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

Orphanet Journal of Rare Diseases

Ludger Schöls²  Peter Bauer^1,12  Friedmar Kreuz⁶  Stefan Krüger⁶  Benjamin Bender^1,11  Johannes Schwarz⁷  Patrick MacLeod⁸  Karl-Titus Hoffmann⁹  Jan Senderek¹  Sabine Rudnik-Schöneborn⁴  Saskia Biskup³  Martin Schöning^1,10  Tobias B Haack⁵  Rebecca Schüle²  Kathrin N Karle²  Julia Schicks²  Janina Gburek-Augustat^1,10  Anne S Soehn^1,12  Matthis Synofzik² 

[1] Department of Neurology, Friedrich-Baur Institute, Ludwig-Maximilian University Munich, Munich, Germany;German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany;CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany;Institute of Human Genetics, RWTH Aachen University, Aachen, Germany;Institute of Human Genetics, Technische Universität München, Munich, Germany;Gemeinschaftspraxis für Humangenetik, Dresden, Germany;Hospital Mühldorf am Inn, Mühldorf, Germany;Medical Genetics Clinic, Victoria General Hospital, Victoria, Canada;Department of Neuroradiology, University of Leipzig, Leipzig, Germany;Department of Neuropediatrics, University of Tübingen, Tübingen, Germany;Dept. of Neuroradiology, University of Tübingen, Tübingen, Germany;Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

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

Others  :  864086
DOI  :  10.1186/1750-1172-8-41

 received in 2013-01-04, accepted in 2013-03-09,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Synofzik et al.; licensee BioMed Central Ltd.

【 图 表 】

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