Early-onset familial Alzheimer’s disease related to presenilin 1 mutation resembling autosomal dominant spinocerebellar ataxia

Abstract

Dear Sirs,Early-onset familial Alzheimer’s disease (EOFAD) is acondition characterized by early onset dementia associ-ated with a positive family history [1]. Presenilin 1 (PS1)mutations account for the majority cases and comprise anenormous phenotype variability. In special cases, ataxiahas also been reported during the course of the disease, butnot as a major symptom [2].The spinocerebellar ataxias (SCA) are a group of auto-somal dominant inherited neurological disorders, charac-terized by heterogeneous clinical presentations and a broadcombination of cerebellar signs [3]. Cognitive and neuro-psychological deficits have been described in some SCAsubtypes over the last years [4].Herein, we describe a family whose predominant neu-rological features were cerebellar ataxia and memoryimpairment. Bearing in mind that ataxia was one of thepredominant symptoms, genetic investigation was focusedon SCA. In this report, we call attention for atypical pre-sentation of presenilin 1 mutation that might mimick SCA.In Table 1, we summarize the main clinical, demographic,neuroimaging and neuropsychological features of thepatients evaluated.A 37-year-old-man (patient IV.4) presented to our clinicwith a 5-year history of progressive gait disturbances. Onneurological examination, there was axial and appendicularataxia, spasticity and brisk tendon reflexes. The Mini-Mental State Examination (MMSE) score was 13. Brainmagnetic resonance imaging (MRI) disclosed moderatecortical and cerebellar atrophy. His family history wasremarkable, since other family members were affected.Considering cerebellar symptoms as the most relevant,SCA subtypes 1, 2, 3, 6, 10, 17 and dentato-rubro-pallido-luysian (DRPLA) were investigated, and all genetic testsresulted in a negative. Huntington’s disease also was ruledout. For the following 2 years, he developed progressivememory impairment with disorientation in time. Hedeveloped mutism, and his communication is incompre-hensible for no relation to people. Severe stage of dementia(Clinical Dementia Rating-CDR = 3) and neuropsychiatricsymptoms (Neuropsychiatric Inventory-NPI = 45), asaggressiveness, irritability and sleep disturbance, indicate ahigh degree of dependence of daily activities and beingunwieldy for caregivers. Cognitive functions rapidlyworsened and he could not be evaluated by our neuro-psychological battery.A 35-year-old-man (patient IV.11), a cousin of patient 1,came to our hospital with progressive memory impairmentfor the last 6 years and gait instability and dysarthria forthe last 4 years. Neurological examination showed axialand appendicular ataxia, brisk tendon reflexes, and pyra-midal signs. Brain MRI disclosed moderate cortical andcerebellar atrophy. He presented a rapid worsening, and isnow confined to bed. Cognitive functions could not beevaluated, indicating a severe stage of dementia.(CDR = 3; MMSE not testable).A 33-year-old-woman (patient IV.13), a cousin ofpatients 1 and sister of patient 2, complained of progressivememory impairment for the last 4 years and gait instabilityfor the last 3 years. Neurological examination revealed