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Hereditary hyperekplexia is a hereditary neurological disorder characterized by excessive startle responses.
ORPHA:3197Classification level: Disorder
- Congenital stiff man syndrome
- Familial startle disease
- Hereditary hyperexplexia
- Kok disease
- Stiff baby syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant or Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: G25.8
- OMIM: 149400 614618 614619 618011
- UMLS: C1835614
- MeSH: -
- GARD: 3129
- MedDRA: -
To date about 150 cases have been reported in the literature.
Hereditary hyperekplexia manifests shortly after birth with violent jerking to noise and touch, and massive and sustained stiffening of the trunk and limbs, clenching fists, and attacks of a high-frequency trembling. Newborns are at risk for sudden infant death due to laryngospasm and cardiorespiratory failure. Stiffness attacks may resemble epileptic seizures, although sleep can reduce or even abolish stiffness and jerking and EEG is normal. In the months after birth, muscle stiffness subsides, but excessive jerking to external stimulation or excitement persists. Motor milestones are often mildly delayed, but intellectual development is usually normal. Affected children walk toddling, and often seek assistance or a hold. Gait disturbance increases when in a hurry, amongst a crowd, or if forced. Stumbling or an unexpected jolt may induce uncontrolled falls (''like a log'') with the risk of serious injuries.
Mutations in the GLRA1 gene (5q32) are found in about 30% of patients with hereditary hyperekplexia (and a considerable number of patients without an obviously affected parent). These mutations are transmitted as an autosomal dominant or recessive trait. The GLRA1 gene encodes the alpha1 subunit of the juvenile neuronal receptor for the inhibitory neurotransmitter, glycine. Mutations of this subunit cause a variety of dysfunctions of the neuronal chloride (Cl-) channel, and therefore hereditary hyperekplexia is regarded as a channelopathy. Mutations in the GLRB, GPHN and SLC6A5 genes (4q31.3, 14q24 and 11p15.2-p15.1) have also been observed.
Diagnosis is based on the clinical signs, molecular genetic testing and electrophysiology.
Differential diagnoses include symptomatic hyperekplexia and spasticity, and epilepsy in perinatal brain damage and metabolic brain diseases, which can be excluded by normal EEG and reduction or abolition of stiffness and jerking with sleep.
Management and treatment
Symptomatic treatment in adults involves clonazepam (1mg per day). In children lower doses are required. Vigabatrin is ineffective. Children gain benefit from repeated trials of physical exercise rather than from established physiotherapies or from resolute or demanding training. Extensive activities on soft or sandy ground are particularly effective. Intervention against incomprehension, mockery or pressure from uninformed teachers, relatives and friends may be required.
In most patients, fear of falling and the toddling gait normalizes in adolescence. However, brisk startle and jerkiness to unexpected stimulation persist lifelong, and a minority of patients suffer phobic anxiety of crossing open spaces and an insecure and hesitating gait disorder.