Physiological studies of spinal inhibitory pathways in patients with hereditary hyperekplexia

Hereditary hyperekplexia, also known as startle disease, is an unusual movement disorder characterized in infancy by increased muscle tone and excessive startle. ^[1,2] During childhood, the muscle tone improves, but prominent startle responses to noises, unexpected movements, or touch persists into adult life, frequently resulting in unchecked falls and injuries. Some adults complain of a sense of muscle stiffness or slowness, particularly when walking, although muscle tone may be normal during passive movement. Many of these symptoms can be alleviated with clonazepam, a benzodiazepine. ^[3]

The disorder is frequently inherited in an autosomal-dominant manner, and in careful linkage studies of affected families a genetic defect on chromosome 5 was mapped. ^[3] Through physiologic studies over the past few years investigators found that the hallmark of this disease, the excessive startle response, is an exaggeration of the normal startle reflex. ^[4,5] Matsumoto et al ^[5] noted excessive excitability of several vestigial withdrawal reflexes and suggested that hyperekplexia is a disease of ``widespread neural hyperexcitability in normal pathways, the most prominent of which is the startle circuit.'' ^[1] Shiang et al ^[6] identified the defect in four families with hyperekplexia as a point mutation in the alpha₁ subunit of the strychnine-sensitive glycine receptor, a multisubunit chloride ion channelreceptor complex. This mutation results in a single amino acid substitution that alters glycine binding to the receptor. ^[7] This class of glycine receptors is most abundant in the lower brainstem and spinal cord and is expressed by neurons in the intermediate gray and motor neurons. ^[8]

In animals, glycine is a neurotransmitter used by several classes of spinal interneurons that inhibit motor neurons, including Renshaw cells, Ia inhibitory interneurons, ^[9,10] and some classes of Ib interneurons. These interneurons are thought to mediate several types of inhibition of stretch reflexes in humans, including recurrent …