Contributions to the study of spinocerebellar ataxia type 38 (SCA38)

Gazulla, José; Orduna‐Hospital, Elvira; Benavente, Isabel; Rodríguez-Valle, Ana; Osorio-Caicedo, Pedro; Andrés, Sara Alvarez-de; García-González, Elena; Fraile-Rodrigo, Jesús; Fernández‐Tirado, F. J.; Berciano, José

doi:10.1007/s00415-020-09840-1

Cited by 15 publications

(8 citation statements)

References 22 publications

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“…Improvement in cerebellar features was also corroborated by signi cant improvement of cerebellar hypometabolism [3]. The favorable response to prolonged DHA supplementation in the patient here reported is in line with other reports [4,6].…”

Section: Discussionsupporting

confidence: 90%

Interpretation of Variants of Uncertain Significance in the Clinical Setting: A Case of Treatable Ataxia

Wilken¹,

Rossi²,

Merello³

2020

Preprint

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Background: Spinocerebellar ataxia type 38 (SCA38) is an autosomal dominant cerebellar ataxia caused by pathogenic variants in the elongation of very long chain fatty acids-like 5 gene (ELOVL5). Improvement of ataxia with a docosahexaenoic acid (DHA) replacement therapy has been reported.Case presentation: A 73-year-old man of Hispanic descent presented with gait and limb ataxia, dysarthria, slow and hypometric saccades, hearing loss, mild cognitive impairment, and hypopalesthesia. The initial scale for the assessment and rating of ataxia (SARA) score was 11. After a negative routine workout for ataxia and testing for common forms due to expanded repeats, whole-exome sequencing (WES) identified a heterozygous variant (c.327+1G>A) in the ELOVL5 gene that was predicted to have a negative effect on splicing but was categorized as a Variant of Uncertain Significance (VUS). The patient was started on DHA 600 mg/day. Four months later, the patient showed a considerable reduction in the scale for the assessment and rating of ataxia (SARA) score, from 11 to 5 points, with a clear improvement in gait and limb ataxia that was sustained at 24 months of follow-up.Conclusions: We illustrate the case of a patient presenting with a variant considered genetically and biochemically of uncertain significance. Despite being a VUS, its location in a gene that is known to cause ataxia (SCA38), as well as a compatible phenotype, led to the interpretation of this variant as probably pathogenic from a clinical practice standpoint, especially considering prior reports that showed clinical improvement with a specific, over-the-counter, pharmacological treatment. A further satisfactory response to treatment supported our clinical approach.

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Section: Discussionsupporting

confidence: 90%

Interpretation of Variants of Uncertain Significance in the Clinical Setting: A Case of Treatable Ataxia

Wilken¹,

Rossi²,

Merello³

2020

Preprint

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“…Later reports of that same kinship, and of 2 other families related to it, included downbeat and gaze-evoked nystagmus, concomitant esotropia, altered ocular pursuit, progressive cerebellar ataxia and a lack of response to acetazolamide [26, 27]. With utmost respect for the work of those early authors and with the benefit of hindsight, as well as that of recent advances in the fields of episodic and progressive hereditary ataxias, it could be hypothesized that SCA6 or SCA38 could constitute possible alternative diagnoses for those kindreds because those diseases display downbeat nystagmus, vestibular dysfunction, diplopia and transient worsening of ataxia, while EA1, EA2, SCA1, 2, 3, 4, 5, and dentatorubral-pallidoluysian atrophy, had been discarded by molecular studies [28, 29].…”

Section: Discussionmentioning

confidence: 99%

Episodic Vestibulocerebellar Ataxia Associated with a CACNA1G Missense Variant

Gazulla¹,

Álvarez²,

Ruiz-Fernández³

et al. 2021

Case Rep Neurol

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Episodic vestibulocerebellar ataxias are rare diseases, frequently linked to mutations in different ion channels. Our objective in this work was to describe a kindred with episodic vestibular dysfunction and ataxia, associated with a novel CACNA1G variant. Two individuals from successive generations developed episodes of transient dizziness, gait unsteadiness, a sensation of fall triggered by head movements, headache, and cheek numbness. These were suppressed by carbamazepine (CBZ) administration in the proband, although acetazolamide and topiramate worsened instability, and amitriptyline and flunarizine did not prevent headache spells. On examination, the horizontal head impulse test (HIT) yielded saccadic responses bilaterally and was accompanied by cerebellar signs. Two additional family members were asymptomatic, with normal neurological examinations. Reduced vestibulo-ocular reflex gain values, overt and covert saccades were shown by video-assisted HIT in affected subjects. Hearing acuity was normal. Whole-exome sequencing demonstrated the heterozygous CACNA1G missense variant c.6958G>T (p.Gly2320Cys) in symptomatic individuals. It was absent in 1 unaffected member (not tested in the other asymptomatic individual) and should be considered likely pathogenic. CACNA1G encodes for the pore-forming, α1G subunit of the T-type voltage-gated calcium channel (VGCC), in which currents are transient owing to fast inactivation, and tiny, due to small conductance. Mutations in CACNA1G cause generalized absence epilepsy and adult-onset, dominantly inherited, spinocerebellar ataxia type 42. In this kindred, the aforementioned CACNA1G variant segregated with disease, which was consistent with episodic vestibulocerebellar ataxia. CBZ proved successful in bout prevention and provided symptomatic benefit in the proband, probably as a result of interaction of this drug with VGCC. Further studies are needed to fully determine the vestibular and neurological manifestations of this form of episodic vestibulocerebellar ataxia. This novel disease variant could be designated episodic vestibulocerebellar ataxia type 10.

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“…Until recently, saltatory nerve conduction was considered the only purpose of myelin, but myelinating oligodendrocytes can also provide metabolic support to neurons, and regulate ion and water homeostasis by adapting to activity-dependent neuronal signals [50]. Mutations in very long chain fatty acid elongase 4 and 5 (Elovl4 and ElovL5) are reported to cause spinocerebellar ataxia [51][52][53] and accumulation of the branched-chain acid fatty acid was reported to be associated with Refsum disease caused by mutations in Phytanic acid alpha-oxidation (in AOA gene panel) [54]. Additionally, MECR mutations cause a mitochondrial fatty-acid synthesis disorder and is characterized by a childhood-onset dystonia [55].…”

Section: Discussionmentioning

confidence: 99%

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology

et al. 2020

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In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD+), are still unclear. In 80 EOA-patients, we determined the EOAD+-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD+-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD+-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus (p = 0.001)). Genetic network and functional enrichment analysis in EOAD+-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD+-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD+-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.

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Contributions to the study of spinocerebellar ataxia type 38 (SCA38)

Cited by 15 publications

References 22 publications

Interpretation of Variants of Uncertain Significance in the Clinical Setting: A Case of Treatable Ataxia

Interpretation of Variants of Uncertain Significance in the Clinical Setting: A Case of Treatable Ataxia

Episodic Vestibulocerebellar Ataxia Associated with a <b><i>CACNA1G</i></b> Missense Variant

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology

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