Is the ataxia of Charlevoix–Saguenay a developmental disease?

Gazulla, José; Vela, Antonio; Marín, Miguel Ángel Fernández-Villacañas; Júlvez, Luis Pablo; Santorelli, Filippo M.; Benavente, Isabel; Modrego, Pedro J.; Tintoré, María; Berciano, José

doi:10.1016/j.mehy.2011.05.011

Cited by 20 publications

(20 citation statements)

References 30 publications

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“…Three major results, which confirm and add to previous findings [10][11][12] , can be derived from our data: 1) Large TPF with increased FA and AD and decreased RD squeezed and displaced the pontine CST with decreased FA, increased RD, and increased mean diffusivity, as was also observed on tractography.…”

Section: Discussionsupporting

confidence: 91%

“…In agreement with Gazulla et al, 10,11 the pontine CST was not only engulfed by the TPF (TPF was thick because of hypermyelination and/or axonal hypertrophy), but was also dislocated on directionally encoded FA images. The presence of hypermyelinated or thickened peripapillar retinal fibers has been considered a pathognomonic feature of ARSACS for quite some time.…”

Section: Discussionsupporting

confidence: 89%

“…7 By measuring anisotropic diffusion of water in the WM, DTI detects abnormalities in the myelin, axon, or orientation of fibers within the bundle. 8,9 Gazulla et al 10,11 described nonquantitative abnormalities of the TPF and CST by DTI in 2 studies with 5 patients. These authors suggested a developmental basis for ARSACS by showing interruption of the CST in the pons by large TPF.…”

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confidence: 99%

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Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Oğuz

Haliloğlu²,

Temuçin

et al. 2013

AJNR Am J Neuroradiol

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

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Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Oğuz

Haliloğlu²,

Temuçin

et al. 2013

AJNR Am J Neuroradiol

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“…For example, it is even unclear whether progressive neuronal death in the cerebellum is responsible for evolution of the ataxia, the major symptom, or whether the disease is predominantly developmental (28). To explore the neurodevelopmental and neurodegenerative aspects of ARSACS, a transgenic KO mouse model was generated in which most of the gigantic 12,794 bp exon 10 of SACS was replaced with an IRES-βGal cassette (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

Girard

Larivière²,

Parfitt³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

162

182

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset neurological disease resulting from mutations in the SACS gene encoding sacsin, a 4,579-aa protein of unknown function. Originally identified as a founder disease in Québec, ARSACS is now recognized worldwide. Prominent features include pyramidal spasticity and cerebellar ataxia, but the underlying pathology and pathophysiological mechanisms are unknown. We have generated an animal model for ARSACS, sacsin knockout mice, that display agedependent neurodegeneration of cerebellar Purkinje cells. To explore the pathophysiological basis for this observation, we examined the cell biological properties of sacsin. We show that sacsin localizes to mitochondria in non-neuronal cells and primary neurons and that it interacts with dynamin-related protein 1, which participates in mitochondrial fission. Fibroblasts from ARSACS patients show a hyperfused mitochondrial network, consistent with defects in mitochondrial fission. Sacsin knockdown leads to an overly interconnected and functionally impaired mitochondrial network, and mitochondria accumulate in the soma and proximal dendrites of sacsin knockdown neurons. Disruption of mitochondrial transport into dendrites has been shown to lead to abnormal dendritic morphology, and we observe striking alterations in the organization of dendritic fields in the cerebellum of knockout mice that precedes Purkinje cell death. Our data identifies mitochondrial dysfunction/mislocalization as the likely cellular basis for ARSACS and indicates a role for sacsin in regulation of mitochondrial dynamics.

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“…In addition, our hypothesis of RNFL hypertrophy is strengthened by the following findings: tensor diffusion sequences indicate that the hypointense striation corresponds with hyperplasia of the pontocerebellar fibres, which leads to abnormally thick middle cerebellar peduncles;5 6 T2 and T2-fluid attenuation inversion recovery-weighted MRI sequences reveal cerebellar atrophy and a hypointense linear striation at the pons;5 6 ultrastructural observations do not corroborate the notion that hypermyelinated fibres constitute the basic pathophysiology of the retinal abnormities in ARSACS patients;4 genetic studies indicate that SACS functions in nerve fibre development; and nerve biopsies in patients published to date reveal only a depletion of myelinated fibres, and not hypermyelinated fibres (figure 2). 4…”

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confidence: 86%