Гиперэкплексия: генетикалық себептері мен диагностикасы

Genetic disorder causing an exaggerated startle response

The three main signs of hyperekplexia are generalized stiffness, excessive startle beginning at birth and nocturnal myoclonus. Affected individuals are fully conscious during episodes of stiffness, which consist of forced closure of the eyes and an extension of the extremities followed by a period of generalised stiffness and uncontrolled falling at times. Initially, the disease was classified into a "major" and a "minor" form, with the minor form being characterized by an excessive startle reflex, but lacking stiffness. Wild type glycine receptors are thus presumed to be pentameric heteromers of the alpha 1 and beta subunits, in either a 3:2 or 2:3 ratio. Thus far, the general rule is that mutations causing structurally normal proteins that cannot bind glycine or cannot properly undergo a required conformational change in response to glycine will result in a dominant form of the disease, while mutations that result in truncated or greatly malformed subunits that cannot be integrated into a receptor protein will result in a recessive form. however, the beta subunit is essential for proper receptor localization, through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft. As such, the defects within the GLRB gene show autosomal recessive inheritance.

The SLC6A5 gene encodes the GlyT2 transporter, a neuronal pre synaptic glycine re uptake transporter. In comparison to the GlyT1 transporter, found mostly in glial cells, GlyT2 helps maintain a high concentration of glycine within the axon terminal of glycinergic neurons. Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive inheritance pattern. Defects within this gene are hypothesized either to affect the incorporation of the transporter into the cellular membrane or to affect its affinity for the molecules it transports: sodium ions, chloride ions and glycine. Gephyrin is essential for glycine receptor clustering at synaptic junctions, through its action of binding both the glycine receptor beta subunit and internal cellular microtubule structures. Because of gephyrin's multi functional nature, in mutated form it is not presumed to be a common genetic source of hyperekplexia. Since the ARHGEF9 gene is on the X chromosome, this gene displays X linked recessive heritance. The collybistin protein is responsible for proper gephyrin targeting, which is crucial for the proper localization of glycine and GABA receptors. Deficiencies in collybistin function would result in a lack of glycine and GABA receptors at the synaptic cleft. A combination of electroencephalogram and an electromyogram may help diagnose this condition in patients who have not displayed symptoms as children. The electroencephalogram will not show abnormal activity other than a spike in wakefulness or alertness, while the electromyogram will show rapid muscular responses and hyperreflexia. Otherwise, genetic testing is the only definitive diagnosis. During attacks of hypertonia and apnea, the limbs and head may be forcibly manipulated towards the trunk in order to resolve the symptoms. This is referred to as the "Vigevano maneuver'.

The disorder was first described in 1958 by Kirstein and Silfverskiold, who reported a family with 'drop seizures'. In 1962 Drs. Kok and Bruyn reported an unidentified hereditary syndrome, which initially presented as hypertonia in infants. Genetic analysis within this large Dutch pedigree revealed a mutation within the GLRA1 gene, the first gene to be implicated in hyperekplexia.