A new candidate mutation (N528S) within the von Willebrand factor propeptide identified in a Japanese patient with phenotype IIC of von Willebrand disease.

Phenotype IIC of von Willebrand disease (vWD) is a subtype of type 2A vWD characterized by recessive inheritance and an impaired multimerization of von Willebrand factor (vWF) molecules beyond dimers. The 5 patients with phenotype IIC whose vWF gene defect has been characterized so far are either homozygous or double heterozygotes for mutations localized in exons 11, 12, 14 or 15. We report here the identification of a new candidate mutation in a previously described Japanese patient affected with phenotype IIC vWD. The propositus is homozygous for the A1833G nucleotide substitution, in exon 14 of vWF gene, responsible for the N528S mutation within the vWF propeptide. This finding is in agreement with the consanguineous origin of the propositus, whose parents are first cousins. Six patients' relatives who are asymptomatic were studied and found heterozygous for the N528S mutation. The screening of the whole vWF gene, either by SSCP or sequencing, did not reveal any other deleterious sequence alteration in the patient. Furthermore, the N528S nonconservative substitution identified is located in the vWF propeptide region, where the other phenotype IIC mutations described so far are clustered. The N528S candidate mutation characterized is, therefore, most probably responsible for the multimerization defect of vWF observed in this patient.

    Phenotype IIC of von Willebrand disease (vWD)
    DIAGNOSIS

 is a subtype of

    type 2A vWD
    DIAGNOSIS

 characterized by

    recessive inheritance
    GENETICS

 and an

    impaired multimerization of von Willebrand factor (vWF) molecules beyond dimers
    BIOCHEMICAL

. The 5 patients with

    phenotype IIC
    DIAGNOSIS

 whose

    vWF gene defect
    GENETICS

 has been characterized so far are either

    homozygous or double heterozygotes for mutations localized in exons 11, 12, 14 or 15
    GENETICS

. We report here the identification of a

    new candidate mutation
    GENETICS

 in a previously described

    Japanese
    ETHNICITY

 patient affected with

    phenotype IIC vWD
    DIAGNOSIS

. The propositus is

    homozygous for the A1833G nucleotide substitution, in exon 14 of vWF gene, responsible for the N528S mutation within the vWF propeptide
    GENETICS

. This finding is in agreement with the

    consanguineous origin of the propositus, whose parents are first cousins
    FAMILY

. Six patients' relatives who are

    asymptomatic
    NEG_FINDINGS

 were studied and found

    heterozygous for the N528S mutation
    GENETICS

. The

    screening of the whole vWF gene, either by SSCP or sequencing
    PARACLINICAL

,

    did not reveal any other deleterious sequence alteration
    NEG_FINDINGS

 in the patient. Furthermore, the

    N528S nonconservative substitution identified is located in the vWF propeptide region
    GENETICS

, where the other

    phenotype IIC
    DIAGNOSIS

 mutations described so far are clustered. The

    N528S candidate mutation
    GENETICS

 characterized is, therefore, most probably responsible for the

    multimerization defect of vWF
    BIOCHEMICAL

 observed in this patient.


Hematological complications of Gaucher's disease in pregnancy.

A case is presented of a 31-year-old Filipino female, gravida 5 para 2, at 38 weeks plus 5 days gestation, with known type I Gaucher's disease who underwent repeat cesarean delivery. After cesarean delivery, the patient developed disseminated intravascular coagulation and required transfusion of eight 6-packs of platelets, 6 units of fresh frozen plasma, two 10-packs of cryoprecipitate, and 6 units of packed red blood cells. Pregnancy is generally well tolerated in patients with type I Gaucher's disease, an autosomal recessive lysosomal storage disorder in which lipid deposits accumulate in the liver, spleen, and bone marrow. Hemorrhagic problems secondary to severe thrombocytopenia may develop postpartum in pregnancies complicated by Gaucher's disease, requiring significant support with blood and blood products.

A case is presented of a

    31-year-old
    AGE

    Filipino
    ETHNICITY

    female
    GENDER

,

    gravida 5 para 2
    FAMILY

, at

    38 weeks plus 5 days gestation
    MEDICATION

, with known

    type I Gaucher's disease
    DIAGNOSIS

 who underwent

    repeat cesarean delivery
    MEDICATION

. After

    cesarean delivery
    MEDICATION

, the patient developed

    disseminated intravascular coagulation
    BIOCHEMICAL

 and required

    transfusion of eight 6-packs of platelets, 6 units of fresh frozen plasma, two 10-packs of cryoprecipitate, and 6 units of packed red blood cells
    MEDICATION

.

    Pregnancy
    MEDICATION

 is generally well tolerated in patients with

    type I Gaucher's disease
    DIAGNOSIS

, an

    autosomal recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 in which

    lipid deposits accumulate in the liver, spleen, and bone marrow
    MICROSCOPIC

.

    Hemorrhagic problems
    SYMPTOMS

 secondary to

    severe thrombocytopenia
    BIOCHEMICAL

 may develop

    postpartum
    SYMPTOMS

 in

    pregnancies
    DIAGNOSIS

 complicated by

    Gaucher's disease
    DIAGNOSIS

, requiring

    significant support with blood and blood products
    MEDICATION

.

type I Gaucher's disease
type I Gaucher's disease
lysosomal storage disorder
pregnancies
Gaucher's disease

disseminated intravascular coagulation
severe thrombocytopenia


Enzyme replacement therapy decreases hypergammaglobulinemia in Gaucher's disease.

We report the effects of enzyme replacement therapy in a patient with Gaucher's disease associated with a monoclonal gammopathy. Alglucerase induces a linear decline in immunoglobulin and beta 2-microglobulin levels. This observation suggests that this treatment decreases the chronic antigenic stimulation commonly found in Gaucher's disease.

We report the effects of

    enzyme replacement therapy
    MEDICATION

 in a patient with

    Gaucher's disease
    DIAGNOSIS

 associated with a

    monoclonal gammopathy
    DIAGNOSIS

.

    Alglucerase
    MEDICATION

 induces a

    linear decline in immunoglobulin and beta 2-microglobulin levels
    BIOCHEMICAL

. This observation suggests that this treatment decreases the

    chronic antigenic stimulation
    MICROSCOPIC

 commonly found in

    Gaucher's disease
    MICROSCOPIC

.


[Gaucher disease type 1--therapeutic results of enzyme substitution].

Gaucher's disease is the most common inherited lysosomal storage disorder, displaying hepato-splenomegaly, thrombocytopenia, anaemia and bone pain as characteristic features. Substitution therapy with a modified enzyme alglucerase has revolutionized the treatment and prognosis of Gaucher's disease. The first Danish patients treated with alglucerase are reported.

    Gaucher's disease
    DIAGNOSIS

 is the most common

    inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, displaying

    hepato-splenomegaly
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

,

    anaemia
    BIOCHEMICAL

 and

    bone pain
    SYMPTOMS

 as characteristic features.

    Substitution therapy with a modified enzyme alglucerase
    MEDICATION

 has revolutionized the treatment and prognosis of

    Gaucher's disease
    DIAGNOSIS

. The first

    Danish
    ETHNICITY

 patients

    treated with alglucerase
    MEDICATION

 are reported.

Gaucher's disease
lysosomal storage disorder
Gaucher's disease


A novel mutation of the beta-glucocerebrosidase gene associated with neurologic manifestations in three sibs.

We report on a sibship in which three members were affected by Gaucher disease. Molecular analysis of the patients showed homozygosity for a novel mutation (C5390G) of the beta-glucocerebrosidase gene, resulting in the substitution of the arginine 353 with a glycine. Western blot analysis showed a reduced amount of beta-glucocerebrosidase-related polypeptides in fibroblasts. The phenotype resulting from this mutation is characterized by visceral and skeletal manifestations. In addition, the presence of seizures and electrophysiological abnormalities only in the 3 patients and in none of the other unaffected sibs suggests that the mutation is responsible for neurologic involvement.

We report on a

    sibship in which three members were affected by Gaucher disease
    FAMILY

.

    Molecular analysis
    PARACLINICAL

 of the patients showed

    homozygosity for a novel mutation (C5390G) of the beta-glucocerebrosidase gene, resulting in the substitution of the arginine 353 with a glycine
    GENETICS

.

    Western blot analysis
    PARACLINICAL

 showed a

    reduced amount of beta-glucocerebrosidase-related polypeptides in fibroblasts
    BIOCHEMICAL

. The phenotype resulting from this mutation is characterized by

    visceral and skeletal manifestations
    SYMPTOMS

. In addition, the presence of

    seizures
    SYMPTOMS

 and

    electrophysiological abnormalities
    SYMPTOMS

 only in the 3 patients and in

    none of the other unaffected sibs
    FAMILY

 suggests that the mutation is responsible for

    neurologic involvement
    SYMPTOMS

.

visceral and skeletal manifestations
seizures
electrophysiological abnormalities
neurologic involvement


Type 2 Gaucher disease with hydrops fetalis in an Ashkenazi Jewish family resulting from a novel recombinant allele and a rare splice junction mutation in the glucocerebrosidase locus.

Gaucher disease, the deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45), is frequently encountered in the Ashkenazi Jewish population. Carrier screening for Gaucher disease by enzyme analysis performed during a routine pregnancy indicated that both Ashkenazi parents were carriers. Screening for four common Gaucher mutations was subsequently performed on fetal and parental DNA. None of the common Ashkenazi mutations were identified. However, when exons 9-11 were amplified and digested with NciI to detect the L444P mutation, it appeared that the mother and the fetus had an unusual allele and that the expected paternal allele was not present. When the fetal amniocytes were found to have less than 2% of the normal glucocerebrosidase activity and a fetal sonogram revealed hydrops fetalis, the pregnancy was terminated. The diagnosis of severe type 2 Gaucher disease was confirmed at autopsy. Ultrastructural studies of epidermis from the fetus revealed the characteristic disruption of lamellar bilayers, diagnostic for type 2 Gaucher disease. In subsequent studies of the fetal DNA, long-template polymerase chain reaction amplification revealed one appropriately sized band (approximately 6.5 kb) and one smaller (approximately 5.2 kb) band. Sequencing of the approximately 5.2-kb fragment identified a novel fusion allele resulting from recombination between the glucocerebrosidase gene and its pseudogene beginning in intron 3. This fusion allele was inherited from the father. The result was confirmed by Southern blot analysis using the enzyme S8tII. Sequencing of the 6.5-kb fragment identified a previously described, although rare, T-to-G splice junction mutation in intron 10 of the maternal allele, which introduced an NciI site. The couple had a subsequent pregnancy which was also found to be affected. This case study identifies a novel recombinant allele and an unusual splice junction mutation, and demonstrates that even in the Ashkenazi population, screening for common mutations may not accurately identify the most severe forms of the disease.

    Gaucher disease
    DIAGNOSIS

, the

    deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45)
    BIOCHEMICAL

, is frequently encountered in the

    Ashkenazi Jewish
    ETHNICITY

 population.

    Carrier screening
    PARACLINICAL

 for

    Gaucher disease
    DIAGNOSIS

 by

    enzyme analysis
    PARACLINICAL

 performed during a routine

    pregnancy
    PARACLINICAL

 indicated that

    both Ashkenazi parents were carriers
    FAMILY

.

    Screening for four common Gaucher mutations
    PARACLINICAL

 was subsequently performed

    on fetal and parental DNA
    PARACLINICAL

.

    None of the common Ashkenazi mutations were identified
    NEG_FINDINGS

. However, when

    exons 9-11 were amplified and digested with NciI
    PARACLINICAL

 to detect the

    L444P mutation
    GENETICS

, it appeared that

    the mother and the fetus had an unusual allele
    FAMILY

 and that

    the expected paternal allele was not present
    GENETICS

. When the

    fetal amniocytes were found to have less than 2% of the normal glucocerebrosidase activity
    MICROSCOPIC

 and a

    fetal sonogram
    PARACLINICAL

 revealed

    hydrops fetalis
    DIAGNOSIS

, the

    pregnancy was terminated
    MEDICATION

. The diagnosis of

    severe type 2 Gaucher disease
    DIAGNOSIS

 was confirmed at

    autopsy
    PARACLINICAL

.

    Ultrastructural studies of epidermis from the fetus
    PARACLINICAL

 revealed the

    characteristic disruption of lamellar bilayers
    MICROSCOPIC

, diagnostic for

    type 2 Gaucher disease
    MICROSCOPIC

. In subsequent

    studies of the fetal DNA
    PARACLINICAL

,

    long-template polymerase chain reaction amplification
    PARACLINICAL

 revealed one

    appropriately sized band (approximately 6.5 kb) and one smaller (approximately 5.2 kb) band
    GENETICS

.

    Sequencing of the approximately 5.2-kb fragment
    PARACLINICAL

 identified a

    novel fusion allele resulting from recombination between the glucocerebrosidase gene and its pseudogene beginning in intron 3
    GENETICS

. This

    fusion allele was inherited from the father
    GENETICS

. The result was confirmed by

    Southern blot analysis using the enzyme S8tII
    PARACLINICAL

.

    Sequencing of the 6.5-kb fragment
    PARACLINICAL

 identified a

    previously described, although rare, T-to-G splice junction mutation in intron 10 of the maternal allele, which introduced an NciI site
    GENETICS

. The

    couple had a subsequent pregnancy which was also found to be affected
    FAMILY

. This case study identifies a

    novel recombinant allele and an unusual splice junction mutation
    GENETICS

, and demonstrates that even in the

    Ashkenazi
    ETHNICITY

 population, screening for

    common mutations
    GENETICS

 may not accurately identify the most severe forms of the disease.

Gaucher disease
Gaucher disease
hydrops fetalis
severe type 2 Gaucher disease


[Gaucher's disease suspected by abdominal echography findings].

Abdominal ultrasonographic findings of Gaucher's disease had been reported, but a specific pattern has not been described. We report here a patient with an abdominal sonographic pattern which was concluded to be strongly suggestive of Gaucher's disease: solid focal splenic lesions with different patterns (hypoechoic, hiperechoic and mixed nodules associated with hypoechoic irregular areas) and bright liver and spleen echo pattern with posterior beam attenuation. Gaucher's disease was subsequently confirmed by determination of leukocyte beta-glucosidase activity and mutations of glucocerebrosidase gene.

    Abdominal ultrasonographic
    PARACLINICAL

 findings of

    Gaucher's disease
    DIAGNOSIS

 had been reported, but a specific pattern has not been described. We report here a patient with an

    abdominal sonographic pattern
    SYMPTOMS

 which was concluded to be strongly suggestive of

    Gaucher's disease
    DIAGNOSIS

:

    solid focal splenic lesions with different patterns (hypoechoic, hiperechoic and mixed nodules associated with hypoechoic irregular areas)
    SYMPTOMS

 and

    bright liver and spleen echo pattern with posterior beam attenuation
    SYMPTOMS

.

    Gaucher's disease
    DIAGNOSIS

 was subsequently confirmed by determination of

    leukocyte beta-glucosidase activity
    BIOCHEMICAL

 and

    mutations of glucocerebrosidase gene
    GENETICS

.

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


Reconversion of bone marrow in Gaucher disease treated with enzyme therapy documented by MR.

Skeletal complications are responsible for significant morbidity in Gaucher patients. Plain radiographs have been unreliable in assessing bone marrow infiltration and activity. A way to assess bone marrow improvement is needed during enzyme therapy.

The purpose of this paper is to assess the usefulness of MR in following improvement of abnormal bone marrow in Gaucher patients on enzyme therapy.

Three patients aged 2, 7, and 24 years underwent serial MR scans of the lower extremities before and during treatment with Alglucerase (two patients) and Imiglucerase (one patient). T1-weighted, T2-weighted, STIR and FSE T2-weighted images were utilized. Two patients were imaged after 16 months of therapy, and one patient was imaged after 6 months of therapy.

All patients had improvement in marrow signal consistent with partial reconversion to fatty marrow during treatment. The findings were more marked after prolonged therapy. T1-weighted images demonstrated findings most clearly.

MR consistently showed improvement in marrow signal in Gaucher patients on enzyme therapy. As smaller doses of enzyme therapy are the trend, MR can be utilized to determine if therapy is effecting a change in the bone marrow.

    Skeletal complications
    SYMPTOMS

 are responsible for significant morbidity in

    Gaucher
    DIAGNOSIS

 patients.

    Plain radiographs
    PARACLINICAL

 have been unreliable in assessing

    bone marrow infiltration and activity
    NEG_FINDINGS

. A way to assess bone marrow improvement is needed during

    enzyme therapy
    MEDICATION

.

The purpose of this paper is to assess the usefulness of

    MR
    PARACLINICAL

 in following

    improvement of abnormal bone marrow
    MICROSCOPIC

 in

    Gaucher
    DIAGNOSIS

 patients on

    enzyme therapy
    MEDICATION

.

Three patients

    aged 2, 7, and 24 years
    AGE

 underwent

    serial MR scans of the lower extremities
    PARACLINICAL

 before and during

    treatment with Alglucerase
    MEDICATION

 (two patients) and

    Imiglucerase
    MEDICATION

 (one patient).

    T1-weighted, T2-weighted, STIR and FSE T2-weighted images
    PARACLINICAL

 were utilized. Two patients were imaged

    after 16 months of therapy
    MEDICATION

, and one patient was imaged after

    6 months of therapy
    MEDICATION

.

All patients had

    improvement in marrow signal consistent with partial reconversion to fatty marrow
    SYMPTOMS

 during treatment. The findings were more marked after

    prolonged therapy
    MEDICATION

.

    T1-weighted images
    PARACLINICAL

 demonstrated findings most clearly.

    MR
    PARACLINICAL

 consistently showed

    improvement in marrow signal
    SYMPTOMS

 in

    Gaucher
    DIAGNOSIS

 patients on

    enzyme therapy
    MEDICATION

. As

    smaller doses of enzyme therapy
    MEDICATION

 are the trend,

    MR
    PARACLINICAL

 can be utilized to determine if therapy is effecting a change in the bone marrow.

enzyme therapy
enzyme therapy
treatment with Alglucerase
Imiglucerase
after 16 months of therapy
6 months of therapy
prolonged therapy
enzyme therapy
smaller doses of enzyme therapy


Membranous lamellar cytoplasmic inclusions in histiocytes and mesothelial cells of serous fluids. Their relationship to phagocytosis of red blood cells.

To define the composition of cytoplasmic inclusions forming stacks and concentric whorls in histiocytes and mesothelial cells of serous fluids, imparting to them a resemblance to Gaucher cells, and to draw conclusions on the mechanism of their formation.

Three serous fluids (one pleural and two pericardial) containing a fair number of the cells referred to were progressively subjected to the following studies: (1) cytochemistry for mucopolysaccharides, proteins, phospholipids and hemoglobin; (2) immunocytochemistry for immunoglobulins IgA, IgG, IgM and lysozyme; (3) transmission electron microscopy (TEM), and (4) scanning electron microscopy-based energy dispersive X-ray microanalysis (SEM-EDAX).

All three specimens were blood stained and contained large numbers of histiocytes and mesothelial cells, arranged singly and in groups, with abundant cytoplasmic inclusions. The inclusions stained strongly positive for phospholipids, weakly positive for hemoglobin and negative for all other substances examined by cytochemistry and immunocytochemistry. By TEM the inclusions had a concentric lamellar membranous structure, reminiscent of myelinosomes or lamellar bodies of lipid-forming or -storing cells. There was also phagocytosis by histiocytes and mesothelial cells of red blood cells, which were mostly in a degenerated state. SEM-EDAX of inclusion-bearing cells showed a modest peak for phosphorus and a variable but small peak for iron, which corroborated the cytochemical and TEM findings.

Since there was not metabolic or other systemic disease in the patients to account for these cells, we posit that phospholipids derived from cell membranes of phagocytized cells, especially red blood cells, provide the building blocks for the formation of such inclusions as they enter the metabolic pathway of phagocytic cells (mesothelial cells and histiocytes) and appear in their lysosomal structures. It is advantageous for cytologists to be familiar with significance of such changes and not to mistake them for metabolic or other systemic disease.

To define the

    composition of cytoplasmic inclusions forming stacks and concentric whorls in histiocytes and mesothelial cells of serous fluids
    MICROSCOPIC

, imparting to them a

    resemblance to Gaucher cells
    MICROSCOPIC

, and to draw conclusions on the mechanism of their formation.

    Three serous fluids (one pleural and two pericardial) containing a fair number of the cells referred to
    MICROSCOPIC

 were progressively subjected to the following studies: (1)

    cytochemistry for mucopolysaccharides, proteins, phospholipids and hemoglobin
    PARACLINICAL

; (2)

    immunocytochemistry for immunoglobulins IgA, IgG, IgM and lysozyme
    PARACLINICAL

; (3)

    transmission electron microscopy (TEM)
    PARACLINICAL

, and (4)

    scanning electron microscopy-based energy dispersive X-ray microanalysis (SEM-EDAX)
    PARACLINICAL

.

All three specimens were

    blood stained
    MICROSCOPIC

 and contained

    large numbers of histiocytes and mesothelial cells, arranged singly and in groups, with abundant cytoplasmic inclusions
    MICROSCOPIC

.

    The inclusions stained strongly positive for phospholipids
    MICROSCOPIC

,

    weakly positive for hemoglobin
    BIOCHEMICAL

 and

    negative for all other substances examined
    NEG_FINDINGS

 by

    cytochemistry and immunocytochemistry
    PARACLINICAL

. By

    TEM
    PARACLINICAL

    the inclusions had a concentric lamellar membranous structure, reminiscent of myelinosomes or lamellar bodies of lipid-forming or -storing cells
    MICROSCOPIC

. There

    was also phagocytosis by histiocytes and mesothelial cells of red blood cells, which were mostly in a degenerated state
    MICROSCOPIC

.

    SEM-EDAX of inclusion-bearing cells
    PARACLINICAL

 showed a

    modest peak for phosphorus and a variable but small peak for iron
    MICROSCOPIC

, which corroborated the

    cytochemical and TEM
    PARACLINICAL

 findings.

Since there was

    not metabolic or other systemic disease in the patients
    NEG_FINDINGS

 to account for these cells, we posit that

    phospholipids derived from cell membranes of phagocytized cells, especially red blood cells, provide the building blocks for the formation of such inclusions as they enter the metabolic pathway of phagocytic cells (mesothelial cells and histiocytes) and appear in their lysosomal structures
    MICROSCOPIC

. It is advantageous for

    cytologists
    PARACLINICAL

 to be familiar with significance of such changes and not to mistake them for

    metabolic or other systemic disease
    NEG_FINDINGS

.


Bone marrow transplantation from a cadaveric donor.

A 2.5-year-old girl with neurogenic Gaucher's disease was transplanted with donor bone marrow from her HLA-compatible 12-year-old brother whose marrow was harvested 30 min post-mortem, after he suffered a severe head and neck injury. The marrow was stored in liquid nitrogen for 30 days prior to infusion. The post-transplantation period was uneventful with good engraftment and no signs of graft-versus-host disease. Currently, 6 months post-allogeneic bone marrow transplantation (alloBMT), analysis of both bone marrow and blood samples by PCR documented only cells of donor origin. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells. To our knowledge, this patient is the only survivor of alloBMT from a cadaveric donor.

A

    2.5-year-old
    AGE

    girl
    GENDER

 with

    neurogenic Gaucher's disease
    DIAGNOSIS

 was

    transplanted with donor bone marrow from her HLA-compatible 12-year-old
    MEDICATION

    brother
    GENDER

 whose marrow was harvested 30 min

    post-mortem
    PARACLINICAL

, after

    he
    GENDER

 suffered a

    severe head and neck injury
    SYMPTOMS

.

    The marrow was stored in liquid nitrogen for 30 days prior to infusion
    MEDICATION

. The

    post-transplantation
    MEDICATION

 period was uneventful with

    good engraftment
    SYMPTOMS

 and

    no signs of graft-versus-host disease
    NEG_FINDINGS

. Currently, 6 months

    post-allogeneic bone marrow transplantation (alloBMT)
    MEDICATION

,

    analysis of both bone marrow and blood samples by PCR
    PARACLINICAL

 documented

    only cells of donor origin
    MICROSCOPIC

. This case demonstrates the feasibility of

    cadaveric marrow as a source of donor cells
    MEDICATION

. To our knowledge, this patient is the only survivor of

    alloBMT from a cadaveric donor
    MEDICATION

.

severe head and neck injury
good engraftment


Pseudotumor formation in tibia in Gaucher's disease.

A very rare case of type 1 Gaucher's disease with pseudotumor formation in the right tibia is presented. In addition to the characteristic radiographic finding of distal femoral flaring (Erlenmeyer flask deformity), a lobulated osteolytic area with surrounding sclerosis was seen in the proximal metaphysis of the right tibia. Adjacent to this pseudotumor appearance was an old pathologic fracture and no significant soft tissue swelling was evident, both of these features being reported for the first time in association with Gaucher's disease.

A very rare case of

    type 1 Gaucher's disease
    DIAGNOSIS

 with

    pseudotumor formation in the right tibia
    SYMPTOMS

 is presented. In addition to the characteristic radiographic finding of

    distal femoral flaring (Erlenmeyer flask deformity)
    SYMPTOMS

, a

    lobulated osteolytic area with surrounding sclerosis was seen in the proximal metaphysis of the right tibia
    SYMPTOMS

. Adjacent to this

    pseudotumor appearance
    SYMPTOMS

 was an

    old pathologic fracture
    SYMPTOMS

 and

    no significant soft tissue swelling was evident
    NEG_FINDINGS

, both of these features being reported for the first time in association with

    Gaucher's disease
    DIAGNOSIS

.

type 1 Gaucher's disease
Gaucher's disease


Management of neutralizing antibody to Ceredase in a patient with type 3 Gaucher disease.

The beneficial effects of macrophage-targeted glucocerebrosidase (Ceredase) in patients with Gaucher disease are well established. A minority of recipients develop transient nonneutralizing antibodies to the exogenous enzyme. A 7-year-old patient with type 3 Gaucher disease whose clinical course began to deteriorate while receiving Ceredase developed a progressively increasing titer of IgG antibody that blocked the catalytic activity of Ceredase. We sought to develop a strategy that would restore the benefit of enzyme replacement therapy in this patient.

The patient was treated with two courses of a combination of plasma exchange, cyclophosphamide, intravenous IgG, and large doses of Ceredase.

After the second course of this regimen, the titer of the neutralizing antibody in the blood gradually declined to negligible levels. Clinical parameters that had been deteriorating (reduction of hemoglobin level, increased serum acid phosphates activity, repeated skeletal infarctions, progressive enlargement and infarction of the spleen) all improved. There has been no recurrence of the neutralizing antibody in this patient.

Very few patients with Gaucher disease who are treated with Ceredase develop a neutralizing antibody to the exogenous enzyme. In the rare instances where this phenomenon occurs, it is likely that the strategy we have used (plasma exchange, cyclophosphamide, intravenous IgG, and large doses of enzyme) may provide benefit to such individuals. It is also likely that this technique may be helpful when enzyme replacement therapy is attempted in patients with other disorders in which the genetic mutation abrogates the production of the protein (CRIM-negative individuals).

The beneficial effects of

    macrophage-targeted glucocerebrosidase (Ceredase)
    MEDICATION

 in patients with

    Gaucher disease
    DIAGNOSIS

 are well established. A minority of recipients develop

    transient nonneutralizing antibodies to the exogenous enzyme
    BIOCHEMICAL

. A

    7-year-old
    AGE

 patient with

    type 3 Gaucher disease
    DIAGNOSIS

 whose

    clinical course began to deteriorate
    SYMPTOMS

 while

    receiving Ceredase
    MEDICATION

 developed a

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

. We sought to develop a strategy that would restore the benefit of

    enzyme replacement therapy
    MEDICATION

 in this patient.

The patient was

    treated with two courses of a combination of plasma exchange, cyclophosphamide, intravenous IgG, and large doses of Ceredase
    MEDICATION

.

After the

    second course of this regimen
    MEDICATION

,

    the titer of the neutralizing antibody in the blood gradually declined to negligible levels
    BIOCHEMICAL

.

    Clinical parameters that had been deteriorating
    SYMPTOMS

 (

    reduction of hemoglobin level
    BIOCHEMICAL

,

    increased serum acid phosphates activity
    BIOCHEMICAL

,

    repeated skeletal infarctions
    SYMPTOMS

,

    progressive enlargement and infarction of the spleen) all improved
    SYMPTOMS

. There has been

    no recurrence of the neutralizing antibody
    NEG_FINDINGS

 in this patient.

Very few patients with

    Gaucher disease
    DIAGNOSIS

 who are treated with

    Ceredase
    MEDICATION

 develop a

    neutralizing antibody to the exogenous enzyme
    BIOCHEMICAL

. In the rare instances where this phenomenon occurs, it is likely that the strategy we have used (

    plasma exchange, cyclophosphamide, intravenous IgG, and large doses of enzyme)
    MEDICATION

 may provide benefit to such individuals. It is also likely that this technique may be helpful when

    enzyme replacement therapy
    MEDICATION

 is attempted in patients with other disorders in which the

    genetic mutation abrogates the production of the protein
    GENETICS

 (

    CRIM-negative individuals
    NEG_FINDINGS

).

Gaucher disease
type 3 Gaucher disease
Gaucher disease


Genotypic heterogeneity and phenotypic variation among patients with type 2 Gaucher's disease.

Gaucher's disease, the inherited deficiency of glucocerebrosidase, manifests with vast phenotypic variation. Even among patients with type 2 (acute neuronopathic) Gaucher's disease, there is a spectrum of clinical presentations. DNA samples from 14 patients with type 2 Gaucher's disease with a course ranging from intrauterine death at 22 wk of gestation to survival until age 30 mo were studied. L444P was the only common mutation identified, found in 15 patients' alleles. Sequencing of genomic DNA amplified by long template PCR revealed that mutation L444P occurred as a single point mutation in seven mutant alleles and as part of a recombinant allele in eight mutant alleles. Two patients had a deletion of 55 bp in exon 9; in one patient the deletion was part of a recombinant allele, and in a second the deletion occurred alone. Direct sequencing identified R120W on one allele, P415R on another, and one fetus was homoallelic for a deletion of a C nucleotide at codon 139 in exon 5. Eight of the mutant alleles remain unidentified. Northern blots revealed an appropriately sized mRNA in all except one of the patients studied. Of the 14 type 2 Gaucher patients, three had hydrops fetalis and died in utero or at birth, five had congenital ichthyosis, and seven survived 5 mo or more. Patients who died in the neonatal period had decreased protein detected by Western blot, regardless of genotype observed. These studies demonstrate that genotypic heterogeneity exists in patients with type 2 Gaucher's disease, even among infants with the most severe phenotypes.

    Gaucher's disease
    DIAGNOSIS

, the

    inherited deficiency of glucocerebrosidase
    GENETICS

, manifests with vast phenotypic variation. Even among patients with

    type 2 (acute neuronopathic) Gaucher's disease
    DIAGNOSIS

, there is a spectrum of clinical presentations.

    DNA samples
    PARACLINICAL

 from 14 patients with

    type 2 Gaucher's disease
    DIAGNOSIS

 with a course ranging from

    intrauterine death at 22 wk of gestation
    SYMPTOMS

 to

    survival until age 30 mo
    SYMPTOMS

 were studied.

    L444P
    GENETICS

 was the only common mutation identified, found in 15 patients' alleles.

    Sequencing of genomic DNA amplified by long template PCR
    PARACLINICAL

 revealed that

    mutation L444P occurred as a single point mutation in seven mutant alleles and as part of a recombinant allele in eight mutant alleles
    GENETICS

. Two patients had a

    deletion of 55 bp in exon 9
    GENETICS

; in one patient

    the deletion was part of a recombinant allele
    GENETICS

, and in a second

    the deletion occurred alone
    GENETICS

.

    Direct sequencing
    PARACLINICAL

 identified

    R120W on one allele, P415R on another
    GENETICS

, and one

    fetus was homoallelic for a deletion of a C nucleotide at codon 139 in exon 5
    GENETICS

.

    Eight of the mutant alleles remain unidentified
    GENETICS

.

    Northern blots
    PARACLINICAL

 revealed an

    appropriately sized mRNA
    BIOCHEMICAL

 in all except one of the patients studied. Of the 14

    type 2 Gaucher
    DIAGNOSIS

 patients, three had

    hydrops fetalis
    DIAGNOSIS

 and

    died in utero or at birth
    SYMPTOMS

, five had

    congenital ichthyosis
    SYMPTOMS

, and seven

    survived 5 mo or more
    AGE

. Patients who

    died
    SYMPTOMS

    in the neonatal period
    AGE

 had

    decreased protein detected by Western blot
    BIOCHEMICAL

, regardless of genotype observed. These studies demonstrate that genotypic heterogeneity exists in patients with

    type 2 Gaucher's disease
    DIAGNOSIS

, even among

    infants
    AGE

 with the most severe phenotypes.


Imprint cytology of Gaucher's disease presenting as a splenic mass. A case report with molecular approaches.

Gaucher's disease is an autosomally transmitted lysosomal storage disease caused by a defect in the lysosomal enzyme, beta-glucosidase.

A 43-year-old male presented with splenomegaly and anemia. Magnetic resonance imaging examination of the abdomen revealed huge, round masses in the spleen. Intraoperative cytology of the spleen showed Gaucher cells that resembled macrophages, with eccentric, small, oval nuclei, but distinguished by their abundant cytoplasm with the characteristic "wrinkled tissue paper" appearance. The cytologic features of the smears correlated well with the histologic sections from the splenectomized specimen. The DNA from this patient was examined for seven glucocerebrosidase mutations that are known to cause Gaucher's disease. The patient was heterozygous for the 754 mutation. Diagnosis was confirmed by a deficiency of beta-glucosidase. The residual activity was 15% of control values.

Diagnosis of Gaucher's disease was made cytologically and subsequently confirmed by the polymerase chain reaction. Imprint cytology is a sensitive diagnostic test, and the combined use of histology and molecular techniques offers the highest probability of identifying this common lysosomal storage disorder.

    Gaucher's disease
    DIAGNOSIS

 is an

    autosomally transmitted
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a

    defect in the lysosomal enzyme, beta-glucosidase
    BIOCHEMICAL

.

A

    43-year-old
    AGE

    male
    GENDER

 presented with

    splenomegaly
    SYMPTOMS

 and

    anemia
    BIOCHEMICAL

.

    Magnetic resonance imaging examination of the abdomen
    PARACLINICAL

 revealed

    huge, round masses in the spleen
    SYMPTOMS

.

    Intraoperative cytology of the spleen
    PARACLINICAL

 showed

    Gaucher cells that resembled macrophages, with eccentric, small, oval nuclei, but
    MICROSCOPIC

 distinguished by their

    abundant cytoplasm with the characteristic "wrinkled tissue paper" appearance
    MICROSCOPIC

. The

    cytologic features of the smears
    PARACLINICAL

 correlated well with the

    histologic sections from the splenectomized specimen
    PARACLINICAL

. The

    DNA from
    PARACLINICAL

 this patient was examined for

    seven glucocerebrosidase mutations
    GENETICS

 that are known to cause

    Gaucher's disease
    DIAGNOSIS

. The patient was

    heterozygous for the 754 mutation
    GENETICS

. Diagnosis was confirmed by a

    deficiency of beta-glucosidase
    BIOCHEMICAL

. The

    residual activity was 15% of control values
    BIOCHEMICAL

.

Diagnosis of

    Gaucher's disease
    DIAGNOSIS

 was made

    cytologically
    PARACLINICAL

 and subsequently confirmed by the

    polymerase chain reaction
    PARACLINICAL

.

    Imprint cytology
    PARACLINICAL

 is a sensitive diagnostic test, and the combined use of

    histology and molecular techniques
    PARACLINICAL

 offers the highest probability of identifying this common

    lysosomal storage disorder
    DIAGNOSIS

.

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

autosomally transmitted
seven glucocerebrosidase mutations
heterozygous for the 754 mutation

splenomegaly
huge, round masses in the spleen


Anaesthetic management of children with type II and III Gaucher disease.

The anaesthetic management of two children with Gaucher disease is described. The cases were a girl aged 12 and a boy aged 4 who had undergone 13 and 3 anaesthetic interventions respectively for endoscopic, orthopaedic, general, otolaryngologic and dental surgical procedures over a total period of 11 years. Anaesthetic management of these patients can be achieved with various agents and techniques, but care is needed to identify preoperative end-organ dysfunction and prevent postoperative respiratory insufficiency. In particular, regional anaesthesia, when suitable, has certain advantages that have made it a worthwhile alternative to general anaesthesia.

The

    anaesthetic management
    MEDICATION

 of two

    children
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 is described. The cases were a

    girl
    GENDER

    aged 12
    AGE

 and a

    boy
    GENDER

    aged 4
    AGE

 who had undergone 13 and 3

    anaesthetic interventions
    MEDICATION

 respectively for

    endoscopic, orthopaedic, general, otolaryngologic and dental surgical procedures
    MEDICATION

 over a

    total period of 11 years
    MEDICATION

.

    Anaesthetic management
    MEDICATION

 of these patients can be achieved with various agents and techniques, but care is needed to identify preoperative

    end-organ dysfunction
    SYMPTOMS

 and prevent

    postoperative respiratory insufficiency
    SYMPTOMS

. In particular,

    regional anaesthesia
    MEDICATION

, when suitable, has certain advantages that have made it a worthwhile alternative to

    general anaesthesia
    MEDICATION

.

end-organ dysfunction
postoperative respiratory insufficiency


Pseudo-Gaucher histiocytes identified up to 1 year after transplantation for CML are BCR/ABL-positive.

The results of polymerase chain reaction (PCR) analysis after transplantation for chronic myelogenous leukemia (CML) are difficult to interpret clinically. Positive findings for BCR/ABL can be seen not only in patients who go on to relapse but also in patients who, after years of follow-up, remain in complete remission. The cause for the lack of concordance between PCR findings and relapse is not clear. We identified two patients with CML who had rare pseudo-Gaucher cells in their bone marrow aspirate specimens prior to, and at 1, and 6 or 12 months following syngeneic or allogeneic hematopoietic transplantation. After the transplant, the patients obtained clinical remission and were shown to be cytogenetically normal and to have germline MBCR in blood or bone marrow by Southern analysis. One patient was PCR-positive for BCR/ABL in the marrow at 12 months. In order to determine whether the pseudo-Gaucher histiocytes were BCR/ABL-positive, we used fluorescence in situ hybridization and probes for MBCR and ABL and analyzed Wright-stained smears to correlate molecular cytogenetic findings with cell type. On three aspirate smears from each patient (at 6 or 12 months post-transplant), all of the pseudo-Gaucher cells studied (10/10 in one patient and 12/12 in the other) showed the fusion for BCR/ABL. Other cells analyzed randomly (erythroid precursors, granulocytes and rare monocytes, lymphocytes and plasma cells) did not. Our cases provide the first proof that pseudo-Gaucher cells carry the BCR/ABL fusion. Furthermore, they illustrate that these cells can be found in the marrow for up to 12 months following transplantation. Our results permit speculation that pseudo-Gaucher cells or other long-lived histocytes may be one cause of persistent PCR positivity after transplantation that is not predictive of disease relapse.

The results of

    polymerase chain reaction (PCR) analysis
    PARACLINICAL

 after

    transplantation
    MEDICATION

 for

    chronic myelogenous leukemia (CML)
    DIAGNOSIS

 are difficult to interpret clinically.

    Positive findings for BCR/ABL
    BIOCHEMICAL

 can be seen not only in patients who go on to relapse but also in patients who, after years of follow-up,

    remain in complete remission
    NEG_FINDINGS

. The cause for the

    lack of concordance between PCR findings
    NEG_FINDINGS

 and

    relapse
    NEG_FINDINGS

 is not clear. We identified two patients with

    CML
    DIAGNOSIS

 who had

    rare pseudo-Gaucher cells in their bone marrow aspirate specimens
    MICROSCOPIC

 prior to, and at 1, and 6 or 12 months following

    syngeneic or allogeneic hematopoietic transplantation
    MEDICATION

. After the

    transplant
    MEDICATION

, the patients obtained

    clinical remission
    SYMPTOMS

 and were shown to be

    cytogenetically normal
    NEG_FINDINGS

 and to have

    germline MBCR in blood or bone marrow
    NEG_FINDINGS

 by

    Southern analysis
    PARACLINICAL

. One patient was

    PCR-positive for BCR/ABL in the marrow
    MICROSCOPIC

 at 12 months. In order to determine whether the

    pseudo-Gaucher histiocytes
    MICROSCOPIC

 were

    BCR/ABL-positive
    MICROSCOPIC

, we used

    fluorescence in situ hybridization and probes for MBCR and ABL
    PARACLINICAL

 and

    analyzed Wright-stained smears
    PARACLINICAL

 to correlate

    molecular cytogenetic findings
    PARACLINICAL

 with cell type. On three

    aspirate smears
    PARACLINICAL

 from each patient (at 6 or 12 months

    post-transplant
    MEDICATION

),

    all of the pseudo-Gaucher cells studied (10/10
    MICROSCOPIC

 in one patient

    and 12/12
    MICROSCOPIC

 in the other

    ) showed the fusion for BCR/ABL
    MICROSCOPIC

. Other cells analyzed randomly

    (erythroid precursors, granulocytes and rare monocytes, lymphocytes and plasma cells) did not
    MICROSCOPIC

. Our cases provide the first proof that

    pseudo-Gaucher cells carry the BCR/ABL fusion
    MICROSCOPIC

. Furthermore, they illustrate that

    these cells can be found in the marrow for
    MICROSCOPIC

 up to 12 months following

    transplantation
    MEDICATION

. Our results permit speculation that

    pseudo-Gaucher cells or other long-lived histocytes
    MICROSCOPIC

 may be one cause of

    persistent PCR positivity
    BIOCHEMICAL

 after

    transplantation
    MEDICATION

 that is

    not predictive of disease relapse
    NEG_FINDINGS

.

Positive findings for BCR/ABL
persistent PCR positivity


First long-term results of imiglucerase therapy of type 1 Gaucher disease.

In the early 1990s, enzyme replacement therapy with modified placental glucocerebrosidase (alglucerase, Genzyme Corporation, Cambridge, MA, USA) was shown to arrest or reverse complications and to improve quality of life in patients with type 1 Gaucher's disease. More recently, modified recombinant glucocerebrosidase (imiglucerase, Genzyme Corporation) has been shown to be safe, effective and clinically equivalent to alglucerase by two studies which presented data for 12 months' follow-up. This case report, with 30 months' follow-up, represents the first publication of long-term results of imiglucerase therapy of type 1 Gaucher's disease in Europe.

Retrospective analysis of safety and efficacy of 30 months' imiglucerase infusions, 40 U/kg body weight every 2 weeks for 17 months, then 60 U/kg every 2 weeks for 13 months, in an elderly male patient with severe type 1 Gaucher's disease.

No adverse reactions occurred, and anti-imiglucerase antibody assay was negative at 17 months. Clinically, the patient responded rapidly and markedly. Within several months, bone pain decreased notably, enabling him to abandon crutches. Abdominal pain abated, fatigue decreased and physical fitness and general well-being improved. Nosebleeds and haematomas ceased. Dosage increase massively reduced hepatosplenomegaly and produced much greater improvement in laboratory values, especially platelet count. Bone pain diminished further, so that this formerly disabled patient now walks and climbs stairs without complains. Also of note, aminotransferases, gamma-GT, total protein, and prothrombine time improved, suggesting improvement of liver function.

This case documents long-term safety and efficacy of recombinant enzyme replacement in type 1 Gaucher's disease.

In the early 1990s,

    enzyme replacement therapy with modified placental glucocerebrosidase (alglucerase
    MEDICATION

, Genzyme Corporation, Cambridge, MA, USA) was shown to

    arrest or reverse complications
    SYMPTOMS

 and to

    improve quality of life
    SYMPTOMS

 in patients with

    type 1 Gaucher's disease
    DIAGNOSIS

. More recently,

    modified recombinant glucocerebrosidase (imiglucerase, Genzyme Corporation)
    MEDICATION

 has been shown to be safe, effective and clinically equivalent

    to alglucerase
    MEDICATION

 by two studies which presented data for 12 months' follow-up. This case report, with 30 months' follow-up, represents the first publication of long-term results of

    imiglucerase therapy
    MEDICATION

 of

    type 1 Gaucher's disease
    DIAGNOSIS

 in

    Europe
    ETHNICITY

.

Retrospective analysis of safety and efficacy of

    30 months' imiglucerase infusions, 40 U/kg body weight every 2 weeks for 17 months, then 60 U/kg every 2 weeks for 13 months
    MEDICATION

, in an

    elderly
    AGE

    male
    GENDER

 patient with

    severe type 1 Gaucher's disease
    DIAGNOSIS

.

    No adverse reactions
    NEG_FINDINGS

 occurred, and

    anti-imiglucerase antibody assay was negative at 17 months
    NEG_FINDINGS

. Clinically, the patient responded rapidly and markedly. Within several months,

    bone pain decreased notably
    SYMPTOMS

, enabling

    him
    GENDER

 to

    abandon crutches
    MEDICATION

.

    Abdominal pain abated
    SYMPTOMS

,

    fatigue decreased
    SYMPTOMS

 and

    physical fitness and general well-being improved
    SYMPTOMS

.

    Nosebleeds
    SYMPTOMS

 and

    haematomas ceased
    SYMPTOMS

.

    Dosage increase massively reduced hepatosplenomegaly
    MEDICATION

 and produced

    much greater improvement in laboratory values, especially platelet count
    BIOCHEMICAL

.

    Bone pain diminished further
    SYMPTOMS

, so that this formerly disabled patient now

    walks and climbs stairs
    MEDICATION

    without complains
    NEG_FINDINGS

. Also of note,

    aminotransferases, gamma-GT, total protein, and prothrombine time improved
    BIOCHEMICAL

, suggesting

    improvement of liver function
    SYMPTOMS

.

This case documents long-term safety and efficacy of

    recombinant enzyme replacement
    MEDICATION

 in

    type 1 Gaucher's disease
    DIAGNOSIS

.

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


The nature and extent of jaw involvement in Gaucher disease: observations in a series of 28 patients.

A wide variety of osteoarticular pathoses plague the clinical course of many patients with Gaucher disease. Osseous lesions involving the jaws have been described, usually as isolated case reports. The purpose of this study was to ascertain the nature and extent of mandibulo-maxillofacial pathosis in 28 patients with documented Gaucher disease by means of panoramic radiography. Twenty-five of the 28 patients displayed radiographic evidence of jaw involvement. The most prevalent finding was gross widening of marrow spaces; frank radiolucencies, endosteal scalloping, cortical thinning, root resorption, and inferior displacement of the mandibular canal or effacement of its cortices were also seen. A previously unreported finding was delayed eruption of permanent teeth, which was seen in more than one half of the patients who were under 20 years of age. Osseous changes throughout the jaws may be more common than previously suspected and may alert the dentist to the presence of the disease.

A wide variety of

    osteoarticular pathoses
    SYMPTOMS

 plague the clinical course of many patients with

    Gaucher disease
    DIAGNOSIS

.

    Osseous lesions involving the jaws
    SYMPTOMS

 have been described, usually as isolated case reports. The purpose of this study was to ascertain the nature and extent of

    mandibulo-maxillofacial pathosis
    SYMPTOMS

 in 28 patients with documented

    Gaucher disease
    DIAGNOSIS

 by means of

    panoramic radiography
    PARACLINICAL

. Twenty-five of the 28 patients displayed

    radiographic evidence of jaw involvement
    SYMPTOMS

. The most prevalent finding was

    gross widening of marrow spaces
    SYMPTOMS

;

    frank radiolucencies
    SYMPTOMS

,

    endosteal scalloping
    SYMPTOMS

,

    cortical thinning
    SYMPTOMS

,

    root resorption
    SYMPTOMS

, and

    inferior displacement of the mandibular canal or effacement of its cortices
    SYMPTOMS

 were also seen. A previously unreported finding was

    delayed eruption of permanent teeth
    SYMPTOMS

, which was seen in more than one half of the patients who were

    under 20 years of age
    AGE

.

    Osseous changes throughout the jaws
    SYMPTOMS

 may be more common than previously suspected and may alert the dentist to the presence of the disease.


[Anesthetic management involving difficult intubation in a child with Gaucher disease].

Gaucher disease is the most common of the glycolipid storage disorders caused by the deficiency of glucocerebrosidase, an enzyme which hydrolyzes glucocerebroside to glucose and ceramide. Accumulation of the substrate leads to multiorgan dysfunction involving the brain, spleen, liver, lymph node and bone marrow. In anesthetic management, gastroesophageal reflux leading to recurrent aspiration, pancytopenia and airway difficulties due to trismus, neck extension and upper airway infiltration with glucocerebroside must be considered. We report a case of a 9-year-old boy presenting developmental delay, mild pancytopenia, splenomegary gastroesophageal reflux. He was scheduled for measurement of intra-esophageal pressure, total splenectomy and Nissen fundoplication. Preoperative examination showed trismus and opisthotonic posturing. We predicted difficult airway maintenance and assessed his airway with airway radiograph. Airway narrowing was not shown. For this difficult airway, we made a special mask that has an introducer port for fiberbronchoscope. For the first time, we tried to insert a laryngeal mask, but the insertion was difficult due to trismus and narrowed oral cavity. Then, we used this special mask for the next time. Tracheal intubation was much safer by using this mask for fiberoptic intubation. In Gaucher disease, preoperative assessment of airway difficulties and preparation for this situation are necessary and anesthesiologist must be concerned about aspiration and airway difficulties.

    Gaucher disease
    DIAGNOSIS

 is the most common of the

    glycolipid storage disorders
    DIAGNOSIS

 caused by the

    deficiency of glucocerebrosidase
    BIOCHEMICAL

, an enzyme which

    hydrolyzes glucocerebroside to glucose and ceramide
    BIOCHEMICAL

.

    Accumulation of the substrate
    MICROSCOPIC

 leads to

    multiorgan dysfunction
    SYMPTOMS

    involving the brain, spleen, liver, lymph node and bone marrow
    MICROSCOPIC

. In anesthetic management,

    gastroesophageal reflux
    SYMPTOMS

 leading to

    recurrent aspiration
    SYMPTOMS

,

    pancytopenia
    BIOCHEMICAL

 and

    airway difficulties
    SYMPTOMS

 due to

    trismus
    SYMPTOMS

,

    neck extension
    SYMPTOMS

 and

    upper airway infiltration with glucocerebroside
    MICROSCOPIC

 must be considered. We report a case of a

    9-year-old
    AGE

    boy
    GENDER

 presenting

    developmental delay
    SYMPTOMS

,

    mild pancytopenia
    BIOCHEMICAL

,

    splenomegary gastroesophageal reflux
    SYMPTOMS

.

    He
    GENDER

 was scheduled for

    measurement of intra-esophageal pressure
    PARACLINICAL

,

    total splenectomy
    MEDICATION

 and

    Nissen fundoplication
    MEDICATION

. Preoperative examination showed

    trismus
    SYMPTOMS

 and

    opisthotonic posturing
    SYMPTOMS

. We predicted

    difficult airway maintenance
    SYMPTOMS

 and

    assessed his airway with airway radiograph
    PARACLINICAL

.

    Airway narrowing was not shown
    NEG_FINDINGS

. For this

    difficult airway
    SYMPTOMS

, we made a

    special mask that has an introducer port for fiberbronchoscope
    MEDICATION

. For the first time, we tried to

    insert a laryngeal mask
    MEDICATION

, but the

    insertion was difficult
    NEG_FINDINGS

 due to

    trismus
    SYMPTOMS

 and

    narrowed oral cavity
    SYMPTOMS

. Then, we used this

    special mask
    MEDICATION

 for the next time.

    Tracheal intubation
    MEDICATION

 was much safer by using this

    mask for fiberoptic intubation
    MEDICATION

. In

    Gaucher disease
    DIAGNOSIS

, preoperative assessment of airway difficulties and preparation for this situation are necessary and

    anesthesiologist
    PARACLINICAL

 must be concerned about

    aspiration
    SYMPTOMS

 and

    airway difficulties
    SYMPTOMS

.

Gaucher disease
glycolipid storage disorders
Gaucher disease

multiorgan dysfunction
gastroesophageal reflux
recurrent aspiration
airway difficulties
trismus
neck extension
developmental delay
splenomegary gastroesophageal reflux
trismus
opisthotonic posturing
difficult airway maintenance
difficult airway
trismus
narrowed oral cavity
aspiration
airway difficulties

Airway narrowing was not shown
insertion was difficult


Use of enzyme replacement therapy for Gaucher disease during pregnancy.

To date there has been little published experience with enzyme replacement therapy in pregnant women with symptomatic type I Gaucher disease.

We describe six patients, including three with repeated early pregnancy loss, five of whom successfully carried pregnancies to term; the last pregnancy was terminated because of pulmonary hypertension.

All pregnancies were uneventful and five resulted in healthy newborns.

We concluded that in patients with Gaucher disease of childbearing age,for whom obstetric complications are an important symptom of the disease, pregnancy is not contraindicated (unless there is evidence or suspicion of pulmonary hypertension) and treatment should not be interrupted because the clinical improvement engendered by enzyme replacement therapy is conducive to fewer complications during pregnancy and delivery and post partum.

To date there has been little published experience with

    enzyme replacement therapy
    MEDICATION

 in

    pregnant
    AGE

    women
    GENDER

 with

    symptomatic type I Gaucher disease
    DIAGNOSIS

.

We describe six patients, including three with

    repeated early pregnancy loss
    SYMPTOMS

, five of whom

    successfully carried pregnancies to term
    MEDICATION

; the

    last pregnancy was terminated
    MEDICATION

 because of

    pulmonary hypertension
    SYMPTOMS

.

All

    pregnancies were uneventful
    SYMPTOMS

 and five resulted in healthy newborns.

We concluded that in patients with

    Gaucher disease
    DIAGNOSIS

 of

    childbearing age
    AGE

,for whom

    obstetric complications
    SYMPTOMS

 are an important symptom of the disease,

    pregnancy
    NEG_FINDINGS

 is

    not contraindicated
    NEG_FINDINGS

 (unless there is evidence or suspicion of

    pulmonary hypertension
    SYMPTOMS

) and treatment should

    not be interrupted
    NEG_FINDINGS

 because the

    clinical improvement
    SYMPTOMS

 engendered by

    enzyme replacement therapy
    MEDICATION

 is conducive to

    fewer complications during pregnancy and delivery and post partum
    SYMPTOMS

.

symptomatic type I Gaucher disease
Gaucher disease

pregnancy
not contraindicated
not be interrupted


Multiple myeloma arising from monoclonal gammopathy of undetermined significance in a patient with Gaucher's disease.

We report the case of a 64-year-old woman who, 12 years after receiving a diagnosis of Gaucher's disease with concurrent monoclonal gammopathy of undetermined significance, developed worsening thrombocytopenia and bone pain. Bone marrow biopsy at this time revealed 50% plasma cells with a serum monoclonal immunoglobulin A-lambda level of 3.2 g/L. Roentgenography revealed a lytic clavicular lesion, and a diagnosis of multiple myeloma was made. To our knowledge, this case is the first to document the evolution of a monoclonal gammopathy of undetermined significance to multiple myeloma in a patient with Gaucher's disease. The importance of investigating cytopenias and increased bone pain in such patients, perhaps by bone marrow biopsy, to rule out potentially malignant plasma cell dyscrasias is stressed.

We report the case of a

    64-year-old
    AGE

    woman
    GENDER

 who, 12 years after receiving a diagnosis of

    Gaucher's disease
    DIAGNOSIS

 with concurrent

    monoclonal gammopathy of undetermined significance
    DIAGNOSIS

, developed

    worsening thrombocytopenia
    BIOCHEMICAL

 and

    bone pain
    SYMPTOMS

.

    Bone marrow biopsy
    PARACLINICAL

 at this time revealed

    50% plasma cells
    MICROSCOPIC

 with a serum monoclonal immunoglobulin A-lambda level of 3.2 g/L.

    Roentgenography
    PARACLINICAL

 revealed a

    lytic clavicular lesion
    SYMPTOMS

, and a diagnosis of

    multiple myeloma
    DIAGNOSIS

 was made. To our knowledge, this case is the first to document the evolution of a

    monoclonal gammopathy of undetermined significance
    DIAGNOSIS

 to

    multiple myeloma
    DIAGNOSIS

 in a patient with

    Gaucher's disease
    DIAGNOSIS

. The importance of investigating

    cytopenias
    BIOCHEMICAL

 and

    increased bone pain
    SYMPTOMS

 in such patients, perhaps by

    bone marrow biopsy
    PARACLINICAL

, to rule out

    potentially malignant plasma cell dyscrasias
    NEG_FINDINGS

 is stressed.

bone pain
lytic clavicular lesion
increased bone pain


Should repeated partial splenectomy be attempted in patients with hematological diseases? Technical pitfalls and causes of failure in Gaucher's disease.

The awareness of the risk of overwhelming sepsis after splenectomy prompted surgeons to attempt splenic preservation in patients who had hematologic diseases for which splenectomy was the conventional treatment. Partial splenectomy for Gaucher's disease was widely performed before the introduction of alglucerase. In sporadic cases a second partial splenectomy had also been attempted.

The authors present three cases of failed repeated partial splenectomy attempted before alglucerase was available. The role of angiography in planning operative strategy and the surgical pitfalls of this unusual reintervention are discussed.

New indications for partial splenectomy in other hematologic diseases makes the experience gained with Gaucher's disease valuable for management decisions.

The awareness of the risk of

    overwhelming sepsis
    SYMPTOMS

 after

    splenectomy
    MEDICATION

 prompted surgeons to attempt

    splenic preservation
    MEDICATION

 in patients who had

    hematologic diseases
    DIAGNOSIS

 for which

    splenectomy
    MEDICATION

 was the conventional treatment.

    Partial splenectomy
    MEDICATION

 for

    Gaucher's disease
    DIAGNOSIS

 was widely performed before the introduction of

    alglucerase
    MEDICATION

. In sporadic cases a

    second partial splenectomy
    MEDICATION

 had also been attempted.

The authors present three cases of

    failed repeated partial splenectomy
    MEDICATION

 attempted

    before alglucerase was available
    NEG_FINDINGS

. The role of

    angiography
    PARACLINICAL

 in planning operative strategy and the surgical pitfalls of this unusual

    reintervention
    MEDICATION

 are discussed.

New indications for

    partial splenectomy
    MEDICATION

 in other

    hematologic diseases
    DIAGNOSIS

 makes the experience gained with

    Gaucher's disease
    DIAGNOSIS

 valuable for management decisions.

splenectomy
splenic preservation
splenectomy
Partial splenectomy
alglucerase
second partial splenectomy
failed repeated partial splenectomy
reintervention
partial splenectomy

hematologic diseases
Gaucher's disease
hematologic diseases
Gaucher's disease


Type I Gaucher disease due to homozygosity for the 259T mutation in a Bedouin patient.

A 26-year-old Bedouin with moderate thrombocytopenia and enlarged spleen and liver was diagnosed as having type I Gaucher disease based on the presence of Gaucher cells in the bone marrow biopsy and enzymatic determination of glucocerebrosidase activity. Molecular analysis excluded 10 common mutations in the glucocerebrosidase gene. Homozygosity for the C --> T mutation in nucleotide 259 of the cDNA (1763 genomic) was detected by digestion with restriction enzyme StyI after an amplification of a portion of exon 3 by mismatched primers. This is the first known case of homozygosity for this mutation. The fact that it produces a very mild phenotype, confirms a previous suggestion that 259T can be classified as a "mild" mutation. Association of the 259T mutation with the "Pv 1.1 +" haplotype is consistent with a common origin of the mutated alleles.

A

    26-year-old
    AGE

    Bedouin
    ETHNICITY

 with

    moderate thrombocytopenia
    BIOCHEMICAL

 and

    enlarged spleen and liver
    SYMPTOMS

 was diagnosed as having

    type I Gaucher disease
    DIAGNOSIS

 based on the

    presence of Gaucher cells in the bone marrow biopsy
    MICROSCOPIC

 and

    enzymatic determination of glucocerebrosidase activity
    BIOCHEMICAL

.

    Molecular analysis
    PARACLINICAL

    excluded 10 common mutations in the glucocerebrosidase gene
    GENETICS

.

    Homozygosity for the C --> T mutation in nucleotide 259 of the cDNA (1763 genomic)
    GENETICS

 was detected by digestion with restriction enzyme StyI after an

    amplification of a portion of exon 3 by mismatched primers
    PARACLINICAL

. This is the first known case of

    homozygosity for this mutation
    GENETICS

. The fact that it produces a

    very mild phenotype
    SYMPTOMS

, confirms a previous suggestion that

    259T
    GENETICS

 can be classified as a "mild" mutation.

    Association of the 259T mutation with the "Pv 1.1 +" haplotype
    GENETICS

 is consistent with a

    common origin of the mutated alleles
    GENETICS

.

enlarged spleen and liver
very mild phenotype


Identification of two novel and four uncommon missense mutations among chinese Gaucher disease patients.

Gaucher disease is the most prevalent lysosomal storage disease. It is panethnic and results from an inherited deficiency of glucocerebrosidase. Most mutations to date have been identified among Jewish and non-Jewish Caucasian patients; mutations in Chinese patients are largely unknown. We have performed nucleotide sequence analysis of PCR-amplified glucocerebrosidase genomic DNA from five unrelated Chinese patients affected with type 1 (non-neuropathic) Gaucher disease. A novel heterozygous C --> T mutation at cDNA nucleotide position 475 (R120W) was detected in a patient who is also heterozygous for a C --> T transition at cDNA nucleotide position 259 (R48W). In a second patient, a novel, heterozygous T --> G transversion at cDNA 226 (F37V) was detected. Mutation 1448 (L444P), the most prevalent mutation among non-Jewish Caucasian Gaucher patients, was found in the heterozygous form in four patients. The mutations in the second Gaucher allele in the other three patients are mutations 254 (G46E), 680 (N188S), and 754 (F213I), which were recently reported in Korean, Arab, and Chinese (Taiwanese) patients. We have developed screening methods that utilize PCR amplification of glucocerebrosidase genomic DNA and Eco571, Nci1, Hinc11, BsaJ1, and Bsr1 restriction endonuclease analyses for the detection of each of these mutations. The population genetics of some of these Gaucher alleles and their implications in genotype/phenotype correlation are discussed.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disease
    DIAGNOSIS

. It is

    panethnic
    GENETICS

 and results from an

    inherited deficiency of glucocerebrosidase
    GENETICS

. Most mutations to date have been identified among

    Jewish
    ETHNICITY

 and

    non-Jewish Caucasian
    ETHNICITY

 patients; mutations in

    Chinese
    ETHNICITY

 patients are largely unknown. We have performed

    nucleotide sequence analysis of PCR-amplified glucocerebrosidase genomic DNA
    PARACLINICAL

 from five unrelated

    Chinese
    ETHNICITY

 patients affected with

    type 1 (non-neuropathic) Gaucher disease
    DIAGNOSIS

. A

    novel heterozygous C --> T mutation at cDNA nucleotide position 475 (R120W)
    GENETICS

 was detected in a patient who is also

    heterozygous for a C --> T transition at cDNA nucleotide position 259 (R48W)
    GENETICS

. In a second patient, a

    novel, heterozygous T --> G transversion at cDNA 226 (F37V)
    GENETICS

 was detected.

    Mutation 1448 (L444P)
    GENETICS

, the most prevalent mutation among

    non-Jewish Caucasian
    ETHNICITY

    Gaucher patients
    DIAGNOSIS

, was found

    in the heterozygous form
    GENETICS

 in four patients. The

    mutations in the second Gaucher allele
    GENETICS

 in the other three patients

    are mutations 254 (G46E), 680 (N188S), and 754 (F213I)
    GENETICS

, which were recently reported in

    Korean
    ETHNICITY

,

    Arab
    ETHNICITY

, and

    Chinese
    ETHNICITY

 (

    Taiwanese
    ETHNICITY

) patients. We have developed screening methods that utilize

    PCR amplification of glucocerebrosidase genomic DNA
    PARACLINICAL

 and

    Eco571, Nci1, Hinc11, BsaJ1, and Bsr1 restriction endonuclease analyses
    PARACLINICAL

 for the detection of each of these mutations. The population genetics of some of these

    Gaucher alleles
    GENETICS

 and their implications in genotype/phenotype correlation are discussed.

Jewish
non-Jewish Caucasian
Chinese
Chinese
non-Jewish Caucasian
Korean
Arab
Chinese
Taiwanese


Prenatal ultrasound findings in a fetus diagnosed with Gaucher's disease (type 2) at birth.

A 26-year-old woman with no significant history was found to have a fetus with hepatosplenomegaly and neurological abnormalities in utero on ultrasound. The baby was found to have a severe clinical manifestation of type 2 Gaucher's disease.

A

    26-year-old
    AGE

    woman
    GENDER

 with

    no significant history
    NEG_FINDINGS

 was found to have a

    fetus with hepatosplenomegaly
    SYMPTOMS

 and

    neurological abnormalities in utero
    SYMPTOMS

 on

    ultrasound
    PARACLINICAL

. The

    baby
    AGE

 was found to have a

    severe clinical manifestation of type 2 Gaucher's disease
    SYMPTOMS

.


Gaucher disease: enzyme therapy in the acute neuronopathic variant.

The responses to regular intravenous enzyme infusions were compared in two sibs with Gaucher disease type 2, the acute neuronopathic variant. Enzyme administration was begun at 7 months in patient 1 who had severe progressive visceral and neuronopathic disease. No significant effect of enzyme infusions was noted. Death occurred at 9 months. Patient 2 was prenatally diagnosed and enzyme infusions were initiated at age 4 days. Overall development progressed at a rate similar to her unaffected full sib until her death at 15.1 months. Slowly progressive esotropia, ocular paresis and dysphagia began at 8 months as did infiltrative pulmonary disease. Comparison of these clinical courses show significant visceral and neurologic effects of anticipatory enzyme therapy, but with unaltered outcome, for Gaucher disease type 2.

The responses to

    regular intravenous enzyme infusions
    MEDICATION

 were compared in two

    sibs with Gaucher disease type 2, the acute neuronopathic variant
    FAMILY

.

    Enzyme administration
    MEDICATION

 was begun

    at 7 months
    AGE

 in patient 1 who had

    severe progressive visceral and neuronopathic disease
    DIAGNOSIS

.

    No significant effect of enzyme infusions
    NEG_FINDINGS

 was noted.

    Death
    SYMPTOMS

 occurred at

    9 months
    AGE

. Patient 2 was

    prenatally diagnosed
    GENETICS

 and

    enzyme infusions
    MEDICATION

 were initiated at

    age 4 days
    AGE

.

    Overall development progressed at a rate similar to her unaffected full sib
    SYMPTOMS

 until

    her
    GENDER

    death
    SYMPTOMS

 at

    15.1 months
    AGE

.

    Slowly progressive esotropia
    SYMPTOMS

,

    ocular paresis
    SYMPTOMS

 and

    dysphagia
    SYMPTOMS

 began

    at 8 months
    AGE

 as did

    infiltrative pulmonary disease
    DIAGNOSIS

. Comparison of these clinical courses show

    significant visceral and neurologic effects
    SYMPTOMS

 of

    anticipatory enzyme therapy
    MEDICATION

, but with unaltered outcome, for

    Gaucher disease type 2
    DIAGNOSIS

.

regular intravenous enzyme infusions
Enzyme administration
enzyme infusions
anticipatory enzyme therapy


Enzyme therapy in Gaucher disease type 1: effect of neutralizing antibodies to acid beta-glucosidase.

Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid beta-glucosidase locus. Periodic infusions of macrophage-targeted acid beta-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid beta-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid beta-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression and need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid beta-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid beta-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.

    Gaucher disease type 1
    DIAGNOSIS

, a

    non-neuronopathic lysosomal storage disease
    DIAGNOSIS

, is caused by

    mutations at the acid beta-glucosidase locus
    GENETICS

.

    Periodic infusions of macrophage-targeted acid beta-glucosidase
    MEDICATION

 reverse

    hepatosplenomegaly
    SYMPTOMS

,

    hematologic, and bony findings
    SYMPTOMS

 in many patients. Two patients receiving

    enzyme therapy
    MEDICATION

 developed

    neutralizing antibodies to acid beta-glucosidase
    BIOCHEMICAL

 that were associated with a

    lack of improvement or progressive disease
    NEG_FINDINGS

.

    After initial improvement
    NEG_FINDINGS

, case 1 had

    no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy
    NEG_FINDINGS

. Similarly, case 2 initially showed a

    favorable response to enzyme therapy
    NEG_FINDINGS

 that plateaued after

    1 year of treatment
    MEDICATION

. Both patients developed

    minor allergic reactions
    SYMPTOMS

 and

    antibodies to acid beta-glucosidase
    BIOCHEMICAL

 within the first 6 months of treatment.

    Enzyme therapy was discontinued
    MEDICATION

 in case 1, with resultant

    disease progression
    SYMPTOMS

 and need for

    splenectomy
    MEDICATION

. An

    immunosuppression/tolerization protocol
    MEDICATION

 was initiated in case 2 because of

    disease progression
    SYMPTOMS

 and

    stable neutralizing antibody titers
    BIOCHEMICAL

. The

    IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid beta-glucosidase in vitro
    BIOCHEMICAL

.

    Antibodies to human serum albumin and chorionic gonadotropin also developed
    BIOCHEMICAL

. The finding of

    neutralizing antibodies to acid beta-glucosidase
    BIOCHEMICAL

 during

    enzyme therapy
    MEDICATION

 for

    Gaucher disease
    DIAGNOSIS

 has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for

    Gaucher disease
    DIAGNOSIS

.

hepatosplenomegaly
hematologic, and bony findings
minor allergic reactions
disease progression
disease progression


Two new mild homozygous mutations in Gaucher disease patients: clinical signs and biochemical analyses.

Gaucher disease (GD) is a lysosomal storage disorder resulting from impaired activity of lysosomal beta-glucocerebrosidase. More than 60 mutations have been described in the GBA gene. They have been classified as lethal, severe, and mild on the basis of the corresponding phenotype. The fact that most GD patients are compound heterozygous and that most type 1 patients bear the N370S allele, which by itself causes a mild phenotype, make it difficult to correlate the clinical signs with the mutations. Besides N370S, about 10 mild mutations have been described, but only one undoubtedly classified as mild was found at homozygosity. Here we report 2 novel mutations, I402T and V375L, at homozygosity in 2 adult Italian type 1 GD patients. Some properties of the I402T fibroblast enzyme have been compared to those of the enzyme from cells of several N370S/N370S patients. Analysis of the catalytic properties and heat stability as well as the response to phosphatidylserine and sphingolipid activator protein indicate a marked similarity between the 2 enzymes. The finding of another, unrelated patient bearing the I402T mutation (in this case as a compound heterozygote with mutation N370S) suggests that this allele might be quite frequent in the area of Sicily from where both patients originated. In conclusion, the phenotypic expression in the 2 homozygous patients presented here and the biochemical data for one of them allowed the classification of these mutations as mild thus extending the group of mild mutations found at homozygosity.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 resulting from

    impaired activity of lysosomal beta-glucocerebrosidase
    BIOCHEMICAL

. More than 60 mutations have been described in the

    GBA gene
    GENETICS

. They have been classified as lethal, severe, and mild on the basis of the corresponding phenotype. The fact that most

    GD
    DIAGNOSIS

 patients are

    compound heterozygous
    GENETICS

 and that most

    type 1
    DIAGNOSIS

 patients bear the

    N370S allele
    GENETICS

, which by itself causes a mild phenotype, make it difficult to correlate the clinical signs with the mutations. Besides

    N370S
    GENETICS

, about 10

    mild mutations
    GENETICS

 have been described, but only one undoubtedly classified as mild was found

    at homozygosity
    GENETICS

. Here we report 2

    novel mutations, I402T and V375L, at homozygosity
    GENETICS

 in 2

    adult
    AGE

    Italian
    ETHNICITY

    type 1 GD
    DIAGNOSIS

 patients. Some properties of the I402T fibroblast enzyme have been compared to those of the enzyme from cells of several N370S/N370S patients. Analysis of the catalytic properties and heat stability as well as the response to phosphatidylserine and

    sphingolipid activator protein
    BIOCHEMICAL

 indicate a marked similarity between the 2 enzymes. The finding of another, unrelated patient bearing the

    I402T mutation
    GENETICS

    (in this case as a compound heterozygote with mutation N370S
    FAMILY

) suggests that this allele might be quite frequent in the area of

    Sicily
    ETHNICITY

 from where

    both patients originated
    FAMILY

. In conclusion, the phenotypic expression in the 2 homozygous patients presented here and the biochemical data for one of them allowed the classification of these mutations as mild thus extending the group of

    mild mutations
    GENETICS

 found at homozygosity.

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


[Type 1 Gaucher disease in a pediatric patient: 12 year's evolution].

A 14 years old patient, diagnosed in early childhood of type 1 Gaucher's disease is reported to show his unusual genotype and clinical course. The patient is heterozygous for mutation D409H, that in the homozygous patient determines an aggressive disease accompanied by neurological signs, and for a new mutation, which must be considered of mild effects. Early detection of bone involvement is emphasized as a factor to consider when indicating of enzyme replacement therapy.

A

    14 years old
    AGE

 patient, diagnosed in

    early childhood
    AGE

 of

    type 1 Gaucher's disease
    DIAGNOSIS

 is reported to show his unusual genotype and clinical course. The patient is

    heterozygous for mutation D409H
    GENETICS

, that in the

    homozygous patient
    GENETICS

 determines an

    aggressive disease
    SYMPTOMS

 accompanied by

    neurological signs
    SYMPTOMS

, and for a

    new mutation
    GENETICS

, which must be considered of mild effects. Early detection of

    bone involvement
    SYMPTOMS

 is emphasized as a factor to consider when indicating of

    enzyme replacement therapy
    MEDICATION

.

heterozygous for mutation D409H
homozygous patient
new mutation

aggressive disease
neurological signs
bone involvement


[Uncoupling of cerebellar blood flow and metabolism in paraneoplastic cerebellar degeneration: report of a case].

We report a 65-year-old woman with paraneoplastic cerebellar degeneration (PCD) who showed reduced cerebellar metabolism with preserved blood flow. She was admitted to Gunma University Hospital because of progressive gait and speech disturbances. Neurologic examination revealed nystagmus, dysphagia, explosive speech, reduced muscle tone in limbs, and marked truncal and limb ataxia, and mild hypesthesia in hands and feet. Cranial MRI demonstrated slight cerebellar atrophy. Laboratory findings disclosed high levels of serum CA19-9 and other tumor markers, and positive anti-Yo antibody, indicating that she had PCD. A specimen obtained from an axillary lymph node revealed metastasis of poorly differentiated adenocarcinoma, although systemic and vigorous checkup failed to find its origin. Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were measured using positron emission tomography (PET) 15 months after the onset. CMRO2 was clearly decreased in the cerebellum, while CBF was almost normal. Moreover, PET with 2 18F-fluoro-2-deoxy-D-glucose (FDG) revealed that glucose metabolism was also reduced in the cerebellum. Single photon emission tomography using 99mTc-ethyl cysteinate dimer (ECD) showed a normal blood flow pattern in the whole brain. These results indicated that uncoupling of circulation and metabolism in the cerebellum of this patient. There are several reports showing uncoupling of cerebral perfusion and metabolism in ischemic disorders, encephalitis, mitochondrial diseases, brain tumors, epilepsy and Gaucher disease, although its pathophysiology is not elucidated. Because anti-Yo antibody evidently gives a suppressive influence on the cerebellar neurons, understanding the way the autoantibody acts may give a clue to the mechanism of reduced cerebellar metabolism with preserved perfusion in PCD.

We report a

    65-year-old
    AGE

    woman
    GENDER

 with

    paraneoplastic cerebellar degeneration (PCD)
    DIAGNOSIS

 who showed

    reduced cerebellar metabolism
    SYMPTOMS

 with

    preserved blood flow
    NEG_FINDINGS

.

    She
    GENDER

 was admitted to Gunma University Hospital because of

    progressive gait and speech disturbances
    SYMPTOMS

.

    Neurologic examination
    PARACLINICAL

 revealed

    nystagmus
    SYMPTOMS

,

    dysphagia
    SYMPTOMS

,

    explosive speech
    SYMPTOMS

,

    reduced muscle tone in limbs
    SYMPTOMS

, and

    marked truncal and limb ataxia
    SYMPTOMS

, and

    mild hypesthesia in hands and feet
    SYMPTOMS

.

    Cranial MRI
    PARACLINICAL

 demonstrated

    slight cerebellar atrophy
    SYMPTOMS

.

    Laboratory findings
    PARACLINICAL

 disclosed

    high levels of serum CA19-9 and other tumor markers
    BIOCHEMICAL

, and

    positive anti-Yo antibody
    BIOCHEMICAL

, indicating that

    she
    GENDER

 had

    PCD
    DIAGNOSIS

. A

    specimen obtained from an axillary lymph node
    PARACLINICAL

 revealed

    metastasis of poorly differentiated adenocarcinoma
    MICROSCOPIC

,

    although systemic and vigorous checkup failed to find its origin
    NEG_FINDINGS

.

    Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were measured using positron emission tomography (PET)
    PARACLINICAL

 15 months after the onset.

    CMRO2 was clearly decreased in the cerebellum
    SYMPTOMS

, while

    CBF was almost normal
    NEG_FINDINGS

. Moreover,

    PET with 2 18F-fluoro-2-deoxy-D-glucose (FDG)
    PARACLINICAL

 revealed that

    glucose metabolism was also reduced in the cerebellum
    SYMPTOMS

.

    Single photon emission tomography using 99mTc-ethyl cysteinate dimer (ECD)
    PARACLINICAL

 showed a

    normal blood flow pattern in the whole brain
    NEG_FINDINGS

. These results indicated that

    uncoupling of circulation and metabolism in the cerebellum
    SYMPTOMS

 of this patient. There are several reports showing

    uncoupling of cerebral perfusion and metabolism
    SYMPTOMS

 in

    ischemic disorders
    DIAGNOSIS

,

    encephalitis
    DIAGNOSIS

,

    mitochondrial diseases
    DIAGNOSIS

,

    brain tumors
    DIAGNOSIS

,

    epilepsy
    DIAGNOSIS

 and

    Gaucher disease
    DIAGNOSIS

, although its pathophysiology is not elucidated. Because

    anti-Yo antibody
    BIOCHEMICAL

 evidently

    gives a suppressive influence on the cerebellar neurons
    SYMPTOMS

, understanding the way the autoantibody acts may give a clue to the mechanism of

    reduced cerebellar metabolism with preserved perfusion
    SYMPTOMS

 in

    PCD
    DIAGNOSIS

.


Allogeneic bone marrow transplantation for Gaucher disease--a case report.

A Chinese patient who presented painful disability of right hip was diagnosed as having type 1 Gaucher disease four years later when hepatosplenomegaly was found. Splenectomy was performed but her condition did not improve. So human leukocyte antigen (HLA)-matched sibling allogeneic bone marrow transplantation (BMT) was performed. The transplantation course was smooth. Although her bone marrow was in mixed chimeric state, symptoms disappeared and her growth caught up with normal level after BMT. Gaucher disease should be considered in cases with hepatosplenomegaly and bone disorder of unknown causes. Allogeneic BMT is an effective treatment, but the treatment-related risk should be seriously evaluated and the late complications should be closely monitored.

A

    Chinese
    ETHNICITY

 patient who presented

    painful disability of right hip
    SYMPTOMS

 was diagnosed as having

    type 1 Gaucher disease
    DIAGNOSIS

 four years later when

    hepatosplenomegaly
    SYMPTOMS

 was found.

    Splenectomy
    MEDICATION

 was performed but

    her
    GENDER

    condition did not improve
    NEG_FINDINGS

. So

    human leukocyte antigen (HLA)-matched sibling allogeneic bone marrow transplantation (BMT)
    MEDICATION

 was performed. The transplantation course was smooth. Although

    her
    GENDER

    bone marrow was in mixed chimeric state
    MICROSCOPIC

,

    symptoms disappeared
    SYMPTOMS

 and

    her
    GENDER

    growth caught up with normal level
    SYMPTOMS

 after

    BMT
    MEDICATION

.

    Gaucher disease
    DIAGNOSIS

 should be considered in cases with

    hepatosplenomegaly
    SYMPTOMS

 and

    bone disorder of unknown causes
    SYMPTOMS

.

    Allogeneic BMT
    MEDICATION

 is an effective treatment, but the treatment-related risk should be seriously evaluated and the late complications should be closely monitored.

painful disability of right hip
hepatosplenomegaly
symptoms disappeared
growth caught up with normal level
hepatosplenomegaly
bone disorder of unknown causes


"Cold bone scans" as a sign of hemorrhagic infarcts of the spine in Gaucher's disease.

The most common form of Gaucher's disease, type 1 (chronic non-neuronopathic), results in accumulation of glucocerebroside in reticuloendothelial cells of the spleen, liver and bone marrow, with frequent occurrence of bone pain due to vaso-occlusive crisis. We report the finding of a "cold" vertebral body on bone scan in two patients with Gaucher's disease and bone crisis. Photopenia was so striking as to give the appearance of a "missing" vertebra. Concurrent plain films appeared normal. In one patient Gaucher's disease had not previously been diagnosed.

The most common form of

    Gaucher's disease
    DIAGNOSIS

,

    type 1 (chronic non-neuronopathic)
    DIAGNOSIS

, results in

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

, with frequent occurrence of

    bone pain
    SYMPTOMS

 due to

    vaso-occlusive crisis
    SYMPTOMS

. We report the finding of

    a "cold" vertebral body
    SYMPTOMS

 on

    bone scan
    PARACLINICAL

 in two patients with

    Gaucher's disease
    DIAGNOSIS

 and

    bone crisis
    SYMPTOMS

.

    Photopenia was so striking as to give the appearance of a "missing" vertebra
    SYMPTOMS

.

    Concurrent plain films appeared normal
    NEG_FINDINGS

. In one patient

    Gaucher's disease had not previously been diagnosed
    DIAGNOSIS

.


Identification and expression of acid beta-glucosidase mutations causing severe type 1 and neurologic type 2 Gaucher disease in non-Jewish patients.

Gaucher disease, the most prevalent lysosomal storage disease, occurs in three subtypes, all resulting from mutations in the acid beta-glucosidase gene. Molecular studies in five severely affected type 1 and two type 2 Gaucher disease patients of non-Jewish descent identified six new mutations: K74X, W179X, G195E, S271N, V352L, and a two-base deletion in exon 10 (1450del2). Two additional mutations identified in these patients (R48W and G202R) have been reported previously, but were not expressed or characterized. Heterologous expression in Sf 9 cells using the baculovirus system revealed that the missense mutations, R48W and V352L, had 14 and 7%, respectively, of the specific activity based on cross-reacting immunologic material expressed by the normal allele. In contrast, the G195E, G202R, and S271N mutant alleles were more severely compromised with only 1-2% of the normal expressed specific activity based on cross-reacting immunologic material. Structural distortion at the active site was probed by comparing the interaction of the mutant enzymes with active site-directed inhibitors (castanospermine, conduritol B epoxide and deoxynojirimycin). R48W, G202R, and S271N were normally inhibited, whereas the V352L and G195E mutant enzymes had significantly decreased binding affinity. These mutations further expand the genetic heterogeneity in the lesions causing Gaucher disease types 1 and 2, and further delineate genotype/phenotype correlations and functional domains within the acid beta-glucosidase gene.

    Gaucher disease
    DIAGNOSIS

, the most prevalent

    lysosomal storage disease
    DIAGNOSIS

, occurs in three subtypes, all resulting from

    mutations in the acid beta-glucosidase gene
    GENETICS

.

    Molecular studies
    PARACLINICAL

 in five severely affected

    type 1
    DIAGNOSIS

 and two

    type 2 Gaucher disease
    DIAGNOSIS

 patients of

    non-Jewish descent
    ETHNICITY

 identified

    six new mutations: K74X, W179X, G195E, S271N, V352L, and a two-base deletion in exon 10 (1450del2)
    GENETICS

. Two additional mutations identified in these patients (

    R48W and G202R)
    GENETICS

 have been reported previously, but were not expressed or characterized.

    Heterologous expression in Sf 9 cells using the baculovirus system
    PARACLINICAL

 revealed that the

    missense mutations, R48W and V352L
    GENETICS

, had

    14 and 7%
    BIOCHEMICAL

, respectively,

    of the specific activity based on cross-reacting immunologic material expressed by the normal allele
    BIOCHEMICAL

. In contrast, the

    G195E, G202R, and S271N mutant alleles
    GENETICS

 were more severely compromised with

    only 1-2% of the normal expressed specific activity based on cross-reacting immunologic material
    BIOCHEMICAL

. Structural distortion at the active site was probed by comparing the interaction of the mutant enzymes with

    active site-directed inhibitors (castanospermine, conduritol B epoxide and deoxynojirimycin)
    MEDICATION

.

    R48W
    GENETICS

,

    G202R
    GENETICS

, and

    S271N
    GENETICS

    were normally inhibited
    NEG_FINDINGS

, whereas the

    V352L and G195E mutant enzymes
    GENETICS

 had

    significantly decreased binding affinity
    BIOCHEMICAL

. These mutations further expand the genetic heterogeneity in the lesions causing

    Gaucher disease types 1 and 2
    DIAGNOSIS

, and further delineate genotype/phenotype correlations and functional domains within the

    acid beta-glucosidase gene
    GENETICS

.

Gaucher disease
lysosomal storage disease
type 1
type 2 Gaucher disease
Gaucher disease types 1 and 2


[Gaucher's disease in pregnancy].

A case of Gaucher's disease associated with pregnancy is reported. Although clinical symptoms were not present, portal hypertension was detected by ultrasound in the 13th week of pregnancy. Maternal anemia implied the use of erythropoietin from the 33rd week onwards. Good perinatal and maternal outcomes were achieved and there were no hemorrhagic complications.

A case of

    Gaucher's disease associated with pregnancy
    DIAGNOSIS

 is reported.

    Although clinical symptoms were not present
    NEG_FINDINGS

,

    portal hypertension
    SYMPTOMS

 was detected by

    ultrasound
    PARACLINICAL

 in the 13th

    week of pregnancy
    AGE

.

    Maternal anemia
    BIOCHEMICAL

 implied the

    use of erythropoietin from the 33rd week onwards
    MEDICATION

.

    Good perinatal and maternal outcomes
    SYMPTOMS

 were achieved and there were

    no hemorrhagic complications
    NEG_FINDINGS

.

portal hypertension
Good perinatal and maternal outcomes


Obliteration of maxillary and sphenoid sinuses in Gaucher's disease.

Paranasal sinus obliteration is described in a patient with adult type Gaucher's disease. Plain radiographs and computed tomography showed obliteration of paranasal sinuses due to medullary expansion of surrounding bone. The mandible and maxilla are rarely affected in Gaucher's disease and obliteration of paranasal sinuses due to bony expansion has not previously been reported.

    Paranasal sinus obliteration
    SYMPTOMS

 is described in a patient with

    adult type Gaucher's disease
    DIAGNOSIS

.

    Plain radiographs
    PARACLINICAL

 and

    computed tomography
    PARACLINICAL

 showed

    obliteration of paranasal sinuses due to medullary expansion of surrounding bone
    SYMPTOMS

. The mandible and maxilla are rarely affected in

    Gaucher's disease
    DIAGNOSIS

 and

    obliteration of paranasal sinuses due to bony expansion
    SYMPTOMS

 has not previously been reported.

adult type Gaucher's disease
Gaucher's disease


Torsion of autotransplanted splenic tissue in Gaucher disease.

A 12-year-old girl who underwent a splenectomy followed by heterotopic splenic autotransplantation for treatment of hypersplenism secondary to Gaucher disease at the age of 3 years presented with acute lower abdominal pain. Radiological investigations were highly suggestive of torsion of the autotransplanted splenic tissue, which was confirmed during subsequent laparotomy. This is the first known report of torsion of autotransplanted splenic tissue.

A

    12-year-old
    AGE

    girl
    GENDER

 who

    underwent a splenectomy followed by heterotopic splenic autotransplantation
    MEDICATION

 for treatment of

    hypersplenism
    DIAGNOSIS

 secondary to

    Gaucher disease
    DIAGNOSIS

 at the

    age of 3 years
    AGE

 presented with

    acute lower abdominal pain
    SYMPTOMS

.

    Radiological investigations
    PARACLINICAL

 were highly suggestive of

    torsion of the autotransplanted splenic tissue
    SYMPTOMS

, which was confirmed during subsequent

    laparotomy
    PARACLINICAL

. This is the first known report of

    torsion of autotransplanted splenic tissue
    SYMPTOMS

.


[Indications for splenectomy in Gaucher's disease. Case report].

Gaucher's disease is a rare metabolic disorder characterized by the lack of beta-glucocerebrosidase enzyme. In this case report a 26-year-old male patient was, first diagnosed as having splenomegaly and a huge haemangioma, therefore managed by total splenectomy. Histologic examination and specific colouring techniques using PAS and Black Sudan dyes allowed the diagnosis of Gaucher's disease. Preoperative diagnosis is hence fundamental to establish the correct management procedure, which currently may be surgical or medical and/or combined. In fact, following the diagnosis the second step includes the decision-making about splenectomy. Other therapeutic approaches are enzyme replacement therapy and genic therapy. The first may be combined to partial splenectomy, while the latter still needs further evaluations.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare metabolic disorder
    DIAGNOSIS

 characterized by the

    lack of beta-glucocerebrosidase enzyme
    BIOCHEMICAL

. In this case report a

    26-year-old
    AGE

    male
    GENDER

 patient was, first diagnosed as having

    splenomegaly
    SYMPTOMS

 and a

    huge haemangioma
    SYMPTOMS

, therefore managed by

    total splenectomy
    MEDICATION

.

    Histologic examination
    PARACLINICAL

 and specific colouring techniques using

    PAS and Black Sudan dyes
    PARACLINICAL

 allowed the diagnosis of

    Gaucher's disease
    DIAGNOSIS

.

    Preoperative diagnosis
    PARACLINICAL

 is hence fundamental to establish the correct management procedure, which currently may be

    surgical or medical and/or combined
    MEDICATION

. In fact, following the diagnosis the second step includes the decision-making about

    splenectomy
    MEDICATION

. Other therapeutic approaches are

    enzyme replacement therapy
    MEDICATION

 and

    genic therapy
    MEDICATION

. The first may be

    combined to partial splenectomy
    MEDICATION

, while the latter still needs further evaluations.

Gaucher's disease
rare metabolic disorder
Gaucher's disease

total splenectomy
surgical or medical and/or combined
splenectomy
enzyme replacement therapy
genic therapy
combined to partial splenectomy