Introduction

Gaucher disease (GD) is a sphingolipidoses, a subgroup of lysosomal storage diseases. It is the most common lysosomal storage disease, having an autosomal recessive inheritance and resulting from a deficiency of the glucocerebrosidase enzyme due to a genetic defect on the glucosylceramidase beta (GBA1) gene. The enzyme deficiency results in the inability to break down glucosylceramide in lysosomes, and lipid-laden macrophages accumulate in the tissues. The central nervous system (type 2 and type 3), liver, spleen and bone marrow are mainly affected. GD is divided into three types according to the severity of the disease and neurological findings. In type 1 GD (non-neuropathic type), there is no neurological involvement, and visceral findings are milder. It is usually diagnosed in adolescence or adulthood. Type 2 GD is the acute neuronopathic type, which progresses to very severe neurological and visceral involvement. It usually results in death before the age of 2 years. Type 3 GD is the chronic neuronopathic type, where the neurological involvement is more moderate and the life span is longer than that in type 2. Type 2 and type 3 are generally diagnosed in the first years of life, and such individuals do not reach adulthood because there is no effective active treatment. GD is panethnic, affecting approximately 40–50 thousand live births. The most common form of GD is type 1 GD, accounting for approximately 90% of the patients [1]. Studies related to Gaucher disease in Turkey are limited and are not found in the national registration system. Studies generally consist of paediatric patients and include patients with type 3 GD [2, 3]. Herein, we have shared the data of and our experience with patients with type 1 GD that were followed up at our clinic.

Materials and methods

Patients with type 1 GD who were diagnosed and/or followed up at the Endocrinology and Metabolism Diseases Clinic at Erciyes University’s Faculty of Medicine between December 2018 and December 2021 were evaluated retrospectively. Erciyes University is a tertiary referral hospital in the city of Kayseri, east of Central Anatolia. All the patients in our study were adults. Patients whose hospital records could be accessed and followed up were included in the study. Blood parameters such as haemoglobin level, platelet count, liver and kidney function tests and vitamin D and ferritin levels were screened. Glucocerebrosidase enzyme levels was measured from dried blood spot using tandem mass spectrometry. DNA extracted from dried blood spots was analysed; using polymerase chain reaction, all the coding exons and flanking intronic regions were amplified and sequenced. Variants were described using the Human Genome Variation Society nomenclature. The patient’s liver and spleen size or their volumes were evaluated using abdominal imaging [ultrasonography (US), tomography or magnetic resonance imaging (MRI)]. Hepatomegaly is conceded to be defined as liver mass > 1.25 times the estimated normal volume which is 2.5% of total body weight. The liver size is in the mid-clavicular line to craniocaudal dimension (length), and upper limit is 16 cm. The upper limit of the spleen length is accepted as 12 cm. The average volume is about 150 cc for women and 200 cc for men. Bone densitometry measurements were also obtained. The main criteria for the diagnosis of Gaucher disease was a low glucocerebrosidase enzyme level and genetic analysis. Other laboratory tests were used as supportive evidence. Data were obtained by directly interviewing all the patients. Ethical approval was obtained from the Ethics Committee of Erciyes University (no: 2021/800; dated 08.12.2021).

Statistical analysis

All data have been summarised descriptively, and statistical tests were not performed. Descriptive data are expressed as means, standard deviations and minimum and maximum values for continuous variables and as numbers and percentages for categorical variables. The calculations were performed using SPSS (version 22.0, IBM Corporation, NY, USA).

Results

We evaluated 13 patients with type 1 GD, who were diagnosed or followed up at our centre and whose data could be accessed. Four of the patients were male, and nine were female. The mean age at diagnosis was 33 (± 11.32) years. Our youngest patient was diagnosed using bone marrow aspiration biopsy specimen at the age of 16 years. Our oldest patient was 57 years old and was diagnosed while being evaluated for secondary osteoporosis. While eleven of our patients had a first-degree relative with the disease, there was no such finding in two of our patients.

Glucocerebrosidase activity and genetic analyses are important cornerstones for the diagnosis of the disease. The enzyme activity of all the patients was below the reference range. Six patients had a homozygous N409S mutation. Four patients had a combined heterozygous GBA1 gene mutation carrying the N409S mutation in one allele. Of these combined heterozygotes, two had the L483P (L444P) mutation, while the other two had the D448H (D409H) mutation. In two siblings, there was a homozygous c.[593C > A];[593C > A] mutation, which has not been detected in the literature before. One of these siblings was diagnosed when an examination during pregnancy revealed splenomegaly and a low platelet count. Her sister was diagnosed during the screening of the family members. Patients clinically had hepatosplenomegaly and thrombocytopenia. There was no bone crisis, neurological findings, or heart and lung involvement. The mutations and glucocerebrosidase activity of the patients are shown in Table 1.

Table 1 Mutations and enzyme levels of the study participants
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The blood parameters of the patients at the time of diagnosis are important in determining the severity of the disease and complications. In addition, disease biomarkers provide valuable information at the time of diagnosis and during follow-up. A low platelet count is the most common laboratory finding. The platelet count was < 150,000 at the time of diagnosis in eight of the patients. The platelet count could not be evaluated in two of the patients before they underwent a splenectomy. The platelet count in three of the 10 patients without a history of splenectomy was normal. In two of the patients, the platelet count was < 50,000. The blood parameter data of our patients at the time of diagnosis are listed in Table 2.

Table 2 Patient’s blood parameters at the time of diagnosis
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MRI and abdominal US were performed in nine patients. In four patients, only US was performed. Hepatomegaly was present in 11 of the 13 patients. Eight of the 13 patients had splenomegaly. Three patients underwent splenectomy. The liver and spleen dimensions of two patients were normal. While the sister (patient no. 5) and daughter (patient no. 7) of patient no. 6 had undergone splenectomy for hypersplenism, hepatosplenomegaly could not be detected in patient no. 6 on US or MRI. Gallstones were present in one patient. Three patients had undergone surgery for gallstones (Table 3).

Table 3 General characteristics of the study participants
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Patients 5, 7 and 12 had undergone splenectomy at the ages of 16, 17 and 13 years, respectively. GD could not be diagnosed using the splenectomy material of patient 12; the patient was diagnosed with GD 21 years after the surgery. All the patients who underwent splenectomy had a homozygous N409S mutation.

Bone densitometry revealed that six patients had a lumbar z-score of ≤  − 2.5. Five patients had a z-score between − 1 and − 2.5. Two patients had a normal z-score. One of our patients (no. 12) had undergone recurrent joint surgeries and had a knee and hip prostheses in situ (Fig. 1).

Fig. 1
figure 1

Right knee and left hip prostheses of patient no. 12 and enlargement of both the femurs are visualised (Erlenmeyer flask deformity)

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The mean treatment duration was 36 (± 19.46) months. All of our patients received enzyme replacement therapy. While 12 of the patients were administered imiglucerase, one was prescribed taliglucerase. No serious side effects or unresponsiveness to the treatment was observed in any of the patients. There were only three patients with low platelet at the end of follow-up. Platelet values of patients numbered 8, 9 and 11 are 93, 97 and 137 thousand per microlitre, respectively. Anaemia was resolved in all patients with anaemia. Three patients with lyso-gl-1 measurement, a disease biomarker, before starting treatment had significant decreases in post-treatment values. Ferritin value decreased in 3 of 4 patients with high initial ferritin value. Bone densitometry improvement was observed in 8 patients, while it remained the same in 3 patients. Regression was observed in two patients. The treatment duration of the patients and their response to treatment are summarised in Table 4.

Table 4 The treatment duration of the patients and their response to treatment
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Discussion

Gaucher disease is one of the most common storage diseases inherited in an autosomal recessive manner. The disease is definitively diagnosed by detecting the mutations and enzyme deficiency in patients who present with symptoms and signs [4]. At our clinic, enzyme level determination is performed first in patients with suspected GD, and genetic analysis is performed in patients with low enzyme levels. In the Gaucher Registry study published in 2000, the data of 522 clinicians and 1698 patients with GD from 38 different countries were compiled. The genetic analysis of 766 of these patients was obtained, and the N409S (N370S) mutation was detected in 53% of the 1532 alleles. The L483P (L444P) mutation was the second most common mutation observed (16%) [5]. The most common genetic mutation observed in our patients was the N409S mutation, which was present in 16 (61.5%) of the 26 alleles. The N409S mutation was homozygous in six of our patients. Two patients had compound heterozygous N409S and L483P mutations. Two patients had the c.[593C > A];[593C > A] mutation, which has not been reported in literature. Clinically, these had predominant thrombocytopenia, moderate organomegaly, moderate osteoporosis, no painful bony symptoms and no neurological signs. Additionally, the heart and lungs were not involved. Thus, these two patients with a novel mutation had a mild disease [6]. The L483P (L444P) mutation was the most common mutation observed in two Turkish studies, which included 57 and 38 patients with all GD types. In patients with type 1 GD, the most common mutation observed was the N409S mutation [2, 3]. Thus, considering the results of previous studies and our study, the most common mutation in patients with type 1 GD in Turkey is N409S. Currently, there is no national database for GD in Turkey. The studies on GD in Turkey include only a small number of patients; a large study that includes more centres in Turkey is required.

The most common finding in GD is splenomegaly. It is detected in approximately 90% of the patients [5, 7]. The upper limit of the spleen length is generally accepted as 12 cm. The average volume is about 150 cc for women and 200 cc for men [8]. During the years where enzyme replacement therapy was not common, patients with severe splenomegaly had to undergo splenectomy because of hypersplenism or its complications. Currently, splenectomy is not recommended for GD, except for some absolute indications such infarct and rupture. Pulmonary involvement increases in patients who have undergone splenectomy. In our study, splenomegaly and hepatomegaly were seen at the same rate (85%). A homozygous N409S mutation was detected in all three patients who underwent splenectomy. Although the N409S mutation has a mild course, there is heterogeneity. While most of the patients are diagnosed in adulthood with skeletal system findings, some of them are diagnosed at an early age with visceral involvement. In a study of 216 patients with a homozygous N409S mutation, 25 (11.9%) had undergone splenectomy [9].

The second most common finding in GD is hepatomegaly. In the Gaucher Registry study, 77% of the patients with a spleen had hepatomegaly; this rate increased to 88% in patients who had undergone splenectomy [5]. Hepatomegaly is generally conceded to be defined as liver mass N 1.25 times the estimated normal volume which is 2.5% of total body weight [10]. The liver size is in the mid-clavicular line to craniocaudal dimension (length), and upper limit is 16 cm [11]. In our study, only two patients did not have hepatomegaly; all other patients had hepatomegaly. Hepatomegaly was detected on the MRI of two patients who were determined to have a normal US. In 2004, the International Collaborative Gaucher Group (ICGG) recommended volumetric evaluation of the liver and spleen with MRI or CT when performing abdominal imaging [12]. Especially during the first evaluation, MRI is preferred because the images can be retrospectively re-evaluated and compared.

In the Gaucher Registry study, osteopenia was seen in 42% of the patients, and skeletal system involvement was higher in the group without a spleen than in the group with a spleen [5]. In our study, except for two patients, the lumbar z-score was <  − 1 in five patients and ≤ –2.5 in six patients. One patient (patient no. 12), whose lomber z scores were normal, had severe skeletal system involvement, and the proximal femoral bone densitometry could not be performed due to the presence of a prosthesis. However, the distal-third radius z-score was − 6.4. The same patient had undergone splenectomy at the age of 13 years. He also provided a history of bone crisis, avascular necrosis of the hip and joint surgery. In patients whose clinical findings and lumbar density are contradictory, imaging can be performed at other regions. Except for patient 12, although some patients had bone pain, no serious complication or spinal deformity (scoliosis or kyphosis) was observed. The reason osteopenia and osteoporosis were common in our study may be attributed to the fact that osteoporosis is more common in the Turkey population than in other European countries [13]. Furthermore, we screened for GD in osteoporosis of unknown origin.

Enzyme replacement therapy, which was introduced in the 1990s, is an effective treatment for GD. It significantly reduces the morbidity of the disease and prolongs life expectancy. In a study on the 20-year treatment results of imiglucerase that was published by IGCC in 2021, significant improvements were observed in the first 10 years; these gains were maintained in the 20th year [14]. We also observed improvements in the morbidity with enzyme replacement therapy among the patients we followed up.

Conclusion

GD is a rare lysosomal storage disease that affects many systems. It can cause irreversible morbidity in patients in whom the diagnosis is delayed. The main treatment modality is enzyme replacement therapy. Because it is a rare and multisystemic disease, patients should be followed up at centres that have experience in treating the Gaucher disease.