Abstract
The association between type 1 Gaucher disease and PD has been reported in the literature. The clinical picture is characterized by the predominance of bilateral akinetic-rigid signs and poor response to levodopa therapy. The authors describe four patients (two siblings) with type 1 Gaucher disease presenting with the following signs of typical PD: asymmetric onset of rigidity, resting tremor, bradykinesia, and a favorable response to Parkinson therapies.
Gaucher disease (GD) is the most prevalent autosomal recessive lysosomal disorder. GD results from deficiency of the lysosomal enzyme acid β-glucosidase, leading to the systemic storage of glycosphingolipids. The gene has been mapped on chromosome 1q21. Three phenotypes are described: GD1, non-neuronopathic form, which involves essentially peripheral organs; GD2, acute neuronopathic form, a rapidly fatal neurologic disease presenting in infancy; GD3, chronic neuronopathic form, a progressive neurologic disease with a later onset, generally fatal within the second or third decade of life. Heterogeneity has been described in all the three phenotypes, particularly in GD1. Genotype/phenotype studies demonstrated that the most common mutation in patients with GD1, N370S, has less CNS involvement, even in the heterozygous form.1 GD is the most common glycosphingolipid disease with an estimated prevalence of 1:57,000 live births in the general population.2
Currently, enzyme replacement therapy (ERT) with recombinant enzyme (imiglucerase) is available for patients with GD. The therapy corrects systemic manifestations, but its impact on neurologic symptoms is limited.3
Case reports.
A total of 7 (13.8%) of 58 patients with GD1 (29 women and 29 men; mean age 37 years) studied at the Gaucher Center of our Institute presented with some form of neurologic involvement: three subjects had perceptive hearing loss, two showed typical idiopathic PD, and two patients had both.
Patients with PD (table) included three women and one man: mean age was 61.7 years (range 50 to 72 years), mean age at PD onset was 50.2 years (range 43 to 59 years), and mean duration of the disease was 7.25 years (range 3 to 17 years). Two probands were siblings. Three subjects were treated with ERT. All underwent clinical examination and laboratory testing including genotyping, quantification of β-glucosidase activity, hemoglobin, platelet, ferritin, transaminase, calcium, phosphate, alkaline and acid phosphatase, chitotriosidase, creatinine, and plasma proteins. They underwent cerebral MRI, EEG, ocular movement analysis (OMA) using the limbus tracking technique, visual evoked potentials (VEP), and auditory brain responses (ABR). Liver and spleen volumes were assessed by abdominal CT scan. In one subject (Case 2), regional cerebral blood flow was studied with 99mTc-ECD single-photon emission tomography (SPET). Patients were followed up for a period ranging from 4 to 11 years. None of the patients had a family history of PD.
Table 1 Clinical and laboratory data of parkinsonian patients with Gaucher disease (GD)
Results.
The table summarizes the clinical and laboratory data. The clinical severity of the disease did not permit extensive testing on Case 4. Two patients, Cases 1 and 2, were diagnosed with GD1 at a young age; both presented with parkinsonian symptoms many years later. All the subjects manifested hepatosplenomegaly, anemia, and thrombocytopenia at presentation; two underwent splenectomy. They all had elevated ferritin levels and deficient residual enzyme activity, ranging from 1.57 to 2.15 nmol/mg protein/h (normal 11.37 ± 2.85).
The parkinsonian symptoms seen were typical of PD in all of the patients and included the asymmetric onset of a resting tremor, rigidity, bradykinesia, and a favorable initial response to l -dopa and to surgical interventions (Cases 1 and 2). The age at onset of PD symptoms was younger than usual in all of the patients. Each also showed the gradual appearance of a wearing-off phenomenon, motor fluctuations, and levodopa-induced dyskinesias during the follow-up. Furthermore, Cases 1 and 2 showed mild signs of cortical atrophy on cerebral MRI, mild EEG abnormalities, and an abnormal ABR pattern with perceptive hearing loss. Cerebral SPET demonstrated left basal ganglia hypoperfusion in Case 2. The OMA studied did not show saccadic impairment in any of the examined patients. All the subjects had normal cognitive capacities at the time of PD diagnosis.
ERT was demonstrated to be effective in reducing the peripheral storage process and correcting hematologic abnormalities, but had no effect on PD symptoms. Patients initially responded to l -dopa. However, after 4 to 5 years, in Cases 1, 2, and 3, neurologic involvement progressed, with marked motor fluctuations, off periods, and levodopa-induced dyskinesias. Seventeen years after the onset of the disease, Case 4 developed severe disabling bilateral parkinsonism with motor block, festinating gait, and postural instability. A bilateral pallidectomy was performed in Case 1 after 6 years of PD, whereas Case 2 underwent subthalamic deep brain stimulation after 5 years. Both improved.
Case 1 was found to have genotype N370S/L444P, whereas Case 2 was homozygous for mutation G377S. Cases 3 and 4, siblings, carried one N370S allele. Complete sequencing was not possible because of inadequate quantities of DNA. No rearrangements or deletions were detected on Southern blots for Cases 1 and 2.
Discussion.
Neuronal dysfunction in GD has not yet been completely explained. The literature suggests that the disease has a phenotypic continuum ranging from the acute neuronopathic form, GD2, to the systemic form, GD1. The latter is, nonetheless, not without neurologic involvement and an atypical parkinsonian syndrome (PS), presenting severe symmetric rigidity, bradykinesia, aggressive progression, and poor responsiveness to levodopa therapy, has been described in some patients with GD1.1,4,5⇓⇓ ERT was not effective in correcting these manifestations. In our patients, the clinical symptoms were more similar to typical PD, except for the precocity of the age at onset.
It has been recently hypothesized that glucosylceramide storage plays a role in inducing neuronal apoptosis in neuronopathic GD.6 Conversely, some authors also discussed the role of ceramide-dependent damage in the death of substantia nigra dopaminergic neurons in PD.7 In both cases, the neuronal damage is secondary to the impairment of the cellular oxido-reduction mechanisms, with a consequent intracellular increase of free radicals and Ca2+, an event that can trigger off apoptosis. Moreover, the pro-oxidant activity of ferritin stored iron has been hypothesized to explain the damage of the dopaminergic neurons in PD.8,9⇓ All of our patients, as frequently observed in GD, showed a marked elevation of serum ferritin. Although the role of iron in PD is debated, its storage could play a part in the pathogenesis of the disease. Furthermore, the increased quantity of reactive oxygen species could modulate the mitochondrial permeability pore releasing proteins, also activating apoptosis.10
The analysis of our data compared to those provided by other authors seems to demonstrate a range of parkinsonian features in patients with both GD1 and PS. Some have more typical PD clinical signs and others have more extrapyramidal features and a poorer response to l -dopa, although generally there is a relatively early onset of symptoms. It is possible that toxic processes related to different metabolites can cause differing degrees of damage to the dopaminergic system, leading to variability in clinical presentation. Actually, the SPET pattern observed in Case 2 could potentially be the result of such a cellular death process. Further biochemical and morpho-histologic studies of this cerebral region are needed. Finally, a detailed molecular analysis of these patients is necessary to clarify the possible role of specific genetic modifiers.
Acknowledgments
Supported by the research project Malattie Rare: dal Registro Nazionale a modelli sperimentali di studio finalizzati al miglioramento delle modalità di prevenzione, diagnosi e trattamento (D.LGS 502/99 Istituto Superiore di Sanità).
Acknowledgment
The authors thank Dr. Sarah Tripepi for assistance with translation and editing.
- Received December 5, 2002.
- Accepted March 5, 2003.
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