New variant of type II von Willebrand's disease with structural abnormality of plasma von Willebrand factor in a patient with very mild bleeding history.

A new variant of von Willebrand's disease has been discovered in 2 members of a Macedonian family of 6. The proband, an 8-year-old boy, showed a prolonged bleeding episode on 1 occasion. Ristocetin-induced platelet aggregation and bleeding time were normal. In plasma, ristocetin cofactor activity (RCo) and von Willebrand factor (vWf) antigen were reduced to the same clearly low level. The determination of vWf antigen of platelets resulted in borderline values, while RCo was clearly reduced. Low- and intermediate-resolution agarose gel electrophoresis showed absence of the largest multimers in plasma vWf, and slight reduction in platelet vWf. High-resolution gels revealed abnormal multimeric structure only in plasma vWf. The smaller multimers could be resolved in a broad central band flanked by 4 fainter satellite bands; however, satellite bands close to the central band were more intense, and more distant ones were fainter, compared to normal plasma. The central band of the fastest-moving multimer was markedly intensified, and the mobility of the whole quintuplet was slightly reduced. Heredity seems to be autosomal-dominant. No mutation was found in exon 28 of the vWf gene. Because there was only 1 mild bleeding episode in the family, this structural variation seems to have only little clinical consequence. We conclude that this vWf abnormality is different from those observed in other type II variants previously described. Based on the revised classification by the International Society on Thrombosis and Haemostasis, we proposed designation type 2A-Bern for this new subtype.

A

    new variant of von Willebrand's disease
    DIAGNOSIS

 has been discovered in 2 members of a

    Macedonian
    ETHNICITY

    family of 6
    FAMILY

. The proband, an

    8-year-old
    AGE

    boy
    GENDER

, showed a

    prolonged bleeding episode
    SYMPTOMS

 on 1 occasion.

    Ristocetin-induced platelet aggregation and bleeding time were normal
    NEG_FINDINGS

.

    In plasma, ristocetin cofactor activity (RCo) and von Willebrand factor (vWf) antigen were reduced to the same clearly low level
    BIOCHEMICAL

. The

    determination of vWf antigen of platelets resulted in borderline values
    BIOCHEMICAL

, while

    RCo was clearly reduced
    BIOCHEMICAL

.

    Low- and intermediate-resolution agarose gel electrophoresis
    PARACLINICAL

 showed

    absence of the largest multimers in plasma vWf
    BIOCHEMICAL

, and

    slight reduction in platelet vWf
    BIOCHEMICAL

.

    High-resolution gels
    PARACLINICAL

 revealed

    abnormal multimeric structure only in plasma vWf
    BIOCHEMICAL

. The

    smaller multimers could be resolved in a broad central band flanked by 4 fainter satellite bands
    BIOCHEMICAL

; however,

    satellite bands close to the central band were more intense, and more distant ones were fainter
    SYMPTOMS

, compared to normal

    plasma
    BIOCHEMICAL

.

    The central band of the fastest-moving multimer was markedly intensified
    SYMPTOMS

, and the

    mobility of the whole quintuplet was slightly reduced
    SYMPTOMS

.

    Heredity seems to be autosomal-dominant
    GENETICS

.

    No mutation was found in exon 28 of the vWf gene
    NEG_FINDINGS

. Because there was

    only 1 mild bleeding episode in the family
    FAMILY

, this structural variation seems to have only little clinical consequence. We conclude that this

    vWf abnormality
    BIOCHEMICAL

 is different from those observed in other

    type II variants
    DIAGNOSIS

 previously described. Based on the revised classification by the International Society on Thrombosis and Haemostasis, we proposed designation

    type 2A-Bern
    DIAGNOSIS

 for this new subtype.

new variant of von Willebrand's disease
type II variants
type 2A-Bern


Intrahepatic, extramedullary hematopoiesis mimicking hemangioma on technetium-99m red blood cell SPECT examination.

Cavernous hemangiomas are the most common lesion of the liver. Because of the risk of hemorrhage inherent in percutaneous biopsy of such lesions, noninterventional modalities (such as CT, ultrasound, MRI and Technetium-99m red blood cell imaging) have been utilized for differentiating them from other lesions. The sensitivities and specificities of these techniques vary greatly. Technetium-99m red blood cell imaging with planar and SPECT imaging has been shown to have an overall sensitivity of 89%, a specificity of 100%, and an overall accuracy of 92%. Despite its high accuracy, rare false positives have been reported with Technetium-99m red blood cell imaging with SPECT. Review of the literature indicates four cases of hepatocellular carcinoma, one case of hepatic angiosarcoma, and one case of hepatic metastases from colorectal carcinoma as having an appearance identical to hemangioma with this modality. We present an additional false positive of a focal region of intrahepatic extramedullary hematopoiesis in a patient with Gaucher's disease as having an appearance on Technetium-99m red blood cell imaging with SPECT identical to that of hemangioma.

    Cavernous hemangiomas
    DIAGNOSIS

 are the most common lesion of the

    liver
    DIAGNOSIS

. Because of the risk of

    hemorrhage
    SYMPTOMS

 inherent in

    percutaneous biopsy
    PARACLINICAL

 of such lesions, noninterventional modalities (such as

    CT
    PARACLINICAL

,

    ultrasound
    PARACLINICAL

,

    MRI
    PARACLINICAL

 and

    Technetium-99m red blood cell imaging
    PARACLINICAL

) have been utilized for differentiating them from other lesions. The sensitivities and specificities of these techniques vary greatly.

    Technetium-99m red blood cell imaging with planar and SPECT imaging
    PARACLINICAL

 has been shown to have an overall sensitivity of 89%, a specificity of 100%, and an overall accuracy of 92%. Despite its high accuracy, rare false positives have been reported with

    Technetium-99m red blood cell imaging with SPECT
    PARACLINICAL

. Review of the literature indicates four cases of

    hepatocellular carcinoma
    DIAGNOSIS

, one case of

    hepatic angiosarcoma
    DIAGNOSIS

, and one case of

    hepatic metastases
    SYMPTOMS

 from

    colorectal carcinoma
    DIAGNOSIS

 as having an

    appearance identical to hemangioma
    SYMPTOMS

 with this modality. We present an additional false positive of a

    focal region of intrahepatic extramedullary hematopoiesis
    SYMPTOMS

 in a patient with

    Gaucher's disease
    DIAGNOSIS

 as having an appearance on

    Technetium-99m red blood cell imaging with SPECT
    PARACLINICAL

    identical to that of hemangioma
    SYMPTOMS

.

Cavernous hemangiomas
liver
hepatocellular carcinoma
hepatic angiosarcoma
colorectal carcinoma
Gaucher's disease


Morphological and biochemical assessment of the cornea in a Gaucher disease carrier with keratoconus.

Ocular abnormalities such as corneal opacities and some specific alterations in ocular movements have been described in the neuropathic forms of Gaucher disease. This study was designed to correlate the clinical, morphological and biochemical findings in the corneal button obtained after keratoplasty in a Gaucher disease carrier with keratoconus. Morphologically, the cornea showed keratocytes with marked dilatations of the rough endoplasmic reticulum and intracytoplasmic "dark inclusions"; the acidic lipid profiles presented alterations in the cornea of the Gaucher disease carrier when compared with healthy controls and a clear deficiency in beta-glucosidase activity was detected as well. Our data suggest that the cornea may serve as a good marker of an early target organ in lipid metabolism disorders such as Gaucher's disease.

    Ocular abnormalities
    SYMPTOMS

 such as

    corneal opacities
    SYMPTOMS

 and some

    specific alterations in ocular movements
    SYMPTOMS

 have been described in the

    neuropathic forms
    DIAGNOSIS

 of

    Gaucher disease
    DIAGNOSIS

. This study was designed to correlate the clinical, morphological and biochemical findings in the corneal button obtained after

    keratoplasty
    MEDICATION

 in a

    Gaucher disease
    DIAGNOSIS

 carrier with

    keratoconus
    DIAGNOSIS

. Morphologically, the cornea showed

    keratocytes with marked dilatations of the rough endoplasmic reticulum and intracytoplasmic "dark inclusions"
    MICROSCOPIC

;

    the acidic lipid profiles presented alterations in the cornea
    MICROSCOPIC

 of the

    Gaucher disease carrier
    MICROSCOPIC

 when compared with healthy controls and a clear

    deficiency in beta-glucosidase activity
    BIOCHEMICAL

 was detected as well. Our data suggest that the cornea may serve as a good marker of an early target organ in

    lipid metabolism disorders
    DIAGNOSIS

 such as

    Gaucher's disease
    DIAGNOSIS

.

neuropathic forms
Gaucher disease
Gaucher disease
keratoconus
lipid metabolism disorders
Gaucher's disease


Lysosomal storage disorders in Thailand: the Siriraj experience.

Lysosomal storage disorders are a heterogeneous group of biochemical genetic disorders; currently 40-50 are known. The clinical phenotype is determined by the tissue distribution of the storage material and degree of enzyme deficiency. The genetic transmission is mostly autosomal recessive. Lysosomal storage disorders can be divided into three groups according to the major organ system pathology: (1) Primary involvement of the central nervous system without significant somatic or skeletal pathology. Disorders of grey matter, eg gangliosidosis and disorders of white matter eg the leucodystrophy are the most common; (2) Primary involvement of the reticuloendothelial system with or without associated neuropathology, eg Niemann-Pick disease and Gaucher disease; (3) Multisystem involvement in which skeletal manifestations are prominent features. The mucopolysaccharidosis and mucolipidoses are the two major forms with this clinical phenotype. Lysosomal storage disorders identified at Siriraj Hospital are neuronal ceroid lipofuscinosis, GMI gangliosidosis, mucolipidosis II, Maroteaux-Lamy, sialidosis, Sly syndrome, Hunter syndrome, Morquio syndrome, Gaucher disease, Niemann-Pick, Sandhoff disease, Pompe's disease and many more. Most patients came from the provinces where consanguinity is common. Confirmation usually is done by enzyme assays using skin fibroblast culture or leucocytes. Genetic counseling is extremely important and prenatal diagnosis is recommended to high-risk couple.

    Lysosomal storage disorders
    DIAGNOSIS

 are a heterogeneous group of

    biochemical genetic disorders
    DIAGNOSIS

; currently 40-50 are known. The clinical phenotype is determined by the

    tissue distribution of the storage material
    MICROSCOPIC

 and degree of

    enzyme deficiency
    BIOCHEMICAL

. The

    genetic transmission is mostly autosomal recessive
    GENETICS

.

    Lysosomal storage disorders
    DIAGNOSIS

 can be divided into three groups according to the major organ system pathology: (1)

    Primary involvement of the central nervous system
    SYMPTOMS

    without significant somatic or skeletal pathology
    NEG_FINDINGS

.

    Disorders of grey matter
    DIAGNOSIS

, eg

    gangliosidosis
    DIAGNOSIS

 and

    disorders of white matter eg the leucodystrophy
    DIAGNOSIS

 are the most common; (2)

    Primary involvement of the reticuloendothelial system with or without associated neuropathology
    SYMPTOMS

, eg

    Niemann-Pick disease
    DIAGNOSIS

 and

    Gaucher disease
    DIAGNOSIS

; (3)

    Multisystem involvement
    SYMPTOMS

 in which

    skeletal manifestations
    SYMPTOMS

 are prominent features. The

    mucopolysaccharidosis
    DIAGNOSIS

 and

    mucolipidoses
    DIAGNOSIS

 are the two major forms with this clinical phenotype.

    Lysosomal storage disorders
    DIAGNOSIS

 identified at Siriraj Hospital are

    neuronal ceroid lipofuscinosis
    DIAGNOSIS

,

    GMI gangliosidosis
    DIAGNOSIS

,

    mucolipidosis II
    DIAGNOSIS

,

    Maroteaux-Lamy
    DIAGNOSIS

,

    sialidosis
    DIAGNOSIS

,

    Sly syndrome
    DIAGNOSIS

,

    Hunter syndrome
    DIAGNOSIS

,

    Morquio syndrome
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    Niemann-Pick
    DIAGNOSIS

,

    Sandhoff disease
    DIAGNOSIS

,

    Pompe's disease
    DIAGNOSIS

 and many more. Most patients came from the provinces where

    consanguinity
    FAMILY

 is common. Confirmation usually is done by

    enzyme assays using skin fibroblast culture or leucocytes
    PARACLINICAL

.

    Genetic counseling
    MEDICATION

 is extremely important and

    prenatal diagnosis
    MEDICATION

 is recommended to high-risk couple.


Hydrocephalus, corneal opacities, deafness, left ventricle hypertrophy, clinodactyly in an adolescent patient. A new syndrome associated with glucocerebrosidase deficiency.

We report a 12-year-old girl with an unusual phenotype of Gaucher disease type 3. Liver glucocerebrosidase activity was 20% of the normal. In addition to common manifestations such as hepatomegaly, she showed primary communicating hydrocephalus, corneal opacities, deafness, left ventricle hypertrophy, and clinodactyly of hands and feet. We suspect cardiomyopathy to be due to myocardiac infiltration with Gaucher cells, and corneal opacities to result from an accumulation of lipid-like inclusions into the posterior stromal keratinocytes. We were only able to find one previously published sibship disclosing similar features, which could allow the delineation of a new clinical variant of Gaucher disease.

We report a

    12-year-old
    AGE

    girl
    GENDER

 with an unusual phenotype of

    Gaucher disease type 3
    DIAGNOSIS

.

    Liver glucocerebrosidase activity was 20% of the normal
    BIOCHEMICAL

. In addition to common manifestations such as

    hepatomegaly
    SYMPTOMS

,

    she
    GENDER

 showed

    primary communicating hydrocephalus
    SYMPTOMS

,

    corneal opacities
    SYMPTOMS

,

    deafness
    SYMPTOMS

,

    left ventricle hypertrophy
    SYMPTOMS

, and

    clinodactyly of hands and feet
    SYMPTOMS

. We suspect

    cardiomyopathy
    SYMPTOMS

 to be due to

    myocardiac infiltration with Gaucher cells
    MICROSCOPIC

, and

    corneal opacities
    SYMPTOMS

 to result from an

    accumulation of lipid-like inclusions into the posterior stromal keratinocytes
    MICROSCOPIC

. We were only able to find one previously published

    sibship disclosing similar features
    FAMILY

, which could allow the delineation of a new clinical variant of

    Gaucher disease
    DIAGNOSIS

.

hepatomegaly
primary communicating hydrocephalus
corneal opacities
deafness
left ventricle hypertrophy
clinodactyly of hands and feet
cardiomyopathy
corneal opacities


Five new Gaucher disease mutations.

DNA from 17 individuals with 20 unidentified alleles was subjected to single-stranded conformation polymorphism analysis and/or sequencing and 5 previously undescribed mutations have been identified: 245T, 259T, 635G, 914C del, and IVS10(+2). Two of these mutations, 914C del and IVS10(+2), are null, or "lethal" mutations. Because the other mutation each of these two patients carried was "mild", the phenotype was type I disease. In addition to the new mutations we describe, the second example of the rare 1448G mutation has been documented in one of the patients. This mutation is particularly interesting because in samples studied by restriction analysis with NciI it can readily be confused with the common 1448C mutation. Reexamination of 28 patients who had previously been diagnosed as carrying the 1448C mutation were confirmed to be 1448C.

DNA from 17 individuals with 20 unidentified alleles was subjected to

    single-stranded conformation polymorphism analysis and/or sequencing
    PARACLINICAL

 and 5 previously undescribed mutations have been identified:

    245T, 259T, 635G, 914C del, and IVS10(+2)
    GENETICS

.

    Two of these mutations, 914C del and IVS10(+2), are null, or "lethal" mutations
    GENETICS

. Because the

    other mutation each of these two patients carried was "mild"
    FAMILY

, the phenotype was

    type I disease
    DIAGNOSIS

. In addition to the new mutations we describe, the second example of the

    rare 1448G mutation
    GENETICS

 has been documented in one of the patients. This mutation is particularly interesting because in samples studied by

    restriction analysis with NciI
    PARACLINICAL

 it can readily be confused with the common

    1448C mutation
    GENETICS

.

    Reexamination
    PARACLINICAL

 of 28 patients who had previously been diagnosed as carrying the

    1448C mutation
    GENETICS

 were confirmed to be 1448C.


Pulmonary Gaucher's disease: high-resolution computed tomographic features.

CT findings in pulmonary Gaucher's disease have not been previously reported. Chest radiograph of a patient with pulmonary involvement in type I Gaucher's disease proven by biopsy showed linear and reticulo-nodular opacities. High-resolution CT demonstrated thickening of the interlobular septa and between four and six small nodules within secondary lobules, probably each corresponding to an acinus.

    CT
    PARACLINICAL

 findings in

    pulmonary Gaucher's disease
    DIAGNOSIS

 have not been previously reported.

    Chest radiograph
    PARACLINICAL

 of a patient with

    pulmonary involvement
    SYMPTOMS

 in

    type I Gaucher's disease
    DIAGNOSIS

 proven by

    biopsy
    PARACLINICAL

 showed

    linear and reticulo-nodular opacities
    SYMPTOMS

.

    High-resolution CT
    PARACLINICAL

 demonstrated

    thickening of the interlobular septa
    SYMPTOMS

 and

    between four and six small nodules within secondary lobules, probably each corresponding to an acinus
    MICROSCOPIC

.

pulmonary Gaucher's disease
type I Gaucher's disease

pulmonary involvement
linear and reticulo-nodular opacities
thickening of the interlobular septa


Gaucher disease--the orthopaedic aspect. Report of seven cases.

Seven patients with Gaucher type 1 disease are presented: five female and two male. The orthopaedic problems encountered were: avascular necrosis of both femoral heads in two girls, bilateral bone infarctions of the femurs in all three girls, complicated by staphylococcal osteomyelitis of the right femur in one girl and by pathological fractures of both femurs in another girl, osteonecrosis of both humeral heads in one male adult patient, osteonecrosis of the femoral heads in two further adults (male and female), and a pathological fracture of the fourth lumbar vertebra in another adult woman with concomitant humeral head involvement. The patient with osteonecrosis of the humeral head was treated with a total shoulder arthroplasty, and the two patients with osteonecrosis of the femoral heads were treated with total hip arthroplasties, with satisfactory intermediate and long-term results.

Seven patients with

    Gaucher type 1 disease
    DIAGNOSIS

 are presented: five

    female
    GENDER

 and two

    male
    GENDER

. The orthopaedic problems encountered were:

    avascular necrosis of both femoral heads
    SYMPTOMS

 in two

    girls
    GENDER

,

    bilateral bone infarctions of the femurs
    SYMPTOMS

 in all three

    girls
    GENDER

, complicated by

    staphylococcal osteomyelitis of the right femur
    SYMPTOMS

 in one

    girl
    GENDER

 and by

    pathological fractures of both femurs
    SYMPTOMS

 in another

    girl
    GENDER

,

    osteonecrosis of both humeral heads
    SYMPTOMS

 in one

    male
    GENDER

    adult
    AGE

 patient,

    osteonecrosis of the femoral heads
    SYMPTOMS

 in two further

    adults
    GENDER

 (

    male
    GENDER

 and

    female
    GENDER

), and a

    pathological fracture of the fourth lumbar vertebra
    SYMPTOMS

 in another

    adult
    AGE

    woman
    GENDER

 with

    concomitant humeral head involvement
    SYMPTOMS

. The patient with

    osteonecrosis of the humeral head
    DIAGNOSIS

 was

    treated with a total shoulder arthroplasty
    MEDICATION

, and the two patients with

    osteonecrosis of the femoral heads
    DIAGNOSIS

 were treated with

    total hip arthroplasties
    MEDICATION

, with satisfactory intermediate and long-term results.

Gaucher type 1 disease
osteonecrosis of the humeral head
osteonecrosis of the femoral heads


Resolution of a proximal humeral defect in type-1 Gaucher disease by enzyme replacement therapy.

Although rarely they are a normal variant in children, significant defects in the medial aspect of the proximal humeral metaphysis occur in patients with Gaucher disease due to cortical infiltration and erosion of the periosteum by Gaucher cells. Such changes may lead to pathological fractures in Gaucher patients. These crescentic erosions resolved in a 19-year-old patient with type-1 Gaucher disease following enzyme replacement therapy.

Although rarely they are a normal variant in

    children
    AGE

,

    significant defects in the medial aspect of the proximal humeral metaphysis
    SYMPTOMS

 occur in patients with

    Gaucher disease
    DIAGNOSIS

 due to

    cortical infiltration and erosion of the periosteum by Gaucher cells
    MICROSCOPIC

. Such changes may lead to

    pathological fractures
    SYMPTOMS

 in

    Gaucher
    DIAGNOSIS

 patients. These

    crescentic erosions
    SYMPTOMS

 resolved in a

    19-year-old
    AGE

 patient with

    type-1 Gaucher disease
    DIAGNOSIS

 following

    enzyme replacement therapy
    MEDICATION

.

Gaucher disease
Gaucher
type-1 Gaucher disease


Adult and infantile Gaucher disease in one family: mutational studies and clinical update.

Molecular analysis and clinical updates are provided on a previously reported mother and adult son with Gaucher disease; two other children died with acute neuronopathic (type 2) Gaucher disease. The mother and son have the identical genotype (370/444) but very different clinical manifestations. These findings illustrate the need for additional studies before families with newly diagnosed Gaucher disease undergo counseling.

    Molecular analysis
    PARACLINICAL

 and clinical updates are provided on a previously reported

    mother and adult son with Gaucher disease
    FAMILY

;

    two other children died
    FAMILY

 with

    acute neuronopathic (type 2) Gaucher disease
    DIAGNOSIS

.

    The mother and son have the identical genotype (370/444)
    FAMILY

 but very different clinical manifestations. These findings illustrate the need for additional studies before families with newly diagnosed

    Gaucher disease
    DIAGNOSIS

 undergo

    counseling
    MEDICATION

.


Heterotopic splenic autotransplantation for splenomegaly secondary to Gaucher's disease--a case of siblings.

The authors report on siblings with Gaucher's disease who underwent heterotopic splenic autotransplantation for splenomegaly. The efficacy of this treatment is discussed.

The authors report on

    siblings
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

 who underwent

    heterotopic splenic autotransplantation
    MEDICATION

 for

    splenomegaly
    DIAGNOSIS

. The efficacy of this treatment is discussed.


Progression of bone disease without deterioration of hematological parameters in a child with Gaucher disease during low-dose glucocerebrosidase therapy.

Gaucher disease is the most prevalent lysosomal storage disease. Although the efficacy of the macrophage-targeted human placental glucocerebrosidase is well known, it is still difficult to develop definitive guidelines regarding the appropriate therapy schedule. We describe an 8-year-old Japanese boy with Gaucher disease who had avascular necrosis of the right femoral head without deterioration of hematological variables during low-dose enzyme replacement therapy (12-13 IU/kg). This case demonstrates that continuous normal hematological findings may not preclude progression of other aspects of Gaucher disease in some patients during enzyme replacement therapy.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disease
    DIAGNOSIS

. Although the efficacy of the

    macrophage-targeted human placental glucocerebrosidase
    MEDICATION

 is well known, it is still difficult to develop definitive guidelines regarding the appropriate therapy schedule. We describe an

    8-year-old
    AGE

    Japanese
    ETHNICITY

    boy
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 who had

    avascular necrosis of the right femoral head
    SYMPTOMS

    without deterioration of hematological variables
    NEG_FINDINGS

 during

    low-dose enzyme replacement therapy (12-13 IU/kg)
    MEDICATION

. This case demonstrates that

    continuous normal hematological findings
    NEG_FINDINGS

 may not preclude

    progression of other aspects of Gaucher disease
    NEG_FINDINGS

 in some patients during

    enzyme replacement therapy
    MEDICATION

.

Gaucher disease
lysosomal storage disease
Gaucher disease


Homozygous presence of the crossover (fusion gene) mutation identified in a type II Gaucher disease fetus: is this analogous to the Gaucher knock-out mouse model?

Gaucher disease (GD) is an inherited deficiency of beta-glucocerebrosidase (EC 3.1.2.45, gene symbol GBA). In type I GD, the CNS is not involved (nonneuronopathic), whereas in type II GD (acute neuronopathic) CNS involvement is early and rapidly progressive, while in type III GD (subacute neuronopathic) CNS involvement occurs later and is slowly progressive. The T6433C (L444P) substitution is prevalent in type GD II. It may occur alone as a single base-pair mutation but often is found as part of a complex allele containing additional GBA nucleotide substitutions, G6468C (A456P) and G6482C (V460V), without (recNciI) or with (recTL) G5957C (D409H). This complex allele is presumed to have formed by recombination (crossover, fusion) of the structural gene with the pseudogene, which contains the mutated sequences. Two complex alleles have never been demonstrated to coexist in any individual. We devised a selective PCR method for the specific amplification of the normal and/or fusion gene. Using this procedure we demonstrated the fusion gene in homozygous form for the first time, in a Macedonian/Ashkenazi Jewish GD type II fetus. Both parents were carriers of the recombination. This was confirmed by direct sequence analysis. A previous conceptus in this family was stillborn at 36 weeks, with features of severe type II GD. Neonates showing a severe clinical phenotype, analogous to the early neonatal lethal disease occurring in mice homozygous for a null allele produced by targeted disruption of GBA, have been described elsewhere, but the specific mutations in these cases have not yet been characterized.(ABSTRACT TRUNCATED AT 250 WORDS)

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    inherited
    GENETICS

    deficiency of beta-glucocerebrosidase (EC 3.1.2.45
    BIOCHEMICAL

, gene symbol

    GBA)
    BIOCHEMICAL

. In

    type I GD
    DIAGNOSIS

,

    the CNS is not involved (nonneuronopathic)
    NEG_FINDINGS

, whereas in

    type II GD (acute neuronopathic)
    DIAGNOSIS

    CNS involvement is early and rapidly progressive
    SYMPTOMS

, while in

    type III GD (subacute neuronopathic)
    DIAGNOSIS

    CNS involvement
    SYMPTOMS

 occurs later and is

    slowly progressive
    SYMPTOMS

. The

    T6433C (L444P) substitution
    GENETICS

 is prevalent in

    type GD II
    DIAGNOSIS

. It may occur alone

    as a single base-pair mutation
    GENETICS

 but often is found

    as part of a complex allele containing additional GBA nucleotide substitutions, G6468C (A456P) and G6482C (V460V), without (recNciI) or with (recTL) G5957C (D409H)
    GENETICS

. This

    complex allele
    GENETICS

 is presumed to have formed by

    recombination (crossover, fusion) of the structural gene with the pseudogene, which contains the mutated sequences
    GENETICS

.

    Two complex alleles
    GENETICS

 have never been demonstrated to coexist in any individual. We devised a

    selective PCR method for the specific amplification of the normal and/or fusion gene
    PARACLINICAL

. Using this procedure we demonstrated the

    fusion gene in homozygous form
    GENETICS

 for the first time, in a

    Macedonian/Ashkenazi Jewish
    ETHNICITY

    GD type II fetus
    DIAGNOSIS

.

    Both parents were carriers of the recombination
    FAMILY

. This was confirmed by

    direct sequence analysis
    PARACLINICAL

. A

    previous conceptus in this family was stillborn at 36 weeks
    FAMILY

    , with features of severe type II GD
    FAMILY

.

    Neonates
    AGE

 showing a

    severe clinical phenotype
    SYMPTOMS

, analogous to the

    early neonatal lethal disease
    SYMPTOMS

 occurring in mice

    homozygous for a null allele produced by targeted disruption of GBA
    GENETICS

, have been described elsewhere, but the specific mutations in these cases have not yet been characterized.(ABSTRACT TRUNCATED AT 250 WORDS)

Gaucher disease (GD)
type I GD
type II GD (acute neuronopathic)
type III GD (subacute neuronopathic)
type GD II
GD type II fetus


Glucocerebrosidase for treatment of Gaucher's disease: first German long-term results.

Until recently, there was no specific therapy available for patients with Gaucher's disease. Since April 1991 a highly purified human placental preparation of glucocerebrosidase (Ceredase, Genzyme) has been available for clinical studies in Germany. Sequential deglycosylation of the native enzyme yields a mannose-terminated preparation that may preferentially bind to the plasma membrane of macrophages. The present report analyzes the first German (and European) long-term results with glucocerebrosidase therapy in five patients with type I Gaucher's disease (four women and one man, aged 29-40 years). All patients suffered from excessive enlargement of the liver and spleen with subsequent pancytopenia and from skeletal complications. Multiple pathological fractures had already occurred in three of the five patients, requiring several surgical procedures. Fatigue and asthenia were present in all patients. The initial dose of glucocerebrosidase was chosen according to the severity of complications in the individual patient (20-50 U/kg given i.v. every 2nd week) and was performed in the five patients for 12-18 months. After a few weeks all patients reported that fatigue and asthenia were markedly reduced. After 12 months, blood counts of erythrocytes, leukocytes and platelets had completely normalized in all but one of the patients. After 4-6 months a significant reduction in the sizes of liver and spleen could be observed in all patients. No further fractures occurred during treatment. Significant side-effects of glucocerebrosidase treatment did not occur. The new glucocerebrosidase preparation offers the first effective drug therapy for patients with Gaucher's disease. Although the treatment proved effective and harmless, it is, at least initially, very expensive.(ABSTRACT TRUNCATED AT 250 WORDS)

Until recently, there was no specific therapy available for patients with

    Gaucher's disease
    DIAGNOSIS

. Since April 1991 a

    highly purified human placental preparation of glucocerebrosidase (Ceredase
    MEDICATION

, Genzyme) has been available for clinical studies in

    Germany
    ETHNICITY

.

    Sequential deglycosylation of the native enzyme
    MEDICATION

 yields a

    mannose-terminated
    MICROSCOPIC

 preparation that may preferentially

    bind to the plasma membrane of macrophages
    MICROSCOPIC

. The present report analyzes the first

    German
    ETHNICITY

 (and European) long-term results with

    glucocerebrosidase therapy
    MEDICATION

 in five patients with

    type I Gaucher's disease
    DIAGNOSIS

 (four

    women
    GENDER

 and one

    man
    GENDER

,

    aged 29-40 years
    AGE

). All patients suffered from

    excessive enlargement of the liver and spleen
    SYMPTOMS

 with subsequent

    pancytopenia
    BIOCHEMICAL

 and from

    skeletal complications
    SYMPTOMS

.

    Multiple pathological fractures
    SYMPTOMS

 had already occurred in three of the five patients, requiring

    several surgical procedures
    MEDICATION

.

    Fatigue
    SYMPTOMS

 and

    asthenia
    SYMPTOMS

 were present in all patients. The initial

    dose of glucocerebrosidase
    MEDICATION

 was chosen according to the severity of complications in the individual patient

    (20-50 U/kg given i.v. every 2nd week)
    MEDICATION

 and was performed in the five patients

    for 12-18 months
    MEDICATION

. After a few weeks all patients reported that

    fatigue and asthenia were markedly reduced
    SYMPTOMS

. After

    12 months
    MEDICATION

,

    blood counts of erythrocytes, leukocytes and platelets had completely normalized
    BIOCHEMICAL

 in all but one of the patients. After 4-6 months a

    significant reduction in the sizes of liver and spleen could be observed
    SYMPTOMS

 in all patients.

    No further fractures
    NEG_FINDINGS

 occurred during treatment.

    Significant side-effects of glucocerebrosidase treatment did not occur
    NEG_FINDINGS

. The

    new glucocerebrosidase preparation
    MEDICATION

 offers the first effective

    drug therapy
    MEDICATION

 for patients with

    Gaucher's disease
    DIAGNOSIS

. Although the treatment proved effective and harmless, it is, at least initially, very expensive.(ABSTRACT TRUNCATED AT 250 WORDS)

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


Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease.

Genetic studies were performed in two unrelated patients with the IIC phenotype of von Willebrand disease (vWD) characterized by the increased concentration of the protomeric form of von Willebrand factor (vWF). In patient B, the sequencing of both exons 15 and 16 of the vWF gene showed two sequence alterations: a 3-bp insertion in exon 15 resulting in the insertion of a Glycine at position 625 (625insGly) and a 2-bp deletion in exon 16 leading to a premature translational stop at codon 711 (711 ter), at the heterozygote state. Patient A was found homozygous for a single point mutation also localized in exon 15 and responsible for the substitution Cys623Trp. These candidate mutations were not found in a panel of 96 normal chromosomes, suggesting a causal relationship with IIC vWD phenotypic expression. The composite heterozygote or homozygote state of both patients supports the recessive mode of inheritance already described for this phenotype. Furthermore, the localization of these gene defects in the D2 domain of vWF propeptide, known to play an important role in vWF multimerization, provides another argument in favor of their causative effect regarding the peculiar multimeric pattern of vWF in these patients.

    Genetic studies
    PARACLINICAL

 were performed in two unrelated patients with the

    IIC phenotype of von Willebrand disease (vWD)
    DIAGNOSIS

 characterized by the

    increased concentration of the protomeric form of von Willebrand factor (vWF)
    BIOCHEMICAL

. In patient B, the

    sequencing of both exons 15 and 16 of the vWF gene
    PARACLINICAL

 showed

    two sequence alterations: a 3-bp insertion in exon 15 resulting in the insertion of a Glycine at position 625 (625insGly) and a 2-bp deletion in exon 16 leading to a premature translational stop at codon 711 (711 ter), at the heterozygote state
    GENETICS

. Patient A was found

    homozygous for a single point mutation also localized in exon 15 and responsible for the substitution Cys623Trp
    GENETICS

. These candidate mutations were not found in a panel of 96 normal chromosomes, suggesting a causal relationship with

    IIC vWD phenotypic expression
    DIAGNOSIS

. The

    composite heterozygote or homozygote state
    GENETICS

 of both patients supports the

    recessive mode of inheritance
    GENETICS

 already described for this phenotype. Furthermore, the localization of these

    gene defects in the D2 domain of vWF propeptide
    GENETICS

, known to play an important role in

    vWF multimerization
    BIOCHEMICAL

, provides another argument in favor of their causative effect regarding the

    peculiar multimeric pattern of vWF
    BIOCHEMICAL

 in these patients.


Bone marrow transplantation in Gaucher's disease: effect of mixed chimeric state.

The effective dose and schedule of enzyme replacement therapy for Gaucher's disease have not been definitely established. We report a case of mixed chimeric state in an allogeneic BMT patient and followed her clinical and laboratory progress. The result shows that a low but sustained glucocerebrosidase level may provide symptomatic relief for this lysosomal disorder.

The effective dose and schedule of

    enzyme replacement therapy
    MEDICATION

 for

    Gaucher's disease
    DIAGNOSIS

 have not been definitely established. We report a case of

    mixed chimeric state
    DIAGNOSIS

 in an

    allogeneic BMT patient
    MEDICATION

 and followed

    her
    GENDER

 clinical and laboratory progress. The result shows that a

    low but sustained glucocerebrosidase level
    BIOCHEMICAL

 may provide

    symptomatic relief
    MEDICATION

 for this

    lysosomal disorder
    DIAGNOSIS

.

enzyme replacement therapy
allogeneic BMT patient
symptomatic relief

Gaucher's disease
mixed chimeric state
lysosomal disorder


Bronchoalveolar lavage in a girl with Gaucher's disease. A case report.

A case of Gaucher's disease with pulmonary involvement occurred. Numerous Gaucher cells were seen in bronchoalveolar lavage (BAL) fluid on two occasions in a girl with Gaucher's disease and respiratory symptoms. The Gaucher cells resembled macrophages with eccentric, small, oval nuclei but were distinguished by their abundant cytoplasm with the characteristic "rumpled tissue paper" appearance. The Gaucher cells were in a cellular background composed mainly of macrophages. These cells stained strongly positive with periodic acid-Schiff stain. Electron microscopy revealed numerous intracytoplasmic, elongated, membrane-bound lysosomes containing the characteristic twisted tubular structures. Severe pulmonary involvement is seen infrequently in all types of Gaucher's disease, and it is especially rare in the adult and juvenile forms (types I and III). To our knowledge, Gaucher cells have never been found before in BAL fluid. This case shows that BAL can be a useful adjunct in diagnosing and following the progression of pulmonary involvement in patients with Gaucher's disease.

A case of

    Gaucher's disease
    DIAGNOSIS

 with

    pulmonary involvement
    SYMPTOMS

 occurred.

    Numerous Gaucher cells were seen in bronchoalveolar lavage (BAL) fluid
    MICROSCOPIC

 on two occasions in a

    girl
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

 and

    respiratory symptoms
    SYMPTOMS

. The

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

 but were distinguished by their

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

.

    The Gaucher cells were in a cellular background composed mainly of macrophages
    MICROSCOPIC

.

    These cells stained strongly positive with periodic acid-Schiff stain
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 revealed

    numerous intracytoplasmic, elongated, membrane-bound lysosomes containing the characteristic twisted tubular structures
    MICROSCOPIC

.

    Severe pulmonary involvement
    SYMPTOMS

 is seen infrequently in all types of

    Gaucher's disease
    DIAGNOSIS

, and it is especially rare in the

    adult
    AGE

 and

    juvenile forms
    DIAGNOSIS

 (

    types I and III)
    DIAGNOSIS

. To our knowledge,

    Gaucher cells
    MICROSCOPIC

 have never been found before

    in BAL fluid
    MICROSCOPIC

. This case shows that

    BAL
    PARACLINICAL

 can be a useful adjunct in diagnosing and following the progression of

    pulmonary involvement
    SYMPTOMS

 in patients with

    Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease
Gaucher's disease
Gaucher's disease
juvenile forms
types I and III)
Gaucher's disease

pulmonary involvement
respiratory symptoms
Severe pulmonary involvement
pulmonary involvement


DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish-Polish-Russian descent.

Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non-neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the glucocerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genomic DNA nucleotide position 6683) from a Gaucher disease patient of Jewish-Polish-Russian descent with type 1 Gaucher disease. It is a G-->A transition in exon 11 that results in 496Arg-->496His of glucocerebrosidase. This missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A-->G transition at cDNA nucleotide position 1226 which creates an XhoI cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease.(ABSTRACT TRUNCATED AT 250 WORDS)

    Gaucher disease
    DIAGNOSIS

 is the most frequent

    lysosomal lipid storage disease
    DIAGNOSIS

. It results from

    deficient glucocerebrosidase activity
    BIOCHEMICAL

 and is

    transmitted as an autosomal recessive trait
    GENETICS

. Three clinical forms of

    Gaucher disease
    DIAGNOSIS

 have been described:

    type 1, non-neuronopathic
    DIAGNOSIS

;

    type 2, acute neuronopathic
    DIAGNOSIS

; and

    type 3, subacute neuronopathic
    DIAGNOSIS

. We have

    sequenced the full length cDNA of the glucocerebrosidase gene
    PARACLINICAL

 and identified an

    uncommon mutation in nucleotide position 1604 (genomic DNA nucleotide position 6683)
    GENETICS

 from a

    Gaucher disease
    DIAGNOSIS

 patient of

    Jewish-Polish-Russian descent
    ETHNICITY

 with

    type 1 Gaucher disease
    DIAGNOSIS

. It

    is a G-->A transition in exon 11 that results in 496Arg-->496His of glucocerebrosidase
    GENETICS

. This

    missense mutation is present in the heterozygous form
    GENETICS

 and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using

    HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA
    PARACLINICAL

. The

    mutation in the other Gaucher allele of
    GENETICS

 this patient

    is an A-->G transition at cDNA nucleotide position 1226 which creates an
    GENETICS

 XhoI cleavage site after

    PCR mismatch amplification
    PARACLINICAL

. The presence of this mutation was also confirmed by

    sequence analysis
    PARACLINICAL

. Based on previous reports that

    mutation 1226
    GENETICS

 is present only in

    type 1 Gaucher disease
    DIAGNOSIS

 and the observation that there is

    no neurological involvement
    NEG_FINDINGS

 in this patient, we conclude that our patient with the

    1226/1604 genotype
    GENETICS

 is diagnosed as having type 1 Gaucher disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Gaucher disease
lysosomal lipid storage disease
Gaucher disease
type 1, non-neuronopathic
type 2, acute neuronopathic
type 3, subacute neuronopathic
Gaucher disease
type 1 Gaucher disease
type 1 Gaucher disease


Extraosseous extension of Gaucher cell deposits mimicking malignancy.

Two cases are described in which patients with type I Gaucher disease developed extraosseous soft tissue masses consisting of Gaucher cell deposits. In one instance the mass destroyed the posterior cortex of the left distal femur and protruded into the soft tissues. In the second case the lesion involved the proximal tibia and gradually extended into the soft tissues. While the incidence of neoplastic disorder such as lymphoproliferative disease appears to be more common in Gaucher disease patients than in the general population, lesions of benign etiology that mimic these aggressive processes should be considered in the differential diagnosis when cortical destruction with coexisting soft tissue most is found in these patients.

Two cases are described in which patients with

    type I Gaucher disease
    DIAGNOSIS

 developed

    extraosseous soft tissue masses
    SYMPTOMS

    consisting of Gaucher cell deposits
    MICROSCOPIC

. In one instance the

    mass destroyed the posterior cortex of the left distal femur and protruded into the soft tissues
    SYMPTOMS

. In the second case the

    lesion involved the proximal tibia and gradually extended into the soft tissues
    SYMPTOMS

. While the incidence of

    neoplastic disorder
    DIAGNOSIS

 such as

    lymphoproliferative disease
    DIAGNOSIS

 appears to be more common in

    Gaucher disease
    DIAGNOSIS

 patients than in the general population,

    lesions of benign etiology
    SYMPTOMS

 that

    mimic these aggressive processes
    SYMPTOMS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 when

    cortical destruction with coexisting soft tissue most
    SYMPTOMS

 is found in these patients.

type I Gaucher disease
neoplastic disorder
lymphoproliferative disease
Gaucher disease


RecTL: a complex allele of the glucocerebrosidase gene associated with a mild clinical course of Gaucher disease.

We describe 4 Jewish patients with type 1 Gaucher disease and the genotype N370S/recTL. They present either asymptomatic or mild Gaucher disease. RecTL is a complex allele that contains 4 single point mutations in the glucocerebrosidase gene: D409H, L444P, A456P, and V460V. Since patients who have the genotype N370S/L444P usually develop a moderate to severe course of Gaucher disease, and those who are homozygous for the D409H or the L444P mutations develop aggressive disease accompanied by neurological signs, it is of great importance to distinguish between the severe single base pair mutations and the mild complex recTL allele. This distinction should prove useful in assessing the natural history of Gaucher disease and in considering the indications for early enzyme replacement therapy.

We describe 4

    Jewish
    ETHNICITY

 patients with

    type 1 Gaucher disease
    DIAGNOSIS

 and the

    genotype N370S/recTL
    GENETICS

. They present either

    asymptomatic
    NEG_FINDINGS

 or

    mild Gaucher disease
    DIAGNOSIS

. RecTL is a complex allele that contains 4 single point mutations in the glucocerebrosidase gene: D409H, L444P, A456P, and V460V. Since patients who have the

    genotype N370S/L444P
    GENETICS

 usually develop a

    moderate to severe course of Gaucher disease
    DIAGNOSIS

, and those who are

    homozygous for the D409H or the L444P mutations
    GENETICS

 develop

    aggressive disease
    SYMPTOMS

 accompanied by

    neurological signs
    SYMPTOMS

, it is of great importance to distinguish between the

    severe single base pair mutations
    GENETICS

 and the

    mild complex recTL allele
    GENETICS

. This distinction should prove useful in assessing the natural history of

    Gaucher disease
    DIAGNOSIS

 and in considering the indications for

    early enzyme replacement therapy
    MEDICATION

.


Value of bronchoalveolar lavage in lipidoses with pulmonary involvement.

Adult lipid storage disorders with pulmonary involvement are rare and usually diagnosed at autopsy. We report a patient with splenomegaly and reticulonodular pattern on lung computed tomography. Bronchoalveolar lavage was performed and revealed the presence of lipid-containing foamy cells, with the demonstration of both periodic acid-Schiff (PAS) and scharlach red stain positive vacuoles in the cytoplasm of alveolar macrophages. The same cells were found in bone marrow biopsy. As in other rare disorders, bronchoalveolar lavage may be of diagnostic value in lipid storage disorders with pulmonary involvement.

    Adult
    AGE

    lipid storage disorders
    DIAGNOSIS

 with

    pulmonary involvement
    SYMPTOMS

 are rare and usually diagnosed at

    autopsy
    PARACLINICAL

. We report a patient with

    splenomegaly
    SYMPTOMS

 and

    reticulonodular pattern
    SYMPTOMS

 on

    lung computed tomography
    PARACLINICAL

.

    Bronchoalveolar lavage
    PARACLINICAL

 was performed and revealed the

    presence of lipid-containing foamy cells,
    MICROSCOPIC

 with the

    demonstration of both periodic acid-Schiff (PAS) and scharlach red stain positive vacuoles in the cytoplasm of alveolar macrophages
    MICROSCOPIC

. The same cells were found in

    bone marrow biopsy
    PARACLINICAL

. As in other

    rare disorders
    DIAGNOSIS

,

    bronchoalveolar lavage
    PARACLINICAL

 may be of diagnostic value in

    lipid storage disorders
    DIAGNOSIS

 with

    pulmonary involvement
    SYMPTOMS

.

lipid storage disorders
rare disorders
lipid storage disorders

pulmonary involvement
splenomegaly
reticulonodular pattern
pulmonary involvement


Acquired pseudo-pseudo Bernard-Soulier syndrome complicating Gaucher's disease.

To investigate the abnormality in platelet function in two patients with type I Gaucher's disease causing a chronic bleeding tendency despite normalisation of the platelet count after spleen removal.

Routine laboratory methods were used to assess baseline coagulation. Platelet aggregometry was used to assess platelet responses to a range of agonists, and abnormalities were further assessed in mixing experiments using washed platelets and patients' plasma.

Platelets from both patients with Gaucher's disease failed to agglutinate to ristocetin, despite normal platelet surface glycoprotein (GP) Ib and plasma von Willebrand factor activity. The agglutination of normal washed platelets was abolished by incubation in patient plasma. The inhibitory activity did not lie in the IgG fraction of patient plasma, and was found to be loosely associated with the patient platelet surface.

The inhibition of ristocetin induced platelet agglutination in patients with Gaucher's disease causes a prolonged skin bleeding time. This could be due to the accumulated glucocerebroside in the plasma coating the platelet membrane. It is suggested that the term pseudo-pseudo Bernard-Soulier syndrome would be appropriate, as on initial screening, the abnormality has the features of Bernard-Soulier syndrome, but further investigation shows normal plasma von Willebrand activity and platelet surface GP Ib concentrations. The inhibitory activity is not due to a platelet specific antibody as is the case in pseudo-Bernard Soulier syndrome.

To investigate the

    abnormality in platelet function
    BIOCHEMICAL

 in two patients with

    type I Gaucher's disease
    DIAGNOSIS

 causing a

    chronic bleeding tendency
    SYMPTOMS

    despite normalisation of the platelet count after spleen removal
    NEG_FINDINGS

.

    Routine laboratory methods
    PARACLINICAL

 were used to assess

    baseline coagulation
    PARACLINICAL

.

    Platelet aggregometry was used to assess platelet
    PARACLINICAL

 responses to a range of agonists, and abnormalities were further assessed in

    mixing experiments using washed platelets and patients' plasma
    PARACLINICAL

.

    Platelets
    MICROSCOPIC

 from both patients with

    Gaucher's disease
    DIAGNOSIS

    failed to agglutinate to ristocetin
    NEG_FINDINGS

,

    despite normal platelet surface glycoprotein (GP) Ib and plasma von Willebrand factor activity
    NEG_FINDINGS

. The

    agglutination of normal washed platelets
    BIOCHEMICAL

 was abolished by

    incubation in patient plasma
    BIOCHEMICAL

. The

    inhibitory activity did not lie in the IgG fraction of patient plasma
    BIOCHEMICAL

, and was found to be

    loosely associated with the patient platelet surface
    MICROSCOPIC

.

The

    inhibition of ristocetin induced platelet agglutination
    BIOCHEMICAL

 in patients with

    Gaucher's disease
    DIAGNOSIS

 causes a

    prolonged skin bleeding time
    SYMPTOMS

. This could be due to the

    accumulated glucocerebroside in the plasma coating the platelet membrane
    MICROSCOPIC

. It is suggested that the term

    pseudo-pseudo Bernard-Soulier syndrome
    DIAGNOSIS

 would be appropriate, as on initial screening, the

    abnormality has the features of Bernard-Soulier syndrome
    SYMPTOMS

, but further investigation shows

    normal plasma von Willebrand activity and platelet surface GP Ib concentrations
    NEG_FINDINGS

. The

    inhibitory activity is not due to a platelet specific antibody
    NEG_FINDINGS

 as is the case in

    pseudo-Bernard Soulier syndrome
    NEG_FINDINGS

.

type I Gaucher's disease
Gaucher's disease
Gaucher's disease
pseudo-pseudo Bernard-Soulier syndrome


Aminohydroxypropylidene-biphosphonate in the treatment of bone lesions in a case of Gaucher's disease type 3.

Gaucher disease is the most prevalent lysosomal storage disorder. It is characterized by an autosomal recessive inheritance of a deficiency of lysosomal acid glucocerebrosidase. Three clinical phenotypes are recognized: type 1 (non-neuronopathic), type 2 (acute neuronopathic), type 3 (subacute neuronopathic). Bone lesions are associated with type 1 and type 3 Gaucher disease. Skeletal involvement is secondary to the progressive accumulation of histiocytes and macrophages laden with glucosylceramide in bone marrow. Our patient was a female type 3 Gaucher patient who was referred to us at the age of 3 years with a neurological symptomatology and severe bone lesions (bilateral fracture of the femur heads, lytic process of the bone matrix of the femurs and distal flask deformity, kyphoskoliosis and chest deformity). The baby was constrained to a wheel-chair. The use of (3-amino-1-hydroxypropylidene)-1,1-biphosphonate (APD) was described in a case of Gaucher disease with very severe bone lesions. We used periodic iv infusions of APD (10 mg every 3 weeks) in our patient for a period of 20 months; after that, enzyme replacement therapy (alglucerase) was commenced. APD treatment showed normalization of bone density, formation of bone callus at the femural heads, positive calcium balance. The urinary Ca/Cr ratio and TRP were consistently normal during therapy. After 9 months of alglucerase therapy the patient was able to walk again. The data indicate that APD therapy can find an indication in Gaucher patients with severe bone involvement.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disorder
    DIAGNOSIS

. It is characterized by an

    autosomal recessive inheritance
    GENETICS

 of a

    deficiency of lysosomal acid glucocerebrosidase
    BIOCHEMICAL

. Three clinical phenotypes are recognized:

    type 1 (non-neuronopathic)
    DIAGNOSIS

,

    type 2 (acute neuronopathic)
    DIAGNOSIS

,

    type 3 (subacute neuronopathic)
    DIAGNOSIS

.

    Bone lesions
    SYMPTOMS

 are associated with

    type 1 and type 3 Gaucher disease
    DIAGNOSIS

.

    Skeletal involvement
    SYMPTOMS

 is secondary to the

    progressive accumulation of histiocytes and macrophages laden with glucosylceramide in bone marrow
    MICROSCOPIC

. Our patient was a

    female
    GENDER

    type 3 Gaucher
    DIAGNOSIS

 patient who was referred to us at the

    age of 3 years
    AGE

 with a

    neurological symptomatology
    SYMPTOMS

 and

    severe bone lesions (bilateral fracture of the femur heads, lytic process of the bone matrix of the femurs and distal flask deformity
    SYMPTOMS

,

    kyphoskoliosis
    SYMPTOMS

 and

    chest deformity
    SYMPTOMS

    )
    SYMPTOMS

. The

    baby
    MEDICATION

 was

    constrained to a wheel-chair
    MEDICATION

. The

    use of (3-amino-1-hydroxypropylidene)-1,1-biphosphonate (APD)
    MEDICATION

 was described in a case of

    Gaucher disease
    DIAGNOSIS

 with

    very severe bone lesions
    SYMPTOMS

. We used

    periodic iv infusions of APD (10 mg every 3 weeks)
    MEDICATION

 in our patient

    for a period of 20 months
    MEDICATION

; after that,

    enzyme replacement therapy (alglucerase) was commenced
    MEDICATION

.

    APD treatment
    MEDICATION

 showed

    normalization of bone density
    SYMPTOMS

,

    formation of bone callus at the femural heads
    SYMPTOMS

,

    positive calcium balance
    BIOCHEMICAL

.

    The urinary Ca/Cr ratio and TRP were consistently normal
    NEG_FINDINGS

 during therapy. After

    9 months of alglucerase therapy
    MEDICATION

 the patient was

    able to walk again
    SYMPTOMS

. The data indicate that

    APD therapy
    MEDICATION

 can find an indication in

    Gaucher
    DIAGNOSIS

 patients with

    severe bone involvement
    SYMPTOMS

.

Gaucher disease
lysosomal storage disorder
type 1 (non-neuronopathic)
type 2 (acute neuronopathic)
type 3 (subacute neuronopathic)
type 1 and type 3 Gaucher disease
type 3 Gaucher
Gaucher disease
Gaucher


Loosening of a noncemented porous-coated anatomic femoral component in Gaucher's disease. A case report and review of literature.

There are few reports of experiences with hip arthroplasty in patients with Gaucher's disease. Review of the literature shows a high rate of loosening after any type of arthroplasty. The clinical, roentgenographic and histopathological findings of a porous-coated hip arthroplasty in Gaucher's disease necessitating revision after 5 years are reported. Because we found typical lipid-laden Gaucher cells at the bone prosthesis interface we support the hypothesis that loosening in Gaucher's disease is due to continued Gaucher cell proliferation and erosion of bone. Loosening seems to be related to the disease and not to a specific type of prosthetic component.

There are few reports of experiences with

    hip arthroplasty
    MEDICATION

 in patients with

    Gaucher's disease
    DIAGNOSIS

. Review of the literature shows a high rate of

    loosening
    SYMPTOMS

 after any type

    of arthroplasty
    MEDICATION

. The clinical,

    roentgenographic and histopathological
    PARACLINICAL

 findings of a

    porous-coated hip arthroplasty
    MEDICATION

 in

    Gaucher's disease
    DIAGNOSIS

 necessitating

    revision after 5 years
    MEDICATION

 are reported. Because we found

    typical lipid-laden Gaucher cells at the bone prosthesis interface
    MICROSCOPIC

 we support the hypothesis that

    loosening
    SYMPTOMS

 in

    Gaucher's disease
    DIAGNOSIS

 is due to

    continued Gaucher cell proliferation and erosion of bone
    MICROSCOPIC

. Loosening seems to be related to the disease and not to a specific type of prosthetic component.

hip arthroplasty
of arthroplasty
porous-coated hip arthroplasty
revision after 5 years

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


DNA mutational analysis of type 1 and type 3 Gaucher patients: how well do mutations predict phenotype?

The wide spectrum of clinical manifestations resulting from glucocerebrosidase deficiency complicates genetic counseling for Gaucher disease. The identification of mutations in the glucocerebrosidase gene has enabled studies of genotype-phenotype correlation. However, a genotypic analysis of 60 type 1 and type 3 Gaucher patients reveals that the 5 most common Gaucher mutations, N370S, L444P, R463C, 84insG, and IVS2 + 1 G-->A, can be found both in patients with and without neurologic manifestations. Moreover, although some generalizations can be made about mutations that are more frequently encountered in particular patient populations, Gaucher patients sharing identical genotypes can exhibit considerable clinical heterogeneity. Thus in considering rationale for population screening one cannot rely solely on PCR determined DNA mutation analysis to reliably predict prognosis in Gaucher disease.

The wide spectrum of clinical manifestations resulting from

    glucocerebrosidase deficiency
    BIOCHEMICAL

 complicates

    genetic counseling
    MEDICATION

 for

    Gaucher disease
    DIAGNOSIS

. The identification of

    mutations in the glucocerebrosidase gene
    GENETICS

 has enabled studies of genotype-phenotype correlation. However, a

    genotypic analysis
    PARACLINICAL

 of 60

    type 1 and type 3 Gaucher
    DIAGNOSIS

 patients reveals that the

    5 most common Gaucher mutations, N370S, L444P, R463C, 84insG, and IVS2 + 1 G-->A
    GENETICS

, can be found both in patients with and without

    neurologic manifestations
    SYMPTOMS

. Moreover, although some generalizations can be made about mutations that are more frequently encountered in particular patient populations,

    Gaucher
    DIAGNOSIS

 patients sharing identical genotypes can exhibit considerable clinical heterogeneity. Thus in considering rationale for population screening one cannot rely solely on

    PCR determined DNA mutation analysis
    PARACLINICAL

 to reliably predict prognosis in

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
type 1 and type 3 Gaucher
Gaucher
Gaucher disease


[Enzyme replacement therapy in type 1 Gaucher's disease].

Gaucher disease is a sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GC) and the consequent deposition of glucocerebrosides into the cells of the macrophagic system. Among the three types of clinical disease, type 1 leads to hepatosplenomegaly, hypersplenism and skeletal abnormalities including bone pain, osteopenia and fractures. Two pediatric female patients with moderately severe type 1 Gaucher disease were treated with commercially available GC, mannose terminated to be macrophage-targeted. GC was given by intravenous infusion (30 to 60 units per kilogram of body weight every two weeks) for 8 and 18 months. The hemoglobin concentration increased and the serum acid phosphatase decreased in both patients. In the most affected child, hepatic volume decreased significantly and bony symptoms disappeared. Infusions were uneventful except for an episode of anaphylaxis that subsided rapidly, allowed resumption and did not affect efficacy. These observations are in agreement with the international experience in approximately 800 cases, with good tolerance in all type 1 patients who show objective clinical improvement; patterns of response are variable from patient to patient, independent from previous splenectomy, and dose-dependent; the dose can be tapered after a period of time. Antibodies anti-GC are seen in 13% of the patients, but their presence does not have clinical consequences. The cost of the enzyme makes it crucial to define precise indications, optimal dosing schedules, duration of treatment and cost-benefit ratio.

    Gaucher disease
    DIAGNOSIS

 is a

    sphingolipid storage disorder
    DIAGNOSIS

 caused by a

    deficiency of the lysosomal enzyme glucocerebrosidase (GC)
    BIOCHEMICAL

 and the consequent

    deposition of glucocerebrosides into the cells of the macrophagic system
    MICROSCOPIC

. Among the three types of clinical disease,

    type 1
    DIAGNOSIS

 leads to

    hepatosplenomegaly
    SYMPTOMS

,

    hypersplenism
    BIOCHEMICAL

 and

    skeletal abnormalities
    SYMPTOMS

 including

    bone pain
    SYMPTOMS

,

    osteopenia
    SYMPTOMS

 and

    fractures
    SYMPTOMS

. Two

    pediatric
    AGE

    female
    GENDER

 patients with

    moderately severe type 1 Gaucher disease
    DIAGNOSIS

 were treated with

    commercially available GC, mannose terminated to be macrophage-targeted
    MEDICATION

.

    GC was given by intravenous infusion (30 to 60 units per kilogram of body weight every two weeks) for 8 and 18 months
    MEDICATION

. The

    hemoglobin concentration increased
    BIOCHEMICAL

 and

    the serum acid phosphatase decreased
    BIOCHEMICAL

 in both patients. In the most affected

    child
    AGE

,

    hepatic volume decreased significantly
    SYMPTOMS

 and

    bony symptoms disappeared
    SYMPTOMS

. Infusions were

    uneventful
    NEG_FINDINGS

 except for an

    episode of anaphylaxis that subsided rapidly
    SYMPTOMS

, allowed

    resumption
    MEDICATION

 and

    did not affect efficacy
    NEG_FINDINGS

. These observations are in agreement with the international experience in approximately 800 cases, with good tolerance in all

    type 1
    DIAGNOSIS

 patients who show

    objective clinical improvement
    SYMPTOMS

; patterns of response are variable from patient to patient, independent from previous

    splenectomy
    MEDICATION

, and dose-dependent; the dose can be tapered after a period of time.

    Antibodies anti-GC
    BIOCHEMICAL

 are seen in 13% of the patients, but their presence does not have clinical consequences. The cost of the enzyme makes it crucial to define precise indications, optimal dosing schedules, duration of treatment and cost-benefit ratio.


Complex arylsulfatase A alleles causing metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile metachromatic leukodystrophy revealed that the patient is a compound heterozygote of two alleles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation (Gly122 > Ser). The splice donor site mutation and the Gly122 > Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly154 > Asp and a Pro167 > Arg substitution. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into baby hamster kidney cells expression of arylsulfatase A activity could not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients' fibroblasts show that the enzyme carrying both mutations is synthesized in almost normal amounts but is rapidly degraded in an early biosynthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in metachromatic leukodystrophy and as far as lysosomal storage diseases are concerned have so far only been described in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease.

    Metachromatic leukodystrophy
    SYMPTOMS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 caused by the deficiency of arylsulfatase A.

    Sequencing of the arylsulfatase A genes
    PARACLINICAL

 of a patient affected with

    late infantile metachromatic leukodystrophy
    DIAGNOSIS

 revealed that the patient is a

    compound heterozygote of two alleles carrying two deleterious mutation each
    GENETICS

.

    One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation (Gly122 > Ser)
    GENETICS

. The

    splice donor site mutation and the Gly122 > Ser substitution
    GENETICS

 have been described recently but on different alleles. The

    other allele carries two missense mutations causing a Gly154 > Asp and a Pro167 > Arg substitution
    GENETICS

. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into

    baby hamster kidney cells
    MICROSCOPIC

    expression of arylsulfatase A activity could not be detected
    NEG_FINDINGS

.

    Linkage of mutations
    GENETICS

 was verified by

    sequencing of the parental DNAs
    PARACLINICAL

.

    Biosynthesis studies
    PARACLINICAL

 performed with the patients' fibroblasts show that the enzyme carrying both mutations is

    synthesized in almost normal amounts
    BIOCHEMICAL

    but is rapidly degraded in an early biosynthetic compartment
    MICROSCOPIC

. The

    occurence of two disease causing mutations on the same allele
    GENETICS

 is a novel phenomenon in

    metachromatic leukodystrophy
    SYMPTOMS

 and as far as

    lysosomal storage diseases
    DIAGNOSIS

 are concerned have so far only been described in

    Fabry disease
    DIAGNOSIS

 and in the

    complex glucocerebrosidase alleles
    GENETICS

 associated with

    Gaucher disease
    DIAGNOSIS

.

Metachromatic leukodystrophy
metachromatic leukodystrophy


Genotype-phenotype pitfalls in Gaucher disease.

Gaucher disease (GD), caused by inherited deficiency of beta-glucocerebrosidase (beta-Glc, EC 3.1.2.45), is classified type I if the CNS is not involved (non-neuronopathic), type II if CNS involvement is early and rapidly progressive (acute neuronopathic), and type III if CNS involvement occurs later and is slowly progressive (subacute neuronopathic). The clinical course is not predictable by measurement of residual beta-Glc activity. Patient classification by identification of specific mutations is more promising: homozygosity for the common A5841->G (N370S) mutation invariably predicts type I; homozygosity for the T6433->C (L444P) mutation usually indicates type III (Norbottnian). Type II disease patients often carry the T6433->C allele together with a complex allele derived in part from the downstream pseudogene by crossover or gene conversion, producing a T6433->C substitution, plus 2 or 3 additional single base substitutions (fusion gene). Employing selective PCR amplification of the structural gene, we detected homozygous T6433C (L444P) point mutations in a Caucasian boy, initially classified as having GD type I, who succumbed to severe visceral GD before age 3 years. A second novel PCR procedure for discriminating between the normal gene and the fusion gene confirmed the homozygous point mutation results. Post mortem neuropathological findings showed neuronal complex lipid accumulation consistent with late-onset type III disease. Although in Norbottnian patients it is generally accepted that onset of neurological findings is delayed, patients with the L444P/L444P genotype can only be initially classified as type III with this ancestry. Other patients described sporadically elsewhere are invariably considered type I until neurological findings arise.(ABSTRACT TRUNCATED AT 250 WORDS)

    Gaucher disease (GD)
    DIAGNOSIS

, caused by

    inherited deficiency of beta-glucocerebrosidase (beta-Glc, EC 3.1.2.45)
    GENETICS

, is classified

    type I
    DIAGNOSIS

 if

    the CNS is not involved (non-neuronopathic)
    NEG_FINDINGS

,

    type II
    DIAGNOSIS

 if

    CNS involvement is early and rapidly progressive
    SYMPTOMS

    (acute neuronopathic)
    DIAGNOSIS

, and

    type III
    DIAGNOSIS

 if

    CNS involvement occurs later and is slowly progressive
    SYMPTOMS

    (subacute neuronopathic)
    DIAGNOSIS

. The clinical course is not predictable by

    measurement of residual beta-Glc activity
    NEG_FINDINGS

. Patient classification by identification of specific mutations is more promising:

    homozygosity for the common A5841->G (N370S) mutation
    GENETICS

 invariably predicts

    type I
    DIAGNOSIS

;

    homozygosity for the T6433->C (L444P) mutation
    GENETICS

 usually indicates

    type III
    DIAGNOSIS

 (

    Norbottnian
    ETHNICITY

).

    Type II disease
    DIAGNOSIS

 patients often

    carry the T6433->C allele together with a complex allele derived in part from the downstream pseudogene by crossover or gene conversion, producing a T6433->C substitution, plus 2 or 3 additional single base substitutions (fusion gene)
    GENETICS

. Employing

    selective PCR amplification of the structural gene
    PARACLINICAL

, we detected

    homozygous T6433C (L444P) point mutations
    GENETICS

 in a

    Caucasian
    ETHNICITY

    boy
    GENDER

,

    initially classified as having GD type I
    NEG_FINDINGS

, who succumbed to

    severe visceral GD
    DIAGNOSIS

    before age 3 years
    AGE

. A

    second novel PCR procedure for discriminating between the normal gene and the fusion gene
    PARACLINICAL

 confirmed the

    homozygous point mutation results
    GENETICS

.

    Post mortem neuropathological findings
    PARACLINICAL

 showed

    neuronal complex lipid accumulation
    MICROSCOPIC

 consistent with

    late-onset type III disease
    DIAGNOSIS

. Although in

    Norbottnian
    ETHNICITY

 patients it is generally accepted that

    onset of neurological findings
    SYMPTOMS

 is delayed, patients with the

    L444P/L444P genotype
    GENETICS

 can only be initially classified as

    type III
    DIAGNOSIS

 with this ancestry. Other patients described sporadically elsewhere are invariably considered

    type I
    DIAGNOSIS

 until

    neurological findings
    SYMPTOMS

 arise.(ABSTRACT TRUNCATED AT 250 WORDS)

Gaucher disease (GD)
type I
type II
(acute neuronopathic)
type III
(subacute neuronopathic)
type I
type III
Type II disease
severe visceral GD
late-onset type III disease
type III
type I


Gaucher's disease, type I (adult type), with massive involvement of the kidneys and lungs.

A 33-year-old Japanese male, first diagnosed as having Gaucher's disease at the age of 3 years, died of renal and pulmonary failure. Autopsy findings disclosed the proliferation of Gaucher's cells in the liver, bone marrow, lymph nodes, kidneys and lungs. Electron-microscopical findings suggested that the Gaucher's cells observed in the renal glomeruli might be derived from circulating macrophages.

A

    33-year-old
    AGE

    Japanese
    ETHNICITY

    male
    GENDER

, first diagnosed as having

    Gaucher's disease
    DIAGNOSIS

 at the

    age of 3 years
    AGE

,

    died
    SYMPTOMS

 of

    renal and pulmonary failure
    SYMPTOMS

.

    Autopsy findings
    PARACLINICAL

 disclosed the

    proliferation of Gaucher's cells in the liver, bone marrow, lymph nodes, kidneys and lungs
    MICROSCOPIC

.

    Electron-microscopical findings
    PARACLINICAL

 suggested that

    the Gaucher's cells observed in the renal glomeruli might be derived from circulating macrophages
    MICROSCOPIC

.


Gaucher's disease and pregnancy.

For a long time, pregnancy has been discouraged for patients with Gaucher's disease. Because of the scarcity of complications found in the literature, the obstetrical attitude is favorable towards an authorization of pregnancy for patients with Gaucher's disease. We describe the evolution of pregnancy of a woman suffering from Gaucher's disease type I and the anesthesiological support provided.

For a long time,

    pregnancy
    NEG_FINDINGS

 has been discouraged for patients with

    Gaucher's disease
    DIAGNOSIS

. Because of the scarcity of complications found in the literature, the obstetrical attitude is favorable towards an

    authorization of pregnancy
    MEDICATION

 for patients with

    Gaucher's disease
    DIAGNOSIS

. We describe the evolution of

    pregnancy
    DIAGNOSIS

 of a

    woman
    GENDER

 suffering from

    Gaucher's disease type I
    DIAGNOSIS

 and the

    anesthesiological support
    MEDICATION

 provided.

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

authorization of pregnancy
anesthesiological support


Erroneous assignment of Gaucher disease genotype as a consequence of a complete gene deletion.

Two sisters with moderately severe Gaucher disease were diagnosed as having the usually relatively benign 1226G/1226G genotype by examination of DNA amplified from exon 9, where this mutation is located. Because of the discrepancy between the apparent genotype and the phenotype, we suspected that one of the alleles had not amplified. Therefore, the DNA of both parents was examined. The father was heterozygous for the 1226G mutation but the mother did not have this abnormality. It was shown that the mother and both daughters had a deletion of the glucocerebrosidase gene: only about one-half of the polymerase chain reaction (PCR) amplification product of the glucocerebrosidase gene in this region was found, compared to internal controls consisting of the glucocerebrosidase pseudogene and of the adjacent liver pyruvate kinase (PKLR) gene. The appearance of Southern blots developed with full length glucocerebrosidase cDNA probes showed that the band unique to the functional glucocerebrosidase gene had reduced intensity, and no abnormal bands were present after digestion with any restriction endonuclease, indicating that the entire coding region was deleted.

Two

    sisters with moderately severe Gaucher disease
    FAMILY

 were diagnosed as having the

    usually relatively benign 1226G/1226G genotype
    GENETICS

 by

    examination of DNA amplified from exon 9, where this mutation is located
    PARACLINICAL

. Because of the discrepancy between the apparent genotype and the phenotype, we suspected that

    one of the alleles had not amplified
    GENETICS

. Therefore, the

    DNA of both parents was examined
    PARACLINICAL

. The

    father was heterozygous for the 1226G mutation
    FAMILY

 but

    the mother did not have this abnormality
    FAMILY

. It was shown that the

    mother and both daughters had a deletion of the glucocerebrosidase gene
    FAMILY

:

    only about one-half of the polymerase chain reaction (PCR) amplification product of the glucocerebrosidase gene in this region was found
    GENETICS

, compared to internal controls consisting of

    the glucocerebrosidase pseudogene and of the adjacent liver pyruvate kinase (PKLR) gene
    NEG_FINDINGS

. The appearance of

    Southern blots developed with full length glucocerebrosidase cDNA probes
    PARACLINICAL

 showed that the

    band unique to the functional glucocerebrosidase gene had reduced intensity
    BIOCHEMICAL

, and

    no abnormal bands were present after digestion with any restriction endonuclease
    NEG_FINDINGS

, indicating that

    the entire coding region was deleted
    GENETICS

.


Fatal hemorrhage caused by disease progression after partial splenectomy for type III Gaucher's disease.

An 18-month-old boy with Gaucher's disease, massive hepatosplenomegaly, and hypersplenism underwent partial (85%) splenectomy and recovered without complication. During the next 4 months, his residual splenic segment showed progressive enlargement from 2 to 6 cm below the left costal margin. By this time, genetic typing had indicated central nervous system involvement (type III). A compatible donor was not available for bone marrow transplantation. Complete splenectomy was not recommended despite continued enlargement of the organ into the pelvis and across the abdominal midline by 7 1/2 months postoperatively. The next week he presented to the emergency room in shock with an hematocrit of 6% and a platelet count of 18,000/mm3. During emergency surgery, massive intraabdominal hemorrhage was noted from a splenic rupture on the inferior pole that was opposite the site of prior division. He died in the operating room during attempted splenectomy. This is a report of fatal outcome after partial splenectomy for type III Gaucher's disease. Patients with subacute neuronopathic disease may not be candidates for subtotal splenectomy.

An

    18-month-old
    AGE

    boy
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

,

    massive hepatosplenomegaly
    SYMPTOMS

, and

    hypersplenism
    BIOCHEMICAL

 underwent

    partial (85%) splenectomy
    MEDICATION

 and recovered

    without complication
    NEG_FINDINGS

. During the next 4 months, his

    residual splenic segment showed progressive enlargement from 2 to 6 cm below the left costal margin
    SYMPTOMS

. By this time,

    genetic typing
    GENETICS

 had indicated

    central nervous system involvement (type III)
    DIAGNOSIS

.

    A compatible donor was not available for bone marrow transplantation
    NEG_FINDINGS

.

    Complete splenectomy
    MEDICATION

    was not recommended
    NEG_FINDINGS

 despite

    continued enlargement of the organ into the pelvis and across the abdominal midline by 7 1/2 months postoperatively
    SYMPTOMS

. The next week

    he
    GENDER

 presented to the emergency room in

    shock
    SYMPTOMS

 with an

    hematocrit of 6%
    BIOCHEMICAL

 and a

    platelet count of 18,000/mm3
    BIOCHEMICAL

. During

    emergency surgery
    MEDICATION

,

    massive intraabdominal hemorrhage was noted from a splenic rupture on the inferior pole that was opposite the site of prior division
    SYMPTOMS

.

    He
    GENDER

    died
    SYMPTOMS

 in the operating room during

    attempted splenectomy
    MEDICATION

. This is a report of

    fatal outcome
    SYMPTOMS

 after

    partial splenectomy
    MEDICATION

 for

    type III Gaucher's disease
    DIAGNOSIS

. Patients with

    subacute neuronopathic disease
    DIAGNOSIS

 may not be candidates for

    subtotal splenectomy
    MEDICATION

.

hypersplenism
hematocrit of 6%
platelet count of 18,000/mm3

partial (85%) splenectomy
Complete splenectomy
emergency surgery
attempted splenectomy
partial splenectomy
subtotal splenectomy


Subtotal splenectomy for Gaucher's disease: a follow-up study.

Three patients with Gaucher's disease who underwent partial splenectomy have been followed for 3, 7 3/4, and 8 1/2 years. All have had significant regrowth of the the splenic remnant and some recurrence of hypersplenism. A review of all previously reported cases also substantiates the recurrence of splenomegaly and hypersplenism. Among new options for the therapy of Gaucher's disease, enzyme replacement therapy (Ceredase) holds great promise for effective treatment.

Three patients with

    Gaucher's disease
    DIAGNOSIS

 who underwent

    partial splenectomy
    MEDICATION

 have been followed for 3, 7 3/4, and 8 1/2 years. All have had

    significant regrowth of the the splenic remnant
    SYMPTOMS

 and some

    recurrence of hypersplenism
    SYMPTOMS

. A review of all previously reported cases also substantiates the

    recurrence of splenomegaly
    SYMPTOMS

 and

    hypersplenism
    BIOCHEMICAL

. Among new options for the therapy of

    Gaucher's disease
    DIAGNOSIS

,

    enzyme replacement therapy (Ceredase)
    MEDICATION

 holds great promise for effective treatment.

partial splenectomy
enzyme replacement therapy (Ceredase)


Gaucher's disease. An unusual cause of intrathoracic extramedullary hematopoiesis.

A thoracic paravertebral mass in an asymptomatic woman with type 1 Gaucher's disease proved to be due to extramedullary hematopoiesis. This is, to our knowledge, the first case of intrathoracic extramedullary hematopoiesis reported with Gaucher's disease.

A

    thoracic paravertebral mass
    SYMPTOMS

 in an

    asymptomatic
    NEG_FINDINGS

    woman
    GENDER

 with

    type 1 Gaucher's disease
    DIAGNOSIS

 proved to be due to

    extramedullary hematopoiesis
    MICROSCOPIC

. This is, to our knowledge, the first case of

    intrathoracic extramedullary hematopoiesis
    MICROSCOPIC

 reported with

    Gaucher's disease
    DIAGNOSIS

.

type 1 Gaucher's disease
Gaucher's disease


[Negative myoclonus].

Negative myoclonus is an involuntary movement produced by a short interruption of muscle contraction. In this paper, recent concepts, pathomechanisms and treatment in negative myoclonus are reviewed. Two patients with negative myoclonus are also presented. One is an 18-year-old girl with Gaucher disease, and the other is a 14-year-old boy with simple partial motor epilepsy. Electrical silent period was demonstrated when negative myoclonus was clinically observed. In both patients, somatosensory evoked potentials showed giant responses, which may indicate that mechanisms of negative myoclonus have a relationship with cortical abnormal excitability.

    Negative myoclonus
    SYMPTOMS

 is an

    involuntary movement produced by a short interruption of muscle contraction
    SYMPTOMS

. In this paper, recent concepts, pathomechanisms and treatment in

    negative myoclonus
    SYMPTOMS

 are reviewed. Two patients with

    negative myoclonus
    SYMPTOMS

 are also presented. One is an

    18-year-old
    AGE

    girl
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

, and the other is a

    14-year-old
    AGE

    boy
    GENDER

 with

    simple partial motor epilepsy
    DIAGNOSIS

.

    Electrical silent period
    SYMPTOMS

 was demonstrated when

    negative myoclonus
    SYMPTOMS

 was clinically observed. In both patients, somatosensory evoked potentials showed

    giant responses
    SYMPTOMS

, which may indicate that mechanisms of

    negative myoclonus
    SYMPTOMS

 have a relationship with

    cortical abnormal excitability
    SYMPTOMS

.

Gaucher disease
simple partial motor epilepsy


MRI of multiple platyspondyly in Gaucher disease: response to enzyme replacement therapy.

Vertebra plana and multiple platyspondyly are complications of aggressive Gaucher disease. Magnetic resonance imaging readily identifies vertebra plana and secondary spinal cord compression. We present a case of a 2-year-old boy with clinically aggressive Type 1 Gaucher disease in whom MRI showed partial reconstitution of the height of a collapsed lumbar vertebral body after 16 months of enzyme replacement therapy.

    Vertebra plana
    SYMPTOMS

 and

    multiple platyspondyly
    SYMPTOMS

 are complications of

    aggressive Gaucher disease
    DIAGNOSIS

.

    Magnetic resonance imaging
    PARACLINICAL

 readily identifies

    vertebra plana
    DIAGNOSIS

 and

    secondary spinal cord compression
    SYMPTOMS

. We present a case of a

    2-year-old
    AGE

    boy
    GENDER

 with clinically

    aggressive Type 1 Gaucher disease
    DIAGNOSIS

 in whom

    MRI
    PARACLINICAL

 showed

    partial reconstitution of the height of a collapsed lumbar vertebral body
    SYMPTOMS

 after

    16 months of enzyme replacement therapy
    MEDICATION

.

aggressive Gaucher disease
vertebra plana
aggressive Type 1 Gaucher disease


Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease.

Sphingolipid activator protein (SAP) deficiency, previously described in two sibs and shown to be caused by the absence of the common saposin precursor (prosaposin), was further characterized by biochemical lipid and enzyme studies and by ultrastructural analysis. The 20-week-old fetal sib had increased concentrations of neutral glycolipids, including mono-, di-, tri- and tetrahexosylceramide, in liver, kidney and cultured skin fibroblasts compared with the controls. Glucosylceramide and lactosylceramide were particularly elevated. The kidney of the affected fetus showed additional increases in the concentration of sulphatide, galactosylceramide and digalactosylceramide. Free ceramide was stored in the liver and kidney, and GM3 and GM2 gangliosides were elevated in the liver, but not the brain, of the fetus. Phospholipids, however, were normal in the affected fetus. In the liver biopsy of the propositus, who later died at 16 weeks of age, only a few lipids could be studied. Glucosylceramide, dihexosylceramide and ceramide were elevated in agreement with our previous study. Enzyme studies were undertaken using detergent-free liposomal substrate preparations and fibroblast extracts. The sibs' beta-glucocerebrosidase and beta-galactocerebrosidase activities were clearly reduced, but their sphingomyelinase activities were normal. The normal activity of the latter enzyme and the almost normal tissue concentration of sphingomyelin in prosaposin deficiency suggest that the prosaposin-derived SAPs are not required for sphingomyelinase activity in vivo. In keeping with the biochemical findings, skin biopsies from the sibs showed massive lysosomal storage with a vesicular and membranous ultrastructure. The function of SAPs in sphingolipid degradation and the role of SAPs for enzyme activity in vitro are discussed. In addition, the similarity in neutral glycolipid accumulations in Niemann-Pick disease type C and in prosaposin deficiency are noted. The phenotype of the prosaposin deficient sibs resembled acute neuronopathic (type 2) Gaucher disease more than Farber disease in several aspects, but their genotype was unique.

    Sphingolipid activator protein (SAP) deficiency
    BIOCHEMICAL

, previously described in two

    sibs
    FAMILY

 and shown to be caused by the

    absence of the common saposin precursor (prosaposin)
    BIOCHEMICAL

, was further characterized by

    biochemical lipid and enzyme studies
    PARACLINICAL

 and by

    ultrastructural analysis
    PARACLINICAL

. The

    20-week-old
    AGE

    fetal
    AGE

 sib had

    increased concentrations of neutral glycolipids, including mono-, di-, tri- and tetrahexosylceramide, in liver, kidney and cultured skin fibroblasts
    MICROSCOPIC

 compared with the controls.

    Glucosylceramide and lactosylceramide were particularly elevated
    MICROSCOPIC

. The kidney of the affected

    fetus
    AGE

 showed

    additional increases in the concentration of sulphatide, galactosylceramide and digalactosylceramide
    MICROSCOPIC

.

    Free ceramide was stored in the liver and kidney
    MICROSCOPIC

, and

    GM3 and GM2 gangliosides were elevated in the liver, but not the brain, of the fetus
    MICROSCOPIC

.

    Phospholipids, however, were normal in the affected fetus
    NEG_FINDINGS

. In the

    liver biopsy
    PARACLINICAL

 of the propositus, who later

    died
    SYMPTOMS

 at

    16 weeks of age
    AGE

,

    only a few lipids could be studied
    MICROSCOPIC

.

    Glucosylceramide, dihexosylceramide and ceramide were elevated
    MICROSCOPIC

 in agreement with our previous study.

    Enzyme studies
    PARACLINICAL

 were undertaken using

    detergent-free liposomal substrate preparations and fibroblast extracts
    PARACLINICAL

. The sibs'

    beta-glucocerebrosidase and beta-galactocerebrosidase activities were clearly reduced
    BIOCHEMICAL

, but their

    sphingomyelinase activities were normal
    NEG_FINDINGS

. The

    normal activity of the latter enzyme
    NEG_FINDINGS

 and the

    almost normal tissue concentration of sphingomyelin in prosaposin deficiency
    NEG_FINDINGS

 suggest that the

    prosaposin-derived SAPs are not required for sphingomyelinase activity in vivo
    BIOCHEMICAL

. In keeping with the biochemical findings,

    skin biopsies
    PARACLINICAL

 from the

    sibs
    FAMILY

 showed

    massive lysosomal storage with a vesicular and membranous ultrastructure
    MICROSCOPIC

. The function of

    SAPs in sphingolipid degradation
    BIOCHEMICAL

 and the role of

    SAPs for enzyme activity
    BIOCHEMICAL

 in vitro are discussed. In addition, the similarity in

    neutral glycolipid accumulations
    MICROSCOPIC

 in

    Niemann-Pick disease type C
    DIAGNOSIS

 and in

    prosaposin deficiency
    BIOCHEMICAL

 are noted. The phenotype of the

    prosaposin deficient sibs
    BIOCHEMICAL

 resembled

    acute neuronopathic (type 2) Gaucher disease
    DIAGNOSIS

 more than

    Farber disease
    DIAGNOSIS

 in several aspects, but their genotype was unique.


Gaucher's disease and mesangiocapillary glomerulonephritis in childhood--a coincidence?

A 6-year-old boy, presenting with a nephritic syndrome, was diagnosed as suffering from Gaucher's disease (GD) and mesangiocapillary glomerulonephritis (MCGN). GD was suspected because of aseptic necrosis of the femoral heads on X-ray and later confirmed by bone marrow aspiration and a lack of glucocerebrosidase activity in white blood cells; MCGN was documented on renal biopsy. The child was treated with prednisone, dipyridamole and aspirin, and recovered completely clinically. A second biopsy was not performed. The connection between these two rare diseases, and between nephritis and GD in general, is discussed.

A

    6-year-old
    AGE

    boy
    GENDER

, presenting with a

    nephritic syndrome
    SYMPTOMS

, was diagnosed as suffering from

    Gaucher's disease (GD)
    DIAGNOSIS

 and

    mesangiocapillary glomerulonephritis (MCGN)
    DIAGNOSIS

.

    GD
    DIAGNOSIS

 was suspected because of

    aseptic necrosis of the femoral heads
    SYMPTOMS

 on

    X-ray
    PARACLINICAL

 and later confirmed by

    bone marrow aspiration
    PARACLINICAL

 and a

    lack of glucocerebrosidase activity in white blood cells
    BIOCHEMICAL

;

    MCGN
    DIAGNOSIS

 was documented on

    renal biopsy
    PARACLINICAL

. The

    child
    AGE

 was treated with

    prednisone, dipyridamole and aspirin
    MEDICATION

, and recovered completely clinically.

    A second biopsy was not performed
    NEG_FINDINGS

. The connection between these two

    rare diseases
    DIAGNOSIS

, and between

    nephritis
    DIAGNOSIS

 and

    GD
    DIAGNOSIS

 in general, is discussed.

nephritic syndrome
aseptic necrosis of the femoral heads


Enzyme replacement therapy of infantile Gaucher disease.

We report our experience from enzyme infusion therapy in a girl with infantile (type 2) Gaucher disease. When treatment was started at 5.5 months of age, she already had severe neurological symptoms. After three months of treatment, the hematological parameters and blood glucosylceramide levels were normalized. The spleen and liver sizes were reduced and the neurological deterioration seemed to have stopped. There was, however, no improvement of her existing neurological symptoms. Her lung function deteriorated because of constant aspirations. Enzyme treatment was stopped after seven months. We cannot recommend enzyme substitution therapy when severe neurological signs have already emerged.

We report our experience from

    enzyme infusion therapy
    MEDICATION

 in a

    girl
    GENDER

 with

    infantile (type 2) Gaucher disease
    DIAGNOSIS

. When treatment was started

    at 5.5 months of age
    AGE

,

    she
    GENDER

 already had

    severe neurological symptoms
    SYMPTOMS

. After

    three months of treatment
    MEDICATION

,

    the hematological parameters and blood glucosylceramide levels were normalized
    BIOCHEMICAL

. The

    spleen and liver sizes were reduced
    SYMPTOMS

 and the

    neurological deterioration seemed to have stopped
    SYMPTOMS

. There was, however,

    no improvement of her existing neurological symptoms
    NEG_FINDINGS

.

    Her
    GENDER

    lung function deteriorated
    SYMPTOMS

 because of

    constant aspirations
    SYMPTOMS

.

    Enzyme treatment was stopped after seven months
    MEDICATION

. We cannot recommend

    enzyme substitution therapy
    MEDICATION

 when

    severe neurological signs
    SYMPTOMS

 have already emerged.


Periosteal Gaucher-like cells in beta-thalassemia major.

A 24-year-old Chinese woman who has undergone staged surgery for craniofacial deformity secondary to beta-thalassemia major is presented. Local clusters of Gaucher-like cells were found in the periosteum of the mandible. The histologic and ultrastructural features of these cells are described and the pathogenesis and differential diagnoses discussed. To the best of our knowledge, this is the first reported case of Gaucher-like cells occurring outside the lymphohematopoietic system in thalassemic patients.

A

    24-year-old
    AGE

    Chinese
    ETHNICITY

    woman
    GENDER

 who has undergone

    staged surgery
    MEDICATION

 for

    craniofacial deformity
    MEDICATION

 secondary to

    beta-thalassemia major
    DIAGNOSIS

 is presented.

    Local clusters of Gaucher-like cells were found in the periosteum of the mandible
    MICROSCOPIC

. The histologic and ultrastructural features

    of these cells
    MICROSCOPIC

 are described and the pathogenesis and differential diagnoses discussed. To the best of our knowledge, this is the first reported case of

    Gaucher-like cells occurring outside the lymphohematopoietic system
    MICROSCOPIC

 in

    thalassemic
    DIAGNOSIS

 patients.


Indium-111-leukocyte imaging in Gaucher's disease.

A 29-yr-old man with Gaucher's disease and fever of unknown origin underwent 111In-labeled mixed autologous leukocyte scintigraphy. Although no focus of infection was identified, the resulting images were most unusual and were characterized by massive hepatomegaly, lack of central marrow activity and extensive lymph node uptake of labeled leukocytes. All of these findings could be explained on the basis of the patient's underlying disease. Hepatomegaly and absent central marrow activity correlated with extensive infiltration of these organs by Gaucher cells, while the lymph node findings were attributed to the presence of extramedullary hematopoiesis.

A

    29-yr-old
    AGE

    man
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

 and

    fever of unknown origin
    SYMPTOMS

 underwent

    111In-labeled mixed autologous leukocyte scintigraphy
    PARACLINICAL

. Although

    no focus of infection was identified
    NEG_FINDINGS

, the resulting images were most unusual and were characterized by

    massive hepatomegaly
    SYMPTOMS

,

    lack of central marrow activity
    NEG_FINDINGS

 and

    extensive lymph node uptake of labeled leukocytes
    MICROSCOPIC

. All of these findings could be explained on the basis of the patient's underlying disease.

    Hepatomegaly
    SYMPTOMS

 and

    absent central marrow activity
    NEG_FINDINGS

 correlated with

    extensive infiltration of these organs by Gaucher cells
    MICROSCOPIC

, while the

    lymph node findings
    SYMPTOMS

 were attributed to the

    presence of extramedullary hematopoiesis
    MICROSCOPIC

.

fever of unknown origin
massive hepatomegaly
Hepatomegaly
lymph node findings

no focus of infection was identified
lack of central marrow activity
absent central marrow activity