GLRA1, GLRB and SLC6A5 genes

Also known as: Familial startle disease; Exaggerated startle reaction; Stiff-baby syndrome; Stiff-man syndrome, Congenital stiff-person syndrome; Kok disease




1. The Disease:

Hereditary hyperekplexia (HPX), an inherited neuronal disorder caused by genetic defects leading to dysfunction of glycinergic inhibitory transmission, is characterized by the clinical core features of exaggerated startle responses to unexpected sensory stimuli and stiffness. Establishing the correct diagnosis early is essential so that proper management may be initiated to alleviate stiffness and reduce the risk of complications, such as potentially life-threatening apnoea during episodes of stiffness.

2. The symptoms:

HPX, a rare and underdiagnosed disorder, manifests immediately after birth and commonly improves with age. Lack of early signs or symptoms does not exclude the diagnosis.

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 or if forced. Stumbling or an unexpected jolt may induce uncontrolled falls (”like a log”) with the risk of serious injuries.

Patients with SLC6A5 mutations were significantly more likely to have had recurrent infantile apnoea than those with GLRA1 mutations. Patients with GLRB and SLC6A5 mutations were more likely to have developmental delay than those with GLRA1 mutations.

3. Actions to take in case of early diagnosis:

  • HPX is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.
  • Clonazepam is the treatment of choice for HPX. The stiffness in the neonatal period and stiffness related to startle diminish with the treatment. Suggested daily doses are 0.01 to 0.1 mg/kg for children and 0.8 mg/d for adults.
  • Other drugs, mostly described in case reports, which have shown variable results include carbamazepine, clobazam, phenytoin, diazepam, valproate, 5-hydroxytryptophan, piracetam, and phenobarbital.
  • 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.
  • Physical and cognitive therapy to reduce the fear of falling and thereby improve walking can be considered; no randomized trials have assessed the effectiveness of such treatment.
  • Attacks of tonic neonatal cyanosis can be stopped by the Vigevano manoeuvre, consisting of forced flexion of the head and legs towards the trunk.
  • Genetic counselling should be offered to at-risk family members.

4. For more information: