Familiar Hyperekplexia, a Potential Cause of Cautious Gait: A New Korean Case and
 a Systematic Review of Phenotypes

Lee, Yoonju; Kim, Nan Young; Hong, Sangkyoon; Chung, Su Jin; Jeong, Seong Ho; Lee, Phil Hyu; Sohn, Young H.

doi:10.14802/jmd.16044

Cited by 14 publications

(10 citation statements)

References 6 publications

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“…In patients with hyperekplexia, no abnormalities are observed on routine blood tests, urinalysis, brain imaging studies, or EEG. Because of the overlapping clinical signs, hyperekplexia can be misdiagnosed as epilepsy, cerebral palsy, anxiety disorder, or conversion disorder [ 11 ]. Correct diagnosis is however important as it is potentially treatable [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report

et al. 2019

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BackgroundHyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases.Case presentationIn the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C > T or p.R299X inherited from the mother and c.587C > A or p.D98E inherited from the father.ConclusionsUntil now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.

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Section: Discussionmentioning

confidence: 99%

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report

et al. 2019

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“…1,9 HPX can also be complicated by umbilical/inguinal hernia, hip dislocation, epilepsy, myoclonus, periodic limb movement during sleep, delayed motor development or social dysfunction. 6,9,18 Hypertonicity is noted during neonatal or early infancy time, which may cause prolonged apnea and even sudden death, or gradually diminished spontaneously during the first few years of life. Excessive startle reflexes may persist throughout life, although the severity differs among the patients.…”

Section: Discussionmentioning

confidence: 99%

Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia

et al. 2020

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Background and Purpose Hyperekplexia (HPX), a rare neurogenetic disorder, is classically characterized by neonatal hypertonia, exaggerated startle response provoked by the sudden external stimuli and followed by a shortly general stiffness. Glycine receptor alpha 1 (GLRA1) is the major pathogenic gene of the disease. We described the clinical manifestations of genetically confirmed HPX patients and made a literature review of GLRA1-related HPX to improve the early recognition and prompt the management of the disorder.Methods Extensive clinical evaluations were analyzed in 4 Chinese HPX patients from two unrelated families. Next generation sequencing was conducted in the probands. Sanger sequence and segregation analysis were applied to confirm the findings.Results All four patients including 3 males and 1 female presented with excessive startle reflex, a cautious gait and recurrent falls. Moreover, startle episodes were dramatically improved with the treatment of clonazepam in all cases. Exome sequencing revealed 2 homozygous GLRA1 mutations in the patients. The mutation c.1286T>A p.I429N has been previously reported, while c.754delC p.L252* is novel.Conclusions HPX is a treatable disease, and clonazepam is the drug of choice. By studying and reviewing the disorder, we summarized the phenotype, expanded the genotype spectrum, and discussed the possible pathogenic mechanisms to enhance the understanding and recognition of the disease. Early awareness of the disease is crucial to the prompt and proper administration, as well as the genetic counseling.

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“…Genetic investigation plays a very important role in the diagnosis, because, in many cases, it is an autosomal dominant pathology that already appears at the neonatal level with stiffness and abnormal motor behaviors, in addition to other clinical manifestations sometimes present, such as umbilical and inguinal hernias (1,9). However, cases have also been highlighted in which the manifestation occurs later (10), and it should not be forgotten that the high number of mutations related to this condition (which is also increasing) makes it difficult to accurately identify the pathogenetic basis of the aforementioned condition. In our paper, we wish to underline the importance of considering this pathology in a differential diagnosis of more common disorders (i.e., epilepsy, mood tone, or anxious spectrum disorders), given the possibility, as in the patient described below, of abnormal presentations (compared with those of typical cases described in literature) observed from a genetic, epidemiological, and clinical point of view (i.e., onset of hyperkinesia later than the time of birth and aggravation by the age of 50).…”

Section: Introductionmentioning

confidence: 99%

A Case of Hyperekplexia That Started From Childhood: Clinical Diagnosis With Negative Genetic Investigations

2020

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Here, we report the case of a 63-year-old woman affected by abnormal, excessive, and involuntary reactions to harmless and unexpected sensory stimuli, compatible with the diagnosis of hyperekplexia. It is a pathology that involves the glycinergic system on a hereditary basis, and even if genetic proof compatible with the diagnosis is not present in this case, the fact that an aunt on her father's side suffered from the same disorders supports the clinical suspicion. From an early age, clinical history shows anomalous motor manifestations, initially framed as a form of focal epilepsy or ordinary disorders of the mood sphere, later excluded by the lack of effectiveness of a targeted therapy. Despite this, intellectual, psychological, and socio-emotional development was regular. The manifestations, present throughout childhood, adolescence, and early adulthood in moderate entity, worsened after the age of 50, perhaps due to hormonal changes. The presence of consequent anxiety and depression has compromised her quality of life, and in order to improve it, therapies were resorted, which, however, produced cognitive-attention deficits. No diagnostic exam has confirmed the diagnosis, although some scars in some brain areas involved in the control of reactions are elements favorable to this condition in genetically predisposed subjects. Therapies currently in use attenuate the motor symptomatology without resolving it and cause side effects in the psychological and cognitive sphere. In this case, we want to highlight the difficulty of diagnosing a very rare genetic condition, still not well-known, which presents symptoms easily mistaken for other more common diseases, because there are no specific clinical-diagnostic tools for the time being. In this particular case, we describe a female patient with an atypical onset age and negative genetic investigations compared with what is known in literature regarding this rare disorder. That is why it has been thought she was affected by epilepsy or anxiety-related disorders for several years.

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Familiar Hyperekplexia, a Potential Cause of Cautious Gait: A New Korean Case and a Systematic Review of Phenotypes

Cited by 14 publications

References 6 publications

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report

Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia

A Case of Hyperekplexia That Started From Childhood: Clinical Diagnosis With Negative Genetic Investigations

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