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 21, 2019; expires July 21, 2022

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

Overview

Hyperekplexia is a rare, predominantly hereditary paroxysmal neurologic disorder characterized by pathologic and excessive startle responses to unexpected stimuli, especially loud noise and touch. Onset may be from the intrauterine life, birth, or later at any time from the neonatal period to adulthood. Clinically, there are minor forms with exaggerated startle reflexes only and major forms with excessive startle reflexes, generalized stiffness at birth, and stiffness related to the startle reflex. In untreated babies, the muscle stiffening often causes respiratory impairment and apnea that may be fatal. Hyperekplexia is the first human disease shown to result from mutations within a neurotransmitter gene. It is primarily caused (around 80% of the cases) by inherited mutations in the genes encoding the postsynaptic glycine receptor alpha1 subunit (GLRA1) on chromosome 5q33-35, postsynaptic glycine receptor beta subunit (GLRB) on chromosome 4, and the presynaptic glycine transporter GlyT2 (SLC6A5) on chromosome 11. More uncommon causes of more severe cases are mutations in GPHN on chromosome 14 and ARHGEF9 on X chromosome. Sporadic, nonfamilial cases of hyperekplexia are common and may manifest as ataxia. 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 primarily 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 responses of epileptic or nonepileptic origin have been known for many years (Andermann and Andermann 1988; Bakker et al 2006; Dreissen et al 2012). See also MedLink Neurology articles: Startle epilepsy and Sleep starts.

The term “hyperexplexia” was first coined by Mrs. O Suhren-Kok and associates from Leyden, Netherlands in their monumental study of a “dominant hereditary disease in 25 individuals in the course of 5 generations, characterized by transient congenital hypertonia in the waking state and hypokinesia, a quantitatively abnormal startle reaction occasionally associated with falling, markedly hyperactive brain-stem reflexes, and jerking on falling asleep. In many members of the family inguinal hernias were present. The findings obtained by means of high-speed filming analysis, EEG and EMG examinations, are presented, and interpreted as indicating the dominance of an uninhibited primitive nociceptive reflex pattern due to deficient maturational control by higher nervous system activity, and subserved by a fairly direct pathway from the central sensory nuclei to the a-moto-neurons” (Kok and Bruyn 1962; Suhren et al 1966).

Prior to this, Kirstein and Silfverskjold had described 4 members of 3 generations of a Swedish family with violent falls triggered by fright, stress, unexpected stimuli, or surprise (Kirstein and Silfverskjold 1958).

A review and a 60-year follow-up of this family has been reported by Paucar and associates, who also found that this was due to the R271Q mutation in the GLRA1 gene (Paucar et al 2018). The term hyperxplexia was later corrected to hyperekplexia (from the Greek word ekplexis, meaning surprise; hyper is to emphasize excessive) by Gastaut and Villeneuve in a report describing sporadic cases (Gastaut and Villeneuve 1967).

Hereditary hyperekplexia 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 was the first neurotransmitter gene implicated in hyperekplexia.

Stiff baby syndrome is the neonatal form of hyperekplexia (Lingam et al 1981; Cioni et al 1993) though the term stiff baby syndrome has also been used for ATAD1-related lethal encephalopathy manifesting with hypertonia, absence of spontaneous movements, almost no motor development, and death within the first months of life (Wolf et al 2018).

For the discovery of other genes involved in hyperekplexia (SLC6A5, GLRB, GPHN, and ARHGEF9) see Etiology section.

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