Objective: We report a patient with Spastic Ataxia caused by new homozygous mutations in the GRN gene.

Background: The gene GRN located on chromosome 17 encodes the protein progranulin that is widely expressed in the CNS and has a growth factor-like action. Mutations in this gene are known to cause motor neuron disease, frontotemporal dementia and progressive myoclonus epilepsy. To the best of our knowledge, predominant or pure ataxic or spastic phenotypes have not been described to date. Recessive and sporadic Hereditary Spastic Paraplegia and Ataxias are complex entities that often overlap phenotipically and genotipically with other neurodegenerative diseases.

Methods: Description of clinical features and results of genetic testing. Exome sequencing was performed on an Illumina HiSeq 2500 platform. Variants not present at dbSNP132, ExAC or 1000Genomes databases were filtered. Variants fitting a recessive model were prioritized for further analysis due to the patient phenotype.

Results: A 20 year-old female presented with gait impairment and epileptic seizures. The latter was usually triggered by intermittent light stimuli. Gait disturbance was progressive during the 6 following years with associated diplopia, disarthria and dysphagia. She had longstanding learning difficulties but recently developed aggressive behavior. Examination revealed global ataxia and exagerated reflexes, spasticity of the lower limbs and high arched feet. MRI scan showed Cerebellar Atrophy. Occipital epileptic discharges were observed during EEG. By using WES a homozygous c.767_768insCC mutation was identified at the GRN gene. This variant is predicted to be pathogenic by Mutation Taster and Ingenuity softwares; it results in a a frameshift with aminoacid sequence changes and premature termination of the transcript.

Conclusions: Homozygous GRN mutations may cause a spastic ataxia phenotype. This gene should be included in the differential diagnosis of complicated spastic paraplegias and ataxias, particularly in the presence of concomitant epilepsy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-phenotype-associated-with-grn-mutations-spastic-ataxia/