A juvenile-onset case of autosomal recessive spastic ataxia of charlevoix–saguenay with a novel mutation in the SACS gene

Dear editor, In this article, we describe the case of a 35-year-old man born to consanguineous parents who presented with gait difficulty and imbalance that had started at the age of 16 years. His symptoms progressively deteriorated such that he had been using unilateral assistance for walking for the last 7 years. His family history was unremarkable. On neurological examination, the patient was fully oriented and cooperative. His fundoscopic and cranial nerve examinations were normal. Motor examination showed paraparesis (Medical Research Council muscle scale, 3/5). He had bilateral mild dysmetria and bilateral intention tremor. Sensory examination showed a “stocking-glove” pattern of distal hypoesthesia. The extensor plantar reflexes were bilateral and the patellar reflexes were bilaterally hyperactive, confirming pyramidal system involvement. However, all other deep tendon reflexes were brisk. Of note, bilateral lower limb spasticity, compatible with grade 3 on the modified Ashworth scale, was detected[1] [https://links.lww.com/AOMD/A88]. Notably, bilateral pes cavus and hammer-toe deformities were present. Finally, the extrapyramidal system examination was normal. Routine laboratory work-up, including full blood count with peripheral blood smear, serum biochemistry, thyroid-stimulating hormone, vitamin B12, vitamin E, lipid profile, and cholestanol level were normal. Cranial magnetic resonance imaging (MRI) demonstrated linear pontine hypointensity on T2-weighted images and vermis atrophy [Figure 1]. The nerve conduction study revealed a severe, chronic, and sensorimotor axonal polyneuropathy. Needle electromyography did not reveal evidence of coexisting amyotrophy or myopathy. Genetic investigations for the GAA repeat were normal. Furthermore, genetic investigations for the autosomal recessive hereditary spastic paraplegia subtypes 5, 7, and 11 were negative. Whole-exome sequencing revealed compound heterozygous mutations in the SACS gene c.4611dupC (p. ile153HisfsTer3rs758580198) and c.9413_9415delATT (p. Tyr3138del), yielding the diagnosis of autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS).Figure 1: Cranial magnetic resonance imaging of the patient showing linear pontine hypointensity on axial fluid-attenuated inversion recovery images (a, b, c; arrows) and vermis atrophy (c–f; jagged arrows)Discussion ARSACS is an early-onset, progressive, and hereditary disorder caused by biallelic mutations in the sacsin molecular chaperone gene, known as the SACS gene.[2] The SACS gene encoding the sacsin protein is located in chromosome 13q12.12. It was first identified as the pathogenic gene responsible for ARSACS in 2000. ARSACS is the second most common autosomal recessive ataxia worldwide, as well as in the Turkish cohort.[3,4] Only a small number of cases present during childhood or adulthood; most presentations occur in early childhood.[3] The clinical picture of ARSACS is characterized by early-onset spastic ataxia, peripheral neuropathy, retinal hypermyelination, and hand or foot deformities.[5] However, it should be noted that there is a heterogenous clinical presentation of ARSACS, according to the affection of sacsin expression by the underlying disease-associated variant.[6] Recent studies have reported ARSACS patients without spasticity or retinal hypermyelination.[5,7] However, a genotype–phenotype correlation is currently unavailable.[6,8] In our patient, the clinical onset was juvenile instead of the classic onset during early childhood.[5] Furthermore, fundus examination did not show retinal hypermyelination, which is a characteristic finding of ARSACS.[5] It is remarkable to mention that cognitive dysfunction and intellectual disability are reported to be present in more than half of the patients; however, our patient had no cognitive dysfunction or deterioration.[5,6] Based on the clinical picture of progressive ataxia, peripheral neuropathy, and pyramidal tract involvement and the pattern of autosomal recessive inheritance, Friedreich’s ataxia was initially suspected in our patient. However, the genetic investigations for the GAA repeat were normal. In addition, the plasma cholestanol level was normal, excluding cerebrotendinous xanthomatosis, which is another cause of spastic ataxia with the autosomal recessive inheritance pattern. Considering the prominent feature of the pyramidal system involvement, the genetic investigations for the autosomal recessive hereditary spastic paraplegia subtypes were performed, which were negative. The diagnosis could be established after whole-exome sequencing using next-generation sequencing (NGS). Our patient had certain atypical features. In a crucial report from Turkey including the data of nine ARSACS patients,[8] two of the patients were atypically reported to have a later disease onset (one was during the second decade and the other was during the fifth decade). Among these nine patients, ophthalmological examination yielded prominent retinal nerve fibers in only four patients.[8,9,10] The neuroimaging sign of T2-hypointense stripes in the pons and atrophy of the superior cerebellar vermis are crucial findings present in most patients.[4,6,7] In addition, MRI of our index case presented in this article is indicative of the same. Of note, more than 200 variants of the SACS gene are described, and novel variants are still being identified to date.[7,8,9] At present, the use of the NGS technique has enabled the diagnosis of ARSACS in many patients. In addition, the advanced investigations of the other individuals of the pedigree and in silico bioinformatics tools led to the discovery of novel variants.[7,8] c.4611dupC is registered in the Single Nucleotide Polymorphism Database (rs758580198) but is absent in ClinVar or the literature. According to the Genome Aggregation Database, it has not been detected either in the East Asian or European (Finnish and non-Finnish) population; however, it has a frequency of 0.00000418 in the Ashkenazi Jewish community. Therefore, it had no homozygous individual thereof. The c.4611dupC frameshift mutation targeting the last exon of the SACS gene, which would cause the absence of the protein from that particular allele, is supported by many similar pathogenic frameshift variants in the last exon of the SACS gene registered in the ClinVar database. c.9413_9415del is an in-frame deletion in the last exon of the SACS gene. This variant has not been previously reported in any of the populations in the Genome Aggregation Database. c.9413_9415del is predicted to be a disease-causing variant according to MutationTaster. Nucleotides deleted in this alteration have high conservative scores according to the PhastCons100way and PhyloP100Way tools. Both variants were classified as pathogenic sequence alterations according to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for the classification of sequence variants.[11] Taken together, we report a novel variant; therefore, we have expanded the genetic literature.5 In conclusion, our patient may constitute a smart illustration of juvenile-onset ARSACS, where the diagnosis could be established at the age of 35 years. In this report, we re-emphasize the neuroimaging finding of hypointense stripes in the pons as a pathognomonic sign of ARSACS. In addition, we draw attention to the importance of the NGS technique for the diagnosis of this rare phenotype. Author contribution Concept – H.O.; Design – H.O.; Supervision – S.C.; Materials – H.O, S.C.; Data Collection and/or Processing – H.O.; Analysis and/or Interpretation – HO., S.C.; Literature Search – H.O; Writing Manuscript – H.O. Critical Review – S.C. Ethical compliance statement The manuscript has been prepared in accordance with the Helsinki Declaration of Principles. The informed consent form has been obtained from the patient. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgement None.

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