Abstracts

Rationale: Mutations in SACS are classically known to cause autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Recently, two patients clinically diagnosed with progressive myoclonus epilepsy (PME) were found to have probably pathogenic SACS mutations. [1] In this report, we provide a detailed description of one of these cases of PME due to mutations in SACS.Methods: Case review.Results: The patient is a 25-year-old female who was born to healthy, non-consanguineous parents. Psychomotor development and cognition were normal, except for a mild learning difficulty. At the age of 13 years, she began to experience spontaneous and stimulus-induced myoclonic jerks. Two years later she had her first secondarily generalized convulsive seizure. Over the years, she also presented absence, dyscognitive, atonic, and tonic seizures, as well as photosensitivity. Over the years, seizures became pharmacoresistant, and cognitive function significantly deteriorated. Additionally, she developed exotropia, bilateral dysmetria, dysarthria, and cerebellar ataxia. The latter, in association with her severe action myoclonus, resulted in this patient being wheelchair bound. Further, she had hypertonia and hyperactive reflexes in her lower extremities, bilateral extensor plantar reflex. EEG studies showed bihemispheric slow wave background activity with multifocal interictal epileptiform discharges. Brain MRI revealed diffuse cerebral, cerebellar, and corpus callosum atrophy. Based on the aforementioned evidence, she was clinically diagnosed with PME. Genetic testing as well and skin and muscle biopsies were undertaken to investigate the most frequent causes of PME, including mitochondrial diseases, and these investigations were all normal. She finally underwent whole-exome sequencing [1], which revealed two rare compound heterozygous missense variants in SACS: c.1373C>T (p.Thr458Ile) and c.8393C>A (p.Pro2798Gln). These variants were confirmed by Sanger sequencing and were found to be in trans. Both variants were felt to be probably pathogenic and responsible for the patient’s phenotype. Notably, the variants had been previously reported in patients with ARSACS.Conclusions: Since SACS mutations had never been associated with any human-disease other than ARSACS, it is of paramount importance to clearly distinguish our patient’s phenotype from ARSACS. In this context, although she did develop cerebellar ataxia and pyramidal tract signs in the course of her disease (which are classically seen in ARSACS) [2], our patient presented typical PME characteristics – gradually worsening myoclonus, multiple intractable seizure types, as well as progressive cognitive decline and ataxia. Similarly important, never did the patient have peripheral neuropathy. In conclusion, we describe a patient with PME caused by alterations in the SACS gene. 1. Muona M, et al. Nat Genet. 2015 Jan;47(1):39-46.2011;286:20407-20412. 2. de Bot ST, et al. Neurology. 2012 Oct 2;79(14):1507-1514.