Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay

Saitsu, Hirotomo; Fukai, Ryoko; Ben‐Zeev, Bruria; Sakai, Yasunari; Mimaki, Masakazu; Okamoto, Nobuhiko; Suzuki, Yasuhiro; Monden, Yukifumi; Saitō, Hiroshi; Tziperman, Barak; Torio, Michiko; Akamine, Satoshi; Takahashi, Nagahisa; Osaka, Hitoshi; Yamagata, Takanori; Nakamura, Kazuyuki; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Miyake, Noriko; Shiina, Masaaki; Ogata, Kazuhiro; Matsumoto, Naomichi

doi:10.1038/ejhg.2015.92

Cited by 110 publications

(146 citation statements)

References 18 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…One identified gene, SPAST , was found in two cases (case 6 and 10). Among the causative variants identified in the nine patients, the variants in SPAST , GNAO1 , CACNA1A, and STXBP1 have been previously reported,27, 28, 29, 30, 31, 32 whereas the variants in the other genes ( CTNNB1 , CYP2U1 , AMPD2 , and SCN2A ) were novel. Of all the identified candidate genes, only SPAST , STXBP1 , and SPTBN2 have been previously reported in CP patients 33, 34, 35.…”

Section: Resultsmentioning

confidence: 90%

See 1 more Smart Citation

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveCerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full‐term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders.MethodsA total of 107 patients—all full‐term births—without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole‐exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines.ResultsPathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1,CYP2U1,SPAST,GNAO1,CACNA1A,AMPD2,STXBP1, and SCN2A. Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice‐site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments.InterpretationThe high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full‐term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy.

show abstract

Section: Resultsmentioning

confidence: 90%

“…GNAO1 variants cause both EIEE and neurodevelopmental disorders,29 which manifested in case 7 as an intellectual disability, although no seizures occurred. We identified p.(Ser218Leu) variants in case 9, diagnosed as ataxic CP.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis identifies masqueraders of full‐term cerebral palsy

Takezawa

Kikuchi

Haginoya

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…93 Status dystonicus has also been reported. [94][95][96] Many affected patients present with progressive, potentially life-threatening episodic exacerbations, which often necessitate hospitalization in an intensive care setting. Prominent movement disorders such as chorea, dystonia, facial, and orolingual dyskinesia and complex stereotypies are very commonly reported (Video S1).…”

Section: Infantile-onset Epileptic Encephalopathies Associated With Smentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

View full text Add to dashboard Cite

An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

show abstract

“…GNAO1 may display a genotype–phenotypic correlation, demonstrated in other genetic MDs, but this requires further validation. Patient 3 has late-onset seizures, a feature seen in another reported case with an identical mutation 1. Despite differences in MD at baseline, consistent features are fluctuating nature, severity, treatment resistance and orofaciolingual dyskinesia especially in exacerbations.…”

Section: Discussionmentioning

confidence: 75%