REVIEWARTICLE Autosomal Recessive Michael H Parkinson Spastic Ataxia of is a Clinical Research Fellow in the Department of Molecular Neuroscience, UCL Institute of Neurology, University of London and an Honorary Specialist Registrar in Neurology at the National Hospital for Charlevoix-Saguenay Neurology and Neurosurgery, Queen Square, London, UK. He is currently working on a (ARSACS) PhD in clinical and molecular biological aspects of recessive ataxias with a particular interest in ARSACS and Friedreich’s ataxia. History and origins Québec was one of the first regions of North Summary America to be colonised by Europeans and • ARSACS is a rare autosomal recessive the majority of French Canadians living in disorder characterised clinically by Québec Province today are thought to cerebellar ataxia, spasticity, pyramidal descend from these original founders. As a signs, peripheral neuropathy and result, a number of rare neurogenetic disor- skeletal foot abnormalities ders show increased prevalence or local vari- • It is caused by mutations in the SACS ants in this region, including Friedreich’s gene which encodes the 520kDa ataxia (FRDA), and other hereditary ataxias, protein sacsin Fion Bremner spastic parapareses and neuropathies.1 • The availability of the genetic test is a Consultant Neuro-ophthalmologist at Québec City was founded in 1608 under the the National Hospital for Neurology & has extended the clinical spectrum to Neurosurgery, Queen Square, London, UK. include examples without spasticity rule of the French crown and between 1665 His research interests include evaluation of or ataxia and 1725, around forty families migrated from neurological diseases using pupillometry and • Retinal examination shows retinal there to the isolated mountainous region of ocular coherence tomography (OCT). He is Charlevoix on the north shore of the Saint Honorary Secretary of the European Neuro- striations on fundoscopy and ophthalmological Society (EUNOS). thickening of the retinal nerve fibre Lawrence River. Between 1838 and 1855, layer on ocular coherence further families moved from here to the more tomography (OCT) in the majority of distant Saguenay and Lac Saint Jean regions the cases to the north. It is estimated that the carrier • Neurophysiological studies show an frequency of SACS mutations is 1/22 in these early demyelinating sensorimotor regions. neuropathy with progressive axonal The clinical syndrome of ARSACS was first degeneration described in 1978 in these populations,2 and • MR imaging shows superior vermian this community of more than 300 affected cerebellar atrophy, thinning of the individuals remains the most numerous and cervical spinal cord and pontine the most extensively studied. The clinical Paola Giunti linear hypointensities is a Principal Clinical Research Associate at phenotype was remarkably homogeneous, the Department of Molecular Neuroscience probably because more than 92% of individ- UCL and Head of the Ataxia Centre at uals shared the same mutation, and more than NHNN, UCLH Queen Square London ,UK. RSACS is a rare and disabling, slowly 96% shared one of two mutations.3 The She has a longstanding interest in the 4 genetics of neurological disorders, in progressive neurodegenerative disorder causative gene was first described in 2000 particular the inherited cerebellar ataxias Acharacterised by cerebellar ataxia, spas- enabling the subsequent identification of and other movement disorders. She has ticity, pyramidal signs, peripheral neuropathy, cases in Europe, North Africa, Turkey, Japan been researching the mechanisms that skeletal foot abnormalities and thickening of and Brazil5 with considerable phenotypic underlie neuronal degeneration in the central and peripheral nervous systems. Her the retinal nerve fibre layer (RNFL) visible on heterogeneity, so that now neither spasticity research team focuses on understanding the fundoscopy and by ocular coherence tomog- nor ataxia must be regarded as an obligate cellular and molecular mechanisms of raphy (OCT). The condition was first consid- feature of the condition.6 neurodegenerative diseases with a particular ered to be confined at relatively high emphasis on triplet repeat conditions. frequency to the descendants of founder Genetics and sacsin protein function Correspondence to: populations in the Charlevoix and Saguenay- The causative gene on chromosome 13q12.12 Dr Paola Giunti, Email: [email protected] Lac Saint Jean regions of North-Eastern is named SACS and was originally thought to Acknowledgements: Québec, but the discovery of the causative contain a single giant exon4 (see Figure 1). A This study was supported by a grant from Ataxia UK. SACS gene has permitted its identification further 8 coding exons and a tenth non- throughout the world and has extended the coding exon have subsequently been identi- Conflict of interest statement: The authors state that there are no conflicts diversity of mutations known, and the spec- fied upstream of this, forming a 13,737bp open of interest. trum of clinical features described. ARSACS reading frame.7 More than 100 different patho- 3, 8 Provenance and peer review: is now recognised as one of the important genic mutations have now been described, Commissioned and externally reviewed. causes of autosomal recessive ataxia. In this largely missense, nonsense, frameshift and To cite: review, we summarise the clinical, genetic splice-site mutations spread over 6 of the 10 Parkinson MH, Bremner F, Giunti P, and pathophysiological features of this exons, but still primarily in the giant exon 10.3 ACNR 2014;V13(7):12-16 condition, and the investigations used in its Large deletions have also been described diagnosis. causing atypical features such as late onset or 12 > ACNR > VOLUME 13 NUMBER 7 > JANUARY/FEBRUARY 2014 REVIEWARTICLE (A) Cen 1 2 3 14 5 6 7 8 9 10 Tel (B) H2N UBL SRR SRR SRR XPCB DnaJ HEPN COOH Figure 1: (A) Primary structure of SACS gene showing the 10 exons. Mutations have thus far been described in exons 4, 6, 7, 8, 9 but largely in the giant exon 10. (B) Domain organisation of sacsin protein. UBL, ubiquitin-like domain; SSR, sacsin repeat region; XPCB, xeroderma pigmentosum complementation group C binding domain; DnaJ, J-domain; HEPN, higher eukaryote and prokaryote nucleotide binding domain. prominent hearing loss. These have included dense, lipofuscin-like granules within lyso- being wheelchair-bound was around 40 an intragenic deletion of exons 3-5,8 deletion somes, although testing of an extensive panel (range 17-58) and to death around 50 (range of the whole gene9 and deletion of SACS and of lysosomal enzymes was normal. 21-72). 18 the contiguous gene SGCG causing concomi- Interestingly, lipofuscin deposits have also From childhood, deep tendon reflexes are tant limb girdle muscular dystrophy type 2c.10 been seen in the skin biopsy of a patient with frequently increased, but by adulthood, may The gene encodes a 4,579 amino acid ARSACS performed to exclude Lafora body diminish or become absent due to progressive 520kDa protein called sacsin (see Figure 1) disease.17 Peripheral nerve and muscle biop- neuropathy. Ankle jerks are commonly absent whose true function is currently not fully sies have not shown lipofuscin deposits. The whilst knee jerks may be hyperreflexic but understood11 but may have a protective effect significance of this finding therefore remains patients may have a very mixed and asym- against mutant ataxin-1.12 Sacsin is most highly unclear. metric picture. Sensory deficits usually appear expressed in cerebellar Purkinje cells; thal- later and progressively into adulthood, amic, midbrain, precerebellar and brainstem Clinical aspects involving vibrational sense more than proprio- nuclei; and large pyramidal forebrain Much of the clinical knowledge of ARSACS is ception and cutaneous sensation. Distal neurones.12 Within cells, it is localised to the based on the relatively homogeneous amyotrophy also appears progressively later in cytoplasm and mitochondria, and may have a Québecois cases. However, subsequently iden- the condition.18 The combination of early spas- role in the regulation of mitochondrial tified cases from elsewhere have demon- ticity and progressive neuropathy commonly dynamics, leading to mitochondrial mislocali- strated a genetic and clinical variability which causes skeletal abnormalities of the foot sation and dysfunction.11 continues to extend the phenotypic descrip- including pes cavus, talipes equinus or varus, tion of this condition. In the Québecois cases, and hammer or clawed toes. Unlike FRDA, Histopathology unsteadiness was noted from beginning to spinal scoliosis is not a prominent feature18 but Nerve biopsies most consistently show a walk (12-18 months old) which was rarely has been described in Tunisian14 and Italian21 marked decrement in large myelinated fibres. delayed.16,18 80% initially presented because of series. Straight dorsal spine has been More variably, axonal degeneration with walking difficulties and a tendency to fall. At described in a Spanish series.22 In the hands, condensation of the axoplasm, increased first presentation, approximately 60% were swan-neck deformity of the fingers and claw collagen pockets and accumulation of mito- found to have limb ataxia, 80% showed some hands have been described2,15 with dystonia chondria and vesicular bodies is seen, some- pyramidal involvement and 50% had both sometimes causing abnormal posturing of the times with regenerative axonal sprouting. pyramidal and cerebellar involvement. There