Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease.

Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor ß subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.

Can prompt treatment of childhood UTI prevent kidney scarring?

The aim of the study reported here was to determine whether kidney scarring after urinary tract infections (UTI) in children can be prevented and to identify the risk factors for developing scars. We identified children in the Northern health region of the UK who had been seen to develop scars, identified as new defects on dimercapto-succinic acid (DMSA) scanning. Risk factors were sought by reviewing case-notes and interviews with parents. Twenty girls were identified whose new scarring was strongly associated with having both vesicoureteric reflux (VUR) and a UTI (p = 0.0001); 19/23 (83%) of kidneys exposed to both of these factors developed scars. Children were much more likely to be febrile (94 vs. 30%, p < 0.0001) or unwell (82 vs. 10%, p < 0.0001) during their earlier UTIs when they were of median age 2.8 years (range 0.3-5.0 years) and did not scar, compared to their later UTIs at age 7.3 years (1.2-12.5 years), when they did scar. However, most patients were treated within 1 day of their symptoms for their early UTIs, compared to a wait >or=7 days for later UTIs (p = 0.001). Being febrile or unwell during a UTI does not predict the development of scars, but prompt treatment appears to prevent scarring in children with VUR.