Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A

Segarra, Nuria Garcia; Gautschi, Ivan; Mittaz-Crettol, Lauréane; Zetchi, Christine Kallay; Al‐Qusairi, Lama; Bemmelen, Miguel X. van; Maeder, Philippe; Bonafé, Luisa; Schild, Laurent; Roulet-Perez, Eliane

doi:10.1016/j.jns.2014.04.027

Cited by 40 publications

(36 citation statements)

References 36 publications

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“…In episodic CACNA1A disorders, the most common finding was a developmental delay after a normal birth and an unremarkable neonatal period (25 FHM1 and 10 EA2 pedigrees, respectively) []. Delayed motor milestones or mental retardation were usually observed in the offspring of patients previously diagnosed with EA2 or FHM1, before the onset of episodic symptoms.…”

Section: Resultsmentioning

confidence: 99%

“…Cerebellar signs and/or cerebellar atrophy in imaging studies were found in virtually all FHM1 and EA2 patients who showed cognitive and psychiatric disturbances. Notably, in some cases with unremarkable findings at the first imaging assessment, cerebellar atrophy eventually appeared later in the course of the disease . The cerebellum is involved not only in motor tasks but also in the modulation of higher‐order function .…”

Section: Discussionmentioning

confidence: 99%

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The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature

Indelicato

Nachbauer

Karner

et al. 2018

Euro J of Neurology

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature

Indelicato

Nachbauer

Karner

et al. 2018

Euro J of Neurology

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“…54 Patients with mutations in CACNA1A have an increasingly broad spectrum of phenotypes, including reports of acute onset of hemiplegic episodes after minor head trauma. 55 …”

Section: Differential Diagnosismentioning

confidence: 99%

The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

Sweney

Newcomb

Swoboda

2015

Pediatric Neurology

132

114

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“…While the disease phenotypes for EA2 and FHM appear to relate to different underlying genetic mechanisms, considerable phenotypic overlap between FHM and EA2 means that some individuals exhibit features of both disorders [ 23 , 24 ]. Indeed even within the same family, the same CACNA1A variants can produce phenotypes more similar to FHM than EA2 [ 23 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially

et al. 2017

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Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

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Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A

Cited by 40 publications

References 36 publications

The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature

The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature

The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially

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