Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.

AIM: The aim of the study was to determine clinical and genetic characteristics of Japanese patients with hyperekplexia. METHOD: Clinical courses, responses to antiepileptic drugs, outcomes, and genetic testing were investigated in 17 Japanese patients (nine males, eight females, median age 1y, range birth-45y) with hyperekplexia. RESULTS: In all patients, muscle stiffness and startle responses appeared soon after birth. Only seven patients were diagnosed with hyperekplexia before 1 year of age. Seven patients had been misdiagnosed with other disorders such as epilepsy and adult-onset anxiety neurosis. Umbilical/inguinal hernias were seen in 10 patients. Life-threatening events were noted in four patients. Clonazepam was the most effective drug. Muscle stiffness completely disappeared in 12 patients before 5 years of age, whereas startle responses resolved in only three patients. Mutations in the GLRA1 and GLRB genes were identified in 16 patients and one patient respectively. In 14 patients, the mutation showed autosomal dominant inheritance; in the other three, inheritance was autosomal recessive. p.R271Q of GLRA1 was the most frequent mutation, found in 10 patients. Novel mutations, p.A272P and p.A384P of GLRA1, were detected. Clinical severity and outcome varied even in the same family. INTERPRETATION: Early correct diagnosis is essential for prevention of accidental injuries and to provide appropriate treatments for hyperekplexia. Clonazepam is effective, although the time taken for startle responses to resolve varied.

A 14-year-old girl with hyperekplexia having GLRB mutations.

Hyperekplexia manifests as generalized stiffness and an excessive startle reflex to stimuli. It starts in the neonatal period and is transmitted in many cases via autosomal dominant inheritance. The etiology is an abnormality of the glycinergic neurotransmission system that is involved in inhibitory neurotransmission. Aberrations of five genes related to this neurotransmission system have been identified. The patient was a 14-year-old girl with mild mental retardation. None of her family members had a neuromuscular disease. An excessive startle reflex and generalized stiffness were noted immediately after birth and she was diagnosed with epilepsy because epileptic discharges were observed. However, the disease was resistant to various antiepileptic drugs and the startle responses persisted. GLRB gene mutations (R50X/Q216fsx222) were identified, after which the patient was diagnosed with hyperekplexia. The startle reflex improved when clonazepam treatment was initiated. When patients have a persistent startle reflex, it is necessary to consider hyperekplexia, even if epileptic discharges are observed. Only four cases with GLRB mutations, including the present patient, have been reported. To make a definite diagnosis of hyperekplexia, it may be useful to screen for genes that are involved in the glycinergic neurotransmission system.