Different and unusual presentation of Gaucher’s disease with the same mutation in the glucocerebrosidase enzyme (F266L) in two patients: a case report

Abstract

Background

Gaucher is an autosomal recessive inherited lysosomal storage disorder. The incidence of this disease is rare with a global estimate of around 1 in 57,000 to 1 in 75,000. Gaucher’s disease is caused by a mutation in the glucocerebrosidase gene. Common symptoms of this disease include hepatosplenomegaly, moderate neurological symptoms, and late‑onset skeletal alterations. However, Gaucher can sometimes have rare presentations that lead to a delayed diagnosis in patients. This report discusses two adult cases of Gaucher’s disease (type 1) with the same mutation but with unusual symptoms.

Case presentation

One patient was a 44-year-old man who had been experiencing chronic cough since he was 10 years old, and the other patient was a 27-year-old woman with itching, both atypical symptoms of Gaucher. Bronchodilators and prednisolone were administered for chronic cough and antihistamines and prednisolone were given for the itching, but little to no improvement was seen. Sonography tests revealed that both cases had splenomegaly, hepatomegaly, and liver malfunction, characteristic of Gaucher’s disease. Bone marrow aspiration tests confirmed the presence of Gaucher’s cells in their bones. The level of glucocerebrosidase enzyme in both cases was less than 1.5 nmol/mL/hour. Whole exon sequencing confirmed a mutation on exon 8 of the GBA1 gene in a homozygous form in both cases, resulting in a transversion mutation (C > G) at position c.798, leading to the substitution of phenylalanine 266 with leucine. Both patients were of Bakhtiyari ethnicity and had parents who were in a consanguineous marriage. After receiving Cerezyme treatment, both cases experienced a disappearance of their cough and itching symptoms.

Conclusion

This report highlights the importance of recognizing the unusual presentation of Gaucher’s disease especially in regions with high rates of consanguineous marriage and thalassemia. This knowledge can aid physicians in making accurate diagnoses and providing appropriate treatment.

Background

Gaucher’s disease is a rare metabolic disorder with an inherited autosomal recessive pattern [1] that causes systemic lysosomal storage disorder due to a deficiency in the glucocerebrosidase enzyme. This enzyme is characterized as a housekeeping gene and is located on the first chromosome (1q22) [2]. The defective activity of this enzyme leads to the accumulation of glucosylceramide (GlcCer), especially in macrophage cells, which are called lipid-laden macrophages or Gaucher’s cells. These cells have characteristic appearances such as cytoplasmic granular enlargement and round displaced nuclei. The infiltration of Gaucher’s cells in different organs such as the liver, spleen, bone marrow, and lung causes significant clinical manifestations in this disease such as hepatosplenomegaly, pancytopenia, skin pigmentation, neurological symptoms, osteoporosis, severe bone pain, and respiratory symptoms [2, 3].

Gaucher is categorized into three subgroups based on age of presentation, severity, clinical features signs, and neurological association. Type 1 of this disease is seen in early adulthood or adolescence. This form of the disease is chronic and non‑neuropathic with anemia, massive hepatosplenomegaly, and bone marrow involvement presentation. Type 2 is characterized as an acute neuropathic or infantile form. Severe progressive neurological deterioration with an aggressive course is observed in this type. Hepatosplenomegaly is also detected. Bone involvement is rare in this form. Type 3 of Gaucher’s disease, which is the least common form, is the juvenile or subacute form that affects patients between 2 and 6 years. The most common presentation of this type is hepatosplenomegaly and moderate neurological symptoms with late‑onset skeletal alterations [3]. Additionally, any symptom of weakness, pallor, and a progressively growing abdominal girth associated with unexplained splenomegaly should be considered as Gaucher’s disease, especially in children [4]. Lung involvement in this disease is rare and can vary from being clinically asymptomatic with normal or mild changes to severe respiratory symptoms that are confirmed by radiographic findings [3]. Gaucher’s disease can be characterized by a genetic test but due to limited resources for genetic testing in underdeveloped countries, this method has its limitations. The gold standard method for confirming Gaucher’s disease is still bone marrow examination, which is an invasive but affordable technique, especially in underdeveloped countries [5]. However, pseudo-Gaucher’s cell can also be seen in other diseases such as chronic myelogenous leukemia (CML), type II congenital dyserythropoietic anemia, thalassemia, Hodgkin’s lymphoma, multiple myeloma, acquired immunodeficiency syndrome (AIDS), and deficiency in β-glucosidase activity [4].

Only two studies have reported on the association of Gaucher’s disease with pulmonary involvement [3, 6] and no cases have been reported regarding the association of itching with Gaucher’s disease. This case report presents two cases from Bakhtiyari ethnicity with the same mutation in position F266L of the glucocerebrosidase enzyme but with different clinical symptoms. The tests and symptoms that help us recognize Gaucher’s disease in these patients are presented here. This case report could help physicians be aware of unusual and varied symptoms of Gaucher’s disease, especially in patients with the same mutation in the GBA1 gene.

Case presentation 1

The first case is a 44-year-old man who presented with a chronic cough. He had experienced this symptom since he was 10 years old (Table 1). The severity of his cough did not worsen over time. He has been on therapy with bronchodilators and prednisolone for years to manage his asthma and cough, but he has not shown any improvement. During this time, his chest x-ray report indicated a reticular field lung pattern. The complete blood count test showed a normal level of white blood cell count (6.5 × 10³/µL) and a low platelet count of 52 × 10³/µL indicating mild thrombocytopenia and a suspicion of immune thrombocytopenia (ITP). The levels of alkaline phosphatase and aspartate transaminase (AST) liver enzymes were within the normal range, except for alanine transaminase (ALT; 57U/L), which was slightly elevated. Additionally, his ferritin level was 492 ng/mL (Table 2). This suggested that his liver was mildly impaired, despite a negative viral profile (Table 3). The longitudinal spleen span was 16 mm above normal, indicating splenomegaly (Fig. 1). Bone marrow aspiration revealed foamy cells consistent with Gaucher’s disease (Fig. 2). To determine the specific mutation, whole exon sequencing was performed. The genetic test result identified a mutation in exon 8 of the GBA1 gene (NM_001005742) in a homozygous form, resulting in a C > G transversion at position c.798. This mutation led to the substitution of phenylalanine 266 with leucine (F266L), which was predicted to be likely pathogenic for Gaucher type 1 disease. The analysis of the family history revealed that the patient had Bakhtiyari ethnicity. Furthermore, it was discovered that the patient’s parents had a second-degree cousin’s consanguineous marriage. However, none of the patients’ siblings were affected by Gaucher’s disease. He was administered 400 U of Cerezyme every 15 days. Surprisingly, the patient’s cough ceased after receiving the first dose of Cerezyme, and his platelet count increased to 83 × 10³/µL, with AST, ALT, and alkaline phosphatase levels returning to normal (Table 2).

Table 1 Demographic data and clinical details of the patient

Table 2 Complete blood test count and liver enzyme assay before and after treatment of Gaucher’s disease by Cerezyme

Table 3 Viral profile by enzyme-linked immunosorbent assay (ELISA) method

Fig. 1

Sonography of the spleen represents Splenomegaly

Fig. 2

The photomicrograph representation of foamy cells which are named Gaucher’s cells (black arrows) in bone marrow aspiration with Giemsa staining ×400

Case presentation 2

The 27-year-old woman began experiencing itching as the first symptom associated with bone pain (Fig. 3). Her demographic data are presented in Table 4. She was given antihistamines and prednisolone for itching; however, she only partially responded to these medications. A sonography test revealed portal hypertension. The patient did not report any neurological symptoms. Her white blood cell count and platelet count were 73 × 10³/µL and 4.6 × 10³/µL, respectively. The blood test result is shown in Table 5. The ELISA test for autoantibodies was negative, indicating that no autoantibodies were present in this patient (Table 6). Sonography tests also showed mild hepatomegaly and moderate splenomegaly. Her glucocerebrosidase level was 0.3 nmol/ml/hour, which is lower than the normal level of 1.5 nmol/ml/hour, indicating a deficiency in this enzyme. The enzyme assay result is presented in Table 7. Due to symptoms resembling Gaucher’s disease, a bone marrow aspiration test was conducted. The test revealed foamy cells in her bone marrow, characteristic of Gaucher’s disease (Fig. 4). Whole exon sequencing showed a homozygous transversion mutation (C > G) in position c.798 in exon 8 of the GBA1 gene, resulting in the substitution of phenylalanine 266 with leucine (F266L) as a pathogenic mutation. The family history analysis indicated that the patient had Bakhtiyari ethnicity and her parents had a consanguineous marriage (second-degree cousins). However, none of her siblings were affected by Gaucher ‘s disease. The administration of 400 U Cerezyme every 15 days successfully stopped her itching.

Fig. 3

The symptom of itching is represented in patients with Gaucher’s disease

Table 4 Demographic and clinical data of the patient

Table 5 The blood test data before and after treatment

Table 6 ELISA test to assay autoantibodies. Data show that autoantibodies against nuclear, mitochondrial, and smooth muscle were negative

Table 7 Enzyme assay result. All enzymes except for β-glucocerebrosidase (ABG) are in the normal range

Fig. 4

Bone aspiration photomicrograph represents foamy cells called Gaucher’s cells (black arrows) with Giemsa staining ×400

Discussion

Gaucher’s disease is a metabolic disorder that occurs due to a deficiency in lysosomal glucocerebrosidase. This disease has three types of phenotypes based on age and neurological deficit. Type 2 and 3 of this disease are characterized as an infantile and juvenile subtype of Gaucher’s disease that are associated with acute and chronic neuronopathic representation, respectively. In the infantile form, death occurs before the age of 3 years, while in the juvenile form death typically occurs in the third or fourth decade of life. Type one Gaucher’s disease affects adults, who can lead a normal life with enzyme replacement therapy [5]. The deficiency of glucocerebrosidase is caused by a mutation in the GBA1 gene that is responsible for the enzyme. Among the 300 mutations in the GBA1 gene, more than 80% are single-nucleotide polymorphisms (SNPs) [7]. Different mutations in this protein lead to different types of Gaucher’s disease; for example, the N370S mutation causes the adult form of Gaucher, while the L444P mutation causes the juvenile form of the disease. Various mutations in the glucosylceramidase protein have been observed in the infantile form [5]. In this report, whole exon sequencing in both cases revealed a missense mutation (F266L) in a homozygous format in the GBA1 gene. Both patients’ ethnicities were Bakhtiari and they lived in Izeh, which is one of the cities in the Khuzestan province. The pathogenic role of the F266L mutation in Gaucher’s disease was previously reported by Machaczka and Klimkowska [8]. They reported on a woman who lived in Sweden but originally came from Ahvaz, Khuzestan. They found that she had a heterozygous mutation in the GBA1 gene. After sequencing, they discovered that she harbored F266L and I347S mutations in GBA1 [8]. This could mean that this type of GBA1 mutation may be more common in this region, although further analysis with a larger number of patients with Gaucher’s disease is needed to confirm this. This data aligns with the findings of Sheth et al., who reported that the L483P mutation in the GBA1 gene was more prevalent in patients with Gaucher’s disease in India [9]. The family history analysis in the current study did not show any familial relation between these two patients, even though both patients were born from consanguineous marriages. All siblings of both patients were healthy and unaffected by Gaucher’s disease. This data is consistent with previous studies that found consanguinity among parents of patients with Gaucher’s disease [8, 10], as well as cases where patients were from non-consanguineous marriages but located in the same region [1, 3, 5], increasing the risk of Gaucher’s disease. This suggests that the prevalence of Gaucher’s disease is high in certain areas in countries with limited populations, where consanguinity is common [11].

The symptoms of Gaucher’s disease are associated with liver and spleen size, hemoglobin concentration, platelet levels, and bone appearance, which are used for the identification of Gaucher’s disease [12]. These symptoms are common in patients with thalassemia as well, which can make it difficult to recognize Gaucher’s disease in regions where the prevalence of patients with thalassemia is high [13], such as Iran [14]. In this study, both reported cases had splenomegaly and hepatomegaly, which are compatible with Gaucher’s symptoms in a 23-year-old woman in India [1], a 3-year-old boy in Iran [4], an 18-year-old African-American female patient in Cuba [15], and a 17-year-old woman who lived in Sweden but originally came from Iran and had a heterozygous form of the F266L mutation in GBA1 [8]. The additional symptom of Gaucher’s disease in this woman was skeletal deformation [8], which was not observed among patients in this case report. Although the 27-year-old woman in this report had bone pain, no skeletal deformation was observed in this patient. The chronic cough in the 44-year-old patient in the current work is compatible with a 6-year-old female child who had recurrent episodes of cough and cold with enlargement of the liver and spleen. This lung symptom could be due to the infiltration of Gaucher’s cells into alveoli, interstitium, bronchi, or pulmonary vasculature [3]. This data follows the Santamari et al. work which showed the homozygous form of the L444P mutation in the GBA1 gene could increase the risk of pulmonary disease in patients with Gaucher’s disease [6], although in the current report, the homozygous form of F266L represented pulmonary symptoms.

Although both cases had the same mutation in the GBA1 gene, they exhibited different symptoms of Gaucher’s disease. Maor et al. demonstrated that various glucosylceramidase variants were substrates for different E3 ubiquitin ligases in various cells to degrade unfold or misfold glucosylceramidase in the endoplasmic reticulum (ER) [16]. Therefore, differences in E3 ubiquitin ligases in the ER may be the causes of different symptoms of Gaucher’s disease in patients. The diagnosis of Gaucher’s disease in both cases was confirmed by the presence of Gaucher’s cells in bone aspiration, low glucosylceramidase enzyme activity, and genetic test mutation analysis. This is consistent with previous research indicating that bone marrow examination is essential for diagnosing of Gaucher’s disease and should be conducted for all suspicious patients [17].

In both case reports, symptoms of Gaucher’s disease ceased after the administration of Cerezyme. This outcome aligns with the finding of Machaczka and Klimkowska, who treated a woman with Gaucher’s disease and the same mutation in GBA1 with Cerezyme. They observed normalization of liver size and function, and cessation of acute skeletal pain, despite occasional skeletal deformations [8]. This result is also consistent with other patients with Gaucher’s disease who have undergone enzyme replacement therapy and experienced a reduction in their Gaucher’s symptoms [2, 18]. This indicates that enzyme replacement therapy is effective in treating this disease [19], although the expensive price of Cerezyme in developing and underdeveloped countries poses a significant challenge for patients [1, 5, 20].

Conclusions

Diagnosing Gaucher’s disease can be challenging due to its rarity and varying symptoms. Additionally, the lack of awareness among physicians and the limited availability of genetic testing centers, particularly in low-income countries, contribute to delays in diagnosis. Therefore, increasing knowledge about the different symptoms of Gaucher’s disease could help physicians make earlier diagnoses and reduce the morbidity and side effects experienced by patients, especially in regions with small populations, high rates of consanguineous marriage, and a high prevalence of thalassemia.