Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
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.
• 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.
Excessive startle responses of epileptic or nonepileptic origin have been known for many years (01; 03; 12). 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” (20; 39).
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 (18).
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 (31). 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 (16).
Hereditary hyperekplexia was found to be linked to chromosome 5 (33; 34), 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 (37). GLRA1 was the first neurotransmitter gene implicated in hyperekplexia.
Stiff baby syndrome is the neonatal form of hyperekplexia (23; 07) 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 (46).
For the discovery of other genes involved in hyperekplexia (SLC6A5, GLRB, GPHN, and ARHGEF9) see Etiology section.
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.