Pilar Alfonso

Neurological evaluation of patients with Gaucher disease diagnosed as type 1

Type 1 Gaucher disease (GD1) is characterised by lack of central nervous system involvement; however, there are several reports of associated neurological manifestations. The aim of this study was to systematically evaluate neurological manifestations in 31 patients with GD1 (12 males and 19 females; mean age 39.4 (range 5–77) years). Participants underwent a complete neurological examination and cognitive tests. Investigation of symptoms and medication intake, and motor and sensory electroneurograms were obtained. 30.7% of adult patients had neurological deficits, including psychomotor delay, parkinsonism, dementia, impaired saccadic ocular movements and peripheral nerve dysfunction. Three patients were redefined as type 3 GD. Electrodiagnosis was performed on 15 patients; 26.7% had reduced amplitude and/or abnormal waveforms in at least three nerves, 33.3% had a mild reduction in amplitude of two nerves and 40% had amplitude reduction in one nerve. Patients with three or more affected nerves had additional neurological symptoms. Our results demonstrate that neurological alterations occur in patients diagnosed with GD1, and subclinical peripheral neuropathy is a frequent finding.

Neurologic improvement in a type 3 gaucher disease patient treated with imiglucerase/miglustat combination

Summary:  Purpose: Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and miglustat.

Real-world clinical experience with long-term miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project

There are few published data from real-world clinical experience with miglustat, an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. This study suggests that miglustat is an effective therapy for the long-term maintenance of patients with type 1 Gaucher disease previously stabilized with enzyme replacement therapy. There are few published data from real-world clinical experience with miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.

Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain

AbstractMutations in the glucocerebrosidase (GBA) gene cause Gaucher disease (GD). The aim of this study was to characterise the GBA mutations and analyze genotype/phenotype relationships in 193 unrelated patients from the Spanish GD Registry. We have identified 98.7% of the mutated GBA alleles, finding 56 different GBA mutations and 66 genotypes causing GD in Spain: 47 previously described mutations and 9 novel mutations (4 missense R395C, R463H, W312R and V398I, 1 nonsense R359X, 4 frameshift c.708delC, c.1214-1215delGC, c.1439-1445del7 and c.42-65del24). The most prevalent mutations were N370S and L444P, accounting for 68.7% of the mutated alleles. A wide phenotypic difference was observed within each genotypic group, and 9% of diagnosed type 1 patients developed neurological involvement including parkisonism, tremor, hypoacusia and eye movements. All of these findings indicate that there is a significant genotypic heterogeneity that explains the huge phenotypic variation among Spanish GD patients.

Therapeutic Strategies for Gaucher Disease: Miglustat (NB-DNJ) as a Pharmacological Chaperone for Glucocerebrosidase and the Different Thermostability of Velaglucerase Alfa and Imiglucerase

Gaucher disease (GD) is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal glucocerebrosidase (GlcCerase) activity, due to conformationally or functionally defective variants, resulting in progressive deposition of glycosylceramide in macrophages. The glucose analogue, N-butyldeoxynojirimycin (NB-DNJ, miglustat), is an inhibitor of the ceramide-specific glycosyltransferase, which catalyzes the first step of glycosphingolipid biosynthesis and is currently approved for the oral treatment of type 1 GD. In a previous work, we found a GlcCerase activity increase in cell cultures in the presence of NB-DNJ, which could imply that this compound is not only a substrate reducer but also a pharmacological chaperone or inhibitor for GlcCerase degradation. In this work we compare imiglucerase (the enzyme currently used for replacement therapy) and velaglucerase alfa (a novel therapeutic enzyme form) in terms of conformational stability and enzymatic activity, as well as the effect of NB-DNJ on them. The interaction between these enzymes and NB-DNJ was studied by isothermal titration calorimetry. Our results reveal that, although velaglucerase alfa and imiglucerase exhibit very similar activity profiles, velaglucerase alfa shows higher in vitro thermal stability and is less prone to aggregation/precipitation, which could be advantageous for storage and clinical administration. In addition, we show that at neutral pH NB-DNJ binds to and enhances the stability of both enzymes, while at mildly acidic lysosomal conditions it does not bind to them. These results support the potential role of NB-DNJ as a pharmacological chaperone, susceptible of being part of pharmaceutical formulation or combination therapy for GD in the future.

Bicyclic Derivatives of l-Idonojirimycin as Pharmacological Chaperones for Neuronopathic Forms of Gaucher Disease

New human β-glucocerebrosidase (GCase) ligands with rigid 1,6-anhydro-β-L-idonojirimycin cores have been designed with the aid of molecular modeling. Efficient pharmacological chaperones for the L444P (trafficking-incompetent) mutant GCase enzyme associated with type 2 and 3 Gaucher disease (GD) were identified.

Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula

BackgroundGaucher disease (GD) is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics.MethodsWe evaluated the distribution, and clinical and genetic characteristics of GD patients in the Iberian Peninsula (IP). We analysed geographical distribution, demographic, genetic and clinical data, age at diagnosis, type, and years of therapy in 436 GD patients from the IP.ResultsThe prevalence of GD was 1/149,000 inhabitants; 88.3% were type 1, 6.7% type 2, and 5.0% type 3. The mean age at diagnosis in type 1 was 28.7 years. A total of 72.7% were classified as having mild forms, 25.5% moderate, and 1.7% severe. Anemia and thrombocytopenia were present in 56% and 55%, respectively. Bone disease and hepatomegaly were reported in 62% and 68%, respectively, and were more likely in asplenic than in non-splenectomized patients. Sixty-nine mutant alleles were identified, and five mutations accounted for 75% of the GBA alleles. Several patients described in our series had interesting phenotypes. A total of 58.7% of patients had received enzyme replacement therapy and 12.6% were treated with miglustat.ConclusionsA broad spectrum of GBA mutations is present in the IP, with 98.2% of type 1 GD being mild and 23.0% never treated. These data highlight genetic and phenotypic heterogeneities among geographic populations.

Evaluation of Spanish Gaucher disease patients after a 6-month imiglucerase shortage.

Recently, an acute restriction of imiglucerase has occurred as a result of viral contamination and manufacturing problems. A position statement from the European Working Group for Gaucher Disease and European Gaucher Alliance established a set of key recommendations for identifying and monitoring at-risk patients. In Spain, a profile of the shortage situation was obtained through follow-up of patients with Gaucher disease (GD) and compliance with the therapy recommendations. Here we describe a group of patients, with modified doses of imiglucerase, during the shortage. Fifty adult GD1 patients (25 males/25 females), previously on ERT, were analysed before and after the 6-month shortage. The mean age was 45.3 ± 15.3 years (range: 18-84). The mean Severity Score Index at diagnosis was 8.7 ± 3.8 (range: 3-19); 20% of patients were splenectomized; and 78% had bone disease. During the shortage, 23 patients (46%) discontinued therapy; as complications in this group only one patient suffered a bone crisis and another anaemia (Hb <10.0 g/dL). The mean reduction of haemoglobin level (-2.7%) and platelet counts (-5.4%) were non-significant. Chitotriosidase (CT) activity was increased 135% (p<0.03) and CCL18/PARC 8.2% (p<0.08) in this group. Imiglucerase was reduced by 50% in 17 patients (34%) in this group, seven patients (41.0%) suffered bone pain, three of them true bone crisis and four (23.5%) required support therapy. The mean reduction of haemoglobin (-2.8%) and platelet counts (-10.7%), CT activity was increased 48.2% (p<0.03) and no changes were observed in CCL18/PARC concentration. In both groups no significant changes in visceral size were observed. In 3 patients (6%), imiglucerase was reduced 75% and 7 patients (14%) needed to switch to another ERT (4 patients) or miglustat (3 patients) due to a restart of symptomatic disease. In Spain the 6 first months shortage of imiglucerase have produced a 20% incidence of bone pain, one case of anaemia, and a significant increase in CT activity. Fourteen percent of patients had to switch to another therapy. No significant changes in blood counts, visceral volumes and CCL18/PARC concentration were observed.

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders.

In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using LC–MS/MS, we comparatively investigated the occurrence of abnormal lyso-glycosphingolipids in tissues and plasma of mice with deficiencies in lysosomal α-galactosidase A, glucocerebrosidase and galactocerebrosidase. The nature and specificity of lyso-glycosphingolipid abnormalities are reported and compared to that in correspondingly more abundant N-acylated glycosphingolipids. Specific elevations in tissue and plasma globotriaosylsphingosine were detected in α-galactosidase A-deficient mice; glucosylsphingosine in glucocerebrosidase-deficient mice and galactosylsphingosine in galactocerebrosidase-deficient animals. A similar investigation was conducted for two mouse models of Niemann Pick type C (Npc1nih and Npc1nmf164), revealing significant tissue elevation of several neutral glycosphingolipids and concomitant increased plasma glucosylsphingosine. This latter finding was recapitulated by analysis of plasma of NPC patients. The value of plasma glucosylsphingosine in biochemical confirmation of the diagnosis of NPC is discussed.

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

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.