Sep. 27, 2023
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Hyperekplexia is a rare, predominantly hereditary neurologic disorder characterized by pathologic and excessive startle responses. Onset varies from the perinatal period through adulthood. Hyperekplexia may be inherited, sporadic, or acquired and is divided clinically into minor and major forms. Minor forms may present with exaggerated startle reflexes alone, whereas major forms are defined by the clinical triad of generalized stiffness at birth, excessive startle reflexes, and prolonged generalized stiffness related to the startle reflex. In untreated babies, truncal stiffening may cause respiratory impairment and apnea with fatal consequences. Hyperekplexia is the first human disease shown to result from mutations within a neurotransmitter gene. It is primarily caused 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. 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. Prolonged stiffness in infants is terminated with the simple maneuver of forced flexion. Pharmacological treatment of hyperekplexia with clonazepam is often life altering. In this article, the author details developments in etiology, genetics, clinical manifestations, and treatment.
• Hyperekplexia is a rare disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden unexpected stimuli with major and minor forms.
• It is primarily caused by genetic defects resulting in aberrant glycinergic neurotransmission.
• In infants, prolonged hypertonia causes respiratory impairment and potentially fatal apnea, though symptoms may be apparent as early as the third trimester of pregnancy.
• A simple maneuver of forced neck flexion may be lifesaving when prolonged stiffness impedes respiration.
• Clonazepam is the most effective treatment.
Excessive startle responses of epileptic or nonepileptic origin have been known for many years (03; 14; 13). See also MedLink Neurology articles: Startle epilepsy and Sleep starts.
The first description of hyperekplexia was published by Kirstein and Silfverskjold in 4 members of 3 generations of a Swedish family with violent falls triggered by fright, stress, unexpected stimuli, or surprise (16).
Soon thereafter, Suhren, Kok, and Bruyn described 29 affected individuals in 6 generations and later coined the term “hyperexplexia” in the monumental work “Hyperexplexia, A Hereditary Startle Syndrome” (18; 37). The term hyperexplexia was later corrected to hyperekplexia (from the Greek word ekplexis, meaning surprise; hyper to emphasize excessive) by Gastaut and Villeneuve in a report describing sporadic cases (12).
It wasn’t until the 1990s that Ryan and colleagues linked the disease to chromosome 5q, later identified by Shiang and colleagues as a mutation in the alpha 1 subunit of the inhibitory glycine receptor (GLRA1) (31; 32; 35). A review and a 60-year follow-up of Kok’s described family reported by Paucar and associates attributed their disease to the R271Q mutation in the GLRA1 gene (29).
“An autosomal dominant congenital disorder resembling stiff-man syndrome” was described in 1972 and was later named hereditary stiff-baby syndrome by Lingam in 1981, though these disorders actually represent the neonatal form of hyperekplexia (20; 41). 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 (44). This phenotype was assigned the name hyperekplexia-4 (HKPX4, #618011) in OMIM despite its genetic, pathophysiologic, and prognostic differences from the other forms discussed in this article (33). It is important to distinguish these and other genetic encephalopathies and epileptic disorders as treatment and prognosis differ.
For the discovery of other genes involved in hyperekplexia (SLC6A5, GLRB, GPHN, ARHGEF9, and others) see Etiology section.
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