To provide a case review of a unique patient presentation of multiple neurogenetic abnormalities resulting in both polyneuropathy and epilepsy.

Charcot-Marie-Tooth disease (CMT) is a collection of hereditary polyneuropathies that may vary in severity and presentation. The range of phenotypes observed is related to multiple genes associated with CMT, but clinical variability is also observed in those with similar gene variants.  The phenotype is characterized by deficits of sensory and motor polyneuropathy.  Rubinstein-Taybi syndrome (RTS), meanwhile, is an autosomal dominantly inherited disorder often resulting in distinctive facial features, short stature, and intellectual disability. Most cases represent simplex cases occurring because of mutations in CREBBP or EP300 genes.

A 22-year-old male presented with distal weakness, wasting and gait abnormality, as well as intellectual disability, syndromic facial appearance, and medically-refractory epilepsy with no identified structural brain abnormalities. This presentation painted a complicated diagnostic picture that had led to years of extensive workup and diagnostic testing. Ultimately, due to the complex clinical picture, whole exome sequencing (WES) was recommended and performed. This testing revealed a de novo pathogenic mutation in the DYNC1H1 gene, associated with CMT type 20, and a de novo likely pathogenic mutation in the CREBBP gene, supportive of RTS.

This case demonstrates the utility and yield of WES in patients with complex neurological presentations. In the present case, broad diagnostic testing demonstrated two distinct neurogenetic abnormalities that accounted for his especially complicated phenotype. The de novo genetic mutations in this case resulted in no relevant family history, and thus WES was able to resolve that multiple, concomitant abnormalities were present. Ultimately, this case demonstrates how a blurred phenotypic picture may require genetic testing resulting in multiple diagnoses. It demonstrates that many patients with hereditary neuropathies may be medically complex and require multidisciplinary collaboration and care.