Elsevier

Parkinsonism & Related Disorders

Volume 35, February 2017, Pages 82-87
Parkinsonism & Related Disorders

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Frontotemporal dementia as the presenting phenotype of p.A53T mutation carriers in the alpha-synuclein gene

https://doi.org/10.1016/j.parkreldis.2016.12.002Get rights and content

Highlights

  • The p.A53T mutation in SNCA gene may have a frontotemporal dementia-like phenotype.

  • Brain MRI showed fronto-temporo-parietal atrophy resembling FTD.

  • CSF tau protein levels were elevated in patients with early cognitive decline.

  • CSF tau protein levels were normal in non-demented p.A53T carriers.

Abstract

Introduction

The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinson's disease (PD).

Methods

Here, we describe two apparently unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Aβ42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia.

Results

Both patients exhibited an early onset frontal-dysexecutive dysfunction with apathy and emotional blunting resembling frontotemporal dementia (FTD). Motor symptoms typical of Parkinson's disease appeared only later in the disease course and were less prominent than cognitive ones, which included language impairment. Autonomic dysfunction and myoclonus also emerged in a more advanced disease stage. In both patients, Brain Magnetic Resonance Imaging showed fronto-temporo-parietal atrophy, and CSF analysis showed elevated tau protein levels. In contrast, tau protein levels were normal in a cohort of 7 other p.A53T mutation carriers (5 symptomatic/2 asymptomatic). A screen of Greek patients presenting with frontotemporal dementia failed to identify any additional subjects with the p.A53T SNCA mutation.

Conclusion

Although cognitive decline has been recognized as a feature of the full-blown clinical picture of p.A53T related parkinsonism, a predominant frontotemporal dementia-like phenotype at presentation has not been previously described. This may represent a subtype of this disorder, with distinctive clinical, imaging and CSF biochemical characteristics, in which additional genetic or epigenetic factors may play a role.

Introduction

The G209A missense mutation in the alpha-synuclein (SNCA) gene leading to a p.A53T substitution is associated with autosomal dominant Parkinson's disease (PD) [1], [2] (Supplementary Table 1).Despite the fact that cognitive deterioration has been previously described as a feature of p.A53T related Parkinson's disease, a clear-cut non motor onset of the disorder with frontotemporal phenotype has not been reported before. Here, we report two cases of p.A53T SNCA mutation carriers whose initial manifestation was indicative of early onset dementia resembling frontotemporal dementia (FTD), rather than PD. This prompted further investigations in additional subjects with the p.A53T SNCA mutation and in a cohort of Greek FTD patients. The study received ethical approval and informed written consent was obtained from participants.

Case 1 is a 34-year-old computer scientist from North Western Peloponnese (Greece), with 16 years of education and no relevant past medical history. At age 30, he developed significant difficulty in performing complex cognitive tasks at work due to severe executive dysfunction and inability to concentrate, coupled with an intense anxiety. Over the following 12 months a tremor-dominant parkinsonism, postural instability with falls, short-term memory complaints and urinary urgency appeared. Both motor and cognitive disability led to early retirement. He was treated with levodopa with moderate response (100 mg L-Dopa qid).

On examination two months following initiation of levodopa he had mild hypomimia, eye lid opening apraxia, logopenic speech and hypophonia. He had a mild bilateral 5 Hz rest-tremor, rigidity, and severe bradykinesia (attributed in part to cognitive slowing); hyperreflexia was also noted on the right > left. His gait was short stepped and pull-test was severely abnormal. The patient showed frontal release signs on examination with significant pallilalia and grasping reflex. The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score was 42 (attributed to cognitive problems and apraxia and to a lesser degree to motor skill deterioration). Formal neuropsychological examination showed frontal executive dysfunction [CLOX1: 3/15, Verbal Fluency Test (category animals: 3 in 1 min)], with relatively preserved memory, and additional visuo-constructive difficulty. The patient's Mini Mental State Examination (MMSE) score was 23/30, the FAB (Frontal Assessment Battery) was 12/18, and NPI (neuropsychiatric inventory) score was 37/144 (apathy subscore 4, anxiety 8, euphoria 4). He fulfilled the criteria for possible behavioral variant frontotemporal dementia (B1.Early apathy, C2. Diminished social interest, F.Executive deficits) [3].

Four years after disease onset, the patient had deteriorated further, mostly cognitively. He demonstrated pseudoeuphoria and had no meaningful speech output except for stereotypical phrases. He was still able to ambulate independently, albeit with some difficulty. He was receiving Levodopa at a total dose of 400 mg/day. He was dependent on all activities of daily living. Prominent myoclonus was noted.

He is the first offspring born to non-consanguineous parents. His father was diagnosed with PD at age of 47, followed by dementia 10 years later. His paternal aunt and grandmother were also diagnosed with PD (Fig. 1).

Routine blood tests were normal. Serum ceruloplasmin and 24-h urine copper levels were within normal range. Cerebrospinal fluid (CSF) analysis showed elevated tau protein (τT): 548.66 pg/l (normal values of our lab <320 pg/ml). CSF amyloid Aβ42 and phospho-tau (τP-181) levels were both normal: 907 and 36.9 pg/ml respectively (>570 and <62 pg/ml respectively). Routine CSF findings were normal. There were no oligoclonal bands and IgG-Index was normal (0.59 reference <0,65).

Brain Magnetic Resonance Imaging (MRI) at the time of his first evaluation one year after disease onset revealed marked frontal, parietal and temporal, neocortical atrophy and atrophy in the mesial temporal lobe (hippocampal formation) (Fig. 1). Dopamine Transporter Imaging (DaTSCAN) revealed no uptake of dopamine transporter radioligand in the right putamen and significantly reduced uptake in the left putamen (Fig. 1).

Upon genetic testing the proband and his father were found positive for the p.A53T mutation of SNCA. He was not screened for other PARK genes. Molecular analysis of Mircrotubuli-associated protein tau (MAPT), progranulin (PGRN) and C9ORF72 did not reveal any relevant mutations.

Case 2 is a 51-year-old lawyer from Northern Peloponnese, with 16 years of education and no relevant past medical history. At age 49 he developed mild short term memory and speech deficits. Moreover, he faced difficulties in recognizing famous or familiar people, excluding his close relatives. An early onset dementia was diagnosed and he was started on donepezil with no obvious clinical benefit. During the following year, progressive gait impairment with postural instability leading to falls and urinary incontinence emerged. His behavior was altered and he showed marked apathy, emotional blunting and loss of initiative which resulted in poor occupational and social skills.

Upon examination a year and a half into his illness he was well oriented in time and space but presented severe attention/concentration deficits and pseudoephoria. He exhibited mild hypomimia, camptocormia, a shuffling gait with short steps, mild bradykinesia and right lower limb rigidity but no resting or position tremor. His tendon reflexes were normal, with flexor plantar response. Stimulus-sensitive upper limb myoclonus was occasionally present. The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score was 35 (also mainly attributed to cognitive problems and apraxia). Treatment with L-Dopa 200 mg tid led to a modest response (Video 1, suppl. Material).

The following are the Supplementary data related to this article:

Detailed neuropsychological assessment revealed severe executive dysfunction, a prominent semantic speech disorder, prosopagnosia, poor verbal recall ability and visuospatial memory deficits. His MMSE score was 25/30, FAB score 10/18 and NPI score 15/144. This patient exhibited a mixed phenotype of semantic dementia and behavioral variant frontotemporal dementia.

He is the first offspring born to non-consanguineous parents. His mother was diagnosed with PD at age of 55, followed by dementia approximately 10 years later. His maternal grandmother and three of his grandmother's sisters presented parkinsonism before the age of 60 years, along with dementia as the disease progressed (Fig. 2).

Routine blood testing was normal. CSF tau protein (τT) was elevated at 700 pgm/l whereas CSF amyloid Aβ42 and τP-181 level were normal at 971 pg/ml and 58 pg/ml respectively.

The patient underwent a brain MRI scan a year and a half into his illness that revealed bilateral temporal lobe atrophy which was more prominent on the right side along with a milder frontoparietal atrophy. Dopamine Transporter imaging revealed significantly reduced uptake of the radiotracer in the putamen bilaterally and in the right caudate nucleus (Fig. 2).

Following genetic testing, he was found positive for the p.A53T mutation of the SNCA gene (he was not screened for other PARK genes).

In order to assess the neurochemical impact of p.A53T related neurodegeneration, CSF levels of tau, p-tau and amyloid Aβ42 were measured in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia. These measurements showed normal tau and p-tau protein CSF levels in all patients. CSF amyloid Aβ42 level was marginally decreased in two symptomatic p.A53T carriers (Supplementary Fig. 1).

In order to assess whether the p.A53T mutation could be identified at any appreciable frequency in Greek patients with frontotemporal dementia, we screened a population of 66 subjects with this diagnosis, through the assessment of DNA available in the Neurogenetics Unit of Eginition Hospital. Patients with either Behavioral variant (bvFTD, n = 50) or Primary Progressive Aphasia (PPA, n = 16) were assessed. Diagnosis was made at the Dementia in-patient Unit of Eginition Hospital, according to standardized criteria [3]. The only mutation carrier identified was Case 1, presented above.

Section snippets

Discussion

We herein describe the clinical, imaging and biochemical features of two patients carrying the p.A53T SNCA mutation presenting with an early-onset FTD phenotype, whereas motor parkinsonian symptoms, more prominent in case 1, gradually appeared as the disease progressed. Nevertheless, cognitive and behavioral deficits, coupled with signs of involvement of the frontal lobe, such as apathy, pseudoeuphoria, prominent attention and executive deficits, poverty of speech and urinary incontinence,

Acknowledgements

This work was supported by grants from the following programs: MULTISYN European Program (FP7-HEALTH.2013.1.2–1, number 602646), MEFOPA (FP7-HEALTH-241791) and THALIS (Hellenic Ministry of Education and Religion THALIS grant number 377206) to LS. Moreover, it was supported by funding from the Michael J. Fox Foundation (PPMI study, Parkinson's Progression Markers Initiative).

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