Whole-exome sequencing as a diagnostic tool in a family with episodic ataxia type 1

Abstract

Complex neurologic phenotypes are inherently difficult to diagnose. Whole-exome sequencing (WES) is a new tool in the neurologist's diagnostic armamentarium. Whole-exome sequencing can be applied to investigate the "diagnostic odyssey" cases. These cases involve patients with rare diseases that likely have a genetic etiology but have failed to be diagnosed by clinical evaluation and targeted gene testing. We describe such a case, a 22-year-old man who had mild intellectual developmental disability and episodes of jerking ataxic movements that affected his whole body. He underwent numerous multidisciplinary and multicentric evaluations throughout his life that failed to establish a clear diagnosis. Following his visit to Mayo Clinic in Jacksonville, Florida, WES was applied for genetic determination of the unknown disorder in the proband and his biological parents and sister. Additional clinical evaluation, magnetic resonance neuroimaging, electromyography, and electroencephalography of the proband were performed to verify the phenotype after the WES results were available. To our knowledge, this is the first report of the application of WES to facilitate the diagnosis of episodic ataxia type 1. This case illustrates that WES supported by clinical data is a useful and time-saving tool in the evaluation of patients with rare and complex hereditary disorders.

Figure 1

Pedigree structure of the family, Standard symbols were used. Round symbols indicate females, squares indicate males, diagonal lines indicate that the individual is deceased. Diamonds were used to disguise gender, numbers inside symbols indicate number of children. The solid arrowhead indicates the proband. Black full-filled symbols indicate individuals with clinical features of EA1. Asterisks indicate those family members that underwent whole-exome sequencing (proband and parents) or co-segregation analysis (sister).

Figure 2

Sagittal T1-weighted magnetic resonance image (a) and axial T2-weighted magnetic resonance image with fat saturation (b) demonstrate mild vermian atrophy (white arrow) and prominent cisterna magna (red arrow).

Figure 3

Electromyography showed the myokymic discharges (inner head of left gastrocnemius muscle).