Novel frameshift mutation in the SACS gene causing spastic ataxia of charlevoix-saguenay in a consanguineous family from the Arabian Peninsula: A case report and review of literature

Abstract

BACKGROUND

Familial cases of autosomal recessive spastic ataxia of charlevoix-saguenay have not been reported in the Arabian Peninsula, although the consanguineous marriage rate is very high. We report the first family from the Arabian Peninsula harboring a novel frameshift mutation in the SACS gene.

CASE SUMMARY

A 33-year-old man presented to our neurology clinic with balance problems and weakness of distal upper and lower limbs. He was previously clinically diagnosed with Friedreich's ataxia. However, the severity of polyneuropathy and the electrodiagnostic studies (EDX) findings are atypical features of Friedreich’s ataxia, and the deterioration was attributed to diabetic neuropathy. Close examination of other family members identified cerebellar ataxia, lower-limb pyramidal signs, peripheral neuropathy, and magnetic resonance imaging findings characterized by pontine linear hypointensities. Genetic testing for Friedreich’s ataxia did not yield a diagnosis. Whole exome sequencing identified a novel frameshift germline mutation in the SACS gene termed c.5824_5827delTACT using the transcript NM_014363.5, which is predicted to cause premature termination of the sacsin protein at amino acid position 1942 (p.Tyr1942Metfs*9) and disrupts the sacsin SRR3 and domains downstream from it. The mutation segregated with the disease in the family.

CONCLUSION

Our data add to the spectrum of mutations in the SACS gene and argues for a need to implement suitably integrated clinical and diagnostic services, including next generation sequencing technology, to better classify ataxia in this area of the world.

Keywords: Ataxia, Autosomal recessive spastic ataxia of charlevoix-saguenay, Sacsin, Autosomal recessive spastic ataxia of charlevoix-saguenay, SACS mutation, Arabia, Next generation sequencing, Case report

Core tip: Autosomal recessive spastic ataxia of charlevoix-saguenay has not been reported previously in the Arabian peninsula where the consanguinity rate is high. We present herein, the first family with autosomal recessive spastic ataxia of charlevoix-saguenay harboring a novel SACS gene frameshift pathogenic mutation and argue that the disease may be underdiagnosed due to the lack of proper laboratory-clinical integration. This case highlights the importance of integrating the next generation sequencing pipeline for optimal diagnosis of neurological disorders.