Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38)

Borroni, Barbara; Gregorio, Eleonora Di; Orsi, Laura; Vaula, Giovanna; Costanzi, Chiara; Tempia, Filippo; Mitro, Nico; Caruso, Donatella; Manes, Marta; Pinessi, Lorenzo; Padovani, Alessandro; Brusco, Alfredo; Boccone, Loredana

doi:10.1016/j.parkreldis.2016.04.030

Cited by 30 publications

(36 citation statements)

References 24 publications

(33 reference statements)

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“…Several brainstem nuclei and mitral cells of the olfactory bulb also express high levels of Elovl5 (Figure 1 and Allen Mouse Brain Atlas). Such expression pattern is in line with the principal SCA38 symptoms, which are cerebellar ataxia and anosmia (Borroni et al, 2016 ). In cerebellar PCs, the ELOVL5 protein is localized in the soma and proximal dendrites (Di Gregorio et al, 2014 ), but the products of its activity can be delivered to other cellular regions including axon, dendrites and dendritic spines.…”

Section: Introductionsupporting

confidence: 68%

“…We used an olfactory test to evaluate the ability of Elovl5 −/− mice to smell volatile odors because one of the presenting clinical features of SCA38 patients is hyposmia (Borroni et al, 2016 ). We tested Elovl5 −/− and wild type mice at 3- (mice: wild type n = 16; Elovl5 −/− n = 11), 6- (mice: wild type n = 22; Elovl5 −/− n = 17), and 12-month of age (mice: wild type n = 24; Elovl5 −/− n = 19).…”

Section: Methodsmentioning

confidence: 99%

“…The Spino-Cerebellar-Ataxia type 38 (SCA38) is caused by missense mutations in the very long chain fatty acid elongase 5 gene, ELOVL5 (Di Gregorio et al, 2014 ). SCA38 patients show a progressive motor impairment starting with gait ataxia, nystagmus and a reduction of olfactory function (hyposmia; Borroni et al, 2016 ). At the magnetic resonance imaging (MRI), mild cerebellar atrophy is present, and functional positron electron tomography (FDG-PET) shows selective hypometabolism of the cerebellum, more prominent in the vermis (Borroni et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice

Hoxha

Gabriele

Balbo

et al. 2017

Front. Cell. Neurosci.

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Spino-Cerebellar-Ataxia type 38 (SCA38) is caused by missense mutations in the very long chain fatty acid elongase 5 gene, ELOVL5. The main clinical findings in this disease are ataxia, hyposmia and cerebellar atrophy. Mice in which Elovl5 has been knocked out represent a model of the loss of function hypothesis of SCA38. In agreement with this hypothesis, Elovl5 knock out mice reproduced the main symptoms of patients, motor deficits at the beam balance test and hyposmia. The cerebellar cortex of Elovl5 knock out mice showed a reduction of thickness of the molecular layer, already detectable at 6 months of age, confirmed at 12 and 18 months. The total perimeter length of the Purkinje cell (PC) layer was also reduced in Elovl5 knock out mice. Since Elovl5 transcripts are expressed by PCs, whose dendrites are a major component of the molecular layer, we hypothesized that an alteration of their dendrites might be responsible for the reduced thickness of this layer. Reconstruction of the dendritic tree of biocytin-filled PCs, followed by Sholl analysis, showed that the distribution of distal dendrites was significantly reduced in Elovl5 knock out mice. Dendritic spine density was conserved. These results suggest that Elovl5 knock out mice recapitulate SCA38 symptoms and that their cerebellar atrophy is due, at least in part, to a reduced extension of PC dendritic arborization.

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Section: Introductionsupporting

confidence: 68%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice

Hoxha

Gabriele

Balbo

et al. 2017

Front. Cell. Neurosci.

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“…Genetic test confirmed the c.689G>T (p.Gly230Val) variant 5. Patients had already been included in a previous work on clinical features of SCA38 6. Written informed consent was obtained from all patients.…”

Section: Methodsmentioning

confidence: 99%

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Manes

Alberici

Gregorio

et al. 2017

Annals of Neurology

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ObjectiveSpinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients.MethodsWe enrolled 10 SCA38 patients, and carried out a double‐blind randomized placebo‐controlled study for 16 weeks, followed by an open‐label study with overall 40‐week DHA treatment. At baseline and at follow‐up visit, patients underwent standardized clinical assessment, brain 18‐fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis.ResultsAfter 16 weeks, we showed a significant pre–post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40‐week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients’ blood at 40 weeks as compared to baseline. No side effect was recorded.InterpretationDHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615–621

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“…In later stages of the disease, dysphagia, ophthalmoparesis, sensory loss and sometimes, pyramidal symptoms also developed with slow progression rates. Brain MRI revealed mild cerebellar atrophy with predominance in the vermis [125].…”

Section: Sca38mentioning

confidence: 99%

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

Szpisjak

Zádori

Klivényi

et al. 2019

CNSNDDT

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Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year’s promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

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Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38)

Cited by 30 publications

References 24 publications

Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice

Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

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