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

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.

Neuronopathic Forms in Subjects with Mutations in GBA Gene

“…As we mentioned before the N370S mutation has been traditionally associated with the absence of neurological disease; however, several studies reported a high proportion of patients with the N370S mutation were diagnosed with GD 1 and showed mild neurological symptoms such tremor, peripheral neuropathy, uncoordinated movements, and hearing loss (as well as Parkinson disease. (Capablo et al, 2008;Giraldo et al, 2011;Pastores et al, 2003). These findings are 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).…”

“…This survey revealed that a significant proportion of patients with GD I experience neurological symptoms. In addition, we found that GD1 patients have a greater risk of suffering other common unrelated diseases than carriers or their healthy relatives (Giraldo et al, 2011). The wide spectrum phenotypic variation and neurological involvement within all types, and the recognition of an increasing number of subgroups of patients, support the view that GD is a disorder with a phenotypic continuum ranging from prenatal lethality to asymptomatic adults (Sidransky, 2004).…”

“…The lack of a shared genotype for patients and the variability in clinical presentations suggesting the existence of other modifying factors contributing to this rare phenotype (Park et al, 2003). Have also been documented cases in Spanish population with symptoms of myoclonic epilepsy (Giraldo et al, 2011). In a study of a Spanish patient with neuronopathic type 3 GD and myoclonic epilepsy symptomatic improvement was observed using a combination of substrate reduction therapy with enzyme replacement therapy (Capablo et al, 2007).…”

“…These findings are 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 GD (Sidransky et al, 2004 In a recent study, aimed to determine the presence of neurological symptoms and Parkinson's disease in Spanish GD patients and their relatives, we have found that relatives with PD exhibited a wide spectrum of GBA mutations L444P, N370S, V398I, R257Q, G202R, c.1439-1445del7, [E326K; N188S], and c.953delT in the other hand PD was more frequent in carriers of L444P mutation and other rare GBA mutations than carriers of N370S (Giraldo et al, 2011).…”

Characteristics of Parkinson’s disease course in the heterozygous carriage of mutations in the glucocerebrosidase A gene

“…БП выявляется у 1-2% населения старше 65 лет, поэтому ее относят к наиболее распространенным заболеваниям среди лиц пожилого возраста [2]. В последние годы отмечено частое сочетание БП с мутацией в гене лизосомального фермента β-глюко-цереброзидазы А (GBA) [4].…”