Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide

Dougherty, Sean C.

Haines, Scott R.

Harper, Amy

Saif, Hind Al

Vorona, Gregory

Frontiers in Neurology

English

Sean C. Dougherty

Amy Harper

Hind Al Saif

Gregory Vorona

Scott R. Haines

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CASE REPORTpublished: 15 November 2018doi: 10.3389/fneur.2018.00956Frontiers in Neurology | www.frontiersin.org 1 November 2018 | Volume 9 | Article 956Edited by:Kette D. Valente,Universidade de São Paulo, BrazilReviewed by:Duccio Maria Cordelli,Università degli Studi di Bologna, ItalyAnna Lecticia Pinto,Boston Children’s Hospital,United StatesRudá Alessi,Faculdade de Medicina do ABC, Brazil*Correspondence:Scott R. Hainesscott.haines@vcuhealth.orgSpecialty section:This article was submitted toPediatric Neurology,a section of the journalFrontiers in NeurologyReceived: 07 September 2018Accepted: 25 October 2018Published: 15 November 2018Citation:Dougherty SC, Harper A, Al Saif H,Vorona G and Haines SR (2018) AChromosomal Deletion and NewFrameshift Mutation Cause ARSACSin an African-American.Front. Neurol. 9:956.doi: 10.3389/fneur.2018.00956A Chromosomal Deletion and NewFrameshift Mutation Cause ARSACSin an African-AmericanSean C. Dougherty 1, Amy Harper 1, Hind Al Saif 2, Gregory Vorona 3 and Scott R. Haines 1*1Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States, 2Department of Human andMolecular Genetics, Virginia Commonwealth University, Richmond, VA, United States, 3Department of Radiology, VirginiaCommonwealth University, Richmond, VA, United StatesAutosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare,progressive, neurodegenerative disease characterized by ataxia, spasticity andpolyneuropathy. First described in the French-Canadian population of Quebec in 1978,ARSACS has since been identified in multiple patients worldwide. In this clinical casereport, we describe the evaluation of an 11-years-old African-American male whopresented to neuromuscular clinic for assessment of a gait abnormality. He had a historyof gross motor delay since early childhood, frequent falls and a below average IQ.Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, whichincludes the SACS gene. Next Generation Sequencing then showed a novel, predictedto be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentationand neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge,this is the first reported case of this disease in the African-American population of theUnited States. This case report further highlights the growing trend of identifying geneticdiseases previously restricted to single, ethnically isolated regions in many different ethnicgroups worldwide.Keywords: ARSACS, ataxia, Charlevoix-Saguenay, cerebellum, neurogenetics, polyneuropathy, spasticity, retinaBACKGROUNDAutosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerativecondition initially identified in the French-Canadian population in 1978 (1). Secondary to amutation of the SACS gene on chromosome 13q, this disease is characterized by cerebellar ataxia,spasticity, polyneuropathy, nystagmus and retinal changes (2). It is inherited in an autosomalrecessive manner and typically manifests in early childhood as difficulty with ambulation and gaitunsteadiness. ARSACS is slowly progressive, eventually leading to loss of ambulation around age40 (range 17–58) and death around age 50 (range 21–72) (3).Originally characterized in two regions of northeastern Quebec previously settled by individualsof French descent (4), ARSACS has since been identified in multiple patients worldwide. Whereas,most of the affected patients in French-Canada had the same single nucleotide deletion in the exonof the SACS gene, newmissensemutations have been identified in individuals fromTunisia, Turkey,Italy, Japan and multiple countries in Europe (5–11).The worldwide incidence of ARSACS is unknown, though it is thought to be underdiagnosed.Within the Saguenay-Lac-St-Jean region of Quebec, however, the estimated incidence is betweenDougherty et al. ARSACS in an African-AmericanFIGURE 1 | (A) Midsagittal MRI at age 3 showing no cerebellar changes at that time. (B) Midsagittal MRI at age 11 showing evidence of asymmetric volume losswithin the superior and middle components of the cerebellar vermis with preserved volume of the inferior component (red outline). (C) Axial plane MRI exhibiting faintlinear/T2 signal hypointensities within the Pons (red arrow).1 in 1,500 to 2,000 individuals. The estimated carrier frequencyof SACS pathogenic variants is 1 in 21 individuals based onpopulation data accumulated between 1941 and 1985 (4, 12, 13).In this clinical case report, we detail the first published caseof ARSACS in an African-American patient in the United States,highlighting the clinical presentation, neurological imaging andgenetic analysis involved in diagnosis. Furthermore, we identifieda novel, predicted to be pathogenic missense mutation in theSACS gene (c.11824dup) resulting in the ARSACS phenotype.CASE PRESENTATIONAn 11 years-old African-American male presented to pediatricneuromuscular clinic for evaluation of gait abnormality. He hada history of grossmotor delay since age 3 andwas enrolled in bothphysical and occupational therapy. His mother noted frequentfalls, particularly when running or getting onto the schoolbus, as well as chronic headaches and blurry vision. Previouslyperformed neuropsychological testing showed a below averageIQ and an MRI of the brain at age 3 was normal (Figure 1A).An MRI of the lumbosacral spine from age 5 was also reportedlynormal. Prior laboratory evaluation, including CPK, ANA andAcetylcholine receptor antibodies, was normal. He had neverhad a formal eye exam. Family history was significant for amaternal great grandfather who required leg braces starting atage 6 (with removal around age 10), who also reportedly had asimilar posture as the patient. There was also a family historyof non-specific visual symptoms in multiple family members onhis mother’s side as well as an older sibling who previously hadseizures. He was not of French-Canadian descent, was the childof a non-consanguineous conception and had two half-brothersand one half-sister, all of whom were alive and well aside fromthe aforementioned seizures. Both of his parents and all of hisgrandparents were African-American as well.On examination, he had gaze-evoked nystagmus and saccadicdysmetria with undershoot saccades in all directions, prominentwhite striations emanating adjacent to the optic nerve withAbbreviations: ARSACS, Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.distinct optic disc margins on fundoscopy (Figure 2A), andsymmetric pupils with no afferent defect. Subtle choreiformmovements were noted in the fingers with outstretched handsand end point tremor on finger to nose testing was present. Inthe lower extremities, there was increased tone of spastic nature.Patellar reflexes were brisk and ankle jerks were decreased withassociated weakness. Cross adduction was present. His gait waswide based and staggering; he was unable to perform tandem gaittesting. Spasticity with mild scissoring was apparent with casualgait testing.Brain MRI revealed asymmetric volume loss within thesuperior and middle aspects of the cerebellar vermis relativeto the inferior aspect (Figure 1B) and faint linear T2 signalhypointensities within the pons (Figure 1C), findings thathave been shown to be associated with ARSACS (14, 15).Fundoscopic photography and Optical Coherence Tomographyboth demonstrated hypertrophy of the retinal nerve fiber layerand other retinal layers (Figures 2B,C), findings also observed inARSACS (16). Electromyography performed was abnormal forboth sensory and motor components in multiple nerves tested,providing electrophysiological evidence for a sensory greaterthan motor axonal polyneuropathy.Initial chromosome microarray then showed a 1.422megabase loss in the 13q12.12 region (Figure 3), of whichthere are 14 genes present. Three of these genes haveautosomal recessive genetic conditions associated withthem, including Limb-girdle muscular dystrophy type 2C(SGCG gene), ARSACS (SACS gene), and Combined oxidativephosphorylation deficiency 31 (MIPEP gene). SubsequentNext Generation Sequencing of these genes revealed thatthe patient had hemizygous, likely pathogenic variant in theSACS gene (c.11824dup), which was predicted to result ina frameshift mutation with premature protein termination(p.Met3942Asnfs∗4). Taken together, these clinical and geneticfindings are consistent with the diagnosis of ARSACS.Current treatment is focused on symptomatic managementand improvement of daily life. Gait stabilization with thewearing of ankle foot orthoses has been observed andhe has been receiving scheduled botox injections to thebilateral hamstrings every 90 days with improvement inflexibility.Frontiers in Neurology | www.frontiersin.org 2 November 2018 | Volume 9 | Article 956Dougherty et al. ARSACS in an African-AmericanFIGURE 2 | (A) Fundus photography of the right and left eyes demonstrating peripapillary retinal nerve fiber hypertrophy and white striations emanating adjacent tothe optic nerve. (B) Posterior pole Optical Coherence Tomography demonstrating hypertrophy of the retinal nerve fiber layer and other inner retinal layers. (C) Selectedcross sections of the right and left eye demonstrating hypertrophy of the retinal nerve fiber layer and other inner retinal layers. Colors correspond to the retinal layersdepicted above.DISCUSSIONWith the implementation of targeted high throughputsequencing and identification of novel genetic mutations,ARSACS, a disease previously reported primarily in theFrench-Canadian population of Quebec, is now beingidentified worldwide (17). Here, we have described theclinical presentation, diagnostic evaluation and management ofthe first reported case of ARSACS in the African-Americanpopulation. Furthermore, we identified a previouslyunreported mutation in the SACS gene, designated c.11824dup.A number of different mutations have been shown to cause theARSACS phenotype (18–20), which is thought to result from lossof function of the encoded protein Sacsin. The exact role of thislarge, 520-kDa cytoplasmic protein remains unknown, thoughit has been proposed to have roles in mitochondrial function(21), protein chaperoning (22), and the ubiquitin-proteasomesystem (23). Further studies have shown that Sacsin knockoutresults in increased reactive oxygen species production (24) andalterations in synaptic input and intrinsic firing in cerebellarPurkinje cells (25).The observed genetics in this patient are atypical in that he isa compound heterozygote, wherein full chromosomal deletion ofFrontiers in Neurology | www.frontiersin.org 3 November 2018 | Volume 9 | Article 956Dougherty et al. ARSACS in an African-AmericanFIGURE 3 | Chromosomal microarray showing 1.422 megabase loss in the 13q12.12 region containing 14 different genes, including the SACS gene.one of the SACS genes combined with the observed frameshiftmutation (hemizygous) resulted in the ARSACS phenotype. Ahemizygous presentation of this disease has previously beendescribed in the Belgian population (26). These two cases areunique in that they involve gross chromosomal deletion of theSACS gene, whereas all previously reported mutations in patientswith ARSACS involved either point mutations or missensemutations in this gene. Moderate perceptive hearing loss wasdescribed as the only feature by which the Belgian patient withARSACS differed from other cases of the disease, however thisfeature was not present in our patient.Despite a family history of gait abnormalities on his mother’sside, we cannot comment specifically on the nature of thispatient’s inheritance without formal genetic testing of his parents,which has not been performed at this time. De novo or inheriteddeletion of the SACS gene from one parent combined withanother de novo or inherited likely pathogenic variant from theother parent would be a theory of inheritance compatible withthe history and known genetics of this patient.CONCLUDING REMARKSIn sum, a high index of clinical suspicion combined withappropriate genetic testing should allow for continuedidentification of the ARSACS phenotype, a disease whoseworldwide prevalence will undoubtedly continue to rise asfurther novel mutations are characterized.ETHICS STATEMENTAll clinical data in this case report was collected with the consentof the patient and his mother. A written informed consent wasobtained from the patient and his parents for the participationin the study and the publication of this report. The case report isexempt from institutional review board approval.AUTHOR CONTRIBUTIONSSD wrote the manuscript under the mentorship of SH.AH acquired and interpreted clinical data and aidedin diagnosis. HA interpreted genetic data and providedcommentary. GV interpreted radiologic images and providedcommentary. SH acquired ophthalmologic photographs andclinical data, interpreted data and supervised case reportformulation.ACKNOWLEDGMENTSThe authors would like to thank the patient and his familymembers for entrusting them with his care.Frontiers in Neurology | www.frontiersin.org 4 November 2018 | Volume 9 | Article 956Dougherty et al. ARSACS in an African-AmericanREFERENCES1. Bouchard JP, Barbeau A, Bouchard R, Bouchard RW. Autosomal recessivespastic ataxia of Charlevoix-Saguenay. Can J Neurol Sci. (1978) 5:61–9.2. Engert JC, Berube P,Mercier J, Dore C, Lepage P, Ge B, et al. ARSACS, a spasticataxia common in northeastern Quebec, is caused by mutations in a new geneencoding an 11.5-kb ORF. Nat Genet. (2000) 24:120–5. doi: 10.1038/727693. Bouchard JP. Ressesive spastic ataxia of Charlevoix-Saguenay. In: deJong MBV, editors. 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Breckpot J, Takiyama Y, Thienpont B, Van Vooren S, Vermeesch JR, OrtibusE, et al. A novel genomic disorder: a deletion of the SACS gene leading tospastic ataxia of Charlevoix-Saguenay. Eur J Hum Genet. (2008) 16:1050–4.doi: 10.1038/ejhg.2008.58Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2018 Dougherty, Harper, Al Saif, Vorona and Haines. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and that theoriginal publication in this journal is cited, in accordance with accepted academicpractice. No use, distribution or reproduction is permitted which does not complywith these terms.Frontiers in Neurology | www.frontiersin.org 5 November 2018 | Volume 9 | Article 956

A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

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A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

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