To describe a novel mutation of the DNA polymerase subunit gamma (POLG) gene with a phenotypic presentation of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis Syndrome (SANDO).

The nuclear-encoded POLG gene encodes gamma subunit of the mitochondrial DNA polymerase that is responsible for the replication of the mitochondrial DNA (mtDNA). Mutations of the POLG gene can have multiple phenotypic presentations including sensory ataxic neuropathy with dysarthria and ophthalmoplegia or SANDO syndrome, first described in 1997. At the molecular level, A467T and W748S POLG mutations have been described in SANDO.

A 69-year-old female presented with two years of progressive ophthalmoplegia, ataxia, falls, hoarseness and dysphagia. Her mother also suffered from ataxia and falls. Neurological exam showed multifocal dystonia, significant truncal ataxia with postural instability, minimal appendicular ataxia, diffuse hyperreflexia, abnormal Hoffman and Babinski reflexes and frontal release signs. She had minimal rigidity and bradykinesia without tremors. Neuro-ophthalmological exam showed near-total absence of both vertical and horizontal eye movements bilaterally, esotropia and right hypertropia and weak orbicularis oculi and oris weakness bilaterally. She had abnormalities of alternate trail marking, figure copying, and clock drawing indicating visuospatial and executive dysfunction. Extensive workup including CSF, blood work and MRI Brain were unremarkable. Growth differentiation factor 15 levels were elevated suggesting a mitochondrial cytopathy. Genetic evaluation revealed single nucleotide heterozygous gene mutation of the POLG gene (c.3614G>C p.Gly1205Ala). This mutation has previously not been associated with pathology and hence felt to be of uncertain significance.

We report the phenotypic presentation of SANDO syndrome with a gene mutation previously classified as uncertain significance. Due to the clinical heterogeneity, overlapping phenotypes, diagnosis of mitochondrial diseases relies on the molecular detection of genetic mutations.