Congenital ichthyosis with restrictive dermopathy and Gaucher disease: a new syndrome with associated prenatal diagnostic and pathology findings.

Since 1988, three nonrelated fatal cases of congenital ichthyosis associated with Gaucher disease have been described in Australia.

We present a case of Gaucher disease with congenital ichthyosis and restrictive dermopathy and describe the associated prenatal sonographic findings and pathology of this new syndrome.

The unusual association of congenital ichthyosis with lipid storage disease may be suspected prenatally. A high index of suspicion may prove this condition to be more common than previously thought.

Since 1988, three

    nonrelated fatal
    SYMPTOMS

 cases of

    congenital ichthyosis associated with Gaucher disease
    DIAGNOSIS

 have been described in

    Australia
    ETHNICITY

.

We present a case of

    Gaucher disease
    DIAGNOSIS

 with

    congenital ichthyosis
    SYMPTOMS

 and

    restrictive dermopathy
    SYMPTOMS

 and describe the associated

    prenatal sonographic
    PARACLINICAL

 findings and pathology of this new syndrome.

The unusual association of

    congenital ichthyosis
    DIAGNOSIS

 with

    lipid storage disease
    DIAGNOSIS

 may be suspected prenatally. A high index of suspicion may prove this condition to be more common than previously thought.

nonrelated fatal
congenital ichthyosis
restrictive dermopathy


Partial splenectomy in Gaucher's disease: follow-up report.

This is a follow-up report of three children who had partial splenectomy and are suffering from Gaucher's disease. A few years following partial splenectomy in every patient, the remaining spleen enlarged and hypersplenism reappeared; partial splenectomy did not prevent bone destruction if it already existed before partial splenectomy. Treatment with Ceredase parallel with partial splenectomy may have theoretical and practical advantages.

This is a follow-up report of three

    children
    AGE

 who had

    partial splenectomy
    MEDICATION

 and are suffering from

    Gaucher's disease
    DIAGNOSIS

. A few years following

    partial splenectomy
    MEDICATION

 in every patient, the

    remaining spleen enlarged
    SYMPTOMS

 and

    hypersplenism
    BIOCHEMICAL

    reappeared
    SYMPTOMS

;

    partial splenectomy
    MEDICATION

    did not prevent bone destruction if it already existed before partial splenectomy
    NEG_FINDINGS

.

    Treatment with Ceredase parallel with partial splenectomy
    MEDICATION

 may have theoretical and practical advantages.


Liver scintigraphy in a patient with Gaucher disease.

Liver scintigraphy including SPECT was performed in a patient with Gaucher disease and compared with other methods. Multiple photon-deficient areas in the liver and spleen were recognized, and in evaluating the reticuloendothelial system of the liver, liver SPECT image was superior to US, CT and MR images.

    Liver scintigraphy including SPECT
    PARACLINICAL

 was performed in a patient with

    Gaucher disease
    DIAGNOSIS

 and compared with other methods.

    Multiple photon-deficient areas in the liver and spleen
    MICROSCOPIC

 were recognized, and in

    evaluating the reticuloendothelial system of the liver
    PARACLINICAL

,

    liver SPECT image
    PARACLINICAL

 was superior to

    US
    PARACLINICAL

,

    CT
    PARACLINICAL

 and

    MR images
    PARACLINICAL

.


Correction of neutrophil chemotaxis defect in patients with Gaucher disease by low-dose enzyme replacement therapy.

We have recently described a chemotactic defect in severely afflicted Gaucher disease patients. Two of the patients were treated with low-dose intravenous enzyme replacement (Ceredase). Marked improvement in their hematological status, organomegaly, and growth was observed. In addition, their chemotactic defect and their tendency towards infections were corrected within 1 year of treatment.

We have recently described a

    chemotactic defect
    BIOCHEMICAL

 in severely afflicted

    Gaucher disease
    DIAGNOSIS

 patients. Two of the patients were treated with

    low-dose intravenous enzyme replacement (Ceredase)
    MEDICATION

.

    Marked improvement in their hematological status
    SYMPTOMS

,

    organomegaly
    SYMPTOMS

,

    and growth
    SYMPTOMS

 was observed. In addition, their

    chemotactic defect
    BIOCHEMICAL

 and their

    tendency towards infections
    SYMPTOMS

 were corrected within 1 year of treatment.


Gaucher disease: a heterogeneous clinical complex for which effective enzyme replacement has come of age.

Gaucher disease, the most common form of lysosomal storage disease, is the result of autosomal recessive inheritance of a lysosomal enzyme glucocerebrosidase deficiency, which produces defective hydrolysis of glucosylceramide that accumulates in reticuloendothelial (tissue macrophage) cells. The current review focuses on Type 1 (the nonneuronopathic) or adult Gaucher disease and defines the clinical manifestations (splenomegaly, hepatomegaly, bony lesions, and clinical metabolic dysfunction) in relationship to the known enzymatic defect. The clinical diversity and variability in symptoms and signs, the age at onset of the clinical manifestations and their rate of progression, and the heterogeneity of the organs involved are reviewed. Extensive delineation of the nature of the enzyme defect and the recent molecular characterization of the enzyme mutants has not provided an explantation for the remarkable clinical phenotypic heterogeneity. Enzyme assays now provide an excellent method for diagnosis. Effective enzyme replacement therapy emphasizes the value of early diagnosis and has altered the costs and potential risks of older therapeutic indications for splenectomy or cytokine therapy. Enzyme efficacy raises questions about the specific indications for replacement treatment and the most desirable rate and duration of enzyme delivery.

    Gaucher disease
    DIAGNOSIS

, the most common form of

    lysosomal storage disease
    DIAGNOSIS

, is the result of

    autosomal recessive inheritance
    GENETICS

 of a

    lysosomal enzyme glucocerebrosidase deficiency
    BIOCHEMICAL

, which produces

    defective hydrolysis of glucosylceramide that accumulates in reticuloendothelial (tissue macrophage) cells
    MICROSCOPIC

. The current review focuses on

    Type 1 (the nonneuronopathic) or adult Gaucher disease
    DIAGNOSIS

 and defines the clinical manifestations (

    splenomegaly
    SYMPTOMS

,

    hepatomegaly
    SYMPTOMS

,

    bony lesions
    SYMPTOMS

, and

    clinical metabolic dysfunction
    SYMPTOMS

) in relationship to the known enzymatic defect. The clinical diversity and variability in symptoms and signs, the age at onset of the clinical manifestations and their rate of progression, and the heterogeneity of the organs involved are reviewed. Extensive delineation of the nature of the enzyme defect and the recent molecular characterization of the enzyme mutants has not provided an explantation for the remarkable clinical phenotypic heterogeneity.

    Enzyme assays
    PARACLINICAL

 now provide an excellent method for diagnosis. Effective

    enzyme replacement therapy
    MEDICATION

 emphasizes the value of early diagnosis and has altered the costs and potential risks of older therapeutic indications for

    splenectomy or cytokine therapy
    MEDICATION

. Enzyme efficacy raises questions about the specific indications for

    replacement treatment
    MEDICATION

 and the most desirable rate and duration of

    enzyme delivery
    MEDICATION

.

splenomegaly
hepatomegaly
bony lesions
clinical metabolic dysfunction

enzyme replacement therapy
splenectomy or cytokine therapy
replacement treatment
enzyme delivery


Gaucher's disease associated with chronic lymphocytic leukemia.

To date, only five cases of associated Gaucher's disease and chronic lymphocytic leukemia (CLL) have been reported in the world literature. The exact relationship of the two diseases to one another has been puzzling, and Gaucher's disease has been viewed as both a cause of and an epiphenomenon to chronic lymphocytic leukemia. In this case, because of the temporal relationship of the two conditions and the confirmation of Gaucher's disease by both histochemical means and electron microscopy, we believe that a cause/effect interaction may exist. However, the exact mechanism by which this may occur is, as yet, speculative.

To date, only five cases of

    associated Gaucher's disease and chronic lymphocytic leukemia (CLL)
    DIAGNOSIS

 have been reported in the world literature. The exact relationship of the two diseases to one another has been puzzling, and

    Gaucher's disease
    DIAGNOSIS

 has been viewed as both a cause of and an epiphenomenon to

    chronic lymphocytic leukemia
    DIAGNOSIS

. In this case, because of the temporal relationship of the two conditions and the confirmation of

    Gaucher's disease
    MICROSCOPIC

 by both

    histochemical means
    PARACLINICAL

 and

    electron microscopy
    PARACLINICAL

, we believe that a cause/effect interaction may exist. However, the exact mechanism by which this may occur is, as yet, speculative.


[A rare etiology of spinal cord compression: Gaucher disease].

Gaucher's disease is a sphingolipidosis transmitted as an autosomal trait. Bone lesions are frequent in type 1 of the disease (i.e. the adult type without neurological manifestation). We report the case of a 70-year old woman suffering from spinal lesions with vertebral collapse and spinal cord compression. Our diagnosis was based on the finding in bone samples of Gaucher cells looking like large macrophages, and on the enzymatic assay of glucocerebrosidase. New treatments, such as replacement of the deficient enzyme by placental glucocerebrosidase, are currently being evaluated.

    Gaucher's disease
    DIAGNOSIS

 is a

    sphingolipidosis
    DIAGNOSIS

    transmitted as an autosomal trait
    GENETICS

.

    Bone lesions
    SYMPTOMS

 are frequent in

    type 1 of the disease
    DIAGNOSIS

 (i.e. the adult type

    without neurological manifestation
    NEG_FINDINGS

). We report the case of a

    70-year old
    AGE

    woman
    GENDER

 suffering from

    spinal lesions
    SYMPTOMS

 with

    vertebral collapse
    SYMPTOMS

 and

    spinal cord compression
    SYMPTOMS

. Our diagnosis was based on the finding in

    bone samples
    MICROSCOPIC

 of

    Gaucher cells looking like large macrophages
    MICROSCOPIC

, and on the

    enzymatic assay of glucocerebrosidase
    PARACLINICAL

. New treatments, such as

    replacement of the deficient enzyme by placental glucocerebrosidase
    MEDICATION

, are currently being evaluated.

Gaucher's disease
sphingolipidosis
type 1 of the disease

Bone lesions
spinal lesions
vertebral collapse
spinal cord compression


Structure determination of glycosphingolipids of cultured human keratinocytes.

From cultured human keratinocytes, seven glycolipid fractions were isolated by DEAE and silica-gel column chromatographies, and further by HPLC on a silica-gel column. By means of 1H-NMR spectroscopy, fast atom bombardment mass spectrometry and GLC-mass spectrometry, one fraction was determined to contain acylglucosylceramides, which consist of amide linked omega-hydroxy fatty acids (C30:0, C30:1, C32:1 and C34:1), fatty acids linked to the omega-hydroxy fatty acids through ester linkages (C14:1, C16:1, C18:1 and C18:2), a long-chain base (d18-sphingenine), and beta-glucose. Five of the other fractions contained glucosylceramides, and the seventh fraction contained a mixture of glucosylceramides and galactosylceramides. Glucosylceramides containing long-chain omega-hydroxy fatty acids, which are assumed to be immediate precursors of the acylglucosylceramides, were hardly detected in these glycolipid fractions. Six glucosylceramide fractions were separated due to differences in their fatty acids and sphingosines. On comparison with the results reported in our previous paper, the acylglucosylceramide content of the cultured human keratinocytes was about half that of human epidermis. Under the culture conditions used, the human keratinocytes did not differentiate into granular or horny cells. Taken together, the results suggest that the synthesis of acylglucosylceramides is not activated much in the cultured keratinocytes, but would be more activated in differentiated cells.

From

    cultured human keratinocytes
    MICROSCOPIC

, seven

    glycolipid fractions
    MICROSCOPIC

 were isolated by

    DEAE and silica-gel column chromatographies
    PARACLINICAL

, and further by

    HPLC on a silica-gel column
    PARACLINICAL

. By means of

    1H-NMR spectroscopy
    PARACLINICAL

,

    fast atom bombardment mass spectrometry
    PARACLINICAL

 and

    GLC-mass spectrometry
    PARACLINICAL

, one fraction was determined to contain

    acylglucosylceramides, which consist of amide linked omega-hydroxy fatty acids (C30:0, C30:1, C32:1 and C34:1), fatty acids linked to the omega-hydroxy fatty acids through ester linkages (C14:1, C16:1, C18:1 and C18:2), a long-chain base (d18-sphingenine), and beta-glucose
    MICROSCOPIC

. Five of the other

    fractions contained glucosylceramides
    MICROSCOPIC

, and the seventh fraction contained a

    mixture of glucosylceramides and galactosylceramides
    MICROSCOPIC

.

    Glucosylceramides containing long-chain omega-hydroxy fatty acids
    MICROSCOPIC

, which are assumed to be immediate precursors

    of the acylglucosylceramides
    MICROSCOPIC

, were hardly detected in these

    glycolipid fractions
    MICROSCOPIC

.

    Six glucosylceramide fractions
    MICROSCOPIC

 were separated due to differences in their

    fatty acids and sphingosines
    MICROSCOPIC

. On comparison with the results reported in our previous paper, the

    acylglucosylceramide content of the cultured human keratinocytes was about half that of human epidermis
    MICROSCOPIC

. Under the culture conditions used, the

    human keratinocytes
    MICROSCOPIC

    did not differentiate into granular or horny cells
    NEG_FINDINGS

. Taken together, the results suggest that the

    synthesis of acylglucosylceramides
    MICROSCOPIC

 is not activated much in the cultured keratinocytes, but would be more activated in differentiated cells.


[Gaucher's disease: study of a family from Friuli].

Gaucher's disease is the most frequent of lysosomal storage diseases. In a family study two affected sisters of a type I patient were identified. Two of them underwent splenectomy, so reaching hematological normalization.

    Gaucher's disease
    DIAGNOSIS

 is the most frequent of

    lysosomal storage diseases
    DIAGNOSIS

. In a family study

    two affected sisters of a type I patient
    FAMILY

 were identified. Two of them underwent

    splenectomy
    MEDICATION

, so reaching

    hematological normalization
    BIOCHEMICAL

.

Gaucher's disease
lysosomal storage diseases


Spinal involvement in children and adolescents with Gaucher disease.

Nineteen patients with type I Gaucher disease with spinal involvement first diagnosed during childhood, were followed for 2 to 24 years (average 9 years), and their clinical and radiologic history reviewed. Patients presented with three types of pain: mild pain that was defined as nonspecific, severe pain due to bone crisis, and pain associated with vertebral collapse. Collapse of vertebra occurred gradually anywhere along the thoraco-lumbar spine, and usually more than one vertebra was involved. In three patients, rectangular collapse was noted. Six patients suffered from central vertebra collapse, and two from anterior wedge compression. Further vertebral collapse with signs of root and cord compression developed in three patients as they grew. Awareness to the possibility of progressive vertebral collapse and periodic follow-up might prevent severe complications.

Nineteen patients with

    type I Gaucher disease
    DIAGNOSIS

 with

    spinal involvement
    SYMPTOMS

 first diagnosed during

    childhood
    AGE

, were followed for

    2 to 24 years (average 9 years)
    AGE

, and their clinical and radiologic history reviewed. Patients presented with three types of

    pain
    SYMPTOMS

:

    mild pain
    SYMPTOMS

 that was defined as nonspecific,

    severe pain due to bone crisis
    SYMPTOMS

, and

    pain associated with vertebral collapse
    SYMPTOMS

.

    Collapse of vertebra occurred gradually anywhere along the thoraco-lumbar spine
    SYMPTOMS

, and usually

    more than one vertebra was involved
    SYMPTOMS

. In three patients,

    rectangular collapse
    SYMPTOMS

 was noted. Six patients suffered from

    central vertebra collapse
    SYMPTOMS

, and two from

    anterior wedge compression
    SYMPTOMS

.

    Further vertebral collapse with signs of root and cord compression
    SYMPTOMS

 developed in three patients as they grew. Awareness to the possibility of

    progressive vertebral collapse
    SYMPTOMS

 and

    periodic follow-up
    PARACLINICAL

 might prevent severe complications.


Gaucher's disease associated with monoclonal gammapathy of undetermined significance: a case report.

We report a case of adult-type Gaucher's disease associated with monoclonal gammapathy of undetermined significance. Bone marrow infiltration by Gaucher's cells and spleen infiltration by Gaucher cells and plasma cells was observed on cytohistologic examination. Splenectomy induced complete recovery of cytopenias and a marked reduction of the monoclonal protein.

We report a case of

    adult-type Gaucher's disease
    DIAGNOSIS

 associated with

    monoclonal gammapathy of undetermined significance
    BIOCHEMICAL

.

    Bone marrow infiltration by Gaucher's cells
    MICROSCOPIC

 and

    spleen infiltration by Gaucher cells and plasma cells
    MICROSCOPIC

 was observed on

    cytohistologic examination
    PARACLINICAL

.

    Splenectomy
    MEDICATION

 induced

    complete recovery of cytopenias
    BIOCHEMICAL

 and a

    marked reduction of the monoclonal protein
    BIOCHEMICAL

.


Anesthetic considerations in the child with Gaucher disease.

We present the case of a 7-month-old girl with Gaucher disease who required anesthetic care during laryngoscopy, bronchoscopy, and central line placement. Gaucher disease is a familial disorder of lipid catabolism with autosomal recessive inheritance. Due to the defective function of the enzyme glucosylceramide beta-glucosidase, glycosphingolipids accumulate, leading to end-organ dysfunction. Three clinical variants of the disease, which differ in age of onset, degree of central nervous system (CNS) involvement, and frequency in the population, have been described. Of concern to the anesthesiologist is the occurrence of significant CNS dysfunction in types II and III, with seizures, gastroesophageal reflux, and chronic aspiration. Bulbar involvement and infiltration of the upper airway with glycolipids may lead to upper airway obstruction. Additionally, hepatosplenomegaly, present in all three variants, may lead to hypersplenism with thrombocytopenia and anemia. Preoperative identification of the associated end-organ dysfunction will allow the safe provision of anesthetic care for these children.

We present the case of a

    7-month-old
    AGE

    girl
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 who required

    anesthetic care
    MEDICATION

 during

    laryngoscopy
    MEDICATION

,

    bronchoscopy
    MEDICATION

, and

    central line placement
    MEDICATION

.

    Gaucher disease
    DIAGNOSIS

 is a

    familial disorder of lipid catabolism
    GENETICS

 with

    autosomal recessive inheritance
    GENETICS

. Due to the

    defective function of the enzyme glucosylceramide beta-glucosidase
    BIOCHEMICAL

,

    glycosphingolipids accumulate
    MICROSCOPIC

, leading to

    end-organ dysfunction
    SYMPTOMS

. Three clinical variants of the disease, which differ in

    age
    AGE

 of onset, degree of

    central nervous system (CNS) involvement
    SYMPTOMS

, and frequency in the population, have been described. Of concern to the

    anesthesiologist
    PARACLINICAL

 is the occurrence of

    significant CNS dysfunction
    SYMPTOMS

 in

    types II and III
    DIAGNOSIS

, with

    seizures
    SYMPTOMS

,

    gastroesophageal reflux
    SYMPTOMS

, and

    chronic aspiration
    SYMPTOMS

.

    Bulbar involvement
    SYMPTOMS

 and

    infiltration of the upper airway with glycolipids
    MICROSCOPIC

 may lead to

    upper airway obstruction
    SYMPTOMS

. Additionally,

    hepatosplenomegaly
    SYMPTOMS

, present in all three variants, may lead to

    hypersplenism
    BIOCHEMICAL

 with

    thrombocytopenia
    BIOCHEMICAL

 and

    anemia
    BIOCHEMICAL

. Preoperative identification of the associated

    end-organ dysfunction
    SYMPTOMS

 will allow the safe provision of

    anesthetic care
    MEDICATION

 for these

    children
    AGE

.

Gaucher disease
Gaucher disease
types II and III

anesthetic care
laryngoscopy
bronchoscopy
central line placement
anesthetic care

familial disorder of lipid catabolism
autosomal recessive inheritance


Mutational analysis in a patient with a variant form of Gaucher disease caused by SAP-2 deficiency.

It is now clear that the lysosomal hydrolysis of sphingolipids requires both lysosomal enzymes and so-called sphingolipid activator proteins (SAPs). One gene, called prosaposin, codes for a precursor protein that is proteolytically cut into four putative SAPs. These four SAPs, of about 80 amino acids, share some structural features but differ somewhat in their specificity. Domain 3 of prosaposin mRNA contains the coding region for SAP-2, an activator of glucocerebrosidase. While most patients with Gaucher disease store glucosylceramide due to defects in glucocerebrosidase, a few patients store this lipid in the presence of normal enzyme levels. In this paper we describe the identification of a point mutation in domain 3 of a patient who died with this variant form of Gaucher disease. Polymerase chain reaction amplification was performed in the small amount of genomic DNA available using primers generated from the intronic sequence surrounding domain 3. The patient was found to have a T-to-G substitution at position 1144 (counting from the A of ATG initiation codon) in half of the M13 recombinant clones. This changes the codon for cysteine382 to glycine. His father and unaffected brother also had this mutation, but his mother did not. She was found to have half of the normal amount of mRNA for prosaposin in her cultured skin fibroblasts. Therefore, this child inherited a point mutation in domain 3 from his father and a deficiency of all four SAPs coded for by prosaposin from his mother.

It is now clear that the

    lysosomal hydrolysis of sphingolipids
    MICROSCOPIC

 requires both

    lysosomal enzymes
    BIOCHEMICAL

 and so-called

    sphingolipid activator proteins (SAPs)
    BIOCHEMICAL

. One gene, called

    prosaposin
    GENETICS

, codes for a precursor protein that is proteolytically cut into four putative SAPs. These four SAPs, of about 80 amino acids, share some structural features but differ somewhat in their specificity.

    Domain 3 of prosaposin mRNA
    GENETICS

 contains the coding region for

    SAP-2
    BIOCHEMICAL

, an

    activator of glucocerebrosidase
    BIOCHEMICAL

. While most patients with

    Gaucher disease
    DIAGNOSIS

    store glucosylceramide
    MICROSCOPIC

 due to

    defects in glucocerebrosidase
    BIOCHEMICAL

, a few patients

    store this lipid
    MICROSCOPIC

 in the presence of

    normal enzyme levels
    NEG_FINDINGS

. In this paper we describe the identification of a

    point mutation in domain 3
    GENETICS

 of a patient who

    died
    SYMPTOMS

 with this

    variant form of Gaucher disease
    DIAGNOSIS

.

    Polymerase chain reaction amplification was performed in the small amount of genomic DNA available
    PARACLINICAL

 using

    primers generated from the intronic sequence surrounding domain 3
    PARACLINICAL

. The patient was found to have

    a T-to-G substitution at position 1144 (counting from the A of ATG initiation codon) in half of the M13 recombinant clones
    GENETICS

. This

    changes the codon for cysteine382 to glycine
    GENETICS

.

    His father and unaffected brother also had this mutation
    FAMILY

, but

    his
    GENDER

    mother did not
    FAMILY

.

    She
    GENDER

 was found to have

    half of the normal amount of mRNA for prosaposin in her cultured skin fibroblasts
    BIOCHEMICAL

. Therefore, this

    child
    AGE

    inherited a point mutation in domain 3 from his father
    FAMILY

 and a

    deficiency of all four SAPs coded for by prosaposin from his mother
    BIOCHEMICAL

.

Gaucher disease
variant form of Gaucher disease


Orthotopic liver transplantation in two adults with Niemann-Pick and Gaucher's diseases: implications for the treatment of inherited metabolic disease.

Two adults were seen with cirrhosis caused by different lipid storage diseases. A 42-yr-old woman with Niemann-Pick disease type B had marked hepatomegaly, ascites and recent variceal bleeding. Her evaluation showed chronic bilateral pulmonary infiltrates, multiple stigmata of chronic liver disease including the recent cessation of menses, diuretic-resistant sterile ascites, hepatic encephalopathy and variceal bleeding. Five percent of normal sphingomyelinase activity was measured in peripheral leukocytes. A 42-yr-old man with Gaucher's disease and a history of bilateral hip replacements presented with hepatomegaly, jaundice, refractory ascites and renal insufficiency. His evaluation showed 20% to 23% of normal glucocerebrosidase activity in peripheral leukocytes. Both patients underwent orthotopic liver transplantation with resolution of all aspects of decompensated liver function. Assessment of the underlying metabolic defect before and 6 to 14 mo after transplantation showed that after transplantation the patient with Niemann-Pick disease had above normal hepatic sphingomyelinase activity, a less-marked increase in peripheral leukocyte enzyme activity and lower than normal hepatic sphingomyelin and cholesterol content. In contrast, the patient with Gaucher's disease had only a 61% increase in hepatic glucocerebrosidase activity but had an elevated hepatic glucocerebroside content that was only 15% of the pretransplant level and decreased peripheral leukocyte enzyme levels. These findings suggest that variable relationships may exist between posttransplant hepatic and peripheral leukocyte enzyme activities in the different lipidoses, which may have implications for recurrence of glycolipid-induced liver damage.

Two

    adults
    GENDER

 were seen with

    cirrhosis
    DIAGNOSIS

 caused by different

    lipid storage diseases
    DIAGNOSIS

. A

    42-yr-old
    AGE

    woman
    GENDER

 with

    Niemann-Pick disease type B
    DIAGNOSIS

 had

    marked hepatomegaly
    SYMPTOMS

,

    ascites
    SYMPTOMS

 and

    recent variceal bleeding
    SYMPTOMS

.

    Her
    GENDER

 evaluation showed

    chronic bilateral pulmonary infiltrates
    SYMPTOMS

,

    multiple stigmata of chronic liver disease
    SYMPTOMS

 including the

    recent cessation of menses
    SYMPTOMS

,

    diuretic-resistant sterile ascites
    SYMPTOMS

,

    hepatic encephalopathy
    SYMPTOMS

 and

    variceal bleeding
    SYMPTOMS

.

    Five percent of normal sphingomyelinase activity was measured in peripheral leukocytes
    BIOCHEMICAL

. A

    42-yr-old
    AGE

    man
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

 and a

    history of bilateral hip replacements
    MEDICATION

 presented with

    hepatomegaly
    SYMPTOMS

,

    jaundice
    SYMPTOMS

,

    refractory ascites
    SYMPTOMS

 and

    renal insufficiency
    SYMPTOMS

.

    His
    GENDER

 evaluation showed

    20% to 23% of normal glucocerebrosidase activity in peripheral leukocytes
    BIOCHEMICAL

. Both patients underwent

    orthotopic liver transplantation
    MEDICATION

 with

    resolution of all aspects of decompensated liver function
    SYMPTOMS

. Assessment of the underlying metabolic defect before and 6 to 14 mo after

    transplantation
    MEDICATION

 showed that after

    transplantation
    MEDICATION

 the patient with

    Niemann-Pick disease
    DIAGNOSIS

 had

    above normal hepatic sphingomyelinase activity
    BIOCHEMICAL

,

    a less-marked increase in peripheral leukocyte enzyme activity
    BIOCHEMICAL

 and

    lower than normal hepatic sphingomyelin and cholesterol content
    BIOCHEMICAL

. In contrast, the patient with

    Gaucher's disease
    DIAGNOSIS

 had

    only a 61% increase in hepatic glucocerebrosidase activity
    BIOCHEMICAL

 but had an

    elevated hepatic glucocerebroside content that was only 15% of the pretransplant level
    BIOCHEMICAL

 and

    decreased peripheral leukocyte enzyme levels
    BIOCHEMICAL

. These findings suggest that variable relationships may exist between

    posttransplant hepatic and peripheral leukocyte enzyme activities
    BIOCHEMICAL

 in the different

    lipidoses
    DIAGNOSIS

, which may have implications for recurrence of

    glycolipid-induced liver damage
    DIAGNOSIS

.

cirrhosis
lipid storage diseases
Niemann-Pick disease type B
Gaucher's disease
Niemann-Pick disease
Gaucher's disease
lipidoses
glycolipid-induced liver damage

history of bilateral hip replacements
orthotopic liver transplantation
transplantation
transplantation


[Course of a case of Gaucher's disease type 1 treated over a year with glucocerebrosidase (Cérédase)].

Gaucher's disease is caused by a deficiency of glucocerebrosidase. Enzyme replacement therapy with glucocerebrosidase (Ceredase) is available in France since 1991. We report the clinical effectiveness in a woman with type 1 Gaucher's disease treated with the enzyme for one year. Hepatomegaly regressed, bone pain decreased but improvement of severe skeletal manifestations were slow and incomplete.

    Gaucher's disease
    DIAGNOSIS

 is caused by a

    deficiency of glucocerebrosidase
    BIOCHEMICAL

.

    Enzyme replacement therapy with glucocerebrosidase (Ceredase)
    MEDICATION

 is available in

    France
    ETHNICITY

 since 1991. We report the clinical effectiveness in a

    woman
    GENDER

 with

    type 1 Gaucher's disease
    DIAGNOSIS

    treated with the enzyme for one year
    MEDICATION

.

    Hepatomegaly regressed
    SYMPTOMS

,

    bone pain decreased
    SYMPTOMS

 but

    improvement of severe skeletal manifestations were slow and incomplete
    SYMPTOMS

.

Gaucher's disease
type 1 Gaucher's disease


[Gaucher's disease in childhood: presentation and treatment].

M. Gaucher is a lysosomal storage disorder. Patients present with hepatosplenomegaly or with complaints of the bones. Clinically 3 subtypes can be distinguished; the 'adult' type I is most frequent found. On the basis of 10 case histories the presentation in childhood is reported. Only recently treatment with enzyme replacement therapy became available. The possibilities for the treatment of M. Gaucher are discussed.

    M. Gaucher
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

. Patients present with

    hepatosplenomegaly
    SYMPTOMS

 or with

    complaints of the bones
    SYMPTOMS

. Clinically 3 subtypes can be distinguished; the '

    adult' type I
    DIAGNOSIS

 is most frequent found. On the basis of 10 case histories the presentation in

    childhood
    AGE

 is reported. Only recently

    treatment with enzyme replacement therapy
    MEDICATION

 became available. The possibilities for the treatment of

    M. Gaucher
    DIAGNOSIS

 are discussed.

M. Gaucher
lysosomal storage disorder
adult' type I
M. Gaucher

hepatosplenomegaly
complaints of the bones


Magnetic resonance imaging assessment of sacroiliac joint involvement in Gaucher's disease.

A young woman with Gaucher's disease experienced acute pain in her right sacroiliac (SI) joint. Although pelvic radiographs and computed tomographic scan showed no significant change in the right SI joint, magnetic resonance imaging demonstrated an area of high signal intensity in the iliac part of the right SI joint, and a periosseous collection of blood. This skeletal location is rarely reported in Gaucher's disease; the mechanism of bone crisis is still controversial and our case suggests the occurrence of a bone infarct.

A

    young
    AGE

    woman
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

 experienced

    acute pain in her right sacroiliac (SI) joint
    SYMPTOMS

. Although

    pelvic radiographs
    PARACLINICAL

 and

    computed tomographic scan
    PARACLINICAL

    showed no significant change in the right SI joint
    NEG_FINDINGS

,

    magnetic resonance imaging
    PARACLINICAL

 demonstrated an

    area of high signal intensity in the iliac part of the right SI joint
    SYMPTOMS

, and a

    periosseous collection of blood
    MICROSCOPIC

. This

    skeletal location
    SYMPTOMS

 is rarely reported in

    Gaucher's disease
    DIAGNOSIS

; the mechanism of

    bone crisis
    SYMPTOMS

 is still controversial and our case suggests the occurrence of a

    bone infarct
    SYMPTOMS

.


Anaerobic osteomyelitis in patients with Gaucher's disease.

Bone involvement in patients with Gaucher's disease is common, and some of its clinical manifestations may resemble acute osteomyelitis. In addition, many studies have emphasized the high risk of secondary infection when surgical procedures are performed at the site of the involved bone. Nevertheless, these infections have never been well documented in the literature. Presentation of a patient with Gaucher's disease and osteomyelitis due to Prevotella (Bacteroides) melaninogenica provided us the opportunity to review 10 other similar case reports documented in the literature since 1966. This review suggests that acute hematogenic osteomyelitis is an uncommon complication of Gaucher's disease, but it is of interest that in most cases it is due to unusual organisms, particularly anaerobes.

    Bone involvement
    SYMPTOMS

 in patients with

    Gaucher's disease
    DIAGNOSIS

 is common, and some of its clinical manifestations may resemble

    acute osteomyelitis
    DIAGNOSIS

. In addition, many studies have emphasized the high risk of

    secondary infection
    SYMPTOMS

 when

    surgical procedures
    MEDICATION

 are performed at the site of the involved bone. Nevertheless, these infections have never been well documented in the literature. Presentation of a patient with

    Gaucher's disease
    DIAGNOSIS

 and

    osteomyelitis due to Prevotella (Bacteroides) melaninogenica
    DIAGNOSIS

 provided us the opportunity to review 10 other similar case reports documented in the literature since 1966. This review suggests that

    acute hematogenic osteomyelitis
    DIAGNOSIS

 is an uncommon complication of

    Gaucher's disease
    DIAGNOSIS

, but it is of interest that in most cases it is due to unusual organisms, particularly

    anaerobes
    SYMPTOMS

.

Bone involvement
secondary infection
anaerobes


[A case of adult Gaucher disease].

The authors describe a case of an adult patient having Gaucher's disease, who had hepatosplenomegaly and pancytopenia. The diagnosis was established by the low level of leukocyte beta-glucosidase and by histology of bone marrow, liver and spleen. The patient had no bone pain, but MRI described characteristic lesions of the femur. Serum acid phosphatase was characteristically elevated. The hypersplenism was reduced after splenectomy. The patient has a daughter with central nervous system dysfunction. Her chromosome examination is normal, but she has lower leukocyte beta-glucosidase activity too. She may have a Gaucher's disease of type II, the acute neuropathic form.

The authors describe a case of an

    adult
    AGE

 patient having

    Gaucher's disease
    DIAGNOSIS

, who had

    hepatosplenomegaly
    SYMPTOMS

 and

    pancytopenia
    BIOCHEMICAL

. The diagnosis was established by the

    low level of leukocyte beta-glucosidase
    BIOCHEMICAL

 and by

    histology of bone marrow, liver and spleen
    PARACLINICAL

. The patient had

    no bone pain
    NEG_FINDINGS

, but

    MRI
    PARACLINICAL

 described

    characteristic lesions of the femur
    SYMPTOMS

.

    Serum acid phosphatase was characteristically elevated
    BIOCHEMICAL

. The

    hypersplenism was reduced
    BIOCHEMICAL

 after

    splenectomy
    MEDICATION

. The

    patient has a daughter with central nervous system dysfunction
    FAMILY

.

    Her
    GENDER

    chromosome examination is normal
    NEG_FINDINGS

, but

    she
    GENDER

 has

    lower leukocyte beta-glucosidase activity too
    BIOCHEMICAL

.

    She
    GENDER

 may have a

    Gaucher's disease of type II, the acute neuropathic form
    DIAGNOSIS

.

hepatosplenomegaly
characteristic lesions of the femur

no bone pain
chromosome examination is normal


[Complications of Gaucher's disease].

We discuss two cases of Gaucher's disease of the adult with neurological complications. First of the patients came to Hospital due to sudden pain in dorso-lumbar region and motor weakness of lower extremities. In the neurological exploration there were no concluding objective deficit signs except an unstable deambulation. After several hours of rest, symptoms disappeared progressively. In the radiology of the raquis a crushed in the last three dorsal vertebral was seen; this finding together with the clinic the patient showed, suggested a mild and transitory medullar compression. Second patient suffered an intraparenchymatous brain hemorrhage on the course of a platelet depletion and with other mild coagulation disorders. This type of complication have never been described in Gaucher's disease.

We discuss two cases of

    Gaucher's disease
    DIAGNOSIS

 of the

    adult
    AGE

 with

    neurological complications
    SYMPTOMS

. First of the patients came to Hospital due to

    sudden pain in dorso-lumbar region
    SYMPTOMS

 and

    motor weakness of lower extremities
    SYMPTOMS

. In the

    neurological exploration
    PARACLINICAL

 there were

    no concluding objective deficit signs
    NEG_FINDINGS

 except an

    unstable deambulation
    SYMPTOMS

. After

    several hours of rest
    MEDICATION

,

    symptoms disappeared progressively
    SYMPTOMS

. In the

    radiology of the raquis
    PARACLINICAL

 a

    crushed in the last three dorsal vertebral
    SYMPTOMS

 was seen; this finding together with the clinic the patient showed, suggested a

    mild and transitory medullar compression
    SYMPTOMS

. Second patient suffered an

    intraparenchymatous brain hemorrhage
    SYMPTOMS

 on the course of a

    platelet depletion
    BIOCHEMICAL

 and with other

    mild coagulation disorders
    BIOCHEMICAL

. This type of complication have never been described in

    Gaucher's disease
    DIAGNOSIS

.

platelet depletion
mild coagulation disorders


Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene.

A group of neonates with Gaucher disease with a particularly devastating clinical course is described. The phenotype of these infants is analogous to that of a Gaucher mouse, which was created by targeted disruption of the mouse glucocerebroside gene. Similar to the homozygous mutant mice with glucocerebrosidase deficiency, these infants present at or shortly after birth, have rapidly progressing fulminant disease, and many have associated ichthyotic skin and/or hydrops fetalis. This transgenetic mouse model of Gaucher disease has helped us to appreciate a distinct Gaucher phenotype. Potentially, as this technology is applied to create other animal models of metabolic diseases, it may enable the recognition of other, as yet unappreciated presentations of inherited disorders.

A group of

    neonates
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 with a particularly devastating clinical course is described. The phenotype of these

    infants
    AGE

 is analogous to that of a

    Gaucher mouse
    DIAGNOSIS

, which was created by

    targeted disruption of the mouse glucocerebroside gene
    GENETICS

. Similar to the

    homozygous
    GENETICS

 mutant mice with

    glucocerebrosidase deficiency
    BIOCHEMICAL

, these

    infants
    AGE

 present

    at or shortly after birth
    AGE

, have

    rapidly progressing fulminant disease
    SYMPTOMS

, and many have associated

    ichthyotic skin
    SYMPTOMS

 and/or

    hydrops fetalis
    SYMPTOMS

. This

    transgenetic
    GENETICS

 mouse model of

    Gaucher disease
    DIAGNOSIS

 has helped us to appreciate a distinct

    Gaucher
    DIAGNOSIS

 phenotype. Potentially, as this technology is applied to create other animal models of

    metabolic diseases
    DIAGNOSIS

, it may enable the recognition of other, as yet unappreciated presentations of

    inherited disorders
    GENETICS

.

Gaucher disease
Gaucher mouse
Gaucher disease
Gaucher
metabolic diseases

rapidly progressing fulminant disease
ichthyotic skin
hydrops fetalis


Gaucher disease: A G+1----A+1 IVS2 splice donor site mutation causing exon 2 skipping in the acid beta-glucosidase mRNA.

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent Jewish genetic disease. About 30 identified missense mutations are causal to the defective activity of acid beta-glucosidase in this disease. cDNAs were characterized from a moderately affected 9-year-old Ashkenazi Jewish Gaucher disease type 1 patient whose 80-year-old, enzyme-deficient, 1226G (Asn370----Ser [N370S]) homozygous grandfather was nearly asymptomatic. Sequence analyses revealed four populations of cDNAs with either the 1226G mutation, an exact exon 2 (delta EX2) deletion, a deletion of exon 2 and the first 115 bp of exon 3 (delta EX2-3), or a completely normal sequence. About 50% of the cDNAs were the delta EX2, the delta EX2-3, and the normal cDNAs, in a ratio of 6:3:1. Specific amplification and characterization of exon 2 and 5' and 3' intronic flanking sequences from the structural gene demonstrated clones with either the normal sequence or with a G+1----A+1 transition at the exon 2/intron 2 boundary. This mutation destroyed the splice donor consensus site (U1 binding site) for mRNA processing. This transition also was present at the corresponding exon/intron boundary of the highly homologous pseudogene. This new mutation, termed "IVS2 G+1----A+1," is the first splicing mutation described in Gaucher disease and accounted for about 3.4% of the Gaucher disease alleles in the Ashkenazi Jewish population. The occurrence of this "pseudogene"-type mutation in the structural gene indicates the role of acid beta-glucosidase pseudogene and structural gene rearrangements in the pathogenesis of this disease.

    Gaucher disease
    DIAGNOSIS

 is the most frequent

    lysosomal storage disease
    DIAGNOSIS

 and the most prevalent

    Jewish genetic disease
    ETHNICITY

. About 30 identified

    missense mutations
    GENETICS

 are causal to the

    defective activity of acid beta-glucosidase
    BIOCHEMICAL

 in this disease. cDNAs were characterized from a moderately affected

    9-year-old
    AGE

    Ashkenazi Jewish
    ETHNICITY

    Gaucher disease type 1
    DIAGNOSIS

 patient whose

    80-year-old
    AGE

,

    enzyme-deficient, 1226G (Asn370----Ser [N370S]) homozygous grandfather was nearly asymptomatic
    GENETICS

.

    Sequence analyses
    PARACLINICAL

 revealed four populations of cDNAs with either

    the 1226G mutation, an exact exon 2 (delta EX2) deletion, a deletion of exon 2 and the first 115 bp of exon 3 (delta EX2-3)
    GENETICS

, or a

    completely normal sequence
    GENETICS

. About 50% of the cDNAs were the

    delta EX2, the delta EX2-3
    GENETICS

, and the normal cDNAs, in a ratio of 6:3:1.

    Specific amplification and characterization of exon 2 and 5' and 3' intronic flanking sequences from the structural gene
    PARACLINICAL

 demonstrated

    clones with either the normal sequence or with a G+1----A+1 transition at the exon 2/intron 2 boundary. This mutation destroyed the splice donor consensus site (U1 binding site) for mRNA processing
    GENETICS

.

    This transition also was present at the corresponding exon/intron boundary of the highly homologous pseudogene
    GENETICS

. This

    new mutation, termed "IVS2 G+1----A+1,"
    GENETICS

 is the first

    splicing mutation
    GENETICS

 described in

    Gaucher disease
    DIAGNOSIS

 and accounted for about 3.4% of the

    Gaucher disease
    DIAGNOSIS

 alleles in the

    Ashkenazi Jewish
    ETHNICITY

 population. The occurrence of

    this "pseudogene"-type mutation in the structural gene
    GENETICS

 indicates the role of

    acid beta-glucosidase pseudogene and structural gene rearrangements
    GENETICS

 in the pathogenesis of this disease.

Gaucher disease
lysosomal storage disease
Gaucher disease type 1
Gaucher disease
Gaucher disease

Jewish genetic disease
Ashkenazi Jewish
Ashkenazi Jewish


Cardiac tamponade in a patient with Gaucher's disease.

Gaucher's disease, a familial inborn error of metabolism associated with hepatosplenomegaly and hypersplenism, was first described by Earnest Gaucher in 1882. By 1959, Hsia found published reports on more than 300 cases. Most reports mentioned the bleeding tendencies of patients with Gaucher's, but show that major hemorrhagic complications are rare. We report a case of hemorrhagic pericarditis with cardiac tamponade in a patient with Type I Gaucher's disease.

    Gaucher's disease
    DIAGNOSIS

, a

    familial inborn error of metabolism
    GENETICS

 associated with

    hepatosplenomegaly
    SYMPTOMS

 and

    hypersplenism
    BIOCHEMICAL

, was first described by Earnest Gaucher in 1882. By 1959, Hsia found published reports on more than 300 cases. Most reports mentioned the

    bleeding tendencies
    SYMPTOMS

 of patients with

    Gaucher's
    DIAGNOSIS

, but show that

    major hemorrhagic complications
    SYMPTOMS

 are rare. We report a case of

    hemorrhagic pericarditis with cardiac tamponade
    SYMPTOMS

 in a patient with

    Type I Gaucher's disease
    DIAGNOSIS

.

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


Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells.

We describe three adult siblings with communicating hydrocephalus, corneal opacities, deafness, valvular heart disease, and deformed toes associated with glucosylceramide (glc-cer)-beta-glucosidase deficiency. The common manifestations of Gaucher disease were not evident. Supranuclear gaze palsies characteristic of type 3 were noted from early childhood, although the major signs were undeveloped until early adult life. Autopsy disclosed thickened leptomeninges with perivascular fibrosis, non-rheumatic calcified aortic and mitral stenosis with marked fibrosis, and mild infiltration of Gaucher cells in the reticuloendothelial organs. In contrast to the slight accumulation of glc-cer in the liver and spleen, the activity of glc-cer-beta-glucosidase was markedly decreased in the tissues, as much as in a patient with type 2 Gaucher disease. Common mutations were not found in the glucocerebrosidase gene.

We describe three

    adult
    AGE

 siblings with

    communicating hydrocephalus
    SYMPTOMS

,

    corneal opacities
    SYMPTOMS

,

    deafness
    SYMPTOMS

,

    valvular heart disease
    SYMPTOMS

, and

    deformed toes
    SYMPTOMS

 associated with

    glucosylceramide (glc-cer)-beta-glucosidase deficiency
    BIOCHEMICAL

. The

    common manifestations of Gaucher disease were not evident
    NEG_FINDINGS

.

    Supranuclear gaze palsies
    SYMPTOMS

 characteristic of

    type 3
    DIAGNOSIS

 were noted

    from early childhood
    AGE

, although the major signs

    were undeveloped
    NEG_FINDINGS

 until

    early adult life
    AGE

.

    Autopsy
    PARACLINICAL

 disclosed

    thickened leptomeninges with perivascular fibrosis
    SYMPTOMS

,

    non-rheumatic calcified aortic and mitral stenosis with marked fibrosis
    SYMPTOMS

, and

    mild infiltration of Gaucher cells in the reticuloendothelial organs
    MICROSCOPIC

. In contrast to the

    slight accumulation of glc-cer in the liver and spleen
    MICROSCOPIC

, the

    activity of glc-cer-beta-glucosidase was markedly decreased in the tissues
    BIOCHEMICAL

, as much as in a patient with

    type 2 Gaucher disease
    DIAGNOSIS

.

    Common mutations were not found in the glucocerebrosidase gene
    NEG_FINDINGS

.


[Response criteria for enzyme substitution in Gaucher disease].

Recently the intravenous enzyme replacement therapy with modified beta-glucocerebrosidase has become available for patients with M. Gaucher. We report here the considerable improvement of activity and vigor in a 5 year old girl with type 1 M. Gaucher administering 60 IU/kg every two weeks for 6 months. The platelet count increased from 82-96/nl to more than 150/nl and hemoglobin from 10.8 to more than 12 g/dl. Serum acid phosphatase decreased from 14.6 U/l to 5.9. U/l and angiotensin-converting enzyme from 327 to 102 U/l. The estimation of splenic volume by MRT showed a decrease by 40%, while liver size was not reduced within 6 months of therapy. MRT proved to be useful to demonstrate the bone marrow infiltration by Gaucher cells. The enzyme replacement therapy resulted in an objective response. No side effects have been observed so far. The extreme high treatment costs enforce a considerable dose reduction for maintenance therapy.

Recently the

    intravenous enzyme replacement therapy with modified beta-glucocerebrosidase
    MEDICATION

 has become available for patients with

    M. Gaucher
    DIAGNOSIS

. We report here the

    considerable improvement of activity and vigor
    SYMPTOMS

 in a

    5 year old
    AGE

    girl
    GENDER

 with

    type 1 M. Gaucher
    DIAGNOSIS

    administering 60 IU/kg every two weeks for 6 months
    MEDICATION

. The

    platelet count increased from 82-96/nl to more than 150/nl
    BIOCHEMICAL

 and

    hemoglobin from 10.8 to more than 12 g/dl
    BIOCHEMICAL

. Serum acid phosphatase decreased from 14.6 U/l to 5.9. U/l and angiotensin-converting enzyme from 327 to 102 U/l. The

    estimation of splenic volume by MRT
    PARACLINICAL

    showed a decrease by 40%
    SYMPTOMS

, while

    liver size was not reduced within 6 months of therapy
    NEG_FINDINGS

.

    MRT
    PARACLINICAL

 proved to be useful to demonstrate the

    bone marrow infiltration by Gaucher cells
    MICROSCOPIC

. The

    enzyme replacement therapy
    MEDICATION

 resulted in an

    objective response
    SYMPTOMS

.

    No side effects
    NEG_FINDINGS

 have been observed so far. The extreme high treatment costs enforce a considerable

    dose reduction for maintenance therapy
    MEDICATION

.


Long-term follow-up of a total articular resurfacing arthroplasty and a cup arthroplasty in Gaucher's disease.

Patients with Gaucher's disease, a well-described lipid storage disorder with many systemic manifestations, often present to the orthopaedic surgeon with osteonecrosis of the femoral head. This can be a difficult orthopaedic problem because of the patient's young age at presentation and abnormal bone stock. Review of the literature leaves uncertainty as to the ideal treatment of femoral-head avascular necrosis in this disease. This article reports the long-term results of a cup arthroplasty and a total articular resurfacing arthroplasty procedure for bilateral hip involvement. In light of the less-than-satisfactory results of total hip arthroplasty for young patients with Gaucher's disease, resurfacing arthroplasty may warrant more serious consideration. For the older patient with Gaucher's disease, total hip arthroplasty may be preferable.

Patients with

    Gaucher's disease
    DIAGNOSIS

, a well-described

    lipid storage disorder
    DIAGNOSIS

 with many

    systemic manifestations
    SYMPTOMS

, often present to the

    orthopaedic surgeon
    PARACLINICAL

 with

    osteonecrosis of the femoral head
    DIAGNOSIS

. This can be a difficult orthopaedic problem because of the patient's

    young age
    AGE

 at presentation and

    abnormal bone stock
    SYMPTOMS

. Review of the literature leaves uncertainty as to the ideal treatment of

    femoral-head avascular necrosis
    DIAGNOSIS

 in this disease. This article reports the long-term results of a

    cup arthroplasty and a total articular resurfacing arthroplasty procedure
    MEDICATION

 for

    bilateral hip involvement
    MEDICATION

. In light of the

    less-than-
    NEG_FINDINGS

satisfactory results of

    total hip arthroplasty
    MEDICATION

 for

    young
    AGE

 patients with

    Gaucher's disease
    DIAGNOSIS

,

    resurfacing arthroplasty
    MEDICATION

 may warrant more serious consideration. For the

    older
    AGE

 patient with

    Gaucher's disease
    DIAGNOSIS

,

    total hip arthroplasty
    MEDICATION

 may be preferable.

Gaucher's disease
lipid storage disorder
osteonecrosis of the femoral head
femoral-head avascular necrosis
Gaucher's disease
Gaucher's disease

systemic manifestations
abnormal bone stock


Wolman disease: morphological, clinical and genetic studies on the first Scandinavian cases.

On the Aland Islands, a 1-month-old girl was diagnosed as having Wolman disease. The diagnosis was confirmed neurochemically; a decreased activity of acid lipase was noted in the proband and her parents had typical carrier values. This is the first Scandinavian case reported. The skin biopsy revealed cytoplasmic accumulations identical to those noted in two sibs who highly probably had Wolman disease during the 1950s. Both these sibs died at the age of about 3 months and presented a heavy accumulation of lipid material in lymph nodes, spleen, adrenal glands, liver, gut, and also some pathological alterations in other organs. Electron microscopic findings from deparaffinized samples showed cytoplasmic accumulation of lipid material similar to that noted in Wolman disease. Genealogical analyses revealed that the index families had ancestors from the same restricted area and also common ancestors during the 17th century. The parents of the two affected sibs were born on a small island and were related in many different ways. On the basis of genealogical studies and other genetic investigations performed, the importance of founder and drift effect for manifestations of rare hereditary disorder in isolates is stressed.

On the

    Aland Islands
    ETHNICITY

, a

    1-month-old
    AGE

    girl
    GENDER

 was diagnosed as having

    Wolman disease
    DIAGNOSIS

. The diagnosis was confirmed neurochemically; a

    decreased activity of acid lipase was noted in the proband
    BIOCHEMICAL

 and

    her
    GENDER

    parents had typical carrier values
    FAMILY

. This is the first

    Scandinavian
    ETHNICITY

 case reported. The

    skin biopsy
    PARACLINICAL

 revealed

    cytoplasmic accumulations identical to those noted in two sibs who highly probably had Wolman disease during the 1950s
    MICROSCOPIC

.

    Both these sibs died
    FAMILY

    at the age of about 3 months
    AGE

 and presented a

    heavy accumulation of lipid material in lymph nodes, spleen, adrenal glands, liver, gut
    MICROSCOPIC

, and also

    some pathological alterations in other organs
    SYMPTOMS

.

    Electron microscopic findings from deparaffinized samples
    PARACLINICAL

 showed

    cytoplasmic accumulation of lipid material similar to that noted in Wolman disease
    MICROSCOPIC

.

    Genealogical analyses
    FAMILY

 revealed that

    the index families had ancestors from the same restricted area and also common ancestors
    FAMILY

 during the 17th century.

    The parents of the two affected sibs were born on a small island and were related in many different ways
    FAMILY

. On the basis of

    genealogical studies
    PARACLINICAL

 and other genetic investigations performed, the importance of founder and drift effect for manifestations of

    rare hereditary disorder
    DIAGNOSIS

 in isolates is stressed.


Successful treatment of bone marrow failure in Gaucher's disease with low-dose modified glucocerebrosidase.

We report the beneficial effects of enzyme replacement therapy with mannose-terminated human glucocerebrosidase ('Ceredase') in a patient suffering from transfusion-dependent bone marrow failure due to Gaucher's disease. Treatment with low-dose enzyme infusions, given twice weekly, rapidly reversed the haematopoietic failure and incapacitating skeletal disease. It appears likely that prior splenectomy favourably influenced the response to this therapy.

We report the beneficial effects of

    enzyme replacement therapy with mannose-terminated human glucocerebrosidase ('Ceredase')
    MEDICATION

 in a patient suffering from

    transfusion-dependent bone marrow failure
    SYMPTOMS

 due to

    Gaucher's disease
    DIAGNOSIS

.

    Treatment with low-dose enzyme infusions, given twice weekly
    MEDICATION

,

    rapidly reversed the haematopoietic failure
    SYMPTOMS

 and

    incapacitating skeletal disease
    SYMPTOMS

. It appears likely that

    prior splenectomy
    MEDICATION

 favourably influenced the response to this therapy.


["Spontaneous" hematoma of the psoas in Gaucher's disease].

The authors report a case of iliac muscle haematoma responsible for inguinal pain in a patient with Gaucher's disease type I. This exceptional cause of pain must now be considered side by side with the classical femoral head osteonecrosis and infectious coxitis. Magnetic resonance imaging appears to be the most sensitive and most specific examination for the aetiological diagnosis of hip pain in Gaucher's disease. In the absence of thrombocytopenia and franck abnormality of coagulation, the spontaneousness of the haematoma is discussed.

The authors report a case of

    iliac muscle haematoma
    SYMPTOMS

 responsible for

    inguinal pain
    SYMPTOMS

 in a patient with Gaucher's disease type I. This exceptional cause of

    pain
    SYMPTOMS

 must now be considered side by side with the classical

    femoral head osteonecrosis
    DIAGNOSIS

 and

    infectious coxitis
    DIAGNOSIS

.

    Magnetic resonance imaging
    PARACLINICAL

 appears to be the most sensitive and most specific examination for the aetiological diagnosis of

    hip pain
    SYMPTOMS

 in

    Gaucher's disease
    DIAGNOSIS

. In the

    absence of thrombocytopenia and franck abnormality of coagulation
    NEG_FINDINGS

, the

    spontaneousness of the haematoma
    SYMPTOMS

 is discussed.

iliac muscle haematoma
inguinal pain
pain
hip pain
spontaneousness of the haematoma

femoral head osteonecrosis
infectious coxitis
Gaucher's disease


[Pyogenic osteomyelitis in Gaucher's disease].

Gaucher's disease is a sphingolipidosis which may be accompanied by severe pain in the bones. We report a case of Bacteroides fragilis osteomyelitis consecutive to surgical biopsy. The bone pain may be due to ischaemia of the bone or to a pyogenic osteomyelitis which is iatrogenic in most cases. The clinical and paraclinical features of these two entities are described after a review of the literature, and the main complementary examinations leading to their diagnosis are presented.

    Gaucher's disease
    DIAGNOSIS

 is a

    sphingolipidosis
    DIAGNOSIS

 which may be accompanied by

    severe pain in the bones
    SYMPTOMS

. We report a case of

    Bacteroides fragilis osteomyelitis
    DIAGNOSIS

 consecutive to

    surgical biopsy
    MEDICATION

. The

    bone pain
    SYMPTOMS

 may be due to

    ischaemia of the bone
    SYMPTOMS

 or to a

    pyogenic osteomyelitis
    DIAGNOSIS

 which is iatrogenic in most cases. The clinical and paraclinical features of these two entities are described after a review of the literature, and the main complementary examinations leading to their diagnosis are presented.

Gaucher's disease
sphingolipidosis
Bacteroides fragilis osteomyelitis
pyogenic osteomyelitis

severe pain in the bones
bone pain
ischaemia of the bone


Allogenic bone marrow transplantation in severe Gaucher disease.

Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disease
    DIAGNOSIS

. This

    autosomal recessive disease
    GENETICS

 is caused by the

    defective activity of the enzyme acid beta-glucosidase
    BIOCHEMICAL

 and the resultant

    accumulation of glucosylceramide primarily within cells of the reticuloendothelial system
    MICROSCOPIC

. Because the primary manifestations of

    Gaucher disease
    DIAGNOSIS

 are due to

    involvement of monocyte/macrophage-derived cells
    MICROSCOPIC

, this disease is thought to be an excellent candidate for

    curative intervention via bone marrow transplantation (BMT)
    MEDICATION

. A

    Hispanic
    ETHNICITY

    female
    GENDER

 with

    subacute neuronopathic Gaucher disease
    DIAGNOSIS

 and

    rapidly progressing visceral manifestations
    SYMPTOMS

 underwent

    BMT
    MEDICATION

 at

    23 mo of age
    AGE

 using

    her
    GENDER

    histocompatible normal brother
    FAMILY

 as the donor.

    Cytogenetic analyses
    PARACLINICAL

 demonstrated

    complete, stable engraftment
    SYMPTOMS

 by 1 mo

    post-BMT
    MEDICATION

. During the subsequent 24 mo,

    clinical, biochemical, enzymatic, and histologic studies
    PARACLINICAL

 demonstrated

    nearly complete correction in the viscera
    SYMPTOMS

.

    Her
    GENDER

    neuropathic manifestations did not progress
    NEG_FINDINGS

.

    Complete reconstitution of enzymatic activity in peripheral blood leukocytes
    BIOCHEMICAL

 was achieved by 1 mo.

    Cytogenetic analyses
    PARACLINICAL

 demonstrated

    complete engraftment
    SYMPTOMS

 by d 79 and

    nearly complete loss of bone marrow Gaucher cells
    MICROSCOPIC

 was observed by 8 mo.

    Plasma glucosylceramide levels normalized
    BIOCHEMICAL

 by

    8-12 mo
    AGE

.

    Nearly coincident improvements in hepatic size, enzyme levels
    SYMPTOMS

,

    and histology
    SYMPTOMS

 were found by 12-24 mo

    post-BMT
    MEDICATION

.

    Fatal sepsis
    SYMPTOMS

 occurred at 24

    mo post-BMT
    AGE

.

    Autopsy
    PARACLINICAL

 revealed

    sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs
    MICROSCOPIC

 as well as the

    lack of periadventitial Gaucher cells surrounding brain vessels
    MICROSCOPIC

. The findings provide the time course and rationale for studies directed to

    gene therapy via BMT
    MEDICATION

 for this disease after

    introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells
    MEDICATION

 of selected

    Gaucher disease
    DIAGNOSIS

 patients.

Gaucher disease
lysosomal storage disease
Gaucher disease
subacute neuronopathic Gaucher disease
Gaucher disease


Enzyme augmentation in moderate to life-threatening Gaucher disease.

Gaucher disease type 1 (GD type 1) is the most prevalent lysosomal storage disease and has its highest frequency in the Ashkenazi Jewish population. Deficiency of the enzyme, acid beta-glucosidase, results in the deposition of glucocerebroside primarily in macrophages. The accumulation of such "Gaucher cells" leads to visceromegaly, hepatic and bone marrow dysfunction, hypersplenism, and bony disease. Eleven GD type 1 patients, ages 4-52 y, with moderate to life-threatening manifestations, received 6-12 mo of enzyme augmentation with a macrophage-targeted acid beta-glucosidase preparation. Within 6 mo, substantial increases in Hb levels (mean = +30%) and platelet counts (mean = +39%) were observed. Hepatic and splenic volumes decreased by approximately 20% (range = 3-35%) and approximately 35% (20-52%), respectively. Hematologic and hepatic volume improvements were similar in the splenectomized (n = 4) and nonsplenectomized (n = 7) patient groups. In this patient population, no major differences were observed in the hematologic and visceral improvements with enzyme doses of 30, 50, or 60 IU/kg administered every 2 wk. Normal levels of acid beta-glucosidase activity were present in hepatic autopsy samples from one patient 11 d after enzyme infusion. In comparison, exogenous activity was absent from brain and lung specimens of the same patient. High levels (approximately 10-fold normal) were present in bone marrow samples from two patients obtained at 1 and 11 d after infusions. These studies demonstrate biochemical and clinical improvements by targeted enzyme augmentation in GD type 1, even in far advanced, life-threatening involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

    Gaucher disease type 1 (GD type 1)
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disease
    DIAGNOSIS

 and has its highest frequency in the

    Ashkenazi Jewish
    ETHNICITY

 population.

    Deficiency of the enzyme, acid beta-glucosidase
    BIOCHEMICAL

, results in the

    deposition of glucocerebroside primarily in macrophages
    MICROSCOPIC

. The

    accumulation of such "Gaucher cells"
    MICROSCOPIC

 leads to

    visceromegaly
    SYMPTOMS

,

    hepatic and bone marrow dysfunction
    SYMPTOMS

,

    hypersplenism
    BIOCHEMICAL

, and

    bony disease
    SYMPTOMS

. Eleven

    GD type 1
    DIAGNOSIS

 patients,

    ages 4-52 y
    AGE

, with

    moderate to life-threatening manifestations
    SYMPTOMS

,

    received 6-12 mo of enzyme augmentation with a macrophage-targeted acid beta-glucosidase preparation
    MEDICATION

. Within 6 mo,

    substantial increases in Hb levels (mean = +30%) and platelet counts (mean = +39%)
    BIOCHEMICAL

 were observed.

    Hepatic and splenic volumes decreased by approximately 20% (range = 3-35%) and approximately 35% (20-52%)
    SYMPTOMS

, respectively.

    Hematologic and hepatic volume improvements
    SYMPTOMS

 were similar in the

    splenectomized
    MEDICATION

 (n = 4) and

    nonsplenectomized
    MEDICATION

 (n = 7) patient groups. In this patient population,

    no
    NEG_FINDINGS

 major differences were observed in the

    hematologic and visceral improvements
    SYMPTOMS

 with

    enzyme doses of 30, 50, or 60 IU/kg administered every 2 wk
    MEDICATION

.

    Normal levels of acid beta-glucosidase activity were present in hepatic autopsy samples
    NEG_FINDINGS

 from one patient 11 d after

    enzyme infusion
    MEDICATION

. In comparison,

    exogenous activity was absent from brain and lung specimens
    NEG_FINDINGS

 of the same patient.

    High levels (approximately 10-fold normal) were present in bone marrow samples
    BIOCHEMICAL

 from two patients obtained at 1 and 11

    d after infusions
    BIOCHEMICAL

. These studies demonstrate

    biochemical and clinical improvements
    SYMPTOMS

 by

    targeted enzyme augmentation
    MEDICATION

 in

    GD type 1
    DIAGNOSIS

, even in far advanced, life-threatening involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Gaucher disease type 1 (GD type 1)
lysosomal storage disease
GD type 1
GD type 1


Gaucher's disease in an infant diagnosed by fine needle aspiration of the liver and spleen. A case report.

A case of Gaucher's disease diagnosed by means of fine needle aspiration of the liver and spleen in a 12-month-old boy with hepatosplenomegaly is presented. The diagnosis was based on the finding of large, macrophagelike cells with abundant, pale, fibrillary cytoplasm and small nuclei. The patient had no family history of Gaucher's disease, and the diagnosis was not suspected clinically.

A case of

    Gaucher's disease
    DIAGNOSIS

 diagnosed by means of

    fine needle aspiration of the liver and spleen
    PARACLINICAL

 in a

    12-month-old
    AGE

    boy
    GENDER

 with

    hepatosplenomegaly
    SYMPTOMS

 is presented. The diagnosis was based on the finding of

    large, macrophagelike cells with abundant, pale, fibrillary cytoplasm and small nuclei
    MICROSCOPIC

. The patient had

    no family history of Gaucher's disease
    NEG_FINDINGS

, and the diagnosis was

    not suspected clinically
    NEG_FINDINGS

.

no family history of Gaucher's disease
not suspected clinically


Gaucher's disease in the presence of normal glucocerebrosidase activity.

We encountered an infant with clinical and histopathologic features of Gaucher's disease (infantile, type 2) with normal glucocerebrosidase (D-glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45) activity. Biochemical analysis was performed on leukocytes, cultured skin fibroblasts, and liver. Normal activity of glucocerebrosidase previously has been reported in an older child with juvenile onset (type 3) Gaucher's disease and attributed to a deficiency of a sphingolipid activator protein. These rare cases illustrate and expand our concept of Gaucher's disease and may have both diagnostic and therapeutic implications.

We encountered an

    infant
    AGE

 with

    clinical and histopathologic features of Gaucher's disease (infantile, type 2)
    SYMPTOMS

 with

    normal glucocerebrosidase (D-glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45) activity
    NEG_FINDINGS

.

    Biochemical analysis was performed on leukocytes, cultured skin fibroblasts, and liver
    PARACLINICAL

.

    Normal activity of glucocerebrosidase
    NEG_FINDINGS

 previously has been reported in an

    older child
    AGE

 with

    juvenile onset (type 3) Gaucher's disease
    DIAGNOSIS

 and attributed to a

    deficiency of a sphingolipid activator protein
    BIOCHEMICAL

. These rare cases illustrate and expand our concept of

    Gaucher's disease
    DIAGNOSIS

 and may have both diagnostic and therapeutic implications.


Multiple space-occupying lesions of the spleen in a case of Gaucher's disease.

A 50-year-old female patient was admitted because of an enormously enlarged spleen and thrombocytopenia. Ultrasonography and magnetic resonance imaging revealed multiple space-occupying lesions in the spleen. She was diagnosed as having Gaucher's disease based on the low level of beta-glucosidase activity in leukocytes and Gaucher's cells present in bone marrow aspirate. Severe hypersplenism necessitated splenectomy. Pathological studies of the excised spleen, including ultrastructural examinations, demonstrated that multiple space-occupying lesions in the spleen were composed of typical Gaucher cells.

A

    50-year-old
    AGE

    female
    GENDER

 patient was admitted because of an

    enormously enlarged spleen
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

.

    Ultrasonography
    PARACLINICAL

 and

    magnetic resonance imaging
    PARACLINICAL

 revealed

    multiple space-occupying lesions in the spleen
    SYMPTOMS

.

    She
    GENDER

 was diagnosed as having

    Gaucher's disease
    DIAGNOSIS

 based on the

    low level of beta-glucosidase activity in leukocytes
    BIOCHEMICAL

 and

    Gaucher's cells present in bone marrow aspirate
    MICROSCOPIC

.

    Severe hypersplenism
    BIOCHEMICAL

 necessitated

    splenectomy
    MEDICATION

.

    Pathological studies of the excised spleen
    PARACLINICAL

, including

    ultrastructural examinations
    PARACLINICAL

, demonstrated that

    multiple space-occupying lesions in the spleen were composed of typical Gaucher cells
    MICROSCOPIC

.


Pseudo-Gaucher cells.

A case of acute lymphoblastic leukaemia, associated with cells resembling Gaucher cells in the bone marrow, is reported. The patient had no evidence of inherited Gaucher's disease and the ultrastructural appearance of the cells was consistent with pseudo-Gaucher cells described in other haematological diseases. This is the first report of these cells in association with acute lymphoblastic leukaemia.

A case of

    acute lymphoblastic leukaemia
    DIAGNOSIS

, associated with

    cells resembling Gaucher cells in the bone marrow
    MICROSCOPIC

, is reported. The patient had

    no evidence of inherited Gaucher's disease
    NEG_FINDINGS

 and the

    ultrastructural appearance of the cells was consistent with pseudo-Gaucher cells described in other haematological diseases
    MICROSCOPIC

. This is the first report of

    these cells
    MICROSCOPIC

 in association with

    acute lymphoblastic leukaemia
    DIAGNOSIS

.

acute lymphoblastic leukaemia
acute lymphoblastic leukaemia


Skeletal scintigraphy of pseudo-osteomyelitis in Gaucher's disease. Two case reports and a review of the literature.

Two patients with known type 1 Gaucher's disease had signs and symptoms of osteomyelitis. Decreased perfusion and impaired uptake were seen on bone scan. Patient 1 had a culture-negative aspirate of the site. Patient 2 had no surgical procedures. Both improved on bed rest and nonsteroidal anti-inflammatory agents. It is difficult to distinguish osteomyelitis clinically from pseudo-osteomyelitis. The authors suggest that photopenia on bone scan performed within 1 to 3 days of presentation is suggestive of pseudo-osteomyelitis in Gaucher's disease.

Two patients with known

    type 1 Gaucher's disease
    DIAGNOSIS

 had

    signs and symptoms of osteomyelitis
    SYMPTOMS

.

    Decreased perfusion and impaired uptake
    SYMPTOMS

 were seen on

    bone scan
    PARACLINICAL

. Patient 1 had a

    culture-negative aspirate of the site
    PARACLINICAL

. Patient 2 had

    no surgical procedures
    NEG_FINDINGS

. Both improved on

    bed rest
    MEDICATION

 and

    nonsteroidal anti-inflammatory agents
    MEDICATION

. It is difficult to distinguish

    osteomyelitis
    DIAGNOSIS

 clinically from

    pseudo-osteomyelitis
    DIAGNOSIS

. The authors suggest that

    photopenia
    BIOCHEMICAL

 on

    bone scan
    PARACLINICAL

 performed within 1 to 3 days of presentation is suggestive of

    pseudo-osteomyelitis
    DIAGNOSIS

 in

    Gaucher's disease
    DIAGNOSIS

.

type 1 Gaucher's disease
osteomyelitis
pseudo-osteomyelitis
pseudo-osteomyelitis
Gaucher's disease

signs and symptoms of osteomyelitis
Decreased perfusion and impaired uptake

bed rest
nonsteroidal anti-inflammatory agents


Dose-dependent responses to macrophage-targeted glucocerebrosidase in a child with Gaucher disease.

Long-term studies of a child with Gaucher disease indicated that the response to treatment with macrophage-targeted glucocerebrosidase (glucosylceramidase) is dose dependent, and that the hematologic response precedes the skeletal response.

Long-term studies of a

    child
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 indicated that the response to

    treatment with macrophage-targeted glucocerebrosidase (glucosylceramidase)
    MEDICATION

 is dose dependent, and that the

    hematologic response
    BIOCHEMICAL

 precedes the

    skeletal response
    SYMPTOMS

.


Gaucher's disease involving the spleen.

Gaucher's disease is a rare inherited disorder that results from progressive accumulation of glucocerebrosides within the reticuloendothelial system and affects the liver, the spleen, the bone marrow and the lymph nodes. Ultrasonography of the spleen typically demonstrates hypoechoic focal masses; however, the lesions may be hyperechoic if they contain extensive fibrosis or infarction. The authors describe a young Ashkenazi man who presented with splenomegaly as the single clinical manifestation and in whom were found splenic masses of mixed echogenicity, none of which demonstrated fibrosis or infarction when studied pathologically.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare inherited disorder
    GENETICS

 that results from

    progressive accumulation of glucocerebrosides within the reticuloendothelial system
    MICROSCOPIC

 and

    affects the liver, the spleen, the bone marrow and the lymph nodes
    MICROSCOPIC

.

    Ultrasonography of the spleen
    PARACLINICAL

 typically demonstrates

    hypoechoic focal masses
    SYMPTOMS

; however, the lesions may be

    hyperechoic
    SYMPTOMS

 if they contain

    extensive fibrosis
    SYMPTOMS

 or

    infarction
    SYMPTOMS

. The authors describe a

    young
    AGE

    Ashkenazi
    ETHNICITY

    man
    GENDER

 who presented with

    splenomegaly
    SYMPTOMS

 as the single clinical manifestation and in whom were found

    splenic masses of mixed echogenicity
    SYMPTOMS

,

    none of which demonstrated fibrosis or infarction
    NEG_FINDINGS

 when

    studied pathologically
    PARACLINICAL

.

hypoechoic focal masses
hyperechoic
extensive fibrosis
infarction
splenomegaly
splenic masses of mixed echogenicity


Gaucher's disease with mitral and aortic involvement: echocardiographic findings.

Cardiac involvement in Gaucher's disease has been reported in only a few patients, mostly adults with pericardial changes. We describe findings in two siblings with Gaucher's disease, aged 15 and 9 years respectively, in whom mitral and aortic valve lesions were evaluated by auscultation and echocardiography. In both cases the mitral and aortic valves were thick and restricted in motion. Continuous Doppler echocardiography revealed significant mitral regurgitation and mitral stenosis. At the aortic valve level there was a systolic pressure gradient. Echocardiographic investigation of patients with suspected cardiac involvement with Gaucher's disease is recommended.

    Cardiac involvement
    SYMPTOMS

 in

    Gaucher's disease
    DIAGNOSIS

 has been reported in only a few patients, mostly

    adults
    AGE

 with

    pericardial changes
    SYMPTOMS

. We describe findings in two

    siblings
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

,

    aged 15 and 9 years
    AGE

 respectively, in whom

    mitral and aortic valve lesions
    SYMPTOMS

 were evaluated by

    auscultation
    PARACLINICAL

 and

    echocardiography
    PARACLINICAL

. In both cases

    the mitral and aortic valves were thick and restricted in motion
    SYMPTOMS

.

    Continuous Doppler echocardiography
    PARACLINICAL

 revealed

    significant mitral regurgitation and mitral stenosis
    SYMPTOMS

.

    At the aortic valve level
    SYMPTOMS

 there was a

    systolic pressure gradient
    SYMPTOMS

.

    Echocardiographic investigation
    PARACLINICAL

 of patients with suspected

    cardiac involvement
    SYMPTOMS

 with

    Gaucher's disease
    DIAGNOSIS

 is recommended.

Gaucher's disease
Gaucher's disease
Gaucher's disease


Fatal respiratory failure caused by pulmonary infiltration by pseudo-Gaucher cells.

Pseudo-Gaucher cells are reticuloendothelial cells that are found in several diseases. We report a case of pulmonary tuberculosis in which extensive pulmonary involvement with these cells resulted in fatal respiratory failure.

    Pseudo-Gaucher cells are reticuloendothelial cells
    MICROSCOPIC

 that are found in several diseases. We report a case of

    pulmonary tuberculosis
    DIAGNOSIS

 in which

    extensive pulmonary involvement with these cells
    MICROSCOPIC

 resulted in

    fatal respiratory failure
    SYMPTOMS

.


[Retinal involvement in Gaucher's disease].

Gaucher's disease, a storage disease, causes storage of the sphingolipid glucosylceramide in the reticulo endothelial system. The manifestations of such deposits within the retina consist of the appearance of numerous whitish spots, such as preretinian infiltrates. Several authors have noticed the higher frequency of appearance of such spots in splenectomized patients, with marked extrasplenic infiltration. In our case, the systemic infiltration was massive at the time of the ophthalmoscopic examination, as confirmed by the bone-marrow biopsy and computerized axial tomography study, in spite of the fact that the spleen had not been removed. Our hypothesis is that the appearance of the whitish preretinian deposits in the course of the disease is connected with the degree of systemic infiltration, stressing the importance of examination of the eye fundus in Gaucher's disease.

    Gaucher's disease
    DIAGNOSIS

, a

    storage disease
    DIAGNOSIS

, causes

    storage of the sphingolipid glucosylceramide in the reticulo endothelial system
    MICROSCOPIC

. The manifestations of such

    deposits within the retina
    MICROSCOPIC

 consist of the appearance of

    numerous whitish spots, such as preretinian infiltrates
    SYMPTOMS

. Several authors have noticed the higher frequency of

    appearance of such spots
    SYMPTOMS

 in

    splenectomized
    MEDICATION

 patients, with

    marked extrasplenic infiltration
    MICROSCOPIC

. In our case, the

    systemic infiltration was massive
    SYMPTOMS

 at the time of the

    ophthalmoscopic examination
    PARACLINICAL

, as confirmed by the

    bone-marrow biopsy
    PARACLINICAL

 and

    computerized axial tomography study
    PARACLINICAL

, in

    spite of the fact that the spleen had not been removed
    NEG_FINDINGS

. Our hypothesis is that the appearance of the

    whitish preretinian deposits
    SYMPTOMS

 in the course of the disease is connected with the degree of

    systemic infiltration
    SYMPTOMS

, stressing the importance of

    examination of the eye fundus
    PARACLINICAL

 in

    Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease
storage disease
Gaucher's disease


Gaucher's disease: case report of mandibular trauma.

Gaucher's disease is a disturbance of lipid storage that results in the accumulation of histiocytes filled with glucosyl ceramide in various organs and bones. Clinical features include history of epistaxis, hemoptysis, and spontaneous gingival hemorrhage. This article reviews Gaucher's disease with reference to its importance to dental practitioners and a case involving mandibular trauma is presented.

    Gaucher's disease
    DIAGNOSIS

 is a

    disturbance of lipid storage
    MICROSCOPIC

 that results in the

    accumulation of histiocytes filled with glucosyl ceramide in various organs and bones
    MICROSCOPIC

. Clinical features include

    history of epistaxis
    SYMPTOMS

,

    hemoptysis
    SYMPTOMS

, and

    spontaneous gingival hemorrhage
    SYMPTOMS

. This article reviews

    Gaucher's disease
    DIAGNOSIS

 with reference to its importance to dental practitioners and a case involving

    mandibular trauma
    MEDICATION

 is presented.

history of epistaxis
hemoptysis
spontaneous gingival hemorrhage


Foamy transformed Gaucher cells.

Two cases of Gaucher's disease (Types I and III) are described with a substantial part of the storage cell population in several organs (liver, adrenal cortex) intensively vacuolized and transformed into non-specific foam cells. The transformation process encompassed massive three-dimensional distension of the lysosomal system filled with typical lipid tubules as well as severe reduction of the intervening cytoplasm and decrease or disappearance of histochemically detectable enzyme activities, high in typical Gaucher cell (GC). Such an extensive GC foamy transformation may cause diagnostic embarrassment in microscopic interpretation especially of liver biopsies.

Two cases of

    Gaucher's disease (Types I and III)
    DIAGNOSIS

 are described with a

    substantial part of the storage cell population in several organs (liver, adrenal cortex) intensively vacuolized and transformed into non-specific foam cells
    MICROSCOPIC

. The

    transformation process
    MICROSCOPIC

 encompassed

    massive three-dimensional distension of the lysosomal system filled with typical lipid tubules
    MICROSCOPIC

 as well as

    severe reduction of the intervening cytoplasm
    MICROSCOPIC

 and

    decrease or disappearance of histochemically detectable enzyme activities, high in typical Gaucher cell (GC)
    MICROSCOPIC

. Such an

    extensive GC foamy transformation
    MICROSCOPIC

 may cause

    diagnostic embarrassment
    NEG_FINDINGS

 in

    microscopic interpretation
    PARACLINICAL

 especially of

    liver biopsies
    PARACLINICAL

.


Gaucher's disease. Plain radiography, US, CT and MR diagnosis of lungs, bone and liver lesions.

We report our observations made by conventional radiography, ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI) on a 3 1/2-year-old girl with Gaucher's disease. The interest of the case consists in the exceptional lungs involvement, the demonstration by MRI of the bone marrow involvement and the necrosis and fibrosis of the liver, as shown by CT. This liver complication has been previously reported only once.

We report our observations made by

    conventional radiography
    PARACLINICAL

,

    ultrasound
    PARACLINICAL

,

    computerized tomography (CT)
    PARACLINICAL

, and

    magnetic resonance imaging (MRI)
    PARACLINICAL

 on a

    3 1/2-year-old
    AGE

    girl
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

. The interest of the case consists in the

    exceptional lungs involvement
    SYMPTOMS

, the demonstration by

    MRI
    PARACLINICAL

 of the

    bone marrow involvement
    SYMPTOMS

 and the

    necrosis and fibrosis of the liver
    MICROSCOPIC

, as shown by

    CT
    PARACLINICAL

. This

    liver complication
    DIAGNOSIS

 has been previously reported only once.

exceptional lungs involvement
bone marrow involvement


Neurologic complications of nonneuronopathic Gaucher's disease.

We describe eight patients with type 1 Gaucher's disease who developed neurologic complications that were secondary to systemic features of the illness. Four patients experienced neurologic difficulties because of coagulopathy, and the other four patients had involvement of the nervous system secondary to skeletal disease. Early recognition of these complications in patients with type 1 Gaucher's disease may lead to improved neurologic outcome.

We describe eight patients with

    type 1 Gaucher's disease
    DIAGNOSIS

 who developed

    neurologic complications
    SYMPTOMS

 that were secondary to

    systemic features of the illness
    SYMPTOMS

. Four patients experienced

    neurologic difficulties
    SYMPTOMS

 because of

    coagulopathy
    BIOCHEMICAL

, and the other four patients had

    involvement of the nervous system
    SYMPTOMS

 secondary to

    skeletal disease
    DIAGNOSIS

. Early recognition of these complications in patients with

    type 1 Gaucher's disease
    DIAGNOSIS

 may lead to improved

    neurologic outcome
    SYMPTOMS

.

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

neurologic complications
systemic features of the illness
neurologic difficulties
involvement of the nervous system
neurologic outcome


A new glucocerebrosidase-gene missense mutation responsible for neuronopathic Gaucher disease in Japanese patients.

We have identified a new T-to-A single-base substitution at nucleotide 3548 (in the genomic sequence) in exon 6 in the glucocerebrosidase gene from a patient with Gaucher disease type 3. This mutation caused a substitution of isoleucine for phenylalanine at amino acid residue 213 (of 497 residues in the mature protein). By in vitro expression study in cultured mammalian cells, this mutation resulted in deficient activity of glucocerebrosidase. By allele-specific oligonucleotide hybridization of selectively PCR-amplified DNA from eight unrelated Japanese Gaucher disease patients, this mutant allele was observed in other neuronopathic Japanese Gaucher disease patients, in moderately frequent occurrence (three of six neuronopathic patients). This observation suggests that this allele was one of severe [corrected] alleles which were related to the development of neurological manifestations of Gaucher disease.

We have identified a

    new T-to-A single-base substitution at nucleotide 3548 (in the genomic sequence) in exon 6 in the glucocerebrosidase gene
    GENETICS

 from a patient with

    Gaucher disease type 3
    DIAGNOSIS

. This

    mutation caused a substitution of isoleucine for phenylalanine at amino acid residue 213 (of 497 residues in the mature protein)
    GENETICS

. By

    in vitro expression study in cultured mammalian cells
    PARACLINICAL

, this mutation resulted in

    deficient activity of glucocerebrosidase
    BIOCHEMICAL

. By

    allele-specific oligonucleotide hybridization of selectively PCR-amplified DNA from
    PARACLINICAL

 eight unrelated

    Japanese
    ETHNICITY

    Gaucher disease
    DIAGNOSIS

 patients, this

    mutant allele
    GENETICS

 was observed in other

    neuronopathic
    DIAGNOSIS

    Japanese Gaucher disease
    ETHNICITY

 patients, in moderately frequent occurrence (three of six

    neuronopathic
    DIAGNOSIS

 patients). This observation suggests that this allele was one of

    severe [corrected] alleles
    GENETICS

 which were related to the development of

    neurological manifestations
    SYMPTOMS

 of

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease type 3
Gaucher disease
neuronopathic
neuronopathic
Gaucher disease


Partial splenectomy for massive splenomegaly secondary to Gaucher's disease.

A 16 year old girl with Type 1 Gaucher's disease presented with massive splenomegaly, hypersplenism and abdominal discomfort. Traditionally hypersplenism has been treated with splenectomy, but this results in a high incidence of overwhelming sepsis and accelerated sphingolipid deposition in both liver and bone. A 90% partial splenectomy was therefore performed leaving a fully vascularized inferior segment of the spleen and resecting 5.8 kg of splenic tissue. The patient made an uneventful recovery with a marked improvement in her haematological parameters and general condition.

A

    16 year old
    AGE

    girl
    GENDER

 with

    Type 1 Gaucher's disease
    DIAGNOSIS

 presented with

    massive splenomegaly
    SYMPTOMS

,

    hypersplenism
    BIOCHEMICAL

 and

    abdominal discomfort
    SYMPTOMS

. Traditionally

    hypersplenism
    BIOCHEMICAL

 has been treated with

    splenectomy
    MEDICATION

, but this results in a high incidence of

    overwhelming sepsis
    SYMPTOMS

 and

    accelerated sphingolipid deposition in both liver and bone
    MICROSCOPIC

. A

    90% partial splenectomy
    MEDICATION

 was therefore performed

    leaving a fully vascularized inferior segment of the spleen and resecting 5.8 kg of splenic tissue
    MEDICATION

. The patient made an uneventful recovery with a

    marked improvement in her haematological parameters and general condition
    SYMPTOMS

.


[Recurrent coxopathy, isolated manifestation of Gaucher's disease].

A case of Gaucher's disease is reported in a 12 year-old girl. Presenting signs consisted of relapsing hip arthritis, while no splenomegaly was detectable. The authors comment the inflammatory or moderately hemorrhagic nature of articular fluid and the diagnostic value of an early decreased uptake on bone scintiscan. The value of magnetic resonance imaging for evaluating bone involvement is emphasized.

A case of

    Gaucher's disease
    DIAGNOSIS

 is reported in a

    12 year-old
    AGE

    girl
    GENDER

. Presenting signs consisted of

    relapsing hip arthritis
    SYMPTOMS

, while

    no splenomegaly was detectable
    NEG_FINDINGS

. The authors comment the

    inflammatory or moderately hemorrhagic nature of articular fluid
    MICROSCOPIC

 and the diagnostic value of an

    early decreased uptake on bone scintiscan
    SYMPTOMS

. The value of

    magnetic resonance imaging
    PARACLINICAL

 for evaluating

    bone involvement
    PARACLINICAL

 is emphasized.


[Acute infantile cerebral form of Gaucher disease].

A foetus causing attention by disharmonic growth retardation and suspected CTG, died within the 34th week of gestation. The infantile cerebral form (type II) of Gaucher's disease was detected by histological examination. In another pregnancy a second afflicted child was discovered by decreased cerebroside-beta-glucosidase activity in amniotic fluid cells. Abortion was therefore induced.

A

    foetus
    AGE

 causing attention by

    disharmonic growth retardation
    SYMPTOMS

 and

    suspected CTG
    SYMPTOMS

,

    died
    SYMPTOMS

    within the 34th week of gestation
    AGE

. The

    infantile cerebral form (type II) of Gaucher's disease
    DIAGNOSIS

 was detected by

    histological examination
    PARACLINICAL

. In another

    pregnancy
    DIAGNOSIS

 a second afflicted child was discovered by

    decreased cerebroside-beta-glucosidase activity in amniotic fluid cells
    BIOCHEMICAL

.

    Abortion
    MEDICATION

 was therefore induced.

disharmonic growth retardation
suspected CTG
died


Hematologic improvement in a patient with Gaucher disease on long-term enzyme replacement therapy: evidence for decreased splenic sequestration and improved red blood cell survival.

We describe here an investigation of the hematologic response of a child with Gaucher disease to a six-year therapeutic trial of human placental mannose-terminated glucocerebrosidase. While on enzyme replacement therapy, the patient's hemoglobin and platelet count significantly increased (6.9 g/dl to 12.2 g/dl, and 39,000/microliters to 74,000/microliters, respectively). Over the same time interval his absolute reticulocyte count decreased (88.1 x 10(3)/microliters to 31.5 x 10(3)/microliters). The patient's splenic volume decreased by over 60% (2108ml to 797ml) and his bone marrow demonstrated a dramatic clearing of Gaucher cell infiltration. Serum erythropoietin levels were at the lower range of normal at points in time when he was severely anemic and did not change with improvement in hemoglobin. Coincident with the improvement in the patient's hemoglobin, in vivo survival of autologous radiolabeled RBCs increased 34%. The improved hematopoietic profile appeared to result primarily from an increase in the in vivo survival of mature hematopoietic elements secondary to a decrease in splenic sequestration. Improved marrow function secondary to the clearing of Gaucher cell infiltrates may also play a role in his improved hematologic status.

We describe here an investigation of the hematologic response of a

    child
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 to a

    six-year therapeutic trial of human placental mannose-terminated glucocerebrosidase
    MEDICATION

. While on

    enzyme replacement therapy
    MEDICATION

, the patient's

    hemoglobin and platelet count significantly increased (6.9 g/dl to 12.2 g/dl, and 39,000/microliters to 74,000/microliters, respectively)
    BIOCHEMICAL

. Over the same time interval his

    absolute reticulocyte count decreased (88.1 x 10(3)/microliters to 31.5 x 10(3)/microliters)
    BIOCHEMICAL

. The patient's

    splenic volume decreased by over 60% (2108ml to 797ml)
    SYMPTOMS

 and his

    bone marrow
    PARACLINICAL

 demonstrated a

    dramatic clearing of Gaucher cell infiltration
    MICROSCOPIC

.

    Serum erythropoietin levels were at the lower range of normal
    BIOCHEMICAL

 at points in time when he was

    severely anemic
    BIOCHEMICAL

 and

    did not change
    NEG_FINDINGS

 with

    improvement in hemoglobin
    BIOCHEMICAL

. Coincident with the

    improvement in the patient's hemoglobin
    BIOCHEMICAL

,

    in vivo survival of autologous radiolabeled RBCs increased 34%
    BIOCHEMICAL

. The

    improved hematopoietic profile
    BIOCHEMICAL

 appeared to result primarily from an

    increase in the in vivo survival of mature hematopoietic elements
    MICROSCOPIC

 secondary to a

    decrease in splenic sequestration
    MICROSCOPIC

. Improved marrow function secondary to the

    clearing of Gaucher cell infiltrates
    MICROSCOPIC

 may also play a role in his improved

    hematologic status
    SYMPTOMS

.