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Startle Disease (Hyperekplexia): a Hereditary Disorder with Abnormal Startle, Falling Spells, and Attacks of Spontaneous Clonus

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Startle Disease (Hyperekplexia): a Hereditary Disorder with Abnormal Startle, Falling Spells, and Attacks of Spontaneous Clonus CONTRIBUTION • Startle disease (hyperekplexia): a hereditary disorder with abnormal startle, falling spells, and attacks of spontaneous clonus FREDERICK ANDERMANN, MD; EVA ANDERMANN, MD, PHD; AND DANIEL GENDRON, MD TARTLE is a basic alerting reaction common CASE HISTORIES to all mammals. A rapid reflex not amenable to voluntary control, startle was studied exten- Twenty years ago a mother brought her two daugh- sively by Strauss in 1929,1 and is the subject of ters, who had been diagnosed and treated for epilepsy, S 2 a 1939 monograph by Landis and Hunt and of a more complaining that the older girl was falling when star- recent study by Gogan.3 In the human adult, except for tled. Both girls had a mechanical, broad-based gait minor interpersonal variations, a stereotyped motor which suggested cerebellar dysfunction, but they were pattern is seen consisting of eye blinking; facial grimac- not ataxic; they were hyperreflexic. Since extensive ing; flexion of the head; elevation of the shoulders; and questioning did not solve the problem, a kidney basin flexion of the elbows, trunk and knees. With repeated was dropped to the stone floor and the older girl fell stimulation, the intensity of the surprise reaction de- forward like a log, hit her head on the foot of the metal creases, but it never completely disappears. Tension, examining table, and began to cry. This response was fatigue and heightened expectation of the stimulus far greater than anticipated. The patient, the family, enhance it. The intensity is greater in infancy, when and the examiner were quite mortified, and the girl has the startle reflex appears at the same time as the Moro since always been wary in her neurologist's presence. reflex (an extensor response to sudden stimuli). How- Kirstein and Silfverskiold first described startle dis- ever, startle becomes more noticeable in time, while ease in 1958.6 Two sisters, their father, and the the Moro reflex disappears.4 daughter of one of the sisters suffered from sudden This reflex, so basic to man, can be present in a violent falls precipitated by stress, fright or surprise. pathologically exaggerated form which is always embar- Three of these family members also had nocturnal rassing, sometimes interfering with normal activities; myoclonus. The authors cautiously considered the dis- occasionally, it may even be dangerous. The pathophys- order to represent an unusual, genetically determined iology of startle was recently reviewed by Wilkins et al.5 form of drop seizures. Abnormal, excessive startle is a feature of three distinct conditions (Table I): startle disease (hyperek- Minor and major forms of startle disease plexia), jumping (the "jumping Frenchmen of In a letter to the Lancet in 1962, Kok and Bruyn7 Maine"), and startle epilepsy. The first of these disor- drew attention to a hereditary disease affecting 29 ders, hyperekplexia, is described here. individuals in six generations of a German-Dutch family totaling 127 members. In 1966, Suhren (née Kok), Bruyn and Tuynman8 described this family in From the Montreal Neurological Institute and Hospital, Mon- treal, Quebec, Canada. Address reprint requests to: F.A., Mon- greater detail. The affected individuals had a strikingly treal Neurological Institute, 3801 University Street, Montreal, excessive response to startle elicited by visual, auditory Quebec H3A 2B4. and proprioceptive stimuli that failed to produce a S-54 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 57 SUPPL. Downloaded from www.ccjm.org on December 22, 2013. For personal use only. All other uses require permission. STARTLE DISEASE • ANDERMANN AND ASSOCIATES TABLE 1 It was increased by emotional tension, nervousness, STARTLE DISORDERS OF MAN fatigue, and the expectation of being frightened; alco- Startle disease Startle hol, phenobarbital, and chlordiazepoxide lessened its (hyperekplexia) Jumping epilepsy intensity to some degree. In the major form, there was also transient general- Onset Birth, rarely Variable Variable later ized hypertonia during infancy. As babies, when awak- Excessive startle + + + ened or handled, affected individuals had an immediate Stiffness + - - increase in muscle tone in flexion, which disappeared Generalized + - - hyperreflexia during sleep. This abnormality diminished as sponta- Attacks of + - - neous activity increased during the first year of life. spontaneous Around the time of its disappearance, frequent violent clonus Falling + Rarely With some and often repetitive jerks of the limbs were described as attack the child fell asleep. The jerks could lift the child off patterns the bed. Insecure gait + - + Echolalia - + - Echopraxia - + - Neonatal manifestations - + - Forced obedience The neonatal form of this condition was redescribed Crying out, - + - 9 swearing by Klein et al as a "familial congenital disorder Fighting stance - + - resembling Stiff-Man Syndrome" occurring in 10 indi- Epileptic seizures, Rarely - Sometimes viduals from three generations of a family. The family nonstartle related Epileptogenic EEG Rarely - Usually stressed the onset of stiffness within 4 or 5 hours after abnormality birth, the absence of crawling (with the children Inheritance Autosomal Autosomal Acquired scooting about in a seated position, propelling them- dominant or dominant sporadic with selves with their arms), and some delay in walking. variable Stiffness disappeared during sleep. Difficulty swallowing penetrance and frequent choking were also described. The infants Treatment Clonazepam, Antiepileptic valproic acid drugs had hard, tense shoulder-girdle muscles and their faces were set in a somewhat unhappy and inappropriate expression. Lingam, Wilson and Hart,10 in a second startle response in most normal individuals. The disor- report on the hereditary stiff baby syndrome, suggested der occurred in two forms, both of which usually, but the identity of this condition with startle disease. A not always, started in infancy: a minor form, in which third report, again not identifying the disorder with the the response was only quantitatively different from manifestations of hyperekplexia early in life was pub- normal (ie, the startle response was more violent); and lished by Sander et al.11 a major form, which included additional clinical symp- Infants with startle disease have a high incidence of toms. When startled, patients with the major form umbilical and other hernias, previously noted by Suh- experienced momentary generalized muscular stiffness, ren et al,8 probably related to their hypertonicity. with loss of voluntary postural control causing them to Associated congenital dislocation of the hip has also fall as if frozen with their arms at their sides, unable to been described by Morley et al.12 A boy with a carry out protective movements. As soon as they hit convincing history of hyperekplexia also had a thoracic the ground, muscle tone and control of voluntary meningomyelocele, Arnold-Chiari malformation, and movements returned, and there was never evidence of hydrocephalus.13 While these disorders may have been loss of consciousness. (Although Kirstein and fortuitously associated, the intrauterine hypertonicity Silfverskiod6 did describe, in 1958, brief loss of con- could perhaps be a factor in the development of the sciousness in association with these falls, it was proba- closure defect. Interestingly, the symptoms of hyperek- bly related to concussion.) According to Suhren et al,8 plexia were relieved by surgical decompression of the urinary incontinence may also occur in the major form cervicomedullary region. The association of startle of startle disease, probably due to increased intra- disease with symphalangia has been described by Peter abdominal pressure associated with the extensor spasm. Camfield (personal communication). Apnea due to This abnormal response was almost always present, spasm of respiratory muscles may also occur; in a from the time the affected child first attempted to walk. patient mentioned by Kurczynski, 4 the apnea led to VOLUME 57 SUPPL. CLEVELAND CLINIC JOURNAL OF MEDICINE S-55 Downloaded from www.ccjm.org on December 22, 2013. For personal use only. All other uses require permission. STARTLE DISEASE • ANDERMANN AND ASSOCIATES the child's death. those occurring in familial cases. The incidence of mild retardation or low intelligence in these 12 patients was Phenotypic variations higher than in the general population and similar to Exceptionally, the symptoms of startle disease arise that noticed by Andermann et al16 and by Suhren et later in life. Dooley and Andermann15 recently studied al.8 Nine had nocturnal jerking of the legs. The authors an adolescent boy with normal neonatal history who felt that their patients differed from those described by had developed generalized stiffness making it impossi- Suhren et al,8 though it seems likely that at least a few ble for him to participate in sports, as well as falling had the same disorder but without an obvious family attacks. Rare members of the family described by history. It is also possible that some of these patients Suhren et al8 also had onset of symptoms later than in had excessive startle, as seen in the jumping French- the neonatal period. men of Maine or in related disorders such as latah, The major and the minor forms of startle disease can myriachit or "goosey". The junior author of that report, occur in the same family, as illustrated in the large currently professor of psychiatry in Quebec City, was family reported by Suhren et al,8 or in those reported hy impressed
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