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Parkinsonism in Patients with Neuronopathic (Type 3) Gaucher Disease: A Case Series Emory Ryan, CPNP-BC,1 Dominick Amato, MD,2 Jennifer J. MacKenzie, MD,3,4 Ellen Sidransky, MD,1,* and Grisel Lopez, MD1

ABSTRACT: Background: Background The link between Parkinson’s disease (PD), the second most common neurodegenerative disorder, and nonneuronopathic Gaucher disease (GD) is well established. Currently, PD is primarily associated with nonneuronopathic GD; however, with currently available treatments, patients with chronic neuronopathic GD, who historically had a shortened life span, are now living well into their 50s and beyond. Cases: Cases We highlight 4 patients with chronic neuronopathic GD with parkinsonian features, describing their GD genotype and phenotype as well as the presentation and progression of their parkinsonism. Symptoms presented in their fourth or fifth decade of life, and include unilateral bradykinesia and/or tremor. Of the patients, 3 had cognitive impairment. The fourth patient has not shown cognitive decline 6 years after PD onset. Conclusion: Conclusion This small series highlights that PD is not exclusively associated with nonneuronopathic GD and that as the chronic neuronopathic GD population ages, the clinical spectrum and heterogeneity of neurological manifestations may include parkinsonism.

Introduction Autosomal recessive mutations in GBA1, the gene encoding for the lysosomal enzyme glucocerebrosidase, cause the lysosomal storage disorder Gaucher disease (GD). Glucocerebrosidase deficiency results in substrate accumulation in cells of the reticuloendothelial system, mainly macrophages. In the past 15 years, the link between parkinsonism and heterozygous or homozygous mutations in GBA1 has been well established.1 In GD, this association has been primarily described in a subset of patients with mutations and clinical history consistent with a diagnosis of nonneuronopathic GD (GD1). These patients manifest with visceral, hematological, and skeletal involvement of various degrees of severity. In contrast, patients with neuronopathic GD present with acute progressive neurological deterioration and early death or chronic neurological manifestations that may include slow horizontal saccadic eye movement, seizures, myoclonus, developmental delay, and/or learning disabilities (GD3).2 GD is

treated with either enzyme replacement therapy (ERT), intravenous infusions of glucocerebrosidase, or substrate reduction therapy, an orally administered inhibitor of glucocerebroside synthesis. Both therapies ameliorate the systemic manifestations of GD, but do not penetrate into the brain. The clinical diagnosis of PD is based on motor deficits that include bradykinesia in the presence of rigidity and/or rest tremor,3 although nonmotor features can be present years prior to motor deficits.4 The most important risk factor for developing PD is aging, although environmental and genetic risk factors also play a role. While the number of cases of PD in the GD population is small, overall, patients with PD have an odds ratio of >5 of carrying at least 1 GBA1 mutation.1 The association between GD and PD has mainly focused on GD1. Before the development and implementation of ERT for the treatment of GD in 1990, patients with GD3 had a shortened life expectancy into their second and third decades of life, mostly attributed to severe visceral involvement. However, with ERT,

1

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA; 2Mark Freedman and Judy Jacobs Program for Gaucher Disease, Mount Sinai Hospital, Toronto, Ontario, Canada; 3McMaster University, Hamilton, Ontario, Canada; 4Queen’s University, Kingston, Ontario, Canada

*Correspondence to: Dr. Ellen Sidransky, Medical Genetics Branch, National Human Genome Research Institute, NIH, Building 35A Room 1E623, 35A Convent Drive, MSC 3708, Bethesda, MD 20892-3708; E-mail: [email protected] Keywords: lysosomal storage disorders, GBA1, neurodegeneration, Parkinson’s disease. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 28 May 2020; revised 6 July 2020; accepted 13 July 2020. Published online 17 August 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.13031

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these patients are now living longer, some well into their fifth and sixth decades, and now patients with GD3 may have an increased risk of developing PD. Here, we highlight 4 patients with GD3 who developed PD, describing their GD genotype and phenotype as well as PD presentation and progression. Three patients participated in GD research protocols at the National Institutes of Health. The fourth was identified after literature searches in PubMed and Web of Science completed on December 1, 2019, using the following key words: neuronopathic Gaucher disease, Parkinson disease, Gaucher disease type 3, and GBA1 Parkinson disease.

Case Series Case 1 Patient 1 is a 54-year-old right-handed female Canadian with French/Irish ancestry who presented with hepatosplenomegaly at age 6 months. GD was confirmed via bone marrow biopsy, and her genotype was later identified as p.L483P/p.L483P. She also developed nosebleeds, anemia, and thrombocytopenia, which led to a splenectomy at age 2 years. She had bone pain crises throughout childhood, once requiring a weeklong hospital stay. ERT therapy was initiated at age 39, which was switched to substrate reduction therapy at age 41 with good hematological and visceral response. She developed bilateral sensorineural hearing loss, requiring hearing aids at age 44. A neuro-ophthalmologist well versed in neuronopathic GD confirmed slowing of the horizontal saccadic eye movements. Her parkinsonian symptoms started at age 49, and PD was diagnosed at age 51. She developed a right leg tremor, followed by right hand tremor responsive to dopaminergic therapy. Her examination demonstrated hypomimia, mild right lower extremity bradykinesia, moderate body bradykinesia, en bloc turning, bilateral rest tremor, and anosmia (University of Pennsylvania Smell Identification Test: 19/40). Her nonconsanguineous family history is significant for both PD and dementia in her mother, with symptom onset in her mid-60s. Her father died at age 77 from multiple myeloma. An electroencephalogram demonstrated mild background slowing. Skeletal X-rays identified kyphoscoliosis, previously unreported.

Case 2 Patient 2, as previously reported,5 was initially examined at age 48 at the National Institutes of Health. She reported normal growth and development during childhood, with an onset of decreased blood counts and splenomegaly at age 19 following a febrile illness. Leukemia was suspected, and a bone marrow biopsy confirmed a diagnosis of GD. Her genotype was later determined to be p.L483P/p.D448H + Rec 7. After her illness, her blood counts normalized, and splenomegaly appeared to resolve. Significant postpartum bleeding occurred after the delivery of her child at age 28. A splenectomy was performed at age 34. At age 48, mild kyphoscoliosis was noted, which progressed rapidly and became

severe by age 50. She also reported bilateral hearing loss of unknown etiology, requiring hearing aids at age 53. An electroencephalogram at age 53 showed mild background slowing. Her initial parkinsonian manifestations appeared to be typical, with unilateral onset of left hand tremor, rigidity, and bradykinesia at age 42. However, there was rapid progression of symptoms with an atypical presentation that included supranuclear gaze palsy, early cognitive dysfunction, visual hallucinations, and frequent falls. Some of these symptoms were responsive to carbidopa/levodopa. She underwent a right hemispheric pallidotomy at age 47 with a very brief response. Her cognition rapidly declined, and she died at age 53 as a result of aspiration pneumonia. Histopathology at autopsy confirmed the presence of substantia nigra gliosis, neurodegeneration, and frequent Lewy bodies, which were also noted in neurons of the cortex, hippocampus, red nucleus, and oculomotor nucleus. Her nonconsanguineous family history is negative for both GD and parkinsonism.

Case 3 Patient 3, a previously briefly reported Canadian, was of Swedish/Norwegian/British ancestry.6 His genotype was p.R502C/p. R159W, and slowed horizontal saccadic eye movements were verified by a neuro-ophthalmologist. His GD symptoms prior to treatment included thrombocytopenia, splenomegaly, osteopenia, and avascular necrosis of the hip. GD was diagnosed some years prior to his PD diagnosis, exact age unknown. The onset of parkinsonian symptoms began in his fifth decade, described as tremor, rigidity, shuffling gait, and bradyphrenia with subsequent progression to significant bulbar and memory dysfunction. He died at age 63. His nonconsanguineous family history includes several GBA1 mutation carriers with PD, 1 with onset of disease in the 40s, but otherwise onset occurring in their 60s.

Case 4 Patient 4, identified from the literature,7 is a 38-year-old Japanese male with genotype p.F252I/p.L483P. He was diagnosed with GD at age 6 by bone biopsy due to splenomegaly. He was classified as GD3 after he developed tonic–clonic seizures at age 7 and was noted to have slowed horizontal saccades. The patient started ERT at age 33 with resolution of his abdominal and bone pain. He then developed left-handed clumsiness, start hesitation, and experienced gait freezing when turning, leading to the diagnosis of PD at age 38. Other parkinsonian symptoms reported include rigidity, reduced arm swing, hypophonia, and gait abnormalities. His nonconsanguineous family history is positive for PD in his father, diagnosed at age 71, with symptom onset at age 63.

Discussion The wide phenotypic variability of GD is mirrored in the chronic neuronopathic subtype. In this small series, the patients generally had mild manifestations of neuronopathic GD, with

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p.L483P/p.D448H + Rec 7

p.R502C/p.R159W

p.L483P/p.F252I

2

3

4a Spl

Unk

Spl, abnormal blood counts

Hsp

Presenting Symptoms

6y

Unk

19 y

6 mos

Age of Onset

Yes

Yes

Yes

Yes

Slowed Horizonal Saccades

Generalized seizures onset at age 7

Unk

Shl, Kyp, EEG mild background slowing

Shl, Kyp, EEG mild background slowing

Other Neuronopathic Features

Hsp, splenectomy at age 7, bone pain

Spl, thrombocytopenia, osteopenia

Spl, splenectomy at age 34

Spl, splenectomy at age 2, anemia, thrombocytopenia, bone pain/crises

Other Prominent GD Symptoms

ERT age 33

ERT age 61

ERT age 48

ERT at age 39, SRT age 41

Treatment

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 834–837. doi: 10.1002/mdc3.13031

a

37

51

Age at Diagnosis

Patient 4 reported by Kono et al.7

34

40s

3

4

42

2

a

49

1

Patient No.

Age of Onset

Bradykinesia

Tremor

Left hand tremor

Right hand tremor

Initial Symptoms

TABLE 2 Defining Parkinson’s disease manifestations

Dyskinesias, hypophonia, gait abnormalities, rigidity

Bradykinesia, rigidity

Bradykinesia, dyskinesias, gait disturbance, rigidity, visual hallucinations

Bradykinesia, gait disturbance, rigidity

Other Reported Symptoms

Underlying cognitive delay, dementia

Dementia

Dementia

None

Cognitive Involvement/Type

63

53

Age at Death

Yes

Yes

Yes

Yes

Responsive to Levodopa Treatment

Patient 4 reported by Kono et al.7 GD, Gaucher disease; Hsp, hepatosplenomegaly; Shl, sensorineural hearing loss; Kyp, Kyphoscoliosis; EEG, electroencephalogram; Spl, splenomegaly; Unk, unknown; ERT, enzyme replacement therapy; SRT, substrate reduction therapy.

a

p.L483P/p.L483P

Genotype

1

Patient No.

TABLE 1 Defining GD manifestations

CASE SERIES PARKINSONISM IN NEURONOPATHIC GAUCHER DISEASE

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slowed saccades being the defining feature (Table 1). The onset of parkinsonism was relatively early, with symptoms beginning in their fourth to fifth decades (Table 2). Each presented with unilateral symptoms, including bradykinesia and tremor. No shared genotype was observed, although none carried mutation N370S (p.N409S). Of the 4 patients, 3 showed progressive cognitive dysfunction, and the 1 in which an autopsy was performed demonstrated cortical Lewy bodies, with Lewy bodies also found in the hippocampus CA2-4 regions, areas specifically affected in neuronopathic GD.8 Although some of the patients had an early death, currently patient 1 continues to do well 6 years after her PD onset. Although it is unlikely that the same mechanism of action that causes neuronal injury in GD3 also causes parkinsonism, there is some evidence that the severity of the GBA1 mutation may impact the parkinsonian course.9 However, mild GBA1 mutations are also reported in severe progressive cases with Lewy body pathology, and genotype should not be used in a predictive manner. A recent cross-sectional assessment of a cohort of 24 children and young adult patients with GD (average age 15.9 years) described them as “preparkinsonian” and suggested that 12 of the 16 patients with GD3 had parkinsonism.10 However, although this cohort indeed has interesting manifestations, the use of the Unified Parkinson Disease Rating Scale in individuals without a clinical diagnosis of PD is not validated. This may be misleading, especially in a cohort with skeletal involvement that can affect gait and movement. Moreover, juvenile parkinsonism is a rare syndrome not previously associated with GBA1 mutations. In contrast, our case series describes patients with dopamine-responsive neurodegenerative progression consistent with a clinical diagnosis of PD. Overall, even in this limited series of patients with GD3, there is marked heterogeneity in the parkinsonian presentation and course. Currently, there is insufficient data to ascertain whether the risk of parkinsonism is higher in GD3 than in the general population, although the early disease onset in this cohort is remarkable. It is also possible, as in the case of patient 1, some patients with a putative diagnosis of GD1 may actually have a diagnosis of GD3. Horizontal saccades should be assessed, especially in patients without the N370S allele. These cases highlight that GBA1-associated parkinsonism is not exclusive to GD1 and that as the GD3 population ages, clinicians should be aware that the clinical spectrum of neurological manifestations may include parkinsonism.

Draft, B. Review and Critique. (3) Data: A. Analysis, B. Acquisition. E.R.: 1A, 1B, 1C, 3A, 3B, 4A, 4B D.A.: 1A, 3B, 4B J.J.M.: 3B, 4B E.S.: 1A, 1B, 1C, 3B, 4A, 4B G.L.: 1A, 1B, 1C, 3A, 3B, 4A, 4B

Disclosures Funding Sources and Conflict of Interest: E.R., G.L., and E.S. were supported by the Intramural Research Program of the National Institutes of Health. Financial Disclosures for the Previous 12 Months: E.R., G.L., D.A., and E.S. have no conflicts of interest relevant to this work. J.J.M. has received reimbursement as a consultant to Takeda in the past 12 months unrelated to this current research. Ethical Compliance Statement: This study was approved by the institutional review board of the National Human Genome Research Institute, and all patients provided written informed consent at the National Institutes of Health or their home institutions. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

References 1. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009; 361(17):1651–1661. 2. Schiffmann R, Sevigny J, Rolfs A, et al. The definition of neuronopathic Gaucher disease [published online ahead of print April 3, 2020]. J Inherit Metab Dis. https://doi.org/10.1002/jimd.12235. 3. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55(3):181–184. 4. Schaeffer E, Postuma RB, Berg D. Prodromal PD: a new nosological entity. Prog Brain Res 2020;252:331–356. 5. Tayebi N, Callahan M, Madike V, et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 2001; 73(4):313–321. 6. Varkonyi J, Rosenbaum H, Baumann N, et al. Gaucher disease associated with parkinsonism: four further case reports. Am J Med Genet A 2003; 116A(4):348–351. 7. Kono S, Shirakawa K, Ouchi Y, et al. Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier. J Neurol Sci 2007;252(2):181–184. 8. Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82(3): 192–207.

Author Roles (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First

9. Liu G, Boot B, Locascio JJ, et al. Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. Ann Neurol 2016; 80(5):674–685. 10. Tantawy AAG, Adly AAM, Abdeen M, Salah NY. Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients. Neurogenetics 2020;21:159–167.

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