Hyperekplexia in two siblings
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《美国医学杂志》
Department of Pediatrics, JJMMC, Davangere, Karnataka, India
Hyperekplexia is a rare, hereditary, non-epileptic disorder characterized by an exaggerated startle reaction to unexpected auditory, somatosensory and visual stimuli. The authors describe a one-day-old term neonate, who presented with jitteriness and episodic tonic spasms, and his elder sister with hyperekplexia. Hyperekplexia though is a rare disorder is one of the differential diagnoses for refractory tonic spasms in infancy. The prognosis is generally good in hereditary hyperekplexia. Recent molecular studies have revealed many associated mutations in the glycine receptor alpha and beta subunit genes.
Keywords: Hyperekplexia; Startle response; Glycine receptor
Hyperekplexia is a rare, hereditary, non epileptic disorder characterized by two abnormal forms of response to unexpected auditory, visual and somesthetic stimuli, namely the sustained tonic spasm and exaggerated startle response.[1],[2],[3],[4] Till now more than 150 cases of hyperekplexia have been reported in the world literature and there has been only one earlier report in the Indian medical literature.[5],[6] Awareness of the existence of such a condition, that mimics seizure but has a relatively benign outcome, is vital for its diagnosis and management.
In this report are described 2 siblings with hyperekplexia. This is the second case report, of hyperekplexia, and the first one that documents it among siblings, from India. The literature regarding hyperekplexia has been briefly reviewed and the current advances in the understanding of the molecular and neurophysiological basis of this disorder have been dealt with.
Case report
A one-day-old term neonate was brought to authors NICU with history of stiffening and frequent jerking of the whole body. The baby's birth events were normal and weighed 3 Kgs at birth with a length of 49cm and head circumference of 34cms. History pertaining to antenatal and mother's previous obstetric history was uneventful. Parents were biologically related (uncle and niece) and the older sibling had similar problems. On examination the baby was conscious and had episodes of tonic spasm involving all four limbs when it was handled. These episodes were associated with apnea and bradycardia lasting for 15 seconds and the baby remained conscious throughout and after the episode. The spasms were stimulus sensitive. A glabellar tap or a loud noise elicited a flexor spasm of the whole body (startle reflex) which was non-habituating. The rest of the systemic examination was within normal limits.
The baby had normal blood glucose and calcium levels during the attacks of tonic spasm. Complete blood count and CSF study were within normal limits. Screening for inborn errors of metabolism did not reveal any abnormality. CT and MRl studies of the brain were normal. EEG did not reveal any epileptiform activity but the stimulus induced startle response was accompanied by muscle artifacts.
The elder sibling of the index case had a similar history of stiffening in her infancy. But the condition improved gradually and she was symptom free by 2 years of age. She is now a 4-year-old girl of normal intelligence, attending kindergarten. A glabellar tap or a sudden loud noise elicited a startle response in her. Other wise her general physical and systemic examination did not reveal any abnormality. Just like her sister she was subjected to a battery of investigations and all of them turned out to be normal.
Based on the classical clinical signs of episodic stiffening and exaggerated startle response, a positive family history and normal laboratory, electrophysiological and neuroimaging studies, a diagnosis of hyperekplexia was made. Both the siblings were started on oral clonazepam at a dose of 0.03 mg/Kg/day and gradually raised to 0.05 mg/Kg/day. After 6 months of treatment there was considerable decrease in frequency and severity of the tonic spasms in the younger sibling. But the exaggerated startle response persisted. The baby was neurodevelopmentally normal, having attained motor, cognitive, social and adaptive milestones that were appropriate for her age.
Discussion
First described in 1958[7] disorder was named as hyperexplexia, after the Greek word for startle.[8] And later the Greek spelling was changed to hyperekplexia.[9] Congenital Stiffman syndrome, stiffbaby syndrome, startle disease are all synonymous.[5],[10],[11] Classic exaggerated startle response and episodic tonic spasms in neonatal period are the presenting features.[5],[12] Startle reflex is a basic alerting reaction consisting of facial grimacing with blinking followed by head flexion, hunching of shoulders, adduction of the arms and flexion of the trunk and knees. The consistent, non-habituating, generalized flexor spasm in response to tapping of the nasal bridge (glabella) is the clinical hallmark.[1],[4],[13],[14] Older children present with startle on glabellar tap and frequent fall in response to loud noise.[1],[3],[14] SIDS, developmental delay and effects of intrauterine hypertonia like hernias and dislocation of hip have been reported in this syndrome.[3],[4],[15],[16],[17],[18]
Normal EEG, permanent muscular activity on EMG, lowered threshold in pontomedullary reticular neurons resulting in gain of vestigial reflexes are some of the findings on neurophysiological studies.[19] Decreased GABA in CSF[20] and vidence of subtle cortical dysfunction in spectroscopic studies are other observations.[21] Both hereditary and sporadic hyperekplexia have been described. Linkage analysis showed mutations in a gene in the 5q 33-35 region.[2],[22] Two heterozygous mutations in the GLRA-l gene (Glycine receptor alpha 1 subunit gene) were noted, in patients with the autosomal dominant form.[23] In this case since both sibijngs were affected, whose parents were phenotypically normal, probably autosomal recessive pattern of inheritance was operational. Various autosomal recessive mutations and incidences of compound heterozygosity have been mentioned in literature pertaining to this topic.[24],[25] Rees et al in 2001 reported novel missense mutations and the first nonsense point mutations in the GLRAI gene related with hyperekplexia.[25] Population studies conducted by the same investigator revealed that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA 1 mutations or as part of a compound heterozygote.[25] Humeny et al identified homozygosity for a 1073C-G transversion in exon 7 of the GLRAI gene, leading to a mutation in the transmembrane region.[26]
Sporadic hyperekplexia has been reported in patients with brain stem pathology[27],[28],[29],[30],[31] and occasionally with GLRA-I mutations.[32],[33] Recently mutations in the GLRB (Glycine receptor b subunit) gene were also discovered.[34] mutations uncouple the ligand binding and "chloride channel function of the inhibitory glycine receptor and result in increased excitability of the pontomedullary reticular neurons.[34],[35] Recent report have thrown light upon the association of hyperekplexia with molybdenum cofactor deficiency and impaired gephyrin function, a protein related to the glycine receptor, causing seizures, mental retardation and spasticity.[36],[37],[38] Clonazepam is the drug of choice for hypertonia and apneic episodes.[2],[4],[5],[39] A maneuver of forced flexion of heads and legs is life saving when prolonged tonic spasms impede respiration.[40]
References
1.Anderman F, Keene DL, Anderman E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain 1980; 103 : 985-997.
2.Ryan SO, Sherman SL, Terry JC, Sparkes RS, Torres MC, Mackey RW. Startle disease or hyperekplexia: response to c10nazepam and assignment of the gene (STHE) to chromosome 5Q by linkage analysis. Ann Neurol 1992; 31: 663-668.
3.Saenz-lope E, Herranz tannaro FJ, Masden JC, Chacon Pena JR. Hyperekplexia a syndrome of pathological startle responses. Ann Neurol 1984; 15: 36-41.
4.Volpe JJ. Neurology of the Newborn, 4th Edition. U.S.A; Philadelphia; WB Saunders Company 2001; 196.
5.Praveen V, Patole SK, Whitehall JS. Hyperekplexia in neonates. Postgrad Med J 2001; 77: 570-572. [PUBMED] [FULLTEXT]
6.Rajadhyaksha SB, Bahl VB. Hyperekplexia, a non-epileptic seIzure disorder. Indian Pediatr 2002; 39 : 773-776 [PUBMED] [FULLTEXT]
7.Kirstein L, Silfverskiold B. A family with emotionally precipitated drop seizures. Acta Paediatr Scand 1958; 33: 471-476.
8.Suhren O, Bruyn GW, Tunyman JA. Hyperexplexia, a hereditary startle syndrome. J Neurol Sci 1966; 3: 577-605.
9.Gastaut H, Villeneuve A. The startle disease or hyperekplexia. Pathological surprise reaction. J Neurol Sci 1967; 5 : 523-542.
10.Lingam S, Wilson J, Hart EW. Hereditary stiff-baby syndrome. Am J Dis Child 1981; 135: 909-911. [PUBMED]
11.Kok O, Bruyn GW. An unidentified hereditary disease (Letter). Lancet 1962; I: 1359.
12.Leventer RJ, Hopkins JJ, Shield HK. Hyperekplexia as a cause of abnormal intrauterine movements (letter). Lancet 1995; 345 : 461.
13.Gogan P. The startle and orienting reactions in man: a study of their characteristics and habituation. Brain Res 1970; 18 : 117-135. [PUBMED] [FULLTEXT]
14.Valls-Sole J. Function and dysfunction of the startle reaction in humans. Rev Neurol 2004; 39(10) : 946-955.
15.Giacoia GP, Ryan SG. Hyperekplexia associated with apnoea and sudden infant death syndrome. Arch Pediatr Adolesc Med 1994; 148 : 540-543. [PUBMED]
16.Gordon N. Startle disease or hyperekplexia. Dev Med Child Neurol 1993; 35 : 1 015-1024. [PUBMED]
17.Praveen V, Patole SK, Ryan P, Whitehall 11. Unusual presentation of cerebral dysgenesis in a neonate. Int Pediatr 2002; 17: 164-165.
18.Tohier C, Roze JC, David A. Hyperekplexia or stiff baby syndrome. Arch Dis Child 1991; 66:460-461.
19.Matsumoto J, Fuhr P, Nigro M, Hallett M. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol 1992; 32 : 41-50. [PUBMED]
20.Bernasconi A, Cendes F, Shoubridge EA, Andermann E, Li LM, Arnold DL, Andermann F. Spectroscopic imaging of frontal neuronal dysfunction in hyperekplexia. Brain 1998; 121 : 1507-1512. [PUBMED] [FULLTEXT]
21.Dubowitz LMS, Bouza H, Hird MF, Jaeken J. Low CSF concentration of free GABA in startle disease. Lancet 1992; 340: 80-81.
22.Ryan SG, Dixon MJ, Nigro MA, Kelts KA, Markand ON, Terry JC, Shiang R, Wasmuth JJ, O'Connell P. Genetic and radiation hybrid mapping of the hyperekplexia region on chromosome 5q. Am J Hum Genet 1992; 51: 1334-1343. [PUBMED] [FULLTEXT]
23.Shiang R, Ryan SG, Zhu YZ, Hahn AF, O'Connell P, Wasmuth JJ. Mutations in the alpha-1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nature Genet 1993; 5 : 351-357. [PUBMED] [FULLTEXT]
24.Rees MI, Andrew M, Jawad S, Owen MJ. Evidence for recessive as well as dominant forms of startle disease caused by mutations in the alpha 1 subunit of inhibitory glycine receptor. Hum Molec Genet 1994; 3: 2175-2179. [PUBMED]
25.Rees MI, Lewis TM, Vafa B, Ferrie C, Corry P, Muntoni F, Jungbluth H, Stephenson JB, Kerr M, Snell RG, Schofield PR, Owen MJ. Compound heterozygosity and nonsense mutations in the alpha(1 )-subunit of the inhibitory glycine receptor in hyperekplexia. Hum Genet 2001; 109(3) : 267-270.
26.Humeny A, Bonk T, Becker K, Jafari-Boroujerdi M, Stephani U, Reuter K, Becker C. A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking. Europ J Hum Genet 2002; 10 : 188-196.
27.Salvi F, Mascalchi M, Bortolotti C, Meletti S, Plasmati R, Rubboli G, Stecchi S, Villari N, Calbucci F, Tassinari CA. Hypertension, hyperekplexia and pyramidal paresis due to vascular compression of the medulla. Neurology 2000; 55: 1381-1385. [PUBMED] [FULLTEXT]
28.Ruprecht K, Warmuth-Metz M, Waespe W, Gold R. Symptomatic hyperekplexia in a patient with multiple sclerosis. Neurology 2002; 12 : 58: 503-504.
29.Krauss JK, Trankle R, Kopp KH. Post traumatic movement disorders after moderate or mild head injury. Mov Disord 1997; 12 : 428-431. [PUBMED]
30.Gambardella A, Valentino P, Annesi G, Oliveri RL, Bono F, Mazzei RL, Conforti FL, Aguglia U, Zappia M, Pardatscher K, Quattrone A. Hyperekplexia in a patient with a brainstem vascular anomaly. Acta Neurol Scand 1999; 99 : 255-259. [PUBMED]
31.Kellett MW, Humphrey PR, Tedman BM, Steiger MJ. Hyperekplexia and trismus due to brainstem encephalopathy. J Neurol Neurosurg Psychiatry 1998; 65: 122-125. [PUBMED] [FULLTEXT]
32.Miraglia Del Giudice E, Coppola G, Bellini G, Ledaal P, Hertz JM, Pascotto A. A novel mutation (R218Q) at the boundary between the Nterminal and the first transmembrane domain of the glycine receptor in a case of sporadic hyperekplexia. J Med Genet 2003; 40(5) : e71.
33.Shiang R, Ryan SG, Zhu YZ, Fielder TJ, Allen RJ, Fryer A, Yamashita S, O'Connell P, Wasmuth n. Mutational analysis of familial and sporadic hyperekplexia. Ann Neurol 1995; 38 : 85-91.
34.Rees MI, Lewis TM, Kwok JBJ, Mortier GR, Govaert P, Snell R G, Schofield PRo Owen MJ. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Molec Genet 2002; 11: 853-860.
35.Andrew M, Owen MJ. Hyperekplexia, abnormal startle response due to glycine receptor mutation. Br J Psychiatr 1997; 170: 106-108. [PUBMED]
36.Macaya A, Brunso L, Fernandez-Castillo N, Arranz JA, Ginjaar HB, Cuenca-Leon E, Corominas R, Roig M, Cormand B. Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Neuropediatrics 2005; 36(6) : 389-394.
37.Rees MI, Harvey K, Ward H, White JH, Evans L, Duguid IC, Hsu CC, Coleman SL, Miller J, Baer K, Waldvogel HJ, Gibbon F, Smart TG, Owen MJ, Harvey RJ, Snell RG. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J BioI Chern 2003; 278(27) : 24688-24696.
38.Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 1998; 282(5392) : 1321-1324.
39.Kelts KA, Harrison J. Hyperekplexia: effective treatment with clonazepam. Ann Neurol 1988; 24 : 309-312.
40.Vigevano F, Di Capua M, Dalla Bernadina B. Startle disease: an avoidable cause of sudden infant death. Lancet 1989; i: 216(Kulkarni ML, Kannan B, Mathadh Prakash)
Hyperekplexia is a rare, hereditary, non-epileptic disorder characterized by an exaggerated startle reaction to unexpected auditory, somatosensory and visual stimuli. The authors describe a one-day-old term neonate, who presented with jitteriness and episodic tonic spasms, and his elder sister with hyperekplexia. Hyperekplexia though is a rare disorder is one of the differential diagnoses for refractory tonic spasms in infancy. The prognosis is generally good in hereditary hyperekplexia. Recent molecular studies have revealed many associated mutations in the glycine receptor alpha and beta subunit genes.
Keywords: Hyperekplexia; Startle response; Glycine receptor
Hyperekplexia is a rare, hereditary, non epileptic disorder characterized by two abnormal forms of response to unexpected auditory, visual and somesthetic stimuli, namely the sustained tonic spasm and exaggerated startle response.[1],[2],[3],[4] Till now more than 150 cases of hyperekplexia have been reported in the world literature and there has been only one earlier report in the Indian medical literature.[5],[6] Awareness of the existence of such a condition, that mimics seizure but has a relatively benign outcome, is vital for its diagnosis and management.
In this report are described 2 siblings with hyperekplexia. This is the second case report, of hyperekplexia, and the first one that documents it among siblings, from India. The literature regarding hyperekplexia has been briefly reviewed and the current advances in the understanding of the molecular and neurophysiological basis of this disorder have been dealt with.
Case report
A one-day-old term neonate was brought to authors NICU with history of stiffening and frequent jerking of the whole body. The baby's birth events were normal and weighed 3 Kgs at birth with a length of 49cm and head circumference of 34cms. History pertaining to antenatal and mother's previous obstetric history was uneventful. Parents were biologically related (uncle and niece) and the older sibling had similar problems. On examination the baby was conscious and had episodes of tonic spasm involving all four limbs when it was handled. These episodes were associated with apnea and bradycardia lasting for 15 seconds and the baby remained conscious throughout and after the episode. The spasms were stimulus sensitive. A glabellar tap or a loud noise elicited a flexor spasm of the whole body (startle reflex) which was non-habituating. The rest of the systemic examination was within normal limits.
The baby had normal blood glucose and calcium levels during the attacks of tonic spasm. Complete blood count and CSF study were within normal limits. Screening for inborn errors of metabolism did not reveal any abnormality. CT and MRl studies of the brain were normal. EEG did not reveal any epileptiform activity but the stimulus induced startle response was accompanied by muscle artifacts.
The elder sibling of the index case had a similar history of stiffening in her infancy. But the condition improved gradually and she was symptom free by 2 years of age. She is now a 4-year-old girl of normal intelligence, attending kindergarten. A glabellar tap or a sudden loud noise elicited a startle response in her. Other wise her general physical and systemic examination did not reveal any abnormality. Just like her sister she was subjected to a battery of investigations and all of them turned out to be normal.
Based on the classical clinical signs of episodic stiffening and exaggerated startle response, a positive family history and normal laboratory, electrophysiological and neuroimaging studies, a diagnosis of hyperekplexia was made. Both the siblings were started on oral clonazepam at a dose of 0.03 mg/Kg/day and gradually raised to 0.05 mg/Kg/day. After 6 months of treatment there was considerable decrease in frequency and severity of the tonic spasms in the younger sibling. But the exaggerated startle response persisted. The baby was neurodevelopmentally normal, having attained motor, cognitive, social and adaptive milestones that were appropriate for her age.
Discussion
First described in 1958[7] disorder was named as hyperexplexia, after the Greek word for startle.[8] And later the Greek spelling was changed to hyperekplexia.[9] Congenital Stiffman syndrome, stiffbaby syndrome, startle disease are all synonymous.[5],[10],[11] Classic exaggerated startle response and episodic tonic spasms in neonatal period are the presenting features.[5],[12] Startle reflex is a basic alerting reaction consisting of facial grimacing with blinking followed by head flexion, hunching of shoulders, adduction of the arms and flexion of the trunk and knees. The consistent, non-habituating, generalized flexor spasm in response to tapping of the nasal bridge (glabella) is the clinical hallmark.[1],[4],[13],[14] Older children present with startle on glabellar tap and frequent fall in response to loud noise.[1],[3],[14] SIDS, developmental delay and effects of intrauterine hypertonia like hernias and dislocation of hip have been reported in this syndrome.[3],[4],[15],[16],[17],[18]
Normal EEG, permanent muscular activity on EMG, lowered threshold in pontomedullary reticular neurons resulting in gain of vestigial reflexes are some of the findings on neurophysiological studies.[19] Decreased GABA in CSF[20] and vidence of subtle cortical dysfunction in spectroscopic studies are other observations.[21] Both hereditary and sporadic hyperekplexia have been described. Linkage analysis showed mutations in a gene in the 5q 33-35 region.[2],[22] Two heterozygous mutations in the GLRA-l gene (Glycine receptor alpha 1 subunit gene) were noted, in patients with the autosomal dominant form.[23] In this case since both sibijngs were affected, whose parents were phenotypically normal, probably autosomal recessive pattern of inheritance was operational. Various autosomal recessive mutations and incidences of compound heterozygosity have been mentioned in literature pertaining to this topic.[24],[25] Rees et al in 2001 reported novel missense mutations and the first nonsense point mutations in the GLRAI gene related with hyperekplexia.[25] Population studies conducted by the same investigator revealed that a proportion of sporadic hyperekplexia is accounted for by the homozygous inheritance of recessive GLRA 1 mutations or as part of a compound heterozygote.[25] Humeny et al identified homozygosity for a 1073C-G transversion in exon 7 of the GLRAI gene, leading to a mutation in the transmembrane region.[26]
Sporadic hyperekplexia has been reported in patients with brain stem pathology[27],[28],[29],[30],[31] and occasionally with GLRA-I mutations.[32],[33] Recently mutations in the GLRB (Glycine receptor b subunit) gene were also discovered.[34] mutations uncouple the ligand binding and "chloride channel function of the inhibitory glycine receptor and result in increased excitability of the pontomedullary reticular neurons.[34],[35] Recent report have thrown light upon the association of hyperekplexia with molybdenum cofactor deficiency and impaired gephyrin function, a protein related to the glycine receptor, causing seizures, mental retardation and spasticity.[36],[37],[38] Clonazepam is the drug of choice for hypertonia and apneic episodes.[2],[4],[5],[39] A maneuver of forced flexion of heads and legs is life saving when prolonged tonic spasms impede respiration.[40]
References
1.Anderman F, Keene DL, Anderman E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain 1980; 103 : 985-997.
2.Ryan SO, Sherman SL, Terry JC, Sparkes RS, Torres MC, Mackey RW. Startle disease or hyperekplexia: response to c10nazepam and assignment of the gene (STHE) to chromosome 5Q by linkage analysis. Ann Neurol 1992; 31: 663-668.
3.Saenz-lope E, Herranz tannaro FJ, Masden JC, Chacon Pena JR. Hyperekplexia a syndrome of pathological startle responses. Ann Neurol 1984; 15: 36-41.
4.Volpe JJ. Neurology of the Newborn, 4th Edition. U.S.A; Philadelphia; WB Saunders Company 2001; 196.
5.Praveen V, Patole SK, Whitehall JS. Hyperekplexia in neonates. Postgrad Med J 2001; 77: 570-572. [PUBMED] [FULLTEXT]
6.Rajadhyaksha SB, Bahl VB. Hyperekplexia, a non-epileptic seIzure disorder. Indian Pediatr 2002; 39 : 773-776 [PUBMED] [FULLTEXT]
7.Kirstein L, Silfverskiold B. A family with emotionally precipitated drop seizures. Acta Paediatr Scand 1958; 33: 471-476.
8.Suhren O, Bruyn GW, Tunyman JA. Hyperexplexia, a hereditary startle syndrome. J Neurol Sci 1966; 3: 577-605.
9.Gastaut H, Villeneuve A. The startle disease or hyperekplexia. Pathological surprise reaction. J Neurol Sci 1967; 5 : 523-542.
10.Lingam S, Wilson J, Hart EW. Hereditary stiff-baby syndrome. Am J Dis Child 1981; 135: 909-911. [PUBMED]
11.Kok O, Bruyn GW. An unidentified hereditary disease (Letter). Lancet 1962; I: 1359.
12.Leventer RJ, Hopkins JJ, Shield HK. Hyperekplexia as a cause of abnormal intrauterine movements (letter). Lancet 1995; 345 : 461.
13.Gogan P. The startle and orienting reactions in man: a study of their characteristics and habituation. Brain Res 1970; 18 : 117-135. [PUBMED] [FULLTEXT]
14.Valls-Sole J. Function and dysfunction of the startle reaction in humans. Rev Neurol 2004; 39(10) : 946-955.
15.Giacoia GP, Ryan SG. Hyperekplexia associated with apnoea and sudden infant death syndrome. Arch Pediatr Adolesc Med 1994; 148 : 540-543. [PUBMED]
16.Gordon N. Startle disease or hyperekplexia. Dev Med Child Neurol 1993; 35 : 1 015-1024. [PUBMED]
17.Praveen V, Patole SK, Ryan P, Whitehall 11. Unusual presentation of cerebral dysgenesis in a neonate. Int Pediatr 2002; 17: 164-165.
18.Tohier C, Roze JC, David A. Hyperekplexia or stiff baby syndrome. Arch Dis Child 1991; 66:460-461.
19.Matsumoto J, Fuhr P, Nigro M, Hallett M. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol 1992; 32 : 41-50. [PUBMED]
20.Bernasconi A, Cendes F, Shoubridge EA, Andermann E, Li LM, Arnold DL, Andermann F. Spectroscopic imaging of frontal neuronal dysfunction in hyperekplexia. Brain 1998; 121 : 1507-1512. [PUBMED] [FULLTEXT]
21.Dubowitz LMS, Bouza H, Hird MF, Jaeken J. Low CSF concentration of free GABA in startle disease. Lancet 1992; 340: 80-81.
22.Ryan SG, Dixon MJ, Nigro MA, Kelts KA, Markand ON, Terry JC, Shiang R, Wasmuth JJ, O'Connell P. Genetic and radiation hybrid mapping of the hyperekplexia region on chromosome 5q. Am J Hum Genet 1992; 51: 1334-1343. [PUBMED] [FULLTEXT]
23.Shiang R, Ryan SG, Zhu YZ, Hahn AF, O'Connell P, Wasmuth JJ. Mutations in the alpha-1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nature Genet 1993; 5 : 351-357. [PUBMED] [FULLTEXT]
24.Rees MI, Andrew M, Jawad S, Owen MJ. Evidence for recessive as well as dominant forms of startle disease caused by mutations in the alpha 1 subunit of inhibitory glycine receptor. Hum Molec Genet 1994; 3: 2175-2179. [PUBMED]
25.Rees MI, Lewis TM, Vafa B, Ferrie C, Corry P, Muntoni F, Jungbluth H, Stephenson JB, Kerr M, Snell RG, Schofield PR, Owen MJ. Compound heterozygosity and nonsense mutations in the alpha(1 )-subunit of the inhibitory glycine receptor in hyperekplexia. Hum Genet 2001; 109(3) : 267-270.
26.Humeny A, Bonk T, Becker K, Jafari-Boroujerdi M, Stephani U, Reuter K, Becker C. A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking. Europ J Hum Genet 2002; 10 : 188-196.
27.Salvi F, Mascalchi M, Bortolotti C, Meletti S, Plasmati R, Rubboli G, Stecchi S, Villari N, Calbucci F, Tassinari CA. Hypertension, hyperekplexia and pyramidal paresis due to vascular compression of the medulla. Neurology 2000; 55: 1381-1385. [PUBMED] [FULLTEXT]
28.Ruprecht K, Warmuth-Metz M, Waespe W, Gold R. Symptomatic hyperekplexia in a patient with multiple sclerosis. Neurology 2002; 12 : 58: 503-504.
29.Krauss JK, Trankle R, Kopp KH. Post traumatic movement disorders after moderate or mild head injury. Mov Disord 1997; 12 : 428-431. [PUBMED]
30.Gambardella A, Valentino P, Annesi G, Oliveri RL, Bono F, Mazzei RL, Conforti FL, Aguglia U, Zappia M, Pardatscher K, Quattrone A. Hyperekplexia in a patient with a brainstem vascular anomaly. Acta Neurol Scand 1999; 99 : 255-259. [PUBMED]
31.Kellett MW, Humphrey PR, Tedman BM, Steiger MJ. Hyperekplexia and trismus due to brainstem encephalopathy. J Neurol Neurosurg Psychiatry 1998; 65: 122-125. [PUBMED] [FULLTEXT]
32.Miraglia Del Giudice E, Coppola G, Bellini G, Ledaal P, Hertz JM, Pascotto A. A novel mutation (R218Q) at the boundary between the Nterminal and the first transmembrane domain of the glycine receptor in a case of sporadic hyperekplexia. J Med Genet 2003; 40(5) : e71.
33.Shiang R, Ryan SG, Zhu YZ, Fielder TJ, Allen RJ, Fryer A, Yamashita S, O'Connell P, Wasmuth n. Mutational analysis of familial and sporadic hyperekplexia. Ann Neurol 1995; 38 : 85-91.
34.Rees MI, Lewis TM, Kwok JBJ, Mortier GR, Govaert P, Snell R G, Schofield PRo Owen MJ. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Molec Genet 2002; 11: 853-860.
35.Andrew M, Owen MJ. Hyperekplexia, abnormal startle response due to glycine receptor mutation. Br J Psychiatr 1997; 170: 106-108. [PUBMED]
36.Macaya A, Brunso L, Fernandez-Castillo N, Arranz JA, Ginjaar HB, Cuenca-Leon E, Corominas R, Roig M, Cormand B. Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Neuropediatrics 2005; 36(6) : 389-394.
37.Rees MI, Harvey K, Ward H, White JH, Evans L, Duguid IC, Hsu CC, Coleman SL, Miller J, Baer K, Waldvogel HJ, Gibbon F, Smart TG, Owen MJ, Harvey RJ, Snell RG. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J BioI Chern 2003; 278(27) : 24688-24696.
38.Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 1998; 282(5392) : 1321-1324.
39.Kelts KA, Harrison J. Hyperekplexia: effective treatment with clonazepam. Ann Neurol 1988; 24 : 309-312.
40.Vigevano F, Di Capua M, Dalla Bernadina B. Startle disease: an avoidable cause of sudden infant death. Lancet 1989; i: 216(Kulkarni ML, Kannan B, Mathadh Prakash)