JMD https://doi.org/10.14802/jmd.16044 / J Mov Disord 2017;10(1):53-58 pISSN 2005-940X / eISSN 2093-4939 CASE REPORT Familiar Hyperekplexia, a Potential Cause of Cautious Gait: A New Korean Case and a Systematic Review of Phenotypes Yoonju Lee1, Nan Young Kim2, Sangkyoon Hong2, Su Jin Chung1, Seong Ho Jeong1, Phil Hyu Lee1, Young H. Sohn1 1Department of Neurology, Yonsei University College of Medicine, Seoul, Korea 2Hallym Institute of Translational Genomics and Bioinformatics, Hallym University College of Medicine, Anyang, Korea ABSTRACT Familial hyperekplexia, also called startle disease, is a rare neurological disorder characterized by excessive startle responses to noise or touch. It can be associated with serious injury from frequent falls, apnea spells, and aspiration pneumonia. Familial hy- perekplexia has a heterogeneous genetic background with several identified causative genes; it demonstrates both dominant and recessive inheritance in the α1 subunit of the glycine receptor (GLRA1), the β subunit of the glycine receptor and the presynaptic sodium and chloride-dependent glycine transporter 2 genes. Clonazepam is an effective medical treatment for hyperekplexia. Here, we report genetically confirmed familial hyperekplexia patients presenting early adult cautious gait. Additionally, we re- view clinical features, mode of inheritance, ethnicity and the types and locations of mutations of previously reported hyperek- plexia cases with a GLRA1 gene mutation. Key WordsaaHyperekplexia; GLRA1; deep phenotyping. Hyperekplexia, or startle disease, is an uncommon nonepi- history were not remarkable. There was no developmental de- leptic disorder classically characterized by exaggerated startle lay or neurologic deficit; however, her parents had noticed sud- responses to unexpected stimuli. It can occur as a hereditary den falling events since she was five years old. In response to disorder and is typically caused by a mutation in the alpha 1 unexpected tactile stimulation, she felt her body become rigid subunit of the glycine receptor (GLRA1) gene.1 The major form for a few seconds, which resulted in injurious falling down of hyperekplexia refers to the type that occurs in neonates, who events with spared consciousness. She usually kept indoors have hypertonia or stiffness that tends to resolve over time.2 We and walked cautiously in order to avoid unexpected falling ac- report a new case of genetically confirmed familial hyperek- cidents. In childhood, the frequency of her falls was approxi- plexia caused by GLRA1 mutation and systematically review mately four or five times per year, but after her teenage years, the phenotypes reported in the literature. the frequency decreased to once or twice per year. She remem- bered that drinking alcohol ameliorated the symptoms. Her fa- CASE REPORT ther and older sister had similar symptoms (Figure 1A). On physical examination, she had numerous scars on her forehead A 20-year-old woman visited the neurology clinic for gener- from previous falling accidents. Apart from cautious gait, her alized stiffness and frequent falling episodes secondary to tac- neurological examination was normal. Brain MRI and EEG tile stimuli. She was born at term, and her antenatal and birth were not remarkable. Received: September 22, 2016 Revised: November 3, 2016 Accepted: November 4, 2016 Corresponding author: Young H. Sohn, MD, PhD, Department of Neurology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea / Tel: +82-2-2228-1601 / Fax: +82-2-393-0705 / E-mail: [email protected] cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2017 The Korean Movement Disorder Society 53 JMD J Mov Disord 2017;10(1):53-58 Whole exome sequencing with genomic DNA sequence: NM_001146040.1) in GLRA1. No muta- extracted from peripheral blood identified a het- tions were found in other genes known to cause fa- erozygous missense mutation c.896G>A (reference milial hyperekplexia, such as GLRB, SLC6A5, GPHN, A B c.896G>A (p.Arg299Gln) Frequency of clinical features C % yes % no % NA % yes Hypertonicity 76 Exaggerated startle response 73 Frequentfalls 57 Hyperactive brainstem reflexes 40 Good response to clonazepam 37 Episodic generalized skeletal muscle contractions 27 Myoclonus 25 Apnea spell 20 Developmental delay 17 Umbilical hemia 15 Inguinal hemia 11 Infants may die from apnea or aspiration 7 Hip dislocation 7 Cautious gait 4 Noctumal seizures 2 EEG during episodes shows desynchronization 2 Club foot 2 Feeding difficulty 2 Paralytic ileus 1 EMG shows continuous motor unit fining at rest 1 D Types and locations of mutations E p.Ile71Phe 1 AD 73.9% Ethnicity p.Arg246Gln 1 Number of patients with p.Ile272Asp 1 unknown data: 51 (31.7%) p.Val288Met 1 p.Gln294His 4 African 3% p.Arg299Gln 45 p.Arg299Leu 29 Arabic p.Arg299Pro 4 p.Arg299X 1 8% p.Ala300Pro 2 Turkish p.Lys304Gln 1 14% Caucasian p.Lys304Glu 10 42% p.Tyr307Cys 18 p.Try307Ser 1 Deletion of exons 1–7 13 Asian AR 26.1% p.Arg100His 3 33% p.Lys132Argfs*15 5 p.Trp198Ser 9 p.Tyr256Cys 2 p.Ser259Arg 1 p.Arg280His 2 p.Gly342Ser 1 p.Arg420His 1 p.Trp96Cys/p.Arg344X 2 p.Cys166Ser/p.Asp176Metfs*16 1 p.Ala412Pro/p.Arg420His 1 p.Arg344X/p.Arg420His 1 Color Figure 1. A pedigree of a Korean family with hyperekplexia (A). An arrow indicates the proband. Selected sequences from GLRA1 exon 7 indicating the c.896G>A mutation using reverse primers (B). The results of systematic review of the literature regarding hyperekplexia caused by GLRA1 mutation are shown with respect to percentage of clinical features (C) and types and locations of mutations with mode of inheritance (D) and ethnicity (E). In the percentage bar graph (C), blue refers to present, red refers to absent, and green means not available. Numbers beside the bars in graph D represent number of cases with the specified mutation. NA: not available, AD: autosomal domi- nant, AR: autosomal recessive. 54 Hyperekplexia with Cautious Gait Lee Y, et al. and ARHGEF9. The change in the patient’s GLRA1 agnose hyperekplexia. The patients also suffered sequence alters the arginine codon at 299 to a gly- from severe complications, such as developmental cine codon (p.Arg299Gln). This mutation was con- delay (16.8%) and apnea spells (20.7%). External ab- firmed by Sanger sequencing (Figure 1B). The same normalities, such as umbilical (13.9%) and inguinal mutation was also found in her sister, who was symp- hernia (11.2%), hip dislocation (6.8%) and club foot tomatic; however, we could not perform a genetic (1.9%), were not uncommonly observed (Figure 1C). study on her parents. Clonazepam was administered These findings are consistent with a previous case at a dose of 0.5 mg per day, which resulted in an im- series that is not included in our analysis.4 Clinical provement in the startle response. features that helped differentiate hyperekplexia from epilepsy included unexpected stimulus-induc- DISCUSSION ing falling accidents, short episodes lasting only a few seconds, and spared consciousness, with no oth- Hyperekplexia, known as a hereditary startle dis- er abnormal movements accompanying the event. ease, is characterized by an exaggerated startle re- Cautious gait, face lacerations and family history sponse and neonatal hypertonia. This disorder is a may be helpful for differentiating hyperekplexia rare neurogenetic condition, but it is potentially from conversion disorder. Frequent falls were ob- treatable.1 The symptom spectrum can vary from served in 39.8% of cases for which information was an exaggerated startle response to infantile apnea available, and cautious gait was reported infrequent- spells and even injurious falls. The disease can be ly (4%). Data regarding falls and gait might have accompanied by abdominal hernia, hip dislocation been biased by patients’ age, and therefore, there is and developmental delay.2 A previous case study a potential for missed information. Six out of 161 reported a possible association with sudden infant reviewed patients exhibited a wide-based and stiff death syndrome.3 In patients with hyperekplexia, no gait due to considerable fear of an unexpected fall- abnormalities are observed on routine blood tests, ing event, and two patients lacked confidence in out- urinalysis, brain imaging studies, or EEG.1 Hyper- door environments, resulting in impaired social be- ekplexia could be misdiagnosed as epilepsy, cere- havior. Presentation of a cautious gait resulting from bral palsy, anxiety disorder, or conversion disorder unexpected falling episodes might be an indication and therefore can be mistreated. Early diagnosis and of hyperekplexia. Clonazepam, which enhances GA- treatment are important, as they not only prevent BA-gated chloride channel function and presum- injuries but may also influence the quality of life of ably compensates for defective glycine-gated chlo- a patient. ride channel function, has been considered the first To conduct a systematic review of the literature re- choice for the treatment of hyperekplexia. Antiepi- garding hyperekplexia cases caused by mutation in leptic drugs, including carbamazepine, phenytoin, the GLRA1 gene, we retrieved articles from the valproate, and vigabatrin, have also been used for PubMed database using the keywords “Hyperek- treatment.1 In this review, 60 out of 70 cases (85.7%) plexia AND GLRA1, English” and “Hyperekplexia showed good response to clonazepam, which is AND case, English”. The references used in this sys- similar to a previous study.4 tematic review are listed in the supplementary in- Among genes causing familial hyperekplexia, formation. Clinical features, ethnicity, types and lo- GLRA1 is the most common causative gene, ac- cations of mutations and mode of inheritance, as counting for 80% of hereditary cases.5,6 Our patients obtained from the retrieved literature, are summa- carried a heterozygous mutation, p.Arg299Gln, rized in Table 1.