Journal of Inherited Metabolic Disease

, Volume 34, Issue 3, pp 781–787 | Cite as

Neurological manifestations in patients with Gaucher disease and their relatives, it is just a coincidence?

  • Pilar Giraldo
  • Jose Luis Capablo
  • Pilar Alfonso
  • Beatriz Garcia-Rodriguez
  • Paz Latre
  • Pilar Irun
  • Alicia Saenz de Cabezon
  • Miguel Pocovi
Original Article

Abstract

Gaucher disease (GD) is an autosomal recessive disorder characterized by defective function of glucocerebrosidase. GD presents a wide spectrum of manifestations, and patients and their relatives may develop neurological abnormalities more frequently than the general population. This study aims to determine the presence of neurological symptoms (NS) and Parkinson’s disease (PD) in Spanish GD patients and their relatives. We surveyed 87 GD Spanish families and validated the information obtained on the neurological involvement through their physicians, as well as the historical data included in the Spanish Gaucher Disease Registry. Neurological abnormalities were correlated with the genetic characteristics. Statistical analyses included descriptive parameters, ANOVA, t-test, correlation study and Pearson coefficient. Information was obtained from 118 patients and 324 relatives. Out of 110 patients with type 1 GD, 32 (29.1%) reported NS and 7 (6.4%) had PD. In relatives, a total of 39 (13.1%) subjects had NS, including 16 with PD (5.3%). The prevalence of NS in genetic carriers (15.9%) was greater than that in non-carriers (5.9%; p < 0.01). Patients with PD carried the following GBA mutations: S364R, D409H, L444P, R257Q, IVS4-2A > G, c.500insT, and L336P. Relatives with PD exhibited a wide spectrum of mutations: L444P, N370S, V398I, R257Q, G202R, c.1439-1445del7, [E326K; N188S], and c.953delT. We observed a high incidence of PD in type 1 GD and relative’s carriers. PD was more frequent in carriers of L444P and other rare GBA mutations. Therefore, it is important to perform a systematic neurological exam in patients with type 1 GD and carriers with high risk mutations.

Introduction

Gaucher disease (GD) is the most common lysosomal storage disorder (OMIM 230806). It is a recessively inherited disease caused by genetic mutations and rearrangements that lead to deficiencies in the function of the lysosomal enzyme, glucocerebrosidase (GBA) (EC 3.2.1.45) (Beutler and Grabowski 2001). This deficiency produces an intracellular accumulation of glucocerebroside, primarily within the reticuloendothelial system. With a prevalence of 1:57,000, GD is clinically characterized by extensive phenotypic heterogeneity, with manifestations ranging from death in uterus to asymptomatic individuals. GD can be classified into three clinical subtypes, defined by the presence and rate of progression of neurological manifestations. Usually, type 1 GD (GD1), the most frequent subtype, has been considered a non-neuronopathic entity (Sidransky 2004; Pastores et al. 2004).

There is growing evidence that neurological symptoms, particularly peripheral neuropathy and Parkinsonism, may also occur as late complications of GD1 (Pastores et al. 2003; Halperin et al. 2007; Capablo et al. 2008; Giraldo et al. 2008). Despite the improvements in GD symptoms and quality of life offered by enzymatic replacement therapy (ERT), in the follow-ups, skeletal complications and neurological symptoms appeared more frequently in patients with GD1 than in the general population (Pastores et al. 2003; Halperin et al. 2007; Capablo et al. 2008). In addition, several studies have reported Parkinsonism in asymptomatic carriers (Giraldo et al. 2008; Halperin et al. 2006).

Parkinson’s disease (PD) is the second most common neurodegenerative disease. It arises predominantly with selective loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of dopamine in their projections. The prevalence of PD is around 180:100,000 (Rijk et al. 1997). Despite some controversy (Farrer et al. 2009), reports of case-control studies performed in the Ashkenazi and other populations showed a higher prevalence of GBA mutations in patients with PD compared to the general population (Aharon-Peretz et al. 2004; Ziegler et al. 2007; Clark et al. 2007; Kalinderi et al. 2009; Sidransky et al. 2009). Although PD apparently is more frequent in families with GD, not all carriers develop a neurodegenerative disorder. Nowadays, the pathogenesis of PD remains unclear and mutations in GBA gene are just one of a multitude of potential risk factors that contribute to the development of parkinsonism.

Several different strategies are employed to elucidate the relationship between GD and parkinsonism including family studies and screening for GBA gene mutations in PD subjects (Sidransky 2004).

In previous and preliminary studies we have performed a systematic neurological/neurophisyological exam in 30 GD1 patients (Capablo et al. 2008) and analyzed the incidence of neurological problems in Spanish GD families (Giraldo et al. 2008). Here we try to determine the prevalence of neurological manifestations with special emphasis in PD in a large group of GD patients and their relatives. To that end, we performed a survey to establish the frequency of neurological problems in a large number of Spanish GD families.

Patients and methods

From June 2006 to July 2009, we performed a survey in 111 families with the aims to detect neurological abnormalities associated with GD, with special emphasis on PD. In order to validate the information related with the neurological involvement, only the diagnosis confirmed by a neurologist was considered. Additional information was obtained from the database of the Spanish Gaucher Disease Registry (SGDR) including patients and relatives mutations. This SGDR was initiated in 1993 and has collected demographic, clinical, genetic, analytical, and imaging data from 346 patients that were diagnosed with GD and monitored in follow-up (Giraldo et al. 2000). The clinical and analytical data included biomarker measurements of patients with and without therapy. When a case was identified with enzymatic and genetic tests, we planned and performed a family study in order to identify carriers and other GD patients (Alfonso et al. 2007).

All patients and relatives included in this study were previously genotyped (Alfonso et al. 2007) and the data were obtained from the SGDR. The additional information had been obtained from SGDR including demographic, clinical, and genetic data (type of GBA mutation, carrier and non carrier status, degree of family relationship, analytical data (biomarkers, vitamine B12, ferritine concentration, serum protein distribution…). The SGDR is associated with a Biobank that complies with current legislation, is independent of the pharmaceutical industry, and is supported by the Spanish Foundation for the Study and Treatment of Gaucher Disease (FEETEG).

The survey questioned patients and first and second degree relatives about neurological symptoms and related diseases including age, gender, degree of family relationship to the proband, comorbilities (diabetes, hypertension, vitamin deficiencies, monoclonal gammopathy undetermined significance) and neurological manifestations assessed by a neurologist (tremor and type of tremor), uncoordinated movements, lack of concentration, hearing loss, slow saccadic eye movements, stroke (lacunae or atherosclerotic), epilepsy, dementia and Parkinson disease. Dichotomous variables were (yes/no) and when the answer was yes, they were asked when the diagnosis was made and when symptoms had appeared. Data were correlated with the genetic and clinical characteristics of the disease derived from historic data collected in the SGDR. The study was approved by the Ethics Committee of the “Instituto Aragonés de Ciencias de la Salud” (CEICA) and all procedures were conducted in accordance with standards of good clinical practice of the Helsinki 1975 Declaration, revised in 1983. Data analysis was carried out with SPSS version 15.0 software (SPSS Inc.,Chicago, IL). We performed descriptive statistical analyses and comparing carrier vs non carrier groups with ANOVA, t-test, and correlation studies based on the Pearson coefficient.

Results

Of a total of 111 families surveyed, 87 (78.4%) completed the questionnaires and had data available in the SGDR. We have obtained information from 118 GD patients (110 type 1 and eight type 3) and 324 relatives (average 3.7 relatives per family).

The NS observed in GD1 patients and relatives are summarized in Table 1. A more detailed Table with the general characteristics of patients is shown in supplementary material (S-table 1).
Table 1

Type and number of neurological symptoms observed in Type 1 GD patients and first and second degree relatives of GD patients

 

GD1 patients

Relative carriers

Relative non carriers

Parkinson disease

8

15

1

Epilepsy

1

6

3

Tremor

2

7*

0

Peripheral neuropathy

10

1

0

Uncoordinated movements

1

0

0

Lack of concentration

4

0

0

Hearing loss

9

1

1

Strabismus

2

0

0

Saccadic movements

1

0

0

Others#

5

5

0

*6 rest tremor, 1 action tremor; #Including: stroke, dementia, neurosis, depression, Psychomotor retardation, autism

The majority of patients were under ERT (82%) mean time on therapy 4 years. The mean age of type 1 GD was 40.0 y (range: 2-72) and the mean age at diagnosis 26.7 y (range: 0.1- 68). No differences between patients on therapy vs untreated patients related to neurological symptoms (data not shown). We found 32 out of 110 type 1 GD with neurological manifestations (29.1 %), nine (8.3%) of them had more than two different NS, with respect to gender the neurological manifestations were significantly higher in females than in males (40.4 vs. 27.5%, p < 0.005). The manifestations were reported as follows: three patients (2.7%) reported tremors, seven(6.4%) uncoordinated movements, four(3.6%) lack of concentration, two (1.8%) strabismus, and seven (6.4%) hearing loss; other symptoms were diagnosed, including ten (9.1%) patients that had been diagnosed with peripheral neuropathy (PN) and seven (6.4%) with early onset of PD < 50 years old. All PN cases were not associated with diabetes, monoclonal gammopathy of undetermined significance (MGUS) or B12 vitamin deficiency. Patients with PD had the following GBA genotypes N370S/S364R(N = 1), L444P/D409H(N = 1), N370S/L444P(N= 1), N370S/[IVS4-2a > g; c.(-203) A > G] (N= 2), N370S/c.500insT(N = 1), N370S/R257Q(N= 1) and N370S/L336P(N= 1).

The general characteristics of GD relatives are included in Table 2. Among first and second degree relatives, 39 (13.1%) reported neurological manifestations, including: 16 (5.3%) PD; nine (3.0%) epilepsy; eight (2.7%) essential tremor; two (0.6%) hypoacusia, and five (1.5%) other disorders.
Table 2

General characteristics of GD relatives (n = 324)

ID family

GBA genotype index case

Carriers

Non carriers

Type of neurological disorder: carrier and non carrier status

  

F

M

F

M

 

1

N370S/T134P

3

0

0

2

NO

2

N370S/G202R

1

1

0

0

NO

3

N370S/c.500insT

2

0

0

0

NO

4

N370S/L444P

3

3

1

1

NO

5

N370S/L444P

4

3

4

1

NO

6

N370S/L444P

2

0

1

0

NO

8

N370S/L444P

2

3

0

0

Rest tremor: N370S(1); L444P(2) Deafness: N370S(1)

9

N370S/R257X

2

3

0

1

NO

11

N370S/R120W

1

1

0

0

NO

14

N370S/L444P

0

2

1

1

NO

15

N370S/L444P

0

7

0

0

Peripheral neuropathy: N370S(1)

18

N370S/N370S

2

1

0

0

NO

19

N370S/N370S

1

1

0

0

NO

22

N370S/L444P

0

2

3

1

NO

23

G195W/G377S

1

1

0

0

NO

24

N370S/IVS4-2c.203A > G

5

8

3

2

NO

25

N370S/G195W

1

1

0

0

NO

26

L444P/E326K + N188S

1

2

0

0

NO

28

N370S/L444P

2

2

0

0

Epilepsy: N370S(1)

31

G377S/D409H

0

1

1

0

Epilepsy: non carrier(1)

32

N370S/L336P

0

1

1

0

Rest tremor: L336P(1)

36

N370S/c.708delC

0

2

1

0

NO

37

N370S/S364R

1

1

0

0

NO

41

N370S/c.953delT

1

1

0

1

PD: c.953delT(1) Epilepsy: N370S(1)

44

N370S/E326K + N188S

1

1

1

1

PD: E326K + N188S(1)

51

N370S/del55

1

2

1

1

NO

55

N370S/L444P

1

1

0

0

NO

62

N370S/P391L

1

1

0

0

NO

63

N370S/G202R

2

1

0

0

PD: G202R(1) Rest tremor: G202R(1) Epilepsy:N370S(1)

65

N370S/G195W

1

1

0

0

NO

69

N370S/L444P

2

2

0

0

NO

73

R463C/G377S

1

2

2

3

NO

76

N370S/E326K + N188S

1

1

0

0

NO

91

N370S/L444P

1

1

0

0

NO

106

N370S/L444P

1

0

0

1

NO

107

N370S/N370S

1

1

0

0

NO

108

N370S/L444P

1

2

2

2

Lewy bodies disease :.L444P(1) Deafness L444P(1)

109

N370S/L444P

4

1

1

0

PD:/L444P(1)

110

N370S/L444P

1

1

0

0

NO

111

N370S/N370S

1

1

0

0

NO

112

L444P/L444P

1

0

0

1

NO

115

N370S/c.1439-1445del7

0

1

1

0

PD: c.1439-1445del7(1)

119

N370S/G195W

2

0

0

0

Epilepsy:G195W(1)

122

N370S/L444P

0

1

1

1

NO

123

N370S/c.84insG

1

1

0

1

NO

124

N370S/N370S

1

1

0

0

NO

127

N370S/L444P

4

1

0

2

PD: L444P(1)

129

N370S/del55

1

1

0

0

NO

131

N370S/G202R

1

1

1

0

Stroke: N370S(1); non carrier(1)

135

N370S/G202R

1

1

0

0

PD N370S(1)

137

N370S/L444P

1

1

0

0

NO

140

N370S/L444P

1

1

0

0

NO

143

N370S/P182L

1

1

0

0

NO

146

N370S/W(-4)X

2

2

3

4

NO

148

N370S/R47X

1

1

0

0

Rest tremor: N370S(1)

151

N370S/V398I

1

2

0

0

PD: V398I(1)

153

N370S/L444P

1

1

0

0

NO

154

L444P/L444P

1

1

0

1

Autism: non carrier(1)

155

N370S/L444P

1

1

1

2

PD/L444P(3)

156

N370S/L444P

1

1

0

0

NO

158

L444P/L444P

2

3

2

0

NO

163

N370S/N370S

1

1

0

0

NO

182

N370S/c.500insT

1

1

0

0

NO

197

N370S/R163X

0

1

2

0

NO

198

N370S/N370S

0

2

0

0

NO

201

N370S/L444P

1

1

1

2

PD: L444P(1) Deafness: non carrier(1) Epilepsy: non carrier(1)

205

N370S/L444P

1

0

0

1

NO

218

N370S/L444P

0

1

2

3

NO

219

L444P/D409H

1

1

0

0

Epilepsy: D409H(1)

220

N370S/R120W

1

1

1

1

Epilepsy:non carrier(1)

222

N370S/N370S

0

1

2

1

PD: non carrier(1)

223

N370S/L444P

1

1

0

0

NO

227

L444P/D409H

4

1

0

0

NO

233

N370S/RecNci1

0

1

6

4

NO

238

N370S/R120W

1

1

1

0

No

239

N370S/N370S

2

1

0

0

PD:/N370S(1), Action tremor:N370S(1) Cerebral palsy: N370S(1)

240

L444P/L444P

1

2

1

0

NO

241

N370S/c.1207insA

1

1

0

0

Dementia: N370S(1)

242

L444PL444P

1

1

0

0

No

243

N370S/1098insA

3

3

1

1

Depression: 1098insA(1)

244

N370S/L444P

1

1

0

1

NO

245

N370S/T134P

1

3

0

0

Epilepsy: T134P(1)

246

N370S/G202R

1

1

1

0

NO

066

N370S/Y313H

1

2

0

0

NO

074

N370S/R257Q

3

4

1

0

PD : R257Q(1) Depression: N370S(1) Cerebral palsy N370S(1)

206

N370S/N370S

0

1

2

3

NO

318

N370S/c.1249-1251delTGC

1

0

1

3

PD: c.1249-1251delTGC(1)

Total 87

 

109

122

53

50

NS: 39 (13.1%) PD: 16 (5.3%)

aN family members = the total number (number of carriers). M = male; F = female

Dx = diagnosis; GBA = glucocerebrosidase; NO = no symptoms; NS = neurological symptoms, PD = Parkinson’s disease

In 16 relatives that developed PD, the GBA mutations found were: N370S (N= 2), c.1249-1251 delTGC, R257Q, L444P (N= 7), K398I, G202R, G1438-1445del7, S364R, N188S + E326K. After distributing the relatives into two groups, including carriers (N= 213) and non-carriers (N= 84) of GBA mutations, we found 34 (15.9%) cases with NS in the carrier group, versus only five (5.9%) cases with NS (one PD, three with epilepsy, and one with hearing loss) among the non–carriers. These differences between carriers and non-carriers were statistically significant (p = 0.01). In carriers with other neurological symptoms, like epilepsy, tremor, or peripheral neuropathy, we detected the following GBA mutations: D409H, G195W, R120W, R47X, G377S, and L336P.

Discussion

In this study, the overall prevalence of neurological manifestations in patients with type 1 GD, and in relatives that were carriers of GBA mutations was higher than relatives non-carriers, and higher than expected prevalence in the general population (Sánchez 2010). We assume that the study may be biased due to an overestimation of subjects with NS that arose as a consequence of the method used to obtain the data. That is, subjects with problems were motivated to complete the survey more than individuals without problems (only 32% of the latter group replied). However, our results can be considered valid, because the size of the sample was large enough to detect significant differences between groups. It should also be noted that, in one previous study performed by systematic neurological examination in patients diagnosed with type 1 GD, the incidence of neurological disorders was similar (30.7%) (Giraldo et al. 2000). This also agrees with other studies (Pastores et al. 2003; Halperin et al. 2007) that showed that patients with type 1 GD had a higher incidence of neurological symptoms than that observed in the general population (Capablo et al. 2008, Sanchez 2010). This fact does not seem to be influenced by ERT, because previous observational studies carried out in patients with type 1 GD with and without ERT revealed a higher incidence of peripheral neuropathy in all patients than in the general population (Pastores et al. 2003; Halperin et al. 2007; Capablo et al. 2008; Giraldo et al. 2008). We do not find any plausible explanation related to the higher incidence of neurological manifestations in women than in men in this cohort of type 1 GD patients. Further studies will be required in order to confirm this observation.

In the present study, we also found that the prevalence of Parkinson’s disease in patients with type 1 GD was 19 times higher than that estimated for the general population (Giraldo et al. 2008; Sanchez 2010). Furthermore, the prevalence of PD was higher (16 times) in relatives that carried a GBA mutation than in the general population. In several studies performed in different ethnic populations, there were conflicting findings concerning the susceptibility of PD in carriers of GBA mutations (Goker-Alpan et al. 2004; Kono et al. 2007; Mitsui et al. 2009). The prevalence of GBA mutations associated with Parkinsonism was variable; this variability may have been related to the method of mutation screening or to population characteristics (Goker-Alpan et al. 2008; Tayebi et al. 2003).

Moreover, other neurological manifestations, including tremor, peripheral neuropathy, uncoordinated movements, and hearing loss appeared more frequently in patients with type 1 GD than in the general population. It is relevant that isolated lack of concentration is not a specific neurological symptom and then only has been considered when this event appeared associated with other neurological manifestation. On the other hand, strabismus is not necessarily neurological and the incidence observed in GD1 patients was similar to that described in the Spanish general population (Sánchez 2010).

The N370S mutation has been traditionally associated with the absence of neurological disease; however, in this study, a high proportion of patients with the N370S mutation were diagnosed with type 1 GD and showed neurological symptoms (30/35; 85.7%). This finding is consistent with the recently established contention that the mutation could not fully protect the patient from the appearance of neurological symptoms (Halperin et al. 2007). These observations reinforce the hypothesis that phenotypes reflect the continuum of the disease (Sidransky 2004).

Although the inheritance of GD is autosomal recessive, it has been shown that carriers have some metabolic abnormalities, including a reduction in the concentration of cholesterol carried by high density lipoproteins (Pocovi et al. 1998).

Although, our study has a limitation because we do not have complete data about intake of drugs that may causes tremor or another neurological adverse event, we think that this fact is not relevant because it would only affect a few cases.

With the aim of identifying early neurological abnormalities, one practical recommendation that can be derived from our study is that it is important to conduct a systematic examination in patients with type 1 GD and relatives that carry GBA mutations.

Notes

Acknowledgments

This study was partially supported by the grants: FIS 06/1253, EC07/90737, FIS PS 09/2556, FEETEG and CIBERER U-752. The authors would like to thank all the members of the Spanish Gaucher Disease Group (SGDG) who provided clinical data and samples. The complete list of physicians of the SGDG who have contributed is available at: www.feeteg.org. The authors are also extremely grateful to the patients and their families whose participation made this work possible.

Disclosure

All the authors are members of the Spanish Study Group on Gaucher Disease, a group supported by the Spanish Gaucher Disease Foundation (FEETEG). The corresponding author and the majority of the others authors are researchers at the Aragonés Institute of Public Health (I + CS) and members of the Centro de Investigación Biomédica En Red de Enfermedades Raras (CIBERER), ISCIII, Zaragoza, Spain.

Supplementary material

10545_2011_9298_MOESM1_ESM.doc (134 kb)
SupplementaryTablel 1General characteristics of GD patients (DOC 133 kb)

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Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • Pilar Giraldo
    • 1
    • 3
    • 4
    • 5
    • 6
  • Jose Luis Capablo
    • 2
    • 4
    • 6
  • Pilar Alfonso
    • 3
    • 4
    • 5
  • Beatriz Garcia-Rodriguez
    • 5
  • Paz Latre
    • 6
  • Pilar Irun
    • 3
    • 4
    • 8
  • Alicia Saenz de Cabezon
    • 4
    • 7
  • Miguel Pocovi
    • 3
    • 4
    • 6
    • 8
  1. 1.Hematology DepartmentMiguel Servet University HospitalZaragozaSpain
  2. 2.Neurology DepartmentMiguel Servet University HospitalZaragozaSpain
  3. 3.Instituto Aragonés de Ciencias de la Salud (I+CS)ZaragozaSpain
  4. 4.Centro de Investigación Biomédica En Red de Enfermedades Raras (CIBERER), ISCIIIZaragozaSpain
  5. 5.Traslational Research UnitMiguel Servet University HospitalZaragozaSpain
  6. 6.FEETEGZaragozaSpain
  7. 7.Neurophysiology DepartmentMiguel Servet University HospitalZaragozaSpain
  8. 8.Biochemistry, Cellular and Molecular Biology DepartmentUniversity of ZaragozaZaragozaSpain

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