) [1][2][3] . Genetic heterogeneity has been confirmed in isolated sporadic cases with mutations in other postsynaptic glycinergic proteins including the GlyR β subunit (GLRB) 4 , gephyrin (GPHN) 5 and RhoGEF collybistin (ARHGEF9) 6 . However, many sporadic patients diagnosed with hyperekplexia do not carry mutations in these genes 2-7 . Here we reveal that missense, nonsense and frameshift mutations in the presynaptic glycine transporter 2 (GlyT2) gene (SLC6A5) 8 also cause hyperekplexia. Patients harbouring mutations in SLC6A5 presented with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. GlyT2 mutations result in defective subcellular localisation and/or decreased glycine uptake, with selected mutations affecting predicted glycine and Na + binding sites. Our results demonstrate that SLC6A5 is a major gene for hyperekplexia and define the first neurological disorder linked to mutations in a Na + /Cl − -dependent transporter for a classical fast neurotransmitter. By analogy, we suggest that in other human disorders where Correspondence and requests for materials (subject to a Material Transfer Agreement) should be addressed to R.J.H. (robert.harvey@pharmacy.ac.uk) or M. I.R. (m.i.rees@swansea.ac.uk).. † these authors contributed equally to this work. COMPETING INTERESTS STATEMENT:The authors declare that they have no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Genet. Author manuscript; available in PMC 2011 October 31. Glycine transporters (GlyTs) are members of the Na + /Cl − -dependent neurotransmitter transporter superfamily 9,10 , integral membrane proteins that utilise electrochemical gradients to control the concentration of neurotransmitters at central synapses. This superfamily also includes transporters for GABA, biogenic amines (norepinephrine, dopamine, serotonin, proline), betaine, taurine and creatine. GlyTs have dual functions at both inhibitory and excitatory synapses, resulting from the differential localisation of two distinct transporters 9,10 , GlyT1 and GlyT2. GlyT1 is predominantly expressed in glial cells 9,10 , exhibits a 2 Na + /1 Cl − /1 glycine stoichiometry and bi-directional glycine transport 11 . These properties are appropriate for the control of extracellular glycine concentrations in the submicromolar range for modulation of N-methyl-D-aspartate receptors 12 , and also for lowering extracellular glycine levels at inhibitory glycinergic synapses 13,14 . By contrast, GlyT2 is found in glycinergic axons, exhibits a 3 Na + /1 Cl − /1 glycine stoichiometry and does not display reverse uptake 11 , reflecting an essential role for GlyT2 in maintaining a high presynaptic pool of neurotransmitter at glycinergic synapses 15 . Na + /Cl − -dependent tr...

Two cases of rotavirus gastroenteritis associated with neurological involvement, one with encephalitis (defined by abnormal neurological signs, cerebrospinal fluid (CSF) pleocytosis and detection of rotavirus genomic nucleic acid in the CSF) and one with a non-inflammatory encephalopathy (defined by abnormal neurological signs, an entirely normal CSF and detection of rotavirus genomic nucleic acid in the CSF), are presented and used as a basis to review and explore potential pathogenetic mechanisms, including direct viral replication within neurons and indirect effects of the newly described rotavirus 'enterotoxin'.

Adams-Oliver syndrome (AOS) is characterised by aplasia cutis congenita of the scalp and variable degrees of terminal transverse limb defects. Short fingers and hypoplastic nails also occur in this predominantly autosomal dominant syndrome which displays marked variability of expression and lack of penetrance in some cases. We describe a boy with AOS whose sister is also mildly affected. Their mother has hypoplastic fifth toenails which may represent very mild expression of the syndrome. Brain (computed tomography) imaging to investigate mild left hemiparesis in the boy demonstrated severe cortical dysplasia of central, occipital and anterior regions of the right cerebral hemisphere. A variety of brain and cranial malformations has been reported in AOS but dysplasia of the cerebral cortex has not been noted previously. In addition, the boy and his sister have apparent constriction rings present on the toes which are uncommon in AOS.

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.

The records of 20 children with seizures who had cerebral tumor confirmed histologically between 1979 and 1989 have been reviewed. These patients represented 2.9% of all children presenting with seizures. Forty percent were aged 15 months or younger, all of whom presented with partial seizures. Initial misdiagnosis of seizures occurred in 25% of these infants. Examination was normal in 75% of the study group. Behavior disturbance was present in 50%, with deterioration occurring in 60% of these. Electroencephalograms revealed focal abnormalities in 62% and generalized abnormalities in 25% when performed. Cranial ultrasound was performed in two cases, with false-negative results. Computed tomographic scan findings were not diagnostic of tumor in 40%. Magnetic resonance imaging confirmed the presence of tumor in all children in whom it was performed. Tumors most frequently involved the temporal lobes (55%) and the frontal lobes (40%). Surgical intervention resulted in considerable improvement in seizure control in 75%. Surgery is useful in the control of tumor-related seizures and should be considered early in the treatment of this disorder. Suspicion of tumor should increase when seizures are partial or refractory, particularly if intelligence and physical examination are normal or if there is progressive deterioration in behavior. The most appropriate type of brain imaging is magnetic resonance imaging scan.