Phenotypic Variability in a Four Generation Family With a p.Thr666Met CACNA1A Gene Mutation

García-Baró-Huarte, María; Iglesias-Mohedano, Ana María; Slöcker, M.; Vázquez-López, M; García‐Morín, Marina; Miranda-Herrero, María Concepción; Castro-Castro, Pedro

doi:10.1016/j.pediatrneurol.2014.07.008

Cited by 11 publications

(7 citation statements)

References 10 publications

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“…Acetazolamide, used to treat headaches associated with FHM, has been shown to decrease the frequency of attacks, and its effectiveness has been suggested to be due to improvements in ion channel function ( 93 , 94 ). In the central nervous system, acetazolamide penetrates the blood–brain barrier slowly and causes carbonic acidosis through carbonic anhydrase inhibition ( 95 ); this acidosis may also serve to selectively reduce the buffering of rapid pH changes occurring in SD.…”

Section: Sd In Disease Conditionsmentioning

confidence: 99%

Understanding Spreading Depression from Headache to Sudden Unexpected Death

et al. 2018

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Spreading depression (SD) is a neurophysiological phenomenon characterized by abrupt changes in intracellular ion gradients and sustained depolarization of neurons. It leads to loss of electrical activity, changes in the synaptic architecture, and an altered vascular response. Although SD is often described as a unique phenomenon with homogeneous characteristics, it may be strongly affected by the particular triggering event and by genetic background. Furthermore, SD may contribute differently to the pathogenesis of widely heterogeneous clinical conditions. Indeed, clinical disorders related to SD vary in their presentation and severity, ranging from benign headache conditions (migraine syndromes) to severely disabling events, such as cerebral ischemia, or even death in people with epilepsy. Although the characteristics and mechanisms of SD have been dissected using a variety of approaches, ranging from cells to human models, this phenomenon remains only partially understood because of its complexity and the difficulty of obtaining direct experimental data. Currently, clinical monitoring of SD is limited to patients who require neurosurgical interventions and the placement of subdural electrode strips. Significantly, SD events recorded in humans display electrophysiological features that are essentially the same as those observed in animal models. Further research using existing and new experimental models of SD may allow a better understanding of its core mechanisms, and of their differences in different clinical conditions, fostering opportunities to identify and develop targeted therapies for SD-related disorders and their worst consequences.

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Section: Sd In Disease Conditionsmentioning

confidence: 99%

Understanding Spreading Depression from Headache to Sudden Unexpected Death

et al. 2018

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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 ]. Several de novo missense alleles in CACNA1A have been reported in children with congenital ataxia and intellectual disability [ 26 ], as well as with non-progressive congenital ataxia with seizures[ 27 ].…”

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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“…6 While our patient's CACNA1A variant was de novo , individuals with epilepsy and inherited pathogenic variants in CACNA1A have been described within families with phenotypic features more consistent with episodic ataxia. 5,17 This family history should be sought.…”

Section: Discussionmentioning

confidence: 75%

Dramatic Response After Lamotrigine in a Patient With Epileptic Encephalopathy and a De Novo CACNA1A Variant

Byers

Beatty

Hahn

et al. 2016

Pediatric Neurology

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BACKGROUND Channelopathies are a group of monogenic disorders that affect a single ion channel and can result in neurologic disease. While a rare cause of epilepsy, channelopathies offer unique insight to the molecular basis of epilepsy and treatment opportunities. Calcium homeostasis is tightly regulated by a series of interacting subunits. CACNA1A encodes the principal pore-forming subunit of the voltage-gated P/Q-type calcium channel, alpha1. Patients with epileptic encephalopathy due to pathogenic variants in CACNA1A have been previously described and are challenging to treat. METHODS Case report of a child with epileptic encephalopathy, ataxia, cognitive impairment and significant social behavioral abnormalities due to a de novo pathogenic variant, p.S1373L in the CACNA1A gene. RESULTS After failing zonisamide and divalproex sodium, the child had a dramatic response to lamotrigine with a precipitous decrease in seizure frequency and severity. This improvement has persisted over one year. CONCLUSION While classically thought to act at sodium channels, lamotrigine also modulates the activity of the P/Q-type calcium channel, making it a candidate for precision therapy for patients with epileptic encephalopathy due to CACNA1A pathogenic variants. The rarity and clinical heterogeneity of epilepsy due to variants in CACNA1A presents challenges to clinical diagnosis. However, genetic analysis for patients with epilepsy continues to expand, additional patients are likely to be identified molecularly. Lamotrigine should be considered as a first line treatment in patients with epileptic encephalopathy due to pathogenic variants in CACNA1A.

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Phenotypic Variability in a Four Generation Family With a p.Thr666Met CACNA1A Gene Mutation

Cited by 11 publications

References 10 publications

Understanding Spreading Depression from Headache to Sudden Unexpected Death

Understanding Spreading Depression from Headache to Sudden Unexpected Death

Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially

Dramatic Response After Lamotrigine in a Patient With Epileptic Encephalopathy and a De Novo CACNA1A Variant

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