First case of Autosomal recessive spastic ataxia of Charlevoix-Saguenay in the Middle east

doi:10.21203/rs.3.rs-4809310/v1

Download PDF

Case Report

First case of Autosomal recessive spastic ataxia of Charlevoix-Saguenay in the Middle east

https://doi.org/10.21203/rs.3.rs-4809310/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Introduction:

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder of distinctive triad of ataxia, spasticity and axonal-demyelinating sensorimotor neuropathy. Owing to its eponymous name, ARSACS was first reported in the Charlevoix–Saguenay region of Quebec, but epidemiologically speaking it is far more common globally. It is the genetic implication of biallelic mutations in the Spastic Ataxia of Charlevoix-Saguenay (SACS) gene that usually manifests from childhood.

Clinical presentation:

We report a 20-year-old Omani male of consanguineous parents, with progressive frequent falls and ataxia with delayed motor milestones, found to have homozygous variant mutation of SACS 13q12.12, suggestive of autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS). Magnetic resonance imaging (MRI) of the head and cervical spine showed bilateral hypointense stripes in pons (tigroid appearance), atrophy of the superior cerebellar vermis, and midbody atrophy of corpus callosum and hyperintense thalamic rim signs. Electromyography (EMG) and nerve conduction studies (NCS) show sensory-motor polyneuropathy. Blood workups for vitamin B12, tocopherols (vitamin E), and peripheral smear were unremarkable. Management encompassed a multidisciplinary approach with tizanidine, Botulinum toxin B injection, and extensive physical and balance rehabilitation.

Conclusions:

ARSACS is reported across the globe representing the second comments form of hereditary ataxia. As per the literature, there have been no reported cases in the Middle East, making this the first reported case of Omani origin in the Middle East.

Autosomal

recessive

spastic

ataxia

Charlevoix–Saguenay (ARSACS)

Spastic ataxia of the Charlevoix-Saguenay type (SACS, or ARSACS) is autosomal recessive and caused by homozygous or compound heterozygous mutation in the gene encoding the sacsin protein.
The gene responsible for ARSACS has been mapped to chromosome 13q11-12.
Two founder mutations, a single-base deletion at position 6594 (g.6594delT) and a g.5354C>T nonsense mutation, have been reported in individuals from North-eastern Québec.
Other common mutation is (SACS):c.2182C>T (p.Arg728Ter) NM_014363.6. on 13q12.12.
Recently, new mutations have been described in Tunisian, Italian, Turkish, Iranian, Japanese, and Spanish patients.

First case of SACS 13q12.12 with spastic cerebellar ataxia and sensorimotor polyneuropathy with Variation Report for NM_014363.6 (SACS):c.2182C>T (p.Arg728Ter) in the Middle East.

Due to the scarcity of reports on ARSACS in Middle-east, SACS pathological variants presenting with early-onset Charcot-Marie-Tooth-like phenotype sensorimotor neuropathy would warrant further follow-up and meticulous examination for spasticity and radiological hallmarks, where neurologists must consider ARSACS as possible etiology with genetic counseling.

In 1978, Bouchard et al. first described a distinguishing form of early onset spastic ataxia known as autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS; MIM#270550). (Bouchard et al. 1978 ; Kniffin et al. 2024) Formerly described in the Northeastern regions of Québec, Canada, in families of French ancestry with an incidence at birth and the carrier rate was estimated at 1/1,932 live-born infants and 1/22 inhabitants, respectively in this region. (Kniffin et al. 2024; Palau et al. 2006) Although ARCAS is the most prevalent in a series of patients in Quebec, over the last decades, several reports across the continents (Vermeer et al. 1993; Synfozik et al. 2013; Habibzadeh et al. 2020; Kuchay et al. 2019; Çakar et al. 2022) has shown this condition to be more prevalent notching as the second most common form of spastic ataxia after Friedreich's Ataxia and other autosomal recessive cerebellar ataxias (ARCAs). (Palau et al. 2006)

ARSACS most commonly reported pathogenic mutation reported in Spastic Ataxia of Charlevoix-Saguenay (SACS) gene (OMIM #604490), coding for a multidomain protein called sacsin, which represent the most highly expressed protein in large motor system neurons, especially in cerebellar, Purkinje cells. (Kniffin et al. 2024) As an early-onset neurodegenerative disorder, the onset of symptoms can be as early as 12 to 18 months with delayed motor milestones. (Palau et al. 2006) it encompasses a clinical triad of early onset cerebellar ataxia, pyramidal tract signs of progressive spastic ataxia of all limbs with paraplegia, sensorimotor polyneuropathy evident with electromyographic features of axonal and demyelinating neuropathy. (Palau et al. 2006) Despite not being present in all cases, retinal hypermyelination has been reported in patients from Québec, and Iran, but absent in patients from France, Tunisia, and Turkey. (Palau et al. 2006, Habibzadeh et al. 2020, (Qavi et al. 2020) El Euch-Fayache et al. 2003) The first and most commonly identified causative mutation of sacsin molecular chaperone gene (SACS) on chromosome 13q with a spectrum of new pathogenic mutations is still being reported to date. (Kniffin et al. 2024)

We report the first case in the middle east of early onset ataxia known as autosomal recessive spastic ataxia of Charlevoix–Saguenay due to autosomal recessive homozygous variant mutation of SACS 13q12.12 with spastic cerebellar ataxia and sensorimotor polyneuropathy with Variation Report for NM_014363.6 (SACS):c.2182C > T (p.Arg728Ter).

A 20-year-old right-handed Omani male, a product of consanguineous parents with no known past medical history was referred to the neurology clinic with progressive lower limb stiffness and unsteady gait since childhood. The patient was diagnosed in India with Charcot-Marie-Tooth type 1 (CMT1) disease, four years before our assessment. He is a product of normal vaginal delivery of first-degree consanguineous parents with an unremarkable family history of no reported unsteadiness or neurological diseases. Developmental milestones review revealed delayed walking around the age of 18–20 months with recurrent falls. His symptoms continued to progress until the age of 18 years when he was seen in a neurology clinic. Alongside unsteady gate and lower limb stiffness, he noted difficulty with speech articulation and activities of daily living of baseline modified Ranken score (mRS ) of 2 associated with lower limb numbness starting at the age of 15. The patient denied any diplopia or blurring of vision and no urinary or fecal symptoms. A review of the system was unremarkable, with no relevant constitutional symptoms. He is a high school graduate without exposure to heavy metals, recreational drugs, or alcohol.

Initial vitals were within normal parameters; a temperature of 36.4°C, respiratory rate of 17 breaths per minute, oxygen saturation of 98% on room air, and blood pressure of 129/62mmHg with no orthostatic component. On general inspection, no noted dysmorphism with normal-average height to his family with a Body Mass Index (BMI) of 15.64 (weight 49 kg). Higher functional status revealed no cognitive dysfunction (mini-mental state examination, MMSE 30). Neurological examination was remarkable for bilateral ocular saccadic intrusions, with no gaze-evoked nystagmus. Lower limb examination on inspection showed Pes Cavus with spasticity in the lower limb with enhanced deep tendon reflexes in the lower limbs associated with bilateral Babinski’s and Chaddock signs.

A cerebellar exam is remarkable for bilateral ocular saccadic intrusions, wide-based spastic ataxic gait and inability to tandem or heel-walk with bilateral dysmetria. He showed positive Romberg's sign suggestive of deep sensory impairment in the lower extremities. Overall, the baseline functional status of the patient is measured using a modified Ranken score of 2 (mRS) with assistance in some activities of daily living (ADLs) due to unsteadiness and lower limb spasticity.

Blood workup revealed normal complete blood count, Hb electrophoresis, and glucose 6-phosphate dehydrogenase (G6PD) levels. Creatine kinase 214 U/L (29–308)U/L, HbA1c, Vitamin B12, Serum protein electrophoresis (SPEP), Thyroid function (TFT), Vitamin E, B1, and pyridoxine were within normal parameters.

Magnetic resonance imaging (MRI) brain and cervical-thoracic spine with contrast, Axial and midsagittal FLAIR shows showed bilateral hypointense stripes in pons (tigroid appearance), atrophy of the superior cerebellar vermis, and midbody atrophy of corpus callosum and hyperintense thalamic rim signs showed in Fig. 1A-D. Nerve conduction study and electromyography revealed demyelinating sensory-motor polyneuropathy shown in Fig. 2A-B. Transthoracic echocardiogram (TTE) was normal with no valvular disease or cardiomyopathy. The ophthalmological assessment revealed a normal retinal exam with pending optical coherence tomography (OCT).

Management encompassed a multidisciplinary approach, with a trial of baclofen 20mg three times a day (TID) with minimal effect, warranting the use of tizanidine 4mg TID and botulinum B toxin injection. He is undergoing intensive physical therapy targeting spasticity and balance with routine neurology clinic follow-up.

Molecular results

Further genetic testing of whole exome sequence (WES) analysis revealed a pathogenic gene variant of the SACS gene as an autosomal recessive homozygous mutation of sacsin protein in the sequencing data.p.(Arg728Ter) (CGA > TGA): c.2182 C > T in exon 9 of the SACS gene (NM_014363.4). Other pathogenic variants were identified in missense mutation on the KIDINS220 gene in the whole-exome sequencing study. Further in-silico analysis supports that this missense variant does not alter protein structure as opposed to a nonsense variant that manifests with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome for which our patient does not exhibit its phenotype. (Zhang et al. 2021)

Autosomal recessive cerebellar ataxia (ARCA) constitutes a heterogeneous spectrum of disorders. (Palau et al. 2006) A common ground across these neurodegenerative disorders is their early onset (age before 20 years) and the characteristic degeneration of the cerebellum and spinal cord, being of Mendelian autosomal recessive inheritance. (Palau et al. 2006) Koenig et al. proposed differentiating criteria based on topographical and pathophysiological criteria for ARCA, distinguishing sensory and spinocerebellar ataxia, and cerebellar ataxia with sensory motor neuropathy from pure cerebellar ataxia. (Koenig et al 2003)

Hallmark pathogenic mutations in the SACS gene are known to cause ARSACS and are well reported across the globe such as in India, Tunisia, Iran, and Europe, there have been no reported cases in the Middle East or to be exact in the Gulf region. (Habibzadeh et al. 2020) Qavi et al. 2020) and El Euch-Fayache et al. 2003) SACS gene encodes a pivotal protein known as, Sacsin which is alleged to incorporate the 70-kDa heat shock protein (Hsp70) chaperone and ubiquitin-proteasome systems. (Bouchard et al. 1978) Recent compelling evidence shows the protective nature of normal sacsin protein against at least one mutation of the ataxin-1 gene known to cause spinocerebellar ataxia type 1. (Habibzadeh et al. 2020; Scaravilli et al. 2024) Clinically speaking, ARCAS early onset ataxia could stem from its pathophysiology of SACS domains facilitate intermediate filament assembly, where Lariverie et al, in vitro study, has showed SACS-knockout mice to manifest early ataxia and abnormal bundling of neurofilaments across various neuronal population. (Lariviere et al. 2015; Synfozik et al. 2013; Gentil et al. 2019)

On a note of comparison to the other autosomal recessive cerebellar ataxias, ARSACS harbors unique radiological features of superior cerebellar vermis atrophy with relative sparing of if inferior aspect, cervical cord atrophy, T-2 hyperintensities thalamic rim sign, corpus callosum thinning and tigroid appearance of the pons on T2/FLAIR sequences of MRI head. (St-Amant et al. 2024) Scaravilli et al. in a recent multicenter study, proposed an imaging index relative to pons-to-superior vermis area ratio to differentiate ARSACS from hereditary spastic paraplegia type 7 (SPG7) with a cut-off value equal to 1.67 of the pons-to-superior vermis area ratio proved to have a diagnostic accuracy and sensitivity 93 and 97%, respectively in discriminating between ARSACS and SPG7. (Scaravilli et al. 2024)

Historically, the first two founder mutations, a single-base deletion at position 6594 (g.6594delT) and a g.5354C > T nonsense mutation, have been reported in individuals from North-eastern Québec. Since then, over 12 allelic variants have been reported worldwide across patients with ARSACS. (Kniffin et al. 2024) Our patient pathological variant mutation of (SACS):c.2182C > T (p.Arg728Ter) NM_014363.6. on 13q12.12, which has been reported previously to cause ARSACS and spastic paraplegia. (Çakar et al. 2022)

The observed wide array of phenotypical spectrum in SACS variants from isolated Charcot-Marie-Tooth-like phenotype to full-blow spastic ataxia with radiological features as described in a case series of nine patients of unrelated families with SACS variants; one cannot disregard the possibility of rare pleomorphic genetic variants contributing to heterogeneous presentations and age of onset. (Çakar et al. 2022) Our patient was initially diagnosed with as Charcot-Marie-Tooth-like phenotype based on electrographic demyelinating sensory-motor neuropathy, where spasticity and recurrent falls show the light on rather a syndromic triad. Further genetic and molecular studies are warranted to understand the pathophysiology of such a disease entity which could aid in a better understanding of possible gene therapy and prognosis.

ARSACS

Autosomal recessive spastic ataxia of Charlevoix-Saguenay

ARCA

Autosomal recessive cerebellar ataxia

SACS

Spastic Ataxia of Charlevoix-Saguenay

ADLs

activities of daily living

mRS

Modified Ranken Score

MRI

magnetic resonance imaging

DTR

deep tendon reflexes

NCS

Nerve conduction Studies

EMG

Electromyography

SNAP

Sensory nerve action potential

CMAP

compound muscle action potential

FLAIR

fluid attenuated inversion recovery

ANA

autoimmune screen (anti-nuclear antibody)

ANCA

antineutrophil cytoplasmic antibody

Ethics approval and consent to participate

This case report was approved by the Hamad Medical Corporation’s Medical Research Center.

Consent for Publication

Written informed consent was obtained from the patient for publication of this case report, any accompanying images and photography. A copy of the written consent is available for review from the Editor of this journal.

Author contributions

All authors have read and approved the manuscript.

Writing the initial draft of the manuscript: AS

Conceptualization and supervision: AS, DD

Medical management of the case: AS, DD

Critically revising the manuscript and literature review: AS, DD

Funding

Qatar National Library funded the open access publication fees of this case report.

Competing Interest

The authors have no conflicts of interest to disclose.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on request.

Acknowledgment

The authors would like to acknowledge Qatar National Library (QNL) for this publication's funding.

Bouchard, J. P., Barbeau, A., Bouchard, R., & Bouchard, R. W. (1978). Autosomal recessive spastic ataxia of Charlevoix-Saguenay. The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques, 5(1). https://pubmed.ncbi.nlm.nih.gov/647499/ (Bouchard et al. 1978)
Cassandra L. Kniffin, Entry - #270550 - SPASTIC ATAXIA, CHARLEVOIX-SAGUENAY TYPE; SACS - OMIM. (n.d.). Omim.org. Retrieved July 15, 2024, from https://omim.org/entry/270550 (Kniffin et al. 2024)
Palau, F., & Espinós, C. (2006). Autosomal recessive cerebellar ataxias. Orphanet Journal of Rare Diseases, 1(1), 47. https://doi.org/10.1186/1750-1172-1-47 (Palau et al. 2006)
Koenig, M. (2003). Rare forms of autosomal recessive neurodegenerative ataxia. Seminars in Pediatric Neurology, 10(3), 183–192. https://doi.org/10.1016/s1071-9091(03)00027-5 (Koenig et al 2003)
Habibzadeh, P., Tabatabaei, Z., Inaloo, S., Nashatizadeh, M. M., Synofzik, M., Ostovan, V. R., & Faghihi, M. A. (2020). Case report: Expanding the genetic and phenotypic spectrum of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Frontiers in Genetics, 11, 585136. https://doi.org/10.3389/fgene.2020.585136 (Habibzadeh et al. 2020)
Qavi, A., Agarwal, A., Garg, D., & Kharat, A. (2020). Autosomal recessive spastic ataxia of charlevoix-saguenay (ARSACS): Case report of a novel nonsense mutation in the SACS gene. Annals of Indian Academy of Neurology, 23(3), 395. https://doi.org/10.4103/aian.aian_670_19 (Qavi et al. 2020)
El Euch-Fayache, G., Lalani, I., Amouri, R., Turki, I., Ouahchi, K., Hung, W.-Y., Belal, S., Siddique, T., & Hentati, F. (2003). Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Archives of Neurology, 60(7), 982. https://doi.org/10.1001/archneur.60.7.982 (El Euch-Fayache et al. 2003)
St-Amant M, Sharma R, Glick Y, et al. Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Reference article, Radiopaedia.org (Accessed on 15 Jul 2024) https://doi.org/10.53347/rID-18851 (St-Amant et al. 2024)
Scaravilli, A., Negroni, D., Senatore, C., Ugga, L., Cosottini, M., Ricca, I., Bender, B., Traschütz, A., Başak, A. N., Vural, A., van de Warrenburg, B. P., Durr, A., La Piana, R., Timmann, D., Schüle, R., Synofzik, M., Santorelli, F. M., Cocozza, S., & PROSPAX Consortium. (2024). MRI‐ARSACS: An imaging index for autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) identification based on the multicenter PROSPAX study. Movement Disorders: Official Journal of the Movement Disorder Society. https://doi.org/10.1002/mds.29871 (Scaravilli et al. 2024)
Çakar, A., İnci, M., Özdağ Acarlı, A. N., Çomu, S., Candayan, A., Battaloğlu, E., Tekgül, Ş., Başak, A. N., Durmuş, H., & Parman, Y. (2022). Phenotypical spectrum of SACS variants: Neuromuscular perspective of a complex neurodegenerative disorder. Acta Neurologica Scandinavica, 145(5), 619–626. https://doi.org/10.1111/ane.13592 (Çakar et al. 2022)
Vermeer, S., Van De Warrenburg, B. P., Kamsteeg, E. J., Brais, B., and Synofzik, M. (1993). “Arsacs,” in GeneReviews, eds M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, et al. (Seattle, WA: University of Washington). [ Vermeer et al. 1993]
Synofzik, M., Soehn, A. S., Gburek-Augustat, J., Schicks, J., Karle, K. N., Schüle, R., Haack, T. B., Schöning, M., Biskup, S., Rudnik-Schöneborn, S., Senderek, J., Hoffmann, K.-T., MacLeod, P., Schwarz, J., Bender, B., Krüger, S., Kreuz, F., Bauer, P., & Schöls, L. (2013). Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet Journal of Rare Diseases, 8(1), 41. https://doi.org/10.1186/1750-1172-8-41 (Synfozik et al. 2013 )
Kuchay, R. A. H., Mir, Y. R., Zeng, X., Hassan, A., Musarrat, J., Parwez, I., et al. (2019). ARSACS as a worldwide disease: novel SACS mutations identified in a consanguineous family from the remote tribal jammu and kashmir region in India. Cerebellum 18, 807–812. 10.1007/s12311-019-01028-2 (Kuchay et al. 2019)
Parfitt, D. A., Michael, G. J., Vermeulen, E. G. M., Prodromou, N. V., Webb, T. R., Gallo, J.-M., Cheetham, M. E., Nicoll, W. S., Blatch, G. L., & Chapple, J. P. (2009). The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Human Molecular Genetics, 18(9), 1556–1565. https://doi.org/10.1093/hmg/ddp067 (Parfitt et al. 2009)
Lariviere, R., Gaudet, R., Gentil, B. J., Girard, M., Conte, T. C., Minotti, S., et al. (2015). Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay. Hum. Mol. Genet. 24, 727–739. doi: 10.1093/hmg/ddu491 (Lariviere et al. 2015)
Gentil, B. J., Lai, G. T., Menade, M., Lariviere, R., Minotti, S., Gehring, K., et al. (2019). Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics. FASEB J. 33, 2982–2994. doi: 10.1096/fj.201801556r (Gentil et al. 2019)
Zhang, K., Sun, W., Liu, Y., Lv, Y., Hou, D., Lin, Y., Xu, W., Zhao, J., Gai, Z., Zhao, S., & Yuan, Y. (2021). SINO Syndrome Causative KIDINS220/ARMS Gene Regulates Adipocyte Differentiation. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.619475 (Zhang et al. 2021)

No competing interests reported.

Download PDF

Editorial decision: Revision requested
29 Jul, 2024
Editor assigned by journal
29 Jul, 2024
Submission checks completed at journal
29 Jul, 2024
First submitted to journal
26 Jul, 2024

You are reading this latest preprint version

First case of Autosomal recessive spastic ataxia of Charlevoix-Saguenay in the Middle east

Status:

Version 1

Abstract

Figures

Established Facts

Novel Insights

Key Clinical Message

Background

Case presentation

Molecular results

Discussion and conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1