Introduction
Although the general causes and classification of early-onset (<65 years) dementia do not differ from old life dementia (Lambert et al., Reference Lambert2014), familial dementia syndromes, such as monogenetic Alzheimer's disease due to amyloid precursor protein (APP) and presenelin (PSEN1, PSEN2) gene mutations, often present as early onset disease (Kasuga et al., Reference Kasuga2015). Regarding familial tauopathies, the clinician should consider MAPT (microtubule-associated protein tau) mutations (Im et al., Reference Im, Kim and Kim2015; Irwin, Reference Irwin2015). These mutations are associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (Sperfeld et al., Reference Sperfeld1999), but for specific MAPT mutations Alzheimer's disease-like phenotypes have been described (Rademakers et al., Reference Rademakers2003; Wszolek et al., Reference Wszolek, Tsuboi, Ghetti, Pickering-Brown, Baba and Cheshire2006; Kasuga et al., Reference Kasuga2015). A genetic overlap between Alzheimer's disease and Parkinson's disease in the MAPT locus has been reported recently (Desikan et al., Reference Desikan2015). Patients with MAPT mutations may show highly variable clinical syndromes including frontotemporal lobar degeneration with parkinsonism, behavioral variant of frontotemporal dementia, as well as progressive supranuclear palsy- and corticobasal degeneration-like syndromes (Im et al., Reference Im, Kim and Kim2015; Irwin, Reference Irwin2015). FTDP-17 is a rare autosomal dominant neurodegenerative disease with three core features: (a) behavioral and personality changes, (b) cognitive dysfunction, and (c) parkinsonism-like motor symptoms (Wszolek et al., Reference Wszolek, Tsuboi, Ghetti, Pickering-Brown, Baba and Cheshire2006). Approximately, 40 MAPT mutations have been described (Wszolek et al., Reference Wszolek, Tsuboi, Ghetti, Pickering-Brown, Baba and Cheshire2006). The parkinsonism often presents as a parkinson-plus syndrome with poor Dopa-responsiveness, frequent falls, supranuclear gaze palsy, and sometimes apraxia or dystonia (Wszolek et al., Reference Wszolek, Tsuboi, Ghetti, Pickering-Brown, Baba and Cheshire2006). FTDP-17 patients may suffer from a parkinson-plus predominant disease, but a dementia predominant phenotype is more common (Reed et al., Reference Reed, Wszolek and Hutton2001).
Case report
In 2013, a 56-year-old Caucasian woman presented to our memory clinic with an approximately three-year history of progressive memory impairment, orientation deficits, and subtle behavioral changes. Her husband told us about a new preference for chintzy things, which he considered inconsistent with her rational character before symptom onset. He also remembered an episode of compulsive behavior when his wife repeatedly checked their locked apartment entrance door. Finally, he reported a tendency to fall when riding her bicycle. Our patient had a positive family history of early onset dementia. Her mother with severe dementia died at the age of 56. Due to a detailed psychiatric evaluation her mother had to undergo because of her incapacity to work, we learned about her cognitive, dysexecutive, and behavioral symptoms that were similar to our patient's. Her maternal grandfather committed suicide at the age of 54 being affected by severe cognitive deficits despite his young age.
In the clinical and neurological examination, we initially observed increased right-lateralized tone and vivid reflexes, accompanied by a general psychomotor slowing, depressed mood, and a tendency to dissimulate cognitive deficits. Brain magnetic resonance imaging (MRI) showed no abnormalities. Cerebrospinal fluid (CSF) analysis did not reveal amyloid or tau pathology and fluodesoxyglucose positron emission tomography (FDG-PET) showed a normal glucose metabolism except for subtle hypometabolic changes in the posterior cingulate cortex. Detailed neuropsychological testing revealed deficits in verbal and visual memory, concentration performance, and verbal fluency.
We first discussed a frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum disorder. However, candidate gene analyses for the chromosome 9 open reading frame 72 (C9ORF72) gene, fused in sarcoma (FUS) gene, and granulin encoding (GRN) gene yielded negative results. In the course of the disease, the patient's husband reported new behavioral abnormalities. His wife started to watch children's programs on TV, and could not select adequate clothes for herself. However, in the neurological examination there were neither relevant signs of frontal disinhibition nor an obvious progression of motor symptoms, such as paralysis or dysphagia. In addition to FTD-ALS, we therefore considered a behavioral variant of early-onset familial Alzheimer disease, but we did not find mutations in the APP, PSEN1, and PSEN2 genes. In early 2016, the cognitive impairment showed moderate progression, however, the motor signs changed significantly to a poorly Dopa-responsive, right-lateralized hypokinetic-rigid Parkinson syndrome. We obtained follow-up MRI- and FDG-PET brain imaging, now showing global atrophy and widespread hypometabolism with pronounced changes in the posterior cingulate cortex and in both hippocampi. Follow-up CSF analysis again showed negative results for amyloid-, tau, and hyperphosphorlated tau protein. The patient's family history still pointed to a fully penetrant monogenetic neurodegenerative disease. Because of the changes in motor symptoms over time, we considered MAPT genotyping, and we finally detected a heterozygous exon 10 splice side mutation in the MAPT gene (c.915+16C>T; Ex10 splice + 16) which has been previously described in families in the USA, UK, and in Australia (Hutton et al., Reference Hutton1998).
Discussion
This case illustrates various clinical symptoms of a FTDP-17 patient even during the course of the disease. For clinicians, it is important to recognize the value of longitudinal changes in cognitive, behavioral, and motor symptoms, and to evaluate rare neurodegenerative diseases in patients with unusual dementia presentations. Even though MAPT mutations are named FTDP-17, it is of note that clinical symptoms vary even in between family members (Reed et al., Reference Reed, Wszolek and Hutton2001; Wszolek et al., Reference Wszolek, Tsuboi, Ghetti, Pickering-Brown, Baba and Cheshire2006). Although treatment options may be limited, as in our case, pedigree data and genetic assessments can be crucial for how to educate patients and their families.
Conflict of interest
None.
Description of authors’ roles
R. Haußmann and M. Donix formulated the concept and design, collected and/or assembled the data, and drafted the manuscript. M. Wysocki, M. Brandt, and A. Hermann were involved in the collection and/or assembly of data and critical revision of manuscript.
