We report the cognitive features and progression of Parkinson’s disease (PD) in five patients with concurrent Gaucher dis- ease. The patients presented at an earlier age than patients with sporadic PD, as previously noted by others; but in contrast to many previous reports, our patients followed a variable clinical course. While two patients developed early cognitive deficits and dementia, three others remained cognitively intact over the follow-up period. Thus, in this small case series, PD in the context of GD more closely resembles idiopathic PD in terms of its clinical heterogeneity in contrast to PD associated with GBA heterozygote mutations. Keywords Gaucher Disease · Parkinson’s Disease · Cognitive function · GBA mutations Introduction is one of the most frequent Lysosomal Storage Disorders (LSDs) and is caused by biallelic defects in the GBA1 gene Heterozygous mutations in the acid glucocerebrosidase gene [13, 16]. In patients with both GD and PD, the manifesta- (GBA1) are the most important genetic risk factor associated tions of Gaucher disease are usually reported to be mild [12, with so called “sporadic” Parkinson’s Disease (PD) [1–9]. 17] and the risk factors for developing PD in such patients However, the link between mutations in glucocerebrosi- are similar to those for idiopathic PD, namely male gender dase and PD was not discovered through genetic studies and older age [2, 15]. In these patients, GD usually predates but through astute clinical observations of the association the onset of PD, although rare reports of patients developing of PD in patients with Gaucher Disease (GD) patients [1, PD before their GD have been described [1, 3, 10, 18, 19]. In 10–13]. Furthermore, large-scale genetic studies failed con- the less frequently reported patients with concurrent PD/GD sistently to identify the associated GBA mutations because hitherto described, the motor features have been reported as of the apparent absence of a gene-dose effect or because of typical of those in idiopathic PD, including an asymmetric the association in Parkinson disease with multiple distinct onset of bradykinesia, rigidity, and resting tremor [1, 12, 14, mutant GBA1 alleles; these alleles, moreover, have divergent 20] and where pathological data is available, Lewy bodies distributions in different human populations [8 ]. have been found within the brainstem, cortex and hippocam- PD, a progressive neurodegenerative disorder, typically pus [13, 17, 21, 22]. Detailed neuropsychological and longi- presenting in patients over 65 years of age, in whom it pre- tudinal characterization of PD/GD cases has not previously sents with a triad of motor impairments including bradyki- been reported. Here, we describe a series of five patients nesia, rigidity and tremor - as well as non-motor features [1, with concurrent PD and GD in whom detailed clinical and 12, 14, 15]. GD, multisystem glycosphingolipid disorder, neuropsychological data were collected prospectively for up to 2 years. * Lucy M. Collins email@example.com John Van Geest Centre for Brain Repair, Cambridge, UK Lysosomal Disorders Unit, Department of Medicine, Addenbrooke’s hospital, University of Cambridge, Cambridge, UK Vol.:(0123456789) 1 3 1790 Journal of Neurology (2018) 265:1789–1794 Methods Case 1 Patients with GD and either concurrent PD or Parkinsonism Case 1 was diagnosed with GD aged 27 years and had a were identified from medical case note review of patients past medical history of splenectomy, cholecystectomy, oste- attending the LSD clinic at Addenbrooke’s hospital, Cam- oarthritis of the knees, tendinosis of the right shoulder and bridge. Informed, written consent was taken from all par- thrombocytopaenia. She was compound heterozygous for ticipants following ethical approval of the study (REC 13/ N370S/L444P. She was a right-handed non-smoker with no EE/0171). This study has been performed in accordance with family history of PD. Medications included 400 IU imiglu- the ethical standards established in the 1964 Declaration of cerase weekly and prophylactic penicillin. At her baseline Helsinki and its later amendments. The diagnosis of PD was visit (age 50) her walking was slow and she scored highly confirmed using UK PD Brain Bank criteria [1 , 12, 14, 15, for apathy but had no tremor or rigidity, so did not meet 23]. Patients were assessed annually for up to 2 years. At UKPDS Brain Bank diagnostic criteria for PD. She had no each visit a detailed medical history was taken and neurolog- significant cognitive deficits. When seen 1 year later, she ical evaluation performed to assess features of Parkinsonism, had developed more overt bradykinetic hand movements on and Hoehn and Yahr stage (H&Y). Cognitive function was the right, and right upper limb rigidity as well as a shuffling assessed using the Addenbrooke’s Cognitive Examination - gait. No significant cognitive deficits were present but her Revised (ACE-R), [2, 18] Mini-Mental State Examination apathetic symptoms persisted. A diagnosis of PD was made (MMSE), [19, 24] verbal fluency tests (including phonemic at this time. At the 2 year follow-up after baseline assess- fluency for letters F,A,S and semantic fluency), the penta- ment, 1 year after being diagnosed with PD, her motor state gon copying test  and the Frontal Assessment Battery had deteriorated with increasing right-sided bradykinesia, (FAB) [12, 20, 26]. The Beck Depression Inventory (BDI) rigidity and tremor and worsening gait impairment but no was used to assess depression [21, 27, 28] and the Behav- postural instability. Overall her symptoms remained mild ioural questionnaire apathy evaluation scale (AES), was with no cognitive deterioration and she did not require any used to rate apathy . Daytime sleepiness was assessed PD medication. using the Epworth Sleepiness Scale (ESS). The EuroQol five dimensions health questionnaire (EQ-5D) was used to assess overall health. One patient who lived abroad was unable to Case 2 attend the clinic and so was assessed via Skype using similar cognitive and motor tools, but rigidity assessments and pos- Case 2 was assessed via Skype. GD was detected 33 years tural stability were omitted and the behavioral component of before entry to study when she presented following a road the FAB could not be completed (Table 1). traffic accident when an enlarged spleen was detected along Table 1 Demographics of the GD/PD patients a b c ID Gender GBA mutation Age Edu PD GD Family history of PD Presenting PD fea- Presenting GD features disease disease tures a a duration duration Case 1 Female N370S/L444P 50 27 − 1 23 No Bradykinesia and Splenomegaly rigidity Case 2 Female N370S/L444P 60 21 1 33 No Tremor, bradykinesia Splenomegaly and rigidity Case 3 Female N370S/L444P 72 15 5 22 Yes Olfactory loss and Osteoporosis, throm- tremor bocytopenia Case 4 Male L444P/R463C 56 16 8 14 No Tremor, bradykinesia Splenomegaly, oste- and rigidity onecrosis Case 5 Female R463C/R463C 58 16 10 20 Unknown Tremor, bradykinesia Splenomegaly, osteo- and REM sleep porosis disturbance Five patients with both PD and GD were recruited. All patients had genetically confirmed GD. All were of non-Jewish descent and from the UK or Ireland At entry into the study Age at leaving full time education (Edu) In first degree relative 1 3 Journal of Neurology (2018) 265:1789–1794 1791 with unaccountable bruising on her legs. The current spe- Co-careldopa, amantadine and Co-beneldopa. At his first cific GD treatment was imiglucerase. She was a right-handed assessment at the age of 56 years, motor examination non-smoker with a compound heterozygous mutation revealed a Parkinsonian gait and postural instability. Neu- N370S/L444P. The participant had no family history of PD ropsychological testing revealed visuospatial dysfunction but had a sibling with GD now aged 68 years, who is unaf- with impaired pentagon copying. He had a moderate depres- fected by Parkinson disease. She was diagnosed with PD at sion score of 24 on the BDI. 1 year later he had developed the age of 59. On her initial assessment at the age of 60, she more axial features, including speech disturbance and pos- had moderate bradykinesia and mild tremor in the left upper tural instability. Neuropsychological testing again showed limb. Cognition was intact, although mild depression and predominantly visuospatial dysfunction but with a normal excessive daytime sleepiness were noted. At her first follow- ACE-R score of 94 and moderate depression. up assessment at 1 year, her motor symptoms had progressed but remained unilateral with left upper limb bradykinesia, rigidity and rest tremor. Her cognitive function remained Case 5 intact and she was not receiving any anti-PD medication. Case 5 was diagnosed with GD at the age of 38 when she had a splenectomy, and was noted to have osteoporosis. PD was Case 3 diagnosed at the age of 48 when she presented with a REM sleep disturbance, tremor and bradykinesia. She was treated Case 3 was diagnosed with GD at the age of 50 years when with imiglucerase therapy and PD medication that included she presented with mild osteoporosis and thrombocytopenia Madopar, entacapone and rivastigmine for cognitive impair- and was found to be compound heterozygous for N370S/ ment. Other medications included ibuprofen, paracetamol, L444P. She was a right-handed non-smoker. She had two simvastatin, alfacalcidol and senna, 9-alpha fludrocortisone, siblings, one brother had been diagnosed with both PD and mirtazapine and penicillin V. She was first assessed at the GD and a second brother had a diagnosis of GD. She was age of 58 years, and by this stage she had developed motor diagnosed with PD at the age of 67. Her presenting features fluctuations and dyskinesias. She was unable to complete of PD included loss of smell, depression, tremor, slowness formal cognitive testing but she had symptomatic cognitive and stiffness in the right hand/arm. Her medications included dysfunction and visual hallucinations. She died within a year imiglucerase therapy, bisoprolol, lansoprazole, citalopram, of her first assessment so no longer term follow-up data was Co-benelodopa, ropinirole, domperidone and rivastigmine. available (Table 2). On her first assessment at the age of 72 years, she reported pain, stiffness and mild tremor in the right arm, and there was objective evidence of unilateral bradykinesia, rigidity and tremor. She also had the evidence of significant cogni- Discussion tive impairment with an ACE-R 78/100 and an inability to copy the intersecting pentagons figure. She met Movement In this study, a series of five cases of PD associated with Disorder Society criteria for a diagnosis of PD dementia. Type I GD are reported. The occurrence of PD in GD She was noted to be apathetic (scoring highly on the AES). patients has not been associated with any particular GBA She was followed up and 1 year later she had developed mutation : all patients in this series, harboured one copy bilateral motor features but without postural instability, her of the GBA1 L444P mutation in trans with either N370S or cognitive function remained stable (ACE-R 80/100) and she R463C. Presenting features were similar in all cases, with had developed mild depression. all having the typical motor features seen in sporadic PD. Tremor was seen in most cases and consistent with other studies of such patients [1, 12, 14, 23]. The average age of Case 4 PD onset was 53.8 years in our cases, and three presented before the age of 50 years. In comparison, the average age Case 4 was diagnosed with GD at the age of 42 after present- of onset of idiopathic PD is about 70 years . From the ing with osteonecrosis, and was found to carry compound first publication of six patients in 1996, other authors have heterozygous mutations, L444P and R463C. He was a left- similarly noted an earlier age of onset of PD in patients with handed ex-smoker, with no family history of PD. PD was established GD [12, 26]. diagnosed at the age of 48 when he presented with a mild In our small case series, we found that cognitive func- right upper limb tremor, mild bilateral rigidity, bradykin- tion was well preserved in three of the five patients. We esia, poor postural reflexes, poor balance and hypophonia. acknowledge that two of these cases were assessed in the Medications included imiglucerase therapy, pramipexole, early stages of PD with relatively short follow-up durations, 1 3 1792 Journal of Neurology (2018) 265:1789–1794 Table 2 Baseline and follow-up Case 1 Case 2 Case 3 Case 4 clinical data for PD/GD patients Visit 1 Visit 2 Visit 3 Visit 1 Visit 2 Visit 1 Visit 2 Visit 1 Visit 2 ACE-R total 100 99 100 92 95 78 80 94 93 MMSE total 30 29 30 29 30 21 26 28 29 Attention 18 18 18 18 18 11 16 17 18 Memory 26 26 26 24 24 23 24 25 24 Fluency 14 14 14 10 11 7 6 11 13 Language 26 25 26 24 26 24 25 26 25 Visuospatial 16 16 16 16 16 14 7 15 13 Pentagon 2 2 2 2 2 1 0 1 1 Phonemic fluency 19 18 21 8 16 6 7 16 22 SF 60 s 23 22 20 18 16 13 9 16 17 SF 90 s 29 32 30 23 19 15 9 21 22 VF FAS 51 50 50 26 45 49 AES 21 29 27 57 BDI 1 0 9 23 24 FAB 18 18 18 18 H&Y 0 1 1 1 1 1 2 3 3 ACE-R Addenbrooke’s cognitive examination revised, MMSE mini mental state examination, AES apathy evaluation scale, BDI beck depression inventory, H&Y Hoehn and Yahr scale, SF semantic fluency, VF FAS verbal fluency for letters F, A, S, FAB frontal assessment battery. Visits were 12 months apart but it is noteworthy that case 4 had global cognitive scores For Gaucher’s patients receiving ERT, the therapy is not (ACE-R) within the normal range even at 8–9 years into predicted to cross the blood brain barrier (BBB). However, the course of their PD. This is compatible with growing there is evidence to suggest that the BBB is dysfunctional evidence suggesting that cognition in GD patients with PD in Parkinson’s disease , which may mean that it is can be preserved or only mildly impaired even in the late partially permeable to circulating molecules including pro- stages of the disease, [27, 28]; it, moreover, suggests that GD teins. If this were the case in patients with PD and GD the mutations are not a reliable predictor of rapid progression ERT might protect vulnerable dopaminergic neurons from to dementia in PD. cytotoxic injury. Alternatively systemic ERT could influ- Our findings should be considered in the context of ence the peripheral immune system (known to be disturbed several large-scale studies that describe more rapid cog- in GD), and dampen the activated immunity with cytotoxic nitive decline in patients with PD who are heterozygotes effects that have been documented in PD . for mutations in GBA1 [29–31]. This cognitive decline has In conclusion, in this case series of adults with the rare tentatively been linked to diminished lysosomal acid glu- combination of GD and PD, assessed using a range of cosidase activity, but if this were the causal explanation, motor and non-motor assessments over a 12–24 month then one would expect patients with PD in the context of period of follow-up, rapid disease progression and early established GD to show consistent early decline of their cog- cognitive impairment were not consistently found. We thus nitive powers. However, this is not necessarily the case—at contend that these are not universal features of this condi- least as shown in this small case series. It is remotely pos- tion during its early phases of evolution; as such patients sible that the enzyme replacement therapy (ERT) taken by are clinically and cognitively heterogeneous. This con- our GD patients may affect progression of PD as all of the trasts with the often-stated stereotypic clinical picture patients in our cohort were receiving long-term ERT. How- of rapid progression and early dementia in patients with ever, this ERT, a macrophage-targeted large glycoprotein PD who are heterozygous for GBA1 mutations; it, moreo- (MW ≈ 68 kDa) is considered not to cross the blood–brain ver, suggests that the link between PD, Parkinson’s Dis- barrier . Alternatively, ERT may have systemic effects; ease Dementia (PDD) and its associated alpha-synuclein which in turn indirectly affects the central pathology of PD. pathology is not simply related to the residual activity of This is a putative mechanism that we have suggested may lysosomal glucocerebrosidase. apply to the peripheral immune changes that are associated Acknowledgements This study was supported by the Rosetrees Trust, with PD . and the NIHR Cambridge Biomedical Research Centre (Metabolic and 1 3 Journal of Neurology (2018) 265:1789–1794 1793 Neurological Themes). We are grateful to the patients and their carers 13. Tayebi N (2003) Gaucher disease with parkinsonian manifesta- involved for volunteering and committing valuable time to participation tions: does glucocerebrosidase deficiency contribute to a vulner - in this research project. ability to parkinsonism? Mol Genet Metab 79:104–109 14. 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Published: May 29, 2018
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