[Rapidly developing bone destruction in a patient with type 1 Gaucher disease].

The authors report on a 25 year-old male Gaucher patient who developed rapid bone deterioration. The patient was splenectomised at age 3 and had no signs and symptoms of bone involvement for more than 20 years. In addition to the infarction in the right tibia, severe bone necrosis was detected in components of the left hip. This report suggests that bone deterioration may develop insidiously at any time in Gaucher patients, and that long-term and regular follow up is warranted.

The authors report on a

    25 year-old
    AGE

    male
    GENDER

    Gaucher
    DIAGNOSIS

 patient who developed

    rapid bone deterioration
    SYMPTOMS

. The patient was

    splenectomised
    MEDICATION

 at

    age 3
    AGE

 and had

    no signs and symptoms of bone involvement
    NEG_FINDINGS

    for more than 20 years
    NEG_FINDINGS

. In addition to the

    infarction in the right tibia
    SYMPTOMS

,

    severe bone necrosis was detected in components of the left hip
    SYMPTOMS

. This report suggests that

    bone deterioration
    SYMPTOMS

 may develop insidiously at any time in

    Gaucher
    DIAGNOSIS

 patients, and that long-term and regular follow up is warranted.


Splenic lymphoma arising in a patient with Gaucher disease. A case report and review of the literature.

Patients with Gaucher disease have an increased risk of malignancies, especially the lymphoreticular type. To our knowledge, this is the first reported case of Gaucher disease diagnosed during the workup and diagnosis of a splenic marginal-zone lymphoma with progression to diffuse large B-cell lymphoma. There are several theories as to how Gaucher disease leads to malignancies. The accumulated glucocerebroside in the reticuloendothelial organs, histologically visible as Gaucher cells, is thought to provide chronic antigenic stimulus to the immune system. Polyclonal hypergammaglobulinemia develops, and monoclonal populations of lymphocytes and plasma cells may arise from this premalignant proliferative state. How Gaucher disease is related to nonlymphoid malignancies remains unclear.

Patients with

    Gaucher disease
    DIAGNOSIS

 have an increased risk of

    malignancies
    DIAGNOSIS

, especially the

    lymphoreticular type
    DIAGNOSIS

. To our knowledge, this is the first reported case of

    Gaucher disease
    DIAGNOSIS

 diagnosed during the workup and diagnosis of a

    splenic marginal-zone lymphoma
    DIAGNOSIS

 with progression to

    diffuse large B-cell lymphoma
    DIAGNOSIS

. There are several theories as to how

    Gaucher disease
    DIAGNOSIS

 leads to

    malignancies
    DIAGNOSIS

. The

    accumulated glucocerebroside in the reticuloendothelial organs, histologically visible as Gaucher cells
    MICROSCOPIC

, is thought to provide

    chronic antigenic stimulus to the immune system
    SYMPTOMS

.

    Polyclonal hypergammaglobulinemia
    BIOCHEMICAL

 develops, and

    monoclonal populations of lymphocytes and plasma cells
    MICROSCOPIC

 may arise from this

    premalignant proliferative state
    MICROSCOPIC

. How

    Gaucher disease
    DIAGNOSIS

 is related to

    nonlymphoid malignancies
    DIAGNOSIS

 remains unclear.

Gaucher disease
malignancies
lymphoreticular type
Gaucher disease
splenic marginal-zone lymphoma
diffuse large B-cell lymphoma
Gaucher disease
malignancies
Gaucher disease
nonlymphoid malignancies


The osteodystrophy of mucolipidosis type III and the effects of intravenous pamidronate treatment.

Mucolipidosis type III (ML III; McKusick 252600) is a rare lysosomal storage disease in which skeletal involvement is prominent, in particular the destruction of vertebral bodies and the femoral heads. We describe studies in two siblings with ML III that suggest the presence of a distinct metabolic bone disorder. Biochemical indices of bone turnover were increased, and transiliac bone biopsy demonstrated both trabecular osteopenia and marked subperiosteal bone resorption. Intravenous pamidronate treatment given monthly for a year was well tolerated and produced dramatic clinical effects, with reduction in bone pain and improvements in mobility, despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria. Bisphosphonate therapy may have an important role in the management of bone pain in ML III, as it does in the related lysosomal disorder of Gaucher disease.

    Mucolipidosis type III (ML III
    DIAGNOSIS

; McKusick 252600) is a

    rare lysosomal storage disease
    DIAGNOSIS

 in which

    skeletal involvement
    SYMPTOMS

 is prominent, in particular the

    destruction of vertebral bodies and the femoral heads
    SYMPTOMS

. We describe studies in two siblings with

    ML III
    DIAGNOSIS

 that suggest the presence of a distinct

    metabolic bone disorder
    DIAGNOSIS

.

    Biochemical indices of bone turnover were increased
    BIOCHEMICAL

, and

    transiliac bone biopsy
    PARACLINICAL

 demonstrated

    both trabecular osteopenia
    SYMPTOMS

 and

    marked subperiosteal bone resorption
    SYMPTOMS

.

    Intravenous pamidronate treatment given monthly for a year
    MEDICATION

 was well tolerated and produced

    dramatic clinical effects
    SYMPTOMS

, with

    reduction in bone pain
    SYMPTOMS

 and

    improvements in mobility
    SYMPTOMS

,

    despite incomplete suppression of bone resorption as assessed by biochemical, radiographic and histological criteria
    NEG_FINDINGS

.

    Bisphosphonate therapy
    MEDICATION

 may have an important role in the management of

    bone pain
    DIAGNOSIS

 in

    ML III
    DIAGNOSIS

, as it does in the related

    lysosomal disorder of Gaucher disease
    DIAGNOSIS

.

Mucolipidosis type III (ML III
rare lysosomal storage disease
ML III
metabolic bone disorder
bone pain
ML III
lysosomal disorder of Gaucher disease


Enzyme replacement therapy reduces Gaucher cell burden but may accelerate osteopenia in patients with type I disease - a histological study.

Enzyme replacement treatment (ERT) is effective in controlling the clinical and biochemical manifestation of type I Gaucher disease. Little is known on the evolution of bone marrow histology caused by ERT. We compared the pretreatment trephine bone marrow biopsies in five patients (F32, F41, F50, M55, and M46) with the control biopsies performed after 26-32 months of imiglucerase treatment. The planimetric estimates revealed significant decrease in Gaucher cell burden in all the patients. The post-ERT values ranged from 24% to 65% of the initial total volumes occupied by the Gaucher cells. This resulted mainly from disappearance of Gaucher cells, and to a lesser extent from their shrinkage. Normal hemopoiesis was markedly increased in four of five patients, fat tissue in all the five patients. Surprisingly, the estimated volumes of trabecular bone in the control biopsies were significantly smaller than in the pre-ERT trephines (0.61%, 0.64%, 0.64%, 0.97%, and 0.22% of the initial volumes, P = 0.043). The bone loss correlated rather with the degree of reconstitution of normal hemopoiesis than with the decrease in the Gaucher cell burden. The histological response did not correlate strictly with initial clinical parameters and the genotype, with different reactions to ERT in two sibs (cases 3 and 4). Particularly, ERT alleviated bone manifestations in all four patients with previous bone pains or fractures. ERT may accelerate progress of osteopenia in men and premenopausal women. The clinical significance of this phenomenon remains to be established. Its mechanism may be linked to increased osteolytic activity exerted directly or indirectly by regenerating hemopoietic cells.

    Enzyme replacement treatment (ERT)
    MEDICATION

 is effective in controlling the clinical and biochemical manifestation of

    type I Gaucher disease
    DIAGNOSIS

. Little is known on the evolution of bone marrow histology caused by

    ERT
    MEDICATION

. We compared the

    pretreatment trephine bone marrow biopsies
    PARACLINICAL

 in five patients (F32, F41, F50, M55, and M46) with the

    control biopsies
    PARACLINICAL

 performed after

    26-32 months of imiglucerase treatment
    MEDICATION

. The

    planimetric estimates
    PARACLINICAL

 revealed

    significant decrease in Gaucher cell burden
    MICROSCOPIC

 in all the patients. The

    post-ERT values ranged from 24% to 65% of the initial total volumes occupied by the Gaucher cells
    PARACLINICAL

. This resulted mainly from

    disappearance of Gaucher cells
    MICROSCOPIC

, and to a lesser extent from

    their shrinkage
    MICROSCOPIC

.

    Normal hemopoiesis was markedly increased
    BIOCHEMICAL

 in four of five patients,

    fat tissue
    MICROSCOPIC

 in all the five patients. Surprisingly, the

    estimated volumes of trabecular bone in the control biopsies were significantly smaller than in the pre-ERT trephines (0.61%, 0.64%, 0.64%, 0.97%, and 0.22% of the initial volumes
    MICROSCOPIC

, P = 0.043). The

    bone loss
    SYMPTOMS

 correlated rather with the degree of

    reconstitution of normal hemopoiesis
    BIOCHEMICAL

 than with the

    decrease in the Gaucher cell burden
    BIOCHEMICAL

. The histological response did not correlate strictly with initial clinical parameters and the genotype, with

    different reactions to ERT in two sibs (cases 3 and 4)
    FAMILY

. Particularly,

    ERT
    MEDICATION

    alleviated bone manifestations
    SYMPTOMS

 in all four patients with

    previous bone pains or fractures
    SYMPTOMS

.

    ERT
    MEDICATION

 may accelerate progress of

    osteopenia
    SYMPTOMS

 in

    men
    GENDER

 and

    premenopausal
    AGE

    women
    GENDER

. The clinical significance of this phenomenon remains to be established. Its mechanism may be linked to

    increased osteolytic activity
    BIOCHEMICAL

 exerted directly or indirectly by

    regenerating hemopoietic cells
    MICROSCOPIC

.

Enzyme replacement treatment (ERT)
ERT
26-32 months of imiglucerase treatment
ERT
ERT

bone loss
alleviated bone manifestations
previous bone pains or fractures
osteopenia


Enzyme therapy of gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies.

The clinical impact of neutralizing antibodies directed against the therapeutic enzyme was investigated in patients with Gaucher disease. Two patients with Gaucher disease type 1 were followed for their clinical progression during antibody development and clinical changes during tolerization. Patient 1 developed neutralizing antibodies to imiglucerase (GCase) at the 10th month of enzyme therapy. Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose enzyme (60 IU/kg/week) alone. Patient 1 continues to improve up to 100 months of enzyme therapy despite the presence of low level in vitro neutralizing antibodies. Patient 2 developed neutralizing antibodies to GCase at the 29th month of enzyme therapy that correlated with clinical deterioration. Clinical stabilization has been observed with increased enzyme therapy (60 IU/kg/week) even in the presence of the neutralizing antibodies. Patient 2 is the first to develop neutralizing antibodies after 12 months of enzyme therapy. Plasma chitotriosidase activities were not well correlated with the clinical course in either patient. The presence of neutralizing antibodies should be suspected in Gaucher disease patients on enzyme therapy who experience diminished response or deterioration. The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression.

The clinical impact of

    neutralizing antibodies directed against the therapeutic enzyme
    BIOCHEMICAL

 was investigated in patients with

    Gaucher disease
    DIAGNOSIS

. Two patients with

    Gaucher disease type 1
    DIAGNOSIS

 were followed for their clinical progression during antibody development and clinical changes during

    tolerization
    MEDICATION

. Patient 1 developed

    neutralizing antibodies to imiglucerase (GCase)
    BIOCHEMICAL

 at the 10th month

    of enzyme therapy
    MEDICATION

.

    Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose enzyme (60 IU/kg/week) alone
    MEDICATION

. Patient 1

    continues to improve
    SYMPTOMS

 up to

    100 months of enzyme therapy
    MEDICATION

    despite the presence of low level in vitro neutralizing antibodies
    NEG_FINDINGS

. Patient 2 developed

    neutralizing antibodies to GCase
    BIOCHEMICAL

 at the 29th month

    of enzyme therapy
    MEDICATION

 that correlated with

    clinical deterioration
    SYMPTOMS

.

    Clinical stabilization
    SYMPTOMS

 has been observed with

    increased enzyme therapy (60 IU/kg/week)
    MEDICATION

 even in the presence of the

    neutralizing antibodies
    BIOCHEMICAL

. Patient 2 is the first to develop

    neutralizing antibodies
    BIOCHEMICAL

 after

    12 months of enzyme therapy
    MEDICATION

.

    Plasma chitotriosidase activities were not well correlated with the clinical course
    NEG_FINDINGS

 in either patient. The presence of

    neutralizing antibodies
    BIOCHEMICAL

 should be suspected in

    Gaucher disease
    DIAGNOSIS

 patients on

    enzyme therapy
    MEDICATION

 who experience

    diminished response or deterioration
    SYMPTOMS

. The

    persistence of minimal amounts of in vitro neutralizing antibodies
    BIOCHEMICAL

 does

    not interfere with the therapeutic effectiveness
    NEG_FINDINGS

.

    Chitotriosidase
    NEG_FINDINGS

 is not a sensitive marker for the severity of disease or disease progression.

Gaucher disease
Gaucher disease type 1
Gaucher disease

continues to improve
clinical deterioration
Clinical stabilization
diminished response or deterioration


Lymphoplasmacytic lymphoma with monoclonal gammopathy-related pseudo-Gaucher cell infiltration in bone marrow and spleen--diagnostic and therapeutic dilemmas.

Gaucher-like cells have occasionally been described in various haematological malignancies including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma (MM) and chronic myelogenous leukaemia (CML). A special type of this phenomenon is crystal-storing histocytosis or the so-called pseudo-pseudo Gaucher cells (PPGC) in which crystalline protein storage in macrophages is induced by paraproteinemia. Here we describe a 54-year-old man with an initial suspicion of Gaucher disease and monoclonal IgA gammopathy in whom a correct diagnosis of lymphoplasmacytic lymphoma (LPL) with massive infiltration of bone marrow and spleen by PPGC was confirmed by immunological, ultrastructural and molecular characterisation. The activity of leukocyte beta-glucocerebrosidase was only slightly elevated (7.3 nmol/mg protein/1 h) which ruled out the diagnosis of classic Gaucher's disease. The patient received two courses of CHOP without improvement and anti-CD20 monoclonal antibody (rituximab) with only temporary stabilisation. Subsequently, he underwent splenectomy because of prolonged severe pancytopenia and a suspicion of hypersplenism. After splenectomy significant haematological improvement was observed. Following anti-CD20 therapy, changes in immunoprofile and morphology of tumour cells were evident. Before treatment the population of LPL was more divergent, with expression of LCA, CD20, CD38 and CD138. However, after the treatment, there were more mature plasma cells which no longer expressed CD20 antigen-this picture was more consistent with the diagnosis of plasma cell myeloma. Similarly, in the spleen there were no CD-20-positive cells evident. Finally, the patient received two courses of VAD vincristine, doxorubicin, dexamethasone) with further haematological improvement but complete response was not achieved.

    Gaucher-like cells
    MICROSCOPIC

 have occasionally been described in various

    haematological malignancies
    DIAGNOSIS

 including

    Hodgkin's disease
    DIAGNOSIS

,

    non-Hodgkin's lymphoma
    DIAGNOSIS

,

    multiple myeloma (MM)
    DIAGNOSIS

 and

    chronic myelogenous leukaemia (CML)
    DIAGNOSIS

. A special type of this phenomenon is

    crystal-storing histocytosis
    MICROSCOPIC

 or the so-called

    pseudo-pseudo Gaucher cells (PPGC)
    MICROSCOPIC

 in which

    crystalline protein storage in macrophages
    MICROSCOPIC

 is induced by

    paraproteinemia
    BIOCHEMICAL

. Here we describe a

    54-year-old
    AGE

    man
    GENDER

 with an initial suspicion of

    Gaucher disease
    DIAGNOSIS

 and

    monoclonal IgA gammopathy
    DIAGNOSIS

 in whom a correct diagnosis of

    lymphoplasmacytic lymphoma (LPL)
    MICROSCOPIC

 with

    massive infiltration of bone marrow and spleen by PPGC
    MICROSCOPIC

 was confirmed by

    immunological, ultrastructural and molecular characterisation
    PARACLINICAL

. The

    activity of leukocyte beta-glucocerebrosidase was only slightly elevated (7.3 nmol/mg protein/1 h)
    BIOCHEMICAL

 which

    ruled out the diagnosis of classic Gaucher's disease
    NEG_FINDINGS

. The patient

    received two courses of CHOP without improvement
    NEG_FINDINGS

 and

    anti-CD20 monoclonal antibody (rituximab) with only temporary stabilisation
    MEDICATION

. Subsequently,

    he
    GENDER

 underwent

    splenectomy
    MEDICATION

 because of

    prolonged severe pancytopenia
    BIOCHEMICAL

 and a suspicion of

    hypersplenism
    BIOCHEMICAL

. After

    splenectomy
    MEDICATION

    significant haematological improvement
    SYMPTOMS

 was observed. Following

    anti-CD20 therapy
    MEDICATION

,

    changes in immunoprofile and morphology of tumour cells
    MICROSCOPIC

 were evident. Before treatment the

    population of LPL was more divergent, with expression of LCA, CD20, CD38 and CD138
    MICROSCOPIC

. However, after the treatment,

    there were more mature plasma cells which no longer expressed CD20 antigen
    MICROSCOPIC

-this picture was more consistent with the diagnosis of

    plasma cell myeloma
    DIAGNOSIS

. Similarly, in the spleen there were

    no CD-20-positive cells evident
    NEG_FINDINGS

. Finally, the patient

    received two courses of VAD vincristine, doxorubicin, dexamethasone)
    MEDICATION

 with

    further haematological improvement
    SYMPTOMS

 but

    complete response was not achieved
    NEG_FINDINGS

.

haematological malignancies
Hodgkin's disease
non-Hodgkin's lymphoma
multiple myeloma (MM)
chronic myelogenous leukaemia (CML)
Gaucher disease
monoclonal IgA gammopathy
plasma cell myeloma

significant haematological improvement
further haematological improvement


Gaucher disease type I complicated with Parkinson's syndrome.

Gaucher disease type I is the so-called non-neuronal adult form of the autosomally inherited lysosomal storage disease. The simultaneous occurrence of Gaucher disease with Parkinson's syndrome has been reported to aggravate both disorders, leading to an unusually early onset and therapy resistance. Neurological alterations in Gaucher disease type I are mostly related to CNS bleeding and skeletal complications. The patient presented here was sensitive to combination therapy for 5 years.

    Gaucher disease type I
    DIAGNOSIS

 is the so-called

    non-neuronal adult form of the autosomally inherited
    DIAGNOSIS

    lysosomal storage disease
    DIAGNOSIS

. The

    simultaneous occurrence of Gaucher disease with Parkinson's syndrome
    DIAGNOSIS

 has been reported to aggravate both disorders, leading to an unusually early onset and

    therapy resistance
    NEG_FINDINGS

.

    Neurological alterations
    SYMPTOMS

 in

    Gaucher disease type I
    DIAGNOSIS

 are mostly related to

    CNS bleeding
    SYMPTOMS

 and

    skeletal complications
    SYMPTOMS

. The patient presented here was sensitive to

    combination therapy for 5 years
    MEDICATION

.

Neurological alterations
CNS bleeding
skeletal complications


Severe pathologic compression of three consecutive vertebrae in Gaucher's disease: a case report and review of the literature.

To date, only one patient with spinal affection of Gaucher's disease requiring surgery for spinal compression has been reported. We present an additional case with extensive affection of three consecutive vertebral bodies, and present a review of the literature relating to the management of therapy and follow-up of this disease.

To date, only one patient with

    spinal affection
    SYMPTOMS

 of

    Gaucher's disease
    DIAGNOSIS

 requiring

    surgery for spinal compression
    MEDICATION

 has been reported. We present an additional case with

    extensive affection of three consecutive vertebral bodies
    SYMPTOMS

, and present a review of the literature relating to the management of therapy and follow-up of this disease.


A patient with type 2 Gaucher's disease with respiratory disease.

A 5-month-old boy had respiratory problems and gastroesophageal reflux. Electron microscopy of a tracheal biopsy specimen showed accumulation of lamellar bodies in the columnar cells indicative of lysosomal storage disease. Subsequently, the child had neurologic symptoms and hepatosplenomegaly, and the diagnosis of Gaucher's disease type 2 was made.

A

    5-month-old
    AGE

    boy
    GENDER

 had

    respiratory problems
    SYMPTOMS

 and

    gastroesophageal reflux
    SYMPTOMS

.

    Electron microscopy of a tracheal biopsy specimen
    PARACLINICAL

 showed

    accumulation of lamellar bodies in the columnar cells indicative of lysosomal storage disease
    MICROSCOPIC

. Subsequently, the

    child
    AGE

 had

    neurologic symptoms
    SYMPTOMS

 and

    hepatosplenomegaly
    SYMPTOMS

, and the diagnosis of

    Gaucher's disease type 2
    DIAGNOSIS

 was made.

respiratory problems
gastroesophageal reflux
neurologic symptoms
hepatosplenomegaly


Rebound hepatosplenomegaly in type 1 Gaucher disease.

A 19-year-old male patient with type 1 Gaucher disease was put on regular biweekly infusions of alglucerase. After 1 yr of treatment, hepatic and splenic volumes decreased from 38 and 45 mL/kg to 31 and 34 mL/kg, respectively. In addition, hemoglobin concentration, platelet count and white cell count increased, acid phosphatase level decreased, and the patient gained weight and energy. Despite improvement, the patient refused enzyme replacement therapy (ERT) because of muscle rigidity, chest pain, trembling and anxiety, which he attributed to enzyme substitution. Two and 4.5 year after cessation of therapy, hepatic and splenic volumes increased to 36 and 53 mL/kg and to 53 and 110 mL/kg, respectively. The patient developed non-tractable hematuria because of compression and dislocation of the left kidney by the enlarged spleen, which necessitated splenectomy. This report suggests that cessation of ERT in Gaucher disease may result in severe and complicated rebound visceromegaly.

A

    19-year-old
    AGE

    male
    GENDER

 patient with

    type 1 Gaucher disease
    DIAGNOSIS

 was

    put on regular biweekly infusions of alglucerase
    MEDICATION

.

    After 1 yr of treatment
    MEDICATION

,

    hepatic and splenic volumes decreased from 38 and 45 mL/kg to 31 and 34 mL/kg
    SYMPTOMS

, respectively. In addition,

    hemoglobin concentration, platelet count and white cell count increased
    BIOCHEMICAL

,

    acid phosphatase level decreased
    BIOCHEMICAL

, and the patient

    gained weight and energy
    SYMPTOMS

.

    Despite improvement
    NEG_FINDINGS

, the patient

    refused enzyme replacement therapy (ERT)
    NEG_FINDINGS

 because of

    muscle rigidity
    SYMPTOMS

,

    chest pain
    SYMPTOMS

,

    trembling
    SYMPTOMS

 and

    anxiety, which he attributed to enzyme substitution
    NEG_FINDINGS

. Two and 4.5 year after

    cessation of therapy
    MEDICATION

,

    hepatic and splenic volumes increased to 36 and 53 mL/kg and to 53 and 110 mL/kg
    SYMPTOMS

, respectively. The patient developed

    non-tractable hematuria
    SYMPTOMS

 because of

    compression and dislocation of the left kidney by the enlarged spleen
    SYMPTOMS

, which necessitated

    splenectomy
    MEDICATION

. This report suggests that

    cessation of ERT
    MEDICATION

 in

    Gaucher disease
    DIAGNOSIS

 may result in

    severe and complicated rebound visceromegaly
    SYMPTOMS

.


Neonatal cholestasis and infantile Gaucher disease: a case report.

To report on clinical complications of liver disease occurring during Gaucher disease.

A case of Gaucher disease was revealed by neonatal cholestasis and early onset of portal hypertension.

At 7 d of age, a newborn was admitted for cholestasis associated with hepatosplenomegaly and thrombocytopenia. At that time, bone marrow aspirate and liver biopsy did not reveal any engorged cells. The clinical course was marked by early progressive portal hypertension, and the patient died of uncontrollable upper gastrointestinal bleeding. The histological results of the postmortem showed that Gaucher cells were present in the liver, spleen and bone marrow. The diagnosis was confirmed by enzymatic studies.

Isolated neonatal cholestasis could be the first sign of Gaucher disease. Gaucher disease should always be considered in such circumstances, even if, initially, the bone marrow aspirate and liver biopsy do not reveal any engorged cells.

To report on

    clinical complications of liver disease
    SYMPTOMS

 occurring during

    Gaucher disease
    DIAGNOSIS

.

A case of

    Gaucher disease
    DIAGNOSIS

 was revealed by

    neonatal
    AGE

    cholestasis
    SYMPTOMS

 and

    early onset of portal hypertension
    SYMPTOMS

.

    At 7 d of age
    AGE

, a

    newborn
    AGE

 was admitted for

    cholestasis
    DIAGNOSIS

 associated with

    hepatosplenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

. At that time,

    bone marrow aspirate and liver biopsy
    PARACLINICAL

    did not reveal any engorged cells
    NEG_FINDINGS

. The clinical course was marked by

    early progressive portal hypertension
    SYMPTOMS

, and the patient

    died
    SYMPTOMS

 of

    uncontrollable upper gastrointestinal bleeding
    SYMPTOMS

. The

    histological results of the postmortem
    PARACLINICAL

 showed that

    Gaucher cells were present in the liver, spleen and bone marrow
    MICROSCOPIC

. The diagnosis was confirmed by

    enzymatic studies
    PARACLINICAL

.

    Isolated neonatal cholestasis
    SYMPTOMS

 could be the first sign of

    Gaucher disease
    DIAGNOSIS

.

    Gaucher disease
    DIAGNOSIS

 should always be considered in such circumstances, even if, initially, the

    bone marrow aspirate
    PARACLINICAL

 and

    liver biopsy
    PARACLINICAL

    do not reveal any engorged cells
    NEG_FINDINGS

.

Gaucher disease
Gaucher disease
cholestasis
Gaucher disease
Gaucher disease

did not reveal any engorged cells
do not reveal any engorged cells


Gaucher disease associated with parkinsonism: four further case reports.

Type 1 Gaucher disease is considered the non-neuronopathic form of this autosomal recessively inherited lysosomal storage disease. We report the simultaneous occurrence of Gaucher disease with parkinsonian in four adult patients. The patients had a relatively early onset of parkinsonian manifestations, and their disease was rapidly progressive and refractory to therapy. Each had a different Gaucher genotype, although four alleles carried the common N370S mutation. No mutations were identified in the genes for parkin or alpha-synuclein. The concurrence of these two phenotypes, both in this series of patients and in others in the literature, suggests a shared pathway, modifier, or other genetic etiology.

    Type 1 Gaucher disease
    DIAGNOSIS

 is considered the

    non-neuronopathic
    DIAGNOSIS

 form of this

    autosomal recessively inherited
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

. We report the

    simultaneous occurrence of Gaucher disease with parkinsonian
    DIAGNOSIS

 in four

    adult
    AGE

 patients. The patients had a relatively

    early onset of parkinsonian manifestations
    SYMPTOMS

, and their disease was

    rapidly progressive
    SYMPTOMS

 and

    refractory to therapy
    NEG_FINDINGS

. Each had a

    different Gaucher genotype
    GENETICS

, although

    four alleles carried the common N370S mutation
    GENETICS

.

    No mutations were identified in the genes for parkin or alpha-synuclein
    NEG_FINDINGS

. The concurrence of these two phenotypes, both in this series of patients and in others in the literature, suggests a shared pathway, modifier, or other genetic etiology.


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.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare genetic disorder
    GENETICS

 characterized by

    lack or functional insufficiency of glucocerebrosidase
    BIOCHEMICAL

, an enzyme accountable for

    intracellular hydrolysis of glucosyl ceramide and other glycosphingolipids
    MICROSCOPIC

, which results in

    macrophage storage in the mononuclear-macrophage system
    MICROSCOPIC

. The severity of

    Gaucher's disease
    DIAGNOSIS

 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
    MICROSCOPIC

, but is specifically diagnosed by showing

    enzyme acid beta-glucosidase activity in a sample of blood leukocyte
    BIOCHEMICAL

    or cultured macrophages from skin biopsy
    MICROSCOPIC

. In the last 10 years, an

    enzyme replacement therapy (alglucerase)
    MEDICATION

 for the disease has been available, which has significantly changed approaches to its treatment. Here we report the case of a

    56-year-old
    AGE

    female
    GENDER

 patient with

    type I Gaucher's disease
    DIAGNOSIS

 who underwent

    surgery for subcapital hip fracture
    MEDICATION

 with

    subarachnoid anesthesia
    MEDICATION

.

    Type I Gaucher's disease
    DIAGNOSIS

 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
    MEDICATION

 of patients with

    type I Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease
Gaucher's disease
type I Gaucher's disease
Type I Gaucher's disease
type I Gaucher's disease


Gaucher's disease: morphological findings in a case studied with fine needle aspiration.

Fine needle aspiration (FNA) is a diagnostic tool whose inexpensiveness, simplicity and innocuousness have led it to be increasingly accepted in daily medical practice. This method, which is useful for the study of lesions that are accessible by radiological exploration or palpation, provides information about the cytological aspects of punctured lesions. Sometimes, such information can be extended to the histological area through study of cell blocks, true microbiopsies, which are of great diagnostic use. This was the technique used in the case described in the present report.

    Fine needle aspiration (FNA)
    PARACLINICAL

 is a diagnostic tool whose inexpensiveness, simplicity and innocuousness have led it to be increasingly accepted in daily medical practice. This method, which is useful for the study of lesions that are accessible by

    radiological exploration
    PARACLINICAL

 or

    palpation
    PARACLINICAL

, provides information about the cytological aspects of punctured lesions. Sometimes, such information can be extended to the

    histological area
    PARACLINICAL

 through

    study of cell blocks, true microbiopsies
    PARACLINICAL

, which are of great diagnostic use. This was the technique used in the case described in the present report.


Gaucher disease: in vivo evidence for allele dose leading to neuronopathic and nonneuronopathic phenotypes.

Gaucher disease, a common lysosomal storage disorder, is associated with mutations at the acid beta-glucosidase (GCase) locus. Two affected individuals are described to share a common mutant allele, but manifest different clinical categorical phenotypes. A 57-year-old female, with Gaucher disease type 1 and Cherokee ancestry, was homozygous for a rare mutant allele encoding Lys79Asn (K79N). A 2-year-old Caucasian male, with Gaucher disease type 3 and Cherokee ancestry, was a heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele). The shared alleles were identical as determined by complete gene sequencing, suggesting a founder effect. The discrepant phenotypes (types 1 and 3) in these two patients provide support for a threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.

    Gaucher disease
    DIAGNOSIS

, a common

    lysosomal storage disorder
    DIAGNOSIS

, is associated with

    mutations at the acid beta-glucosidase (GCase) locus
    GENETICS

. Two affected individuals are described to share a

    common mutant allele
    GENETICS

, but manifest different clinical categorical phenotypes. A

    57-year-old
    AGE

    female
    GENDER

, with

    Gaucher disease type 1
    DIAGNOSIS

 and

    Cherokee ancestry
    ETHNICITY

, was

    homozygous for a rare mutant allele encoding Lys79Asn (K79N)
    GENETICS

. A

    2-year-old
    AGE

    Caucasian
    ETHNICITY

    male
    GENDER

, with

    Gaucher disease type 3
    DIAGNOSIS

 and

    Cherokee ancestry
    ETHNICITY

, was a

    heteroallelic homozygote for this same allele (K79N) and a novel complex mutation (null allele)
    GENETICS

.

    The shared alleles were identical
    GENETICS

 as determined by

    complete gene sequencing
    PARACLINICAL

, suggesting a

    founder effect
    GENETICS

. The

    discrepant phenotypes (types 1 and 3)
    SYMPTOMS

 in these two patients provide support for a

    threshold of residual activity necessary to "protect" the central nervous system (CNS) from the pathogenic effects of Gaucher disease
    BIOCHEMICAL

, indicating an allele dose-effect. Designation of genotype associations with specific phenotypes must be assessed with this perspective.

Gaucher disease
lysosomal storage disorder
Gaucher disease type 1
Gaucher disease type 3

Cherokee ancestry
Caucasian
Cherokee ancestry


Enzyme replacement therapy for Gaucher Disease: the only experience in Malaysia.

Gaucher Disease may now be treated with enzyme replacement therapy (ERT) or bone marrow transplantation (BMT). Both have their advantages and disadvantages. Results with BMT are curative when successful but limited by the scarcity of an appropriate donor. ERT offers very good relief of symptoms but treatment is lifelong and cost of treatment exorbitant. Patients in developing countries are particularly disadvantaged and management remains a dilemma for both doctor and patient.

    Gaucher Disease
    DIAGNOSIS

 may now be treated with

    enzyme replacement therapy (ERT)
    MEDICATION

 or

    bone marrow transplantation (BMT)
    MEDICATION

. Both have their advantages and disadvantages. Results with

    BMT
    MEDICATION

 are curative when successful but limited by the scarcity of an appropriate donor.

    ERT
    MEDICATION

 offers

    very good relief of symptoms
    SYMPTOMS

 but

    treatment is lifelong
    MEDICATION

 and cost of treatment exorbitant. Patients in developing countries are particularly disadvantaged and management remains a dilemma for both doctor and patient.

enzyme replacement therapy (ERT)
bone marrow transplantation (BMT)
BMT
ERT
treatment is lifelong


Cerebellar granular layer aplasia in congenital hydrocephalus.

An unusual case of cerebellar granular layer aplasia is reported. A 5-year-old boy was born with hydrocephalus and a peritoneal drainage shunt was placed after the delivery. Symptoms of cerebral paralysis, impaired mental function and cerebellar ataxia had developed gradually. Patient's karyotype was 46,XY. Laboratory tests for cytomegalovirus, Herpes simplex virus, Toxoplasma gondii, human immunodeficiency virus, rubella and hepatitis B virus were negative. Further laboratory investigation showed no signs of Tay-Sachs disease, Niemann-Pick disease, Gaucher disease, phenylketonuria, galactosemia or glycogen storage disease. No congenital malformations were traced in other family members for three generations. Radiation exposure and infections during the pregnancy were refuted.

An unusual case of

    cerebellar granular layer aplasia
    SYMPTOMS

 is reported. A

    5-year-old
    AGE

    boy
    GENDER

 was born with

    hydrocephalus
    DIAGNOSIS

 and a

    peritoneal drainage shunt was placed after the delivery
    MEDICATION

. Symptoms of

    cerebral paralysis
    SYMPTOMS

,

    impaired mental function
    SYMPTOMS

 and

    cerebellar ataxia
    SYMPTOMS

 had developed gradually. Patient's

    karyotype was 46,XY
    GENETICS

.

    Laboratory tests for cytomegalovirus, Herpes simplex virus, Toxoplasma gondii, human immunodeficiency virus, rubella and hepatitis B virus were negative
    NEG_FINDINGS

. Further

    laboratory investigation
    PARACLINICAL

 showed

    no signs of Tay-Sachs disease, Niemann-Pick disease, Gaucher disease
    NEG_FINDINGS

,

    phenylketonuria
    DIAGNOSIS

,

    galactosemia
    DIAGNOSIS

    or glycogen storage disease
    NEG_FINDINGS

.

    No congenital malformations were traced in other family members for three generations
    FAMILY

.

    Radiation exposure and infections during the pregnancy were refuted
    NEG_FINDINGS

.

cerebellar granular layer aplasia
cerebral paralysis
impaired mental function
cerebellar ataxia


Enzyme replacement therapy in the management of longstanding skeletal and soft tissue salmonella infection in a patient with Gaucher's disease.

A splenectomised patient with Gaucher's disease who developed multiple foci of osteomyelitis and soft tissue abcesses, after a severe episode of group C salmonella sepsis, is described. Aggressive antibiotic treatment and surgical drainage had little effect and the patient's condition continued to deteriorate. With initiation of enzyme replacement therapy (ERT) in addition to specific antibiotic treatment, defervescence and gradual healing occurred. Complete resolution of the infection was seen after 15 months. The possible role of ERT in healing bacterial infections in Gaucher's disease is discussed.

A

    splenectomised
    MEDICATION

 patient with

    Gaucher's disease
    DIAGNOSIS

 who developed

    multiple foci of osteomyelitis and soft tissue abcesses
    SYMPTOMS

, after a

    severe episode of group C salmonella sepsis
    DIAGNOSIS

, is described.

    Aggressive antibiotic treatment and surgical drainage had little effect
    NEG_FINDINGS

 and the patient's condition

    continued to deteriorate
    SYMPTOMS

. With

    initiation of enzyme replacement therapy (ERT) in addition to specific antibiotic treatment
    MEDICATION

,

    defervescence
    SYMPTOMS

 and

    gradual healing
    SYMPTOMS

 occurred.

    Complete resolution of the infection
    SYMPTOMS

 was seen after

    15 months
    MEDICATION

. The possible role of

    ERT
    MEDICATION

 in

    healing bacterial infections
    DIAGNOSIS

 in

    Gaucher's disease
    DIAGNOSIS

 is discussed.


Multiple hypoechoic hepatic lesions in a patient with Gaucher disease.

The most common symptoms of Gaucher disease include hepatosplenomegaly and anemia and thrombocytopenia due to hypersplenism. We describe the case of a patient with Gaucher disease who had cachexia, massive hepatomegaly, and multiple focal hepatic lesions. The clinical and radiologic findings suggested malignancy. A biopsy specimen was taken from a hepatic lesion and revealed infiltration by Gaucher cells. We discuss our findings in light of the putative increased incidence of hematologic malignancies in patients with Gaucher disease.

The most common symptoms of

    Gaucher disease
    DIAGNOSIS

 include

    hepatosplenomegaly
    SYMPTOMS

 and

    anemia
    BIOCHEMICAL

 and

    thrombocytopenia
    BIOCHEMICAL

 due to

    hypersplenism
    BIOCHEMICAL

. We describe the case of a patient with

    Gaucher disease
    DIAGNOSIS

 who had

    cachexia
    SYMPTOMS

,

    massive hepatomegaly
    SYMPTOMS

, and

    multiple focal hepatic lesions
    SYMPTOMS

. The clinical and radiologic findings suggested

    malignancy
    DIAGNOSIS

. A

    biopsy specimen was taken from a hepatic lesion
    PARACLINICAL

 and revealed

    infiltration by Gaucher cells
    MICROSCOPIC

. We discuss our findings in light of the putative increased incidence of

    hematologic malignancies
    DIAGNOSIS

 in patients with

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
Gaucher disease
malignancy
hematologic malignancies
Gaucher disease

hepatosplenomegaly
cachexia
massive hepatomegaly
multiple focal hepatic lesions


Mesenteric mass in a young girl--an unusual site for Gaucher's disease.

We report the first case of a child with Gaucher's disease and a large mesenteric mass, confirmed histologically to be Gaucher's cell infiltrates. We describe the radiological findings and discuss further management. The advent of enzyme replacement therapy has prolonged survival and the emergence of previously undocumented manifestations of the disease is being observed. The radiologist and clinician should be alert to the possible development of these new problems and the fact that in Gaucher's disease a palpable right upper-quadrant mass need not necessarily represent hepatomegaly.

We report the first case of a

    child
    AGE

 with

    Gaucher's disease
    DIAGNOSIS

 and a

    large mesenteric mass
    SYMPTOMS

, confirmed histologically to be

    Gaucher's cell infiltrates
    MICROSCOPIC

. We describe the radiological findings and discuss further management. The advent of

    enzyme replacement therapy
    MEDICATION

 has prolonged survival and the emergence of previously undocumented manifestations of the disease is being observed. The

    radiologist
    PARACLINICAL

 and clinician should be alert to the possible development of these new problems and the fact that in

    Gaucher's disease
    DIAGNOSIS

 a

    palpable right upper-quadrant mass
    SYMPTOMS

 need not necessarily represent

    hepatomegaly
    NEG_FINDINGS

.

large mesenteric mass
palpable right upper-quadrant mass


Thrombocytosis associated with enzyme replacement therapy in Gaucher disease.

We describe a patient with an intact spleen and moderately severe symptoms of Gaucher disease in whom, after initiation of (low-dose) enzyme replacement therapy (ERT), thrombocytosis (720 x 10(9)/l) was documented. Checking the International Gaucher Registry database revealed that this patient is the only nonsplenectomized patient of more than 1,000 treated patients to experience ERT-induced thrombocytosis. Platelet counts dropped immediately after the discontinuation of ERT.

We describe a patient with an

    intact spleen
    SYMPTOMS

 and

    moderately severe symptoms
    SYMPTOMS

 of

    Gaucher disease
    DIAGNOSIS

 in whom, after

    initiation of (low-dose) enzyme replacement therapy (ERT)
    MEDICATION

,

    thrombocytosis (720 x 10(9)/l)
    BIOCHEMICAL

 was documented. Checking the International Gaucher Registry database revealed that this patient is the only

    nonsplenectomized
    MEDICATION

 patient of more than 1,000 treated patients to experience

    ERT-induced thrombocytosis
    BIOCHEMICAL

.

    Platelet counts dropped immediately after the discontinuation of ERT
    BIOCHEMICAL

.

intact spleen
moderately severe symptoms


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.

    Total hip arthroplasty
    MEDICATION

 in

    Gaucher's disease
    DIAGNOSIS

 has been associated with high rates of loosening after all types

    of arthroplasty
    MEDICATION

. We present a patient with

    type 1 Gaucher's disease
    DIAGNOSIS

 who underwent

    revision cemented total hip arthroplasty
    MEDICATION

 for

    aseptic loosening
    SYMPTOMS

 after

    12 months of enzyme replacement therapy
    MEDICATION

.

    Major osteolysis
    SYMPTOMS

 was managed by

    impaction morcellized bone grafting
    MEDICATION

. An

    excellent clinical and radiographic
    SYMPTOMS

 result was obtained at 5-year

    follow-up
    PARACLINICAL

.

    Enzyme replacement therapy combined with modern revision techniques
    MEDICATION

 may offer improved outcomes for patients with

    Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease
type 1 Gaucher's disease
Gaucher's disease

aseptic loosening
Major osteolysis
excellent clinical and radiographic


Gaucher's disease with myocardial involvement in pregnancy.

Described originally in 1882, Gaucher's disease is the most prevalent of storage disorders. This autosomal recessive disease is caused by a defective gene responsible for coding the beta-glucosidase enzyme, essential in the hydrolysis of glucosylceramide in glucose and ceramide. The accumulation of glucosylceramide in the lysosomes of the reticuloendothelial system produces a heterogeneous clinical picture with neurological involvement, liver and spleen enlargement, hematological disorders and bone lesions.

Two pregnancies of a patient with Gaucher's disease are presented. The patient, who had been asymptomatic following earlier splenectomy, developed congestive heart failure due to myocardial involvement at the beginning of her first pregnancy, and responded to conservative treatment. In spite of this complication and also chronic anemia, hepatomegaly and ascites due to portal hypertension, the patient had two successful pregnancies with good perinatal results. No hemorrhagic complications were observed.

Described originally in 1882,

    Gaucher's disease
    DIAGNOSIS

 is the most prevalent of

    storage disorders
    DIAGNOSIS

. This

    autosomal recessive disease
    GENETICS

 is caused by a

    defective gene responsible for coding the beta-glucosidase enzyme
    GENETICS

, essential in the

    hydrolysis of glucosylceramide in glucose and ceramide
    BIOCHEMICAL

. The

    accumulation of glucosylceramide in the lysosomes of the reticuloendothelial system
    MICROSCOPIC

 produces a heterogeneous clinical picture with

    neurological involvement
    SYMPTOMS

,

    liver and spleen enlargement
    SYMPTOMS

,

    hematological disorders
    SYMPTOMS

 and

    bone lesions
    SYMPTOMS

.

Two

    pregnancies
    MEDICATION

 of a patient with

    Gaucher's disease
    DIAGNOSIS

 are presented. The patient, who had been

    asymptomatic following earlier splenectomy
    NEG_FINDINGS

, developed

    congestive heart failure due to myocardial involvement
    SYMPTOMS

 at the beginning of her first

    pregnancy
    DIAGNOSIS

, and responded to

    conservative treatment
    MEDICATION

. In spite of this complication and also

    chronic anemia
    BIOCHEMICAL

,

    hepatomegaly
    SYMPTOMS

 and

    ascites
    SYMPTOMS

 due to

    portal hypertension
    SYMPTOMS

, the patient had

    two successful pregnancies
    MEDICATION

 with

    good perinatal results
    SYMPTOMS

.

    No hemorrhagic complications
    NEG_FINDINGS

 were observed.

Gaucher's disease
storage disorders
Gaucher's disease
pregnancy

pregnancies
conservative treatment
two successful pregnancies


Is it possible to identify siblings by studying bone marrow under a microscope? Two unusual cases of Gaucher disease.

Two cases of Gaucher disease have been reported in siblings, in whom an unusual similar histological pattern permitted the pathologist (BP) to identify family relation of patients bearing different names.

Two cases of

    Gaucher disease
    DIAGNOSIS

 have been reported in siblings, in whom an

    unusual similar histological pattern
    SYMPTOMS

 permitted the

    pathologist (BP)
    PARACLINICAL

 to identify

    family relation of patients bearing different names
    FAMILY

.


Application of delayed extraction-matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in pericardial fluid, peritoneal fluid and serum from Gaucher disease patients.

Gaucher disease is a glycolipid storage disorder characterized by the accumulation of glucosylceramide. Using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE-MALDI-TOF-MS), we analyzed sphingolipids in pericardial fluid, peritoneal fluid, and serum from two patients with Gaucher disease. Crude lipids were extracted from 1 ml each of pericardial fluid, peritoneal fluid, and serum with chloroform and methanol. After mild alkaline treatment of the crude lipids, a sphingolipid fraction was prepared and analyzed by DE-MALDI-TOF-MS. The results were as follows: (a) in all the specimens, peaks of ceramide monohexoside and sphingomyelin were detected in both the controls and Gaucher disease patients; (b) in pericardial fluid, peritoneal fluid, and serum, the ceramide monohexoside/sphingomyelin ratio was increased in the Gaucher disease patients compared with in the controls. It was indicated that the accumulation of ceramide monohexoside in such samples from Gaucher disease patients can be easily detected with this DE-MALDI-TOF-MS method.

    Gaucher disease
    DIAGNOSIS

 is a

    glycolipid storage disorder
    DIAGNOSIS

 characterized by the

    accumulation of glucosylceramide
    MICROSCOPIC

. Using

    delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE-MALDI-TOF-MS)
    PARACLINICAL

, we

    analyzed sphingolipids in pericardial fluid, peritoneal fluid, and serum
    MICROSCOPIC

 from two patients with

    Gaucher disease
    DIAGNOSIS

.

    Crude lipids were extracted from 1 ml each of pericardial fluid, peritoneal fluid, and serum with chloroform and methanol
    MICROSCOPIC

. After

    mild alkaline treatment of the crude lipids
    MEDICATION

, a

    sphingolipid fraction was prepared and analyzed by DE-MALDI-TOF-MS
    PARACLINICAL

. The results were as follows: (a) in all the specimens,

    peaks of ceramide monohexoside and sphingomyelin were detected
    MICROSCOPIC

 in both the controls and

    Gaucher disease
    DIAGNOSIS

 patients; (b)

    in pericardial fluid, peritoneal fluid, and serum, the ceramide monohexoside/sphingomyelin ratio was increased
    MICROSCOPIC

 in the

    Gaucher disease
    DIAGNOSIS

 patients compared with in the controls. It was indicated that the

    accumulation of ceramide monohexoside in such samples
    MICROSCOPIC

 from

    Gaucher disease
    DIAGNOSIS

 patients can be easily detected with this

    DE-MALDI-TOF-MS method
    PARACLINICAL

.

Gaucher disease
glycolipid storage disorder
Gaucher disease
Gaucher disease
Gaucher disease
Gaucher disease


Failure of resting echocardiography and cardiac catheterization to identify pulmonary hypertension in two patients with type I Gaucher disease.

Pulmonary hypertension (PHT) is a complication of Gaucher disease. Screening with echocardiography is recommended for Gaucher patients. Two patients naive to enzyme replacement therapy are presented in whom resting echocardiography revealed no evidence of PHT. One of the patients also had normal pulmonary artery pressures at cardiac catheterization. The diagnosis of PHT was made with open lung biopsy in one patient and dobutamine echocardiography in the other. In both cases, diagnosis of PHT altered patient management. Resting echocardiographic assessment may fail to identify PHT in patients with Gaucher disease.

    Pulmonary hypertension (PHT)
    SYMPTOMS

 is a complication of

    Gaucher disease
    DIAGNOSIS

.

    Screening with echocardiography
    PARACLINICAL

 is recommended for

    Gaucher
    DIAGNOSIS

 patients. Two patients

    naive to enzyme replacement therapy
    MEDICATION

 are presented in whom

    resting echocardiography
    PARACLINICAL

 revealed

    no evidence of PHT
    NEG_FINDINGS

. One of the patients also had

    normal pulmonary artery pressures at cardiac catheterization
    NEG_FINDINGS

. The diagnosis of

    PHT
    DIAGNOSIS

 was made with

    open lung biopsy
    PARACLINICAL

 in one patient and

    dobutamine echocardiography
    PARACLINICAL

 in the other. In both cases, diagnosis of

    PHT
    DIAGNOSIS

 altered patient management.

    Resting echocardiographic assessment
    PARACLINICAL

 may

    fail to identify PHT
    NEG_FINDINGS

 in patients with

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
Gaucher
PHT
PHT
Gaucher disease


Gaucher disease with nephrotic syndrome: response to enzyme replacement therapy.

Nephrotic syndrome in patients with Gaucher disease is rare; most of the few reported cases have had a well-defined glomerulopathy often with Gaucher cells in the glomeruli. We report the case of a 54-year-old woman with Gaucher disease, who had splenectomy at age 25, preeclampsia with renal biopsy disclosing only endotheliosis at age 32, and improvement of proteinuria and reappearance of heavy proteinuria (7.2 g/24 h) at age 41. Renal biopsy disclosed Gaucher cells in glomeruli and interstitium. The patient did not receive therapy specifically for glomerular disease. Enzyme replacement, begun 4 years later and maintained until now, was associated with amelioration of systemic symptoms and virtual disappearance of proteinuria with a follow-up of 10 years. This case apparently is the first instance of nephrotic syndrome consequent to Gaucher disease itself and successful treatment with specific enzyme replacement.

    Nephrotic syndrome
    DIAGNOSIS

 in patients with

    Gaucher disease
    DIAGNOSIS

 is rare; most of the few reported cases have had a well-defined

    glomerulopathy
    DIAGNOSIS

 often with

    Gaucher cells in the glomeruli
    MICROSCOPIC

. We report the case of a

    54-year-old
    AGE

    woman
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

, who had

    splenectomy
    MEDICATION

 at

    age 25
    AGE

,

    preeclampsia
    DIAGNOSIS

 with

    renal biopsy
    PARACLINICAL

 disclosing

    only endotheliosis
    MICROSCOPIC

 at

    age 32
    AGE

, and

    improvement of proteinuria
    BIOCHEMICAL

 and

    reappearance of heavy proteinuria (7.2 g/24 h)
    BIOCHEMICAL

 at

    age 41
    AGE

.

    Renal biopsy
    PARACLINICAL

 disclosed

    Gaucher cells in glomeruli and interstitium
    MICROSCOPIC

. The patient

    did not receive therapy specifically for glomerular disease
    NEG_FINDINGS

.

    Enzyme replacement
    MEDICATION

, begun 4 years later and maintained until now, was associated with

    amelioration of systemic symptoms
    SYMPTOMS

 and

    virtual disappearance of proteinuria
    BIOCHEMICAL

 with a

    follow-up of 10 years
    PARACLINICAL

. This case apparently is the first instance of

    nephrotic syndrome
    DIAGNOSIS

 consequent to

    Gaucher disease
    DIAGNOSIS

 itself and successful treatment with

    specific enzyme replacement
    MEDICATION

.

Nephrotic syndrome
Gaucher disease
glomerulopathy
Gaucher disease
preeclampsia
nephrotic syndrome
Gaucher disease

splenectomy
Enzyme replacement
specific enzyme replacement


Gaucher's disease and fatal hepatic fibrosis despite prolonged enzyme replacement therapy.

We report on the case of a girl with type 1 Gaucher's disease, treated from age 9 to 15 with high-dose enzyme replacement therapy. This treatment did not avert the development of an extensive mutilating hepatic fibrosis warranting a liver transplantation, which was followed by death. In some cases of Gaucher's disease, alternative strategies such as fractionated or further increased ERT, gene therapy, or glucosyltransferase inhibitor should be explored.

We report on the case of a

    girl
    GENDER

 with

    type 1 Gaucher's disease
    DIAGNOSIS

,

    treated from age 9 to 15
    MEDICATION

 with

    high-dose enzyme replacement therapy
    MEDICATION

. This

    treatment did not avert the development of an extensive mutilating hepatic fibrosis
    NEG_FINDINGS

    warranting a liver transplantation
    NEG_FINDINGS

, which was followed by

    death
    SYMPTOMS

. In some cases of

    Gaucher's disease
    DIAGNOSIS

, alternative strategies such as

    fractionated or further increased ERT
    MEDICATION

,

    gene therapy
    MEDICATION

, or

    glucosyltransferase inhibitor
    MEDICATION

 should be explored.

type 1 Gaucher's disease
Gaucher's disease

treated from age 9 to 15
high-dose enzyme replacement therapy
fractionated or further increased ERT
gene therapy
glucosyltransferase inhibitor


Glycolipid analysis of different tissues and cerebrospinal fluid in type II Gaucher disease.

The lipid composition or the liver, spleen, brain, cerebellum and cerebrospinal fluid of a Gaucher disease type II patient who died at the age of 5 months was examined. The glycolipid analysis demonstrated a marked increase of total amounts not only in the peripheral tissues but also in the brain cerebellum and cerebrospinal fluid, with a prevalence of glucosylceramide. A reduction in gangliosides was observed in all the analysed tissues with a relative increase of GD3 in the nervous tissue. The fatty acid composition of glucosylceramide showed a prevalence of stearic acid in the central nervous system, while in the peripheral tissues palmitic acid was prevalent. This result suggests a different origin of the glucosylceramide stored in different tissues. The generalized reduction of gangliosides and their modified distribution together with the central nervous system GD3 increment represent a new observation. These data could be useful in the effort to clarify the pathophysiological mechanism of brain damage in neuronopathic Gaucher disease.

The

    lipid composition or the liver, spleen, brain, cerebellum and cerebrospinal fluid
    MICROSCOPIC

 of a

    Gaucher disease type II
    DIAGNOSIS

 patient who

    died
    SYMPTOMS

    at the age of 5 months
    AGE

 was examined. The

    glycolipid analysis
    MICROSCOPIC

 demonstrated a

    marked increase of total amounts not only in the peripheral tissues but also in the brain cerebellum and cerebrospinal fluid
    MICROSCOPIC

, with a

    prevalence of glucosylceramide
    MICROSCOPIC

. A

    reduction in gangliosides was observed in all the analysed tissues
    MICROSCOPIC

 with a

    relative increase of GD3 in the nervous tissue
    MICROSCOPIC

. The

    fatty acid composition of glucosylceramide
    MICROSCOPIC

 showed a

    prevalence of stearic acid in the central nervous system
    MICROSCOPIC

, while

    in the peripheral tissues palmitic acid was prevalent
    MICROSCOPIC

. This result suggests a different origin of the

    glucosylceramide stored in different tissues
    MICROSCOPIC

. The

    generalized reduction of gangliosides and their modified distribution
    MICROSCOPIC

 together with the

    central nervous system GD3 increment
    MICROSCOPIC

 represent a new observation. These data could be useful in the effort to clarify the pathophysiological mechanism of

    brain damage
    SYMPTOMS

 in

    neuronopathic Gaucher disease
    DIAGNOSIS

.

Gaucher disease type II
neuronopathic Gaucher disease


Variant Gaucher disease characterized by dysmorphic features, absence of cardiovascular involvement, laryngospasm, and compound heterozygosity for a novel mutation (D409H/C16S).

A 20-month-old girl with developmental delay, dysmorphic features, horizontal supranuclear gaze palsy, retrocollis, and episodes of laryngospasm was diagnosed with variant neuronopathic Gaucher disease. The diagnosis was made enzymatically. Mutation analysis showed compound heterozygosity for D409H and a previously unreported mutation C16S. The presence of dysmorphic features, laryngospasm, absent cardiac findings, and the severe clinical phenotype distinguishes our case from other cases of variant neuronopathic Gaucher disease. We therefore propose to extend the spectrum of variant Gaucher disease.

A

    20-month-old
    AGE

    girl
    GENDER

 with

    developmental delay
    SYMPTOMS

,

    dysmorphic features
    SYMPTOMS

,

    horizontal supranuclear gaze palsy
    SYMPTOMS

,

    retrocollis
    SYMPTOMS

, and

    episodes of laryngospasm
    SYMPTOMS

 was diagnosed with

    variant neuronopathic Gaucher disease
    DIAGNOSIS

. The diagnosis was made enzymatically.

    Mutation analysis
    PARACLINICAL

 showed compound heterozygosity for D409H and a previously unreported mutation C16S. The presence of

    dysmorphic features
    SYMPTOMS

,

    laryngospasm
    SYMPTOMS

,

    absent cardiac findings
    SYMPTOMS

, and the

    severe clinical phenotype
    SYMPTOMS

 distinguishes our case from other cases of

    variant neuronopathic Gaucher disease
    DIAGNOSIS

. We therefore propose to extend the spectrum of

    variant Gaucher disease
    DIAGNOSIS

.

developmental delay
dysmorphic features
horizontal supranuclear gaze palsy
retrocollis
episodes of laryngospasm
dysmorphic features
laryngospasm
absent cardiac findings
severe clinical phenotype

variant neuronopathic Gaucher disease
variant neuronopathic Gaucher disease
variant Gaucher disease


Application of delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in cultured skin fibroblasts from sphingolipidosis patients.

Sphingolipidoses are caused by defects of enzymes involved in the hydrolysis of sphingolipids. Using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS), we analyzed sphingolipids in cultured skin fibroblasts from patients with sphingolipidoses, including: (a) Farber disease (FD, acid ceramidase deficiency); (b) Gaucher disease (GD); (c) Niemann-Pick disease type C (NPDC); and (d) GM1-gangliosidosis (GM1G). Crude lipids were extracted from about 50 mg wet weight of cultured skin fibroblasts. After mild alkaline treatment, a sphingolipid fraction was prepared from the crude lipids and analyzed by DE MALDI-TOF-MS. The results were as follows: (a) in fibroblasts from the FD patient, the ceramide/sphingomyelin and ceramide/monohexosylceramide ratios were both significantly high; (b) in the GD patient, the glucosylceramide/sphingomyelin ratio was increased; on the other hand; (c) in the NPDC patient, the monohexosylceramide/sphingomyelin ratio was within normal range; and (d) in the GM1G patient, no specific data were obtained. Sphingolipids in cultured fibroblasts can be evaluated by DE MALDI-TOF-MS, whereas GM1-ganglioside or its asialo derivatives are not detectable. With this DE MALDI-TOF-MS method, ceramide or monohexosylceramide accumulating in cultured fibroblasts from cases of sphingolipidoses, such as FD and GD, respectively, can be easily detected.

    Sphingolipidoses
    DIAGNOSIS

 are caused by

    defects of enzymes involved in the hydrolysis of sphingolipids
    BIOCHEMICAL

. Using

    delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS)
    PARACLINICAL

, we

    analyzed sphingolipids in cultured skin fibroblasts
    MICROSCOPIC

 from patients with

    sphingolipidoses
    DIAGNOSIS

, including: (a)

    Farber disease (FD, acid ceramidase deficiency)
    DIAGNOSIS

; (b)

    Gaucher disease (GD)
    DIAGNOSIS

; (c)

    Niemann-Pick disease type C (NPDC)
    DIAGNOSIS

; and (d)

    GM1-gangliosidosis (GM1G)
    DIAGNOSIS

.

    Crude lipids were extracted from about 50 mg wet weight of cultured skin fibroblasts
    MICROSCOPIC

. After

    mild alkaline treatment
    MEDICATION

, a

    sphingolipid fraction was prepared from the crude lipids
    MICROSCOPIC

 and analyzed by

    DE MALDI-TOF-MS
    PARACLINICAL

. The results were as follows: (a)

    in fibroblasts
    MICROSCOPIC

 from the

    FD
    DIAGNOSIS

 patient,

    the ceramide/sphingomyelin and ceramide/monohexosylceramide ratios were both significantly high
    MICROSCOPIC

; (b) in the

    GD
    DIAGNOSIS

 patient, the

    glucosylceramide/sphingomyelin ratio was increased
    MICROSCOPIC

; on the other hand; (c) in the

    NPDC
    DIAGNOSIS

 patient,

    the monohexosylceramide/sphingomyelin ratio was within normal range
    BIOCHEMICAL

; and (d) in the

    GM1G
    DIAGNOSIS

 patient,

    no specific data were obtained
    NEG_FINDINGS

.

    Sphingolipids in cultured fibroblasts
    MICROSCOPIC

 can be evaluated by

    DE MALDI-TOF-MS
    PARACLINICAL

, whereas

    GM1-ganglioside or its asialo derivatives are not detectable
    NEG_FINDINGS

. With this

    DE MALDI-TOF-MS method
    PARACLINICAL

,

    ceramide or monohexosylceramide accumulating in cultured fibroblasts
    MICROSCOPIC

 from cases of

    sphingolipidoses
    DIAGNOSIS

, such as

    FD
    DIAGNOSIS

 and

    GD
    DIAGNOSIS

, respectively, can be easily detected.


Successful pregnancy outcome in a patient with Gaucher's disease and antiphospholipid syndrome.

Gaucher's disease is characterized by increased incidence of several autoantibodies, but autoimmune phenomena are rare in Gaucher patients. We report the first occurrence of Gaucher's disease and antiphospholipid syndrome in the same patient. A 27-year-old woman with hepatosplenomegaly and thrombocytopenia who was diagnosed as having Gaucher's disease with the genotype 1226G/1226G developed Coombs'-positive hemolytic anemia, recurrent abortions, and a high titer of IgG and IgM anticardiolipin antibodies constituting the diagnosis of antiphospholipid syndrome. A successful pregnancy outcome was achieved by combined therapy with aspirin, low-molecular-weight heparin, prednisone, and enzyme replacement therapy with imiglucerase. The possible pathogenicity of antiphospholipid antibodies found in the sera of many asymptomatic Gaucher patients should be further clarified.

    Gaucher's disease
    DIAGNOSIS

 is characterized by

    increased incidence of several autoantibodies
    BIOCHEMICAL

, but

    autoimmune phenomena
    SYMPTOMS

 are rare in

    Gaucher
    DIAGNOSIS

 patients. We report the first occurrence of

    Gaucher's disease
    DIAGNOSIS

 and

    antiphospholipid syndrome
    DIAGNOSIS

 in the same patient. A

    27-year-old
    AGE

    woman
    GENDER

 with

    hepatosplenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

 who was diagnosed as having

    Gaucher's disease with the genotype 1226G/1226G
    DIAGNOSIS

 developed

    Coombs'-positive hemolytic anemia
    BIOCHEMICAL

,

    recurrent abortions
    SYMPTOMS

, and a

    high titer of IgG and IgM anticardiolipin antibodies
    BIOCHEMICAL

 constituting the diagnosis of

    antiphospholipid syndrome
    DIAGNOSIS

. A

    successful pregnancy outcome
    SYMPTOMS

 was achieved by

    combined therapy with aspirin, low-molecular-weight heparin, prednisone
    MEDICATION

, and

    enzyme replacement therapy with imiglucerase
    MEDICATION

. The possible pathogenicity of

    antiphospholipid antibodies found in the sera
    BIOCHEMICAL

 of many asymptomatic

    Gaucher
    DIAGNOSIS

 patients should be further clarified.

autoimmune phenomena
hepatosplenomegaly
recurrent abortions
successful pregnancy outcome


Immunohistochemical and ultrastructural features of Gaucher's cells--five case reports.

Gaucher's disease is an autosomal recessive lysosomal storage disease resulting from glucocerebrosidase deficiency. In this report, five patients with adult Gaucher's disease are described. The clinical course of these patients was characterized by progressive diffuse aseptic necrosis in the large bones, so-called Erlenmeyer's flask deformity, and hepatosplenomegaly. Splenomegaly was accompanied by hypersplenism with anemia and thrombocytopenia, therefore splenectomy was performed. The diagnosis of Gaucher's disease was based on the finding of Gaucher's cells on bone marrow biopsy. Tissue blocks were cut and routinely processed. Slides staining for iron (Peris' blue) and PAS (periodic acid--Schiff) including immunohistochemical staining for CD68 and HLA-DR was performed in all five cases. Gaucher's cells were seen as large cells with granular or fibrillar distended cytoplasm, with the characteristic 'wrinkled tissue paper' appearance, and eccentric nuclei. PAS staining showed strongly positive granular or fibrillar material in the cytoplasm. Immunohistochemical stain for CD68 and HLA-DR helped identify isolated Gaucher's cells, which are hystiocytic in nature. This stain accentuates their fine linear striations. Small pieces were ultrastructurally analyzed.

    Gaucher's disease
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 resulting from

    glucocerebrosidase deficiency
    BIOCHEMICAL

. In this report, five patients with

    adult
    AGE

    Gaucher's disease
    DIAGNOSIS

 are described. The clinical course of these patients was characterized by

    progressive diffuse aseptic necrosis in the large bones
    SYMPTOMS

,

    so-called Erlenmeyer's flask deformity
    SYMPTOMS

, and

    hepatosplenomegaly
    SYMPTOMS

.

    Splenomegaly
    SYMPTOMS

 was accompanied by

    hypersplenism
    BIOCHEMICAL

 with

    anemia
    BIOCHEMICAL

 and

    thrombocytopenia
    BIOCHEMICAL

, therefore

    splenectomy
    MEDICATION

 was performed. The diagnosis of

    Gaucher's disease
    DIAGNOSIS

 was based on the finding of

    Gaucher's cells
    MICROSCOPIC

 on

    bone marrow biopsy
    PARACLINICAL

.

    Tissue blocks were cut and routinely processed
    PARACLINICAL

.

    Slides staining for iron (Peris' blue) and PAS (periodic acid--Schiff)
    PARACLINICAL

 including

    immunohistochemical staining for CD68 and HLA-DR
    PARACLINICAL

 was performed in all five cases.

    Gaucher's cells
    MICROSCOPIC

 were seen as

    large cells with granular or fibrillar distended cytoplasm, with the characteristic 'wrinkled tissue paper' appearance, and eccentric nuclei
    MICROSCOPIC

.

    PAS staining
    PARACLINICAL

 showed

    strongly positive granular or fibrillar material in the cytoplasm
    MICROSCOPIC

.

    Immunohistochemical stain for CD68 and HLA-DR
    PARACLINICAL

 helped identify

    isolated Gaucher's cells, which are hystiocytic in nature
    MICROSCOPIC

. This stain accentuates

    their fine linear striations
    MICROSCOPIC

.

    Small pieces
    MICROSCOPIC

 were

    ultrastructurally analyzed
    PARACLINICAL

.

Gaucher's disease
lysosomal storage disease
Gaucher's disease
Gaucher's disease

glucocerebrosidase deficiency
hypersplenism
anemia
thrombocytopenia


Early-onset severe neurological involvement and D409H homozygosity in Gaucher disease: outcome of enzyme replacement therapy.

Gaucher disease, in most cases, is the result of mutations in the beta-glucocerebrosidase gene. More than 150 such mutations have been identified so far. Mutation D409H is the second most frequent in Greek patients, accounting for 15.5% of all identified mutated alleles. D409H homozygosity has, so far, been associated with a unique type III subtype of Gaucher disease that is characterized by the presence of devastating valvular heart disease, oculomotor apraxia, and, sometimes, features normally associated with mucopolysaccharidoses or oligosaccharidoses. Common manifestations of Gaucher disease tend to be less evident or even absent. We report the first Greek patient bearing the D409H/D409H genotype with onset of the disease in the first months of life and a phenotype dominated by severe neurological involvement. Enzyme replacement therapy, while improving the hematological parameters and organomegaly, failed to improve or even arrest the neurological condition.

    Gaucher disease
    DIAGNOSIS

, in most cases, is the result of

    mutations in the beta-glucocerebrosidase gene
    GENETICS

. More than 150 such mutations have been identified so far.

    Mutation D409H
    GENETICS

 is the second most frequent in

    Greek
    ETHNICITY

 patients, accounting for 15.5% of all identified

    mutated alleles
    GENETICS

.

    D409H homozygosity
    GENETICS

 has, so far, been associated with a unique

    type III subtype of Gaucher disease
    DIAGNOSIS

 that is characterized by the presence of

    devastating valvular heart disease
    SYMPTOMS

,

    oculomotor apraxia
    SYMPTOMS

, and, sometimes,

    features normally associated with mucopolysaccharidoses or oligosaccharidoses
    SYMPTOMS

. Common manifestations of

    Gaucher disease
    DIAGNOSIS

 tend to be less evident or even absent. We report the first

    Greek
    ETHNICITY

 patient bearing the

    D409H/D409H genotype
    GENETICS

 with

    onset of the disease in the first months of life
    AGE

 and a phenotype dominated by

    severe neurological involvement
    SYMPTOMS

.

    Enzyme replacement therapy
    NEG_FINDINGS

,

    while improving the hematological parameters
    NEG_FINDINGS

 and

    organomegaly
    SYMPTOMS

,

    failed to improve or even arrest the neurological condition
    NEG_FINDINGS

.

Gaucher disease
type III subtype of Gaucher disease
Gaucher disease


Gaucher disease with pulmonary involvement in a 6-year-old girl: report of resolution of radiographic abnormalities on increasing dose of imiglucerase.

We report resolution of ground-glass appearance in high-resolution computed tomography of chest in a 6-year-old girl who had Gaucher disease with pulmonary involvement. This radiographic abnormality, which developed during the course of enzyme replacement therapy at doses between 20 to 60 U/kg/2 weeks, resolved when the dose was increased to 100 U/kg/2 weeks. This case illustrates the importance of trial of escalating dosage in the face of failure of response at lower doses.

We report

    resolution of ground-glass appearance in high-resolution computed tomography of chest
    SYMPTOMS

 in a

    6-year-old
    AGE

    girl
    GENDER

 who had

    Gaucher disease
    DIAGNOSIS

 with

    pulmonary involvement
    SYMPTOMS

. This

    radiographic abnormality
    SYMPTOMS

, which developed during the course of

    enzyme replacement therapy at doses between 20 to 60 U/kg/2 weeks
    MEDICATION

, resolved when

    the dose was increased to 100 U/kg/2 weeks
    MEDICATION

. This case illustrates the importance of

    trial of escalating dosage
    MEDICATION

 in the face of

    failure of response at lower doses
    NEG_FINDINGS

.


Heterologous expression and characterization of a rare Gaucher disease mutation (c.481C > T) from a Canadian aboriginal population using archival tissue samples.

Gaucher disease is an inherited sphingolipidosis resulting from deleterious mutations in the glucocerebrosidase gene. Through direct sequence analysis of genomic DNA from whole blood, fibroblast cultures, and formalin-fixed archival tissue samples, we have identified a rare homozygous C > T transition at cDNA nucleotide 481 of the glucocerebrosidase gene that results in a proline to serine amino acid substitution (p.P122S) in an aboriginal family of Cree descent in northern Alberta, Canada. A 13-month-old boy (JB) presented with severe visceral Gaucher disease and was treated with enzyme replacement. Currently, at 11 years he is developmentally delayed, with oculomotor apraxia. A cousin (MS) had previously died at age 7 from complications of severe Gaucher disease, before enzyme replacement therapy was available. She was also developmentally delayed. Heterologous expression of this allele using a baculovirus expression system revealed 19.2% of normal enzyme activity on the artificial substrate 4-methylumbelliferyl beta-d-glucopyranoside (4MUGP). Genotype/phenotype correlation is complicated by incomplete clinical details, enzyme replacement therapy, and the difficulty in excluding other genetic and environmental causes of developmental delay. However the development of oculomotor apraxia in JB suggests a Type 3 Gaucher phenotype. The only previous report of this mutation was also from a member of the Cree Nation, who has had a rather similar clinical course. A protocol is described for the isolation of genomic DNA from formalin-fixed bone marrow aspirate archival specimens obtained from the deceased for subsequent PCR-based sequence analysis and mutation detection. This technique will be applicable to the screening of this and other populations for the frequency of known Gaucher mutations where traditional DNA sources are unavailable.

    Gaucher disease
    DIAGNOSIS

 is an

    inherited sphingolipidosis
    GENETICS

 resulting from

    deleterious mutations in the glucocerebrosidase gene
    GENETICS

. Through

    direct sequence analysis of genomic DNA from whole blood, fibroblast cultures, and formalin-fixed archival tissue samples
    PARACLINICAL

, we have identified a

    rare homozygous C > T transition at cDNA nucleotide 481 of the glucocerebrosidase gene that results in a proline to serine amino acid substitution (p.P122S)
    GENETICS

 in an

    aboriginal
    ETHNICITY

 family of

    Cree descent
    ETHNICITY

 in

    northern Alberta
    ETHNICITY

,

    Canada
    ETHNICITY

. A

    13-month-old
    AGE

    boy
    GENDER

 (

    JB
    GENDER

) presented with

    severe visceral Gaucher disease
    DIAGNOSIS

 and was

    treated with enzyme replacement
    MEDICATION

. Currently,

    at 11 years
    AGE

    he
    GENDER

 is

    developmentally delayed
    SYMPTOMS

, with

    oculomotor apraxia
    SYMPTOMS

.

    A cousin (MS) had previously died at age 7 from complications of severe Gaucher disease
    FAMILY

, before

    enzyme replacement therapy
    MEDICATION

 was available.

    She
    GENDER

 was also

    developmentally delayed
    SYMPTOMS

. Heterologous expression of this allele using a baculovirus expression system revealed

    19.2% of normal enzyme activity on the artificial substrate 4-methylumbelliferyl beta-d-glucopyranoside (4MUGP)
    BIOCHEMICAL

. Genotype/phenotype correlation is complicated by incomplete clinical details,

    enzyme replacement therapy
    NEG_FINDINGS

, and the difficulty in

    excluding other genetic and environmental causes of developmental delay
    NEG_FINDINGS

. However the development of

    oculomotor apraxia
    SYMPTOMS

 in

    JB
    DIAGNOSIS

 suggests a

    Type 3 Gaucher phenotype
    DIAGNOSIS

. The only previous report of this mutation was also from a member of the

    Cree Nation
    ETHNICITY

, who has had a rather similar clinical course. A protocol is described for the

    isolation of genomic DNA from formalin-fixed bone marrow aspirate archival specimens
    PARACLINICAL

 obtained from the

    deceased
    PARACLINICAL

 for subsequent

    PCR-based sequence analysis and mutation detection
    PARACLINICAL

. This technique will be applicable to the screening of this and other populations for the frequency of known

    Gaucher mutations
    GENETICS

 where

    traditional DNA sources are unavailable
    NEG_FINDINGS

.

Gaucher disease
severe visceral Gaucher disease
JB
Type 3 Gaucher phenotype

aboriginal
Cree descent
northern Alberta
Canada
Cree Nation

treated with enzyme replacement
enzyme replacement therapy

developmentally delayed
oculomotor apraxia
developmentally delayed
oculomotor apraxia


Mutation analysis of the acid beta-glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase.

The beneficial effects of macrophage-targeted glucocerebrosidase (alglucerase, Ceredase) in patients with Gaucher disease are well established. A minority of recipients develop transient non-neutralizing antibodies to the exogenous enzyme. A 7-year-old patient with type 3 Gaucher disease, whose clinical course began to deteriorate while receiving alglucerase developed a progressively increasing titer of IgG antibody, that blocked the catalytic activity of alglucerase. We investigated the acid beta-glucosidase genotype in this patient. Direct sequencing of both cDNA and genomic PCR products was used to characterize the mutations underlying acid beta-glucosidase deficiency. The patient was shown to be a compound heterozygote for a previously reported missense mutation (G377S), and a novel single nucleotide deletion (g5255delT). The transcript originating from the latter allele was undetectable in RT-PCR experiments. We report the first characterization of a GBA genotype associated with the development of neutralizing antibody to alglucerase, in a patient affected with type 3 Gaucher disease. Our results may help to shed light on the mechanisms underlying this phenomenon which, in the rare instances where it occurs, hampers the efficacy of enzyme replacement therapy.

The beneficial effects of

    macrophage-targeted glucocerebrosidase (alglucerase, Ceredase)
    MEDICATION

 in patients with

    Gaucher disease
    DIAGNOSIS

 are well established. A minority of recipients develop

    transient non-neutralizing antibodies to the exogenous enzyme
    BIOCHEMICAL

. A

    7-year-old
    AGE

 patient with

    type 3 Gaucher disease
    DIAGNOSIS

, whose

    clinical course began to deteriorate
    SYMPTOMS

 while

    receiving alglucerase
    MEDICATION

 developed a

    progressively increasing titer of IgG antibody, that blocked the catalytic activity of alglucerase
    BIOCHEMICAL

. We investigated the

    acid beta-glucosidase genotype
    PARACLINICAL

 in this patient.

    Direct sequencing of both cDNA and genomic PCR products
    PARACLINICAL

 was used to characterize the mutations underlying

    acid beta-glucosidase deficiency
    BIOCHEMICAL

. The patient was shown to be a

    compound heterozygote for a previously reported missense mutation (G377S), and a novel single nucleotide deletion (g5255delT)
    GENETICS

.

    The transcript originating from the latter allele was undetectable
    GENETICS

 in

    RT-PCR experiments
    PARACLINICAL

. We report the first characterization of a

    GBA genotype
    GENETICS

 associated with the

    development of neutralizing antibody to alglucerase
    BIOCHEMICAL

, in a patient affected with

    type 3 Gaucher disease
    DIAGNOSIS

. Our results may help to shed light on the mechanisms underlying this phenomenon which, in the rare instances where it occurs, hampers the efficacy of

    enzyme replacement therapy
    MEDICATION

.

Gaucher disease
type 3 Gaucher disease
type 3 Gaucher disease


Gaucher disease type I: analysis of two cases with thalassemic facies and pulmonary arteriovenous fistulas.

Here we report two unusual patients with Gaucher disease type I. Both girls admitted with hepatosplenomegaly, growth retardation, and anemia at four and 2.5 years of age, and Gaucher cells were seen on bone marrow aspirates. Thalassemic face was first noted at 8 and 11 years of age, respectively, with frontal bossing and maxillary hypertrophia. Although they had unconjugated hyperbilirubinemia, high reticulocytes, polychromasia, and normoblasts on peripheral smear, other laboratory tests for hemolytic disease were negative. Radiological examination revealed typical bone involvement of Gaucher disease, as well as costal enlargement and obliteration of paranasal sinuses, the latter two reported in hemolytic diseases. Cyanosis, digital clubbing and recurrent lung infections led to contrast echocardiography that revealed diffuse pulmonary arteriovenous shunting in both. Diagnosis was confirmed by low leukocyte beta glucosidase levels and mutations N370S7/L444P (Case 1) and N370S/? (Case 2). These features, all reported for the first time, may show a new clinical course in Gaucher disease.

Here we report two unusual patients with Gaucher disease type I. Both

    girls
    GENDER

 admitted with

    hepatosplenomegaly
    SYMPTOMS

,

    growth retardation
    SYMPTOMS

, and

    anemia
    BIOCHEMICAL

 at

    four and 2.5 years of age
    AGE

, and

    Gaucher cells were seen on bone marrow aspirates
    MICROSCOPIC

.

    Thalassemic face
    SYMPTOMS

 was first noted at

    8 and 11 years of age
    AGE

, respectively, with

    frontal bossing
    SYMPTOMS

 and

    maxillary hypertrophia
    SYMPTOMS

. Although they had

    unconjugated hyperbilirubinemia
    BIOCHEMICAL

,

    high reticulocytes
    BIOCHEMICAL

,

    polychromasia
    BIOCHEMICAL

, and

    normoblasts on peripheral smear
    MICROSCOPIC

,

    other laboratory tests for hemolytic disease were negative
    NEG_FINDINGS

.

    Radiological examination
    PARACLINICAL

 revealed

    typical bone involvement
    SYMPTOMS

    of Gaucher disease
    MICROSCOPIC

, as well as

    costal enlargement
    SYMPTOMS

 and

    obliteration of paranasal sinuses
    SYMPTOMS

, the latter two reported in

    hemolytic diseases
    DIAGNOSIS

.

    Cyanosis
    SYMPTOMS

,

    digital clubbing
    SYMPTOMS

 and

    recurrent lung infections
    SYMPTOMS

 led to

    contrast echocardiography
    PARACLINICAL

 that revealed

    diffuse pulmonary arteriovenous shunting
    SYMPTOMS

 in both. Diagnosis was confirmed by

    low leukocyte beta glucosidase levels
    BIOCHEMICAL

 and

    mutations N370S7/L444P
    GENETICS

 (Case 1)

    and N370S/?
    GENETICS

 (Case 2). These features, all reported for the first time, may show a new clinical course in

    Gaucher disease
    DIAGNOSIS

.

anemia
unconjugated hyperbilirubinemia
high reticulocytes
polychromasia
low leukocyte beta glucosidase levels


Initiation of enzyme replacement therapy for an adult patient with asymptomatic type 1 Gaucher's disease.

A 27-year-old woman was admitted for further examination of thrombocytopenia. Symptoms were absent, but physical examination demonstrated hepatosplenomegaly without neurological abnormalities. Bone marrow examination revealed many Gaucher cells, and glucocerebrosidase activity from cultured skin fibroblasts was markedly reduced. A 1448C (L444P) mutation was detected on one allele of the glucocerebrosidase gene. Because magnetic resonance imaging (MRI) of the femora indicated severe infiltration of Gaucher cells into bone marrow, enzyme replacement therapy was initiated despite the absence of skeletal symptoms. Hematologic abnormalities, visceral and bone involvement have been improving. In cases of thrombocytopenia or hepatosplenomegaly, Gaucher's disease should be suspected.

A

    27-year-old
    AGE

    woman
    GENDER

 was admitted for further examination of

    thrombocytopenia
    BIOCHEMICAL

.

    Symptoms were absent
    NEG_FINDINGS

, but

    physical examination
    PARACLINICAL

 demonstrated

    hepatosplenomegaly
    SYMPTOMS

    without neurological abnormalities
    NEG_FINDINGS

.

    Bone marrow examination
    PARACLINICAL

 revealed

    many Gaucher cells
    MICROSCOPIC

, and

    glucocerebrosidase activity from cultured skin fibroblasts was markedly reduced
    BIOCHEMICAL

.

    A 1448C (L444P) mutation was detected on one allele of the glucocerebrosidase gene
    GENETICS

. Because

    magnetic resonance imaging (MRI) of the femora
    PARACLINICAL

 indicated

    severe infiltration of Gaucher cells into bone marrow
    MICROSCOPIC

,

    enzyme replacement therapy
    MEDICATION

 was initiated

    despite the absence of skeletal symptoms
    NEG_FINDINGS

.

    Hematologic abnormalities
    BIOCHEMICAL

,

    visceral and bone involvement
    SYMPTOMS

 have been improving. In cases of

    thrombocytopenia
    BIOCHEMICAL

 or

    hepatosplenomegaly
    SYMPTOMS

,

    Gaucher's disease
    DIAGNOSIS

 should be suspected.

hepatosplenomegaly
visceral and bone involvement
hepatosplenomegaly


Gaucher disease and parkinsonism: a phenotypic and genotypic characterization.

Among the many phenotypes associated with Gaucher disease, the inherited deficiency of glucocerebrosidase, are reports of patients with parkinsonian symptoms. The basis for this association is unknown, but could be due to alterations in the gene or gene region. The human glucocerebrosidase gene, located on chromosome 1q21, has a nearby pseudogene that shares 96% identity. Immediately adjacent to the glucocerebrosidase pseudogene is a convergently transcribed gene, metaxin, which has a pseudogene that is located just downstream to the glucocerebrosidase gene. We describe a patient with mild Gaucher disease but impaired horizontal saccadic eye movements who developed a tremor at age 42, followed by rapid deterioration of her gait. A pallidotomy at age 47 was unsuccessful. Her motor and cognitive deterioration progressed despite enzyme replacement therapy. Sequencing of the glucocerebrosidase gene identified mutations L444P and D409H. Southern blot analysis using the enzyme SspI showed that the maternal allele had an additional 17-kb band. PCR amplifications and sequencing of this fragment demonstrated a duplication which included the glucocerebrosidase pseudogene, metaxin gene, and a pseudometaxin/metaxin fusion. Gene alterations associated with this novel rearrangement, resulting from a crossover between the gene for metaxin and its pseudogene, could contribute to the atypical phenotype encountered in this patient.

Among the many phenotypes associated with

    Gaucher disease
    DIAGNOSIS

, the

    inherited deficiency of glucocerebrosidase
    GENETICS

, are reports of patients with

    parkinsonian symptoms
    SYMPTOMS

. The basis for this association is unknown, but could be due to

    alterations in the gene or gene region
    GENETICS

. The

    human glucocerebrosidase gene, located on chromosome 1q21, has a nearby pseudogene that shares 96% identity
    GENETICS

. Immediately adjacent

    to the glucocerebrosidase pseudogene
    GENETICS

 is a

    convergently transcribed gene, metaxin, which has a pseudogene that is located just downstream to the glucocerebrosidase gene
    GENETICS

. We describe a patient with

    mild Gaucher disease
    DIAGNOSIS

 but

    impaired horizontal saccadic eye movements
    SYMPTOMS

 who developed a

    tremor
    SYMPTOMS

 at

    age 42
    AGE

, followed by

    rapid deterioration of her gait
    SYMPTOMS

. A

    pallidotomy
    MEDICATION

 at

    age 47
    AGE

    was unsuccessful
    NEG_FINDINGS

.

    Her
    GENDER

    motor and cognitive deterioration
    SYMPTOMS

 progressed

    despite enzyme replacement therapy
    NEG_FINDINGS

.

    Sequencing of the glucocerebrosidase gene
    PARACLINICAL

 identified mutations L444P and D409H.

    Southern blot analysis using the enzyme SspI
    PARACLINICAL

 showed that

    the maternal allele had an additional 17-kb band
    GENETICS

.

    PCR amplifications and sequencing of this fragment
    PARACLINICAL

 demonstrated a

    duplication which included the glucocerebrosidase pseudogene, metaxin gene, and a pseudometaxin/metaxin fusion
    GENETICS

.

    Gene alterations
    GENETICS

 associated with this

    novel rearrangement, resulting from a crossover between the gene for metaxin and its pseudogene
    GENETICS

, could contribute to the atypical phenotype encountered in this patient.

was unsuccessful
despite enzyme replacement therapy


Bone, bone marrow, and MIBI scintigraphic findings in Gaucher's disease "bone crisis".

The authors report the utility of Tc-99m MIBI imaging in Gaucher's disease, which results in the accumulation of glucocerebroside in macrophages. Inflated macrophages, or Gaucher's cells, involve the reticuloendothelial organs.

A 38-year-old man with type I Gaucher's disease, splenectomy, and early bone involvement was examined for a low back "bone crisis." He had a history of total left hip replacement. Results of pelvic radiographs were normal. Magnetic resonance imaging showed complete infiltration of the bone marrow in the lumbar spine and the sacrum. The left iliac bone, the sacrum, and the adjacent part of L5 showed heterogeneously decreased uptake on bone scintigraphs. Hematopoietic bone marrow was absent in these regions and in the left femur. No infection of the prosthesis was revealed with labeled granulocytes.

Avascular necrosis in the left iliac bone was diagnosed, which is a very unusual location. There was no uptake of MIBI in the iliac bones or the femurs.

These findings suggest that MIBI may not be a good tool for the evaluation of medullary infiltration by Gaucher's cells.

The authors report the utility of

    Tc-99m MIBI imaging
    PARACLINICAL

 in

    Gaucher's disease
    DIAGNOSIS

, which results in the

    accumulation of glucocerebroside in macrophages
    MICROSCOPIC

.

    Inflated macrophages, or Gaucher's cells, involve the reticuloendothelial organs
    MICROSCOPIC

.

A

    38-year-old
    AGE

    man
    GENDER

 with

    type I Gaucher's disease
    DIAGNOSIS

,

    splenectomy
    MEDICATION

, and

    early bone involvement
    SYMPTOMS

 was examined for a

    low back "bone crisis
    SYMPTOMS

."

    He
    GENDER

 had a

    history of total left hip replacement
    MEDICATION

.

    Results of pelvic radiographs were normal
    NEG_FINDINGS

.

    Magnetic resonance imaging
    PARACLINICAL

 showed

    complete infiltration of the bone marrow in the lumbar spine and the sacrum
    MICROSCOPIC

.

    The left iliac bone, the sacrum, and the adjacent part of L5 showed heterogeneously decreased uptake on bone scintigraphs
    SYMPTOMS

.

    Hematopoietic bone marrow was absent in these regions and in the left femur
    NEG_FINDINGS

.

    No infection of the prosthesis was revealed with labeled granulocytes
    NEG_FINDINGS

.

    Avascular necrosis in the left iliac bone
    DIAGNOSIS

 was diagnosed, which is a very unusual location. There was

    no uptake of MIBI in the iliac bones or the femurs
    NEG_FINDINGS

.

These findings suggest that

    MIBI
    PARACLINICAL

 may not be a good tool for the evaluation of

    medullary infiltration by Gaucher's cells
    MICROSCOPIC

.

splenectomy
history of total left hip replacement


Pseudo-osteomyelitic crisis upon presentation of Gaucher disease.

We report on a 4-year-old boy adopted from Paraguay who presented with an acute onset of thigh pain. Initial clinical, imaging, and histopathologic findings suggested florid osteomyelitis. However, the development of pancytopenia on intravenous antibiotics prompted further investigation and the ultimate diagnosis of Gaucher disease. In retrospect, characteristic changes on conventional radiographic and MR images, as well as growth of a contaminant organism, pointed to the diagnosis of pseudo-osteomyelitis rather than osteomyelitis.

We report on a

    4-year-old
    AGE

    boy
    GENDER

 adopted from

    Paraguay
    ETHNICITY

 who presented with an

    acute onset of thigh pain
    SYMPTOMS

. Initial clinical,

    imaging
    PARACLINICAL

, and

    histopathologic findings
    PARACLINICAL

 suggested

    florid osteomyelitis
    DIAGNOSIS

. However, the development of

    pancytopenia
    BIOCHEMICAL

 on

    intravenous antibiotics
    MEDICATION

 prompted further investigation and the ultimate diagnosis of

    Gaucher disease
    DIAGNOSIS

. In retrospect,

    characteristic changes on conventional radiographic and MR images
    SYMPTOMS

, as well as

    growth of a contaminant organism
    MICROSCOPIC

, pointed to the diagnosis of

    pseudo-osteomyelitis
    DIAGNOSIS

 rather than

    osteomyelitis
    DIAGNOSIS

.

florid osteomyelitis
Gaucher disease
pseudo-osteomyelitis
osteomyelitis