American Journal of Medical Genetics 40138-143 (1991)
Hyperekplexia: Pedigree Studies in Two Families Takashi Hayashi, Hidetoshi Tachibana, and Tadashi Kajii Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan
We report on 2 unrelated Japanese families, each with several individuals affected with hyperekplexia, a rare autosomal dominant form of exaggerated startle response of neonatal onset. In the first family, affected relatives included a 4-week-old boy, his mother, grandmother, a maternal uncle, and 2 maternal cousins. In the second family, affected were a 4-week-oldboy, his father, and an elder brother. These 9 individuals had various combinations of transient infantile hypertonia and hypokinesia, exaggerated startle response with falling episodes, nocturnal myoclonus and an easily elicited head retraction reflex, hip dislocation, and umbilical hernia. Treatment with clonazepam was effective in relieving these manifestations in the affected infants and children. Genetic analysis of these 2 families and 4 others in the literature suggests autosomal dominant inheritance with considerable variability but complete penetrance. Another 3 families in the literature were reported, suggesting the existence of startle disorder with an autosomal recessive inheritance. A sporadic case is also known, presumably representing a fresh mutation of a dominantly inherited trait. KEY WORDS: autosomal dominant, startle response, head retraction reflex INTRODUCTION Hyperekplexia is an autosomal dominant disorder with a pathologic startle response first reported by Kirstein and Silfverskiold [ 19581. The disorder manifests itself with transient hypertonia and hypokinesia in infancy. Later in life there are manifestations of an exaggerated startle response, which often results in frequent
Received for publication October 27, 1989; revision received October 2, 1990. Address reprint requests to Takashi Hayashi, M.D., Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi 755, Japan.
0 1991 Wiley-Liss, Inc.
falls without loss of consciousness, nocturnal myoclonus, and exaggerated brain stem responses, especially of the head retraction reflex. Since the report of Kirstein and Silfverskiold [ 19581, 3 additional families have been reported, each with multiple affected relatives [Suhren et al., 1966; Morley et al., 1982; Kurczynski, 19831. Another 3 families with hereditary startle disorder, also were reported in the literature, suggesting a recessive form [Andermann et al., 1980; Saenz-Lopeet al., 1984; Dalla Bernardina et al., 19881. We describe here the clinical, genetic, and neurological aspects of hyperexplexia in 9 affected individuals from 2 unrelated Japanese families. We attempt to classify this disorder based on its genetic aspects. CLINICAL REPORTS AND FAMILY HISTORIES The pedigrees of the 2 families are presented in Figure 1, and the clinical findings of all affected relatives are summarized in Table I. Family 1 Individual IV-8. The propositus (850405)was born after an uneventful pregnancy and delivery. Flexor hypertonia with little spontaneous movements, a staccato cry, and feeding difficulties were noted neonatally (Fig. 2). The hypotonia lessened during sleep, which was shallow, and he was easily awakened by minor stimuli. His serum creatine kinase level was 2,290 U (normal range 44 U to 260 U) at age 3 days. When first seen by us at 4 weeks, he had an umbilical hernia (Fig. 21, muscular hypertonia, little spontaneous movements, a head retraction reflex easily elicited by tapping on the tip of the nose, and an abnormal Moro reflex consisting of continued flexion state without an abduction-extension phase. Neither exaggerated tendon reflexes nor myotonia was noted. Electroencephalograms were normal both awake and asleep. The auditory brainstem response and visual evoked potentials were normal. A surface electromyographic study of the Moro reflex revealed persistent tonic contraction, followed by prolonged phasic contraction in the antagonists of the arms and neck. There was no muscle activity at rest on the needle electromyographic study. Individual IV-1. A girl was the maternal cousin of the propositus. Hypertonia and poor feeding were noted in early infancy, although both lessened gradually during the first year. Bilateral hip dislocation was also noted in early infancy. She started to walk at age 18
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Hayashi et al. TABLE I. Clinical Data of 9 Individuals In The 2 Families Family 1 Family 2 IV-8 IV-1 IV-2 111-7 111-1 11-3 111-3 111-2 11-3Propositus Cousin Cousin Mother Uncle Grandmother Propositus Brother Father M F M F M F M M M 44 66 4 wk 2 29 38 -
Relationship Sex Age at first examination (yr) Clinical manifestations Infantile hypertonia Umbilical or inguinal hernia Hip dislocation Exaggerated startle response Fall Sleep myoclonus Hyperreflexia Head retraction reflex Abnormal gait Effective clonazepam Mental retardation Improvement during adolescence Electrophysiological examinations EEG abnormalities Evoked response abnormalities Auditory brainstem response Visual evoked potential Somatosensory evoked potential Electromyographic abnormalities a
-
-
+ + + ++-
-
+-
+ + +-
+ -
-
-
+
+
NEa
-
NE NE
NE NE
NE
NE
NE
NE
NE; not examined.
Fig. 2. Propositus of family 1, age 4 weeks. Muscular hypertonia when horizontally suspended.
months. She showed an excessive startle response and tended to fall. During a fall, she was unable to protect herself, and with her arms extending downward, she would hit her face on the ground. In order to prevent a fall, she began to walk touching a wall. Neurological examination at age 13 years disclosed a n excessive startle response, prominent nocturnal myoclonus, and head retraction reflex. The nocturnal myoclonus consisted of short-lasting synchronous
generalized contraction in all muscles. It occurred predominantly in dropping off to sleep. The tendon reflexes and muscle tone were normal. She showed a normal forward, sideways, and backward parachute reaction. Her intelligence was normal. All electrophysiological studies, including somatosensory evoked potential, showed normal patterns. Individual IV-2. IV-2 is the younger brother of IV-1. Hypertonia and feeding difficulties were noted during his infancy. Exaggerated startle responses and occasional falling attacks have been noted since he started to walk a t age 12 months. Frequent falling episodes made him withdrawn. He did not participate in sport activities. Muscle biopsy at age 4 years showed no specific abnormalities. When first seen by us a t age 10 years, he showed a head retraction reflex elicited by tapping the philtrum, a n exaggerated startle response, and nocturnal myoclonus. Muscle tone, muscle strength, and deep tendon reflexes were normal. Electrophysiological studies were normal. An electromyographic study showed neither myotonic, nor myogenic, nor neurogenic discharge. Continuous muscle fiber activities were not recorded. Other affected individuals. The mother of the propositus (111-7) and her elder brother (111-1)both had exaggerated startle responses, sleep myoclonus, and an easily elicited head retraction reflex, but both were without a history of infantile hypertonia or hypokinesia. In childhood, they both suffered from frequent falling episodes, which lessened after puberty. The maternal
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141
grandmother of the propositus (11-3)had a head retraction reflex, but no other abnormal neurological findings. The mother was treated in infancy for bilateral hip dislocation. The uncle had an inguinal hernia in infancy.
trophysiological studies were normal. The exaggerated startle response was recorded on the electroencephalograph, but without spike discharges. On a needle electromyographic study, there was no continuous activity at rest. Treatment with clonazepam produced a decrease in the muscle tone and an improvement in feeding. Clonazepam Treatment Other affected individuals. The elder brother of The propositus (IV-8) and his 2 cousins (IV-1 and the propositus (111-2) had a history of infantile hyperIV-2)were treated with 0.1 mg/kg/day clonazepam. The tonia. Their father (11-3)showed a head retraction reflex. propositus was 2 months old when treatment was began. Electrophysiological studies of the brother showed no The treatment removed hypertonia and feeding diffi- abnormalities. culties within a few days. Now a t age 4 years and still on the medication, he leads a normal life without episodes DISCUSSION of abnormal startle or falling. Both IV-1 and IV-2 have been free from falling attacks since clonazepam was Startle “disease” is a non-epileptic disurder with exstarted. IV-2 even won a long-distance running race at cessive startle reaction provoked by unexpected visual, school. Their startle responses have lessened markedly, tactile, or auditory stimuli. Numerous patients have but their head retraction reflex has remained un- been reported in the literature as examples of “hyperexchanged. plexia,” “hyperekplexia,” “neonatal hyperexplexia,”and “congenital stiff-man syndrome.” A few of them had Family 2 positive family history. Thus, startle “disease” may conIndividual III-3. The propositus (0640-64-9)was sist of hereditary and non-hereditary types. Non-heredinoted to be hypertonic at a few days after birth. When tary startle “disease” is caused by organic lesions. seen by us at age 4 weeks, he showed increased deep Hereditary startle disorder has been described in 12 tendon reflexes, transient generalized hypertonia, stiff- families in the literature; 5 families had detailed family ening “like a lead soldier,” and sleep myoclonus. The history [Kirstein and Silfverskiold, 1958;Suhren et al., startle reflex was elicited by weak auditory or tactile 1966; Andermann et al., 1980; Morley et al., 1982; stimuli. Neither myotonic phenomenon nor head retrac- Kurczynski, 19831 (Table 11). Kirstein and Silfverskiold tion reflex was elicited. The Moro reflex elicited a pro- [19581 described a family in Stockholm with 2 sisters, longed flexion state. An EEG (sleep and awake) showed their father, and the daughter of one of the sisters with neither spike discharge nor other abnormalities. Elec- sudden, violent falls precipitated by stress, fright, or
TABLE 11. Clinical Data of 61 Individuals From 6 Families With Hyperexplexia
No. of affected individuals Male Female Clinical manifestations Infantile hypertonia Umbilical or inguinal hernia Hip dislocation Exaggerated startle response Fall Sleep myoclonus Hyperreflexia Head retraction reflex Abnormal gait Effective clonazepam, diazepam or barbiturate Mental retardation Improvement in adolescence Electrophysiological examinations EEG abnormalities Evoked response abnormalities Auditory brainstem response Visual evoked potential Somatosensory evoked potential Electromyographic abnormalities
Present families Familv 1 Familv 2 6 3 3 3 3 0 315 216 216 516 415 415 016 616 215
213 013 013 113 012 113 113 113 012
313
111 012
015
K irstein and Silverskoid rig581 4 1 3
Suhren et al. rig661 24 16 8
Morley et al. [1982] 15 5 10
114
15/17 11/23
919 111
414 414 314
23/23 16/21 7/21
12/12 3/11 6/12 15/15 15/15 12/12
21/21 13/21
212
313
9/10
313
6/12
212 214
0112
Kurczynski [19831 9 5 4
819 819
819
Total (%) 61 33 28 42/50 (84:l 17/44 (39:i 8/21 (391 56/60 (391 47/56 (84) 35/54 (65) 119 (11) 33/35 (94) 15/28 (54) 16/17 (94) 017 8/14 2/28
014
012
013 013
012 012
012
012
417
4/11 (36)
012
011
013
016
015
015
142
Hayashi et al.
surprise. Three of these family members also had nocturnal myoclonus. Suhren et al. 119661reported a Dutch family in which 24 individuals through 4 generations were affected,and coined the term “hyperexplexia.”The correct Greek spelling is hyperekplexia and not hyperexplexia, ((asthe printers’ devil had it in the original report” [Bruyn, 19811. Suhren et al. [19661 proposed that this condition was characterized by the following cardinal symptoms: 1)a hereditary, abnormally exaggerated startle-reaction with occasional falling, 2) transient congenital hypertonia and hypokinesia, 3) unusually active brainstem reflexes, 4)jerking on dropping off to sleep. Morley et al. [1982]reported a family in Indiana with 15 affected individuals through 5 generations, and Markand et al. 119841 carried out electrophysiologic evaluation of 6 of the 15 affected members. Kurczynski [19831 described a family in Ohio with 9 affected individuals through 5 generations. Dooley and Andermann [19891 described a 13-year-old boy with an adolescent onset of startle “disease.” His brother and a granduncle were also affected t o a lesser degree, whereas the parents were apparently unaffected. This family thus may represent a dominant form of startle disease with incomplete penetrance. These reports did not describe details enough to analyze their pedigrees. In view of this, these families were not included in Table 11. Adding the 2 families we described, altogether 6 families are now known with the disorder (Table 11). These 6 pedigrees together contained 34 male and 28 female affected individuals among the 189individuals listed. Their sex ratio was 1.21, not significantly different from parity. Their clinical manifestations were highly variable. The trait was vertically transmitted through 2 to 5 generations. No consanguinity was observed in the 6 families. The segregation ratio (P = 0.551 ? 0.071 calculated with single incomplete ascertainment [Emery, 19861) was not statistically different from even. Male-to-male transmission was observed repeatedly. These findings indicate that the disorder is an autosomal dominant trait with variable expressivity and nearly complete penetrance. Andermann et al. [19801reported a French-Canadian family in Quebec with a hereditary startle disorder. The affected individuals of the family had symptoms common with the previous described dominant form. However, they did not have massive myoclonicjerk in sleep state, but repeatedly clonic jerks of limbs, especially in legs, even in the daytime. These symptoms were different from those described by Kirstein and Silfverskiold [1958], Suhren et al. [19661, Morley et al. [19821, and Kurczynski [19831. Our patients did not have repeated clonicjerks of the legs. In the family described by Andermann et al. [1980], there were 5 individuals affected through 3 generations. However, only 2 of them, the proband and her sister, showed some cardinal symptoms. The other 3 individuals, with the so-called minor form proposed by Andermann’s report, did not show any cardinal symptoms and their detailed clinical manifestations were not described. In view ofthis, the Andermann family was not included in pedigree analysis. Another type of hereditary startle disorder may be present, such as that of the families described by Saenz-
Lope et al. [1984] and Dalla Bernardina et al. [1988]. Saenz-Lope-et al. [19841 reported a family with 5 affected sibs with nocturnal jerking of legs, ages 6 to 23 years, of apparently unaffected parents. An affected parent in the family may have been overlooked, given the highly variable expression of the disorder. Alternatively, they may represent a recessive form of startle disorder. Dalla Bernardina et al. [19881and Vigevano et al. [1989] reported 6 patients with “neonatal hyperexplexia,” of whom 2 were sisters. No details were mentioned of their family members. The mode of inheritance of the disorder is thus either autosomal recessive or dominant with incomplete penetrance. This suspected recessive form of startle “disease”had symptoms similar to the dominant form without myoclonic jerk. The affected individuals with the probable recessive form were characterized by repeated jerkings of limbs for a few minutes and some of them had generalized clonic myoclonic fits accompanied by apnea and cyanosis. We speculate that the family of Andermann may have the recessive form of startle disorder. Unfortunately, the families of Saenz-Lope et al. and Dalla Bernardina et al. were not described in detail. Thus, the pedigree analysis could not be performed. Congenital stiff-man syndrome is an autosomal dominant startle disorder. Its clinical manifestations are similar to hypereplexia in that sudden environmental stimuli provoke muscle stiffening and occasional falling. Stiff-man syndrome was originally thought to be a disorder of adult onset [Gordon et al., 19671, but a congenital form has been reported with apparent autosomal dominant inheritance [Klein et al., 1972;Sander et al., 19791. The presence of continuous electromyographic potentials at rest distinguishes the disorder from the dominant form of startle disorder. Such abnormal potentials were not recorded in the 6 affected individuals tested in our families. Of the 66 individuals with hyperexplexia in the literature, 3 individuals were studied with surface electromyography [Andermann et al., 1980;Morley et al., 19821and another 2 individuals with needle electromyography [Morley et al., 1982; Kurczynski, 19831. None of them showed continuous electromyographicpotentials during muscle relaxation. Some sporadic cases are probably new mutations of a dominantly inherited gene. The other sporadic cases are probably caused by organic brain lesion [Fariello et al., 1983;Winston, 19831. We separate and classify the startle disorders (Table 111)based on our patients and those in the literature. The affected children in the 2 families we described were successfully treated with clonazepam, a serotonin agonist. Clonazepamhas been effective in the treatment of not only hyperekplexia, but also of Tourette syndrome, and startle-induced epileptic seizures. Thus, Andermann et al. [19801implied the existence of a common pathophysiology of all startle disorders, such as a serotoninergic mechanism. However, clonazepam was ineffective in some cases [Kurczynski, 1983;Saenz-Lopeet al., 19841. In some others, drugs such as valproic acid, piracetam, barbiturate, or phenobarbital were helpful [Kirstein and Silfverskiold, 1958; Suhren et al., 1966; Saenz-Lope et al., 1984;Dooley et al., 19891. The neuro-
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143
TABLE 111. SeDarations and Classifications in Startle Disease Hyperexplexia Autosomal dominant form Hereditary startle disease
Hyperekplexia
Hayashi, 1991
Autosomal recessive form
Hypere kplexia Neonatal hyperexplexia
L
Non-hereditary startle diease
Klein, 1972 Lingam, 1981 Sander. 1979
Congenital stiffm a n syndrome Hyperexplexia
Startle diease
I
Kirstein, 1958 Suhren, 1966 Morley, 1982 Kurczynski, 1983
Sporadic case of hereditary startle disease
I
Secondary startle disease caused by organic lesion
-E
Andermann, 1980 Saenz-Lope, 1984
Dalla Bernardina, 1988
- Gastaut, 1967 Fariello, 1983 Winston, 1983
Unknown etiological startle disease
pathological mechanisms of startle disorders thus remain unknown. In conclusion, hereditary startle “disease” is an autosoma1dominant disorder with variable expressivity, but there may be a recessively inherited form. Further studies on well-defined families are needed in order to settle the dispute.
ACKNOWLEDGMENTS We thank Dr. N. Niikawa for his advice on segregation analysis of the pedigrees studied, Dr. Andermann for critical comments, and Dr. B. Dalla Bernardina for providing us with related references. REFERENCES Andermann F, Keene DL, Andermann E, Quesney LF (1980): Startle disease or hyperekplexia. Further delineation of the syndrome. Brain 103:985-997. Bruyn GW (1981): Hyperekplexia (startle disease). In Vinken PJ, Bruyn GW (eds):“Handbook of Clinical Neurology,”Vol42. Amsterdam: North Holland, pp 228-229. Dalla Bernardina B, Fontana E, Colamaria V, La Selva L, Merlin D, Sgro V, Scarpa P (1988):Neonatal hyperexplexia. In Beaumanoir A, Gastaut H, Naquet R (eds);“Reflex Seizures and Reflex Epilepsies.” Geneve: Editions Medicine & Hygiene, pp 409-414. Dooley JM, Andermann F (1989): Startle disease or hyperekplexia: Adolescent onset and response to valproate. Pediatr Neurol 5:126-127.
Emery AEH (1986): “Methodology in Medical Genetics. An Introduction to Statistical Methods.” Edinburgh: Livingstone, pp 37-54. Fariello RG, Schwartzman RJ,Beall SS (1983):Hyperekplexia exacerbated by occlusion of posterior thalamic arteries. Arch Neurol 40:244-246. Gastaut H, Villeneuve A (1967):The startle disease or hyperekplexia. Pathological surprise reaction. J Neurol Sci 5:523-542. Gordon EE, Januszko DM, Kaufman LA (1967): A critical survey of stiff-man syndrome. Am J Med 42582-599. Kirstein L, Silfverskiold BP (1958):A family with emotionally precipitated “drop seizures.” Acta Psychiatr Scand 33:471-476. Klein R, Haddow JE, DeLuca C (1972): Familial congenital disorder resembling stiff-man syndrome. Am J Dis Child 124:730-731. Kurczynski TW (1983): Hyperekplexia. Arch Neurol 40246-248. Lingam S, Wilson J , Hart EW (1981):Hereditary stiff-baby syndrome. Am J Dis Child 135:909-911. Markand ON, Garg BP, Weaver DD (1984): Familial startle disease (hyperexplexia): Electrophysiologic studies. Arch Neurol 41:71-74. Morley DJ, Weaver DD, Garg BP, Markand 0 (1982): Hyperexplexia: An inherited disorder of startle response. Clin Genet 21:388-396. Saenz-Lope E, Herranz-Tannaro FJ, Masdeu JC, Chacon Pena JR (1984): Hyperekplexia: A syndrome of pathological startle responses. Ann Neurol 15:36-41. Sander JE, Layzer RB, Goldsobel AB (1979): Congenital stiff-man syndrome. Ann Neurol 8:195-197. Suhren 0, Bruyn GW, Tuynman JA (1966): Hyperexplexia. A hereditary startle syndrome. J Neurol Sci 3:577-605. Vigevano F, Di Capua M, Dalla Bernardina B (1989):Startle disease: An avoidable cause of sudden infant death. Lancet 1:216. Winston K (9183):Hyperekplexia relieved by surgical decompression of the cervicomedullary region. Neurosurgery 13:708-710.
Hyperekplexia: Pedigree Studies in Two Families Takashi Hayashi, Hidetoshi Tachibana, and Tadashi Kajii Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan
We report on 2 unrelated Japanese families, each with several individuals affected with hyperekplexia, a rare autosomal dominant form of exaggerated startle response of neonatal onset. In the first family, affected relatives included a 4-week-old boy, his mother, grandmother, a maternal uncle, and 2 maternal cousins. In the second family, affected were a 4-week-oldboy, his father, and an elder brother. These 9 individuals had various combinations of transient infantile hypertonia and hypokinesia, exaggerated startle response with falling episodes, nocturnal myoclonus and an easily elicited head retraction reflex, hip dislocation, and umbilical hernia. Treatment with clonazepam was effective in relieving these manifestations in the affected infants and children. Genetic analysis of these 2 families and 4 others in the literature suggests autosomal dominant inheritance with considerable variability but complete penetrance. Another 3 families in the literature were reported, suggesting the existence of startle disorder with an autosomal recessive inheritance. A sporadic case is also known, presumably representing a fresh mutation of a dominantly inherited trait. KEY WORDS: autosomal dominant, startle response, head retraction reflex INTRODUCTION Hyperekplexia is an autosomal dominant disorder with a pathologic startle response first reported by Kirstein and Silfverskiold [ 19581. The disorder manifests itself with transient hypertonia and hypokinesia in infancy. Later in life there are manifestations of an exaggerated startle response, which often results in frequent
Received for publication October 27, 1989; revision received October 2, 1990. Address reprint requests to Takashi Hayashi, M.D., Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi 755, Japan.
0 1991 Wiley-Liss, Inc.
falls without loss of consciousness, nocturnal myoclonus, and exaggerated brain stem responses, especially of the head retraction reflex. Since the report of Kirstein and Silfverskiold [ 19581, 3 additional families have been reported, each with multiple affected relatives [Suhren et al., 1966; Morley et al., 1982; Kurczynski, 19831. Another 3 families with hereditary startle disorder, also were reported in the literature, suggesting a recessive form [Andermann et al., 1980; Saenz-Lopeet al., 1984; Dalla Bernardina et al., 19881. We describe here the clinical, genetic, and neurological aspects of hyperexplexia in 9 affected individuals from 2 unrelated Japanese families. We attempt to classify this disorder based on its genetic aspects. CLINICAL REPORTS AND FAMILY HISTORIES The pedigrees of the 2 families are presented in Figure 1, and the clinical findings of all affected relatives are summarized in Table I. Family 1 Individual IV-8. The propositus (850405)was born after an uneventful pregnancy and delivery. Flexor hypertonia with little spontaneous movements, a staccato cry, and feeding difficulties were noted neonatally (Fig. 2). The hypotonia lessened during sleep, which was shallow, and he was easily awakened by minor stimuli. His serum creatine kinase level was 2,290 U (normal range 44 U to 260 U) at age 3 days. When first seen by us at 4 weeks, he had an umbilical hernia (Fig. 21, muscular hypertonia, little spontaneous movements, a head retraction reflex easily elicited by tapping on the tip of the nose, and an abnormal Moro reflex consisting of continued flexion state without an abduction-extension phase. Neither exaggerated tendon reflexes nor myotonia was noted. Electroencephalograms were normal both awake and asleep. The auditory brainstem response and visual evoked potentials were normal. A surface electromyographic study of the Moro reflex revealed persistent tonic contraction, followed by prolonged phasic contraction in the antagonists of the arms and neck. There was no muscle activity at rest on the needle electromyographic study. Individual IV-1. A girl was the maternal cousin of the propositus. Hypertonia and poor feeding were noted in early infancy, although both lessened gradually during the first year. Bilateral hip dislocation was also noted in early infancy. She started to walk at age 18
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Hayashi et al. TABLE I. Clinical Data of 9 Individuals In The 2 Families Family 1 Family 2 IV-8 IV-1 IV-2 111-7 111-1 11-3 111-3 111-2 11-3Propositus Cousin Cousin Mother Uncle Grandmother Propositus Brother Father M F M F M F M M M 44 66 4 wk 2 29 38 -
Relationship Sex Age at first examination (yr) Clinical manifestations Infantile hypertonia Umbilical or inguinal hernia Hip dislocation Exaggerated startle response Fall Sleep myoclonus Hyperreflexia Head retraction reflex Abnormal gait Effective clonazepam Mental retardation Improvement during adolescence Electrophysiological examinations EEG abnormalities Evoked response abnormalities Auditory brainstem response Visual evoked potential Somatosensory evoked potential Electromyographic abnormalities a
-
-
+ + + ++-
-
+-
+ + +-
+ -
-
-
+
+
NEa
-
NE NE
NE NE
NE
NE
NE
NE
NE; not examined.
Fig. 2. Propositus of family 1, age 4 weeks. Muscular hypertonia when horizontally suspended.
months. She showed an excessive startle response and tended to fall. During a fall, she was unable to protect herself, and with her arms extending downward, she would hit her face on the ground. In order to prevent a fall, she began to walk touching a wall. Neurological examination at age 13 years disclosed a n excessive startle response, prominent nocturnal myoclonus, and head retraction reflex. The nocturnal myoclonus consisted of short-lasting synchronous
generalized contraction in all muscles. It occurred predominantly in dropping off to sleep. The tendon reflexes and muscle tone were normal. She showed a normal forward, sideways, and backward parachute reaction. Her intelligence was normal. All electrophysiological studies, including somatosensory evoked potential, showed normal patterns. Individual IV-2. IV-2 is the younger brother of IV-1. Hypertonia and feeding difficulties were noted during his infancy. Exaggerated startle responses and occasional falling attacks have been noted since he started to walk a t age 12 months. Frequent falling episodes made him withdrawn. He did not participate in sport activities. Muscle biopsy at age 4 years showed no specific abnormalities. When first seen by us a t age 10 years, he showed a head retraction reflex elicited by tapping the philtrum, a n exaggerated startle response, and nocturnal myoclonus. Muscle tone, muscle strength, and deep tendon reflexes were normal. Electrophysiological studies were normal. An electromyographic study showed neither myotonic, nor myogenic, nor neurogenic discharge. Continuous muscle fiber activities were not recorded. Other affected individuals. The mother of the propositus (111-7) and her elder brother (111-1)both had exaggerated startle responses, sleep myoclonus, and an easily elicited head retraction reflex, but both were without a history of infantile hypertonia or hypokinesia. In childhood, they both suffered from frequent falling episodes, which lessened after puberty. The maternal
Hyperekplexia
141
grandmother of the propositus (11-3)had a head retraction reflex, but no other abnormal neurological findings. The mother was treated in infancy for bilateral hip dislocation. The uncle had an inguinal hernia in infancy.
trophysiological studies were normal. The exaggerated startle response was recorded on the electroencephalograph, but without spike discharges. On a needle electromyographic study, there was no continuous activity at rest. Treatment with clonazepam produced a decrease in the muscle tone and an improvement in feeding. Clonazepam Treatment Other affected individuals. The elder brother of The propositus (IV-8) and his 2 cousins (IV-1 and the propositus (111-2) had a history of infantile hyperIV-2)were treated with 0.1 mg/kg/day clonazepam. The tonia. Their father (11-3)showed a head retraction reflex. propositus was 2 months old when treatment was began. Electrophysiological studies of the brother showed no The treatment removed hypertonia and feeding diffi- abnormalities. culties within a few days. Now a t age 4 years and still on the medication, he leads a normal life without episodes DISCUSSION of abnormal startle or falling. Both IV-1 and IV-2 have been free from falling attacks since clonazepam was Startle “disease” is a non-epileptic disurder with exstarted. IV-2 even won a long-distance running race at cessive startle reaction provoked by unexpected visual, school. Their startle responses have lessened markedly, tactile, or auditory stimuli. Numerous patients have but their head retraction reflex has remained un- been reported in the literature as examples of “hyperexchanged. plexia,” “hyperekplexia,” “neonatal hyperexplexia,”and “congenital stiff-man syndrome.” A few of them had Family 2 positive family history. Thus, startle “disease” may conIndividual III-3. The propositus (0640-64-9)was sist of hereditary and non-hereditary types. Non-heredinoted to be hypertonic at a few days after birth. When tary startle “disease” is caused by organic lesions. seen by us at age 4 weeks, he showed increased deep Hereditary startle disorder has been described in 12 tendon reflexes, transient generalized hypertonia, stiff- families in the literature; 5 families had detailed family ening “like a lead soldier,” and sleep myoclonus. The history [Kirstein and Silfverskiold, 1958;Suhren et al., startle reflex was elicited by weak auditory or tactile 1966; Andermann et al., 1980; Morley et al., 1982; stimuli. Neither myotonic phenomenon nor head retrac- Kurczynski, 19831 (Table 11). Kirstein and Silfverskiold tion reflex was elicited. The Moro reflex elicited a pro- [19581 described a family in Stockholm with 2 sisters, longed flexion state. An EEG (sleep and awake) showed their father, and the daughter of one of the sisters with neither spike discharge nor other abnormalities. Elec- sudden, violent falls precipitated by stress, fright, or
TABLE 11. Clinical Data of 61 Individuals From 6 Families With Hyperexplexia
No. of affected individuals Male Female Clinical manifestations Infantile hypertonia Umbilical or inguinal hernia Hip dislocation Exaggerated startle response Fall Sleep myoclonus Hyperreflexia Head retraction reflex Abnormal gait Effective clonazepam, diazepam or barbiturate Mental retardation Improvement in adolescence Electrophysiological examinations EEG abnormalities Evoked response abnormalities Auditory brainstem response Visual evoked potential Somatosensory evoked potential Electromyographic abnormalities
Present families Familv 1 Familv 2 6 3 3 3 3 0 315 216 216 516 415 415 016 616 215
213 013 013 113 012 113 113 113 012
313
111 012
015
K irstein and Silverskoid rig581 4 1 3
Suhren et al. rig661 24 16 8
Morley et al. [1982] 15 5 10
114
15/17 11/23
919 111
414 414 314
23/23 16/21 7/21
12/12 3/11 6/12 15/15 15/15 12/12
21/21 13/21
212
313
9/10
313
6/12
212 214
0112
Kurczynski [19831 9 5 4
819 819
819
Total (%) 61 33 28 42/50 (84:l 17/44 (39:i 8/21 (391 56/60 (391 47/56 (84) 35/54 (65) 119 (11) 33/35 (94) 15/28 (54) 16/17 (94) 017 8/14 2/28
014
012
013 013
012 012
012
012
417
4/11 (36)
012
011
013
016
015
015
142
Hayashi et al.
surprise. Three of these family members also had nocturnal myoclonus. Suhren et al. 119661reported a Dutch family in which 24 individuals through 4 generations were affected,and coined the term “hyperexplexia.”The correct Greek spelling is hyperekplexia and not hyperexplexia, ((asthe printers’ devil had it in the original report” [Bruyn, 19811. Suhren et al. [19661 proposed that this condition was characterized by the following cardinal symptoms: 1)a hereditary, abnormally exaggerated startle-reaction with occasional falling, 2) transient congenital hypertonia and hypokinesia, 3) unusually active brainstem reflexes, 4)jerking on dropping off to sleep. Morley et al. [1982]reported a family in Indiana with 15 affected individuals through 5 generations, and Markand et al. 119841 carried out electrophysiologic evaluation of 6 of the 15 affected members. Kurczynski [19831 described a family in Ohio with 9 affected individuals through 5 generations. Dooley and Andermann [19891 described a 13-year-old boy with an adolescent onset of startle “disease.” His brother and a granduncle were also affected t o a lesser degree, whereas the parents were apparently unaffected. This family thus may represent a dominant form of startle disease with incomplete penetrance. These reports did not describe details enough to analyze their pedigrees. In view of this, these families were not included in Table 11. Adding the 2 families we described, altogether 6 families are now known with the disorder (Table 11). These 6 pedigrees together contained 34 male and 28 female affected individuals among the 189individuals listed. Their sex ratio was 1.21, not significantly different from parity. Their clinical manifestations were highly variable. The trait was vertically transmitted through 2 to 5 generations. No consanguinity was observed in the 6 families. The segregation ratio (P = 0.551 ? 0.071 calculated with single incomplete ascertainment [Emery, 19861) was not statistically different from even. Male-to-male transmission was observed repeatedly. These findings indicate that the disorder is an autosomal dominant trait with variable expressivity and nearly complete penetrance. Andermann et al. [19801reported a French-Canadian family in Quebec with a hereditary startle disorder. The affected individuals of the family had symptoms common with the previous described dominant form. However, they did not have massive myoclonicjerk in sleep state, but repeatedly clonic jerks of limbs, especially in legs, even in the daytime. These symptoms were different from those described by Kirstein and Silfverskiold [1958], Suhren et al. [19661, Morley et al. [19821, and Kurczynski [19831. Our patients did not have repeated clonicjerks of the legs. In the family described by Andermann et al. [1980], there were 5 individuals affected through 3 generations. However, only 2 of them, the proband and her sister, showed some cardinal symptoms. The other 3 individuals, with the so-called minor form proposed by Andermann’s report, did not show any cardinal symptoms and their detailed clinical manifestations were not described. In view ofthis, the Andermann family was not included in pedigree analysis. Another type of hereditary startle disorder may be present, such as that of the families described by Saenz-
Lope et al. [1984] and Dalla Bernardina et al. [1988]. Saenz-Lope-et al. [19841 reported a family with 5 affected sibs with nocturnal jerking of legs, ages 6 to 23 years, of apparently unaffected parents. An affected parent in the family may have been overlooked, given the highly variable expression of the disorder. Alternatively, they may represent a recessive form of startle disorder. Dalla Bernardina et al. [19881and Vigevano et al. [1989] reported 6 patients with “neonatal hyperexplexia,” of whom 2 were sisters. No details were mentioned of their family members. The mode of inheritance of the disorder is thus either autosomal recessive or dominant with incomplete penetrance. This suspected recessive form of startle “disease”had symptoms similar to the dominant form without myoclonic jerk. The affected individuals with the probable recessive form were characterized by repeated jerkings of limbs for a few minutes and some of them had generalized clonic myoclonic fits accompanied by apnea and cyanosis. We speculate that the family of Andermann may have the recessive form of startle disorder. Unfortunately, the families of Saenz-Lope et al. and Dalla Bernardina et al. were not described in detail. Thus, the pedigree analysis could not be performed. Congenital stiff-man syndrome is an autosomal dominant startle disorder. Its clinical manifestations are similar to hypereplexia in that sudden environmental stimuli provoke muscle stiffening and occasional falling. Stiff-man syndrome was originally thought to be a disorder of adult onset [Gordon et al., 19671, but a congenital form has been reported with apparent autosomal dominant inheritance [Klein et al., 1972;Sander et al., 19791. The presence of continuous electromyographic potentials at rest distinguishes the disorder from the dominant form of startle disorder. Such abnormal potentials were not recorded in the 6 affected individuals tested in our families. Of the 66 individuals with hyperexplexia in the literature, 3 individuals were studied with surface electromyography [Andermann et al., 1980;Morley et al., 19821and another 2 individuals with needle electromyography [Morley et al., 1982; Kurczynski, 19831. None of them showed continuous electromyographicpotentials during muscle relaxation. Some sporadic cases are probably new mutations of a dominantly inherited gene. The other sporadic cases are probably caused by organic brain lesion [Fariello et al., 1983;Winston, 19831. We separate and classify the startle disorders (Table 111)based on our patients and those in the literature. The affected children in the 2 families we described were successfully treated with clonazepam, a serotonin agonist. Clonazepamhas been effective in the treatment of not only hyperekplexia, but also of Tourette syndrome, and startle-induced epileptic seizures. Thus, Andermann et al. [19801implied the existence of a common pathophysiology of all startle disorders, such as a serotoninergic mechanism. However, clonazepam was ineffective in some cases [Kurczynski, 1983;Saenz-Lopeet al., 19841. In some others, drugs such as valproic acid, piracetam, barbiturate, or phenobarbital were helpful [Kirstein and Silfverskiold, 1958; Suhren et al., 1966; Saenz-Lope et al., 1984;Dooley et al., 19891. The neuro-
Hyperekplexia
143
TABLE 111. SeDarations and Classifications in Startle Disease Hyperexplexia Autosomal dominant form Hereditary startle disease
Hyperekplexia
Hayashi, 1991
Autosomal recessive form
Hypere kplexia Neonatal hyperexplexia
L
Non-hereditary startle diease
Klein, 1972 Lingam, 1981 Sander. 1979
Congenital stiffm a n syndrome Hyperexplexia
Startle diease
I
Kirstein, 1958 Suhren, 1966 Morley, 1982 Kurczynski, 1983
Sporadic case of hereditary startle disease
I
Secondary startle disease caused by organic lesion
-E
Andermann, 1980 Saenz-Lope, 1984
Dalla Bernardina, 1988
- Gastaut, 1967 Fariello, 1983 Winston, 1983
Unknown etiological startle disease
pathological mechanisms of startle disorders thus remain unknown. In conclusion, hereditary startle “disease” is an autosoma1dominant disorder with variable expressivity, but there may be a recessively inherited form. Further studies on well-defined families are needed in order to settle the dispute.
ACKNOWLEDGMENTS We thank Dr. N. Niikawa for his advice on segregation analysis of the pedigrees studied, Dr. Andermann for critical comments, and Dr. B. Dalla Bernardina for providing us with related references. REFERENCES Andermann F, Keene DL, Andermann E, Quesney LF (1980): Startle disease or hyperekplexia. Further delineation of the syndrome. Brain 103:985-997. Bruyn GW (1981): Hyperekplexia (startle disease). In Vinken PJ, Bruyn GW (eds):“Handbook of Clinical Neurology,”Vol42. Amsterdam: North Holland, pp 228-229. Dalla Bernardina B, Fontana E, Colamaria V, La Selva L, Merlin D, Sgro V, Scarpa P (1988):Neonatal hyperexplexia. In Beaumanoir A, Gastaut H, Naquet R (eds);“Reflex Seizures and Reflex Epilepsies.” Geneve: Editions Medicine & Hygiene, pp 409-414. Dooley JM, Andermann F (1989): Startle disease or hyperekplexia: Adolescent onset and response to valproate. Pediatr Neurol 5:126-127.
Emery AEH (1986): “Methodology in Medical Genetics. An Introduction to Statistical Methods.” Edinburgh: Livingstone, pp 37-54. Fariello RG, Schwartzman RJ,Beall SS (1983):Hyperekplexia exacerbated by occlusion of posterior thalamic arteries. Arch Neurol 40:244-246. Gastaut H, Villeneuve A (1967):The startle disease or hyperekplexia. Pathological surprise reaction. J Neurol Sci 5:523-542. Gordon EE, Januszko DM, Kaufman LA (1967): A critical survey of stiff-man syndrome. Am J Med 42582-599. Kirstein L, Silfverskiold BP (1958):A family with emotionally precipitated “drop seizures.” Acta Psychiatr Scand 33:471-476. Klein R, Haddow JE, DeLuca C (1972): Familial congenital disorder resembling stiff-man syndrome. Am J Dis Child 124:730-731. Kurczynski TW (1983): Hyperekplexia. Arch Neurol 40246-248. Lingam S, Wilson J , Hart EW (1981):Hereditary stiff-baby syndrome. Am J Dis Child 135:909-911. Markand ON, Garg BP, Weaver DD (1984): Familial startle disease (hyperexplexia): Electrophysiologic studies. Arch Neurol 41:71-74. Morley DJ, Weaver DD, Garg BP, Markand 0 (1982): Hyperexplexia: An inherited disorder of startle response. Clin Genet 21:388-396. Saenz-Lope E, Herranz-Tannaro FJ, Masdeu JC, Chacon Pena JR (1984): Hyperekplexia: A syndrome of pathological startle responses. Ann Neurol 15:36-41. Sander JE, Layzer RB, Goldsobel AB (1979): Congenital stiff-man syndrome. Ann Neurol 8:195-197. Suhren 0, Bruyn GW, Tuynman JA (1966): Hyperexplexia. A hereditary startle syndrome. J Neurol Sci 3:577-605. Vigevano F, Di Capua M, Dalla Bernardina B (1989):Startle disease: An avoidable cause of sudden infant death. Lancet 1:216. Winston K (9183):Hyperekplexia relieved by surgical decompression of the cervicomedullary region. Neurosurgery 13:708-710.
