Hyperekplexia 1

A number sign (#) is used with this entry because hyperekplexia-1 (HKPX1) is caused by heterozygous, homozygous, or compound heterozygous mutation in the GLRA1 gene (138491) on chromosome 5q32.

Description

Hyperekplexia is an early-onset neurologic disorder characterized by an exaggerated startle response to sudden, unexpected auditory or tactile stimuli. Affected individuals have brief episodes of intense, generalized hypertonia in response to stimulation. Neonates may have prolonged periods of rigidity and are at risk for sudden death from apnea or aspiration. Many affected infants have inguinal hernias. The symptoms tend to resolve after infancy, but adults may have increased startle-induced falls and/or experience nocturnal muscle jerks (summary by Ryan et al., 1992).

Genetic Heterogeneity of Hyperekplexia

See also HKPX2 (614619), caused by mutation in the GLRB gene (138492) on chromosome 4q31; HKPX3 (614618), caused by mutation in the GLYT2 gene (SLC6A5; 604159) on chromosome 11p15; and HKPX4 (618011), caused by mutation in the ATAD1 gene (614452) on chromsome 10q23.

Hyperekplexia can also occur in early infantile epileptic encephalopathy-8 (EIEE8; 300607), caused by mutation in the ARHGEF9 gene (300429).

See also sporadic stiff-man syndrome (184850) and the 'Jumping Frenchmen of Maine' (244100).

Clinical Features

Ryan et al. (1992) suggested that this disorder was first described by Kirstein and Silfverskiold (1958), who reported a 'family with emotionally precipitated drop seizures.'

Suhren et al. (1966) described a family in which 25 persons spanning 5 generations with numerous instances of male-to-male transmission had transient congenital hypertonia that disappeared with sleep; hypertonia diminished during the first year of life. Later in life, affected individuals showed greatly exaggerated startle responses, which were sometimes associated with falling, markedly hyperactive brainstem reflexes (e.g., head retraction, palmomental and snout reflexes), and a momentary generalized jerking on falling asleep. The authors suggested an uninhibited nociceptive reflex pattern as a result of a defect in maturation. Barbiturate medication resulted in improvement. See also Kok and Bruyn (1962) (Kok and Suhren are the same person Went, 1974).

Klein et al. (1972) reported a family in which 10 persons spanning 3 generations had a congenital form of stiff-man syndrome. Affected members had attacks of stiffness precipitated by surprise or minor physical contact and characterized by difficulty in making sudden movements; signs of myotonia or myokymia were not present. During the episodes, EMG showed continuous activity at rest with normal action potentials. The continuous electrical activity was abolished by diazepam. X-linkage could not be excluded because there was no male-to-male transmission. Sander et al. (1980) reported a large family with dominantly inherited congenital stiff-man syndrome. Affected infants were hypertonic at birth, but their tone became almost normal by 3 years of age. Stiffness reappeared at adolescence, often precipitated by sudden movement or cold. Sander et al. (1980) stated that the inherited form of the disorder is benign and that the sporadic form is more severe.

Lingam et al. (1981) reported an affected family and suggested the term 'stiff-baby syndrome.' They noted that affected infants tend to look alert, frightened, and tense, and have a tendency to vomit due to hiatal hernias.

In a family described by Morley et al. (1982), affected persons showed flexor hypertonia and hypokinesia during infancy. Later and throughout life, they showed an exaggerated startle reaction with involuntary myoclonus (occasionally resulting in a fall) and marked nocturnal myoclonic jerks. Morley et al. (1982) noted a high frequency of congenital dislocation of the hip and of inguinal hernia. The neurologic features could be controlled with clonazepam. Markand et al. (1984) examined 12 of 15 affected members of the family reported by Morley et al. (1982). Startles were best elicited by lightly touching the patient's nose, clapping or making other noises, or suddenly jolting the patient's chair. Electrophysiologic studies found a prominent C response 60 to 75 ms after median and peroneal nerve stimulation. The authors suggested that hyperactive long-loop reflexes may be the physiologic basis for the exaggerated startle.

Saenz-Lope et al. (1984) identified the disorder, which they referred to as 'hyperekplexia,' in 5 of 7 children (3 brothers and 2 sisters) born to unrelated parents. No other members of the family were affected. Clonazepam was ineffective, whereas valproic acid, 5-hydroxytryptophan, or piracetam markedly reduced the abnormal startle.

Ryan et al. (1989) identified a 5-generation kindred in which 30 of 52 persons at risk were affected with this disorder. Continuous and occasionally fatal muscular rigidity was present in infancy and electromyography showed continuous motor unit activity. An exaggerated startle response persisted throughout life; sudden, unexpected acoustic or tactile stimuli could precipitate a brief attack of intense rigidity with falling. Umbilical and inguinal hernias, presumably due to increased intraabdominal pressure, were common, as was nocturnal myoclonus. Dramatic improvement of symptoms followed treatment with clonazepam. Based on EMG findings, Ryan et al. (1989) concluded that startle disease and hereditary stiff-man syndrome are identical disorders.

Hayashi et al. (1991) reported 2 unrelated Japanese families with hyperekplexia. The 9 affected members had various combinations of transient infantile hypertonia and hypokinesia, exaggerated startle response with falling episodes, nocturnal myoclonus, an easily elicited head retraction reflex, hip dislocation, and umbilical hernia. Treatment with clonazepam was effective in infants and children.

Dubowitz et al. (1992) reported the case of a newborn infant with classic features of startle disease in whom the cerebrospinal fluid concentrations of gamma-aminobutyric acid (GABA) were substantially lower than normal during the first weeks of life. She improved greatly on clonazepam treatment. Dubowitz et al. (1992) suggested that the signs of this disorder may be due to a genetic defect or to delayed maturation resulting in low CSF GABA. The disorder may be confused with seizure disorder, but it does not have concomitant discharges on EEG.

Milani et al. (1996) demonstrated a variable combination of clinical signs of hereditary hyperekplexia in an Italian family. The 1-year-old proband had excessive startle response, muscular hypertonia, and a continuing flexion state, whereas only startle response during early infancy was found in the mother, aged 30 years. The proband's second cousin died at the age of 45 days from apnea following myoclonic fits, and her father displayed hypertonia and muscle stiffening. No history of infantile hypertonia was recorded in the grandparents of either the proband or the affected second cousin. In affected members of this family, Milani et al. (1996) identified a mutation in the GLRA1 gene (138491.0005).

Inheritance

Hyperekplexia-1 shows both autosomal dominant (Shiang et al., 1993) and autosomal recessive inheritance (Rees et al., 1994).

Mapping

Ryan et al. (1992) studied a 5-generation family with startle disease and successfully treated 16 affected members, including 1 neonate, with clonazepam. Linkage analysis demonstrated tight linkage of the disorder with CSF1R (164770), which is located at 5q33.2-q33.3 (maximum lod of 7.10 at 3% recombination). The authors suggested that neurotransmitter receptors encoded by genes in the subtelomeric region of 5q are likely candidates for the site of the mutation in this disorder. Clonazepam acts through gamma-aminobutyric acid type A receptors; the GABRA1 gene (137160) is located at 5q34-q35 and the GABRG2 (137164) gene at 5q31.1-q33.1. In a later study, Ryan et al. (1992, 1992) performed linkage analysis in the original family and 3 additional affected pedigrees with 5q microsatellite markers and placed several of the most closely linked markers on an existing radiation hybrid map of the region. The results provided strong evidence for genetic locus homogeneity and assigned the hyperekplexia locus to a 5.9-cM interval defined by CSF1R and D5S379, which are separated by a radiation hybrid (RH) map distance of 74 centirays (approximately 2.2-3.7 Mb). RH mapping eliminated the candidate genes GABRA1 and GABRG2 by showing that they are telomeric to the target region.

Molecular Genetics

In affected members of 4 families with autosomal dominant hyperekplexia, 2 of whom were reported by Ryan et al. (1992), Shiang et al. (1993) identified 2 heterozygous mutations in the GLRA1 gene (138491.0001-138491.0002).

In a sporadic patient with startle disease, the offspring of a consanguineous marriage, Rees et al. (1994) identified a homozygous mutation in the GLRA1 gene (138491.0003). The phenotype was indistinguishable from that of dominant inheritance of GLRA1 mutations.

In affected members of 2 consanguineous Turkish Kurd families with hyperekplexia, Siren et al. (2006) identified a large homozygous deletion, which included exons 1 to 7 of the GLRA1 gene (138491.0013). The deletion breakpoints were determined to be the same as those reported by Gilbert et al. (2004) in another affected Turkish Kurd family. Siren et al. (2006) suggested a founder effect.

Associations Pending Confirmation

For discussion of a possible role of variation in the gephyrin gene (GPHN; 603930) in hyperekplexia, see 603930.0002.

Animal Model

Feng et al. (1998) found that mice mutant for gephyrin (603930) exhibited a phenotype similar to that of humans with hyperekplexia.

Mice homozygous for the 'spastic' (spa) mutation display a complex motor disorder with phenotypic features of hyperekplexia. In spa mice, Mulhardt et al. (1994) found aberrant splicing of the Glrb gene resulting in a truncated mRNA. The mouse mutant phenotype 'spasmodic' (spd), caused by mutation in the Glra1 gene, is inherited as a recessive and is phenotypically similar to hyperekplexia, including an altered startle response (Buckwalter et al., 1994).