GENETIC MUTATIONS IN EARLY-ONSET DEMENTIA: REPORT FROM THE MEMORY CLINIC FROM SERBIA

Abstract

Monogenetic forms of early onset Alzheimer disease (EAOD) are very rare approximately 2.5 % of all dementia cases with three well known mutations in APP gene, Presenilin 1(PSEN1), and Presenilin 2 (PSEN2). Fronto-temporal dementia (FTD) is the second most common cause of early onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). The aim of this study was to assess the genetic mutations in a cohort of 322 Serbian patients with EOD and to report phenotypic features of identified carriers. PSEN1 was recorded in 2.42%, APP in 1.2 %, and PSEN2 in 1.21%. A family history of dementia is found in 30% of cases of FTD and about 10% have a clear autosomal-dominant inheritance. Some patients have an associated movement disorder, either parkinsonism, as in progressive supranuclear palsy and corticobasal syndrome, or motor neuron disease (FTD–MND). There was no MAPT mutation in our cohort. Four patients have been diagnosed with mutation in progranulin gene (GRN). Three patients were classified in the FTD spectrum and one with possible Alzheimer disease. We identified 4 patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer's dementia. Mutations in valosin-containing protein (VCP) was found in 3 patients with isolated bvFTD, and no inclusion body myopathy or Paget disease. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation.