ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

Salles, Philippe A.; Mata, Ignacio; Lal, Dennis; Fernández, Hubert H.

doi:10.3389/fneur.2021.637890

Cited by 44 publications

(27 citation statements)

References 87 publications

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“…These genes are involved in intracellular calcium signaling and insulin secretion (Supplemental Table 2). Atp1a3 encodes a subunit isoform of a major Na + /K + ATPase pump (Salles et al 2021 ), which is important for insulin secretion (Rorsman and Ashcroft 2018 ). Cacna1g codes for a component of the voltage-gated calcium channel, which is also essential for insulin secretion (Yang and Berggren 2006 ).…”

Section: Resultsmentioning

confidence: 99%

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

et al. 2022

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Arsenic is a pervasive environmental toxin that is listed as the top priority for investigation by the Agency for Toxic Substance and Disease Registry. While chronic exposure to arsenic is associated with type 2 diabetes (T2D), the underlying mechanisms are largely unknown. We have recently demonstrated that arsenic treatment of INS-1 832/13 pancreatic beta cells impairs glucose-stimulated insulin secretion (GSIS), a T2D hallmark. We have also shown that arsenic alters the microRNA profile of beta cells. MicroRNAs have a well-established post-transcriptional regulatory role in both normal beta cell function and T2D pathogenesis. We hypothesized that there are microRNA master regulators that shape beta cell gene expression in pathways pertinent to GSIS after exposure to arsenicals. To test this hypothesis, we first treated INS-1 832/13 beta cells with either inorganic arsenic (iAsIII) or monomethylarsenite (MAsIII) and confirmed GSIS impairment. We then performed multi-omic analysis using chromatin run-on sequencing, RNA-sequencing, and small RNA-sequencing to define profiles of transcription, gene expression, and microRNAs, respectively. Integrating across these data sets, we first showed that genes downregulated by iAsIII treatment are enriched in insulin secretion and T2D pathways, whereas genes downregulated by MAsIII treatment are enriched in cell cycle and critical beta cell maintenance factors. We also defined the genes that are subject primarily to post-transcriptional control in response to arsenicals and demonstrated that miR-29a is the top candidate master regulator of these genes. Our results highlight the importance of microRNAs in arsenical-induced beta cell dysfunction and reveal both shared and unique mechanisms between iAsIII and MAsIII.

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Section: Resultsmentioning

confidence: 99%

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

et al. 2022

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“…The two other classic phenotypes include (1) infantile-onset alternating hemiplegia of childhood or (2) cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Myriad rarer phenotypes also exist 54 . Alternating hemiplegia of childhood is an early childhood–onset disorder involving paroxysmal episodes of alternating hemiparesis or hemidystonia and seizures, with progressive motor and cognitive impairment 53 .…”

Section: Genetic Forms Of Dystoniamentioning

confidence: 99%

The Dystonias

Stephen¹

2022

CONTINUUM: Lifelong Learning in Neurology

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PURPOSE OF REVIEW: This article discusses the most recent findings regarding the diagnosis, classification, and management of genetic and idiopathic dystonia.RECENT FINDINGS: A new approach to classifying dystonia has been created with the aim to increase the recognition and diagnosis of dystonia. Molecular biology and genetic studies have identified several genes and biological pathways involved in dystonia.SUMMARY: Dystonia is a common movement disorder involving abnormal, often twisting, postures and is a challenging condition to diagnose. The pathophysiology of dystonia involves abnormalities in brain motor networks in the context of genetic factors. Dystonia has genetic, idiopathic, and acquired forms, with a wide phenotypic spectrum, and is a common feature in complex neurologic disorders. Dystonia can be isolated or combined with another movement disorder and may be focal, segmental, multifocal, or generalized in distribution, with some forms only occurring during the performance of specific tasks (task-specific dystonia). Dystonia is classified by clinical characteristics and presumed etiology. The management of dystonia involves accurate diagnosis, followed by treatment with botulinum toxin injections, oral medications, and surgical therapies (mainly deep brain stimulation), as well as pathogenesis-directed treatments, including the prospect of disease-modifying or gene therapies.

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“…[60] Intermediate phenotypes or affected individuals with atypical features that do not completely express classical signs of the above-mentioned disorders have been reported. [61][62][63]…”

Section: Ahc and Atp1a3-related Disordersmentioning

confidence: 99%

Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

et al. 2022

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Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood–onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.

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ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

Cited by 44 publications

References 87 publications

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis

The Dystonias

Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

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