Novel spastic ataxia of Charlevoix-Saguenay gene compound heterozygous mutations in late onset autosomal recessive spastic ataxia of Charlevoix-Saguenay

Abstract

Objective To investigate the clinical features and laboratory results in a patient with late onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) carrying novel SACS (spastic ataxia of Charlevoix-Saguenay) gene heterozygous mutations. Methods A 26-year-old Chinese man developed since the age of 13 a progressive weakness and stiffness of his bilateral lower limbs and gait unsteadiness. He had pyramidal tract sign in his bilateral lower limbs, cerebellar ataxia and sensory-motor polyneuropathy, with hyperelastica and swan neck-like deformities of the fingers, pes cavus and hammer toes. Funduscopy and optical coherence tomography, brain and cervical MRI, conduction velocity of peripheral nerve, motor evoked potentials, visual and brainstem auditory evoked potentials, ultrasound of peripheral nerve, hips and legs MRI, electronystagmography, and targeted capture and next generation sequencing were performed. Results Funduscopy and optical coherence tomography revealed thickening of the retinal nerve fiber layer with unclear margined optic disc. MRI revealed symmetrical linear hypointensity lesions in the pons on T2 and T2 FLAIR weighted images, thickened bilateral cerebellar peduncles, and flattened and atrophied cervical and upper thoracic spinal cord. Nerve conduction studies showed sensory nerve action potentials were absent in four limbs, motor conduction velocity was slowed, amplitude of muscle response was significantly decreased in lower-limb nerves (decreased by 80%-100%) but normal in upper-limb nerves. Central motor conduction time of motor evoked potential was prolonged. Targeted capture and next generation sequencing revealed novel SACS compound heterozygous mutations, c. 12637_12638delGA (p.Glu4213ArgFs*3) and c. 11274_11276delAAC (p.Ile3758_Thr3759delinsMet) derived from each parent respectively, which were confirmed by Sanger sequencing analyses. Conclusions Recognizing ARSACS triad and its characteristics on fundus and brain MRI is helpful for correct diagnosis. Our findings expand the clinical and genetic spectrum of ARSACS. Key words: Spinocerebellar degenerations; Ataxia; Polyneuropathies; Magnetic resonance imaging; Mutation