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Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients
YBCMD-02093; No. of pages: 7; 4C: Blood Cells, Molecules and Diseases xxx (2016) xxx–xxx
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Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients☆ Maciej Machaczka a,⁎, Martin Paucar b,1, Cecilia Kämpe Björkvall c,1, Nicholas J.C. Smith d, Timothy M Cox e, Lars Forsgren f, Per Svenningsson b,⁎ a
Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, M54, Stockholm, Sweden Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden Department of Medicine, Sunderby Regional Hospital of Norrbotten County, Luleå, Sweden d School of Medicine, University of Adelaide, Adelaide, Australia e Department of Medicine, University of Cambridge, Cambridge, United Kingdom f Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden b c
a r t i c l e
i n f o
Article history: Submitted 29 September 2016 Available online xxxx Keywords: Glucocerebrosidase GBA1 Dystonia Parkinson's disease Gaucher disease
a b s t r a c t Background: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1. Methods: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3 years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken. Results: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40 years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations. Conclusions: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Gaucher disease (GD) is a rare glycosphingolipid disorder, which is caused by autosomal recessive mutations in the gene (GBA1) that encodes β-glucosylceramidase, an acid β-glucosidase, EC 3.2.1.45 [1,2]. This lysosomal enzyme has natural substrates which are mixtures of N-acyl-sphingosyl-1-O-β-D glucosides with varying acyl and sphingosine moieties, including the water-soluble β-glucosylsphingosine, that accumulate when acid β-glucosylceramidase activity is impaired [3].
☆ Funding agencies: This project was supported by an ALF grant (542502) from Stockholm City Council, Sweden and a Wallenberg Clinical Scholarship to PS. ⁎ Corresponding authors. E-mail addresses: [email protected] (M. Machaczka), [email protected] (P. Svenningsson). 1 Equal contribution.
Systemic accumulation of glucosylceramides and congeners occurs principally in mononuclear phagocytes and thrombocytopenia, anemia, splenomegaly, hepatomegaly, and bone manifestations are frequent manifestations of the disease [4]. Historically, GD has been divided into three principal clinical subtypes based on the presence of neurological manifestations and the rate of the disease progression [5]. Type 1 (Online Mendelian Inheritance in Man (OMIM) 230800), the adult or non-neuronopathic type; Type 2 (OMIM 230900), the infantile or acute neuronopathic type; and Type 3 (OMIM 231000), the chronic juvenile or subacute neuronopathic variant [6]. However, the boundaries between types of GD are often described as a phenotypic continuum. Type 3 Gaucher disease (GD3) is over-represented in patients originating from the provinces of Norrbotten and Västerbotten in northern Sweden [7]. The current prevalence is 1:17,500 inhabitants in this region [8]. The Norrbottnian type of GD is associated with homozygosity for the L444P missense mutation (c.1448T NC) in the GBA1 gene and
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Please cite this article as: M. Machaczka, et al., Blood Cells Mol. Diseases (2016), http://dx.doi.org/10.1016/j.bcmd.2016.10.011
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convincingly attributed to a founder effect established in an early 17th century pedigree by settlers in the region [9,10]. Common neurological manifestations include horizontal supranuclear gaze palsy, convergent squint, epilepsy, ataxia, mild spasticity in the legs and cognitive impairment. The severity of the clinical symptoms and signs and the course of the disease differ markedly not only between families but also between siblings [11]. If untreated, the median age of survival is 11.8 years of age. Enzyme replacement therapy (ERT) attenuates the hematological, visceral and skeletal manifestations, but there are no salutary effects on the neurological aspects of the disease. Until 1965, splenectomy was performed early in all Norrbottnian GD3 patients. However, it transpired that splenectomy aggravates progression of the neurological disease [12] and there is evidence that the impaired handling of glucosylceramides in the spleen accelerates accumulation of these metabolites in the brain [13]. Lately, splenectomy has been carried out because of recurrent splenic infarction, often in patients with massive splenomegaly, marked cytopenia, pressure symptoms or a deteriorating general condition. Most patients with so-called type 1 Gaucher disease (GD1) survive into adult life: they have visceromegaly and skeletal disease; involvement of the bone marrow and splenomegaly have consequential effects on the formed elements of the blood but neurological manifestations are characteristically not present early in the course of the disease. However, through case reports [14,15] and larger cohort studies [16, 17], it has become well-established that GD1 patients have a 8–10 fold increased risk of developing Parkinsonism and some have symptoms suggestive of polyneuropathy. At 60 years of age, 4.8% of patients with GD1 develop Parkinson's disease (PD); by 80 years of age this has been estimated to be and 9.1% [17]. Moreover, there is also a severalfold increased risk of development of PD among heterozygote GBA1 gene mutations carriers [18,19]. A recent cohort study with a 2-year follow-up showed that impairment of olfaction, cognition, and parkinsonian motor signs develop more frequently in GBA1 mutation carriers and GD1 patients than in control subjects [20]. Here we report systematic neurological and related examinations of adult GD3 (Norrbottnian) and GD1 patients (25 in total) in Sweden. We moreover studied this adult cohort to determine the course of this disease over a period of 3 years. 2. Methods 2.1. Patients Twenty five patients were enrolled: 12 with GD3 (Table 1A) and 13 with GD1 (Table 1B). The patients are followed systematically at the Departments of Hematology at Sunderby Hospital in Luleå or Karolinska University Hospital in Stockholm. All genotyping has been performed at GMP certified genetic laboratories. The study was approved by the Local Research Ethics Committee (2011/500-31/1) and participants provided written informed consent.
2.2. Longitudinal evaluation The patients were evaluated by standardized assessments of neurological symptoms and signs. Every sixth month, the GD3 patients were assessed with the 12-domain modified Severity Scoring Tool (mSST) [21]. At baseline and at the 3 years follow-up, all patients underwent the 40-item University of Pennsylvania Smell Identification Test (UPSIT) to test olfactory function, the Montreal Cognitive Assessment (MoCA) to assess cognitive function and the Hospital Anxiety and Depression Scale (HADS) to assess anxiety and depression.
2.3. Additional evaluations When clinical signs were present, additional and more intensive examinations were undertaken. Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn & Yahr along with 123I-FP-CIT (DaTSCAN®) SPECT and lumbar puncture were done when Parkinsonism was detected. Electrophysiological studies were carried out in two cases with hyperkinetic dystonia-like movement disorder or symptomatic polyneuropathy was suspected. Electroencephalography was undertaken to investigate patients with suspected epilepsy.
2.4. Statistics Descriptive tests (mean ± SEM) were used. Two-tailed paired t tests were used to explore the statistical significance of differences between baseline and follow-up examinations: a threshold limit of P b 0.05 was used to judge the likelihood of the findings being related to chance. 3. Results 3.1. Demographics and patient characteristics Basic demographics on sex, age, genotype, spleen status, start of enzyme replacement therapy (ERT) in the GD3 and GD1 patients are shown in Tables 1A and 1B. Two severely affected GD3 patients died from pneumonic complications of aspiration before the follow-up examination and four GD1 patients declined to participate in all tests at 3-year follow-up. All GD3 patients show skeletal disease that includes thoracic kyphosis. With two exceptions, all GD3 patients (10 of 12) had splenectomy (83%). All but one patient with GD1 had detectable splenomegaly; and four out of these 13 patients (31%) had undergone splenectomy. Two GD3 patients and one GD1 patient have been treated by allogeneic bone marrow transplantation (allo-BMT) at early age. All other patients with GD3 disease receive ERT. Six GD1 patients received ERT, one substrate reduction therapy (SRT) with N-butyldeoxynojirimycin (miglustat); five have received neither ERT nor SRT.
Table 1A Patient characteristics – Norrbottnian cohort of GD type 3. Pt
Sex/Age #
GBA1 gene mutations
Age atDx
SPC/Age
Therapy/Age
Abnormal Gaze
Epilepsy/Age
Ataxia
Dystonia
1 2 3 4 5 6 7 8 9 10 11 12
M/22 M/26 M/27 F/29 F/36 F/42 F/48 M/49 M/49 F/54 M/57* F/62*
c.1138GNA/c.1448T NC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC
1 3 2 2 7 2 2 1 5 3 1 2
N N Y/2 Y/2partial Y/10partial Y/8 Y/19 Y/10 Y/13 Y/3 Y/1 Y/3
ERT ERT ERT allo-BMT/2 ERT allo-BMT/9 ERT ERT ERT ERT ERT ERT
Y Y Y Y N Y Y Y Y Y Y Y
N Y/14 Y/17 Y/16 N Y/23 N N Seizure/45 N N Y/42
N Y Y N N Y N Y N Y ND Y
N Y N N N Y N Y N Y N N
Other
Myotonica congenita Migraine RA,Migraine Action tremor Degenerative aphasia Action tremor
Please cite this article as: M. Machaczka, et al., Blood Cells Mol. Diseases (2016), http://dx.doi.org/10.1016/j.bcmd.2016.10.011
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Table 1B Patient characteristics - Cohort of GD type 1. Pt
Sex/Age #
GBA1 gene mutations
Age at dx
SPC/Age
Therapy/Age
PD
Other
1 2 3 4 5 6 7 8 9 10 11 12 13
F/26 M/31 M/46 M/49 M/51 F/58 F/60 F/61 M/71 M/70 M/83 M/87 M/88
c.798CNG/c.1040TNG c.1138GNA/c.1448T NC c.1226ANG/c.1448TNC c.437CNT/c.1226A NG c.1226ANG/c.1226ANG c.1226ANG/c.1226ANG c.330delA/c.1226A NG c.1226ANG/c.1226ANG c.721GNA/c.1226ANG c.1226ANG/RecNci c.1448TNC, c.1483GNC, c.1497GNC c.1226ANG/RecNci c.1448TNC, c.1483GNC, c.1497GNC c.1226ANG/c.1448TNC c.115 + 1GNA/c.1226ANG
3 2 34 3 14 55 32 55 61 51 60 20 60
Y/5 Y/3 N Y/12 N N N N N N N Y/22 N
ERT allo-BMT/3 naïve ERT, SRT, ERT naïve naïve SRT, ERT SRT ERT ERT (SRT in 2010) ERT naïve naïve
N N N N N N N N N N Y Y N
N N N N N N N N N N N Epilepsy N
Pt – patient; Dx – diagnosis; SPC – splenectomy; ERT – enzyme replacement therapy; SRT – substrate reduction therapy; allo-BMT – allogeneic bone marrow transplantation; Y- yes; N- no; PD – Parkinsonism; RA- Reumatoid arthritis; ND – not determined; * – deceased; # – age in years at census date (6 April 2015 CE).
3.2. Neurological manifestations (symptoms and signs) With one exception, all patients with GD3 had characteristic horizontal saccadic and smooth pursuit abnormalities, which in four cases progressed to horizontal gaze palsy and reduced vertical eye movements (Video S1). Gross neuroophthalmic involvement was absent in all patients with designated type 1 disease. An intriguing and unexpected movement disorder was observed in four GD3 patients who experienced spontaneous rapid and repetitive hyperkinetic dystonia-like movement disorders in the face and the extremities (Videos S1 and S2). Repetitive blepharospams were also noticed. The patients were unaware of these hyperkinetic movements and could not readily suppress them. The two presented cases (Videos S1 and S2) underwent electrophysiological studies with neurography and electromyography which showed virtually normal results in cranially innervated musculature of the face (incl the masseter muscle) and it in the upper (incl the biceps branchii and dorsalis interosseus) and lower extremities (vastus medialis and tibialis anterior and gastrognemius). No signs of myopathia were detected. All GD3 patients were systematically assessed with the mSST, a validated clinical tool for monitoring neurological progression of GD3 [21]. As shown in Fig. 1, mSST varied markedly between the subjects, but did not change significantly (P = 0.61) over the study period. At baseline the mean score was 9.3 ± 1.8 and after 3 years 9.4 ± 1.9. When subscore mSST data from November 2012 and November 2015 were compared, no significant differences were found (Supplementary Fig. 1).
Fig. 1. Total mSST (modified Severity Scoring Tool) scores in the individual patients with type 3 Gaucher disease (Norrbottnian) from May 2012 until November 2015.
Six GD3 patients (50%) showed ataxic gait in combination with appendicular dysmetria. Two patients with GD1 have clinical manifestations of Parkinsonism. One patient had a tremor-dominant Parkinsonism with an onset at 58 years of age. The diagnosis of Parkinsonism is supported by pathological 123I-FP-CIT (DaTSCAN®) SPECT imaging studies (Supplementary Fig. 2), which show reduced asymmetric dopamine transporter (DAT) abundance. This patient remains anosmic, but cognitively intact; there are no psychiatric symptoms. This patient has had a good response to L-dopa treatment. On examination in ON state at 86 years of age, he has a Hoehn & Yahr score of 1.5 and a total UPDRS score at 33 (3 + 10 + 17 + 3) (Video S3). Another patient has Parkinsonism of akinetic-rigidity type with initial symptoms appearing at 76 years of age. Over more than 25 years, he has suffered from recurrent depression requiring hospitalization. This patient is receiving mirtazapine, but no anti-Parkinsonian medication. On examination at 81 years of age, he has a HADS-A score of 9, HADS-D of 4, Hoehn & Yahr score of 3 and an UPDRS score at 71 (7 + 17 + 41 + 6). He has a cognitive impairment with a MoCA score of 21. A CT scan of the brain shows mild hippocampal atrophy but a lumbar puncture showed normal levels of beta-amyloid 1–42 (922 ng/L); P-Tau (34 ng/L) and total Tau (192 ng/L). One GD3 patient presented with mild asymmetric rigidity and a 123I-FP-CIT SPECT demonstrated in 2014 reduced DAT levels in caudal putamen of the contralateral hemisphere. However, so far, the patient does not show any bradykinesia, impaired fine movements or tremor. Six (50%) GD3 patients had epilepsy. Four of these patients had focal dyscognitive seizures beginning in adolescent or in adulthood, typically with prominent aura including but not limited to taste and olfactory hallucinations, vertigo, feelings of unreality and déjà vu. These events proved self-resolving with a duration b 10 min, mostly 1–2 min, in most cases. In one patient, secondary generalization also occurred, and, at times a postictal period with dysphasia and severe anxiety was evident. Electroencephalography (EEG) showed focal seizure activity fronto-temporally in all four patients, and one also had episodes of bilateral synchronous spike-wave or sharp-wave activity in the middle temporal region. As reported previously [8], one patient had a single witnessed seizure attack at 45 years of age after shortage of ERT for 1.5 years, possibly a symptomatic seizure due to long-term effects of cessation of ERT-therapy. The patient was then put on antiepileptic therapy and has had no more seizures. The six GD3 patients were treated with various antiepileptic drugs, in monotherapy or in combination, resulting in remission of seizures in four patients. One patient also received vagus nerve stimulation. None of the patients manifest episodes of status epilepticus and myoclonic seizures were not evident within this cohort. One patient with GD1 has primary generalized tonic clonic seizures, responding to carbamazepine therapy. An assessment of cognitive performance was done using MoCA (Fig. 2). Unexpectedly, GD3 patients performed significantly (P = 0.01)
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A
B
Fig. 2. Heterogeneous performance in the Montreal Cognitive Assessment (MoCA) among patients with type 3 (A) and type 1 GD (B). Significant improvement (P = 0.01) was noted among the type 3 GD patients at follow-up. *P b 0.05; Paired Student's t-test.
better at the follow-up. The mean score was 23.9 ± 1.5 and after 3 years follow-up 26.3 ± 1.2. A patient with epilepsy who scored 10 at baseline died in the interim from pneumonia and was not included in the comparative analysis. Four patients, of whom three have epilepsy, had a lower score (b26) than the suggested cut-off for cognitive impairment at both examinations. Among the GD1 patients who underwent serial MoCA on two occasions, there was no difference (P = 0.63) between baseline (27.9 ± 0.6) and follow-up (28.3 ± 0.8) scores. At baseline all GD1 patients were included and the mean MoCA score was 25.6 ± 1.3. Four patients had a score indicating cognitive impairment.
Mood was assessed with HADS which addresses anxiety and depression (Fig. 3). Among the GD3 patients, there was no difference (P = 0.62) in anxiety scores between baseline (5.1 ± 1.5) and follow-up (5.9 ± 1.4) scores. Three subjects fulfilled the criteria (N 8) for anxiety at baseline and two at the follow-up. For the GD1 patients, there was a significant (P = 0.049) worsening of anxiety scores from baseline (3.4 ± 1.0) to the follow-up (4.4 ± 1.3). At both baseline and followup, two patients fulfilled the criteria for anxiety. When depression scores were assessed, no difference (P = 0.27) was found between baseline (3.0 ± 0.8) and follow-up (2.5 ± 0.8) among the GD3 patients.
A
B
C
D
Fig. 3. Hospital Anxiety and Depression Scale (HADS) with the anxiety (A, B) and depression (C, D) subscores demonstrates heterogeneity and with three GD type 3 (A) or two GD type 1 (B) patients showing significant anxiety. There is a significant worsening in anxiety subscores (P = 0.049) among the GD type 1 patients at follow up (B). No subscores showed significant depression in any of the GD type 3 (C) or GD type 1 (D) patients. *P b 0.05; Paired Student's t-test.
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Likewise, no difference (P = 0.65) was found between baseline (1.3 ± 0.6) and follow-up (1.5 ± 0.5) among the GD1 patients. None of the GD3 or GD1 patients fulfilled the criteria (N 8) for depression. Olfaction was examined with the 40-item UPSIT test (Fig. 4). Among the GD3 patients that participated at both examinations, there was no difference (P = 0.91) between baseline (27.9 ± 1.5) and follow-up (27.6 ± 1.7). Two patients had severe hyposmia and four had moderate hyposmia. Among the patients with GD1 who underwent UPSIT at two occasions, there was no difference (P = 0.10) between baseline (29.4 ± 2.3) and follow-up (31.9 ± 2.7). At baseline all GD1 patients were included and the mean UPSIT score was 25.4 ± 2.5. Four patients had complete anosmia (of whom two had Parkinsonism), one had moderate hyposmia. 4. Discussion While phenotypic heterogeneity is well recognized among patients with types 1 and 3 Gaucher disease [22], the Swedish population of Gaucher patients is unique in Europe and North America because of its relatively high prevalence of the L444P GBA1 allele - presumed to originate from a common ancestral source [9,10]. The catalytic function of the L444P variant enzyme is markedly impaired because of the inability of the mutated protein to fold efficiently within the secretory pathway, leading to extensive endoplasmic reticulum (ER)-associated proteasomal degradation (ERAD) and reduced delivery of the protein to its destination in the lysosome; patients who are homoallelic for this mutant GBA1 gene are generally afflicted by severe systemic manifestations and prominent neurological features of Gaucher disease. There is a marked heterogeneity in the severity of neurological symptoms in GD3 (Norrbottnian) patients in Sweden [11,12]. Marked diversity in the manifestation of Gaucher disease has been reported in twin pairs. Divergent monozygotic and dizygotic twin pairs have been described with very different phenotypes [23]. For instance, a monozygotic twin pair of Moroccan descent was reported by Biegstraaten et al. [24] with highly discordant neurological manifestations in 22 year-old women homoallelic for the disabling N188S GBA1 missense mutation: one had severe visceral involvement, epilepsy, and a cerebellar syndrome as predicted, but the twin had no clinical manifestations of Gaucher disease but suffered from type 1 diabetes mellitus. Clearly, an identical genetic defect can, despite relatively small differences in residual enzyme activity as determined in vitro, give rise to widely discordant clinical expression of Gaucher disease. A more thorough analysis of interactions between genes and environmental influences, as well as gene-to-gene effects, will be critical for any deeper understanding of the pathogenesis of this condition. Such knowledge may be rewarded by the identification of critical factors that modify expression of the disorder and also may allow the treatment of individuals predisposed to develop Gaucher disease to be refined.
A
5
With one exception, the Swedish patients with GD3 disease reported here are homoallelic for the GBA1 L444P missense mutation (c.1448T N C). Of note however, the exceptional GD3 patient was a compound heterozygote who had inherited one copy of L444P but harboured another rare GBA1 missense mutation encoding A341T (c.1138G NA) in common with another Swedish patient classified as having GD1. None of the patients in the GD1 patient cohort is homozygous for the L444P/L444P GBA1 mutation. Instead, they show numerous different mutations among which, N370S (c.1226A N G) is most common. Moreover, unlike the geographically segregated patients in Norrbotten and Västerbotten, who were homozygous for L444P and have manifestations of GD3, the patients with GD1 are widely distributed throughout Sweden. Our evaluations of the GD3 patients are summarized in the modified SST scale, which is a valid tool for monitoring neurological progression in GD3 [21]. A previous study used mSST to describe disease status and progression of neurological manifestations in 39 GD3 patients from Poland, Germany and UK over a period of 4 years [21]. The mean age in that cohort at baseline was 15.1 years and the mSST score 4.0 and at follow-up 6.0 with a significant progression. For logistical reasons, it had not been possible to include patients from Sweden in the previous European study to determine the evolution of mSST over time. However, it is informative to compare the results obtained here with that formerly reported: the cohort of Norrbottnian patients with GD3 cohort is significantly older, with a mean age of 37.4 years at baseline; moreover, their mean mSST score (at 9.3) is higher than that reported by Davies et al.[21]. In contrast to the combined European cohort, no significant progression was found at 3-year follow-up in our patients. Thus, the Norrbottnian cohort of patients with GD3 is distinct in many aspects when compared with other European cohorts. A notable clinical observation in this study was the presence in four patients of spontaneous rapid and repetitive hyperkinetic dystonic-like movement disorder along with blepharospasm. It is also possible that dystonia-like signs contribute to the severity of kyphoscolios in GD3 patients. Dystonia-like signs were observed independent of manifest epilepsy. Since these hyperkinetic movements were spontaneous and could not be suppressed, they are probably not related to tics. Moreover, since neurography and electromyography were virtually normal, it is unlikely that they represent myokymias. To our knowledge, the movement disorder has not been described previously in GD [22,25,26] and accordingly, the feature is not included among the 12-domain neurological items rated in the mSST scale. We await with interest to learn whether this symptomatic movement disorder indeed occurs in other patients with GD3 disease or whether it is restricted to those originating from Norrbotten. Epilepsy occurred in half of the GD3 patients with onset during adolescence or adulthood: in those patients with an adequate description, the seizures were primarily of a focal dyscognitive semiology, with
B
Fig. 4. University of Pennsylvania smell identification test (UPSIT) revealed hyposmia in six GD type 3 patients (A) and five GD type 1 patients (B).
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rare secondary generalization to tonic-clonic seizures. Neuroimaging was performed in two patients with focal seizures; MRI excluded lesional pathology to the extent of resolution available in one patient, while a static increase in amygdala and anterior hippocampal volume was evident upon serial CT imaging at a 5-year interval in the other. Focal seizure onset was also recorded and documented by EEG. In the early 1980s, epilepsy was reported in 6 of 22 (27%) of patients with GD3 from northern Sweden; the onset was between ages 5–12 years [12]. EEG showed focal epileptiform discharges in three and generalized discharges in the other three patients. There was no overlap between the six patients previously studied and those reported here. A search in publication databases for GD and epilepsy or seizures principally identifies reports describing progressive myoclonic epilepsy. Progressive myoclonic epilepsy and myoclonic seizures were not present in our series of Norrbottnian patients with GD3 and have not been reported previously in the region [12]; it appears instead that focal epilepsy is frequent in the Norrbottnian variant of this disease. It is noteworthy that focal epilepsy is but sparsely reported in the literature pertaining to GD and only in female patients: in a patient with the compound G377S/ Y205C genotype and in a patient with the N370S/L444P genotype cases 14, and 5 respectively in Park et al.[27] and Goker-Alpam et al.[28]; and finally in one discordant twin aged 22 years with neuronopathic GD reported by Biegstraaten et al.[24]. In agreement with a previous report [12], several Norrbottnian patients with GD3 suffered from truncal and appendicular ataxia. Since several of these GD3 patients have reached late middle-age and the L444P mutation is commonly associated with Parkinsonism [18,19], we were surprised to note its absence among the GD3 cohort; and, while one patient manifest isolated asymmetric rigidity, with a corresponding reduction in DAT abundance of the contralateral putamen this has not progressed to clinical Parkinsonism to date. However, it is noteworthy, that several GD3 patients demonstrated hyposmia, the interpretation of which is presently uncertain but might be cautiously interpreted as an early or premotor sign of evolving Parkinsonism. In contrast, we found two cases of Parkinsonism among the GD1 patients. One patient, with the N370S/L444P genotype, had typical manifestations of PD with a salutary response to levodopa. The other patient, harbouring a complex N370S/L444P, A456P, V460L genotype, had severe cognitive impairment which is in line with the evidence for greater cognitive impairment in those with established GBA-related Parkinsonism compared with sporadic Parkinsonism. In this context, it is noteworthy that many patients with PD in Västerbotten are heterozygote L444P mutation carriers [29]. Patients with GD may develop moderate to severe psychological complications, similar to patients with other chronic illnesses [30]. GD1 patients have been reported to exhibit mild deficits in attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory [31]. Indeed, on a group basis, the Swedish GD patients performed below average on MoCA. However, over the course of this study, there was no worsening; indeed, the GD3 patients showed a significantly improved MoCA score over the 3-year period of follow-up. The reason for this is unknown, but learning bias, due to repeated testing, improved antiepileptic therapy and general care may have influenced the performance. According to the macrophage hypothesis for neurological manifestations of GD3 [13,32], macrophages and closely related adventitial cells (pericytes) accumulate glucosylceramide and contribute to the neuropathological aspects of the disease and clinical deterioration, for example, after splenectomy. If this were the case, arrested or attenuated progression of the neurological disease would be predicted to occur in patients treated by allo-BMT [33]. Three of the studied patients have undergone BMT, but their disease course is highly variable and one patient has developed severe neurological manifestations. Thus, our data do not provide consistent support for the role of macrophages in the development or evolution of the neurological manifestations of GD3 in Sweden.
In summary, this is the first comprehensive investigation of the neurological manifestations of middle-aged and older patients with Norrbottnian type 3 and Swedish patients with type 1 Gaucher disease. New information as to the frequency and characteristics of epilepsy in the Norrbottnian GD3 has come to light: this is focal in nature and starts during adolescence and adulthood. Several of these patients suffer from anxiety and mild cognitive impairment which necessitates attention, regular follow-up and improved therapy. Hyposmia was frequent among the patients with both subtypes of disease and may herald a neurodegenerative process which ultimately leads to Parkinsonism although only two patients (with GD1) suffered from this movement disorder. Finally, several patients with GD3 disease in the Norrbottnian cohort suffered from an unusual rapid and repetitive dystonia-like hyperkinetic movement disorder with concomitant blepharospasm. This is a movement disorder hitherto not reported in patients with chronic GD and expands the phenotype for this condition. Supplementary data to this article can be found online at doi:10. 1016/j.bcmd.2016.10.011. Author contributions 1) Research project:
A. Conception; MM, PS B. Organization; MM, CBK, PS C. Execution; MM, CBK, PS
2) Statistical Analysis:
A. Design; MM, PS B. Execution; PS C. Review and Critique; MM
3) Manuscript:
A. Writing of the first draft; PS B. Review and Critique; MM, MP, CBK, NJCS, TMC, LF
Relevant conflicts of interests/financial disclosures Nothing to report. Acknowledgements We would like to thank the participants and their families. We would also like to thank Drs Ruth Walker and Carlo Colosimo for their comments on the phenomenology of the spontaneous dystonia-like hyperkinetic movement disorder found in some GD3 patients. References [1] T.M. Cox, Gaucher disease: clinical profile and therapeutic developments, Biologics 4 (2010) 299–313. [2] G.A. Grabowski, Gaucher disease and other storage disorders, Hematology Am. Soc. Hematol. Educ. Program (2012) 13–18. [3] O. Nilsson, J.-E. Månsson, G. Håkansson, L. Svennerholm, The occurrence of psychosine and other glycolipids in spleen and liver from the three major types of Gaucher's disease, Biochim. Biophys. Acta 712 (1982) 453–463. [4] A. Zimran, How I treat Gaucher disease, Blood 118 (2011) 1463–1471. [5] Genetics of the sphingolipidoses, in: A.G. Knudson Jr., W.D. Kaplan, S.M. Aronson, B.W. (Eds.), Cerebral Sphingolipidoses: A Symposium on Tay-Sachs Disease and Allied Disorders, Academic Press, New York, N.Y 1962, pp. 395–409.
Please cite this article as: M. Machaczka, et al., Blood Cells Mol. Diseases (2016), http://dx.doi.org/10.1016/j.bcmd.2016.10.011
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Novel hyperkinetic dystonia-like manifestation and neurological disease course of Swedish Gaucher patients☆ Maciej Machaczka a,⁎, Martin Paucar b,1, Cecilia Kämpe Björkvall c,1, Nicholas J.C. Smith d, Timothy M Cox e, Lars Forsgren f, Per Svenningsson b,⁎ a
Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, M54, Stockholm, Sweden Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden Department of Medicine, Sunderby Regional Hospital of Norrbotten County, Luleå, Sweden d School of Medicine, University of Adelaide, Adelaide, Australia e Department of Medicine, University of Cambridge, Cambridge, United Kingdom f Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden b c
a r t i c l e
i n f o
Article history: Submitted 29 September 2016 Available online xxxx Keywords: Glucocerebrosidase GBA1 Dystonia Parkinson's disease Gaucher disease
a b s t r a c t Background: Neuronopathic Gaucher disease type 3 (GD3) is frequent in northern Sweden, whereas GD1 is found throughout the country. In a nation-wide study, we examined neurological manifestations and clinical course in 12 patients with GD3 and 13 patients with GD1. Methods: The patients were evaluated by standardized neurological assessments. Every sixth month, the GD3 patients were rated with the modified Severity Scoring Tool. At baseline and at the 3 years follow-up, patients underwent University of Pennsylvania Smell Identification Test, Montreal Cognitive Assessment and Hospital Anxiety and Depression Scale. When clinical signs were present, additional examinations were undertaken. Results: Marked clinical heterogeneity was evident in both GD3 and GD1 groups. Several GD3 patients had a hitherto unreported rapid and repetitive dystonia-like hyperkinetic movement disorder. Most patients with GD3 have abnormalities of horizontal gaze, ataxia and focal epilepsy, some also had cognitive impairment, anxiety and hyposmia. Six GD3 patients, all homoallelic for L444P GBA1 mutations, have lived beyond 40 years of age; and none has developed Parkinsonism. Two of the GD1 patients suffer from Parkinsonism; mild to complete hyposmia was present in six GD3 and five GD1 patients. Neither the group of GD3 nor GD1 patients had detectable progression of their neurological manifestations. Conclusions: These middle-aged and older Swedish GD3 or GD1 patients are clinically stable over time. However, we have identified unusual clinical features, discordant phenotypes and a hyperkinetic dystonia-like movement disorder which appears unique to this Swedish disease variant and expands the phenotype for GD. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Gaucher disease (GD) is a rare glycosphingolipid disorder, which is caused by autosomal recessive mutations in the gene (GBA1) that encodes β-glucosylceramidase, an acid β-glucosidase, EC 3.2.1.45 [1,2]. This lysosomal enzyme has natural substrates which are mixtures of N-acyl-sphingosyl-1-O-β-D glucosides with varying acyl and sphingosine moieties, including the water-soluble β-glucosylsphingosine, that accumulate when acid β-glucosylceramidase activity is impaired [3].
☆ Funding agencies: This project was supported by an ALF grant (542502) from Stockholm City Council, Sweden and a Wallenberg Clinical Scholarship to PS. ⁎ Corresponding authors. E-mail addresses: [email protected] (M. Machaczka), [email protected] (P. Svenningsson). 1 Equal contribution.
Systemic accumulation of glucosylceramides and congeners occurs principally in mononuclear phagocytes and thrombocytopenia, anemia, splenomegaly, hepatomegaly, and bone manifestations are frequent manifestations of the disease [4]. Historically, GD has been divided into three principal clinical subtypes based on the presence of neurological manifestations and the rate of the disease progression [5]. Type 1 (Online Mendelian Inheritance in Man (OMIM) 230800), the adult or non-neuronopathic type; Type 2 (OMIM 230900), the infantile or acute neuronopathic type; and Type 3 (OMIM 231000), the chronic juvenile or subacute neuronopathic variant [6]. However, the boundaries between types of GD are often described as a phenotypic continuum. Type 3 Gaucher disease (GD3) is over-represented in patients originating from the provinces of Norrbotten and Västerbotten in northern Sweden [7]. The current prevalence is 1:17,500 inhabitants in this region [8]. The Norrbottnian type of GD is associated with homozygosity for the L444P missense mutation (c.1448T NC) in the GBA1 gene and
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convincingly attributed to a founder effect established in an early 17th century pedigree by settlers in the region [9,10]. Common neurological manifestations include horizontal supranuclear gaze palsy, convergent squint, epilepsy, ataxia, mild spasticity in the legs and cognitive impairment. The severity of the clinical symptoms and signs and the course of the disease differ markedly not only between families but also between siblings [11]. If untreated, the median age of survival is 11.8 years of age. Enzyme replacement therapy (ERT) attenuates the hematological, visceral and skeletal manifestations, but there are no salutary effects on the neurological aspects of the disease. Until 1965, splenectomy was performed early in all Norrbottnian GD3 patients. However, it transpired that splenectomy aggravates progression of the neurological disease [12] and there is evidence that the impaired handling of glucosylceramides in the spleen accelerates accumulation of these metabolites in the brain [13]. Lately, splenectomy has been carried out because of recurrent splenic infarction, often in patients with massive splenomegaly, marked cytopenia, pressure symptoms or a deteriorating general condition. Most patients with so-called type 1 Gaucher disease (GD1) survive into adult life: they have visceromegaly and skeletal disease; involvement of the bone marrow and splenomegaly have consequential effects on the formed elements of the blood but neurological manifestations are characteristically not present early in the course of the disease. However, through case reports [14,15] and larger cohort studies [16, 17], it has become well-established that GD1 patients have a 8–10 fold increased risk of developing Parkinsonism and some have symptoms suggestive of polyneuropathy. At 60 years of age, 4.8% of patients with GD1 develop Parkinson's disease (PD); by 80 years of age this has been estimated to be and 9.1% [17]. Moreover, there is also a severalfold increased risk of development of PD among heterozygote GBA1 gene mutations carriers [18,19]. A recent cohort study with a 2-year follow-up showed that impairment of olfaction, cognition, and parkinsonian motor signs develop more frequently in GBA1 mutation carriers and GD1 patients than in control subjects [20]. Here we report systematic neurological and related examinations of adult GD3 (Norrbottnian) and GD1 patients (25 in total) in Sweden. We moreover studied this adult cohort to determine the course of this disease over a period of 3 years. 2. Methods 2.1. Patients Twenty five patients were enrolled: 12 with GD3 (Table 1A) and 13 with GD1 (Table 1B). The patients are followed systematically at the Departments of Hematology at Sunderby Hospital in Luleå or Karolinska University Hospital in Stockholm. All genotyping has been performed at GMP certified genetic laboratories. The study was approved by the Local Research Ethics Committee (2011/500-31/1) and participants provided written informed consent.
2.2. Longitudinal evaluation The patients were evaluated by standardized assessments of neurological symptoms and signs. Every sixth month, the GD3 patients were assessed with the 12-domain modified Severity Scoring Tool (mSST) [21]. At baseline and at the 3 years follow-up, all patients underwent the 40-item University of Pennsylvania Smell Identification Test (UPSIT) to test olfactory function, the Montreal Cognitive Assessment (MoCA) to assess cognitive function and the Hospital Anxiety and Depression Scale (HADS) to assess anxiety and depression.
2.3. Additional evaluations When clinical signs were present, additional and more intensive examinations were undertaken. Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn & Yahr along with 123I-FP-CIT (DaTSCAN®) SPECT and lumbar puncture were done when Parkinsonism was detected. Electrophysiological studies were carried out in two cases with hyperkinetic dystonia-like movement disorder or symptomatic polyneuropathy was suspected. Electroencephalography was undertaken to investigate patients with suspected epilepsy.
2.4. Statistics Descriptive tests (mean ± SEM) were used. Two-tailed paired t tests were used to explore the statistical significance of differences between baseline and follow-up examinations: a threshold limit of P b 0.05 was used to judge the likelihood of the findings being related to chance. 3. Results 3.1. Demographics and patient characteristics Basic demographics on sex, age, genotype, spleen status, start of enzyme replacement therapy (ERT) in the GD3 and GD1 patients are shown in Tables 1A and 1B. Two severely affected GD3 patients died from pneumonic complications of aspiration before the follow-up examination and four GD1 patients declined to participate in all tests at 3-year follow-up. All GD3 patients show skeletal disease that includes thoracic kyphosis. With two exceptions, all GD3 patients (10 of 12) had splenectomy (83%). All but one patient with GD1 had detectable splenomegaly; and four out of these 13 patients (31%) had undergone splenectomy. Two GD3 patients and one GD1 patient have been treated by allogeneic bone marrow transplantation (allo-BMT) at early age. All other patients with GD3 disease receive ERT. Six GD1 patients received ERT, one substrate reduction therapy (SRT) with N-butyldeoxynojirimycin (miglustat); five have received neither ERT nor SRT.
Table 1A Patient characteristics – Norrbottnian cohort of GD type 3. Pt
Sex/Age #
GBA1 gene mutations
Age atDx
SPC/Age
Therapy/Age
Abnormal Gaze
Epilepsy/Age
Ataxia
Dystonia
1 2 3 4 5 6 7 8 9 10 11 12
M/22 M/26 M/27 F/29 F/36 F/42 F/48 M/49 M/49 F/54 M/57* F/62*
c.1138GNA/c.1448T NC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC c.1448TNC/c.1448TNC
1 3 2 2 7 2 2 1 5 3 1 2
N N Y/2 Y/2partial Y/10partial Y/8 Y/19 Y/10 Y/13 Y/3 Y/1 Y/3
ERT ERT ERT allo-BMT/2 ERT allo-BMT/9 ERT ERT ERT ERT ERT ERT
Y Y Y Y N Y Y Y Y Y Y Y
N Y/14 Y/17 Y/16 N Y/23 N N Seizure/45 N N Y/42
N Y Y N N Y N Y N Y ND Y
N Y N N N Y N Y N Y N N
Other
Myotonica congenita Migraine RA,Migraine Action tremor Degenerative aphasia Action tremor
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Table 1B Patient characteristics - Cohort of GD type 1. Pt
Sex/Age #
GBA1 gene mutations
Age at dx
SPC/Age
Therapy/Age
PD
Other
1 2 3 4 5 6 7 8 9 10 11 12 13
F/26 M/31 M/46 M/49 M/51 F/58 F/60 F/61 M/71 M/70 M/83 M/87 M/88
c.798CNG/c.1040TNG c.1138GNA/c.1448T NC c.1226ANG/c.1448TNC c.437CNT/c.1226A NG c.1226ANG/c.1226ANG c.1226ANG/c.1226ANG c.330delA/c.1226A NG c.1226ANG/c.1226ANG c.721GNA/c.1226ANG c.1226ANG/RecNci c.1448TNC, c.1483GNC, c.1497GNC c.1226ANG/RecNci c.1448TNC, c.1483GNC, c.1497GNC c.1226ANG/c.1448TNC c.115 + 1GNA/c.1226ANG
3 2 34 3 14 55 32 55 61 51 60 20 60
Y/5 Y/3 N Y/12 N N N N N N N Y/22 N
ERT allo-BMT/3 naïve ERT, SRT, ERT naïve naïve SRT, ERT SRT ERT ERT (SRT in 2010) ERT naïve naïve
N N N N N N N N N N Y Y N
N N N N N N N N N N N Epilepsy N
Pt – patient; Dx – diagnosis; SPC – splenectomy; ERT – enzyme replacement therapy; SRT – substrate reduction therapy; allo-BMT – allogeneic bone marrow transplantation; Y- yes; N- no; PD – Parkinsonism; RA- Reumatoid arthritis; ND – not determined; * – deceased; # – age in years at census date (6 April 2015 CE).
3.2. Neurological manifestations (symptoms and signs) With one exception, all patients with GD3 had characteristic horizontal saccadic and smooth pursuit abnormalities, which in four cases progressed to horizontal gaze palsy and reduced vertical eye movements (Video S1). Gross neuroophthalmic involvement was absent in all patients with designated type 1 disease. An intriguing and unexpected movement disorder was observed in four GD3 patients who experienced spontaneous rapid and repetitive hyperkinetic dystonia-like movement disorders in the face and the extremities (Videos S1 and S2). Repetitive blepharospams were also noticed. The patients were unaware of these hyperkinetic movements and could not readily suppress them. The two presented cases (Videos S1 and S2) underwent electrophysiological studies with neurography and electromyography which showed virtually normal results in cranially innervated musculature of the face (incl the masseter muscle) and it in the upper (incl the biceps branchii and dorsalis interosseus) and lower extremities (vastus medialis and tibialis anterior and gastrognemius). No signs of myopathia were detected. All GD3 patients were systematically assessed with the mSST, a validated clinical tool for monitoring neurological progression of GD3 [21]. As shown in Fig. 1, mSST varied markedly between the subjects, but did not change significantly (P = 0.61) over the study period. At baseline the mean score was 9.3 ± 1.8 and after 3 years 9.4 ± 1.9. When subscore mSST data from November 2012 and November 2015 were compared, no significant differences were found (Supplementary Fig. 1).
Fig. 1. Total mSST (modified Severity Scoring Tool) scores in the individual patients with type 3 Gaucher disease (Norrbottnian) from May 2012 until November 2015.
Six GD3 patients (50%) showed ataxic gait in combination with appendicular dysmetria. Two patients with GD1 have clinical manifestations of Parkinsonism. One patient had a tremor-dominant Parkinsonism with an onset at 58 years of age. The diagnosis of Parkinsonism is supported by pathological 123I-FP-CIT (DaTSCAN®) SPECT imaging studies (Supplementary Fig. 2), which show reduced asymmetric dopamine transporter (DAT) abundance. This patient remains anosmic, but cognitively intact; there are no psychiatric symptoms. This patient has had a good response to L-dopa treatment. On examination in ON state at 86 years of age, he has a Hoehn & Yahr score of 1.5 and a total UPDRS score at 33 (3 + 10 + 17 + 3) (Video S3). Another patient has Parkinsonism of akinetic-rigidity type with initial symptoms appearing at 76 years of age. Over more than 25 years, he has suffered from recurrent depression requiring hospitalization. This patient is receiving mirtazapine, but no anti-Parkinsonian medication. On examination at 81 years of age, he has a HADS-A score of 9, HADS-D of 4, Hoehn & Yahr score of 3 and an UPDRS score at 71 (7 + 17 + 41 + 6). He has a cognitive impairment with a MoCA score of 21. A CT scan of the brain shows mild hippocampal atrophy but a lumbar puncture showed normal levels of beta-amyloid 1–42 (922 ng/L); P-Tau (34 ng/L) and total Tau (192 ng/L). One GD3 patient presented with mild asymmetric rigidity and a 123I-FP-CIT SPECT demonstrated in 2014 reduced DAT levels in caudal putamen of the contralateral hemisphere. However, so far, the patient does not show any bradykinesia, impaired fine movements or tremor. Six (50%) GD3 patients had epilepsy. Four of these patients had focal dyscognitive seizures beginning in adolescent or in adulthood, typically with prominent aura including but not limited to taste and olfactory hallucinations, vertigo, feelings of unreality and déjà vu. These events proved self-resolving with a duration b 10 min, mostly 1–2 min, in most cases. In one patient, secondary generalization also occurred, and, at times a postictal period with dysphasia and severe anxiety was evident. Electroencephalography (EEG) showed focal seizure activity fronto-temporally in all four patients, and one also had episodes of bilateral synchronous spike-wave or sharp-wave activity in the middle temporal region. As reported previously [8], one patient had a single witnessed seizure attack at 45 years of age after shortage of ERT for 1.5 years, possibly a symptomatic seizure due to long-term effects of cessation of ERT-therapy. The patient was then put on antiepileptic therapy and has had no more seizures. The six GD3 patients were treated with various antiepileptic drugs, in monotherapy or in combination, resulting in remission of seizures in four patients. One patient also received vagus nerve stimulation. None of the patients manifest episodes of status epilepticus and myoclonic seizures were not evident within this cohort. One patient with GD1 has primary generalized tonic clonic seizures, responding to carbamazepine therapy. An assessment of cognitive performance was done using MoCA (Fig. 2). Unexpectedly, GD3 patients performed significantly (P = 0.01)
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A
B
Fig. 2. Heterogeneous performance in the Montreal Cognitive Assessment (MoCA) among patients with type 3 (A) and type 1 GD (B). Significant improvement (P = 0.01) was noted among the type 3 GD patients at follow-up. *P b 0.05; Paired Student's t-test.
better at the follow-up. The mean score was 23.9 ± 1.5 and after 3 years follow-up 26.3 ± 1.2. A patient with epilepsy who scored 10 at baseline died in the interim from pneumonia and was not included in the comparative analysis. Four patients, of whom three have epilepsy, had a lower score (b26) than the suggested cut-off for cognitive impairment at both examinations. Among the GD1 patients who underwent serial MoCA on two occasions, there was no difference (P = 0.63) between baseline (27.9 ± 0.6) and follow-up (28.3 ± 0.8) scores. At baseline all GD1 patients were included and the mean MoCA score was 25.6 ± 1.3. Four patients had a score indicating cognitive impairment.
Mood was assessed with HADS which addresses anxiety and depression (Fig. 3). Among the GD3 patients, there was no difference (P = 0.62) in anxiety scores between baseline (5.1 ± 1.5) and follow-up (5.9 ± 1.4) scores. Three subjects fulfilled the criteria (N 8) for anxiety at baseline and two at the follow-up. For the GD1 patients, there was a significant (P = 0.049) worsening of anxiety scores from baseline (3.4 ± 1.0) to the follow-up (4.4 ± 1.3). At both baseline and followup, two patients fulfilled the criteria for anxiety. When depression scores were assessed, no difference (P = 0.27) was found between baseline (3.0 ± 0.8) and follow-up (2.5 ± 0.8) among the GD3 patients.
A
B
C
D
Fig. 3. Hospital Anxiety and Depression Scale (HADS) with the anxiety (A, B) and depression (C, D) subscores demonstrates heterogeneity and with three GD type 3 (A) or two GD type 1 (B) patients showing significant anxiety. There is a significant worsening in anxiety subscores (P = 0.049) among the GD type 1 patients at follow up (B). No subscores showed significant depression in any of the GD type 3 (C) or GD type 1 (D) patients. *P b 0.05; Paired Student's t-test.
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M. Machaczka et al. / Blood Cells, Molecules and Diseases xxx (2016) xxx–xxx
Likewise, no difference (P = 0.65) was found between baseline (1.3 ± 0.6) and follow-up (1.5 ± 0.5) among the GD1 patients. None of the GD3 or GD1 patients fulfilled the criteria (N 8) for depression. Olfaction was examined with the 40-item UPSIT test (Fig. 4). Among the GD3 patients that participated at both examinations, there was no difference (P = 0.91) between baseline (27.9 ± 1.5) and follow-up (27.6 ± 1.7). Two patients had severe hyposmia and four had moderate hyposmia. Among the patients with GD1 who underwent UPSIT at two occasions, there was no difference (P = 0.10) between baseline (29.4 ± 2.3) and follow-up (31.9 ± 2.7). At baseline all GD1 patients were included and the mean UPSIT score was 25.4 ± 2.5. Four patients had complete anosmia (of whom two had Parkinsonism), one had moderate hyposmia. 4. Discussion While phenotypic heterogeneity is well recognized among patients with types 1 and 3 Gaucher disease [22], the Swedish population of Gaucher patients is unique in Europe and North America because of its relatively high prevalence of the L444P GBA1 allele - presumed to originate from a common ancestral source [9,10]. The catalytic function of the L444P variant enzyme is markedly impaired because of the inability of the mutated protein to fold efficiently within the secretory pathway, leading to extensive endoplasmic reticulum (ER)-associated proteasomal degradation (ERAD) and reduced delivery of the protein to its destination in the lysosome; patients who are homoallelic for this mutant GBA1 gene are generally afflicted by severe systemic manifestations and prominent neurological features of Gaucher disease. There is a marked heterogeneity in the severity of neurological symptoms in GD3 (Norrbottnian) patients in Sweden [11,12]. Marked diversity in the manifestation of Gaucher disease has been reported in twin pairs. Divergent monozygotic and dizygotic twin pairs have been described with very different phenotypes [23]. For instance, a monozygotic twin pair of Moroccan descent was reported by Biegstraaten et al. [24] with highly discordant neurological manifestations in 22 year-old women homoallelic for the disabling N188S GBA1 missense mutation: one had severe visceral involvement, epilepsy, and a cerebellar syndrome as predicted, but the twin had no clinical manifestations of Gaucher disease but suffered from type 1 diabetes mellitus. Clearly, an identical genetic defect can, despite relatively small differences in residual enzyme activity as determined in vitro, give rise to widely discordant clinical expression of Gaucher disease. A more thorough analysis of interactions between genes and environmental influences, as well as gene-to-gene effects, will be critical for any deeper understanding of the pathogenesis of this condition. Such knowledge may be rewarded by the identification of critical factors that modify expression of the disorder and also may allow the treatment of individuals predisposed to develop Gaucher disease to be refined.
A
5
With one exception, the Swedish patients with GD3 disease reported here are homoallelic for the GBA1 L444P missense mutation (c.1448T N C). Of note however, the exceptional GD3 patient was a compound heterozygote who had inherited one copy of L444P but harboured another rare GBA1 missense mutation encoding A341T (c.1138G NA) in common with another Swedish patient classified as having GD1. None of the patients in the GD1 patient cohort is homozygous for the L444P/L444P GBA1 mutation. Instead, they show numerous different mutations among which, N370S (c.1226A N G) is most common. Moreover, unlike the geographically segregated patients in Norrbotten and Västerbotten, who were homozygous for L444P and have manifestations of GD3, the patients with GD1 are widely distributed throughout Sweden. Our evaluations of the GD3 patients are summarized in the modified SST scale, which is a valid tool for monitoring neurological progression in GD3 [21]. A previous study used mSST to describe disease status and progression of neurological manifestations in 39 GD3 patients from Poland, Germany and UK over a period of 4 years [21]. The mean age in that cohort at baseline was 15.1 years and the mSST score 4.0 and at follow-up 6.0 with a significant progression. For logistical reasons, it had not been possible to include patients from Sweden in the previous European study to determine the evolution of mSST over time. However, it is informative to compare the results obtained here with that formerly reported: the cohort of Norrbottnian patients with GD3 cohort is significantly older, with a mean age of 37.4 years at baseline; moreover, their mean mSST score (at 9.3) is higher than that reported by Davies et al.[21]. In contrast to the combined European cohort, no significant progression was found at 3-year follow-up in our patients. Thus, the Norrbottnian cohort of patients with GD3 is distinct in many aspects when compared with other European cohorts. A notable clinical observation in this study was the presence in four patients of spontaneous rapid and repetitive hyperkinetic dystonic-like movement disorder along with blepharospasm. It is also possible that dystonia-like signs contribute to the severity of kyphoscolios in GD3 patients. Dystonia-like signs were observed independent of manifest epilepsy. Since these hyperkinetic movements were spontaneous and could not be suppressed, they are probably not related to tics. Moreover, since neurography and electromyography were virtually normal, it is unlikely that they represent myokymias. To our knowledge, the movement disorder has not been described previously in GD [22,25,26] and accordingly, the feature is not included among the 12-domain neurological items rated in the mSST scale. We await with interest to learn whether this symptomatic movement disorder indeed occurs in other patients with GD3 disease or whether it is restricted to those originating from Norrbotten. Epilepsy occurred in half of the GD3 patients with onset during adolescence or adulthood: in those patients with an adequate description, the seizures were primarily of a focal dyscognitive semiology, with
B
Fig. 4. University of Pennsylvania smell identification test (UPSIT) revealed hyposmia in six GD type 3 patients (A) and five GD type 1 patients (B).
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rare secondary generalization to tonic-clonic seizures. Neuroimaging was performed in two patients with focal seizures; MRI excluded lesional pathology to the extent of resolution available in one patient, while a static increase in amygdala and anterior hippocampal volume was evident upon serial CT imaging at a 5-year interval in the other. Focal seizure onset was also recorded and documented by EEG. In the early 1980s, epilepsy was reported in 6 of 22 (27%) of patients with GD3 from northern Sweden; the onset was between ages 5–12 years [12]. EEG showed focal epileptiform discharges in three and generalized discharges in the other three patients. There was no overlap between the six patients previously studied and those reported here. A search in publication databases for GD and epilepsy or seizures principally identifies reports describing progressive myoclonic epilepsy. Progressive myoclonic epilepsy and myoclonic seizures were not present in our series of Norrbottnian patients with GD3 and have not been reported previously in the region [12]; it appears instead that focal epilepsy is frequent in the Norrbottnian variant of this disease. It is noteworthy that focal epilepsy is but sparsely reported in the literature pertaining to GD and only in female patients: in a patient with the compound G377S/ Y205C genotype and in a patient with the N370S/L444P genotype cases 14, and 5 respectively in Park et al.[27] and Goker-Alpam et al.[28]; and finally in one discordant twin aged 22 years with neuronopathic GD reported by Biegstraaten et al.[24]. In agreement with a previous report [12], several Norrbottnian patients with GD3 suffered from truncal and appendicular ataxia. Since several of these GD3 patients have reached late middle-age and the L444P mutation is commonly associated with Parkinsonism [18,19], we were surprised to note its absence among the GD3 cohort; and, while one patient manifest isolated asymmetric rigidity, with a corresponding reduction in DAT abundance of the contralateral putamen this has not progressed to clinical Parkinsonism to date. However, it is noteworthy, that several GD3 patients demonstrated hyposmia, the interpretation of which is presently uncertain but might be cautiously interpreted as an early or premotor sign of evolving Parkinsonism. In contrast, we found two cases of Parkinsonism among the GD1 patients. One patient, with the N370S/L444P genotype, had typical manifestations of PD with a salutary response to levodopa. The other patient, harbouring a complex N370S/L444P, A456P, V460L genotype, had severe cognitive impairment which is in line with the evidence for greater cognitive impairment in those with established GBA-related Parkinsonism compared with sporadic Parkinsonism. In this context, it is noteworthy that many patients with PD in Västerbotten are heterozygote L444P mutation carriers [29]. Patients with GD may develop moderate to severe psychological complications, similar to patients with other chronic illnesses [30]. GD1 patients have been reported to exhibit mild deficits in attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory [31]. Indeed, on a group basis, the Swedish GD patients performed below average on MoCA. However, over the course of this study, there was no worsening; indeed, the GD3 patients showed a significantly improved MoCA score over the 3-year period of follow-up. The reason for this is unknown, but learning bias, due to repeated testing, improved antiepileptic therapy and general care may have influenced the performance. According to the macrophage hypothesis for neurological manifestations of GD3 [13,32], macrophages and closely related adventitial cells (pericytes) accumulate glucosylceramide and contribute to the neuropathological aspects of the disease and clinical deterioration, for example, after splenectomy. If this were the case, arrested or attenuated progression of the neurological disease would be predicted to occur in patients treated by allo-BMT [33]. Three of the studied patients have undergone BMT, but their disease course is highly variable and one patient has developed severe neurological manifestations. Thus, our data do not provide consistent support for the role of macrophages in the development or evolution of the neurological manifestations of GD3 in Sweden.
In summary, this is the first comprehensive investigation of the neurological manifestations of middle-aged and older patients with Norrbottnian type 3 and Swedish patients with type 1 Gaucher disease. New information as to the frequency and characteristics of epilepsy in the Norrbottnian GD3 has come to light: this is focal in nature and starts during adolescence and adulthood. Several of these patients suffer from anxiety and mild cognitive impairment which necessitates attention, regular follow-up and improved therapy. Hyposmia was frequent among the patients with both subtypes of disease and may herald a neurodegenerative process which ultimately leads to Parkinsonism although only two patients (with GD1) suffered from this movement disorder. Finally, several patients with GD3 disease in the Norrbottnian cohort suffered from an unusual rapid and repetitive dystonia-like hyperkinetic movement disorder with concomitant blepharospasm. This is a movement disorder hitherto not reported in patients with chronic GD and expands the phenotype for this condition. Supplementary data to this article can be found online at doi:10. 1016/j.bcmd.2016.10.011. Author contributions 1) Research project:
A. Conception; MM, PS B. Organization; MM, CBK, PS C. Execution; MM, CBK, PS
2) Statistical Analysis:
A. Design; MM, PS B. Execution; PS C. Review and Critique; MM
3) Manuscript:
A. Writing of the first draft; PS B. Review and Critique; MM, MP, CBK, NJCS, TMC, LF
Relevant conflicts of interests/financial disclosures Nothing to report. Acknowledgements We would like to thank the participants and their families. We would also like to thank Drs Ruth Walker and Carlo Colosimo for their comments on the phenomenology of the spontaneous dystonia-like hyperkinetic movement disorder found in some GD3 patients. References [1] T.M. Cox, Gaucher disease: clinical profile and therapeutic developments, Biologics 4 (2010) 299–313. [2] G.A. Grabowski, Gaucher disease and other storage disorders, Hematology Am. Soc. Hematol. Educ. Program (2012) 13–18. [3] O. Nilsson, J.-E. Månsson, G. Håkansson, L. Svennerholm, The occurrence of psychosine and other glycolipids in spleen and liver from the three major types of Gaucher's disease, Biochim. Biophys. Acta 712 (1982) 453–463. [4] A. Zimran, How I treat Gaucher disease, Blood 118 (2011) 1463–1471. [5] Genetics of the sphingolipidoses, in: A.G. Knudson Jr., W.D. Kaplan, S.M. Aronson, B.W. (Eds.), Cerebral Sphingolipidoses: A Symposium on Tay-Sachs Disease and Allied Disorders, Academic Press, New York, N.Y 1962, pp. 395–409.
Please cite this article as: M. Machaczka, et al., Blood Cells Mol. Diseases (2016), http://dx.doi.org/10.1016/j.bcmd.2016.10.011
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