Gaucher disease associated with parkinsonism: Four further case reports

Várkonyi, Judit; Rosenbaum, Hanna; Baumann, Nicole; MacKenzie, Jennifer; Simon, Zsófia; Aharon‐Peretz, Judith; Walker, Jamie M.; Tayebi, Nahid; Sidransky, Ellen

doi:10.1002/ajmg.a.10028

Cited by 59 publications

(32 citation statements)

References 18 publications

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“…Of note, previous studies in Ashkenazi patients, 15 ethnic Chinese patients, 21 and autopsy samples from American PD patients 13 reported the influence of GBA carriage on early age at onset, and the development of parkinsonian symptoms in patients with GD has been reported mainly in patients' fourth and fifth decades. [3][4][5][6][7][8][9][10][11] Moreover, when calculating the average AAO of all homozygous and compound heterozygous GBA carriers published in these studies, together with the six patients from our cohort (a total of 37 patients), the average age at PD onset was 49.0 years, approximately 10 years earlier than the average onset of PD. The high frequency of GBA mutant alleles in the Ashkenazi population together with observations of increased PD risk and early AAO among Ashkenazi carriers suggest that GBA-associated PD might represent a significant health risk in this population.…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset

Gan‐Or

Giladi²,

Rozovski³

et al. 2008

Neurology

333

302

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Section: Discussionmentioning

confidence: 99%

Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset

Gan‐Or

Giladi²,

Rozovski³

et al. 2008

Neurology

333

302

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“…A difficulty in classification may also exist when a patient with type I Gaucher disease and parkinsonism develops abnormal horizontal saccadic eye movements (Tayebi et al 2001;Vá rkonyi et al 2003). Oculomotor signs, especially difficulty or inability to generate saccades, are characteristic of type III Gaucher disease.…”

Section: Discussionmentioning

confidence: 98%

‘Non‐neuronopathic’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature

Biegstraaten

Schaik

Aerts

et al. 2008

J of Inher Metab Disea

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Gaucher disease is a lysosomal storage disorder, which is classically divided into three types. Type I Gaucher disease is differentiated from types II and III disease by the absence of nervous system involvement. However, an increasing number of reports has emerged on neurological manifestations in patients with type I Gaucher disease. Whether a strict division in three different phenotypes is still valid has been the subject of debate. The main objective of this study was to provide scientific arguments whether a distinction between type I (non-neuronopathic) and types II and III (neuronopathic) Gaucher disease should be maintained. We investigated retrospectively a large Dutch cohort of type I Gaucher disease patients for the prevalence of neurological manifestations and provide an overview of the literature on this topic. A diagnosis of a neurological disease was made 34 times in 75 patients. Forty-five patients reported at least one neurological symptom during the median follow-up time of 11 years. The literature search revealed 86 studies in which type I Gaucher disease patients or carriers of a glucocerebrosidase mutation were described with a neurological disease or a condition which is known to be associated with neurological disease. In conclusion, the term non-neuronopathic Gaucher disease does not seem to be an appropriate characterization of type I Gaucher disease. However, the neurological signs and symptoms in type I Gaucher disease are of a totally different kind from and, in the majority of cases, of much less severity than the signs and symptoms associated with types II and III disease Therefore, type I disease should be classified as a separate phenotype.

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“…However, Parkinsonism manifestations [6-8, 11] and α-synuclein/ubiquitin aggregates [7, 15, 22] were found in only some GD type 1 or 3 patients. Thus, the connections between GCase mutations (gain or loss of function or both) and the development of Parkinsonism or PD remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Such associations with Parkinsonism are not related to specific GBA1 mutations [14]. Parkinsonism also occurs in Gaucher disease type 1 or 3 patients and in heterozygotes for GBA1 mutations [6-8, 11], but the risk of GBA1 heterozygotes of developing Parkinsonism is unknown. Parkinson signs and symptoms include memory loss, resting tremor, uncontrolled movements, kinetic rigidity syndrome, asymmetric onset, horizontal myoclonus, supranuclear gaze palsy, typical progression rigidity, difficulty ambulating, and bradykinesia [5-13, 15].…”

Section: Introductionmentioning

confidence: 99%

Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models

Sun

Ran

et al. 2011

Molecular Genetics and Metabolism

131

119

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Gaucher disease, a prevalent lysosomal storage disease, is caused by insufficient activity of acid β-glucosidase (GCase) and resultant glucosylceramide accumulation. Recently in Parkinson disease (PD) patients, heterozygous mutations in GCase have been associated with earlier onset and more progressive PD. To understand the pathogenic relationships between GCase variants and Parkinsonism, α-synuclein and ubiquitin distributions and levels in the brains of several mouse models containing GCase variants were evaluated by immunohistochemistry. Progressive α-synuclein and ubiquitin aggregate accumulations were observed in the cortex, hippocampus, basal ganglia, brainstem, and some cerebellar regions between 4-24 wks in mice that were homozygous for GCase [D409H (9H) or V394L (4L)] variants and also had a prosaposin hypomorphic (PS-NA) transgene. In 4L/PS-NA and 9H/PS-NA mice, this was coincident with progressive neurological manifestations and brain glucosylceramide accumulation. Ultrastructural studies showed electron dense inclusion bodies in neurons and axons of 9H/PS-NA brains. α-Synuclein aggregates were also observed in ventricular, brainstem, and cerebellar regions of older mice (>42-wk) with the GCase variant (D409H/D409H) without overt neurological disease. In a chemically induced GCase deficiency, α-synuclein aggregates and glucosylceramide accumulation also occurred. These studies demonstrate a relationship between glucosylceramide accumulation and α-synuclein aggregates, and implicate glucosylceramide accumulation as risk factor for the α-synucleinopathies.

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Gaucher disease associated with parkinsonism: Four further case reports

Cited by 59 publications

References 18 publications

Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset

Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset

‘Non‐neuronopathic’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature

Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models

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