|Year : 2021 | Volume
| Issue : 3 | Page : 149-152
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) in three brothers of a family from Kerala
Sasikumar Sheetal1, Amith K Sasikumar2, Lovin G Tomy1
1 Department of Neurology, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala, India
2 Department of Neurology, Lourdes Hospital, Kochi, Kerala, India
|Date of Submission||12-Dec-2020|
|Date of Decision||19-Apr-2021|
|Date of Acceptance||10-May-2021|
|Date of Web Publication||22-Dec-2021|
Dr. Sasikumar Sheetal
Department of Neurology, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala.
Source of Support: None, Conflict of Interest: None
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an uncommon spastic-ataxic syndrome that is characterized by cerebellar ataxia, spasticity, and peripheral neuropathy. Though initially reported from Charlevoix-Saguenay-Lac-St-Jean region in Canada, this neurodegenerative disorder has been reported from other regions of the world. There have been very few reports on this condition from Kerala, India. We hereby report a family of three brothers from Kerala who were diagnosed with this condition.
Keywords: Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), cerebellar ataxia, Kerala, peripheral neuropathy, spasticity
|How to cite this article:|
Sheetal S, Sasikumar AK, Tomy LG. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) in three brothers of a family from Kerala. Ann Mov Disord 2021;4:149-52
|How to cite this URL:|
Sheetal S, Sasikumar AK, Tomy LG. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) in three brothers of a family from Kerala. Ann Mov Disord [serial online] 2021 [cited 2022 Jan 18];4:149-52. Available from: https://www.aomd.in/text.asp?2021/4/3/149/329340
| Key Messages:|| |
Although originally described from Canada, this ARSACS should be considered a differential in a patient presenting with ataxia, spasticity, and peripheral neuropathy, even in our part of the world. It is a rare syndrome in our part of the world, only five genetically proven cases have been previously reported from India.
| Introduction|| |
ARSACS is a neurodegenerative disorder, with the characteristic triad of cerebellar ataxia, spasticity, and peripheral neuropathy. It was originally described by Bouchard, et al. in 1978 from Charlevoix-Saguenay-Lac-St-Jean region, Quebec in Canada. Subsequently, it has been reported from other parts of the world, including India. However, only a few genetically proven cases of ARSACS have been reported from India.,,,,, Though the phenotype can be heterogeneous, the characteristic clinical triad includes cerebellar ataxia, spasticity, and peripheral neuropathy. The classical neuroimaging findings in this syndrome include superior vermian atrophy, linear hypointensities in the pons (striped pons), thinning of the splenium of the corpus callosum, and bithalamic stripes. Clinical exome sequencing studies have recognized a variety of variants in the sacs in molecular chaperone gene (SACS) on chromosome 13. We hereby report the case of a 31-year-old gentleman, who presented with the characteristic clinical and neuroimaging findings of ARSACS, and he was detected to have a homozygous single-base-pair deletion in the exon 10 of the SACS gene. His two elder brothers had the same phenotypic manifestations.
| Case History|| |
A 31-year-old gentleman, the third born of non-consanguineous parentage, presented with complaints of progressively increasing difficulty in walking since childhood. He remembers that as a child, he could not run as swiftly as his other friends. He was noticed to have slurred speech by seven years of age. His parents reported that he had started to sway to either side while walking, by around 10 years of age. He had a denied history of paraesthesia over feet. He had no tremor on reaching out for objects. He had no symptoms referable to bowel or bladder. He had two elder brothers and one elder sister. His brothers started having unsteadiness on walking and frequent falls in their childhood. They were noted to have thinning of muscles of the lower limbs. However, the elder sister had no similar symptoms.
On examination, the patient was moderately built, and he had bilateral pes cavus [Figure 1]. He scored 30/30 on mini mental state examination (MMSE). His speech had a scanning quality. Fundus examination was normal. He had normal visual acuity in both eyes. Extraocular movements were notable for slow saccades, and bilateral gaze-evoked nystagmus was noted. Other cranial nerves were normal. Motor system examination showed spasticity of upper and lower limbs with Medical Research Council (MRC) grade 4/5 power. Deep tendon reflexes were exaggerated in the upper limbs and absent in the bilateral lower limbs; the plantars were bilaterally extensor. Examination of the sensory system showed impaired vibration in the bilateral lower limbs, up to the knees. He had no finger nose incoordination, and tandem walking was impaired. Examination of other systems was normal. His hemogram and basic blood biochemistry were normal. His peripheral blood smear did not reveal any acanthocytes, and his alfa-feto protein levels were normal. The differential diagnosis of autosomal recessive ataxia syndromes was considered, including ARSACS, Refsum’s disease, Friedrich’s ataxia, spinocerebellar ataxia, cerebrotendinuous xanthomatosis (CTX), and abetalipoproteinemia. A nerve conduction study showed severe sensory-motor axonal-demyelinating peripheral neuropathy. The presence of demyelinating neuropathy helped in narrowing down the differentials to ARSACS, CTX, and Refsum’s. The very early age at onset, from the early childhood and very slow progression, suggested the possibility of ARSACS compared with others. An MRI of the brain showed significant superior vermian atrophy, linear hypointensities in the pons on T2/ FLAIR sequences (striped pons), and thinning of the splenium of the corpus callosum, all pointing toward the diagnosis of ARSACS [Figure 2]. Genomic DNA from the proband was used to perform exome sequencing and showed a homozygous single-base-pair deletion in exon 10 of the SACS gene (chr13;c.8793delA), which resulted in a frameshift and premature truncation of the protein 22 amino acids downstream to codon 2931 (p.Lys2931AsnfsTer22; ENST00000382292.9), confirming the diagnosis of ARSACS. The IGV snapshot of the variant identified is attached [Figure 3]. The patient’s elder siblings who had the same presentation were also presumed to have the same diagnosis; however, they refused any radiological/genetic testing.
|Figure 2: A: Axial fluid-attenuated inversion recovery (FLAIR) images show linear hypointense striations on either side of the midline of pons—“striped pons” (arrow). B: Sagittal T1 sequence showing enlarged pons (yellow arrow), atrophy of the superior vermis (green arrow), and thinning of the splenium of the corpus callosum (blue arrow)|
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|Figure 3: The IGV snapshot of the variant identified by exome sequencing|
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| Discussion|| |
ARSACS is a neurodegenerative disorder, with the characteristic triad of slowly progressive cerebellar ataxia, spasticity, and peripheral neuropathy., Our patient had this characteristic triad of symptoms. Another characteristic finding described is myelinated nerve fibers radiating from the optic disk, on fundoscopy. However, this finding was not seen in our patient. The same authors have reported another case of ARSACS from Kerala, where myelinated nerve fibers were not present. Characteristic findings seen on the MRI brain are superior vermian atrophy, linear hypointensities in the pons on T2/ FLAIR sequences (striped pons), and thinning of the splenium of the corpus callosum, all of which were seen in our patient. Other imaging features include T2 hyperintense rim around the thalami, known as bithalamic stripes; however, this was not observed in our patient.
Though originally described from Quebec in Canada, it has been reported from other parts of the world, including India. However, only a few genetically proven cases of ARSACS have been reported from India.,,,,,, Our patient, on exome sequencing, showed a homozygous single-base-pair deletion in exon 10 of the SACS gene (chr13;c.8793delA), resulting in c8793 del A variant. The same authors have reported another case of ARSACS, from the same locality in the state of Kerala, and the same homozygous single-base-pair deletion in exon 10 of the SACS gene (c8793 del A variant) was identified. The homozygous nature of the variant in our patient, despite the non-consanguineous parentage, and a previously reported case of ARSACS from the same geographical area (unrelated to the present family) with the same variant suggest a possibility of a founder variant in the population. Further studies have to be done to identify whether there is predilection for this specific variant in other patients with similar illness, from the central Travancore part of Kerala. Other novel variations have been described from other parts of the country [Table 1]. Most of the previous reports show homozygous variations in the exon 10 of the SACS gene; however, Agarwal, et al. have reported compound heterozygous variants in exon 10. Agarwal, et al. have described the first genetically proven ARSACS from India, and they identified a novel duplication in exon 10 of the SACS gene.
|Table 1: Comparison of genetic variants in the SACS gene in studies previously reported from India|
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Taking into consideration the fact that ARSACS is being reported increasingly from all parts of the world, it should be considered in the differential diagnosis of spastic ataxia syndromes. The typical clinical features and neuroimaging findings should prompt the treating physician to order a clinical exome sequencing to identify variations in the SACS gene.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
I want to acknowledge my patient for his cooperation and consent for this publication.
Dr Sasikumar Sheetal: Conception, organization and execution of the project, review and critique of the manuscript and writing of the first draft . Dr Amith K Sasikumar: Organization and execution of the project, writing of the first draft. Dr Lovin G Tomy: Organization and execution of the project, writing of the first draft. There was no statistical analysis involved, as it is a case report.
Ethical compliance statement
Written informed consent was taken from the patient for online publication and dissemination.This being a case-report, requirement for ethical clearance was waived off by the Institute in accordance with the prevailing norms.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sheetal S, Kumar SA, Byju P. SACS mutation-positive autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) from Kerala. Ann Indian Acad Neurol 2020;23:374-6. [Full text]
Bouchard JP, Barbeau A, Bouchard R, Bouchard RW. Electromyography and nerve conduction studies in Friedreich’s ataxia and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Can J Neurol Sci 1979;6:185-9.
Agarwal A, Garg D, Kharat A, Qavi A. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): Case report of a novel nonsense mutation in the SACS gene. Ann Indian Acad Neurol 2020;23:395-7. [Full text]
Agarwal PA, Ate-Upasani P, Ramprasad VL. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)—First report of clinical and imaging features from India, and a novel SACS gene duplication. Mov Disord Clin Pract 2017;4:775-7.
Kuchay RAH, Mir YR, Zeng X, Hassan A, Musarrat J, Parwez I, et al
. ARSACS as a worldwide disease: Novel SACS mutations identified in a consanguineous family from the remote tribal Jammu and Kashmir region in India. Cerebellum 2019;18:807-12.
Menon MS, Shaji CV, Kabeer KA, Parvathy G. SACS gene-related autosomal recessive spastic ataxia of Charlevoix-Saguenay from South India. Arch Med Health Sci .2016;4:122-4.
Faruq M, Narang A, Kumari R, Pandey R, Garg A, Behari M, et al
. Novel mutations in typical and atypical genetic loci through exome sequencing in autosomal recessive cerebellar ataxia families. Clin Genet 2014;86:335-41.
Shakya S, Kumari R, Suroliya V, Tyagi N, Joshi A, Garg A, et al
. Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia. Clin Genet 2019;96:566-74.
Biswas A, Varman M, Yoganathan S, Subhash PK, Mani S. Teaching neuroimages: Autosomal recessive spastic ataxia of Charlevoix-Saguenay: Typical MRI findings. Neurology 2018;90:e1271-2.
[Figure 1], [Figure 2], [Figure 3]