Open Access Research

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

Matthis Synofzik12*, Anne S Soehn3, Janina Gburek-Augustat4, Julia Schicks12, Kathrin N Karle12, Rebecca Schüle12, Tobias B Haack5, Martin Schöning4, Saskia Biskup126, Sabine Rudnik-Schöneborn7, Jan Senderek78, Karl-Titus Hoffmann9, Patrick MacLeod10, Johannes Schwarz11, Benjamin Bender12, Stefan Krüger13, Friedmar Kreuz13, Peter Bauer3 and Ludger Schöls12

Author Affiliations

1 Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, Tübingen, 72076, Germany

2 German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

3 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

4 Department of Neuropediatrics, University of Tübingen, Tübingen, Germany

5 Institute of Human Genetics, Technische Universität München, Munich, Germany

6 CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany

7 Institute of Human Genetics, RWTH Aachen University, Aachen, Germany

8 Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilian University Munich, Munich, Germany

9 Department of Neuroradiology, University of Leipzig, Leipzig, Germany

10 Medical Genetics Clinic, Victoria General Hospital, Victoria, Canada

11 Hospital Mühldorf am Inn, Mühldorf, Germany

12 Dept. of Neuroradiology, University of Tübingen, Tübingen, Germany

13 Gemeinschaftspraxis für Humangenetik, Dresden, Germany

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Orphanet Journal of Rare Diseases 2013, 8:41  doi:10.1186/1750-1172-8-41

Published: 15 March 2013

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.

Keywords:
Ataxia; Recessive ataxia; Spastic ataxia; Early onset ataxia; Spasticity; Genetics; Magnetic resonance imaging; Electrophysiology; Thin corpus callosum; Charcot Marie Tooth; Hereditary spastic paraplegia