The Expression and Secretion Profile of TRAP5 Isoforms in Gaucher Disease.

BACKGROUND: Gaucher disease (GD) is caused by glucocerebrosidase (GCase) enzyme deficiency, leading to glycosylceramide (Gb-1) and glucosylsphingosine (Lyso-Gb-1) accumulation. The pathological hallmark for GD is an accumulation of large macrophages called Gaucher cells (GCs) in the liver, spleen, and bone marrow, which are associated with chronic organ enlargement, bone manifestations, and inflammation. Tartrate-resistant acid phosphatase type 5 (TRAP5 protein, ACP5 gene) has long been a nonspecific biomarker of macrophage/GCs activation; however, the discovery of two isoforms of TRAP5 has expanded its significance. The discovery of TRAP5's two isoforms revealed that it is more than just a biomarker of macrophage activity. While TRAP5a is highly expressed in macrophages, TRAP5b is secreted by osteoclasts. Recently, we have shown that the elevation of TRAP5b in plasma is associated with osteoporosis in GD. However, the role of TRAP isoforms in GD and how the accumulation of Gb-1 and Lyso-Gb-1 affects TRAP expression is unknown. METHODS: 39 patients with GD were categorized into cohorts based on bone mineral density (BMD). TRAP5a and TRAP5b plasma levels were quantified by ELISA. ACP5 mRNA was estimated using RT-PCR. RESULTS: An increase in TRAP5b was associated with reduced BMD and correlated with Lyso-Gb-1 and immune activator chemokine ligand 18 (CCL18). In contrast, the elevation of TRAP5a correlated with chitotriosidase activity in GD. Lyso-Gb-1 and plasma seemed to influence the expression of ACP5 in macrophages. CONCLUSIONS: As an early indicator of BMD alteration, measurement of circulating TRAP5b is a valuable tool for assessing osteopenia-osteoporosis in GD, while TRAP5a serves as a biomarker of macrophage activation in GD. Understanding the distinct expression pattern of TRAP5 isoforms offers valuable insight into both bone disease and the broader implications for immune system activation in GD.

Gaucher-like Cells in Thalassemia Intermedia: Is It a Challenge?

We describe two cases of thalassemia intermedia (TI) patients with the presence of Gaucher-like cells in hematopoietic tissue biopsies, raising diagnostic dilemmas. The first is a 56-year-old female with bone lesions, splenomegaly, hypochromic microcytic anemia and Gaucher-like cells in the bone marrow, with a final diagnosis of TI, and the second is a 69-year-old male with TI, monoclonal gammopathy of undetermined significance (MGUS) that accelerated to multiple myeloma (MM) requiring treatment, bone disease and Gaucher-like cells in the bone marrow and the spleen, and heterozygoty of Gaucher disease (GD). Gaucher-like cells are difficult to differentiate from true Gaucher cells, that are the hallmark of GD suspicion. These cells are usually reported in the lymphohematopoietic system. They have been described in myeloproliferative disorders, hematological malignancies, infectious diseases, hemoglobinopathies and other hemolytic anemias. The presence of Gaucher-like cells in patients with thalassemia major has been well documented, whereas there are limited references regarding cases with thalassemia intermedia. The identification of these cells in thalassemia probably reflects the high cell turnover. The bony complications in GD and TIare not yet fully explained in the literature, and this raises the question of whether Gaucher-like cells could play a pathogenetic role in the bone disease of thalassemia, as Gaucher cells are considered to play a similar role in bone complications of GD. Moreover, given the rarity and similarity of Gaucher and Gaucher-like cells, we would like to highlight that the presence of Gaucher-like cells in the bone marrow should not be overlooked, as they might be obscuring an underlying pathology, in order to ensure that hematologists, internists and hematopathologists will be promptly and accurately diagnosed.

Massive Splenomegaly with Pancytopenia in an Adult: Gaucher's Disease.

INTRODUCTION: Gaucher's disease (GD) is a rare lysosomal storage disease. It is characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. GD presents a broad clinical expression, including hematologic abnormalities (such as pancytopenia), massive hepatosplenomegaly, diffuse infiltrative pulmonary disease, renal involvement in the form of nephropathy and glomerulonephritis, skeletal involvement in the form of bone pain, bony infarct, osteopenia, and pathological fracture. Based on the presence or absence of neurologic involvement, it is differentiated into type 1, type 2, and type 3. Gaucher's disease type 1 is the most common form, having the nonneuropathic form and carrying autosomal recessive traits. Gaucher's disease affects all racial and ethnic groups, while type 1 GD is most prevalent among Ashkenazi Jews. CASE PRESENTATION: A 20-year-old female was admitted to the medicine department with complaints of generalized weakness and easy fatigability, menorrhagia, and a dragging sensation in the abdomen. On clinical evaluation, she had bone marrow failure syndrome features along with massive splenomegaly. Later, she was confirmed with Gaucher disease type 1 disease by clinical and investigation (low ß-glucosidase level) evaluation. CONCLUSION: This case emphasizes keeping a differential diagnosis of glycogen storage disorder while evaluating a case of unexplained pancytopenia with massive splenomegaly in adulthood for an extended period. Currently, enzyme replacement therapy and substrate reduction therapy are the mainstay therapeutic options for GD.

Gaucher's Disease in an Adult Female: A Rare Entity.

Gaucher's disease is a rare inborn error of metabolism with an autosomal recessive pattern of inheritance. With over 26 million births occurring per annum, extrapolation of this figure would give us an estimated burden of 17,000 babies born with lysosomal storage disorder (LSD). Given the large population of India and the high rates of consanguineous marriage that takes place in the subcontinent, LSD might not be as rare as we perceive it to be. We report a rare occurrence of type-1 Gaucher's disease in an adult female patient born of a non-consanguineous marriage, belonging to the tropical area of Chhattisgarh, India where there is a predominance of malaria, thalassemia, and sickling. The diagnosis was challenging in this case since we needed to work out all the differential diagnoses of pancytopenia with hepatomegaly and massive splenomegaly. The key part was her medical history where there was documentation of her elder brother's death due to some mental illness of undiagnosed etiology. Being a difficult time due to coronavirus disease 2019 ( COVID-19) , we were able to diagnose the patient with a bone marrow biopsy followed by glucocerebrosidase enzyme level suggestive of Gaucher's disease.

Case report: Gaucher disease in trepanobiopsy of 16yo woman examined for suspected myelodysplastic syndrome.

Gaucher disease is an autosomal recessive disease belonging to the so-called storage diseases. More than 300 mutations of the GBA1 gene encoding the β-glucocerebrosidase enzyme are known. It is a very rare disease in the Czech Republic. Currently 35 patients are treated. In our case report, we present the case of a 16 year old female patient attending the Clinic of Pediatric Medicine at the University Hospital in Ostrava. Since 2007, the patient has suffered prolonged thrombocytopenia, at the time with progression, and splenomegaly, which has not been further investigated. Trepanobiopsy was sent to the Department of Pathology with suspicion of myelodysplastic syndrome in May of 2018. In the biopsy examination, the individual bloodline did not show dysplastic features and the number of blasts was not increased. The marrow interstitium was 70% permeated with gaucher cells with intraplasmatic fibrous material. Cells were in the appearance of „crumpled paper“ and expressed CD68 in immunohistochemical stain and in histochemical examination of PAS and iron (Fe) staining. Based on a morphological finding, Gauchers disease was suspected. Repeated bone marrow aspirates were subsequently captured by gaucher cells, and a next biochemical examination showed a β-glucocerebrosidase enzyme decrease of activity. Gaucher disease is a progressive disease that requires early diagnosis with the onset of therapy.

Gaucher Disease: An Underdiagnosed Pathology in the Eastern Moroccan Population.

Gaucher disease (GD) is a lysosomal storage disease. It corresponds to a congenital deficit in ß-glucocerebrosidase. This pathology should be considered in the presence of unexplained splenomegaly, with or without signs of haemorrhage, skeletal manifestations or hepatomegaly. The diagnosis is based on the measurement of the ß-glucocerebrosidase activity but the preanalytical process should be respected in order to avoid the under-diagnosis of this disorder and the delay of its management. We report two cases of Gaucher disease collected at Mohammed VI University Hospital and Al Farabi regional hospital in Oujda. We have emphasized the need for a reference center for overload diseases.

Photo Essay: Retinal Changes in Type 3 Gaucher Disease.

Ocular features of Gaucher disease include gaze abnormalities, corneal clouding, ocular deposits and pigmentary changes in the macula. We report the presence of bilateral fovea sparing macular deposits in a 21-year-old woman with type 3 Gaucher disease. Macular deposits occur due to glucocerebroside accumulation within histiocytes and retinal deposits might correlate with the degree of systemic infiltration.

Gaucher Disease Involving Virchow's Lymph Node: a Case Report.

Gaucher disease is a metabolic storage disorder caused by a mutation in the lysosomal enzyme B-glucocerebrosidase. This disease is usually manifested in new born infants, however, an exceptional case of this disease in adult has been recently reported. A 21-year-old Caucasian patient was diagnosed with Gaucher disease, demonstrating Virchow's lymphatic node enlargement and mild splenomegaly. A familial link to this disease was also found. Macrophage infiltration was observed in the aff ected Virchow's lymph node which is not a classic sign of Gaucher disease. DNA analysis and a whole blood count also suggested a manifestation of this disease. In summary, this is the first study to report such case of Gaucher disease in an adult female patient, which may suggest an asymptomatic characteristic of this condition and an importance of the presence of Gaucher cells in the enlarged Virchow's lymph node.

Thrombocytopenia and GBA gene mutation in a patient with adult type 1 Gaucher disease.

A 38-year-old female patient was diagnosed with anemia for 3 years. Medical examination showed slight splenomegaly (250 × 62 mm), thrombocytopenia (platelets 51 × 109/L), anemia (Hb levels 107 g/L), and ß-glucocerebrosidase activity (GBA) in leukocytes was lower than normal. Microscopic findings of bone marrow smear demonstrated that Gaucher cells in bone marrow and periodic acid-Schiff staining of them were positive. Sequencing of GBA genomic and cDNA identified one novel homozygous mutation, c.484A> G (p.Met162Val). This case suggests that we should pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia and one novel homozygous mutation in GBA gene was reported for the first time. The novel mutation in homozygosity is apparently associated with mild, non-neuronopathic type 1 disease which is relatively uncommon in Asian populations.

Histologic findings of femoral heads from patients with Gaucher disease treated with enzyme replacement.

OBJECTIVES: To assess correlations of patient demographics, including enzyme replacement therapy (ERT) with bone histology, to facilitate decisions of whether and when to perform hip replacement surgery in patients with Gaucher disease. METHODS: We examined the histology of surgically removed femoral heads and categorized findings by the presence or extent of osteonecrosis, Gaucher cell (GC) infiltration, and bone regeneration qualifiers using a tripartite histology-based scoring system. RESULTS: Twenty-two patients with 26 bone specimens were evaluated. Seventeen patients (77%) were splenectomized, 16 (73%) received ERT, and 12 (55%) had the putatively milder genotype (N370S/N370S), with the rest putatively at increased risk for skeletal disease (N370S/other). The 3 histology subscores were applicable to all specimens. Osteonecrotic bone was seen in 19 of 26 (73%); osteoarthritis was seen in all cartilage specimens. Gaucher cell infiltration was not correlated with demographics or disease severity. A trend was noted between reduced GC infiltration and ERT (ρ = 0.407), but regeneration qualifiers were not correlated with ERT or other features. CONCLUSIONS: Histologic findings of GC infiltration and bone regeneration qualifiers did not correlate with demographics or with exposure to ERT. Most specimens unexpectedly showed good regenerative responses to osteonecrosis despite heavy GC infiltration.

A Rare Case of Hemoglobin E Hemoglobinopathy with Gaucher's Disease.

Hemoglobin (Hb) E mutation is common in north-east part of our country. The natural history of Hb E thalassemia is highly variable. The phenotype, for patients with similar mutations, can range from asymptomatic to transfusion dependent. Our patient presented at 2 years of age with failure to thrive and hepatosplenomegaly. Routine work up revealed microcytic, hypochromic red blood cells. Hb E homozygous was indicated on electrophoresis and hemoglobin HPLC. Evaluation of parents revealed Haemoglobin E trait in both. Therapeutic splenectomy revealed Gaucher-like cells. ß-Glucocerebrosidase levels were low. Presence of Gaucher-like cells with normal ß-glucocerebrosidase (pseudo-Gaucher cells) are known in leukemia, multiple myeloma, thalassemia and mycobacterial infections. Co-existence of Gaucher's disease with Hb E mutation is not reported to the best of our knowledge.

Gaucher's disease diagnosed by splenectomy.

CONTEXT: Splenectomy continues to find common therapeutic indications for hematologic disorders. In addition, recently it is also performed in surgical clinics to assist diagnose of some illnesses. Gaucher's disease, especially Type I, is the most frequently encountered lysosomal storage disorder in man. Manifestations of it are highly variable. The most frequently found symptoms include splenomegaly with anaemia and thrombocytopenia, mostly due to hypersplenism, hepatomegaly and bone disease. CASES: Four patients were reported in the present study. Three of them were easily diagnosed with Gaucher's disease via bone marrow cytology, and one with Gaucher's disease was detected by pathological examination following the splenectomy. CONCLUSIONS: For the pouse of diagnosis of the Gaucher's disease, performing surgery is generally not necessary. However, for the cases of difficult to diagnose by classical methods, the corect diagnosis of Gaucher's disease can only be made by a special operation.

Solitary Plasmacytoma in the Thoracic Spine with Massive Aggregation of Histiocytes

A Solitary plasmacytoma of bone(SPB) is a rare disease. This paper reports a case of SPB with massive aggregation of histiocytes known as pseudo-Gaucher cells. A 40-year-old male presented with progressive paraparesis and paraesthesia. The Magnetic Resornance Image(MRI) revealed a tumor mass in the thoracic spine that occupied the three colum. The tumor invaded the epidural space of T6 vertebra with compression of the spinal cord. There were no laboratory abnormalities. It was gross totally resected and his neurological symptoms improved. The microscopic examination revealed a plasmacytoma with massive aggregation of histiocytes. Futher neuroradiological studies were carried out and no other lesions were detected.