Parkinsonism in type 1 Gaucher's disease

Gaucher's disease (GD) is the most common hereditary lysosomal storage disorder, with a prevalence of 1:57 000 in the general population.¹ The disease results from mutations in the glucocerebrosidase (GBA) gene, localised in chromosome 1 (the most frequent mutation is N370S) and has an autosomal recessive pattern of transmission. As a result of such mutations, there is decreased activity of the enzyme and subsequent glucocerebroside accumulation in cells of the macrophage‐monocyte system. This process may lead to hepatosplenomegaly, bone disease, and pancytopenia.

GD is classically divided into three types, according to the presence of neurological symptoms and the dynamics of the developing clinical picture.² Type 1 GD is the most common, affects mainly Ashkenazi Jews, and until recently was considered non‐neuronopathic. It may present at any age and its course and presentation are variable. Many type 1 GD patients remain virtually asymptomatic, being diagnosed during evaluation for a non‐related disorder or familial screening of a symptomatic relative.

In juvenile GD (type 3), movement disorders are frequently found, but there is growing evidence that neurological symptoms, particularly parkinsonism, may also occur as a late complication of type 1 GD.

The following case report illustrates such situation.

Case report

A 45 year old white man was referred to our movement disorders unit by his haematologist with the complaint of gait difficulty since 2002.

The patient had been diagnosed with type 1 GD at the age of 22, when routine blood tests showed anaemia. During investigation he was submitted to a bone marrow biopsy, which was suggestive of GD, and later to genetic studies, which showed N370S/L444P mutations in the GBA gene.

The patient is the second child of unrelated parents and had a normal delivery and development as a child. He has a non‐Jewish ethnic background and his family history is negative for GD and Parkinson's disease.

The follow up evaluation by his haematologist revealed hepatosplenomegaly, and the patient complained of bone pain. In 1995 he underwent splenectomy (fig 1). In 1998, enzyme replacement therapy was started (imiglucerase 60 IU/kg every two weeks) and the patient reported improvement of symptoms. There was also reversal of the haematological abnormalities.

Figure 1 Histopathology of the patient's spleen showing Gaucher cells, which are macrophages enlarged by glucocerebroside accumulation, with their typical “wrinkled tissue paper” cytoplasmic appearance

By the age of 43 the patient noticed progressive gait disturbance—he mentioned diminished arm swing and trouble turning. At the same time, he developed bilateral asymmetrical action tremor (predominantly on the left side) and bradykinesia. He was prescribed levodopa/carbidopa and achieved partial improvement of the tremor and gait.

When evaluated at our movement disorders unit, patient was taking levodopa/carbidopa 200/50 mg, half a tablet five times a day. From the beginning he presented with dyskinesias. His Hoehn‐Yahr stage was 2, his UPDRS score was 18, and the Schwab and England Activities of Daily Living was 90%. General physical examination was unremarkable. On neurological examination there was moderate bilateral weakness of ankle dorsiflexion (he had an electroneuromyography in 2002 which revealed bilateral L4–S1 radiculopathy and left fibular nerve neuropathy; lumbosacral spine computed tomography showed spinal stenosis at L3–L4; such abnormalities had been attributed to GD), cogwheel rigidity of both upper and lower limbs, mild bilateral kinetic tremor, lower limb dyskinesias, and loss of ankle reflexes.

The patient was prescribed pramipexole 0.25 mg three times daily and obtained mild symptomatic improvement.

Comment

Recent reports have emphasised the association between GD and parkinsonism.

In 1985 McKeran et al described a 55 year old patient with type 1 GD diagnosed at the age of 17, who developed a parkinsonian syndrome, only initially responsive to levodopa.² Neudorfer et al reported six patients with GD and parkinsonism.³ Four patients were followed up and a poor response to levodopa was observed. In 1999, Machaczka et al reported another patient with parkinsonism preceding the clinical manifestations of GD by 12 years.⁴

More recently, Bembi et al described four patients with GD and parkinsonism.¹ The age of onset was younger than in classical Parkinson's disease, but the clinical picture was indistinguishable. Two patients had been diagnosed with type 1 GD at an early age and developed parkinsonism several years afterwards. Enzyme replacement was effective for systemic symptoms, but had no effect on the parkinsonism.

The patient we report here developed parkinsonism at a young age (43), like most cases described in published reports. This seems to be a consistent feature of patients with type 1 GD who develop parkinsonism. Another interesting point is that the patient presented with parkinsonian symptoms while receiving enzyme replacement therapy, confirming previous published data about the ineffectiveness of this specific GD treatment for correcting neurological manifestations of the disease. He had bilateral signs from the start and so far a suboptimal response to levodopa therapy, which would not be expected in classical Parkinson's disease.

The nature of the association between GD and Parkinson's disease remains to be elucidated. The mechanism involved in the development of parkinsonism in carriers of GBA mutations may be related to protein misfolding. Studies indicate that glucocerebroside accumulation induces apoptosis in cultured neurones and that neurones with high levels of glucocerebroside have a higher sensitivity to agents that lead to cellular death.⁵

In spite of the association described, most patients with GD never develop parkinsonism, suggesting the involvement of other factors, genetic or environmental, in the disease process.

It has been increasingly recognised that parkinsonism may be a clinical feature of type 1 GD and may even precede this diagnosis, so GD must be considered in the differential diagnosis of parkinsonism in subjects with early onset and poor response to levodopa. The basis for this association remains unknown. The treatment of parkinsonism in these cases is similar to classical Parkinson's disease. However, it is usually less effective. Enzyme replacement therapy is an important advance in controlling the systemic manifestations of GD, but its impact on neurological symptoms is limited.