Adult gaucher disease in southern Tunisia: report of three cases

Gaucher disease (GD) is the most frequent lysosomal storage disorder [1]. It is an autosomal recessive inborn defect in the glucocerebrosidase gene (GBA) on1q21 leading to enzymatic deficiency of the β-glucocerebrosidase and the accumulation of glycosylceramide substrate in the macrophage's lysosomes. GD is characterized by a considerable phenotypic and genotypic heterogeneity [2]. There is a wide range of clinical manifestationsfrom nearly asymptomatic patients who have mild bone pain up to full spectrum of severe complications with cytopenia, hepatosplenomegaly and pathologic fractures [3]. More than 200 mutations were identified along GBA gene http://​www.​hgmd.​org. In previous studies, investigation of GD showed that p.N370S, p.L444P and RecNci I mutations were relatively frequent in Tunisian patients [4, 5]. In the present study, we report three Tunisian adult GD patients including one patient with Parkinson disease in whom the disease was incidentally found following bone marrow examination during check up for thrombocytopenia with splenomegaly. These cases were investigated for the p.N370S, p.L444P and RecNci I mutations in GBA gene.

Three patients diagnosed with GD from three unrelated families from southern Tunisia were investigated. The diagnosis was based on the occurrence of hepatosplenomegaly associated with hematological abnormalities and/or bone lesions and was confirmed in all patients by the presence of Gaucher cells.

After the patient's written informed consent, 5 ml of blood were collected. DNA was extracted from peripheral blood mononuclear cells using the standard salting-out procedure. DNA samples were then amplified by polymerase-chain-reaction (PCR) followed by enzymatic restriction using Xho I and Nci I to screen for p.N370S and p.L444P respectively. Sequencing was performed on an ABI 3130 to detect the three mutations (p.N370S, p.L444P and RecNciI).

To the best of our knowledge this is the second report describing adult patients with GD in Tunisia and the first report of an association of GD and Parkinson disease in our Country. The first report by Dandana et al [6] described a 50 year old patient with GD without any neurological disorder. Many adult cases with GD have been reported worldwide. Based on data from the Gaucher Registry (ICGG 2008) the p.N370S mutation was found in 53% of all GD patients and represents the highest prevalence. About 14% of GD patients were diagnosed between the age of 31 to 50 year old [7].

Among the patients we report here, two patients were homozygous for the p.N370S mutation (table 1). Homozygosity for this mutation appears common among GD type I adult patients [8]. So far, this mutation was found in 44% of paediatric Tunisian patients with GD [5]. Unlike most of the autosomal recessive genetic diseases in Tunisia for which the majority of the patients is born to consanguineous marriages and is homozygous for deleterious alleles, the p.N370S mutation is encountered at heterozygous state in combination with other mutated alleles [5].

One patient (case 1) developed Parkinson disease at age 52. The co-morbidity of GD and Parkinson disease has been largely discussed [9‐11]. The incidence of Parkinson disease seems particularly high among patients with GD; Bembi and collaborators found four Parkinson patients (6.9%) among 58 patients with GD [12]. Lachmann and Platt found 3 cases of Parkinson disease in 130 patients (2.3%) [13]. The first signs of Parkinson disease appear at an earlier age in patients with GD compared to the general population: 48 versus 71 years average age, respectively [14]. It has been increasingly recognized that Parkinsonism may be a clinical feature of GD type I and may even precede its diagnosis [15]. In addition, heterozygosity for certain GBA gene mutations predisposes to a higher risk for Parkinson disease according to Chérin and collaborators [16]. Whereas, a recent study presented by Nishioka and collaborators on 395 patients with Parkinson disease and 372 control subjects did not show a statistically significant association with p.K26R, p.K186R and p.N370S in the Tunisian population (P > 0.05) [11]. The p.N370S mutation was identified in only one sporadic patient with Parkinson disease and 3 control subjects indicating that the frequency of this mutation in Tunisian patients is much lower than that observed in Ashkenazi Jews patients with Parkinson disease (31%).Furthermore, Spitz and collaborators reported that most patients with GD never develop Parkinson disease, suggesting the involvement of other genetic and/or environmental factors in the GD process [15].

It has been suggested that only one third of the patients who were homozygote for p.N370S mutation come to medical attention and that about two thirds remain asymptomatic throughout life [17]. Carrier screening programs may lead to the identification of asymptomatic cases. In the literature, carrier screening and termination of pregnancy of GD is controversial, in particular for mild mutations like the p.N370S mutation [18, 19]. In Tunisia, GD like other autosomal recessive disorders [20, 21], is rare and does not represent a major public health concern. We suggest that prenatal diagnosis for couples at risk carrying a severe mutation (L444P, RecNci I) is the best alternative to reduce the incidence of the severe form of the disease.

There is a great variability in the clinical manifestation as well as in the onset and course of GD. This supports the need for a new classification and reinforces the hypothesis of the concept of a phenotypic continuum. Clinicians, especially in hematology and internal medicine, should suspect the diagnosis of GD in any adult patient suffering from abdominal and/or bone pain with unexplained hematological disorder especially in combination with organomegaly.