Rare CACNA1A mutations leading to congenital ataxia

Izquierdo-Serra, Mercè; Fernández-Fernández, José M.; Serrano, Mercedes

doi:10.1007/s00424-020-02396-z

Cited by 22 publications

(17 citation statements)

References 146 publications

(166 reference statements)

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“…Various early‐onset presenting features are seen in the CAMTA1 ‐related disorder. However, these are not disease‐specific and show overlap with other congenital ataxia disorders 33‐35 . In the nine probands with a (likely) pathogenic variant we report, most were referred to a genetic center for motor, speech or cognitive delay.…”

Section: Discussionmentioning

confidence: 92%

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants

et al. 2020

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The CAMTA1‐associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome‐based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N‐ and C‐ terminal functional domains. Clinical heterogeneity is observed, but 3′‐terminal variants seem to associate with less pronounced cerebellar dysfunction.

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Section: Discussionmentioning

confidence: 92%

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants

et al. 2020

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“…Ca V 2.1 channels may play a role in nociception because inflammatory and neuropathic pain is altered in mice with deletion of Ca V 2.1 channels (Pietrobon, 2010 ). Mutations in the CACNA1A gene underlie familial hemiplegic migraine type 1, spinocerebellar ataxia type 6, and episodic ataxia type 2, and may be associated with increased risk of epilepsy (Pietrobon, 2010 ; Rajakulendran et al, 2012 ; Izquierdo-Serra et al, 2020 ).…”

Section: K + Channelsmentioning

confidence: 99%

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Boscia

Elkjaer

Illés

et al. 2021

Front. Cell. Neurosci.

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Despite significant advances in our understanding of the pathophysiology of multiple sclerosis (MS), knowledge about contribution of individual ion channels to axonal impairment and remyelination failure in progressive MS remains incomplete. Ion channel families play a fundamental role in maintaining white matter (WM) integrity and in regulating WM activities in axons, interstitial neurons, glia, and vascular cells. Recently, transcriptomic studies have considerably increased insight into the gene expression changes that occur in diverse WM lesions and the gene expression fingerprint of specific WM cells associated with secondary progressive MS. Here, we review the ion channel genes encoding K+, Ca2+, Na+, and Cl− channels; ryanodine receptors; TRP channels; and others that are significantly and uniquely dysregulated in active, chronic active, inactive, remyelinating WM lesions, and normal-appearing WM of secondary progressive MS brain, based on recently published bulk and single-nuclei RNA-sequencing datasets. We discuss the current state of knowledge about the corresponding ion channels and their implication in the MS brain or in experimental models of MS. This comprehensive review suggests that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain, while the upregulation of a large number of voltage-gated K+ channel genes may be linked to a protective response to limit neuronal excitability. In addition, the altered chloride homeostasis, revealed by the significant downregulation of voltage-gated Cl− channels in MS lesions, may contribute to an altered inhibitory neurotransmission and increased excitability.

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“…Episodes in both conditions (i) may be triggered by head traumatisms, (ii) may present after a period free of symptoms, (iii) hyperthermia is frequent (with the absence of any sign of infection in blood or CSF), (iv) abnormal EEG findings may be present, and finally, (v) hemispheric vasogenic edema may occur (8,15). Interestingly, chronically speaking, clinical, neuroimaging, and neurophysiological features of PMM2-CDG and CACNA1A related phenotypes are also similar, including, ataxia, ocular motor disturbances (particularly nystagmus and tonic upgaze deviation), and progressive cerebellar atrophy (3,8,25).…”

Section: Discussionmentioning

confidence: 99%

Stroke-Like Episodes in PMM2-CDG: When the Lack of Other Evidence Is the Only Evidence

Serrano

2021

Front. Pediatr.

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Phosphomannomutase 2 deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. PMM2-CDG patients develop chronic cerebellar atrophy as a neurological hallmark. However, other acute neurological phenomena such as stroke-like episodes (SLE), epilepsy, migraine, and cerebrovascular events, may also occur, and they are frequently the cause of disability and impaired quality of life. Among these, SLE are among the most stressful situations for families and doctors, as their risk factors are not known, their underlying pathomechanisms remain undiscovered, and clinical guidelines for diagnosis, prevention, and treatment are lacking. In this paper, the recent SLE experiences of two PMM2-CDG patients are examined to provide clinical clues to help improve diagnosis through a clinical constellation of symptoms and a clinical definition, but also to support a neuroelectrical hypothesis as an underlying mechanism. An up-to-date literature review will help to identify evidence-based and non-evidence-based management recommendations. Presently neuropediatricians and neurologists are not capable of diagnosing stroke-like episodes in an unequivocal way, so there is still a need to perform invasive studies (to rule out other acute diseases) that may, in the end, prove unnecessary or even harmful. However, reaching a correct and early diagnosis would lead not only to avoidance of invasive tests but also to better recognition, management, and understanding of the disease itself. There is a great need for understanding of SLE that may ultimately be very informative for the detection of patients at risk, and the future development of preventive and management measures.

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Rare CACNA1A mutations leading to congenital ataxia

Cited by 22 publications

References 146 publications

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Stroke-Like Episodes in PMM2-CDG: When the Lack of Other Evidence Is the Only Evidence

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