Hereditary Hyperekplexia Overview

Conditions with an Abnormal, Exaggerated Startle

Complex genetic neurodevelopmental disorders in which an excessive startle response in infants and children can be associated with developmental delay/intellectual disability often resulting from an inborn error of metabolism or brain malformation (with or without microcephaly and/or epilepsy) (Table 1) are distinct from hereditary hyperekplexia and will not be discussed further in this overview.

Acquired causes of excessive startle

• Structural and other causes of brain stem dysfunction can include post-anoxic reticular myoclonus, infarct, hemorrhage, medullary compression, posterior fossa malformations, neurodegeneration (multisystem atrophy, lateral sclerosis), and infectious or autoimmune encephalitis (reviewed in Balint et al [2018]) including multiple sclerosis [Abboud et al 2019].
• Infection. The most important infectious cause is tetanus, a potentially lethal disorder caused by the toxin of Clostridium tetani which degrades synaptobrevin and thereby prevents neurotransmitter release for glycinergic inhibition. The latter is the common end route with HPX, explaining the phenotypic similarities.
• Glycine receptor antibodies (targeting the same protein affected by pathogenic variants in GLRA) are an autoimmune cause of exaggerated startle and stiffness [Hutchinson et al 2008] and may manifest as brain stem encephalitis or a variant of stiff person spectrum disorder (SPSD), such as progressive encephalomyelitis with rigidity and myoclonus [Balint & Bhatia 2016]. However, SPSD is also seen with glutamic acid decarboxylase, amphiphysin, or DPPX antibodies. They share as core features stiffness, spasms, and hyperekplexia (in varying degrees and body distribution). Onset is typically in adulthood, although infantile onset has been described by Damásio et al [2013]. Other features distinguishing SPSD from HPX are the mostly continuous and prominent muscle stiffness, sometimes co-occurring neurologic signs, and often a strong association with other autoimmune diseases.
• Strychnine is a competitive inhibitor of the postsynaptic glycine receptor. Strychnine poisoning causes acute onset of stiffness, spasms, and hyperekplexia.

Startle-Induced Manifestations in Other Disorders

In this diverse group of disorders, the startle reflex itself is not excessive, but rather induces another clinical feature that is more prominent and characteristic than the startle response [Dreissen & Tijssen 2012]. Examples include the following:

• Startle epilepsy (normal startle triggers seizures)
• Paroxysmal kinesigenic choreoathetosis (See PRRT2-Associated Paroxysmal Movement Disorders; startle can be one of many triggers of sudden movements.)
• Creutzfeldt-Jakob disease (See Genetic Prion Disease.)
• Subacute sclerosing panencephalitis

Neuropsychiatric Startle Syndromes

In addition to excessive startling, behavioral and/or psychiatric findings are observed in the following groups of disorders:

• Culture-specific syndromes, in which an exaggerated startle response, evoked by auditory, sensory, or visual stimuli occurs within a community [Meinck 2006]. The initial brief component of the startle reflex is normal, but the secondary orientating response includes abnormal behaviors such as jumps, echopraxia, or echolalia, spontaneous vocalizations including coprolalia, and automatic execution when startled with vigorous commands ("forced obedience").
• Anxiety disorders, functional neurologic disorders
• Tics and Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals