Clinical features and genetic analysis of two siblings with Startle disease in a family of South Italy

Hyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. To date, mutations in 5 genes, including GLRA1, have been reported to cause hyperekplexia. In the present study, we describe clinical and genetic features of 2 Italian siblings with compound heterozygous mutations in GLRA1 gene. The genetic investigation, performed by NGS approach and validated by direct sequencing, revealed, in both probands, compound heterozygous mutations: c.895C>T or p.R299X inherited from the mother and c.587C>A or p.D98E inherited from the father. Until now, these two identified mutations in GLRA1 have not been reported before as compound mutations. Although both compound heterozygous patients and homozygous mutation carriers have been described in the literature for recessive forms of the disease and dominant forms of hyperekplexia have been attributed to mutations within the pore-lining transmembrane segment (TM2) and adjacent regions while recessive forms have been attributed to mutations within the other transmembrane segments (TM1 and TM3), our data are not consistent with these previous studies whereas the p.R299X nonsense mutation was detected in our patients in exon 7, codifying TM3 domain, and exhibited an autosomal dominant inheritance. No mutations were found in other genes known to cause familial hyperekplexia such as GLRB, SLC6A5, GPHN, and ARHGEF9.