BEHAVIORAL VARIANT FTD CAUSED BY UBQLN2 P525S MUTATION, WITHOUT EVIDENCE OF MOTOR NEURON DISEASE

Abstract

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) represent extremes of a spectrum with significant overlap. Numerous gene mutations are known to cause these diseases in isolation or combination. Ubiquilin 2 (UBQLN2) mutations have recently been described and have been shown to cause either pure ALS or combination ALS/FTD. Presentation of a well characterized case of FTD caused by a UBQLN2 mutation without clinical or familial evidence of ALS. A 69-year-old right-handed man with a 2-year history of personality changes, unwelcomed familiarity, and increased gregariousness and embellishments with growing grandeur, at times delusional. There was “lack of filtering” and more childishness, playing with grandchildren “at their level”. Appetitive changes included a diet of Frappuccino's, jelly beans, and devil dogs. Lost $20 000 in a scam. Unable to maintain gainful employment as an information technology consultant. Past medical and psychiatric history: non-contributory. Family history: father passed from liver cancer at 53, mother from dementia at 83, sister with hypochotdriasis, and “bipolar” brother who passed in his 60s from pancreatic cancer. Examination: mild diffuse extrapyramidal syndrome without evidence of pyramidal or lower motor neuron disease. MoCA was 20/30, moderate deficits in attention/concentration with impact on memory, which was fully recovered with cues. Neuropsychological assessment revealed tangentiallity, impulsivity, and impersistence. There were deficits in aspects of learning, attention, and executive functions, with intact contextual memory, language, and visual spatial functions. MRI and FDG-PET scans showed focal frontal and anterior temporal atrophy and hypometabolism. Whole exome sequencing failed to reveal the better known genetic causes of FTD (MAPT, GRN, and C9orf72), but did show a known pathologic P525S mutation of the UBQLN2 gene. In addition, known risk or modifyier genes variants were also absent. Remains without clinical evidence of motor neuron disease 5 years following initial symptoms. To our knowledge, this is the first documented case of an isolated presentation of behavioral variant FTD without ALS, caused by a mutation in UBQLN2. Although still rare, this case further expands the spectrum of diseases caused by this mutation.