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Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.

ABSTRACT: BACKGROUND: Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype. METHODS: Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants in 3.500 European control chromosomes and extensive phenotypic investigations of all SACS carriers. RESULTS: We identified 11 index patients harbouring 17 novel SACS variants. 9/11 patients harboured two variants of at least probable pathogenicity which were not observed in controls and, in case of missense mutations, were located in highly conserved domains. These 9 patients accounted for at least 11% (9/83) in our series of unexplained early onset ataxia subjects. While most patients (7/9) showed the classical ARSACS triad, the presenting phenotype reached from pure neuropathy (leading to the initial diagnosis of Charcot-Marie-Tooth disease) in one subject to the absence of any signs of neuropathy in another. In contrast to its name "spastic ataxia", neither spasticity (absent in 2/9=22%) nor extensor plantar response (absent in 3/9=33%) nor cerebellar ataxia (absent in 1/9=11%) were obligate features. Autonomic features included urine urge incontinence and erectile dysfunction. Apart from the well-established MRI finding of pontine hypointensities, all patients (100%) showed hyperintensities of the lateral pons merging into the (thickened) middle cerebellar peduncles. In addition, 63% exhibited bilateral parietal cerebral atrophy, and 63% a short circumscribed thinning of the posterior midbody of the corpus callosum. In 2 further patients with differences in important clinical features, VUS class 3 variants (c.1373C>T [p.Thr458Ile] and c.2983 G>T [p.Val995Phe]) were identified. These variants were, however, also observed in controls, thus questioning their pathogenic relevance. CONCLUSIONS: We here demonstrate that each feature of the classical ARSACS triad (cerebellar ataxia, spasticity and peripheral neuropathy) might be missing in ARSACS. Nevertheless, characteristic MRI features - which also extend to supratentorial regions and involve the cerebral cortex - will help to establish the diagnosis in most cases.

SUBMITTER: Synofzik M

PROVIDER: S-EPMC3610264 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.

Synofzik Matthis M Soehn Anne S AS Gburek-Augustat Janina J Schicks Julia J Karle Kathrin N KN Schüle Rebecca R Haack Tobias B TB Schöning Martin M Biskup Saskia S Rudnik-Schöneborn Sabine S Senderek Jan J Hoffmann Karl-Titus KT MacLeod Patrick P Schwarz Johannes J Bender Benjamin B Krüger Stefan S Kreuz Friedmar F Bauer Peter P Schöls Ludger L

Orphanet journal of rare diseases 20130315

<h4>Background</h4>Mutations in SACS, leading to autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), have been identified as a frequent cause of recessive early-onset ataxia around the world. Here we aimed to enlarge the spectrum of SACS mutations outside Quebec, to establish the pathogenicity of novel variants, and to expand the clinical and imaging phenotype.<h4>Methods</h4>Sequencing of SACS in 22 patients with unexplained early-onset ataxia, assessment of novel SACS variants ...[more]

PMID: 23497566

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Project description:Oxidative stress occurs when physiological antioxidant systems do not manage to counteract the excessive intracellular production of reactive oxygen species (ROS), which accumulate leading to irreversible oxidation of DNA and other biomacromolecules, and thus to the onset of pathological conditions. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease characterized by autosomal recessive mutations in the sacsin gene (SACS). It has been demonstrated that cells of ARSACS patients show bioenergetic and mitochondrial impairment, denoted by reduced respiratory chain activities and ATP synthesis. In order to design a suitable therapy for ARSACS, it is essential to consider that treatments need to cross the blood-brain barrier (BBB), a specialized structure that separates the subtle environment of the brain from blood circulation. Nanostructured lipid carriers (NLCs), constituted by a solid lipid shell and a liquid lipid phase in the core, have been fabricated for loading hydrophobic molecules, improving their bioavailability. Idebenone (IDE), a synthetic analogue of coenzyme Q10, is able to inhibit lipid peroxidation and detoxify several free radicals. However, because of its poor solubility, it requires ad hoc drug-delivery systems for enhancing its pharmacokinetic properties, preventing undesired cytotoxicity. In this work, NLCs loaded with idebenone (IDE-NLCs) have been prepared. The nanovectors have been physicochemically characterized, and their biological activity has been evaluated on different central nervous system cell lines. IDE-NLCs demonstrated to be stable in water and in cell culture media, and showed a sustained drug release profile. Interestingly, preliminary data demonstrated their ability to permeate an in vitro BBB model. Their protective antioxidant activity in human healthy primary skin fibroblasts and their therapeutic efficacy in ARSACS-derived primary skin fibroblasts have been also investigated, showing their potential for future development as therapeutic agents.

Dataset Information

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.

Publications

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum.

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