An Adult Case of Genetically Confirmed Hyperekplexia Presenting with Head Trauma

Abstract

Hyperekplexia is a rare neurological disorder that is characterized by an excessive startle response to unexpected stimuli. Recently, heterogeneous causative genes have been identified. Most cases are diagnosed during the neonatal period from hypertonia or stiffness. Adult cases are relatively rare and can cause severe head injury, but they are often misdiagnosed, typically as epilepsy or psychiatric disorders, due to the rarity of the pathology. This report describes a genetically confirmed case of hyperekplexia in an adult with head trauma, highlighting the features of head trauma and discussing potential pitfalls in the diagnosis of adult patients with hyperekplexia.

Introduction

Hyperekplexia is a rare genetic neurodevelopmental disorder that is characterized by an exaggerated startle reflex in response to auditory or tactile stimulation. Recently, it has been linked to inhibitory synapse abnormalities in glycinergic neurotransmission.^1,2) Although this pathology is largely autosomal dominant, it is often unrecognized by general doctors, leading to few reported cases.^3,4) Most cases are diagnosed during the neonatal period from hypertonia or stiffness. Adult cases are relatively rare, thus making them particularly challenging to diagnose, with patients frequently presenting following head trauma and being misdiagnosed with epilepsy or mental illness.^5-7) This report describes a genetically confirmed case of hyperekplexia in an adult with severe head trauma, highlighting key features and diagnostic pitfalls in adult hyperekplexia.

Case Report

A 24-year-old woman was admitted to our hospital with a head injury. While she was walking, she almost collided with a passerby at a corner. At that moment, she experienced rigidity of all four limbs after the unexpected visual stimuli and fell, hitting her head in the right temporal region. Remarkably, she remained conscious throughout the injury event. She had a history of congenital hip dislocation. No other symptoms in the diagnostic guideline in hyperekplexia were observed, such as apnea attacks, abnormal hernia, epilepsy, and learning disability. Contributory family history was not obtained. From the neonatal period, she had experienced muscle stiffness and excessive startle responses to unexpected auditory, visual, and tactile stimulations. Although detailed examinations had been performed, the causes of these startle responses had remained unclear. She had no evidence of developmental delay or neurological deficit, but had experienced sudden falling injury events several times. When walking outside, she always feared unexpected stimulation, avoiding crowds of people. On first examination in our institution, she was alert and orientated, with no neurological abnormalities other than headache and right conductive hearing loss. The nose tapping test (head-retraction reflex), a hallmark of hyperekplexia, was also negative. At first, suspecting cardiac disease or epilepsy, we performed blood tests, electrocardiogram, echocardiogram, and electroencephalogram (EEG), but no abnormality could cause syncope. Computed tomography (CT) revealed skull fracture, brain contusion, and thin subdural hematoma (Fig. 1). Magnetic resonance imaging (MRI) and magnetic resonance angiography revealed no abnormalities other than these traumatic changes (Fig. 2). Therefore, she was admitted for conservative treatment. There was no neurological deterioration or leakage of cerebrospinal fluid, such as rhinorrhea, with the exception of late-onset right peripheral facial nerve palsy 3 days after admission. The head injury was defined as right pyramidal bone fracture and left frontal contusion with contra-coup injury. However, how the patient sustained the head injury while retaining consciousness during the entire falling event represented a key issue. In response to unexpected visual stimulation, she described experiencing body rigidity for a few seconds, resulting in a fall without any ability to assume a defensive posture and protect her head. She was discharged 1 month after admission because her hearing loss and facial nerve palsy were gradually improving. As we suspected hyperekplexia, whole-exome sequencing was performed using genomic DNA extracted from peripheral blood and urine. Genetic analysis revealed that GLRA1 mutation (c.896G>A (p.R896Q); Fig. 3) was the specific mutation and hyperekplexia was the primary disease. We then started administration of clonazepam at 1 mg/day, and her symptoms of excessive startle response and muscle stiffness improved. Fall events showed a considerable decrease in frequency, and she was able to go out and work without anxiety. One year after starting administration of clonazepam, she married and delivered a healthy baby.

Fig. 1

Axial CT shows subarachnoid hemorrhage with brain contusion of the left frontal lobe (A, arrows), subdural hematoma on the right occipital lobe (B, arrowhead), and right pyramidal bone fracture (C, arrows).

Fig. 2

Axial fluid-attenuated inversion recovery (A) and diffusion-weighted (B) MRI demonstrate brain contusion in the left frontal lobe. Axial T2-weighted MRI (C) shows fluid collection in the left mastoid air cells.

Fig. 3

Genetic testing shows direct sequences from the GLRA1 exon, revealing a c.896G>A heterozygous mutation.

Discussion

In this report, we reported an adult case of genetically confirmed hyperekplexia presenting with severe head trauma due to a fall following an exaggerated motor startle reflex. This case emphasizes the importance of recognizing hyperekplexia in adult patients, particularly those presenting with head trauma. The startle reflex in hyperekplexia can lead to dangerous falls, emphasizing the need for accurate diagnosis and differentiation from other conditions such as epilepsy. Hyperekplexia is a rare disorder caused by an inhibitory synaptic abnormality involving glycinergic neurotransmission.⁸⁾ While routine tests such as blood or urinary tests, EEG, and brain imaging⁹⁾ revealed no specific abnormalities in hyperekplexia, a detailed history is crucial for the diagnosis. Few adult cases have been reported, but a presentation with head injuries appears common.^5-7) However, few studies have discussed the mechanisms of head trauma seen in adult cases of hyperekplexia.

In this case, the patient fell to the ground following a motor startle reflex and sustained a direct injury to the right temporal region of the head. She was injured with fracture of the right pyramidal bone and brain contusion of the contralateral side as a contra-coup injury without loss of consciousness. This kind of head trauma frequently occurs in patients with epilepsy or syncope in cases involving falls with unconsciousness. The direct external force applied to the head could be substantial in the absence of any defensive responses from the limbs or trunk. Interestingly, she had remained conscious during the entire fall event, even just before sustaining the head injury. A loss of consciousness during startle responses does not usually occur in patients with hyperekplexia.⁴⁾ Whether the patient remains conscious is an essential clinical feature in diagnosing adult hyperekplexia accompanied by head trauma.

To understand this disease, we should be familiar with the characteristic features and symptoms. In 2018, Dr. Taketani et al. proposed the diagnostic criteria for hyperekplexia (https://mhlw-grants.niph.go.jp/system/files/download_pdf/2018/201811016A.pdf) (Table 1). There have been several symptoms accompanying hyperekplexia, such as neonatal apnea, abdominal hernia, congenital hip dislocation, and mental retardation.⁵⁾ As a physical finding, the nose tapping test is diagnostically useful and highly sensitive during infancy. The positive rate remains probably lower for adults¹⁰⁾ and several genetic abnormalities, involving genes such as GLRA1, GLRB, or SLC, can occur as a rare hereditary disorder.^8,11) In addition to autosomal dominant and autosomal recessive inheritance, isolated cases have been reported.^3,5)GLRA1 mutation is the most common type of mutation. It occurs in 80% of patients with a family history of hyperekplexia and in more than 20% of isolated cases. It is also the most common type of mutation in Japan, according to a recent study regarding genotype-phenotype correlations of hyperekplexia.⁷⁾

Table 1

Diagnostic criteria for hyperekplexia

<Diagnosis>
Definite and probable cases are diagnosed as hyperekplexia.
Definite: At least one of the primary symptoms (Section I) is present, and one of the genetic test criteria (Section IV) is met.
Probable: All primary symptoms (Section I) are present, at least one secondary symptom (Section II) is present, and the nose tapping test is positive.
I. Primary Symptoms
1. Startle response
2. Temporary muscle stiffness following the startle response
3. Muscle hypertonia observed from the neonatal to infant period
II. Secondary Symptoms
1. Apnea attacks in the neonatal period
2. Abdominal hernia (inguinal hernia, umbilical hernia)
3. Hip dislocation
4. Epilepsy
5. Learning disability, developmental delay
III. Positive Nose Tapping Test
IV. Genetic Testing
Presence of any of the following genetic mutations:
1. GLRA1
2. GLRB
3. SLC6A5
4. KCNH5
*Considerations in adulthood
I. Primary Symptoms
A history of muscle hypertonia is not required for diagnosis.
II. Secondary Symptoms
Add alcohol dependence to the pediatric criteria.
III. Positive Nose Tapping Test
In adulthood, this test often remains positive but may disappear in some cases.

We reviewed nine cases in Japanese adults with genetically confirmed hyperekplexia. Table 2 shows clinical features, types, and locations of genetic mutations.^7,12,13) The median age at diagnosis was 38.8 years, 44% were male patients, and all patients showed symptoms from the neonatal period. Seven of the nine cases showed histories of head injury, such as skull bone fracture and brain contusion. Although the details of brain damage apparent on CT or MRI have not been previously described, previous cases could have been complicated by brain injuries. Patients with genetically confirmed hyperekplexia can remain conscious at least until just before the head trauma event, representing an essential observation for differentiating this pathology from diagnoses such as epilepsy or syncope. The genetic abnormality in this case was GLRA1, the most common pattern among Japanese people. Regarding treatment, clonazepam was administered for all cases, providing efficacy in six of nine cases. Thus, this treatment was considered effective. Considerable improvements in life prognosis can be achieved once the correct diagnosis is reached. Therefore, genetic testing should be performed in patients with suspected hyperekplexia after excluding other diseases. Early, accurate diagnosis of this disease is essential for preventing injuries and providing correct treatment. Currently, the cost of this genetic testing is only covered by research funds, which has become a social issue that helps to properly diagnose patients and their families. Based on the established guidelines for this disease, we should consider the need for insurance coverage for testing and treatment and introduce the designation of intractable diseases.

Table 2

Summary of Japanese adult cases with genetically confirmed hyperekplexia

Patient	Author	Age (years)	Sex	Genetic mutation	Family history	Congenital anomaly	Bone fracture	Facial injury	Brain injury	Medicine	Treatment outcome
*Cases 4-7 are from the same family. M, male; F, female; ND, not detailed; UH, umbilical hernia; IH, inguinal hernia; HD, hip dislocation; CZP, clonazepam; NZP, nitrazepam
1	Mine7)	26	M	GLRA1	+	UH	-	-	ND	CZP	Relapse
2	Mine7)	45	M	GLRA1	+	UH, IH	Skull	-	ND	CZP	Persistent
3	Mine7)	36	M	GLRA1	+	-	-	-	ND	CZP	Persistent
4*	Moriyoshi12)	31	F	GLRA1	+	UH	Skull	+	ND	CZP	Remission
5*	Moriyoshi12)	35	F	ND	+	-	Humerus	+	ND	CZP	Remission
6*	Moriyoshi12)	39	F	ND	+	IH	Humerus	+	ND	CZP	Remission
7*	Moriyoshi12)	69	M	GLRA1	+	-	-	+	ND	CZP	Remission
8	Eimoto13)	44	F	GLRA1	+	-	ND	ND	ND	CZP+NZP	Remission
9	Present case	24	F	GLRA1	-	HD	Skull	+	Contusion	CZP	Remission

Conclusion

This report described a case of hyperekplexia in an adult presenting with head trauma. Awareness of the startle reflex in hyperekplexia is essential for accurately diagnosing and distinguishing this pathology from other conditions, particularly adult cases with falls associated with loss of consciousness.

Acknowledgments

We thank Professor Takeshi Taketani for performing genetic analyses and helping with the treatment.

Informed Consent

Informed consent was obtained from the patient in this case report.

Conflicts of Interest Disclosure

The authors declare no conflicts of interest.

References

• 1)   Zhou  L,  Chillag  KL,  Nigro  MA: Hyperekplexia: a treatable neurogenetic disease. Brain Dev 24: 669-674, 2002
• 2)   Chung  SK,  Vanbellinghen  JF,  Mullins  JG, et al.: Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. J Neurosci 30: 9612-9620, 2010
• 3)   Matsumoto  J,  Hallet  M: Startle syndromes, in  Jon  SA (ed): Movement Disorders 3. Boston, Butterworth-Heinemann, 1994, pp 418-431
• 4)   Dreissen  YE,  Tijssen  MA: The startle syndromes: physiology and treatment. Epilepsia 53: 3-11, 2012
• 5)   Becker  K,  Hohoff  C,  Schmitt  B, et al.: Identification of the microdeletion breakpoint in a GLRA1 null allele of Turkish hyperekplexia patients. Hum Mutat 27: 1061-1062, 2006
• 6)   Dreissen  YE,  Bakker  MJ,  Koelman  JH,  Tijssen  MA: Exaggerated startle reactions. Clin Neurophysiol 123: 34-44, 2012
• 7)   Mine  J,  Taketani  T,  Yoshida  K, et al.: Clinical and genetic investigation of 17 Japanese patients with hyperekplexia. Dev Med Child Neurol 57: 372-377, 2015
• 8)   Tijssen  MA,  Voorkamp  LM,  Padberg  GW,  Van Dijk  JG: Startle responses in hereditary hyperekplexia. Arch Neurol 54: 388-393, 1997
• 9)   Al-Futaisi  AM,  Al-Kindi  MN,  Al-Mawali  AM,  Koul  RL,  Al-Adawi  S,  Al-Yahyaee  SA: Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation. Pediatr Neurol 46: 89-93, 2012
• 10)   Bakker  MJ,  van Dijk  JG,  van den Maagdenberg  AM,  Tijssen  MA: Startle syndromes. Lancet Neurol 5: 513-524, 2006
• 11)   Balint  B,  Thomas  R: Hereditary hyperekplexia overview, in  Adam  MP,  Ardinger  HH,  Pagon  RA, et al. (eds): GeneReviews^®. Seattle, University of Washington, 2007, pp 1993-2021
• 12)   Moriyoshi  H,  Hata  Y,  Inagaki  R, et al.: A pedigree of hereditary hyperekplexia. Rinsho Shinkeigaku 58: 435-439, 2018
• 13)   Eimoto  A,  Imai  N,  Igasaki  S, et al.: Example of families with startle disease (Hyperexplexia) whose diagnosis was confirmed by Gene analysis. J Jpn Red Cross Shizuoka Hosp 37: 15-19, 2017 (Japanese)