Metaphyseal undertubulation in gaucher disease: resolution at MRI in a patient undergoing enzyme replacement therapy.

Gaucher disease is a sphingolipid storage disorder that results in the accumulation of Gaucher cells within the reticuloendothelial system. The life span can be near normal in the most common form. Our case illustrates the resolution of the skeletal findings in Gaucher disease following enzyme replacement therapy. We also report the correlation of these findings with clinical improvement.

    Gaucher disease
    DIAGNOSIS

 is a

    sphingolipid storage disorder
    DIAGNOSIS

 that results in the

    accumulation of Gaucher cells within the reticuloendothelial system
    MICROSCOPIC

. The life span can be near normal in the most common form. Our case illustrates the

    resolution of the skeletal findings
    SYMPTOMS

 in

    Gaucher disease
    DIAGNOSIS

 following

    enzyme replacement therapy
    MEDICATION

. We also report the correlation of these findings with

    clinical improvement
    SYMPTOMS

.

Gaucher disease
sphingolipid storage disorder
Gaucher disease

resolution of the skeletal findings
clinical improvement


Type I gaucher disease: extraosseous extension of skeletal disease.

To investigate the frequency and morphology of extraosseous extension in patients with Gaucher disease type I.

MRI examinations of the lower extremities were analyzed in 70 patients with Gaucher disease type I. Additionally, the thoracic spine and the midface were investigated on MRI in two patients.

Four cases are presented in which patients with Gaucher disease type I and severe skeletal involvement developed destruction or protrusion of the cortex with extraosseous extension into soft tissues. In one patient, Gaucher cell deposits destroyed the cortex of the mandible and extended into the masseter muscle. In the second patient, multiple paravertebral masses with localized destruction of the cortex were apparent in the thoracic spine. In the third and fourth patient, cortical destruction with extraosseous tissue extending into soft tissues was seen in the lower limbs.

Extraosseous extension is a rare manifestation of Gaucher bone disease. While an increased risk of cancer, especially hematopoietic in origin, is known in patients with Gaucher disease, these extraosseous benign manifestations that may mimic malignant processes should be considered in the differential diagnosis of extraosseous extension into soft tissues. A narrow neck of tissue was apparent in all cases connecting bone and extraosseous extensions.

To investigate the frequency and morphology of

    extraosseous extension
    SYMPTOMS

 in patients with Gaucher disease type I.

    MRI examinations of the lower extremities
    PARACLINICAL

 were analyzed in 70 patients with Gaucher disease type I. Additionally,

    the thoracic spine and the midface
    PARACLINICAL

 were investigated on

    MRI
    PARACLINICAL

 in two patients.

Four cases are presented in which patients with

    Gaucher disease type I
    DIAGNOSIS

 and

    severe skeletal involvement
    SYMPTOMS

 developed

    destruction or protrusion of the cortex with extraosseous extension into soft tissues
    SYMPTOMS

. In one patient,

    Gaucher cell deposits destroyed the cortex of the mandible and extended into the masseter muscle
    MICROSCOPIC

. In the second patient,

    multiple paravertebral masses with localized destruction of the cortex were apparent in the thoracic spine
    SYMPTOMS

. In the third and fourth patient,

    cortical destruction with extraosseous tissue extending into soft tissues was seen in the lower limbs
    SYMPTOMS

.

    Extraosseous extension
    SYMPTOMS

 is a rare manifestation of

    Gaucher bone disease
    DIAGNOSIS

. While an increased risk of

    cancer
    SYMPTOMS

, especially hematopoietic in origin, is known in patients with

    Gaucher disease
    DIAGNOSIS

, these

    extraosseous benign manifestations
    SYMPTOMS

 that may mimic

    malignant processes
    SYMPTOMS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 of

    extraosseous extension into soft tissues
    SYMPTOMS

. A

    narrow neck of tissue
    SYMPTOMS

 was apparent in all cases connecting

    bone and extraosseous extensions
    SYMPTOMS

.

Gaucher disease type I
Gaucher bone disease
Gaucher disease


MRI in acute neuropathic Gaucher's disease.

We present the cranial MRI findings in a 6-month-old girl with biopsy-proven acute neuropathic Gaucher's disease, which include unilateral cerebral atrophy and dural thickening with contrast enhancement.

We present the

    cranial MRI
    PARACLINICAL

 findings in a

    6-month-old
    AGE

    girl
    GENDER

 with

    biopsy-
    DIAGNOSIS

proven

    acute neuropathic Gaucher's disease
    DIAGNOSIS

, which include

    unilateral cerebral atrophy
    SYMPTOMS

 and

    dural thickening with contrast enhancement
    SYMPTOMS

.

biopsy-
acute neuropathic Gaucher's disease


Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC).

The authors describe four siblings from consanguineous parents who presented with oculomotor deficit in early childhood characterized by impaired volitional horizontal saccades, compensatory lateral head thrust, and preservation of vertical movement. When about 10 years of age, heavily calcified aortic and mitral valves required surgery. Fibroblast beta-glucocerebrosidase activity was markedly reduced. Genotype analysis indicated that the two patients who were tested were homozygous for the D409H (1342G-->C) mutation. Relating this rare phenotype of Gaucher disease to D409H mutation will facilitate management of the disease and counseling of families.

The authors describe four

    siblings from consanguineous parents
    FAMILY

 who presented with

    oculomotor deficit
    SYMPTOMS

 in

    early childhood
    AGE

 characterized by

    impaired volitional horizontal saccades
    SYMPTOMS

,

    compensatory lateral head thrust
    SYMPTOMS

, and

    preservation of vertical movement
    SYMPTOMS

. When

    about 10 years of age
    AGE

,

    heavily calcified aortic and mitral valves
    SYMPTOMS

 required

    surgery
    MEDICATION

.

    Fibroblast beta-glucocerebrosidase activity was markedly reduced
    BIOCHEMICAL

.

    Genotype analysis
    PARACLINICAL

 indicated that the two patients who were tested were

    homozygous for the D409H (1342G-->C) mutation
    GENETICS

. Relating this rare phenotype of

    Gaucher disease
    DIAGNOSIS

 to

    D409H mutation
    GENETICS

 will facilitate management of the disease and counseling of families.


Systemic AL amyloidosis in Gaucher disease. A case report and review of the literature.

Chronic Gaucher disease [GD] in association with systemic AL amyloidosis is extremely rare. We describe a 46-year-old Greek male with chronic GD confirmed by low glucocerebroside activity in fibroblasts and N370S/L444P mutations at the cerebrosidase gene, who also had systemic AL amyloidosis diagnosed by bone marrow diffuse plasmacytosis, serum monoclonal IgA-lambda, severe total proteinuria with monoclonal IgA-lambda, Bence-Jones-lambda and amyloid deposits in bone marrow, liver, spleen and kidney biopsy specimens. Treatment with melphalan and prednizolon has dramatically decreased both levels of serum M-IgA and proteinuria and also improved the clinical symptoms of amyloidosis. He died from restrictive cardiac disease 30 months after the diagnosis of amyloidosis. Previously reported cases of GD in association with AL amyloidosis are reviewed.

    Chronic Gaucher disease [GD]
    DIAGNOSIS

    in association with systemic AL amyloidosis
    DIAGNOSIS

 is extremely rare. We describe a

    46-year-old
    AGE

    Greek
    ETHNICITY

    male
    GENDER

 with

    chronic GD
    DIAGNOSIS

 confirmed by

    low glucocerebroside activity in fibroblasts
    BIOCHEMICAL

 and

    N370S/L444P mutations at the cerebrosidase gene
    GENETICS

, who also had

    systemic AL amyloidosis
    DIAGNOSIS

 diagnosed by

    bone marrow diffuse plasmacytosis
    MICROSCOPIC

,

    serum monoclonal IgA-lambda
    BIOCHEMICAL

,

    severe total proteinuria with monoclonal IgA-lambda
    BIOCHEMICAL

    , Bence-Jones-lambda
    MICROSCOPIC

 and

    amyloid deposits in bone marrow, liver, spleen and kidney biopsy specimens
    MICROSCOPIC

.

    Treatment with melphalan and prednizolon
    MEDICATION

 has

    dramatically decreased both levels of serum M-IgA and proteinuria
    BIOCHEMICAL

 and also

    improved the clinical symptoms of amyloidosis
    SYMPTOMS

.

    He
    GENDER

    died
    SYMPTOMS

 from

    restrictive cardiac disease
    SYMPTOMS

 30 months after the diagnosis of

    amyloidosis
    DIAGNOSIS

. Previously reported cases of

    GD in association with AL amyloidosis
    DIAGNOSIS

 are reviewed.


We present a unique case of Budd-Chiari syndrome caused by Gaucher's disease. The diagnosis was based on Doppler sonography, magnetic resonance imaging, contrast-enhanced three-dimensional magnetic resonance angiography, standard venography, and venous pressure measurements and was confirmed histologically.

We present a unique case of

    Budd-Chiari syndrome
    DIAGNOSIS

 caused by

    Gaucher's disease
    DIAGNOSIS

. The diagnosis was based on

    Doppler sonography
    PARACLINICAL

,

    magnetic resonance imaging
    PARACLINICAL

,

    contrast-enhanced three-dimensional magnetic resonance angiography
    PARACLINICAL

,

    standard venography
    PARACLINICAL

, and

    venous pressure measurements
    PARACLINICAL

 and was confirmed

    histologically
    PARACLINICAL

.


Immunohistochemistry applied to the study of bone marrow Gaucher's cells: a case report.

Gaucher's disease is frequently associated with immunologic abnormalities, e.g. hypergammaglobulinemia, polyclonal gammopathy and benign monoclonal gammopathy. A patient with Gaucher's disease and a selective accumulation of IgM k in Gaucher's cells without serum monoclonal gammopathies is described. The selective accumulation is detected by immunohistochemistry analysis performed on cryostat bone marrow biopsies.

    Gaucher's disease
    DIAGNOSIS

 is frequently associated with

    immunologic abnormalities
    SYMPTOMS

, e.g.

    hypergammaglobulinemia
    BIOCHEMICAL

,

    polyclonal gammopathy
    BIOCHEMICAL

 and

    benign monoclonal gammopathy
    DIAGNOSIS

. A patient with

    Gaucher's disease
    DIAGNOSIS

 and a

    selective accumulation of IgM k in Gaucher's cells
    MICROSCOPIC

    without serum monoclonal gammopathies
    NEG_FINDINGS

 is described. The

    selective accumulation
    MICROSCOPIC

 is detected by

    immunohistochemistry analysis performed on cryostat bone marrow biopsies
    PARACLINICAL

.

Gaucher's disease
benign monoclonal gammopathy
Gaucher's disease


Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation.

A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed "sea-blue histiocytes", vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.

A

    36-year-old
    AGE

    woman
    GENDER

 was admitted for

    hepatosplenomegaly
    SYMPTOMS

 and

    anemia
    BIOCHEMICAL

.

    Bone marrow cytology
    PARACLINICAL

 showed

    "sea-blue histiocytes", vacuolated macrophages and plasma cells
    MICROSCOPIC

. As

    primary liver disease
    NEG_FINDINGS

,

    malignancy or hematologic disorders were excluded
    NEG_FINDINGS

, and

    plasma chitotriosidase activity was increased 27-fold over control
    BIOCHEMICAL

, the presence of a

    lysosomal storage disease
    DIAGNOSIS

 was suspected.

    Biochemical analysis of skin fibroblasts
    PARACLINICAL

 revealed

    normal glucocerebrosidase and sphingomyelinase activity
    NEG_FINDINGS

, but

    lipid analysis
    PARACLINICAL

 showed a

    more than 15-fold accumulation of cholesterol esters within the cells
    MICROSCOPIC

. The

    activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects
    BIOCHEMICAL

.

    Mutational analysis of the patient's blood
    PARACLINICAL

 showed the

    homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD)
    GENETICS

; the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical,

    laboratory, cytological
    PARACLINICAL

 and and biochemical findings,

    CESD
    DIAGNOSIS

 can clearly be separated from other more frequent

    inherited lysosomal storage diseases
    DIAGNOSIS

, e.g.

    atypical forms of Gaucher disease
    DIAGNOSIS

.

lysosomal storage disease
CESD
inherited lysosomal storage diseases
atypical forms of Gaucher disease


Continuous intravenous epoprostenol therapy for pulmonary hypertension in Gaucher's disease.

Gaucher's disease is a rare disorder characterized by a deficiency of lysosomal beta-glucosidase. Pulmonary hypertension, the etiology of which is unclear, has been reported to occur in association with Gaucher's disease. We report the use of continuous intravenous epoprostenol (prostacyclin), which has been used to treat other forms of pulmonary hypertension, in a patient with pulmonary hypertension associated with Gaucher's disease. Although its mechanism of action remains unknown, epoprostenol may be an effective form of therapy for chronic pulmonary hypertension due to a variety of conditions, one of which is Gaucher's disease.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare disorder
    GENETICS

 characterized by a

    deficiency of lysosomal beta-glucosidase
    BIOCHEMICAL

.

    Pulmonary hypertension
    SYMPTOMS

, the etiology of which is unclear, has been reported to occur in association with

    Gaucher's disease
    DIAGNOSIS

. We report the use of

    continuous intravenous epoprostenol (prostacyclin)
    MEDICATION

, which has been used to treat other forms of

    pulmonary hypertension
    SYMPTOMS

, in a patient with

    pulmonary hypertension
    SYMPTOMS

 associated with

    Gaucher's disease
    DIAGNOSIS

. Although its mechanism of action remains unknown,

    epoprostenol
    MEDICATION

 may be an effective form of therapy for

    chronic pulmonary hypertension
    SYMPTOMS

 due to a variety of conditions, one of which is

    Gaucher's disease
    DIAGNOSIS

.

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

Pulmonary hypertension
pulmonary hypertension
pulmonary hypertension
chronic pulmonary hypertension


Intracellular transport of acid beta-glucosidase and lysosome-associated membrane proteins is affected in Gaucher's disease (G202R mutation).

Gaucher's disease (GD) is caused by an inherited deficiency of acid beta-glucosidase with storage of glucosylceramides in the lysosomes of macrophages. This study identifies a G202R mutation in the acid beta-glucosidase gene in an infant with severe neuronopathic (type 2) GD and only slightly reduced acid beta-glucosidase activity. Western blot analysis, pulse chase experiments, and the thin frozen section immunogold method were used to analyse the implications of this mutation on the pathogenesis, clinical heterogeneity and diagnostic evaluation of GD. The results show that acid beta-glucosidase persists in the patient's fibroblasts as a mannose-rich polypeptide in the endoplasmic reticulum and is not transported to the lysosomes. By contrast, high expression of the lysosome-associated membrane proteins LAMP-1 and LAMP-2, saposin C, and cathepsin D was observed in the patient's lysosomes. Immunogold labelling of the integral membrane proteins LAMP-1 and LAMP-2 increases significantly at the cell surface of Kupffer cells and fibroblasts as well as at the apical membrane of hepatocytes. In addition, LAMP-1 and LAMP-2 associate with the bilayer of stored glucosylceramide. It is concluded that defective intracellular transport of mutant acid beta-glucosidase from the endoplasmic reticulum to lysosomes leads to a more severe clinical phenotype than the residual enzyme activity may indicate. Furthermore, the detection of LAMP in the tubular bundles of undigested glucosylceramides, as well as their increased concentration at the surfaces of the affected cells, suggests that these proteins play a role in the storage or removal of substrate in GD. Intracellular targeting of acid beta-glucosidase and LAMP contributes to the broad phenotypic heterogeneity of GD.

    Gaucher's disease (GD)
    DIAGNOSIS

 is caused by an

    inherited deficiency of acid beta-glucosidase
    GENETICS

 with

    storage of glucosylceramides in the lysosomes of macrophages
    MICROSCOPIC

. This study identifies a

    G202R mutation in the acid beta-glucosidase gene
    GENETICS

 in an

    infant
    AGE

 with

    severe neuronopathic (type 2) GD
    DIAGNOSIS

 and

    only slightly reduced acid beta-glucosidase activity
    BIOCHEMICAL

.

    Western blot analysis
    PARACLINICAL

,

    pulse chase experiments
    PARACLINICAL

, and the

    thin frozen section immunogold method
    PARACLINICAL

 were used to analyse the implications of this mutation on the pathogenesis, clinical heterogeneity and diagnostic evaluation of

    GD
    DIAGNOSIS

. The results show that

    acid beta-glucosidase persists in the patient's fibroblasts as a mannose-rich polypeptide in the endoplasmic reticulum and is not transported to the lysosomes
    MICROSCOPIC

. By contrast,

    high expression of the lysosome-associated membrane proteins LAMP-1 and LAMP-2, saposin C, and cathepsin D was observed in the patient's lysosomes
    MICROSCOPIC

.

    Immunogold labelling of the integral membrane proteins LAMP-1 and LAMP-2 increases significantly at the cell surface of Kupffer cells and fibroblasts as well as at the apical membrane of hepatocytes
    MICROSCOPIC

. In addition,

    LAMP-1 and LAMP-2 associate with the bilayer of stored glucosylceramide
    MICROSCOPIC

. It is concluded that

    defective intracellular transport of mutant acid beta-glucosidase from the endoplasmic reticulum to lysosomes
    MICROSCOPIC

 leads to a more severe clinical phenotype than the

    residual enzyme activity may indicate
    NEG_FINDINGS

. Furthermore, the

    detection of LAMP in the tubular bundles of undigested glucosylceramides
    MICROSCOPIC

, as well as

    their increased concentration at the surfaces of the affected cells
    MICROSCOPIC

, suggests that these proteins play a role in the

    storage or removal of substrate
    MICROSCOPIC

 in

    GD
    DIAGNOSIS

.

    Intracellular targeting of acid beta-glucosidase and LAMP
    MICROSCOPIC

 contributes to the broad phenotypic heterogeneity of

    GD
    DIAGNOSIS

.

Gaucher's disease (GD)
severe neuronopathic (type 2) GD
GD
GD
GD


Anaphylactoid reaction to imiglucerase, but not to alglucerase, in a type I Gaucher patient.

Imiglucerase, the recombinantly produced enzyme, is gradually replacing the human placental derived alglucerase in the treatment of gaucher patients. We describe the first case, to the best of our knowledge, of an anaphylactoid reaction to imiglucerase in a patient who tolerated alglucerase. The patient was diagnosed at the age of 2 4/12 years with anemia and hepatosplenomegaly. Over the years he had suffered from marked splenomegaly, thrombocytopenia and recurrent bleeding episodes. At the age of 24 he started treatment with imiglucerase. After 3 months of treatment, immediately after starting an infusion, he experienced flushing, cough, tachycardia, palpitation, chest pain and excessive sweating, which reoccurred on a consecutive administration. Substitution with alglucerase was tolerated well, with only mild rash when he was premedicated with benadryl. Immediate skin tests to alglucerase, imiglucerase and gelatin were negative. IgG against alglucerase was undetectable. The in vitro mast cell degranulation test was positive for alglucerase, imiglucerase heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase). This sensitivity to imiglucerase but not to alglucerase, raises the question of future treatment for this patient, since the production of alglucerase may cease, once imiglucerase production will cover the need for replacement enzyme.

    Imiglucerase, the recombinantly produced enzyme
    MEDICATION

, is gradually

    replacing the human placental derived alglucerase
    MEDICATION

 in the treatment of

    gaucher
    DIAGNOSIS

 patients. We describe the first case, to the best of our knowledge, of an

    anaphylactoid reaction to imiglucerase
    DIAGNOSIS

 in a patient who

    tolerated alglucerase
    MEDICATION

. The patient was diagnosed at the

    age of 2 4/12 years
    AGE

 with

    anemia
    BIOCHEMICAL

 and

    hepatosplenomegaly
    SYMPTOMS

. Over the years

    he
    GENDER

 had suffered from

    marked splenomegaly
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

 and

    recurrent bleeding episodes
    SYMPTOMS

. At the

    age of 24
    AGE

    he
    GENDER

 started

    treatment with imiglucerase
    MEDICATION

. After

    3 months of treatment
    MEDICATION

, immediately after starting an infusion,

    he
    GENDER

 experienced

    flushing
    SYMPTOMS

,

    cough
    SYMPTOMS

,

    tachycardia
    SYMPTOMS

,

    palpitation
    SYMPTOMS

,

    chest pain
    SYMPTOMS

 and

    excessive sweating
    SYMPTOMS

, which

    reoccurred
    SYMPTOMS

 on a consecutive administration.

    Substitution with alglucerase
    MEDICATION

 was tolerated well, with only

    mild rash
    SYMPTOMS

 when

    he
    GENDER

 was

    premedicated with benadryl
    MEDICATION

.

    Immediate skin tests to alglucerase, imiglucerase and gelatin were negative
    NEG_FINDINGS

.

    IgG against alglucerase was undetectable
    NEG_FINDINGS

. The

    in vitro mast cell degranulation test was positive for alglucerase, imiglucerase heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase)
    PARACLINICAL

. This

    sensitivity to imiglucerase but not to alglucerase
    NEG_FINDINGS

, raises the question of future treatment for this patient, since the

    production of alglucerase
    NEG_FINDINGS

 may cease, once

    imiglucerase production
    MEDICATION

 will cover the need for

    replacement enzyme
    MEDICATION

.

gaucher
anaphylactoid reaction to imiglucerase

hepatosplenomegaly
marked splenomegaly
recurrent bleeding episodes
flushing
cough
tachycardia
palpitation
chest pain
excessive sweating
reoccurred
mild rash


Pulmonary pathology in Gaucher's disease.

Gaucher's disease is a familial storage disease caused by a deficiency of the enzyme glucocerebrosidase. Pulmonary involvement is considered rare in Gaucher's disease, especially type I. Sporadic case reports have shown various types of lung involvement, but the spectrum of pulmonary pathology in Gaucher's disease has not been described. Nine cases of Gaucher's disease were retrieved from the autopsy file of Hadassah Medical Center, Jerusalem, Israel. There were six cases with type I Gaucher's disease and three cases with type II. Lung sections were evaluated, and special stains were employed, including immunohistochemical stains for CD68, cytokeratin, and CD34. Gaucher cells were found in the lungs in all nine cases. The involvement was considered pathologically significant in five of nine cases and clinically significant in three of nine cases. Four distinct patterns of pulmonary involvement by Gaucher cells emerged: intracapillary (9 of 9), patchy interstitial infiltrates in a lymphatic distribution (2 of 9), massive interstitial thickening of alveolar septa (1 of 9), and intra-alveolar infiltrates (2 of 9). The universal involvement of pulmonary capillaries indicates that this is probably systemic in nature and not intrinsic to the lungs. Pulmonary involvement in Gaucher's disease is commoner than previously recognized. Immunocytochemical stains help to identify isolated Gaucher cells and distinguish them from native alveolar macrophages.

    Gaucher's disease
    DIAGNOSIS

 is a

    familial storage disease
    DIAGNOSIS

 caused by a

    deficiency of the enzyme glucocerebrosidase
    BIOCHEMICAL

.

    Pulmonary involvement
    SYMPTOMS

 is considered rare in

    Gaucher's disease
    DIAGNOSIS

, especially type I. Sporadic case reports have shown various types of

    lung involvement
    SYMPTOMS

, but the spectrum of

    pulmonary pathology
    SYMPTOMS

 in

    Gaucher's disease
    DIAGNOSIS

 has not been described. Nine cases of

    Gaucher's disease
    DIAGNOSIS

 were retrieved from the

    autopsy
    PARACLINICAL

 file of Hadassah Medical Center,

    Jerusalem
    ETHNICITY

,

    Israel
    ETHNICITY

. There were six cases with

    type I Gaucher's disease
    DIAGNOSIS

 and three cases with

    type II
    DIAGNOSIS

.

    Lung sections were evaluated
    PARACLINICAL

, and

    special stains
    PARACLINICAL

 were employed, including

    immunohistochemical stains for CD68, cytokeratin
    PARACLINICAL

, and

    CD34
    PARACLINICAL

.

    Gaucher cells were found in the lungs
    MICROSCOPIC

 in all nine cases. The involvement was considered pathologically significant in five of nine cases and clinically significant in three of nine cases. Four distinct patterns of

    pulmonary involvement by Gaucher cells
    MICROSCOPIC

 emerged:

    intracapillary
    MICROSCOPIC

 (9 of 9),

    patchy interstitial infiltrates in a lymphatic distribution
    MICROSCOPIC

 (2 of 9),

    massive interstitial thickening of alveolar septa
    SYMPTOMS

 (1 of 9), and

    intra-alveolar infiltrates
    MICROSCOPIC

 (2 of 9). The

    universal involvement of pulmonary capillaries
    MICROSCOPIC

 indicates that this is probably systemic in nature and

    not intrinsic to the lungs
    NEG_FINDINGS

.

    Pulmonary involvement
    SYMPTOMS

 in

    Gaucher's disease
    DIAGNOSIS

 is commoner than previously recognized.

    Immunocytochemical stains
    PARACLINICAL

 help to identify

    isolated Gaucher cells
    MICROSCOPIC

 and distinguish them from

    native alveolar macrophages
    MICROSCOPIC

.

Gaucher's disease
familial storage disease
Gaucher's disease
Gaucher's disease
Gaucher's disease
type I Gaucher's disease
type II
Gaucher's disease


[Gaucher's disease in a 22-year-old female patient].

Gaucher's disease is a sphingolipidosis with a genetically conditioned deficiency of cerebroside-beta-glucosidase which can be encountered in everyday practice and not only in paediatrics. The authors submit the case-history of a 22-year-old Ukrainian patient with a fully developed type 1 Gaucher disease, and a brief review of the diagnostic and therapeutic possibilities. Due to the more extensive migration of the population on the territory of the Czech Republic a more frequent occurrence of the disease can be envisaged.

    Gaucher's disease
    DIAGNOSIS

 is a

    sphingolipidosis
    DIAGNOSIS

 with a

    genetically conditioned
    GENETICS

    deficiency of cerebroside-beta-glucosidase
    BIOCHEMICAL

 which can be encountered in everyday practice and not only in paediatrics. The authors submit the case-history of a

    22-year-old
    AGE

    Ukrainian
    ETHNICITY

 patient with a fully developed

    type 1 Gaucher disease
    DIAGNOSIS

, and a brief review of the diagnostic and therapeutic possibilities. Due to the more extensive migration of the population on the territory of the

    Czech Republic
    ETHNICITY

 a more frequent occurrence of the disease can be envisaged.

Gaucher's disease
sphingolipidosis
type 1 Gaucher disease


Is the perinatal lethal form of Gaucher disease more common than classic type 2 Gaucher disease?

In recent years there has been increased recognition of a severe perinatal lethal form of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase. We previously reported a case of severe type 2 Gaucher disease which was seen in a medical center in Rotterdam and now present three new cases from two other families seen at the same center. Mutational analyses of these cases revealed two novel mutations, H311R and V398F, located in exons 8 and 9, respectively. The identification of four cases of lethal type 2 Gaucher disease in a single center seems to be a function of increased awareness of this phenotype, rather than of geographic clustering. The actual incidence of lethal type 2 Gaucher disease may be underestimated, as many cases may have been misclassified as collodion babies or hydrops of unknown cause.

In recent years there has been increased recognition of a

    severe perinatal lethal form of Gaucher disease
    DIAGNOSIS

, the

    inherited deficiency of lysosomal glucocerebrosidase
    GENETICS

. We previously reported a case of

    severe type 2 Gaucher disease
    DIAGNOSIS

 which was seen in a medical center in

    Rotterdam
    ETHNICITY

 and now present three new cases from two other families seen at the same center.

    Mutational analyses
    PARACLINICAL

 of these cases revealed

    two novel mutations, H311R and V398F, located in exons 8 and 9, respectively
    GENETICS

. The identification of four cases of

    lethal type 2 Gaucher disease
    DIAGNOSIS

 in a single center seems to be a function of increased awareness of this phenotype, rather than of geographic clustering. The actual incidence of

    lethal type 2 Gaucher disease
    DIAGNOSIS

 may be underestimated, as many cases may have been misclassified as

    collodion babies
    DIAGNOSIS

 or

    hydrops of unknown cause
    DIAGNOSIS

.


Type 1 Gaucher disease presenting with extensive mandibular lytic lesions: identification and expression of a novel acid beta-glucosidase mutation.

The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid beta-glucosidase activity. Mutation analysis identified heteroallelism for acid beta-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material approximately 0.21), which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments in Type 1 Gaucher patients should be performed.

The finding of

    extensive lytic lesions in the mandible
    SYMPTOMS

 of a

    19-year-old
    AGE

    Ashkenazi Jewish
    ETHNICITY

    woman
    GENDER

 led to the diagnosis of

    Type 1 Gaucher disease
    DIAGNOSIS

.

    She
    GENDER

 had

    extensive skeletal involvement
    SYMPTOMS

,

    marked hepatosplenomegaly
    SYMPTOMS

, and

    deficient acid beta-glucosidase activity
    BIOCHEMICAL

.

    Mutation analysis
    PARACLINICAL

 identified

    heteroallelism for acid beta-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9
    GENETICS

.

    Expression of the P401L allele
    GENETICS

 resulted in an

    enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material approximately 0.21), which was similar to that of the mild N370S mutant enzyme
    BIOCHEMICAL

. The

    expression studies
    PARACLINICAL

 predicted a

    mild phenotype for the proposita's N370S/P401L genotype
    GENETICS

 which was inconsistent with her

    severe diffuse skeletal disease and organ involvement
    SYMPTOMS

. Since

    lytic mandibular lesions
    SYMPTOMS

 may be complicated by

    osteomyelitis
    SYMPTOMS

,

    pathologic fracture
    SYMPTOMS

, and

    tooth loss
    SYMPTOMS

,

    regular dental assessments
    PARACLINICAL

 in

    Type 1 Gaucher
    DIAGNOSIS

 patients should be performed.


[Diagnostic difficulties in Gaucher disease: report of two cases].

Diagnostic difficulties of Gaucher disease, a disorder resulted from a deficient activity of glucocerebrosidase is reported. Gaucher disease was described in the 16 year old male, 5 years after manifestation of the very first symptoms (fracture and osteomyelitis). At the age of 14, the cirrhosis due to viral hepatitis accompanied with splenomegaly was diagnosed. This findings was not associated with the earlier osseous disorders. Histopathologic examination of the removed spleen facilitate the diagnosis. The second case refers to 20 year old female. Clinical symptoms and additional test pointed to malignant neoplasm of thyroid, the reproductive organs or cancer of indistinguishable primary focus with metastases in the liver. Trepanobiopsy of bone marrow had made an accurate diagnosis possible, while determination of beta-glucosidase activity in peripheral white blood cells, chitotriosidase activity, and molecular investigations of gene specific to beta-glucocerebrosidase proved it.

Diagnostic difficulties of

    Gaucher disease
    DIAGNOSIS

, a disorder resulted from a

    deficient activity of glucocerebrosidase
    BIOCHEMICAL

 is reported.

    Gaucher disease
    DIAGNOSIS

 was described in the

    16 year old
    AGE

    male
    GENDER

, 5 years after manifestation of the very first symptoms (

    fracture and osteomyelitis)
    SYMPTOMS

. At the

    age of 14
    AGE

, the

    cirrhosis due to viral hepatitis
    DIAGNOSIS

 accompanied with

    splenomegaly
    SYMPTOMS

 was diagnosed. This findings was

    not associated with the earlier osseous disorders
    NEG_FINDINGS

.

    Histopathologic examination of the removed spleen
    PARACLINICAL

 facilitate the diagnosis. The second case refers to

    20 year old
    AGE

    female
    GENDER

. Clinical symptoms and additional test pointed to

    malignant neoplasm of thyroid, the reproductive organs
    DIAGNOSIS

 or

    cancer of indistinguishable primary focus with metastases in the liver
    SYMPTOMS

.

    Trepanobiopsy of bone marrow
    PARACLINICAL

 had made an accurate diagnosis possible, while

    determination of beta-glucosidase activity in peripheral white blood cells
    BIOCHEMICAL

,

    chitotriosidase activity
    BIOCHEMICAL

, and

    molecular investigations of gene specific to beta-glucocerebrosidase
    PARACLINICAL

 proved it.


Enzyme therapy in Gaucher disease type 2: an autopsy case.

A Japanese patient with Gaucher disease type 2 was treated with enzyme therapy, alglucerase, from 7 to 22 months of age. Whereas hematologic parameters were normalized and hepatosplenomegaly was alleviated, no improvement in neurologic symptoms occurred, and the patient died of respiratory failure at age 22 months. Postmortem examination revealed massive intra-alveolar infiltration of Gaucher cells in lungs and in the central nervous system, i.e., the presence of Gaucher cells in the perivascular Virchow-Robins spaces in the cortex and deep white matter and extensive lamilar necrosis with reactive proliferation of blood vessels and macrophage infiltration of the cerebral cortex. It is suggested that enzyme therapy, with thus far recommended dose, does not prevent long-term respiratory and central nervous system involvement in severe varients of Gaucher disease.

A

    Japanese
    ETHNICITY

 patient with

    Gaucher disease type 2
    DIAGNOSIS

 was

    treated with enzyme therapy, alglucerase, from 7 to 22 months of age
    MEDICATION

. Whereas

    hematologic parameters were normalized
    BIOCHEMICAL

 and

    hepatosplenomegaly was alleviated
    SYMPTOMS

,

    no improvement in neurologic symptoms
    NEG_FINDINGS

 occurred, and the patient

    died
    SYMPTOMS

 of

    respiratory failure
    SYMPTOMS

 at

    age 22 months
    AGE

.

    Postmortem examination
    PARACLINICAL

 revealed

    massive intra-alveolar infiltration of Gaucher cells in lungs and in the central nervous system
    MICROSCOPIC

, i.e., the

    presence of Gaucher cells in the perivascular Virchow-Robins spaces in the cortex and deep white matter
    MICROSCOPIC

 and

    extensive lamilar necrosis with reactive proliferation of blood vessels and macrophage infiltration of the cerebral cortex
    MICROSCOPIC

. It is suggested that

    enzyme therapy
    MEDICATION

, with thus far recommended dose,

    does not prevent long-term respiratory and central nervous system involvement
    NEG_FINDINGS

 in

    severe varients of Gaucher disease
    DIAGNOSIS

.

Gaucher disease type 2
severe varients of Gaucher disease

hepatosplenomegaly was alleviated
died
respiratory failure


Pregnancy in Gaucher disease.

An 18-year old woman with type I Gaucher disease and two uncomplicated pregnancies is described. Although she experienced one miscarriage and pregnancy was associated with exaggeration of the clinical symptoms, leading to the diagnosis of the disorder, both her 2nd and 3rd pregnancies were uneventful and deterioration of her clinical situation was not observed. The issue of criteria for risk assessment in pregnancy of type I Gaucher disease patients is addressed.

An

    18-year old
    AGE

    woman
    GENDER

 with

    type I Gaucher disease
    DIAGNOSIS

 and two

    uncomplicated pregnancies
    SYMPTOMS

 is described. Although

    she
    GENDER

 experienced one

    miscarriage
    SYMPTOMS

 and

    pregnancy
    SYMPTOMS

 was associated with

    exaggeration of the clinical symptoms
    SYMPTOMS

, leading to the diagnosis of the disorder, both her 2nd and 3rd pregnancies were

    uneventful
    NEG_FINDINGS

 and

    deterioration of her clinical situation was not observed
    NEG_FINDINGS

. The issue of criteria for risk assessment in

    pregnancy
    DIAGNOSIS

 of

    type I Gaucher disease
    DIAGNOSIS

 patients is addressed.

type I Gaucher disease
pregnancy
type I Gaucher disease

uncomplicated pregnancies
miscarriage
pregnancy
exaggeration of the clinical symptoms


Brainstem pathology of infantile Gaucher's disease with only wave I and II of auditory brainstem response.

We studied the auditory brainstem response (ABR) and neuropathology in a female infant who died at six months of age because of typical infantile Gaucher's disease. The patient was hospitalized for hepatosplenomegaly and failure to thrive. Her ABR showed only waves I and II. The neuropathological study disclosed that: (1) Gaucher's cells were found in the perivascular region of the cerebrum and anterior ventral nucleus of the thalamus. (2) Gliosis was found in the dorsal part of the brainstem rather than the ventral part. (3) Neuronal cells in the superior olivary nucleus were lost, and marked gliosis was found in the cochlear nucleus. The disappearance of wave III and later waves of ABR could be supported by these pathological findings.

We studied the

    auditory brainstem response (ABR)
    PARACLINICAL

 and

    neuropathology
    PARACLINICAL

 in a

    female
    GENDER

    infant
    AGE

 who

    died
    SYMPTOMS

    at six months of age
    AGE

 because of typical

    infantile Gaucher's disease
    DIAGNOSIS

. The patient was hospitalized for

    hepatosplenomegaly
    SYMPTOMS

 and

    failure to thrive
    SYMPTOMS

.

    Her
    GENDER

 ABR showed

    only waves I and II
    SYMPTOMS

. The

    neuropathological study
    PARACLINICAL

 disclosed that: (1)

    Gaucher's cells were found in the perivascular region of the cerebrum and anterior ventral nucleus of the thalamus
    MICROSCOPIC

. (2)

    Gliosis was found in the dorsal part of the brainstem rather than the ventral part
    MICROSCOPIC

. (3)

    Neuronal cells in the superior olivary nucleus were lost
    MICROSCOPIC

, and

    marked gliosis was found in the cochlear nucleus
    MICROSCOPIC

. The

    disappearance of wave III and later waves of ABR
    SYMPTOMS

 could be supported by these pathological findings.


Gaucher's disease with valve calcification: possible role of Gaucher cells, bone matrix proteins and integrins.

Gaucher's disease, an autosomal recessive storage disease, leads to deposition of glucocerebrosides in various organs, especially those of the reticuloendothelial system. The heart is not thought to be frequently involved and studies of patients with cardiac involvement have concentrated on myocardial involvement. Despite careful prior investigation Gaucher cells have never been detected in the valves of these patients. Pathological findings of a patient with Gaucher's disease, type IIIc, with prominent cardiac valvular involvement are reported and, for the first time, the presence of Gaucher cells in the valve tissue is documented. There is evidence that the pathogenesis of the valvular injury may be by way of a cell-mediated mechanism involving bone matrix proteins and integrins.

    Gaucher's disease
    DIAGNOSIS

, an

    autosomal recessive
    GENETICS

    storage disease
    DIAGNOSIS

, leads to

    deposition of glucocerebrosides in various organs, especially those of the reticuloendothelial system
    MICROSCOPIC

. The heart is not thought to be frequently involved and studies of patients with

    cardiac involvement
    SYMPTOMS

 have concentrated on

    myocardial involvement
    SYMPTOMS

. Despite careful prior investigation

    Gaucher cells have never been detected in the valves
    MICROSCOPIC

 of these patients. Pathological findings of a patient with

    Gaucher's disease, type IIIc
    DIAGNOSIS

, with

    prominent cardiac valvular involvement
    SYMPTOMS

 are reported and, for the first time, the

    presence of Gaucher cells in the valve tissue
    MICROSCOPIC

 is documented. There is evidence that the pathogenesis of the

    valvular injury
    SYMPTOMS

 may be by way of a cell-mediated mechanism involving bone matrix proteins and integrins.

Gaucher's disease
storage disease
Gaucher's disease, type IIIc

cardiac involvement
myocardial involvement
prominent cardiac valvular involvement
valvular injury


[Gaucher's disease type I: an infrequent cause of portal hypertension].

Portal hypertension associated to Gaucher's disease type I with non cirrhotic liver involvement is a very in-equent finding. We report a case of Gaucher's disease type I without cirrhosis in which portal hypertension is the main manifestation. The mechanism of the portal hypertension is discussed in our report and can be related to an elevation in hepatic fluid resistance due to the Gaucher's cells compression on sinusoids.

    Portal hypertension
    SYMPTOMS

 associated to

    Gaucher's disease type I
    DIAGNOSIS

 with

    non cirrhotic liver involvement
    SYMPTOMS

 is a very in-equent finding. We report a case of

    Gaucher's disease type I
    DIAGNOSIS

    without cirrhosis
    NEG_FINDINGS

 in which

    portal hypertension
    SYMPTOMS

 is the main manifestation. The mechanism of the

    portal hypertension
    SYMPTOMS

 is discussed in our report and can be related to an

    elevation in hepatic fluid resistance
    SYMPTOMS

 due to the

    Gaucher's cells compression on sinusoids
    MICROSCOPIC

.

Portal hypertension
non cirrhotic liver involvement
portal hypertension
portal hypertension
elevation in hepatic fluid resistance

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


Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease.

Gaucher disease is an autosomal recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal hydrolase, acid beta-glucosidase. Three phenotypically distinct subtypes result from different acid beta-glucosidase mutations encoding enzymes with absent or low activity. A severe neonatal type 2 variant who presented with collodion skin, ichthyosis, and a rapid neurodegenerative course had two novel acid beta-glucosidase alleles: a complex, maternally derived allele, E326K+L444P, and a paternally inherited nonsense mutation, E233X. Because the only other non-pseudogene-derived complex allele, D140H+E326K, also had the E326K lesion and was reported in a mild type 1 patient with a D140H+E326K/K157Q genotype, these complex alleles and their individual mutations were expressed and characterized. Because the E233X mutation expressed no activity and the K157Q allele had approximately 1% normal specific activity based on cross-reacting immunologic material (CRIM SA) in the baculovirus system, the residual activity in both patients was primarily from their complex alleles. In the type 1 patient, the D140H+E326K allele was neuroprotective, encoding an enzyme with a catalytic efficiency similar to that of the N370S enzyme. In contrast, the E326K+L444P allele did not have sufficient activity to protect against the neurologic manifestations and, in combination with the inactive E233X lesion, resulted in the severe neonatal type 2 variant. Thus, characterization of these novel genotypes with non-pseudogene-derived complex mutations provided the pathogenic basis for their diverse phenotypes.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    inborn error of glycosphingolipid metabolism
    DIAGNOSIS

 caused by the

    deficient activity of the lysosomal hydrolase, acid beta-glucosidase
    BIOCHEMICAL

. Three phenotypically distinct subtypes result from different

    acid beta-glucosidase mutations
    GENETICS

 encoding

    enzymes with absent or low activity
    BIOCHEMICAL

. A

    severe neonatal type 2 variant
    DIAGNOSIS

 who presented with

    collodion skin
    SYMPTOMS

,

    ichthyosis
    SYMPTOMS

, and a

    rapid neurodegenerative course
    SYMPTOMS

 had two novel acid beta-glucosidase alleles: a complex, maternally derived allele, E326K+L444P, and a paternally inherited nonsense mutation, E233X. Because the

    only other non-pseudogene-derived complex allele, D140H+E326K, also had the E326K lesion
    GENETICS

 and was reported in a

    mild type 1
    DIAGNOSIS

 patient with a

    D140H+E326K/K157Q genotype
    GENETICS

, these

    complex alleles
    GENETICS

 and their individual mutations were expressed and characterized. Because the

    E233X mutation expressed no activity
    GENETICS

 and the

    K157Q allele had approximately 1% normal specific activity based on cross-reacting immunologic material (CRIM SA
    GENETICS

) in the baculovirus system, the residual activity in both patients was primarily from their

    complex alleles
    GENETICS

. In the

    type 1
    DIAGNOSIS

 patient,

    the D140H+E326K allele was neuroprotective
    GENETICS

, encoding an

    enzyme with a catalytic efficiency similar to that of the N370S enzyme
    BIOCHEMICAL

. In contrast, the

    E326K+L444P allele
    GENETICS

    did not have sufficient activity to protect against the neurologic manifestations
    NEG_FINDINGS

 and, in combination with the

    inactive E233X lesion
    GENETICS

, resulted in the

    severe neonatal type 2 variant
    DIAGNOSIS

. Thus, characterization of these

    novel genotypes with non-pseudogene-derived complex mutations
    GENETICS

 provided the pathogenic basis for their diverse phenotypes.

collodion skin
ichthyosis
rapid neurodegenerative course


Hepatopulmonary syndrome in Gaucher disease with right-to-left shunt: evaluation and measurement using Tc-99m MAA.

Hepatomegaly is a common manifestation in Gaucher disease. In some patients with the disease, hepatic fibrosis and portal hypertension are observed. A patient with Gaucher disease with the hepatopulmonary syndrome associated with severe cyanosis and hypoxemia was examined for intrapulmonary right-to-left shunt using Tc-99m MAA. Quantitative evaluation revealed an approximately 50% right to left shunt as indicated by Tc-99m MAA activity in the lungs and systemic organs.

    Hepatomegaly
    SYMPTOMS

 is a common manifestation in

    Gaucher disease
    DIAGNOSIS

. In some patients with the disease,

    hepatic fibrosis
    SYMPTOMS

 and

    portal hypertension
    SYMPTOMS

 are observed. A patient with

    Gaucher disease
    DIAGNOSIS

 with the

    hepatopulmonary syndrome
    SYMPTOMS

 associated with

    severe cyanosis
    SYMPTOMS

 and

    hypoxemia
    SYMPTOMS

 was examined for

    intrapulmonary right-to-left shunt
    SYMPTOMS

 using

    Tc-99m MAA
    PARACLINICAL

.

    Quantitative evaluation
    PARACLINICAL

 revealed an

    approximately 50% right to left shunt
    SYMPTOMS

 as indicated by

    Tc-99m MAA activity in the lungs and systemic organs
    MICROSCOPIC

.

Hepatomegaly
hepatic fibrosis
portal hypertension
hepatopulmonary syndrome
severe cyanosis
hypoxemia
intrapulmonary right-to-left shunt
approximately 50% right to left shunt


[Uveitis masquerade syndrome in Gaucher disease. Causal treatment by alglucerase substitution therapy].

Gaucher's disease, a sphingolipidose transmitted by autosomal-recessive inheritance, is caused by a deficiency of the lysosomal enzyme beta-glucocerebrosidase which is responsible for hydrolysation of glucocerebroside to ceramid and glucose. Thus glucocerebroside is accumulated in the reticuloendothelial cells of spleen, liver and bone marrow and pathognomonic Gaucher's cells are formed.

In May 1997 a 42-year-old female patient presented with left-sided intermediate uveitis of unknown origin and decreasing visual acuity to perception of hand movements and intact projection of light since September 1996. To exclude a systemic disease a thorough medical examination--showing hepatoslpenomegaly, anemia, thrombocytopenia and bone lesions--was initiated and revealed advanced M. Gaucher (Type I) by bone marrow punction. Intravenous therapy with alglucerase was administered promptly. After five months of treatment vitreous opacities resolved almost completely and visual acuity increased to 0.7.

The dramatic improvement occurred under treatment with alglucerase after no response to steroid treatment. Thus intermediate uveitis with severe vitritis can be interpreted as uveitis masquerade syndrome with M. Gaucher. To the best of our knowledge, this is the first case of M. Gaucher presenting initially as intermediate uveitis and showing successful clinical improvement during administration of alglucerase.

    Gaucher's disease
    DIAGNOSIS

, a

    sphingolipidose
    DIAGNOSIS

    transmitted by autosomal-recessive inheritance
    GENETICS

, is caused by a

    deficiency of the lysosomal enzyme beta-glucocerebrosidase
    BIOCHEMICAL

 which is responsible for

    hydrolysation of glucocerebroside to ceramid and glucose
    MICROSCOPIC

. Thus

    glucocerebroside is accumulated in the reticuloendothelial cells of spleen, liver and bone marrow
    MICROSCOPIC

 and

    pathognomonic Gaucher's cells are formed
    MICROSCOPIC

.

In May 1997 a

    42-year-old
    AGE

    female
    GENDER

 patient presented with

    left-sided intermediate uveitis of unknown origin
    SYMPTOMS

 and

    decreasing visual acuity to perception of hand movements
    SYMPTOMS

 and

    intact projection of light
    SYMPTOMS

 since September 1996. To

    exclude a systemic disease
    NEG_FINDINGS

 a

    thorough medical examination
    PARACLINICAL

--showing

    hepatoslpenomegaly
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

 and

    bone lesions
    SYMPTOMS

--was initiated and revealed

    advanced M. Gaucher (Type I)
    MICROSCOPIC

 by

    bone marrow punction
    PARACLINICAL

.

    Intravenous therapy with alglucerase
    MEDICATION

 was administered promptly. After

    five months of treatment
    MEDICATION

    vitreous opacities resolved almost completely
    SYMPTOMS

 and visual acuity increased to 0.7.

The

    dramatic improvement
    SYMPTOMS

 occurred under

    treatment with alglucerase
    MEDICATION

 after

    no response to steroid treatment
    NEG_FINDINGS

. Thus

    intermediate uveitis
    DIAGNOSIS

 with

    severe vitritis
    SYMPTOMS

 can be interpreted as

    uveitis masquerade syndrome with M. Gaucher
    DIAGNOSIS

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

    M. Gaucher
    DIAGNOSIS

 presenting initially as

    intermediate uveitis
    DIAGNOSIS

 and showing

    successful clinical improvement
    SYMPTOMS

 during

    administration of alglucerase
    MEDICATION

.

exclude a systemic disease
no response to steroid treatment

Intravenous therapy with alglucerase
five months of treatment
treatment with alglucerase
administration of alglucerase


Massive splenomegaly and Epstein-Barr virus-associated infectious mononucleosis in a patient with Gaucher disease.

Gaucher disease should be considered in the differential diagnosis of a patient with Epstein-Barr virus (EBV) infection who has unexplained or disproportionate splenomegaly.

A previously asymptomatic adolescent with EBV-associated infectious mononucleosis and massive splenomegaly is described. He was found to have Gaucher disease on bone marrow biopsy, which was performed to exclude a hematologic malignancy. The diagnosis was confirmed by assay of beta-glucosidase enzyme activity.

Regression of splenomegaly and improving hematologic indices.

Patients with infectious mononucleosis and disproportionate organomegaly should be investigated to exclude a hematologic malignancy or an underlying storage disorder such as Gaucher disease.

    Gaucher disease
    DIAGNOSIS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 of a patient with

    Epstein-Barr virus (EBV) infection
    DIAGNOSIS

 who has

    unexplained or disproportionate splenomegaly
    SYMPTOMS

.

A previously

    asymptomatic
    NEG_FINDINGS

    adolescent
    AGE

 with

    EBV-associated infectious mononucleosis
    DIAGNOSIS

 and

    massive splenomegaly
    SYMPTOMS

 is described.

    He
    GENDER

 was found to have

    Gaucher disease
    DIAGNOSIS

 on

    bone marrow biopsy
    PARACLINICAL

, which was performed to

    exclude a hematologic malignancy
    NEG_FINDINGS

. The diagnosis was confirmed by

    assay of beta-glucosidase enzyme activity
    BIOCHEMICAL

.

    Regression of splenomegaly
    SYMPTOMS

 and

    improving hematologic indices
    BIOCHEMICAL

.

Patients with

    infectious mononucleosis
    DIAGNOSIS

 and

    disproportionate organomegaly
    SYMPTOMS

 should be investigated to

    exclude a hematologic malignancy
    NEG_FINDINGS

 or an

    underlying storage disorder such as Gaucher disease
    NEG_FINDINGS

.

Gaucher disease
Epstein-Barr virus (EBV) infection
EBV-associated infectious mononucleosis
Gaucher disease
infectious mononucleosis


Technetium-99m-HmPAO brain SPECT in infantile Gaucher's disease.

The authors report serial technetium-99m hexamethylpropylene-amine-oxime brain single photon emission computed tomography (SPECT) findings in two infants with Gaucher's disease type 2. Detailed neurologic and laboratory examinations, including bone marrow biopsies and enzymatic assays, were described. Serial brain magnetic resonance imaging studies in one patient illustrated the progressive cerebral atrophy in the frontal and temporal lobes. The SPECT in both cases demonstrated positive findings of initial scattered hypoperfusion, with extending to hypoperfusion of the entire cerebrum after 4 months of clinical deterioration. These changes in the SPECT findings may reflect progressive degeneration of the cerebrum in Gaucher's disease type 2. Brain SPECT may provide useful information on cerebral flow and metabolic distribution corresponding to the neurologic deficits of neuronopathic Gaucher's disease.

The authors report

    serial technetium-99m hexamethylpropylene-amine-oxime brain single photon emission computed tomography (SPECT) findings
    PARACLINICAL

 in two

    infants
    AGE

 with

    Gaucher's disease type 2
    DIAGNOSIS

.

    Detailed neurologic and laboratory examinations
    PARACLINICAL

, including

    bone marrow biopsies
    PARACLINICAL

 and

    enzymatic assays
    PARACLINICAL

, were described.

    Serial brain magnetic resonance imaging studies
    PARACLINICAL

 in one patient illustrated the

    progressive cerebral atrophy in the frontal and temporal lobes
    SYMPTOMS

. The

    SPECT
    PARACLINICAL

 in both cases demonstrated

    positive findings of initial scattered hypoperfusion, with extending to hypoperfusion of the entire cerebrum
    SYMPTOMS

 after

    4 months of clinical deterioration
    SYMPTOMS

. These changes in the SPECT findings may reflect

    progressive degeneration of the cerebrum
    SYMPTOMS

 in

    Gaucher's disease type 2
    DIAGNOSIS

.

    Brain SPECT
    PARACLINICAL

 may provide useful information on cerebral flow and metabolic distribution corresponding to the

    neurologic deficits
    SYMPTOMS

 of

    neuronopathic Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease type 2
Gaucher's disease type 2
neuronopathic Gaucher's disease


Pseudogaucher cells in cutaneous Mycobacterium avium intracellulare infection: report of a case.

We report on a patient infected with human immunodeficiency virus, and with cutaneous Mycobacterium avium intracellulare, in whom many cells with abundant reticulated cytoplasm resembling the characteristic cells of Gauchers disease ("pseudogaucher cells") were noted within the dermal infiltrate on biopsy. Although pseudogaucher cells have been reported in association with M. avium intracellulare infection in extracutaneous sites, this is, to our knowledge, the first report of cutaneous pseudogaucher cells in the skin.

We report on a patient

    infected with human immunodeficiency virus
    DIAGNOSIS

, and with

    cutaneous Mycobacterium avium intracellulare
    DIAGNOSIS

, in whom

    many cells with abundant reticulated cytoplasm resembling the characteristic cells of Gauchers disease ("pseudogaucher cells") were noted within the dermal infiltrate
    MICROSCOPIC

 on

    biopsy
    PARACLINICAL

. Although

    pseudogaucher cells
    MICROSCOPIC

 have been reported in association with

    M. avium intracellulare infection
    DIAGNOSIS

 in

    extracutaneous sites
    MICROSCOPIC

, this is, to our knowledge, the first report of

    cutaneous pseudogaucher cells in the skin
    MICROSCOPIC

.


Splenic abscess in a patient with type 3 Gaucher's disease receiving enzyme replacement therapy.

We report the rare complication of a splenic abscess in an 11-year-old girl with type 3 Gaucher's disease, massive splenomegaly, and a splenic cyst after commencement of enzyme replacement therapy. This case highlights potential difficulties in establishing the diagnosis of splenic abscess in the presence of pre-existing splenic pathology.

We report the rare complication of a

    splenic abscess
    DIAGNOSIS

 in an

    11-year-old
    AGE

    girl
    GENDER

 with

    type 3 Gaucher's disease
    DIAGNOSIS

,

    massive splenomegaly
    SYMPTOMS

, and a

    splenic cyst
    SYMPTOMS

 after

    commencement of enzyme replacement therapy
    MEDICATION

. This case highlights potential difficulties in establishing the diagnosis of

    splenic abscess
    DIAGNOSIS

 in the presence of pre-existing

    splenic pathology
    SYMPTOMS

.

splenic abscess
type 3 Gaucher's disease
splenic abscess

massive splenomegaly
splenic cyst
splenic pathology


Neuronopathic juvenile glucosylceramidosis due to sap-C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant.

Glucosylceramide lipidosis results from a defective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme beta-glucocerebrosidase and a sphingolipid activator protein. While most Gaucher cases are due to mutations within the gene that codes for the lysosomal enzyme, only two patients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator protein C (sap-C). Here we present the detailed neurological manifestations, neuropathological findings and brain lipid composition in one sap-C-deficient patient. The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks and generalized seizures resistant to all antiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathological studies demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions but the glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase. Fatty acid composition of the ceramide moiety clearly suggests that gangliosides are the main precursors in the cerebral cortex, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiological significance of these proteins.

    Glucosylceramide lipidosis
    DIAGNOSIS

 results from a

    defective lysosomal degradation of this glycolipid
    MICROSCOPIC

.

    Lipid degradation
    BIOCHEMICAL

 is controlled by two components, the

    enzyme beta-glucocerebrosidase
    BIOCHEMICAL

 and a

    sphingolipid activator protein
    BIOCHEMICAL

. While most

    Gaucher
    DIAGNOSIS

 cases are due to

    mutations within the gene that codes for the lysosomal enzyme
    GENETICS

, only two patients have been described with

    normal enzyme levels
    NEG_FINDINGS

 and

    mutations in the gene for the sphingolipid activator protein C (sap-C)
    GENETICS

. Here we present the detailed neurological manifestations, neuropathological findings and

    brain lipid composition
    PARACLINICAL

 in one

    sap-C-deficient
    BIOCHEMICAL

 patient. The patient was an

    8-year-old
    AGE

    boy
    GENDER

 who presented with

    transient losses of consciousness
    SYMPTOMS

,

    myoclonic jerks
    SYMPTOMS

 and

    generalized seizures
    SYMPTOMS

    resistant to all antiepileptic drugs
    NEG_FINDINGS

.

    He
    GENDER

 developed

    progressive horizontal ophthalmoplegia
    SYMPTOMS

,

    pyramidal and cerebellar signs
    SYMPTOMS

, and

    died
    SYMPTOMS

 at the

    age of 15.5 years
    AGE

.

    Neuropathological studies
    PARACLINICAL

 demonstrated

    neuronal cell loss
    MICROSCOPIC

 and

    neuronophagia
    MICROSCOPIC

,

    massive intraneuronal lipid storage
    MICROSCOPIC

 and

    lack of perivascular Gaucher cells
    MICROSCOPIC

.

    Electron microscopy examination
    PARACLINICAL

 showed

    different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids
    MICROSCOPIC

.

    General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions
    NEG_FINDINGS

 but the

    glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase
    MICROSCOPIC

.

    Fatty acid composition of the ceramide moiety
    MICROSCOPIC

 clearly suggests that

    gangliosides
    MICROSCOPIC

 are the main precursors

    in the cerebral cortex
    MICROSCOPIC

, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic consequences of mutant

    sphingolipid activator proteins
    BIOCHEMICAL

 is critical to a better understanding of the physiological significance of these proteins.

Lipid degradation
enzyme beta-glucocerebrosidase
sphingolipid activator protein
sap-C-deficient
sphingolipid activator proteins

transient losses of consciousness
myoclonic jerks
generalized seizures
progressive horizontal ophthalmoplegia
pyramidal and cerebellar signs
died


Non-Hodgkin's lymphoma associated with Gaucher's disease.

Gaucher's disease is an uncommon disorder which has been reported to be associated with an increased risk of lymphoproliferative disorders, including Non-Hodgkin's lymphoma (NHL). A new instance of such an association is described here. This was a 58 year-old-patient with adult type I Gaucher's disease who, one and a half year after the above diagnosis, presented with supraclavicular lymphadenopathy, massive splenomegaly, prominent retroperitoneal lymphadenopathy and increased serum LDH levels. This led to the diagnosis of large-cell NHL of B-cell type, successfully treated with chemotherapy. The previously published cases of Gaucher's disease associated with NHL as well as the possible mechanisms leading to this association are reviewed here.

    Gaucher's disease
    DIAGNOSIS

 is an

    uncommon disorder
    DIAGNOSIS

 which has been reported to be associated with an increased risk of

    lymphoproliferative disorders
    DIAGNOSIS

, including

    Non-Hodgkin's lymphoma (NHL)
    DIAGNOSIS

. A new instance of such an association is described here. This was a

    58 year-old
    AGE

-patient with

    adult type I Gaucher's disease
    AGE

 who, one and a half year after the above diagnosis, presented with

    supraclavicular lymphadenopathy
    SYMPTOMS

,

    massive splenomegaly
    SYMPTOMS

,

    prominent retroperitoneal lymphadenopathy
    SYMPTOMS

 and

    increased serum LDH levels
    BIOCHEMICAL

. This led to the diagnosis of

    large-cell NHL of B-cell type
    DIAGNOSIS

, successfully treated with

    chemotherapy
    MEDICATION

. The previously published cases of

    Gaucher's disease associated with NHL
    DIAGNOSIS

 as well as the possible mechanisms leading to this association are reviewed here.

Gaucher's disease
uncommon disorder
lymphoproliferative disorders
Non-Hodgkin's lymphoma (NHL)
large-cell NHL of B-cell type
Gaucher's disease associated with NHL


[Persistence of pulmonary lesions in a 6-year-old boy with type I Gaucher's disease treated by alglucerase since the age of 20 months].

Gaucher's disease is a serious disorder which becomes curable by bone marrow transplantation. Enzyme replacement therapy has permitted improvement in quality of life and has been shown to decrease the disease's progression.

A 6-year-old boy was treated by alglucerase (Ceredase) since the age of 20 months. He presented at that time a failure to thrive, pancytopenia, hepatosplenomegaly and bone involvement. The lung X-rays revealed a diffuse reticulonodular pattern. After 4 years and 5 months, there was an improvement of growth and hepatosplenomegaly, associated with hematological parameters and bone changes normalization. However, an important interstitial syndrome without clinical signs persisted.

In our patient it is impossible to note the difference between pulmonary disease from fibrotic origin and pulmonary involvement by Gaucher's cells accumulation.

    Gaucher's disease
    DIAGNOSIS

 is a

    serious disorder
    DIAGNOSIS

 which becomes curable by

    bone marrow transplantation
    MEDICATION

.

    Enzyme replacement therapy
    MEDICATION

 has permitted

    improvement in quality of life
    SYMPTOMS

 and has been shown to decrease the disease's progression.

A

    6-year-old
    AGE

    boy
    GENDER

 was

    treated by alglucerase (Ceredase)
    MEDICATION

    since the age of 20 months
    AGE

.

    He
    GENDER

 presented at that time a

    failure to thrive
    SYMPTOMS

,

    pancytopenia
    BIOCHEMICAL

,

    hepatosplenomegaly
    SYMPTOMS

 and

    bone involvement
    SYMPTOMS

. The

    lung X-rays
    PARACLINICAL

 revealed a

    diffuse reticulonodular pattern
    SYMPTOMS

.

    After 4 years and 5 months
    AGE

, there was an

    improvement of growth and hepatosplenomegaly
    SYMPTOMS

, associated with

    hematological parameters and bone changes normalization
    BIOCHEMICAL

. However, an

    important interstitial syndrome
    SYMPTOMS

    without clinical signs
    NEG_FINDINGS

 persisted.

In our patient it is impossible to note the difference between

    pulmonary disease from fibrotic origin
    DIAGNOSIS

 and

    pulmonary involvement by Gaucher's cells accumulation
    MICROSCOPIC

.

Gaucher's disease
serious disorder
pulmonary disease from fibrotic origin

bone marrow transplantation
Enzyme replacement therapy
treated by alglucerase (Ceredase)


New tongue protector to prevent decubital lingual ulcers caused by tongue thrust with myoclonus.

We treated tongue ulcers in a twenty-two-month-old male child with Gaucher disease and several neuronopathic symptoms, including frequent convulsions. Because the patient was always thrusting his tongue and biting with his upper and lower primary incisors during the myoclonus and convulsions, traumatic decubital ulcers on the dorsum and ventral surface of the tongue were formed. During the convulsions, bleeding and pus discharges were observed. For the protection of the tongue from the teeth, a tongue protector was fabricated from a soft silicone relining material used for dentures. The protector covered the mandibular primary central incisors, the alveolar ridge, and the ventral surface, apex and dorsum of the tongue. The ulcer symptoms completely disappeared after two months of using the protector.

We treated

    tongue ulcers
    SYMPTOMS

 in a

    twenty-two-month-old
    AGE

    male
    GENDER

    child
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 and several

    neuronopathic symptoms
    SYMPTOMS

, including

    frequent convulsions
    SYMPTOMS

. Because the patient was always

    thrusting his tongue and biting with his upper and lower primary incisors
    SYMPTOMS

 during the

    myoclonus
    SYMPTOMS

 and

    convulsions
    SYMPTOMS

,

    traumatic decubital ulcers on the dorsum and ventral surface of the tongue
    SYMPTOMS

 were formed. During the

    convulsions
    SYMPTOMS

,

    bleeding
    SYMPTOMS

 and

    pus discharges
    SYMPTOMS

 were observed. For the

    protection of the tongue from the teeth
    MEDICATION

, a

    tongue protector was fabricated from a soft silicone relining material used for dentures
    MEDICATION

. The

    protector covered the mandibular primary central incisors, the alveolar ridge, and the ventral surface, apex and dorsum of the tongue
    MEDICATION

. The

    ulcer symptoms completely disappeared
    SYMPTOMS

 after

    two months of using the protector
    MEDICATION

.


Corneal opacities in Gaucher disease.

To describe the corneal findings in a variant of Gaucher disease.

Case report. In an 18-year-old man, ophthalmic and general clinical evaluation, and enzymatic and molecular genetics studies were performed.

Diffuse, well-defined, small, linear, or dotlike corneal opacities were observed through, out the posterior two thirds of the corneal stroma in both eyes. The patient had calcific valvular heart disease. Enzymatic and ultrastructural studies were consistent with Gaucher disease. Analysis of the glucocerebrosidase gene disclosed homozygosity for a D409H mutation.

Corneal opacities are a distinguishing ocular feature of the variant of Gaucher disease associated with the D409H mutation and with calcific cardiac disease.

To describe the corneal findings in a variant of

    Gaucher disease
    DIAGNOSIS

.

Case report. In an

    18-year-old
    AGE

    man
    GENDER

,

    ophthalmic and general clinical evaluation
    PARACLINICAL

, and

    enzymatic and molecular genetics studies
    PARACLINICAL

 were performed.

    Diffuse, well-defined, small, linear, or dotlike corneal opacities were observed through, out the posterior two thirds of the corneal stroma in both eyes
    SYMPTOMS

. The patient had

    calcific valvular heart disease
    DIAGNOSIS

.

    Enzymatic and ultrastructural studies
    PARACLINICAL

 were consistent with

    Gaucher disease
    DIAGNOSIS

.

    Analysis of the glucocerebrosidase gene
    PARACLINICAL

 disclosed

    homozygosity for a D409H mutation
    GENETICS

.

    Corneal opacities
    SYMPTOMS

 are a distinguishing ocular feature of the

    variant of Gaucher disease associated with the D409H mutation
    DIAGNOSIS

 and with

    calcific cardiac disease
    DIAGNOSIS

.


Identification of new type 2B von Willebrand disease mutations: Arg543Gln, Arg545Pro and Arg578Leu.

We report the identification in five patients (three families) affected with type 2B von Willebrand disease (VWD) of three heterozygous nucleotide substitutions at the codon for arginine 543, 545 and 578 of the mature von Willebrand factor (VWF) subunit resulting in a glutamine, proline and leucine substitution, respectively. These mutations are located in the A1 loop where prevalent type 2B mutations (Arg543Trp, Arg545Cys and Arg578Gln) have been already identified at the same positions. By in vitro mutagenesis of full-length cDNA of VWF and transient expression in Cos-7 cells, we have shown that the six corresponding mutated recombinant VWFs (Gln543, Trp543, Cys545, Pro545, Leu578 and Gln578 rVWF) exhibited quantitatively normal expression and normal multimeric pattern but increased ristocetin- and botrocetin-induced binding to platelets as compared with that for wild-type rVWF. The two mutations at position 545 induced the greatest reactivity for GPIb of corresponding rVWFs as compared to the two mutations at positions 543 and 578.

We report the identification in five patients (three families) affected with

    type 2B von Willebrand disease (VWD)
    DIAGNOSIS

 of

    three heterozygous nucleotide substitutions at the codon for arginine 543, 545 and 578 of the mature von Willebrand factor (VWF) subunit resulting in a glutamine, proline and leucine substitution
    GENETICS

, respectively. These

    mutations are located in the A1 loop where prevalent type 2B mutations (Arg543Trp, Arg545Cys and Arg578Gln)
    GENETICS

 have been already identified at the same positions. By

    in vitro mutagenesis of full-length cDNA of VWF and transient expression in Cos-7 cells
    PARACLINICAL

, we have shown that the

    six corresponding mutated recombinant VWFs (Gln543, Trp543, Cys545, Pro545, Leu578 and Gln578 rVWF
    GENETICS

) exhibited

    quantitatively normal expression
    BIOCHEMICAL

 and

    normal multimeric pattern
    NEG_FINDINGS

 but

    increased ristocetin- and botrocetin-induced binding to platelets
    BIOCHEMICAL

 as compared with that for wild-type

    rVWF
    BIOCHEMICAL

. The

    two mutations at position 545
    GENETICS

 induced the greatest

    reactivity for GPIb of corresponding rVWFs
    BIOCHEMICAL

 as compared to the

    two mutations at positions 543 and 578
    GENETICS

.


A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease.

Gaucher disease, the most prevalent inherited sphingolipidosis, is characterized by lipid laden histiocytes in the spleen, liver and bone marrow sinusoids of affected individuals. It results from deleterious mutations in the functional gene of glucocerebrosidase (acid beta-glucosidase, EC. 3.2.1.45) and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: Type 1 non-neuronopathic, type 2 acute neuronopathic, and type 3 subacute neuronopathic. In this report, we describe the identification and characterization of three novel mutations from two patients who died with type 2 Gaucher disease. Two heterozygous missense point mutations, one at cDNA nucleotide 238A (E41L) and the other at cDNA nucleotide 508T (R131C) were identified, both in the context of a cDNA nucleotide 1448C (L444P) mutation in the second allele. One of these L444P mutations was identified as a novel complex allele resulting from a crossover involving the glucocerebrosidase functional gene and pseudogene beginning between genomic nucleotides 5689 and 5723 and extending through the rest of the coding sequence. Based on the recent identification and sequence analysis of the metaxin gene and pseudogene contiguous with the glucocerebrosidase pseudogene and functional gene respectively, we have developed a PCR-based method for the analysis of the origin and extent of this recombination.

    Gaucher disease
    DIAGNOSIS

, the most prevalent

    inherited sphingolipidosis
    GENETICS

, is characterized by

    lipid laden histiocytes in the spleen, liver and bone marrow sinusoids of
    MICROSCOPIC

 affected individuals. It results from

    deleterious mutations in the functional gene of glucocerebrosidase (acid beta-glucosidase, EC. 3.2.1.45)
    GENETICS

 and is

    transmitted as an autosomal recessive trait
    GENETICS

. Three clinical forms of

    Gaucher disease
    DIAGNOSIS

 have been described:

    Type 1 non-neuronopathic
    DIAGNOSIS

,

    type 2 acute neuronopathic
    DIAGNOSIS

, and

    type 3 subacute neuronopathic
    DIAGNOSIS

. In this report, we describe the identification and characterization of three

    novel mutations
    GENETICS

 from two patients who

    died
    SYMPTOMS

 with

    type 2 Gaucher disease
    DIAGNOSIS

.

    Two heterozygous missense point mutations, one at cDNA nucleotide 238A (E41L) and the other at cDNA nucleotide 508T (R131C)
    GENETICS

 were identified

    , both in the context of a cDNA nucleotide 1448C (L444P) mutation in the second allele
    GENETICS

.

    One of these L444P mutations was identified as a novel complex allele resulting from a crossover involving the glucocerebrosidase functional gene and pseudogene beginning between genomic nucleotides 5689 and 5723 and extending through the rest of the coding sequence
    GENETICS

. Based on the recent identification and

    sequence analysis of the metaxin gene and pseudogene contiguous with the glucocerebrosidase pseudogene and functional gene respectively
    PARACLINICAL

, we have developed a

    PCR-based method
    PARACLINICAL

 for the analysis of the origin and extent of this recombination.

Gaucher disease
Gaucher disease
Type 1 non-neuronopathic
type 2 acute neuronopathic
type 3 subacute neuronopathic
type 2 Gaucher disease


A novel mutation in the D3 domain of von Willebrand factor markedly decreases its ability to bind factor VIII and affects its multimerization.

In type 2N von Willebrand disease (vWD), von Willebrand factor (vWF) is characterized by normal multimeric pattern, normal platelet-dependent function, but a markedly decreased affinity for factor VIII (FVIII). In this report, we describe the case of a vWD patient who has an abnormal vWF multimers distribution associated with a markedly decreased vWF ability to bind FVIII. Sequencing analysis of patient's vWF gene showed, at heterozygous state, a G-->A transition resulting in the substitution of Asn for Asp at position 116 of the mature vWF subunit and a C-->T transition, changing the codon for Arg 896 into a stop codon. His sister who has a subnormal vWF level, but a normal FVIII/vWF interaction, was found to be heterozygous for the Arg896ter mutation only. Recombinant vWF (rvWF) containing the candidate (Asn116) missense mutation was expressed in COS-7 cells. The expression level of Asn116rvWF was significantly decreased compared with wild-type rvWF. The multimeric pattern of Asn116rvWF was greatly impaired as shown by the decrease in high molecular weight forms. The FVIII binding ability of Asn116rvWF was dramatically decreased. These data show that the Asp116Asn substitution is the cause of both the defective FVIII/vWF interaction and the impaired multimeric pattern observed in the patient's vWF. The monoclonal antibody 31H3 against D' domain of vWF (epitope aa 66-76) that partially inhibits the FVIII binding and recognizes only nonreduced vWF, showed a decreased ability to bind Asn116rvWF when used as capture-antibody in enzyme-linked immunosorbent assay (ELISA). This result suggests that a potential conformation change in the D' domain is induced by the Asp116Asn substitution, which is localized in the D3 domain.

In

    type 2N von Willebrand disease (vWD)
    DIAGNOSIS

,

    von Willebrand factor (vWF)
    BIOCHEMICAL

 is characterized by

    normal multimeric pattern
    NEG_FINDINGS

,

    normal platelet-dependent function
    NEG_FINDINGS

, but a

    markedly decreased affinity for factor VIII (FVIII)
    BIOCHEMICAL

. In this report, we describe the case of a

    vWD
    DIAGNOSIS

 patient who has an

    abnormal vWF multimers distribution
    BIOCHEMICAL

 associated with a

    markedly decreased vWF ability to bind FVIII
    BIOCHEMICAL

.

    Sequencing analysis of patient's vWF gene
    PARACLINICAL

 showed,

    at heterozygous state
    GENETICS

, a

    G-->A transition resulting in the substitution of Asn for Asp at position 116 of the mature vWF subunit and a C-->T transition, changing the codon for Arg 896 into a stop codon
    GENETICS

.

    His sister who has a subnormal vWF level
    FAMILY

, but a

    normal FVIII/vWF interaction
    NEG_FINDINGS

    , was found to be heterozygous for the Arg896ter mutation only
    FAMILY

. Recombinant vWF (rvWF) containing the

    candidate (Asn116) missense mutation
    GENETICS

 was expressed in COS-7 cells. The

    expression level of Asn116rvWF was significantly decreased
    GENETICS

 compared with wild-type

    rvWF
    BIOCHEMICAL

. The

    multimeric pattern of Asn116rvWF was greatly impaired
    BIOCHEMICAL

 as shown by the

    decrease in high molecular weight forms
    BIOCHEMICAL

.

    The FVIII binding ability of Asn116rvWF was dramatically decreased
    BIOCHEMICAL

. These data show that the

    Asp116Asn substitution
    GENETICS

 is the cause of both the

    defective FVIII/vWF interaction
    BIOCHEMICAL

 and the

    impaired multimeric pattern observed in the patient's vWF
    BIOCHEMICAL

. The monoclonal antibody 31H3 against

    D' domain of vWF (epitope aa 66-76
    BIOCHEMICAL

) that

    partially inhibits the FVIII binding
    BIOCHEMICAL

 and recognizes only

    nonreduced vWF
    BIOCHEMICAL

, showed a

    decreased ability to bind Asn116rvWF
    BIOCHEMICAL

 when used as capture-antibody in

    enzyme-linked immunosorbent assay (ELISA)
    PARACLINICAL

. This result suggests that a potential conformation

    change in the D'
    GENETICS

 domain is induced by the

    Asp116Asn substitution
    GENETICS

, which is

    localized in the D3 domain
    GENETICS

.

type 2N von Willebrand disease (vWD)
vWD

normal multimeric pattern
normal platelet-dependent function
normal FVIII/vWF interaction


Negative images due to MAI infection detected in Papanicolaou-stained duodenal brushing cytology.

Atypical mycobacteriosis of the duodenum was diagnosed by duodenal brush cytology in a woman with AIDS. Smears were fixed in alcohol and stained by the method of Papanicolaou. The cytological characteristics of this disease have been described previously in other cytological specimens such as imprints or fine-needle aspirations stained with Diff-Quik or Wright's stain. We found that alcohol fixation and routine Papanicolaou staining allow observation of numerous foamy and striated macrophages (pseudo-Gaucher cells), as well as negative images both within the cytoplasm of the macrophages and in the background of smears in areas of air-drying artifact. These findings should suggest the diagnosis of atypical mycobacteriosis, and special staining techniques such as PAS and Ziehl-Neelsen are useful in corroborating it. This has not been previously described.

    Atypical mycobacteriosis of the duodenum
    DIAGNOSIS

 was diagnosed by

    duodenal brush cytology
    PARACLINICAL

 in a

    woman
    GENDER

 with

    AIDS
    DIAGNOSIS

.

    Smears were fixed in alcohol
    PARACLINICAL

 and

    stained by the method of Papanicolaou
    PARACLINICAL

. The cytological characteristics of this disease have been described previously in other

    cytological specimens
    PARACLINICAL

 such as

    imprints
    PARACLINICAL

 or

    fine-needle aspirations
    PARACLINICAL

 stained with

    Diff-Quik or Wright's stain
    PARACLINICAL

. We found that

    alcohol fixation
    PARACLINICAL

 and

    routine Papanicolaou staining
    PARACLINICAL

 allow observation of

    numerous foamy and striated macrophages (pseudo-Gaucher cells)
    MICROSCOPIC

, as well as

    negative images both within the cytoplasm of the macrophages and in the background of smears in areas of air-drying artifact
    MICROSCOPIC

. These findings should suggest the diagnosis of

    atypical mycobacteriosis
    DIAGNOSIS

, and special staining techniques such as

    PAS and Ziehl-Neelsen
    PARACLINICAL

 are useful in corroborating it. This has not been previously described.


Alglucerase enzyme replacement therapy used safely and effectively throughout the whole pregnancy of a Gaucher disease patient.

We present the case of a woman with Gaucher disease who was being given alglucerase as enzyme replacement therapy. She was found to be pregnant: the treatment was continued. She gave birth to a healthy son after a spontaneous vaginal delivery at term.

We present the case of a

    woman
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 who was being

    given alglucerase as enzyme replacement therapy
    MEDICATION

.

    She
    GENDER

 was found to be

    pregnant
    GENDER

:

    the treatment
    MEDICATION

 was continued.

    She
    GENDER

    gave birth to a healthy son
    MEDICATION

 after a

    spontaneous vaginal delivery at term
    MEDICATION

.


Spontaneous decrease of spleen size in a patient with type 1 Gaucher's disease.

We present a patient with type 1 Gaucher's disease in whom the spleen size during 34 years of follow-up reached a maximum of 6 cm. below the costal margin, but in 1993 began to decrease spontaneously and presently can no longer be felt by abdominal palpation.

We present a patient with

    type 1 Gaucher's disease
    DIAGNOSIS

 in whom the

    spleen size during 34 years of follow-up
    SYMPTOMS

    reached a maximum of 6 cm. below the costal margin
    SYMPTOMS

, but in 1993

    began to decrease
    SYMPTOMS

 spontaneously and presently

    can no longer be felt by abdominal palpation
    NEG_FINDINGS

.


Type 2N von Willebrand disease due to Arg91Gln substitution and a cytosine deletion in exon 18 of the von Willebrand factor gene.

Two members of a family previously classified as type 1 von Willebrand disease (VWD), showed a quantitative defect in von Willebrand factor (VWF) antigen and ristocetin cofactor activity and an abnormal capacity of VWF to bind FVIII. Sequencing of the VWF gene region coding for the FVIII binding domain revealed the most frequent type 2N mutation: a single nucleotide change (G2811A) in exon 20, resulting in substitution of glutamine (Gln) for arginine (Arg) 91 in the mature VWF protein in one allele. The other allele contained a cytosine deletion (2680delC) in exon 18, introducing a premature stop codon at position 79 (Val79X) which produced a quantitative defect in VWF levels. The Arg91Gln defect is usually not evident in heterozygotes; however, in these patients it was expressed due to the lack of VWF production from the other allele. This is the first report of type 2N VWD in Italy.

Two members of a

    family
    FAMILY

 previously classified as

    type 1 von Willebrand disease (VWD)
    DIAGNOSIS

, showed a

    quantitative defect in von Willebrand factor (VWF) antigen and ristocetin cofactor activity
    BIOCHEMICAL

 and an

    abnormal capacity of VWF to bind FVIII
    BIOCHEMICAL

.

    Sequencing of the VWF gene region coding for the FVIII binding domain
    PARACLINICAL

 revealed the

    most frequent type 2N mutation: a single nucleotide change (G2811A) in exon 20, resulting in substitution of glutamine (Gln) for arginine (Arg) 91 in the mature VWF protein in one allele
    GENETICS

.

    The other allele contained a cytosine deletion (2680delC) in exon 18, introducing a premature stop codon at position 79 (Val79X)
    GENETICS

 which produced a

    quantitative defect in VWF levels
    BIOCHEMICAL

. The

    Arg91Gln defect
    GENETICS

 is usually not evident in

    heterozygotes
    GENETICS

; however, in these patients it was expressed due to the

    lack of VWF production
    BIOCHEMICAL

 from the other allele. This is the first report of

    type 2N VWD
    DIAGNOSIS

 in

    Italy
    ETHNICITY

.

type 1 von Willebrand disease (VWD)
type 2N VWD


An autopsy case of fetal Gaucher disease.

A case of fetal form of Gaucher disease in a Japanese fetus is presented.

A macerated baby showing hydrops fetalis was dissected at 29 weeks of gestation. The fetus was heavier in the body, liver and spleen than a normal fetus at the same gestation period. It also suffered from pericardial effusion and ascites. The diagnosis of Gaucher disease was made by histological and biochemical findings. In microscopical examinations 'Gaucher cells', which were periodic acid-Shiff (PAS)-positive, alcian blue-positive and CD68-positive, existed in the lungs, liver, spleen, thymus, adrenal glands, bone marrow and brain. In thin layer chromatography, a large quantity of glucocerebroside was seen to have accumulated in the patient's organs.

A case of

    fetal form of Gaucher disease
    DIAGNOSIS

 in a

    Japanese
    ETHNICITY

    fetus
    AGE

 is presented.

A

    macerated
    SYMPTOMS

    baby
    AGE

 showing

    hydrops fetalis
    DIAGNOSIS

 was dissected at

    29 weeks of gestation
    AGE

. The

    fetus
    SYMPTOMS

 was

    heavier in the body, liver and spleen
    SYMPTOMS

 than a normal

    fetus
    AGE

 at the same gestation period. It also suffered from

    pericardial effusion
    SYMPTOMS

 and

    ascites
    SYMPTOMS

. The diagnosis of

    Gaucher disease
    DIAGNOSIS

 was made by

    histological and biochemical findings
    PARACLINICAL

. In

    microscopical examinations
    PARACLINICAL

    'Gaucher cells', which were periodic acid-Shiff (PAS)-positive, alcian blue-positive and CD68-positive, existed in the lungs, liver, spleen, thymus, adrenal glands, bone marrow and brain
    MICROSCOPIC

. In

    thin layer chromatography
    PARACLINICAL

, a

    large quantity of glucocerebroside was seen to have accumulated in the patient's organs
    MICROSCOPIC

.

fetal form of Gaucher disease
hydrops fetalis
Gaucher disease

macerated
fetus
heavier in the body, liver and spleen
pericardial effusion
ascites


Recurrence of the D409H mutation in Spanish Gaucher disease patients: description of a new homozygous patient and haplotype analysis.

Gaucher disease results, in most patients, from mutations in the gene encoding glucocerebrosidase. Mutation D409H is the third most frequent in Spanish patients, accounting for 5.7% of all mutated alleles. This allele is associated mainly with the neurological forms of the disease. Recently, homozygosity for the D409H mutation has been associated with a particular phenotype, including specific cardiovascular symptoms. Here we report a second Spanish patient bearing the D409H/D409H genotype with a very early manifestation of the disease. The patient started enzyme replacement therapy at 3 months of age. A common origin for the Spanish D409H alleles was ruled out by haplotype analysis using an internal polymorphism of the glucocerebrosidase gene and two external microsatellite markers.

    Gaucher disease
    DIAGNOSIS

 results, in most patients, from

    mutations in the gene encoding glucocerebrosidase
    GENETICS

.

    Mutation D409H
    GENETICS

 is the third most frequent in

    Spanish
    ETHNICITY

 patients, accounting for 5.7% of all mutated alleles. This allele is associated mainly with the

    neurological forms
    DIAGNOSIS

 of the disease. Recently,

    homozygosity for the D409H mutation
    GENETICS

 has been associated with a particular phenotype, including

    specific cardiovascular symptoms
    SYMPTOMS

. Here we report a second

    Spanish
    ETHNICITY

 patient bearing the

    D409H/D409H genotype
    GENETICS

 with a

    very early manifestation of the disease
    SYMPTOMS

. The patient started

    enzyme replacement therapy
    MEDICATION

    at 3 months of age
    AGE

. A

    common origin for the Spanish D409H alleles
    GENETICS

    was ruled out
    NEG_FINDINGS

 by

    haplotype analysis using an internal polymorphism of the glucocerebrosidase gene and two external microsatellite markers
    PARACLINICAL

.

specific cardiovascular symptoms
very early manifestation of the disease


Coincidence of Gaucher's disease due to a private mutation and Ph' positive chronic myeloid leukemia.

We report the case of a 46-year-old female with coexisting type I Gaucher's disease and chronic myeloid leukemia (CML). The diagnosis of Gaucher's disease was made in early childhood by bone marrow biopsy and was recently confirmed by biochemical demonstration of reduced leukocyte beta-glucocerebrosidase activity and the presence of Gaucher cells in a bone marrow aspirate. We analyzed the patient's genomic DNA for the underlying glucocerebrosidase mutations and have found homozygosity for a C-->T transition in cDNA nucleotide 593 (159 Pro-->Leu), presently an undescribed mutation. After initiation of replacement therapy with alglucerase we observed a significant increase of the platelet count in our patient. The diagnosis of CML was based on standard hematological parameters and the detection of the Philadelphia chromosome (Ph). With intermittent treatment with busulfan the patient has remained in chronic phase for nine years. The patient suffered from hepatosplenomegaly and thrombocytopenia, both of which can be caused by Gaucher's disease and CML. The aggravation of skeletal manifestations of Gaucher's disease, which occurred at the time of diagnosis of CML, could be due to increased production of leukocyte-derived glucocerebrosides that were not appropriately degraded because of the genetic beta-glucocerebrosidase deficiency.

We report the case of a

    46-year-old
    AGE

    female
    GENDER

 with

    coexisting type I Gaucher's disease and chronic myeloid leukemia (CML)
    DIAGNOSIS

. The diagnosis of

    Gaucher's disease
    DIAGNOSIS

 was made in

    early childhood
    AGE

 by

    bone marrow biopsy
    PARACLINICAL

 and was recently confirmed by biochemical demonstration of

    reduced leukocyte beta-glucocerebrosidase activity
    BIOCHEMICAL

 and the

    presence of Gaucher cells in a bone marrow aspirate
    MICROSCOPIC

. We

    analyzed the patient's genomic DNA for the underlying glucocerebrosidase mutations
    PARACLINICAL

 and have found

    homozygosity for a C-->T transition in cDNA nucleotide 593 (159 Pro-->Leu), presently an undescribed mutation
    GENETICS

. After initiation of

    replacement therapy with alglucerase
    MEDICATION

 we observed a

    significant increase of the platelet count
    BIOCHEMICAL

 in our patient. The diagnosis of

    CML
    DIAGNOSIS

 was based on

    standard hematological parameters
    PARACLINICAL

 and the detection of the

    Philadelphia chromosome (Ph)
    GENETICS

. With

    intermittent treatment with busulfan
    MEDICATION

 the patient has

    remained in chronic phase for nine years
    MEDICATION

. The patient suffered from

    hepatosplenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

, both of which can be caused by

    Gaucher's disease
    DIAGNOSIS

 and

    CML
    DIAGNOSIS

. The

    aggravation of skeletal manifestations
    SYMPTOMS

 of

    Gaucher's disease
    MICROSCOPIC

, which occurred at the time of diagnosis of

    CML
    DIAGNOSIS

, could be due to

    increased production of leukocyte-derived glucocerebrosides that were not appropriately degraded
    MICROSCOPIC

 because of the

    genetic beta-glucocerebrosidase deficiency
    BIOCHEMICAL

.

hepatosplenomegaly
aggravation of skeletal manifestations