Hyperekplexia

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Originally released February 17, 1997; last updated July 19, 2017; expires July 19, 2020

This article includes discussion of hyperekplexia, familial startle disease, and startle disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Hyperekplexia (familial startle disease) is a rare paroxysmal neurologic disorder caused by defects in glycinergic neurotransmission. Hyperekplexia is characterized by pathologic and excessive startle responses to unexpected stimuli and severe generalized stiffness. In untreated babies, the muscle stiffening often causes respiratory impairment and apnea that may be fatal. It may cause death in untreated infants. It is the first human disease shown to result from mutations within a neurotransmitter gene. Hyperekplexia is primarily caused by inherited mutations in the genes encoding the postsynaptic glycine receptor (GlyR) alpha1 subunit (GLRA1) in chromosome 5q33-35, the presynaptic glycine transporter GlyT2 (SLC6A5), and the postsynaptic GLRB encoding the beta subunit. Onset may be from the intrauterine life, from birth, or later at any time from the neonatal period to adulthood. In this article, the author details developments in etiology, genetics, and clinical manifestations. Pharmacological treatment of hyperekplexia with clonazepam is often lifesaving. Prolonged stiffness is terminated with simple maneuver of forced flexion of the baby.

Key points

 

• Hyperekplexia is a rare paroxysmal disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden unexpected stimuli.

 

• It is genetically determined, caused by defects in glycinergic neurotransmission.

 

• In babies, the muscle stiffening often causes respiratory impairment and apnea that may be fatal. Clinical symptoms may be apparent even before birth.

 

• Clonazepam is the effective treatment.

 

• A simple maneuver of forced flexion of the baby may be lifesaving when prolonged stiffness impedes respiration.

Historical note and terminology

Excessive startle was identified as leading to seizures by Alajouanine and Gastaut (Alajouanine and Gastaut 1955). It then became clear that a pathological surprise reaction could exist apart from an epileptic seizure. A number of sporadic patients were described by Gastaut and by Gastaut and Villeneuve, who coined the term "hyperekplexia" (Gastaut 1967; Gastaut and Villeneuve 1967) from the Greek word ekplexis, meaning surprise. The presence of a genetically determined autosomal dominant form of abnormal startle associated with other features was described first by Kirstein and Silfverskjold in a family with “emotionally precipitated drop seizure” and later in more detail by Kok and Bruyn and by Suhren and colleagues (Kirstein and Silfverskjold 1958; Kok and Bruyn 1962; Suhren et al 1966). The association of this disorder with the stiff baby syndrome, the neonatal form of hyperekplexia, was later established by Lingam and colleagues and by Cioni and colleagues (Lingam et al 1981; Cioni et al 1993). The disorder was found to be linked to chromosome 5 (Ryan et al 1992a; Ryan et al 1992b), and the gene responsible for the disease, a mutation in the alpha 1 subunit of the inhibitory glycine receptor (GLRA1), was identified by Shiang and colleagues in some but not all patients (Shiang et al 1993). GLRA1 gene was the first gene implicated in hyperekplexia. “Familiar startle disease” is a synonym used for the hereditary form of hyperekplexia.

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