Episodic ataxia and SCA6 within the same family due to the D302N CACNA1A gene mutation

Pradotto, Luca; Mencarelli, Monica; Bigoni, Matteo; Milesi, Alessandra; Blasio, Anna Di; Mauro, Alessandro

doi:10.1016/j.jns.2016.10.029

Cited by 22 publications

(19 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, overlapping clinical features described within some families with the same CACNA1A mutation are not infrequent [5][6][7][8]. Conversely, Pradotto reported distinct phenotypes, ranging from EA2 to SCA6, within the same family associated with a common CACNA1A mutation [9]. We report a child with a clinical phenotype characterized by some hemiplegic migraine attacks and neurodevelopmental disorder associated with a novel heterozygous c.4262G > A CACNA1A (NM_023035.2) variant.…”

Section: Introductionmentioning

confidence: 77%

“…But overlapping features, including typical and uncommon symptoms of mentioned disorders, have been reported among the members of the same family [5][6][7][8]. Recently, a common CACNA1A mutation with distinct phenotypes, ranging from epileptic encephalopathy, EA2 to SCA6, was also found within the same family, suggesting that several factors could play a role in the phenotypic variability [9,13].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant

et al. 2020

View full text Add to dashboard Cite

Background: To investigate the genetic and environmental factors responsible for phenotype variability in a family carrying a novel CACNA1A missense mutation. Mutations in the CACNA1A gene were identified as responsible for at least three autosomal dominant disorders: FHM1 (Familial Hemiplegic Migraine), EA2 (Episodic Ataxia type 2), and SCA6 (Spinocerebellar Ataxia type 6). Overlapping clinical features within individuals of some families sharing the same CACNA1A mutation are not infrequent. Conversely, reports with distinct phenotypes within the same family associated with a common CACNA1A mutation are very rare. Case presentation: A clinical, molecular, neuroradiological, neuropsychological, and neurophysiological study was carried out in proband and his carrier mother. The new heterozygous missense variant c.4262G > A (p.Arg1421Gln) in the CACNA1A gene was detected in the two affected family members. The proband showed a complex clinical presentation characterized by developmental delay, poor motor coordination, hemiplegic migraine attacks, behavioral dysregulation, and EEG abnormalities. The mother showed typical episodic ataxia attacks during infancy with no other comorbidities and mild cerebellar signs at present neurological evaluation. Conclusions: The proband and his mother exhibit two distinct clinical phenotypes. It can be hypothesized that other unknown modifying genes and/or environmental factors may cooperate to generate the wide intrafamilial variability.

show abstract

Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Certain CACNA1A mutation types are more frequently associated with distinct phenotypes: missense mutations with FHM, mutations resulting in a premature stop with EA2, and an exonic CAG trinucleotide repeat expansion with SCA6 (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CACNA1A). Recent reports, however, revealed an extensive clinical overlap between these three phenotypes [1,9] and a high intrafamilial phenotypic variability [5,7]. In addition, new phenotypes including seizures and mental retardation have been reported [1].…”

Section: Introductionmentioning

confidence: 99%

A Novel Frameshift CACNA1A Mutation Causing Episodic Ataxia Type 2

et al. 2018

View full text Add to dashboard Cite

“…Traditionally, SCA6 is the only disease to be associated with the polyQ expansion, as episodic ataxia type 2 is associated with a loss of function mutation, while familial hemiplegic migraine-1 is a gain of function mutation. However, familial studies in recent times have suggested that SCA6 phenotypes may also arise from missense mutations rather than expansion of the CAG repeating unit (more detail on these mutations can be found [162,163]). …”

Section: Molecular Geneticsmentioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

View full text Add to dashboard Cite

Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

show abstract

Episodic ataxia and SCA6 within the same family due to the D302N CACNA1A gene mutation

Cited by 22 publications

References 17 publications

Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant

Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant

A Novel Frameshift CACNA1A Mutation Causing Episodic Ataxia Type 2

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

Contact Info

Product

Resources

About