Gaucher disease

Gaucher disease is an inherited recessive autosomal metabolic defect due to a deficiency of the lysosomal enzyme beta-glucocerebrosidase. The enzyme substrate, glucocerebroside, accumulates in the body, predominantly in the liver, spleen, and bone marrow. Osteoarticular manifestations are often inaugural and contribute much of the morbidity and disability associated with Gaucher disease. There are three types of Gaucher disease. The most common is type 1, which can produce a broad range of presentations characterized by cytopenia and involvement of the spleen, liver, and bone marrow. Types 2 and 3 are rarest variants that manifest in infancy and cause neurologic damages. Patients with type 2 Gaucher disease usually die before 2years of age. beta-glucocerebrosidase assays and examination of bone marrow smears and biopsies ensure the diagnosis. Specific mutations in the beta-glucocerebrosidase gene are associated with specific clinical presentations: thus, the N370S mutation (heterozygous or homozygous) confers type 1 disease and the L444P mutation neurologic involvement and type 3 disease. Bone involvement is a feature in 70%-100% of cases. Abnormal bone remodeling, osteonecrosis and bony infarcts, osteopenia with fractures, and more rarely infections may occur. The other manifestations are dominated by cytopenia (thrombocytopenia, neutropenia, or anemia), hypersplenism, and liver enlargement. The risk of myeloma is increased. Parkinson-like syndromes were recently described in patients with type 1 disease. The enzyme chitotriosidase can be assayed to quantify the degree of macrophage activation. The chemokine CCL18 is another valuable marker but is not readily available in everyday practice. The treatment of Gaucher disease includes symptomatic drugs to relieve pain. Splenectomy is rarely necessary now that specific treatments are available. Enzyme replacement therapy (imiglucerase) has considerably improved the management of the highest risk patients. More recently, an enzyme inhibitor that decreases the production of the substrate (miglustat) was introduced. Chemical chaperone therapy and gene therapy hold promise for the future.     

Subarachnoid anesthesia in a patient with type I Gaucher disease

Gaucher's disease is a rare genetic disorder characterized by lack or functional insufficiency of glucocerebrosidase, an enzyme accountable for intracellular hydrolysis of glucosyl ceramide and other glycosphingolipids, which results in macrophage storage in the mononuclear-macrophage system. The severity of Gaucher's disease is correlated with the extent to which the central nervous system is involved. It is associated with the so-called Gaucher's cells in the bone marrow, but is specifically diagnosed by showing enzyme acid beta-glucosidase activity in a sample of blood leukocyte or cultured macrophages from skin biopsy. In the last 10 years, an enzyme replacement therapy (alglucerase) for the disease has been available, which has significantly changed approaches to its treatment. Here we report the case of a 56-year-old female patient with type I Gaucher's disease who underwent surgery for subcapital hip fracture with subarachnoid anesthesia. Type I Gaucher's disease clinical and pathophysiologic aspects relevant to anesthetic management are discussed. As very few similar cases have been reported in the anesthesiology literature, it is our belief that the present case may help to elucidate some controversial issues relating to the perioperative anesthetic management of patients with type I Gaucher's disease.     

Intravenous bisphosphonate treatment and pregnancy: its effects on mother and infant bone health

Introduction  

Type 1 Gaucher's disease (GD1) is a lysosomal storage disorder associated with disabling bone involvement. The choice treatment for Gaucher's disease is enzyme replacement therapy (ERT). The use of bisphosphonate treatment for osteopenia and osteoporosis has been suggested.     

A 56-year-old patient with Gaucher's disease sustaining a pathologic subcapital fracture of the humerus

We present a case of a pathologic humerus fracture in a patient with the initial diagnosis of Gaucher's disease, which is the most frequent form of lipidosis transmitted as an autosomal recessive trait. It often results in orthopaedic complications with pain, osteonecrosis, fractures and joint infractions. If there is cause for suspicion, beta-glucocerebrosidase in white blood cells should be measured because of the important consequences for treatment. Therapy with a modified enzyme is effective in managing the disease.     

Gaucher's disease in the black population of South Africa. A case report

The diagnosis of the non-neuropathic form of Gaucher's disease was confirmed by haematological and enzymatic investigations in a Black girl. The aetiological relationship of this condition with Gaucher's disease in other populations is uncertain, but lack of expression of the enzyme defect in the white blood cells in our patient might be significant in this context. This case serves to emphasize that Gaucher's disease enters into the differential diagnosis of unexplained splenomegaly, irrespective of the ethnic background of the affected person.     

A 27-year experience with splenectomy for Gaucher's disease

Gaucher's disease is an inherited metabolic disorder caused by the defective activity of acid beta-glucosidase and the resultant accumulation of glucosyl ceramide-laden macrophages in the liver, bone, and spleen. Splenectomy is the preferred treatment for patients with Gaucher's disease who develop massive splenomegaly with accompanying hypersplenism and/or mechanical pressure symptoms. The charts of 48 patients with Gaucher's disease undergoing splenectomy at our institution between January 1963 and December 1989 were analyzed to determine the short- and long-term results of this procedure. Thirty-five (73%) patients had total splenectomy, whereas 13 (27%) patients had partial splenectomy. There was one postoperative death (after total splenectomy), and 13 patients (27%) had postoperative complications. Eleven patients (23%) presented with accelerated bone disease after total splenectomy (mean follow-up: 96 months). No patients having partial splenectomy (mean follow-up: 25 months) developed progressive bone disease. Eight patients have died since surgery. All four deaths due to malignant disease occurred in patients after total splenectomy. The results of this largest-ever reported series of splenectomy for Gaucher's disease confirm that while either total or partial splenectomy can be performed with minimal morbidity and mortality, total splenectomy is accompanied by more aggressive bone disease and a predisposition to malignancy. Prospective, randomized trials are needed to substantiate whether partial splenectomy is indeed the treatment of choice for splenomegaly associated with Gaucher's disease.     

Cemented revision total hip arthroplasty with impaction bone grafting in Gaucher's disease

Total hip arthroplasty in Gaucher's disease has been associated with high rates of loosening after all types of arthroplasty. We present a patient with type 1 Gaucher's disease who underwent revision cemented total hip arthroplasty for aseptic loosening after 12 months of enzyme replacement therapy. Major osteolysis was managed by impaction morcellized bone grafting. An excellent clinical and radiographic result was obtained at 5-year follow-up. Enzyme replacement therapy combined with modern revision techniques may offer improved outcomes for patients with Gaucher's disease.     

Spinal cord compression secondary to Gaucher's disease

A case of compression of the spinal cord and cauda equina secondary to collapse of the T-12 and L-3 vertebral bodies in a patient with type 1 Gaucher's disease is presented. Decompressive laminectomies were done at both the T-12 and L-3 levels with moderate improvement of the patient's neurologic findings. Histologic examinations confirmed the presence of Gaucher's cells in the bone. Review of the literature revealed only one previous report.     

Clinical and therapeutic concepts in ischemic femur head necrosis

Bone ischaemia can result from four mechanisms: (1) interruption of arterial inflow (e.g. after femoral neck fracture), (2) occlusion of venous outflow (possibly due to capsular distension), (3) intravascular arteriolar occlusion (as in sickle cell disease); (4) extravascular sinusoidal tamponade (e.g. in Gaucher's disease). Osteonecrosis following high-dosage corticosteroid administration or alcohol abuse could, theoretically, be due to either intravascular fat embolism or sinusoidal tamponade resulting from the marked fat deposition in the marrow. It is proposed here that, except in traumatic osteonecrosis, vascular insufficiency is part of a cycle of events resembling the familiar soft tissue compartment syndrome of the forearm or leg; no matter whether it started with venous stasis, arteriolar occlusion or capillary tamponade, the result is a diffuse and self-enhancing ischaemia involving all three haemodynamic abnormalities in a vicious circle. The very earliest stage of "idiopathic" osteonecrosis is characterised chiefly by marrow changes; for some (undetermined) period the ischaemic effects are potentially reversible-provided the vicious circle is broken by relieving the high intraosseous pressure. Effective management involves: (a) early diagnosis by MR imaging, measurement of intraosseous pressure and venography: (b) decompression of the bone, and (c) elimination of the etiological factor. Later stages of osteonecrosis cannot be treated by decompression and will need realignment osteotomy, prosthetic replacement or arthrodesis.     

Gaucher's disease in the Cape coloured population of the RSA, including a family with 5 affected siblings

Nine Cape Coloured children from 4 families with severe non-neuropathic Gaucher's disease are documented. The diagnosis was confirmed histologically in the bone marrow, spleen and liver, and by serum acid phosphatase and leucocyte beta-glucosidase assays. This represents a minimum prevalence for Gaucher's disease of 1 in 247,350 in this population and an approximate genetic carrier rate of 1 in 230 for the abnormal gene. A family with 5 affected siblings is recorded. The severe early clinical expression documented in these coloured patients is similar to that described in the Afrikaner population and differs from the less severe expression of Gaucher's disease in the South African Ashkenazi Jewish population. Gaucher's disease in the Cape Coloured population presents with a precocious onset, causes severe complications and progresses rapidly.     

Splenectomy for Gaucher's disease.

The records of ten patients who underwent splenectomy for Gaucher's disease were reviewed. All patients had the adult type of the disease. The indications for splenectomy were hypersplenism and mechanical problems. The hematological picture returned to normal in all cases and has remained so throughout the follow-up period. The different forms Gaucher's disease and specific diagnostic tests are discussed. Even though splenectomy is indicated when hematological and mechanical problems exist, selective enzymatic replacement therapy seems to be the preferred future mode of treatment.     

Multiple organ failure and outcome of critically ill patients with haematological malignancy

BACKGROUND: The number of failing organs systems in ICU patients with haematological malignancy is associated with outcome. The objective of this study was to assess short and long-term survival in these patients with special reference to multiple organ failure reflected by the SOFA (Sequential Organ Failure Assessment) score. METHODS: Retrospective chart review of haematological patients admitted to the 10-bed intensive care unit (ICU) of a tertiary level academic teaching hospital from 1994 to 1998. Of 31 admitted patients with the diagnosis of haematological malignancy, the charts of 30 were available for analysis. RESULTS: Univariate logistic regression analysis of factors previously shown to influence survival revealed that only admission SOFA score and untreated status of haematological disease were significantly associated with survival (P < 0.05). ICU, 3-month and one-year survival rates were 57% (17/30), 23% (7/30) and 20% (6/30), respectively. If maximal SOFA score during the ICU stay was included in a multivariate model comprising treatment status and effect, admission day SOFA and APACHE II scores, mechanical ventilation, renal replacement therapy and neutropenia, the maximal SOFA score became the only independent variable. All patients with an admission SOFA score exceeding 11 died in hospital. Leave-one-out method revealed that admission SOFA scores and the status of haematological disease (untreated or not) correctly classified 83% (25 of 30) of patients to survivors or non-survivors. CONCLUSIONS: Multiple organ failure assessed as SOFA score on admission and status of disease were associated with outcome in critically ill patients with haematological malignancy.     

Sinus disease in the bone marrow transplant population: Incidence, risk factors,and complications

BACKGROUND: Fever associated with sinus disease in the immunocompromised bone marrow transplant recipient requires prompt evaluation and therapy. Very little is known about the incidence, risk factors, and sequelae of nonsurgically treated sinus disease in this population. METHODS: A retrospective review of 107 consecutive allogeneic and autologous bone marrow transplant recipients from August 1987 to July 1989 was performed to determine (1) the overall incidence of sinus disease; (2) factors that influence the development of sinus disease; and (3) the sequelae of sinus disease treated nonsurgically. RESULTS: Overall 33 (31%) of 107 bone marrow transplant recipients had sinus disease defined as a radiographic abnormality with clinical symptoms. Eleven (10%) of 107 recipients had preexisting sinus disease. Sinus disease developed in 22 (21%) of 107 recipients after bone marrow transplantation. Sinus abnormalities were significantly higher among allografted bone marrow transplant recipients than among autografted recipients (p = 0.027). The diagnosis, stage of disease, cytoreductive regimen, or graft-vs.-host disease were not different between recipients in whom sinus disease did and did not develop. There were no deaths as a result of sinus complications. CONCLUSIONS: Sinus disease developed in 21% of the studied population after bone marrow transplantation. Allogeneic recipients had a higher incidence of sinus disease than autologous recipients. There were no deaths attributed to sinus complications. All sinus disease in this bone marrow transplant population was treated medically. No patient required surgical intervention either before or after bone marrow transplantation. (OTOLARYNGOL HEAD NECK SURG 1995;113:705-11.)     

Partial splenectomy for Gaucher''s disease.

Gaucher's disease is an autosomal recessive disorder caused by deficiency of beta glucocerebrosidase, resulting in an accumulation of glucocerebroside in the reticuloendothelial system. These patients have massive splenomegaly and bone pain, but may have normal life expectancy. Traditionally, splenectomy has been used to treat hypersplenism, but may be associated with a high incidence of postsplenectomy sepsis and accelerated hepatic and bone lipid deposition. Two children are reported who had partial splenectomy for symptoms of Gaucher's disease. Both patients had laboratory evidence of hypersplenism. A 90% splenectomy was performed, and the residual splenic fragment was wrapped in Vicryl mesh. Both patients are currently asymptomatic with normal hematologic parameters. Postoperative radionuclide scans demonstrate increase in the size of the residual splenic fragment. Partial splenectomy may benefit patients with Gaucher's disease, but long-term follow-up care is necessary.     

Late pulmonary sequelae after childhood bone marrow transplantation

BACKGROUND: Respiratory function in transplanted children is important because of the long life expectancy of bone marrow transplant recipients, particularly children. Attention is now being focused on the late sequelae of treatment on organ system function. A few papers have been published but available data are somewhat conflicting. METHODS: A cross sectional study aimed at evaluating the late effects of transplantation on lung function was performed in a group of 52 young patients who were given autologous or allogeneic bone marrow transplants during childhood for haematological malignancies. RESULTS: No patients reported chronic respiratory symptoms. The distribution of respiratory function patterns showed that only 62% of patients had respiratory function within the normal limits; 23% had a restrictive pattern and 15% had isolated transfer factor impairment. The percentage of patients with lung function abnormalities was higher in those who (1) received a bone marrow transplant after two or three complete remissions compared with those who were transplanted immediately after the first remission (54% vs 21%; p < 0.02), (2) underwent allogeneic bone marrow transplantation rather than an autologous transplantation (45% vs 26%; p = 0.06), and (3) had a pulmonary infection compared with those without (56% vs 26%; p = 0.07). CONCLUSIONS: In spite of the absence of chronic respiratory symptoms there is a high prevalence of children with late pulmonary sequelae after bone marrow transplantation. Regular testing is recommended after transplantation, in particular in subjects at higher risk of lung injuries, such as those receiving transplants after more than one remission, those receiving allogeneic transplants, and those having suffered from pulmonary infections. When lung function abnormalities become apparent, long term follow up is necessary to see whether they become clinically relevant. All patients should remain non-smokers after transplantation and should have active early and aggressive treatment for respiratory illnesses.     

Role of prosaposin in the male reproductive system: effect of prosaposin inactivation on the testis, epididymis, prostate, and seminal vesicles

SGP-1/prosaposin can be secreted or targeted to the lysosomes where it is processed into smaller saposins (A, B, C, and D) required for the hydrolysis of glycosphingolipids. The deficiency of saposins B and C results in variant forms of metachromatic leukodystrophy and Gaucher's disease, respectively, which are characterized by lysosomal storage of undegraded glycosphingolipids. In the nervous system, prosaposin presents trophic activity. A mouse model was recently developed by creating a null allele in embryonic stem cells through gene targeting to investigate the phenotypic diversity of prosaposin mutations and the involvement of this protein in lysosomal storage diseases, and for the development of therapeutic approaches. Mice homozygous mutants die at the age of 35-40 days and neurological disorders contribute to the early demise of the mutant mice. The male reproductive organs in homozygous mutants show several abnormalities, such as a decrease in testis size with reduced spermiogenesis and an involution of the prostate, seminal vesicles, and epididymis. In these animals, the blood levels of testosterone remain normal. In the prostate of homozygous mutants, only the basal epithelial cells appear to be present, while the secretory cells are absent. These findings suggest that prosaposin may be involved in the development and maintenance of the male reproductive organs, as well as, in cellular differentiation.     

Bone formation in spontaneously diabetic Torii-newly established model of non-obese type 2 diabetes rats

It is well known that patients with type 1 diabetes mellitus exhibit bone abnormalities as one of the complications of the disease. Whether this occurs in type 2 diabetes is controversial. This uncertainty could be because type 2 diabetes includes several pathological types such as obese and non-obese. To examine the bone abnormalities in non-obese type 2 diabetes, we used Spontaneously Diabetic Torii (SDT) rats, which is a newly established model of non-obese type 2 diabetes. Sprague-Dawley (SD) rats were used as a control group (n=17). SDT rats were divided into two groups: the diabetic (DM) group (n=18) and the DM+insulin (INS) group (n=18) at 20 weeks of age. The DM+INS group received subcutaneously implanted insulin pellets every 2 weeks. At 36 weeks of age, the rats were killed, and we evaluated bone formation and the effect of insulin on bone formation, blood and urine analyses, bone mineral density (BMD), histomorphometry, and mRNA expression of alkaline phosphatase (ALP) and osteocalcin (OCN). Despite renal function not being impaired, BMD and bone strength were significantly lower in the DM group than in the control group. Osteoid volume per bone volume, osteoblast surface per bone surface, eroded surface per bone surface, osteoclast surface per bone surface, the mineral apposition rate, and the bone formation rate per bone surface were significantly lower in the DM group than in the control and DM+INS groups. The mRNA expression of ALP and OCN was significantly lower in the DM group than in the control group. Furthermore, 8-hydroxydeoxyguanosine, which is an oxidative stress marker, was remarkably elevated in the DM group. These abnormalities were recovered by insulin therapy. Our data support the notion that non-obese type 2 diabetes is associated with a low turnover of bone and that the abnormalities are ameliorated by insulin. The SDT rat may be a useful animal model for examining the mechanisms of bone abnormalities in non-obese type 2 diabetes.     

Long-term follow-up of partial splenectomy in Gaucher's disease.

Seven children with Gaucher's disease who underwent partial splenectomy were followed for 7 to 8 years. None of the children had systemic sepsis or symptoms related to liver enlargement. Bone crisis occurred in only two children who had experienced bone crisis prior to partial splenectomy. This contrasts with the development of bone crises in five of six children who underwent total splenectomy at a similar age and who had previously been free of bone symptoms. Partial splenectomy should be regarded as a temporary solution in the treatment of hypersplenism and the mechanical compression related to the huge spleen. In 71% of the patients, massive enlargement and a severe to moderate degree of pancytopenia occurred again after 3 to 8 years; total splenectomy was required in three patients.     

Investigation of Bone Disease Using Isomerized and Racemized Fragments of Type I Collagen

In the collagen type I C-telopeptide an aspartyl-glycine site within the sequence AHDGGR is susceptible to molecular rearrangement. In newly synthesized collagen this site is in the native form, denoted alpha L. During aging a spontaneous reaction occurs resulting in three age-modified forms: an isomerized form (beta L) a racemized form (alpha D), and an isomerized/racemized form (beta D). In this study, we measured the urinary excretion of the four forms of C-telopeptides (CTX) in healthy adults and in patients with bone diseases. Levels of all CTX forms were higher in healthy postmenopausal women (P<0.001) compared with premenopausal controls. Levels decreased within 3 days of bisphosphonate treatment indicating that all CTX forms reflect bone resorption. In hyperthyroidism, characterized by a generalized increased bone turnover, native (alpha L) and age-modified (beta L, alpha D and beta D) forms increased to a similar extent compared to controls, resulting in normal ratios between the alpha L and age-modified forms of CTX. Conversely, in Paget's disease and prostate cancer-induced bone metastases, conditions characterized by focal increased bone turnover, alpha L CTX levels were more elevated than those of age-related CTX forms, resulting in increased ratios between native and age-modified CTX. For example, the ratio alpha L/alpha D was increased 7-fold in Paget's disease (P<0.001) and 2-fold in prostate cancer-induced bone metastases (P<0.002). In conclusion, the study suggests that in conditions with a localized alteration in bone turnover the ratio between alpha L CTX and the age-modified forms is significantly elevated. This may provide a new diagnostic and monitoring tool for diseases such as metastatic bone cancer and Paget's disease.     

Is aplastic osteodystrophy a disease of malnutrition?

Adynamic bone disease is emerging as a major type of renal osteodystrophy in chronic dialysis patients. Relative hypoparathyroidism is one of the important abnormalities underlying this disease. Recently, several reports have suggested that hypoparathyroidism reflects, at least in part, a state of malnutrition and contributes to the poor prognosis of patients on hemodialysis and chronic ambulatory peritoneal dialysis. Such a risk of survival may result not only from the malnutritional state, but also from unknown mechanisms resulting from parathyroid hormone (PTH) deficiency, or from other abnormalities that suppress PTH secretion. Another major abnormality underlying adynamic bone disease is the skeletal resistance to PTH in patients with uremia. Owing to the recent research on bone turnover at the molecular level, several new mechanisms for this abnormality have been elucidated. Correction of this 'skeletal resistance to PTH' will lead to the optimal management of parathyroid function and bone turnover in the future.