Perinatal lethal phenotype with generalized ichthyosis in a type 2 Gaucher disease patient with the [L444P;E326K]/P182L genotype: effect of the E326K change in neonatal and classic forms of the disease.

Gaucher disease, the most common lysosomal storage disorder, encompasses a wide spectrum of clinical symptoms. The perinatal lethal form is very rare and is considered a distinct form of classic type 2 Gaucher disease. Prominent features of the severe perinatal form are hepatosplenomegaly variable, associated with hydrops fetalis and ichthyosis. Here, we describe a child who presented generalized ichthyosis and died at 25 days of age. Genotype analysis revealed compound heterozygosity for the complex allele [L444P;E326K] and mutation P182L, described for the first time in this patient. Mutations E326K and L444P were on the same chromosome. Expression studies of mutant glucocerebrosidases showed that the double mutant allele had lower activity, 8.5% of wild type, in contrast to the activity of individual E326K and L444P mutant enzymes, 42.7% and 14.1%, respectively. The P182L mutant enzyme showed no glucocerebrosidase activity. A revision of the genotypes identified in a series of Spanish patients with type 2 Gaucher disease showed that the complex allele [L444P;E326K] accounted for 19.2% of patient alleles and that homozygosity for this allele or its heterozygosity with mutation L444P, or another severe mutation such as P182L, was associated with the perinatal lethal presentation of the disease. In contrast, the [L444P;E326K] allele was not detected in patients with classic type 2 diagnosed when several months old. The high frequency of the E326K substitution observed in patients with type 2 as compared to the general population (0.5%) suggests that this change may have a modulating negative effect on the clinical condition of these Gaucher disease patients when present in combination with mutation L444P. The relatively high prevalence of the double mutant allele in Spanish patients prompted us to perform a haplotype analysis, using four polymorphic markers, which suggest a common origin for this allele. During the mutational analysis of the series of type 2 patients, a novel mutation, I260T (c.896T>C), was identified.

    Gaucher disease
    DIAGNOSIS

, the most common

    lysosomal storage disorder
    DIAGNOSIS

, encompasses a wide spectrum of clinical symptoms. The

    perinatal lethal form
    DIAGNOSIS

 is very rare and is considered a distinct form of

    classic type 2 Gaucher disease
    DIAGNOSIS

. Prominent features of the

    severe perinatal form
    DIAGNOSIS

 are

    hepatosplenomegaly variable
    SYMPTOMS

, associated with

    hydrops fetalis
    SYMPTOMS

 and

    ichthyosis
    SYMPTOMS

. Here, we describe a

    child
    AGE

 who presented

    generalized ichthyosis
    SYMPTOMS

 and

    died
    SYMPTOMS

    at 25 days of age
    AGE

.

    Genotype analysis
    PARACLINICAL

 revealed

    compound heterozygosity for the complex allele [L444P;E326K] and mutation P182L
    GENETICS

, described for the first time in this patient.

    Mutations E326K and L444P were on the same chromosome
    GENETICS

.

    Expression studies of mutant glucocerebrosidases
    PARACLINICAL

 showed that the

    double mutant allele had lower activity, 8.5% of wild type
    GENETICS

, in contrast to the

    activity of individual E326K and L444P mutant enzymes, 42.7% and 14.1%
    BIOCHEMICAL

, respectively. The

    P182L mutant enzyme showed no glucocerebrosidase activity
    GENETICS

. A revision of the genotypes identified in a series of

    Spanish
    ETHNICITY

 patients with

    type 2 Gaucher disease
    DIAGNOSIS

 showed that

    the complex allele [L444P;E326K]
    GENETICS

 accounted for 19.2% of patient alleles and that

    homozygosity for this allele or its heterozygosity with mutation L444P, or another severe mutation such as P182L
    GENETICS

, was associated with the

    perinatal lethal presentation of the disease
    SYMPTOMS

. In contrast, the

    [L444P;E326K] allele
    GENETICS

 was not detected in patients with

    classic type 2
    DIAGNOSIS

 diagnosed

    when several months old
    AGE

. The high frequency of the

    E326K substitution
    GENETICS

 observed in patients with

    type 2
    DIAGNOSIS

 as compared to the general population (0.5%) suggests that this change may have a modulating negative effect on the clinical condition of these

    Gaucher disease
    DIAGNOSIS

 patients when present in combination with mutation L444P. The relatively high prevalence

    of the double mutant allele
    GENETICS

 in

    Spanish
    ETHNICITY

 patients prompted us to perform a

    haplotype analysis
    PARACLINICAL

, using four polymorphic markers, which suggest a

    common origin for this allele
    GENETICS

. During the

    mutational analysis
    PARACLINICAL

 of the series of

    type 2
    DIAGNOSIS

 patients, a

    novel mutation, I260T (c.896T>C)
    GENETICS

, was identified.

Gaucher disease
lysosomal storage disorder
perinatal lethal form
classic type 2 Gaucher disease
severe perinatal form
type 2 Gaucher disease
classic type 2
type 2
Gaucher disease
type 2


Secondary G-CSF mobilized blood stem cell transplantation without preconditioning in a patient with Gaucher disease: Report of a new approach which resulted in complete reversal of severe skeletal involvement.

Gaucher disease has been treated by allogeneic bone marrow transplantation (BMT), however, severe bone involvement that is probably the most disabling aspect of this disease is difficult to reverse. Other problem of BMT is the use of intensive preconditioning that adversely affects growth and development of the patients. In this study, a patient with type I Gaucher disease was treated by allogeneic BMT from HLA-matched sibling donor. However, the treatment resulted in late graft failure and the patient developed severe bone involvement. Fifty months after the first BMT, the patient was treated by allogeneic peripheral blood stem cell (PBSC) transplantation without preconditioning. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) was used to mobilize PBSC. Cyclosporine A (CyA) was administered for the prophylaxis of graft-versushost disease (GVHD). Full donor-derived hematopoiesis was obtained, and clinical symptoms including severe bone involvement improved completely with increased glucocerebrosidase activity. It was shown that an engraftment could be obtained without intensive preconditioning when a recipient receives an rhG-CSF-mobilized PBSCs infusion as a secondary transplant. Another important finding of this study is the complete reversal of severe bone involvement by the supply of abundant glucocerebrosidase from high proliferating PBSC graft.

    Gaucher disease
    DIAGNOSIS

 has been treated by

    allogeneic bone marrow transplantation (BMT)
    MEDICATION

, however,

    severe bone involvement
    SYMPTOMS

 that is probably the most disabling aspect of this disease is difficult to reverse. Other problem of

    BMT
    MEDICATION

 is the use of

    intensive preconditioning
    MEDICATION

 that adversely affects growth and development of the patients. In this study, a patient with

    type I Gaucher disease
    DIAGNOSIS

 was treated by

    allogeneic BMT from HLA-matched sibling donor
    MEDICATION

. However, the treatment resulted in

    late graft failure
    SYMPTOMS

 and the patient developed

    severe bone involvement
    SYMPTOMS

. Fifty months after the first

    BMT
    MEDICATION

, the patient was

    treated by allogeneic peripheral blood stem cell (PBSC) transplantation without preconditioning
    MEDICATION

.

    Recombinant human granulocyte-colony stimulating factor (rhG-CSF) was used to mobilize PBSC
    MEDICATION

.

    Cyclosporine A (CyA)
    MEDICATION

 was administered for the

    prophylaxis of graft-versushost disease (GVHD)
    DIAGNOSIS

.

    Full donor-derived hematopoiesis was obtained
    MICROSCOPIC

, and

    clinical symptoms
    SYMPTOMS

 including

    severe bone involvement
    SYMPTOMS

 improved completely with

    increased glucocerebrosidase activity
    BIOCHEMICAL

. It was shown that an

    engraftment
    MEDICATION

 could be obtained

    without intensive preconditioning
    MEDICATION

 when a

    recipient receives an rhG-CSF-mobilized PBSCs infusion as a secondary transplant
    MEDICATION

. Another important finding of this study is the

    complete reversal of severe bone involvement
    SYMPTOMS

 by the

    supply of abundant glucocerebrosidase from high proliferating PBSC graft
    MICROSCOPIC

.


Type I Gaucher disease with exophthalmos and pulmonary arteriovenous malformation.

Gaucher disease type I, the non-neuropathic type, usually presents in adulthood with hepatosplenomegaly. We report here an adult with type I Gaucher disease presented with unusual and severe clinical manifestations.

Hepatosplenomegaly, bone crisis and fractures occurred at early childhood, and splenectomy was performed at the age of 5. Exophthalmos with increase in retrobulbar space was noted when the patient was 30. Cerezyme infusion started at the age of 32; but unfortunately, pulmonary arteriovenous malformation with dyspnea and hypoxemia was found two years later. Gene analysis revealed V375L/L444P mutations in the beta-glucocerebrosidase gene.

Although both eye and lung diseases have been associated with Gaucher disease, this is the first reported demonstration of exophthalmos and pulmonary arteriovenous malformation in the same patient. This case may therefore present an extremely severe and unusual form of type I Gaucher disease.

    Gaucher disease type I
    DIAGNOSIS

, the

    non-neuropathic type
    DIAGNOSIS

, usually presents in

    adulthood
    AGE

 with

    hepatosplenomegaly
    SYMPTOMS

. We report here an

    adult
    AGE

 with

    type I Gaucher disease
    DIAGNOSIS

 presented with

    unusual and severe clinical manifestations
    SYMPTOMS

.

    Hepatosplenomegaly
    SYMPTOMS

,

    bone crisis
    SYMPTOMS

 and

    fractures
    SYMPTOMS

 occurred at

    early childhood
    AGE

, and

    splenectomy
    MEDICATION

 was performed at the

    age of 5
    AGE

.

    Exophthalmos with increase in retrobulbar space
    SYMPTOMS

 was noted when the patient

    was 30
    AGE

.

    Cerezyme infusion
    MEDICATION

 started at the

    age of 32
    AGE

; but unfortunately,

    pulmonary arteriovenous malformation
    SYMPTOMS

 with

    dyspnea
    SYMPTOMS

 and

    hypoxemia
    SYMPTOMS

 was found two years later.

    Gene analysis
    PARACLINICAL

 revealed

    V375L/L444P mutations in the beta-glucocerebrosidase gene
    GENETICS

.

Although both

    eye and lung diseases
    SYMPTOMS

 have been associated with

    Gaucher disease
    DIAGNOSIS

, this is the first reported demonstration of

    exophthalmos
    SYMPTOMS

 and

    pulmonary arteriovenous malformation
    SYMPTOMS

 in the same patient. This case may therefore present an extremely severe and unusual form of

    type I Gaucher disease
    DIAGNOSIS

.

Gaucher disease type I
non-neuropathic type
type I Gaucher disease
Gaucher disease
type I Gaucher disease


Clinical response to sildenafil in pulmonary hypertension associated with Gaucher disease.

There are few reports of pulmonary hypertension in Gaucher disease. We report a patient who showed significant clinical improvement after treatment with sildenafil.

There are few reports of

    pulmonary hypertension
    SYMPTOMS

 in

    Gaucher disease
    DIAGNOSIS

. We report a patient who showed

    significant clinical improvement
    SYMPTOMS

 after

    treatment with sildenafil
    MEDICATION

.

pulmonary hypertension
significant clinical improvement


[Gaucher's disease. Substitutive enzymatic treatment in one case and a review of the literature].

Gaucher's disease, rare, hereditary and potentially mortal affection is characterized by the reduced concentration of the glucocerebroside lipid within the macrophage lysosomes. We report the case of a young 2 years old patient treated by transfusion since he was 9 months because of chronic anemia. According the clinical examination, the general state of the patients was bad ith important delayed stanturoponderal growth, a cutaneomucous paller and enormous splenomegaly. The blood count formula showed anemia with major thrombopenia. The myelogram was poor and the osteomedullar biopsy showed the presence of Gaucher's cells. The diagnosis has been confirmed by enzymatic dosage (Leucocytar b-glucosidase). The treatment of the patient has been substitutive enzymatic (inifucerase) with very favorable response. During Gaucher's disease, the enzymatic deficiency results in the pathologic accumulation of the substrate (glucocerebroside) in the lyososomes, this metabolic overloading may cause polyvisceral disease with spontaneous evolution ofter mortal. The recent discovery of a recombining glucocerebrosidase (imiglucerase) transformed the prognosis of this disease.

    Gaucher's disease
    DIAGNOSIS

, rare,

    hereditary
    GENETICS

 and potentially mortal affection is characterized by the

    reduced concentration of the glucocerebroside lipid within the macrophage lysosomes
    MICROSCOPIC

. We report the case of a

    young 2 years old
    AGE

 patient

    treated by transfusion
    MEDICATION

    since he was 9 months
    AGE

 because of

    chronic anemia
    BIOCHEMICAL

. According the clinical examination, the general state of the patients was

    bad
    SYMPTOMS

 ith

    important delayed stanturoponderal growth
    SYMPTOMS

, a

    cutaneomucous paller
    SYMPTOMS

 and

    enormous splenomegaly
    SYMPTOMS

. The

    blood count formula
    PARACLINICAL

 showed

    anemia
    BIOCHEMICAL

 with

    major thrombopenia
    BIOCHEMICAL

. The

    myelogram was poor
    PARACLINICAL

 and the

    osteomedullar biopsy
    PARACLINICAL

 showed the

    presence of Gaucher's cells
    MICROSCOPIC

. The diagnosis has been confirmed by

    enzymatic dosage (Leucocytar b-glucosidase)
    PARACLINICAL

. The treatment of the patient has been

    substitutive enzymatic (inifucerase)
    MEDICATION

 with very favorable response. During

    Gaucher's disease
    DIAGNOSIS

, the

    enzymatic deficiency
    BIOCHEMICAL

 results in the

    pathologic accumulation of the substrate (glucocerebroside) in the lyososomes
    MICROSCOPIC

, this

    metabolic overloading
    MICROSCOPIC

 may cause

    polyvisceral disease
    DIAGNOSIS

 with

    spontaneous evolution ofter mortal
    SYMPTOMS

. The recent discovery of a

    recombining glucocerebrosidase (imiglucerase)
    MEDICATION

 transformed the prognosis of this disease.

Gaucher's disease
Gaucher's disease
polyvisceral disease

chronic anemia
anemia
major thrombopenia
enzymatic deficiency


Menetrier's disease presenting as an acute protein-losing gastroenteropathy in a 27-year-old man with Gaucher disease.

To describe a unique case of a young man with Gaucher disease who was diagnosed with Menetrier's disease.

After an acute episode of severe gastritis, the patient developed hypoalbuminemia and protein-losing gastroenteropathy, and became unwell.

Endoscopy revealed an abnormal stomach, with rigid, thickened folds covered with viscous greyish exudates. Superficial biopsies revealed foveolar hyperplasia, acute and severe gastritis with massive inflammatory infiltrate of neutrophils in the lamina propria with pit abscess formation. Tissue cultures for Helicobacter pylori were negative.

Snare deep particle biopsy revealed the typical features of Menetrier's disease. Enzyme replacement therapy for Gaucher disease was started.

This case poses a dilemma because the patient improved spontaneously, and as such is dissimilar to other adults who develop Menetrier's disease because of an infection; it is hoped that he may also not be at risk of the potential malignancies that are correlated with adult Menetrier's disease. The value of enzyme treatment is considered.

To describe a unique case of a

    young
    AGE

    man
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 who was diagnosed with

    Menetrier's disease
    DIAGNOSIS

.

After an

    acute episode of severe gastritis
    DIAGNOSIS

, the patient developed

    hypoalbuminemia
    BIOCHEMICAL

 and

    protein-losing gastroenteropathy
    BIOCHEMICAL

, and became

    unwell
    SYMPTOMS

.

    Endoscopy
    PARACLINICAL

 revealed an

    abnormal stomach, with rigid, thickened folds covered with viscous greyish exudates
    SYMPTOMS

.

    Superficial biopsies
    PARACLINICAL

 revealed

    foveolar hyperplasia
    SYMPTOMS

,

    acute and severe gastritis
    MICROSCOPIC

 with

    massive inflammatory infiltrate of neutrophils in the lamina propria with pit abscess formation
    MICROSCOPIC

.

    Tissue cultures for Helicobacter pylori were negative
    NEG_FINDINGS

.

    Snare deep particle biopsy
    PARACLINICAL

 revealed the typical features of

    Menetrier's disease
    MICROSCOPIC

.

    Enzyme replacement therapy for Gaucher disease
    MEDICATION

 was started.

This case poses a dilemma because the patient

    improved spontaneously
    SYMPTOMS

, and as such is dissimilar to other adults who develop

    Menetrier's disease
    DIAGNOSIS

 because of an

    infection
    DIAGNOSIS

; it is hoped that

    he
    GENDER

 may also not be at risk of the potential malignancies that are correlated with

    adult Menetrier's disease
    DIAGNOSIS

. The value of

    enzyme treatment
    MEDICATION

 is considered.

Gaucher disease
Menetrier's disease
acute episode of severe gastritis
Menetrier's disease
infection
adult Menetrier's disease


Neonatal Gaucher disease presenting as persistent thrombocytopenia.

Mutations in the beta-glucocerebrosidase gene cause Gaucher disease with the type 1 variant generally presenting later in life with mild disease and type 2 in infancy with severe neuronopathic symptoms. We describe a neonate homozygous for the D409 H mutation with thrombocytopenia, splenomegaly and cholestasis at birth as the major features.

    Mutations in the beta-glucocerebrosidase gene
    GENETICS

 cause

    Gaucher disease
    DIAGNOSIS

 with the

    type 1 variant
    DIAGNOSIS

 generally presenting

    later in life
    AGE

 with

    mild disease
    SYMPTOMS

 and

    type 2
    DIAGNOSIS

 in

    infancy
    AGE

 with

    severe neuronopathic symptoms
    SYMPTOMS

. We describe a

    neonate
    AGE

    homozygous for the D409 H mutation
    GENETICS

 with

    thrombocytopenia
    BIOCHEMICAL

,

    splenomegaly
    BIOCHEMICAL

 and

    cholestasis
    SYMPTOMS

 at

    birth
    AGE

 as the major features.

mild disease
severe neuronopathic symptoms
cholestasis


A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity.

Only two Gaucher disease (GD) patients bearing mutations in the prosaposin gene (PSAP), and not in the glucocerebrosidase gene (GBA), have been reported. In both cases, one mutant allele remained unidentified. We report here the identification of the second mutation in one of these patients, being the first complete genotype described so far in a SAP-C-deficient GD patient. This mutation, p.Q430X, is the first one reported in the saposin D domain and probably produces a null allele by nonsense mediated mRNA decay.

Only two

    Gaucher disease (GD)
    DIAGNOSIS

 patients bearing

    mutations in the prosaposin gene (PSAP)
    GENETICS

, and

    not in the glucocerebrosidase gene (GBA)
    NEG_FINDINGS

, have been reported. In both cases, one

    mutant allele remained unidentified
    GENETICS

. We report here the identification of the

    second mutation
    GENETICS

 in one of these patients, being the first complete genotype described so far in a

    SAP-C-deficient
    BIOCHEMICAL

    GD
    DIAGNOSIS

 patient. This

    mutation, p.Q430X,
    GENETICS

 is the first one reported

    in the saposin D domain
    GENETICS

 and probably produces a

    null allele by nonsense mediated mRNA decay
    GENETICS

.


Bilateral lung transplant in Gauchers type-1 disease.

We report a case of a patient who received a bilateral lung transplant for end-stage lung disease secondary to Gauchers type-1 disease with no evidence of recurrence of the disease in the transplanted lung.

We report a case of a patient who

    received a bilateral lung transplant
    MEDICATION

 for

    end-stage lung disease
    DIAGNOSIS

 secondary to

    Gauchers type-1 disease
    DIAGNOSIS

 with

    no evidence of recurrence of the disease in the transplanted lung
    NEG_FINDINGS

.

end-stage lung disease
Gauchers type-1 disease


[MALT-type B-cell lymphoma masquerading as scleritis or posterior uveitis].

Diagnostic and therapeutic management of masquerade syndromes associated with MALT-type lymphoma.

We report the cases of three patients referred for acute or chronic severe loss of visual acuity. All of them suffered from uveitis or scleritis resistant to corticoid treatment. Each one had posterior uveitis associated with retinochoroidal infiltration, anterior scleritis associated with uveal effusion syndrome, or bilateral pan-uveitis associated with serous retinal detachment. Two patients had medical records of systemic malignancies. They underwent an extensive work-up. Search for an infectious, immune or malignant disease was negative but orbital imaging showed a posterior scleral thickening in all cases.

Diagnosis of mucosa-associated lymphoid tissue (MALT) ocular lymphoma was assessed in all cases after scleral biopsy. Immunohistochemical analysis showed CD20(+) and CD5(-) scleral lymphocyte infiltrates. The three patients underwent chemotherapy associated with radiotherapy. Lesions were stabilized in the first case, whereas six lines of visual acuity improvement was noted in the second one, and full recovery was achieved after treatment in the third case.

Clinical manifestations of this ocular lesion seem to be multiple, masquerading as different types of posterior uveitis or scleritis. In the three cases, we did found other systemic locations of MALT-type lymphoma. Diagnosis was mainly based on pathological analysis. Fast visual recovery in two cases demonstrated the importance of an early diagnosis and a specific treatment. All cases of chronic and corticoid-resistant posterior uveitis require a specialized radiological evaluation followed, if necessary, by multiple orbital biopsies.

Diagnostic and therapeutic management of

    masquerade syndromes associated with MALT-type lymphoma
    SYMPTOMS

.

We report the cases of three patients referred for

    acute or chronic severe loss of visual acuity
    SYMPTOMS

. All of them suffered from

    uveitis or scleritis
    SYMPTOMS

    resistant to corticoid treatment
    NEG_FINDINGS

. Each one had

    posterior uveitis associated with retinochoroidal infiltration
    SYMPTOMS

,

    anterior scleritis associated with uveal effusion syndrome
    DIAGNOSIS

, or

    bilateral pan-uveitis associated with serous retinal detachment
    SYMPTOMS

. Two patients had medical records of

    systemic malignancies
    DIAGNOSIS

. They underwent an

    extensive work-up
    PARACLINICAL

.

    Search for an infectious, immune or malignant disease was negative
    NEG_FINDINGS

 but

    orbital imaging
    PARACLINICAL

 showed a

    posterior scleral thickening
    SYMPTOMS

 in all cases.

Diagnosis of

    mucosa-associated lymphoid tissue (MALT) ocular lymphoma
    DIAGNOSIS

 was assessed in all cases after

    scleral biopsy
    PARACLINICAL

.

    Immunohistochemical analysis
    PARACLINICAL

 showed

    CD20(+) and CD5(-) scleral lymphocyte infiltrates
    MICROSCOPIC

. The three patients underwent

    chemotherapy associated with radiotherapy
    MEDICATION

.

    Lesions were stabilized
    SYMPTOMS

 in the first case, whereas

    six lines of visual acuity improvement
    SYMPTOMS

 was noted in the second one, and

    full recovery was achieved
    SYMPTOMS

 after treatment in the third case.

Clinical manifestations of this

    ocular lesion
    SYMPTOMS

 seem to be multiple, masquerading as different types of

    posterior uveitis
    SYMPTOMS

 or

    scleritis
    DIAGNOSIS

. In the three cases, we did found other

    systemic locations of MALT-type lymphoma
    SYMPTOMS

. Diagnosis was mainly based on

    pathological analysis
    PARACLINICAL

.

    Fast visual recovery
    SYMPTOMS

 in two cases demonstrated the importance of an early diagnosis and a specific treatment. All cases of

    chronic
    DIAGNOSIS

 and

    corticoid-resistant posterior uveitis
    NEG_FINDINGS

 require a

    specialized radiological evaluation
    PARACLINICAL

 followed, if necessary, by

    multiple orbital biopsies
    PARACLINICAL

.


Fundus abnormalities in a patient with type I Gaucher's disease with 12-year follow-up.

To report a case of type I Gaucher's disease with rare presentation of fundus abnormalities in long-term observation.

Observational case report.

This 53-year-old Taiwanese woman suffered from type I Gaucher's disease for 12 years, with initial presentation of hepatoslpenomegaly in 1992.

At that time, poor vision with unusual macular change and peripheral retinal vessel leakage was also noted. She received a complete ophthalmic examination at the initial visit and again 12 years later in 2003. She was treated with imiglucerase injection during the last 4 years. However, her visual acuity was 10/200 in both eyes. The macular and peripheral retinal degenerative change progressed after 12 years.

Fundus changes associated with Gaucher's disease are uncommon. We should not neglect the possibility of retinal involvement and progression in these patients.

To report a case of

    type I Gaucher's disease
    DIAGNOSIS

 with

    rare presentation of fundus abnormalities
    SYMPTOMS

 in long-term observation.

    Observational case report
    PARACLINICAL

.

This

    53-year-old
    AGE

    Taiwanese
    ETHNICITY

    woman
    GENDER

 suffered from

    type I Gaucher's disease
    DIAGNOSIS

 for 12 years, with initial presentation of

    hepatoslpenomegaly
    SYMPTOMS

 in 1992.

At that time,

    poor vision with unusual macular change
    SYMPTOMS

 and

    peripheral retinal vessel leakage
    SYMPTOMS

 was also noted.

    She
    GENDER

 received a

    complete ophthalmic examination
    PARACLINICAL

 at the initial visit and again 12 years later in 2003.

    She
    GENDER

 was

    treated with imiglucerase injection during the last 4 years
    MEDICATION

. However,

    her
    GENDER

    visual acuity was 10/200 in both eyes
    SYMPTOMS

. The

    macular and peripheral retinal degenerative change
    SYMPTOMS

 progressed after 12 years.

    Fundus changes
    SYMPTOMS

 associated with

    Gaucher's disease
    DIAGNOSIS

 are uncommon. We should not neglect the possibility of

    retinal involvement
    SYMPTOMS

 and progression in these patients.

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


[Gaucher disease--one of the possible causes of splenomegaly--case report].

The aim of this article is to present a case report of Gaucher disease which was diagnosed in patient with hepatosplenomegaly. A 43 years old man has complained of weakness, stomach pain and yellowish skin color for several years. The severity of symptoms has increased during the last 2 years. Laboratory data revealed thrombocytopenia (platelet count 108 G/l) and slightly elevated bilirubin level (1.68 mg/dl). In ultrasound examination hepatosplenomegaly was observed. Computer tomography evaluated the size of the spleen to 20 x 12 cm. Gaucher cells were found in bone marrow. The some type of cells was recognized in liver biopsy. To confirm diagnosis of Gaucher disease enzyme test was performed. Chitotriosidase level in serum was pronouncedly increased (11,540 nmol/mg protein/hr) while normal level is under 150 nmol/mg protein/hr. Glucocerebrosidase activity in leucocytes was within the limit. Thus the enzyme activity was 21.8 nmol/mg protein/hr and was below the normal range which is between 111-455 nmol/mg protein/hr. The last assay, measuring glucolukocerebrosidase activity in cultured fibroblast confirmed the diagnosis of Gaucher disease.

The aim of this article is to present a case report of

    Gaucher disease
    DIAGNOSIS

 which was diagnosed in patient with

    hepatosplenomegaly
    SYMPTOMS

. A

    43 years old
    AGE

    man
    GENDER

 has complained of

    weakness
    SYMPTOMS

,

    stomach pain
    SYMPTOMS

 and

    yellowish skin color
    SYMPTOMS

 for several years. The severity of symptoms has increased during the last 2 years. Laboratory data revealed

    thrombocytopenia (platelet count 108 G/l)
    BIOCHEMICAL

 and

    slightly elevated bilirubin level (1.68 mg/dl)
    BIOCHEMICAL

. In

    ultrasound examination
    PARACLINICAL

    hepatosplenomegaly
    SYMPTOMS

 was observed.

    Computer tomography
    PARACLINICAL

 evaluated the

    size of the spleen to 20 x 12 cm
    SYMPTOMS

.

    Gaucher cells were found in bone marrow
    MICROSCOPIC

.

    The some type of cells was recognized
    MICROSCOPIC

 in

    liver biopsy
    PARACLINICAL

. To confirm diagnosis of

    Gaucher disease
    DIAGNOSIS

    enzyme test
    PARACLINICAL

 was performed.

    Chitotriosidase level in serum was pronouncedly increased (11,540 nmol/mg protein/hr)
    BIOCHEMICAL

 while

    normal level is under 150 nmol/mg protein/hr
    BIOCHEMICAL

.

    Glucocerebrosidase activity in leucocytes was within the limit
    BIOCHEMICAL

. Thus

    the enzyme activity was 21.8 nmol/mg protein/hr and was below the normal range which is between 111-455 nmol/mg protein/hr
    BIOCHEMICAL

. The last assay, measuring

    glucolukocerebrosidase activity in cultured fibroblast
    BIOCHEMICAL

 confirmed the diagnosis of

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
Gaucher disease
Gaucher disease

hepatosplenomegaly
weakness
stomach pain
yellowish skin color
hepatosplenomegaly
size of the spleen to 20 x 12 cm


Plasma chitotriosidase and CCL18: early biochemical surrogate markers in type B Niemann-Pick disease.

Type B Niemann-Pick disease (NPD) is a nonneuronopathic lysosomal storage disorder which is characterized by accumulation of sphingomyelin-laden macrophages. The availability of plasma markers for storage cells may be of great value in facilitating therapeutic decisions. Given the similarity of the storage cells in NPD and Gaucher disease, we studied Gaucher plasma markers (chitotriosidase and CCL18) in two siblings homozygous for the R228C mutation in acid sphingomyelinase (ASM) and a type B course of NPD. The older sibling, first examined at the age of 9 months, showed marked hepatosplenomegaly and pulmonary involvement. The younger sibling has mild asymptomatic hepatosplenomgaly at the age of 5 months. Analysis of plasma specimens revealed markedly increased levels of chitotriosidase and CCL18 in the older sibling. In the younger child also, plasma chitotriosidase and CCL18 were clearly elevated above normal values almost immediately after birth and rapidly increased further. Histochemistry confirmed production of CCL18 by foam cells. In conclusion, plasma chitotriosidase and CCL18 may also serve as markers for the formation of pathological lipid-laden macrophages in type B NPD, in analogy to Gaucher disease. The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of enzyme supplementation therapy that is currently being developed.

    Type B Niemann-Pick disease (NPD)
    DIAGNOSIS

 is a

    nonneuronopathic lysosomal storage disorder
    DIAGNOSIS

 which is characterized by

    accumulation of sphingomyelin-laden macrophages
    MICROSCOPIC

. The availability of plasma markers for

    storage cells
    MICROSCOPIC

 may be of great value in facilitating therapeutic decisions. Given the

    similarity of the storage cells in NPD
    MICROSCOPIC

 and

    Gaucher disease
    MICROSCOPIC

, we studied

    Gaucher plasma markers (chitotriosidase and CCL18)
    BIOCHEMICAL

 in two

    siblings homozygous for the R228C mutation in acid sphingomyelinase (ASM)
    FAMILY

 and a

    type B course of NPD
    DIAGNOSIS

. The older sibling, first examined

    at the age of 9 months
    AGE

, showed

    marked hepatosplenomegaly
    SYMPTOMS

 and

    pulmonary involvement
    SYMPTOMS

. The

    younger sibling has mild asymptomatic hepatosplenomgaly
    FAMILY

    at the age of 5 months
    AGE

.

    Analysis of plasma specimens
    PARACLINICAL

 revealed

    markedly increased levels of chitotriosidase and CCL18
    BIOCHEMICAL

 in the

    older sibling
    AGE

. In the

    younger child
    AGE

 also,

    plasma chitotriosidase and CCL18 were clearly elevated above normal values
    BIOCHEMICAL

 almost

    immediately after birth
    BIOCHEMICAL

 and

    rapidly increased further
    BIOCHEMICAL

.

    Histochemistry
    PARACLINICAL

 confirmed

    production of CCL18 by foam cells
    MICROSCOPIC

. In conclusion,

    plasma chitotriosidase and CCL18
    BIOCHEMICAL

 may also serve as markers for the

    formation of pathological lipid-laden macrophages
    MICROSCOPIC

 in

    type B NPD
    DIAGNOSIS

, in analogy to

    Gaucher disease
    DIAGNOSIS

. The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of

    enzyme supplementation therapy
    MEDICATION

 that is currently being developed.

marked hepatosplenomegaly
pulmonary involvement


Diagnostic and treatment challenges of neuronopathic Gaucher disease: two cases with an intermediate phenotype.

Gaucher disease (GD) is a lysosomal storage disorder with a broad, overlapping clinical spectrum. The presented two case reports highlight the clinical evaluation required in neuronopathic GD to assist with medical management and genetic counselling.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 with a broad, overlapping clinical spectrum. The presented two case reports highlight the clinical evaluation required in

    neuronopathic GD
    DIAGNOSIS

 to assist with medical management and

    genetic counselling
    MEDICATION

.

Gaucher disease (GD)
lysosomal storage disorder
neuronopathic GD


[Uncommon combination of multiple myeloma in three patients].

The authors describe uncommon combinations of multiple myeloma in three men aged 83, 63 and 55 years. In patient no. 1 both diseases--pernicious anaemia and multiple myeloma IgG-kappa were detected simultaneously. In patient no. 2 Crohn's disease preceded multiple myeloma IgA-lambda by more than 30 years. In patient no. 3 Gaucher's disease preceded multiple myeloma with paraproteinaemia IgA-lambda and IgG-kappa by more than 10 years. The diagnosis was facilitated by examination of the bone marrow, immunochemical examination of serum and urine and X-ray examination of the skeleton. In all patients the development of the myeloma had an adverse effect on the general course of the disease and despite treatment it soon proved fatal. In the discussion views on the possible causal associations between these diseases are discussed.

The authors describe

    uncommon combinations of multiple myeloma
    DIAGNOSIS

 in three

    men
    GENDER

    aged 83, 63 and 55 years
    AGE

. In patient no. 1

    both diseases--pernicious anaemia
    DIAGNOSIS

 and

    multiple myeloma IgG-kappa
    DIAGNOSIS

 were detected simultaneously. In patient no. 2

    Crohn's disease
    DIAGNOSIS

 preceded

    multiple myeloma IgA-lambda
    DIAGNOSIS

 by more than

    30 years
    AGE

. In patient no. 3

    Gaucher's disease
    DIAGNOSIS

 preceded

    multiple myeloma
    DIAGNOSIS

 with

    paraproteinaemia IgA-lambda and IgG-kappa by more than 10 years
    BIOCHEMICAL

. The diagnosis was facilitated by

    examination of the bone marrow
    PARACLINICAL

,

    immunochemical examination of serum and urine
    PARACLINICAL

 and

    X-ray examination of the skeleton
    PARACLINICAL

. In all patients the

    development of the myeloma
    DIAGNOSIS

    had an adverse effect on the general course of the disease
    SYMPTOMS

 and

    despite treatment
    NEG_FINDINGS

 it soon proved

    fatal
    SYMPTOMS

. In the discussion views on the possible causal associations between these diseases are discussed.


[Diagnostic image (215). A woman with abdominal pain and hepatosplenomegaly].

A 30-year-old woman presented with abdominal pain, cholelithiasis and hepatosplenomegaly, due to Gaucher's disease.

A

    30-year-old
    AGE

    woman
    GENDER

 presented with

    abdominal pain
    SYMPTOMS

,

    cholelithiasis
    SYMPTOMS

 and

    hepatosplenomegaly
    SYMPTOMS

, due to

    Gaucher's disease
    DIAGNOSIS

.

abdominal pain
cholelithiasis
hepatosplenomegaly


Type I Gaucher disease with severe skeletal destruction, extraosseous extension, and monoclonal gammopathy.

Extraosseous extensions of Gaucher-cell deposits simulate malignant diseases. We describe a 65-year-old male with type-I Gaucher disease, confirmed by low leukocyte glucocerebrosidase activity, high plasma chitotriosidase, and N370/L444P gene-mutations, who had severe skeletal involvement, IgG-kappa monoclonal gammopathy, and a soft-tissue mass within the left iliac muscle. Bone marrow biopsy showed heavy infiltration by Gaucher cells, and histopathology of the excised extraosseous mass revealed infiltration by Gaucher cells. Thus, malignant diseases were excluded and the diagnosis of an extraosseous Gaucher-cell extension was well documented. Our case is reported because it is very interesting and unique in the literature.

    Extraosseous extensions of Gaucher-cell deposits
    MICROSCOPIC

 simulate

    malignant diseases
    DIAGNOSIS

. We describe a

    65-year-old
    AGE

    male
    GENDER

 with

    type-I Gaucher disease
    DIAGNOSIS

, confirmed by

    low leukocyte glucocerebrosidase activity
    BIOCHEMICAL

,

    high plasma chitotriosidase
    BIOCHEMICAL

, and

    N370/L444P gene-mutations
    GENETICS

, who had

    severe skeletal involvement
    SYMPTOMS

,

    IgG-kappa monoclonal gammopathy
    BIOCHEMICAL

, and a

    soft-tissue mass within the left iliac muscle
    SYMPTOMS

.

    Bone marrow biopsy
    PARACLINICAL

 showed

    heavy infiltration by Gaucher cells
    MICROSCOPIC

, and

    histopathology of the excised extraosseous mass
    PARACLINICAL

 revealed

    infiltration by Gaucher cells
    MICROSCOPIC

. Thus,

    malignant diseases were excluded
    NEG_FINDINGS

 and the diagnosis of an

    extraosseous Gaucher-cell extension
    MICROSCOPIC

 was well documented. Our case is reported because it is very interesting and unique in the literature.

malignant diseases
type-I Gaucher disease


Familial calcium pyrophosphate dihydrate deposition disease. A Tunisian kindred.

Familial calcium pyrophosphate dihydrate deposition disease (CPDD) is uncommon, with about 50 affected families identified to date in the world. Genetic studies in familial CPDD are focusing on the ANKH gene. We report a new Tunisian kindred with CPDD.

The development of CPDD in a patient who was only 35 years of age prompted a family study. A medical history, physical examination, and radiographs were performed in 103 family members older than 18 years.

Fifteen family members had CPDD. There were 10 men and five women, with a mean age of 59.4 years. Onset was usually in the third or fourth decade. Four clinical patterns were found: Five patients had pseudogout, five had pseudoosteoarthritis, three had asymptomatic disease, and two had pseudorheumatoid arthritis. Inheritance was autosomal dominant with low penetrance. No associations with specific HLA antigens were found. The disease was mild. These characteristics fit the description of Gaucher type 1 familial CPDD.

Inherited autosomal dominant CPDD with low penetrance was found in 15 members of a Tunisian kindred. The disease was mild. We are planning a genetic study including tests for ANKH gene mutations in this kindred.

    Familial calcium pyrophosphate dihydrate deposition disease (CPDD)
    DIAGNOSIS

 is uncommon, with about 50 affected families identified to date in the world. Genetic studies in

    familial CPDD
    DIAGNOSIS

 are focusing on the

    ANKH gene
    GENETICS

. We report a new

    Tunisian
    ETHNICITY

    kindred with CPDD
    FAMILY

.

The development of

    CPDD
    DIAGNOSIS

 in a patient who was

    only 35 years of age
    AGE

 prompted a

    family study
    PARACLINICAL

. A

    medical history
    PARACLINICAL

,

    physical examination
    PARACLINICAL

, and

    radiographs
    PARACLINICAL

 were performed in 103 family members

    older than 18 years
    AGE

.

    Fifteen family members had CPDD
    FAMILY

. There were 10

    men
    GENDER

 and five

    women
    GENDER

, with a

    mean age of 59.4 years
    AGE

. Onset was usually

    in the third or fourth decade
    AGE

. Four clinical patterns were found: Five patients had

    pseudogout
    DIAGNOSIS

, five had

    pseudoosteoarthritis
    DIAGNOSIS

, three had

    asymptomatic disease
    DIAGNOSIS

, and two had

    pseudorheumatoid arthritis
    DIAGNOSIS

.

    Inheritance was autosomal dominant with low penetrance
    GENETICS

.

    No associations with specific HLA antigens were found
    NEG_FINDINGS

. The disease was mild. These characteristics fit the description of

    Gaucher type 1 familial CPDD
    DIAGNOSIS

.

    Inherited autosomal dominant CPDD
    GENETICS

 with

    low penetrance
    GENETICS

 was found in 15 members of a

    Tunisian
    ETHNICITY

 kindred. The disease was mild. We are planning a genetic study including tests for

    ANKH gene mutations
    GENETICS

 in this kindred.


[Gaucher's disease uncovered late].

Gaucher's disease is an uncommon inborn recessive autosomal disease, due to a deficient activity of the lysosomal enzyme beta glucocerebrosidase. This disease is usually diagnosed in the first or second decade of life with the arising of bone pains, splenomegaly and hemorragic manifestations due to thrombocytopenia. When the enlarged spleen is not evident, or after splenectomy, patients may be mis-identified as having Gaucher's disease. We present here two cases of elderly patients aged 70 and 46 years respectively, in whom the disease was a surprising finding of bone marrow examination, during check up for pancytopenia.

    Gaucher's disease
    DIAGNOSIS

 is an

    uncommon inborn recessive autosomal disease
    GENETICS

, due to a

    deficient activity of the lysosomal enzyme beta glucocerebrosidase
    BIOCHEMICAL

. This disease is usually diagnosed in the

    first or second decade of life
    AGE

 with the arising of

    bone pains
    SYMPTOMS

,

    splenomegaly
    SYMPTOMS

 and

    hemorragic manifestations
    SYMPTOMS

 due to

    thrombocytopenia
    BIOCHEMICAL

. When the

    enlarged spleen is not evident
    NEG_FINDINGS

, or after

    splenectomy
    MEDICATION

, patients may be

    mis-identified as having Gaucher's disease
    NEG_FINDINGS

. We present here two cases of

    elderly
    AGE

 patients

    aged 70 and 46 years
    AGE

 respectively, in whom the disease was a surprising finding of

    bone marrow examination
    PARACLINICAL

, during

    check up
    PARACLINICAL

 for

    pancytopenia
    BIOCHEMICAL

.

bone pains
splenomegaly
hemorragic manifestations


Clinical features of adult GM1 gangliosidosis: report of three Indian patients and review of 40 cases.

Deficiency of enzyme acid beta-galactosidase causes GM1 gangliosidosis. Patients with adult GM1 gangliosidosis typically present with generalized dystonia. We describe clinical, bone marrow, and radiological features of adult GM1 gangliosidosis to help improve its recognition. We report 3 Indian patients and review of reports between 1981 and October 2002. The disease frequently is reported in the Japanese literature (75%). Patients are normal at birth and have normal early motor and mental development. Onset is within the first decade with abnormal gait, or worsening of speech is an initial symptom. Dystonia occurs in 97% of patients. Facial dystonia described as "facial grimacing" observed in approximately 90% could be an important clinical clue. Dysarthria/anarthria (97%) is frequent, and eye movements are normal. Bone marrow examination may show Gaucher-like foam cells (39%). Magnetic resonance imaging (MRI) frequently (90.9%) shows bilateral symmetrical putamenal hyperintensities on T2-weighted and proton density images. Diagnosis is confirmed by demonstrating deficiency of beta-galactosidase. Adult (Type 3) GM1 Gangliosidosis commonly presents with generalized dystonia with prominent facial dystonia, severe speech disturbances, and normal eye movements. Bone marrow frequently shows Gaucher-like foam cells. MRI shows typical lesions in the putamen. Deficiency of beta-galactosidase in fibroblasts confirms the diagnosis.

    Deficiency of enzyme acid beta-galactosidase
    BIOCHEMICAL

 causes

    GM1 gangliosidosis
    DIAGNOSIS

. Patients with

    adult GM1 gangliosidosis
    DIAGNOSIS

 typically present with

    generalized dystonia
    SYMPTOMS

. We describe clinical,

    bone marrow
    PARACLINICAL

, and radiological features of

    adult GM1 gangliosidosis
    DIAGNOSIS

 to help improve its recognition. We report 3

    Indian
    ETHNICITY

 patients and review of reports between 1981 and October 2002. The disease frequently is reported in the

    Japanese
    ETHNICITY

 literature (75%). Patients are

    normal at birth
    NEG_FINDINGS

 and have

    normal early motor and mental development
    NEG_FINDINGS

. Onset is

    within the first decade
    AGE

 with

    abnormal gait
    SYMPTOMS

, or

    worsening of speech
    SYMPTOMS

 is an initial symptom.

    Dystonia
    DIAGNOSIS

 occurs in 97% of patients.

    Facial dystonia
    SYMPTOMS

 described as

    "facial grimacing"
    SYMPTOMS

 observed in approximately 90% could be an important clinical clue.

    Dysarthria/anarthria
    SYMPTOMS

 (97%) is frequent, and

    eye movements are normal
    NEG_FINDINGS

.

    Bone marrow examination
    PARACLINICAL

 may show

    Gaucher-like foam cells
    MICROSCOPIC

 (39%).

    Magnetic resonance imaging (MRI)
    PARACLINICAL

 frequently (90.9%) shows

    bilateral symmetrical putamenal hyperintensities on T2-weighted and proton density images
    SYMPTOMS

. Diagnosis is confirmed by demonstrating

    deficiency of beta-galactosidase
    BIOCHEMICAL

.

    Adult (Type 3) GM1 Gangliosidosis
    DIAGNOSIS

 commonly presents with

    generalized dystonia
    SYMPTOMS

 with

    prominent facial dystonia
    SYMPTOMS

,

    severe speech disturbances
    SYMPTOMS

, and

    normal eye movements
    NEG_FINDINGS

.

    Bone marrow
    PARACLINICAL

 frequently shows

    Gaucher-like foam cells
    MICROSCOPIC

.

    MRI
    PARACLINICAL

 shows

    typical lesions in the putamen
    SYMPTOMS

.

    Deficiency of beta-galactosidase in fibroblasts
    BIOCHEMICAL

 confirms the diagnosis.

GM1 gangliosidosis
adult GM1 gangliosidosis
adult GM1 gangliosidosis
Dystonia
Adult (Type 3) GM1 Gangliosidosis


Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages.

Although the existence of anti-inflammatory alternatively activated macrophages (aamphi) has been accepted widely based on in vitro studies, their in vivo location, phenotype, and function still are debated. Gaucher disease (GD) is caused by a genetic deficiency in the lysosomal enzyme glucocerebrosidase and is characterized by accumulation of glycosphingolipids in so-called Gaucher cells (GCs). By using immunohistochemical analysis, we investigated whether this results in an aamphi phenotype. GCs are macrophage-like cells, expressing acid phosphatase, CD68, CD14, and HLA class II, but not CD11b, CD40, or dendritic cell markers. GCs show infrequent immunoreactivity for mannose receptor GCs did not express proinflammatory cytokines such as tumor necrosis factor alpha and monocyte chemoattractant protein 1, but did express the aamphi markers CD163, CCL18, and interleukin-1 receptor antagonist. Furthermore, CD36 and signal receptor protein alpha, involved in lipid uptake, also were observed on GCs. Thus, GCs represent a distinctive population of myeloid cells that resemble aamphi but differ from previously described in vitro aamphi.

Although the existence of

    anti-inflammatory alternatively activated macrophages (aamphi)
    MICROSCOPIC

 has been accepted widely based on in vitro studies, their in vivo location, phenotype, and function still are debated.

    Gaucher disease (GD)
    DIAGNOSIS

 is caused by a

    genetic deficiency in the lysosomal enzyme glucocerebrosidase
    GENETICS

 and is characterized by

    accumulation of glycosphingolipids in so-called Gaucher cells (GCs)
    MICROSCOPIC

. By using

    immunohistochemical analysis
    PARACLINICAL

, we investigated whether this results in an

    aamphi phenotype
    MICROSCOPIC

.

    GCs are macrophage-like cells
    MICROSCOPIC

,

    expressing acid phosphatase, CD68, CD14, and HLA class II
    GENETICS

, but

    not CD11b, CD40, or dendritic cell markers
    NEG_FINDINGS

.

    GCs show infrequent immunoreactivity for mannose receptor
    MICROSCOPIC

    GCs
    MICROSCOPIC

    did not express proinflammatory cytokines such as tumor necrosis factor alpha and monocyte chemoattractant protein 1
    NEG_FINDINGS

, but did express the

    aamphi markers CD163, CCL18
    GENETICS

, and

    interleukin-1 receptor antagonist
    BIOCHEMICAL

. Furthermore,

    CD36 and signal receptor protein alpha
    GENETICS

, involved in

    lipid uptake
    MICROSCOPIC

, also were observed

    on GCs
    MICROSCOPIC

. Thus,

    GCs
    MICROSCOPIC

 represent a

    distinctive population of myeloid cells
    MICROSCOPIC

 that resemble

    aamphi
    MICROSCOPIC

 but differ from previously described

    in vitro aamphi
    MICROSCOPIC

.


Early visual seizures and progressive myoclonus epilepsy in neuronopathic Gaucher disease due to a rare compound heterozygosity (N188S/S107L).

Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, is characterized by genotypic and phenotypic heterogeneity. We recently characterized the glucocerebrosidase alleles of a patient with an unusual clinical presentation of type 3 Gaucher disease.

Initial clinical manifestations appeared at age 11 years as visual seizures.

Subsequent progressive myoclonus and generalized seizures were consistent with an adolescent-onset form of progressive myoclonus epilepsy. However, a specific diagnosis was established only at age 16, because of the absence of hematologic abnormalities and a fairly moderate hepatomegaly. Bone marrow aspirate was slightly positive for Gaucher cells. Demonstration of reduced glucocerebrosidase in the fibroblasts confirmed the diagnosis. The child died at age 19 years. Postmortem sequencing of the glucocerebrosidase gene from cultured fibroblasts demonstrated a rare compound heterozygote for N188S/S107L.

This unusual presentation of Gaucher disease indicates that if clinical and neurophysiological findings in adolescents with initial visual seizures and myoclonus suggest a progressive disorder, enzymatic assay is mandatory, even in the absence of the classic neurologic and systemic signs of the disease. Early differential diagnosis from other forms of progressive myoclonus epilepsy with similar clinical presentation may help provide appropriate genetic counseling.

    Gaucher disease
    DIAGNOSIS

, the

    inherited deficiency of the lysosomal enzyme glucocerebrosidase
    GENETICS

, is characterized by genotypic and phenotypic heterogeneity. We recently characterized the

    glucocerebrosidase alleles
    GENETICS

 of a patient with an unusual clinical presentation of

    type 3 Gaucher disease
    DIAGNOSIS

.

Initial clinical manifestations appeared at

    age 11 years
    AGE

 as

    visual seizures
    SYMPTOMS

.

Subsequent

    progressive myoclonus
    SYMPTOMS

 and

    generalized seizures
    SYMPTOMS

 were consistent with an

    adolescent-onset form of progressive myoclonus epilepsy
    DIAGNOSIS

. However, a specific diagnosis was established only at

    age 16
    AGE

, because of the

    absence of hematologic abnormalities
    NEG_FINDINGS

 and a

    fairly moderate hepatomegaly
    SYMPTOMS

.

    Bone marrow aspirate
    PARACLINICAL

 was

    slightly positive for Gaucher cells
    MICROSCOPIC

. Demonstration of

    reduced glucocerebrosidase in the fibroblasts
    MICROSCOPIC

 confirmed the diagnosis. The

    child
    AGE

    died
    SYMPTOMS

 at

    age 19 years
    AGE

.

    Postmortem sequencing of the glucocerebrosidase gene from cultured fibroblasts
    PARACLINICAL

 demonstrated a rare compound heterozygote for N188S/S107L.

This unusual presentation of

    Gaucher disease
    DIAGNOSIS

 indicates that if

    clinical and neurophysiological findings
    SYMPTOMS

 in

    adolescents
    AGE

 with

    initial visual seizures
    SYMPTOMS

 and

    myoclonus
    SYMPTOMS

 suggest a

    progressive disorder
    DIAGNOSIS

,

    enzymatic assay
    PARACLINICAL

 is mandatory, even in the

    absence of the classic neurologic and systemic signs of the disease
    NEG_FINDINGS

. Early differential diagnosis from other forms of

    progressive myoclonus epilepsy
    SYMPTOMS

 with similar clinical presentation may help provide appropriate

    genetic counseling
    MEDICATION

.


Homozygous loss of a cysteine residue in the glucocerebrosidase gene results in Gaucher's disease with a hydropic phenotype.

Acute neuronopathic Gaucher's disease is classically considered to be a disease of late infancy, but also includes a spectrum of variant phenotypes such as perinatal lethal hydrops, or the collodian baby phenotype in the newborn period. These extreme phenotypes are frequently associated with recombinant alleles, nonsense mutations and rare missense mutations. In this report, we present a family with multiple incidence of a hydrops where Gaucher's disease was confirmed. Mutational analysis revealed the homozygosity for the missense mutation C16S, which is located in exon 3 and results in the loss of a cysteine residue. This genotype would be predicted to result in virtually zero enzyme activity.

    Acute neuronopathic Gaucher's disease
    DIAGNOSIS

 is classically considered to be a disease of

    late infancy
    AGE

, but also includes a spectrum of variant phenotypes such as

    perinatal lethal hydrops
    DIAGNOSIS

, or the

    collodian baby phenotype in the newborn period
    SYMPTOMS

. These extreme phenotypes are frequently associated with

    recombinant alleles
    GENETICS

,

    nonsense mutations
    GENETICS

 and

    rare missense mutations
    GENETICS

. In this report, we present a

    family with multiple incidence of a hydrops
    FAMILY

 where

    Gaucher's disease
    DIAGNOSIS

 was confirmed.

    Mutational analysis
    PARACLINICAL

 revealed the

    homozygosity for the missense mutation C16S, which is located in exon 3 and results in the loss of a cysteine residue
    GENETICS

. This genotype would be predicted to result in

    virtually zero enzyme activity
    BIOCHEMICAL

.

Acute neuronopathic Gaucher's disease
perinatal lethal hydrops
Gaucher's disease


Intrauterine onset of acute neuropathic type 2 Gaucher disease: identification of a novel insertion sequence.

A subset of patients with type 2 Gaucher disease is characterized by intrauterine onset of rapidly progressive neuropathic disease, arthrogryposis, hydrops fetalis and in some cases restrictive dermopathy. beta-Glucocerebrosidase (beta-glucosidase) activity is usually low or undetectable. In most cases death ensues either in-utero or within hours or days after birth. We report on an infant born to non-consanguineous parents of Caucasian origin presenting at birth with hydrops, arthrogryposis, severe respiratory distress, hepatosplenomegaly, and liver failure. Death occurred within several hours after delivery and autopsy revealed typical Gaucher cells in multiple organs in combination with severe apoptotic neurodegeneration throughout the brain. beta-Glucocerebrosidase activity was 1% of the norm in fibroblasts and a novel heterozygous insertion c.1515_1516insAGTGAGGGCAAT was identified by genomic sequencing and an insertion-specific seminested PCR. In addition, molecular studies revealed a previously described in type 1 Gaucher disease missense mutation c.476G --> A which results in a heterozygous substitution of R120Q. Our observations confirm considerable genotypic heterogeneity in patients with type 2 Gaucher disease. The transheterozygous combination of a mutation, previously described in type 1 Gaucher disease, together with a newly identified insertion may result in this severe phenotype.

A subset of patients with

    type 2 Gaucher disease
    DIAGNOSIS

 is characterized by

    intrauterine onset of rapidly progressive neuropathic disease
    SYMPTOMS

,

    arthrogryposis
    SYMPTOMS

,

    hydrops fetalis
    DIAGNOSIS

 and in some cases

    restrictive dermopathy
    SYMPTOMS

.

    beta-Glucocerebrosidase (beta-glucosidase) activity is
    BIOCHEMICAL

 usually

    low or undetectable
    BIOCHEMICAL

. In most cases

    death
    SYMPTOMS

 ensues either

    in-utero
    AGE

 or

    within hours or days after birth
    AGE

. We report on an

    infant
    AGE

 born to

    non-consanguineous parents of Caucasian origin
    FAMILY

 presenting at

    birth
    AGE

 with

    hydrops
    SYMPTOMS

,

    arthrogryposis
    SYMPTOMS

,

    severe respiratory distress
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

, and

    liver failure
    SYMPTOMS

.

    Death
    SYMPTOMS

 occurred within several hours after

    delivery
    AGE

 and

    autopsy
    PARACLINICAL

 revealed

    typical Gaucher cells in multiple organs
    MICROSCOPIC

 in combination with

    severe apoptotic neurodegeneration throughout the brain
    MICROSCOPIC

.

    beta-Glucocerebrosidase activity was 1% of the norm in fibroblasts
    BIOCHEMICAL

 and a

    novel heterozygous insertion c.1515_1516insAGTGAGGGCAAT
    GENETICS

 was identified by

    genomic sequencing
    PARACLINICAL

 and an

    insertion-specific seminested PCR
    PARACLINICAL

. In addition,

    molecular studies
    PARACLINICAL

 revealed a previously described in type 1 Gaucher disease missense mutation c.476G --> A which results in a heterozygous substitution of R120Q. Our observations confirm considerable genotypic heterogeneity in patients with

    type 2 Gaucher disease
    DIAGNOSIS

. The

    transheterozygous combination of a mutation, previously described in type 1 Gaucher disease
    GENETICS

    , together with a newly identified insertion
    GENETICS

 may result in this severe phenotype.

type 2 Gaucher disease
hydrops fetalis
type 2 Gaucher disease


Congenital ocular motor apraxia associated with idiopathic generalized epilepsy in monozygotic twins.

Identical female twins (age 11 years) with congenital ocular motor apraxia and generalized idiopathic epilepsy are reported. Their presenting symptoms were a long history of abnormal head and eye movements. One twin developed partial sensory seizures. The patients underwent 16-channel EEG, electro-oculographic recordings, MRI of the brain, and genetic and metabolic investigations. EEG findings were consistent with idiopathic generalized epilepsy. Electrooculographic recordings of the saccades confirmed an inability to elicit horizontal saccades without preceding head movement; saccades to the left were better than saccades to the right. MR scans for one twin showed normal findings, however, for the twin who had meningitis they revealed asymmetry between the right and left temporal lobes but no specific abnormality. DNA analysis using a series of autosomal polymorphic markers confirmed the monozygocity of the twins. White blood cell enzyme analysis excluded Sandhoff disease, Tay-Sachs disease, GM1 gangliosidosis, metacromatic leucodystrophy, Gaucher disease, Niemann-Pick disease (A and B), and Krabbe leucodystrophy. Albumin and immunoglobulin (IgA, IgG, and IgM) levels were normal. It is concluded that autosomal recessive inheritance seems the most likely explanation here, as recent studies have found insertion and missense mutations of the aprataxin gene which have been related to an early onset form of ataxia with ocular motor apraxia and hypoalbuminaemia.

Identical

    female
    GENDER

 twins (

    age 11 years
    AGE

) with

    congenital ocular motor apraxia
    SYMPTOMS

 and

    generalized idiopathic epilepsy
    DIAGNOSIS

 are reported. Their presenting symptoms were a

    long history of abnormal head and eye movements
    SYMPTOMS

. One

    twin developed partial sensory seizures
    FAMILY

. The patients underwent

    16-channel EEG
    PARACLINICAL

,

    electro-oculographic recordings
    PARACLINICAL

,

    MRI of the brain
    PARACLINICAL

, and

    genetic and metabolic investigations
    PARACLINICAL

. EEG findings were consistent with

    idiopathic generalized epilepsy
    DIAGNOSIS

.

    Electrooculographic recordings of the saccades
    PARACLINICAL

 confirmed an

    inability to elicit horizontal saccades without preceding head movement
    NEG_FINDINGS

;

    saccades to the left were better than saccades to the right
    NEG_FINDINGS

.

    MR scans for one twin showed normal findings
    NEG_FINDINGS

, however, for the

    twin who had meningitis
    FAMILY

 they revealed

    asymmetry between the right and left temporal lobes
    SYMPTOMS

 but

    no specific abnormality
    NEG_FINDINGS

.

    DNA analysis using a series of autosomal polymorphic markers
    PARACLINICAL

 confirmed

    the monozygocity of the twins
    FAMILY

.

    White blood cell enzyme analysis
    PARACLINICAL

    excluded Sandhoff disease
    NEG_FINDINGS

,

    Tay-Sachs disease
    DIAGNOSIS

,

    GM1 gangliosidosis
    DIAGNOSIS

,

    metacromatic leucodystrophy
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    Niemann-Pick disease (A and B)
    DIAGNOSIS

, and

    Krabbe leucodystrophy
    DIAGNOSIS

.

    Albumin and immunoglobulin (IgA, IgG, and IgM) levels were normal
    NEG_FINDINGS

. It is concluded that

    autosomal recessive inheritance
    GENETICS

 seems the most likely explanation here, as recent studies have found

    insertion and missense mutations of the aprataxin gene
    GENETICS

 which have been related to an

    early onset form of ataxia
    SYMPTOMS

 with

    ocular motor apraxia
    SYMPTOMS

 and

    hypoalbuminaemia
    BIOCHEMICAL

.

generalized idiopathic epilepsy
idiopathic generalized epilepsy
Tay-Sachs disease
GM1 gangliosidosis
metacromatic leucodystrophy
Gaucher disease
Niemann-Pick disease (A and B)
Krabbe leucodystrophy


[A 32-year old male patient with pathological humeral fracture, splenomegaly and thrombocytopenia].

We describe the case of a 32-year old male patient who presented with a pathological fracture of his right humerus, splenomegaly and thrombocytopenia, the typical symptoms of Gaucher's disease, a lysosomal storage disease. Diagnosis was confirmed by bone marrow biopsy (detection of lipid engorged macrophages - Gaucher cells), by a markedly diminished activity of acid, beta-Glucosidase and by showing two different mutations (764T/A, 1187G/A) in the gene encoding acid beta-Glucosidase. The first mutation causes an amino-acid substitution (phenylalanine to tyrosine). The second mutation causes a premature termination at amino-acid position 396. Enzyme replacement therapy was started with 60 Units/kg body weight, because of severe bone symptoms. Following the decrease in spleen size and increase in platelet count the dose was gradually tapered to 20 U/kg. After two years of enzyme replacement therapy platelet count and spleen volume have normalized and the bone lesions have almost disappeared.

We describe the case of a

    32-year old
    AGE

    male
    GENDER

 patient who presented with a

    pathological fracture of his right humerus
    SYMPTOMS

,

    splenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

, the typical symptoms of

    Gaucher's disease
    DIAGNOSIS

, a

    lysosomal storage disease
    DIAGNOSIS

. Diagnosis was confirmed by

    bone marrow biopsy
    PARACLINICAL

 (

    detection of lipid engorged macrophages - Gaucher cells)
    MICROSCOPIC

, by a

    markedly diminished activity of acid, beta-Glucosidase
    BIOCHEMICAL

 and by showing

    two different mutations (764T/A, 1187G/A) in the gene encoding acid beta-Glucosidase
    GENETICS

. The

    first mutation causes an amino-acid substitution (phenylalanine to tyrosine)
    GENETICS

.

    The second mutation causes a premature termination at amino-acid position 396
    GENETICS

.

    Enzyme replacement therapy
    MEDICATION

 was started

    with 60 Units/kg body weight
    MEDICATION

, because of

    severe bone symptoms
    SYMPTOMS

. Following the

    decrease in spleen size
    SYMPTOMS

 and

    increase in platelet count
    BIOCHEMICAL

 the

    dose was gradually tapered to 20 U/kg
    MEDICATION

. After

    two years of enzyme replacement therapy
    MEDICATION

    platelet count and spleen volume have normalized
    BIOCHEMICAL

 and

    the bone lesions have almost disappeared
    SYMPTOMS

.

Gaucher's disease
lysosomal storage disease

Enzyme replacement therapy
with 60 Units/kg body weight
dose was gradually tapered to 20 U/kg
two years of enzyme replacement therapy


[Skeletal manifestations of Gauchers disease. A report of two cases].

Gauchers disease is the most frequent hereditary lysosomal deposit storage disorder. It is characterized by a deficiency of the enzyme glucocerebrosidase that leads to an accumulation of substrate in the interior of the macrophage lysosomes. It is classified in three types, according to the presence of central nervous system involvement (type 2 and 3) or not (type 1). It is a multisystemic disease and in the majority of patients there is hepatosplenomegaly, anemia and thrombocytopenia. Skeletal involvement is also important and it is frequently the most disabling manifestation. We present two cases of Gauchers with skeletal manifestations and we review the literature.

    Gauchers disease
    DIAGNOSIS

 is the most frequent

    hereditary
    GENETICS

    lysosomal deposit storage disorder
    DIAGNOSIS

. It is characterized by a

    deficiency of the enzyme glucocerebrosidase
    BIOCHEMICAL

 that leads to an

    accumulation of substrate in the interior of the macrophage lysosomes
    MICROSCOPIC

. It is classified in three types, according to the presence of

    central nervous system involvement
    SYMPTOMS

 (

    type 2 and 3)
    DIAGNOSIS

 or not (

    type 1)
    DIAGNOSIS

. It is a

    multisystemic disease
    DIAGNOSIS

 and in the majority of patients there is

    hepatosplenomegaly
    SYMPTOMS

,

    anemia
    BIOCHEMICAL

 and

    thrombocytopenia
    BIOCHEMICAL

.

    Skeletal involvement
    SYMPTOMS

 is also important and it is frequently the most disabling manifestation. We present two cases of

    Gauchers
    DIAGNOSIS

 with

    skeletal manifestations
    SYMPTOMS

 and we review the literature.

Gauchers disease
lysosomal deposit storage disorder
type 2 and 3)
type 1)
multisystemic disease
Gauchers

central nervous system involvement
hepatosplenomegaly
Skeletal involvement
skeletal manifestations


Positive heterophile antibody test and massive splenomegaly in an adolescent with previously unsuspected Gaucher disease.

Mild splenomegaly is common in patients with Epstein-Barr virus-associated infectious mononucleosis. Massive splenomegaly, however, is rare and requires further evaluation to exclude other causes. We report an adolescent girl with previously undiagnosed type 1 Gaucher disease who presented with massive splenomegaly. The diagnosis of her underlying condition was hampered by the presence of a positive heterophile antibody test for infectious mononucleosis.

    Mild splenomegaly
    SYMPTOMS

 is common in patients with

    Epstein-Barr virus-associated infectious mononucleosis
    DIAGNOSIS

.

    Massive splenomegaly
    SYMPTOMS

, however, is rare and requires further evaluation to exclude other causes. We report an

    adolescent
    AGE

    girl
    GENDER

 with previously undiagnosed

    type 1 Gaucher disease
    DIAGNOSIS

 who presented with

    massive splenomegaly
    SYMPTOMS

. The diagnosis of her underlying condition was hampered by the presence of a

    positive heterophile antibody test for infectious mononucleosis
    BIOCHEMICAL

.

Mild splenomegaly
Massive splenomegaly
massive splenomegaly


Twin pairs showing discordance of phenotype in adult Gaucher's disease.

Non-neuronopathic (type 1) Gaucher's disease, a recessive disorder caused by glucocerebrosidase deficiency, shows marked variability in the severity and extent of clinical expression: many individuals who harbour two mutant alleles remain mildly affected or asymptomatic. Despite much effort, it is not possible accurately to predict disease severity from the genotype, or to identify those patients destined to develop severe disease and meriting early treatment.

To determine the degree to which variance in Gaucher disease is determined by non-heritable factors.

Case reports of monozygotic and dizygotic twin pairs.

For the monozygotic twin pair, homozygous for the frequent N370S glucocerebrosidase allele, there was no evidence that significant lipid storage was ever initiated in the unaffected twin. In contrast, pathological storage of glucocerebroside has been present in the macrophages of both members of the dizygotic twin pair (compound heterozygotes for the N370S and L444P alleles) from an early age but, by the age of 57 years, only one has developed symptoms.

Non-heritable factors influence Gaucher disease expression in genetically predisposed individuals. Understanding the interactions between heritable and non-heritable factors will be critical for an analysis of pathogenesis, and the treatment of individuals predisposed to Gaucher disease.

    Non-neuronopathic (type 1) Gaucher's disease
    DIAGNOSIS

, a

    recessive disorder
    GENETICS

 caused by

    glucocerebrosidase deficiency
    BIOCHEMICAL

, shows marked variability in the severity and extent of clinical expression: many individuals who harbour

    two mutant alleles
    GENETICS

 remain

    mildly affected or asymptomatic
    NEG_FINDINGS

. Despite much effort, it is not possible accurately to predict disease severity from the genotype, or to identify those patients destined to develop severe disease and meriting

    early treatment
    MEDICATION

.

To determine the degree to which variance in

    Gaucher disease
    DIAGNOSIS

 is determined by

    non-heritable factors
    GENETICS

.

    Case reports of monozygotic and dizygotic twin pairs
    FAMILY

.

For the

    monozygotic twin pair, homozygous for the frequent N370S glucocerebrosidase allele
    FAMILY

, there was

    no evidence that significant lipid storage was ever initiated in the unaffected twin
    NEG_FINDINGS

. In contrast,

    pathological storage of glucocerebroside has been present in the macrophages of both members of the dizygotic twin pair (compound heterozygotes for the N370S and L444P alleles
    MICROSCOPIC

    )
    FAMILY

    from an early age
    AGE

 but, by the

    age of 57 years
    AGE

, only one has developed symptoms.

    Non-heritable factors
    GENETICS

 influence

    Gaucher
    DIAGNOSIS

 disease expression in genetically predisposed individuals. Understanding the interactions between heritable and

    non-heritable factors
    GENETICS

 will be critical for an analysis of pathogenesis, and the treatment of individuals predisposed to

    Gaucher disease
    DIAGNOSIS

.

recessive disorder
two mutant alleles
non-heritable factors
Non-heritable factors
non-heritable factors


Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family.

We have identified six individuals over three generations within a Lebanese-Arab family affected with Gaucher disease. This family is unusual and informative because affected members are homozygous for a previously unidentified mutation, L371V. Clinical symptoms begin in early childhood and progress to moderately severe involvement by young adulthood. There is significant anemia, thrombocytopenia, and bony involvement, but no mental deterioration. The phenotype is more severe than the phenotype observed in the common mutation associated with type 1 Gaucher disease, N370S. It is unknown whether L371V is a private mutation limited to this family, or will prove to be a common mutation within the Lebanese population.

We have identified six individuals over three generations within a

    Lebanese-Arab
    ETHNICITY

    family affected with Gaucher disease
    FAMILY

. This family is unusual and informative because affected members are homozygous for a previously unidentified mutation, L371V.

    Clinical symptoms
    SYMPTOMS

 begin

    in early childhood
    AGE

 and progress to

    moderately severe involvement
    SYMPTOMS

 by

    young adulthood
    AGE

. There is

    significant anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

, and

    bony involvement
    SYMPTOMS

, but

    no mental deterioration
    NEG_FINDINGS

. The phenotype is more severe than the phenotype observed in the common mutation associated with

    type 1 Gaucher disease
    DIAGNOSIS

, N370S. It is unknown whether

    L371V
    GENETICS

 is a

    private mutation
    GENETICS

 limited to this family, or will prove to be a common mutation within the

    Lebanese
    ETHNICITY

 population.

Clinical symptoms
moderately severe involvement
bony involvement


A model of neuronopathic Gaucher disease.

Gaucher disease (GD) is a lysosomal disorder involving the accumulation of glucocerebroside in the liver, spleen, bones and brain. Some patients exhibit only systemic disease (type I), but others have additional neurological signs which may lead to rapid neurodegeneration in infancy (type II) or take a more intermediate course (type III). Types II and III are collectively known as neuronopathic Gaucher disease (NGD). Systemic disease can now be treated by enzyme replacement therapy (ERT), but its efficacy in NGD is limited. Two infants who presented with bulbar palsy and failure to thrive were enzymatically diagnosed at 8 months with NGD. They were started on high-dose ERT (120 IU/kg every 2 weeks). Both underwent serial oculomotor assessment and an audiological battery, including visual reinforcement audiometry, otoacoustic emissions, and the auditory brain stem response (ABR). Biochemical markers showed an incomplete systemic response to ERT, but neurological deterioration was relentless, leading to death at 16 and 25 months. Oculomotor testing revealed a complete absence of saccadic eye movements and progressive bilateral sixth nerve palsy in one. Audiological assessment revealed progressive deterioration of ABRs, but with normal peripheral hearing and otoacoustic emissions. Both infants showed neurological deterioration in spite of high-dose ERT. The audiological findings suggested a loss of inner hair cell pathway function with preserved outer hair function, similar to what is seen in auditory neuropathy. The unusual pattern of audiological and oculomotor abnormalities is consistent with an excitotoxic mechanism predisposing nerve cells to glucocerebroside toxicity. Such excitotoxic damage may be amenable to direct therapeutic intervention.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal disorder
    DIAGNOSIS

 involving the

    accumulation of glucocerebroside in the liver, spleen, bones and brain
    MICROSCOPIC

. Some patients exhibit only

    systemic disease
    DIAGNOSIS

 (

    type I)
    DIAGNOSIS

, but others have

    additional neurological signs
    SYMPTOMS

 which may lead to

    rapid neurodegeneration
    SYMPTOMS

 in

    infancy
    AGE

 (

    type II)
    DIAGNOSIS

 or take a more intermediate course (

    type III)
    DIAGNOSIS

.

    Types II and III
    DIAGNOSIS

 are collectively known as

    neuronopathic Gaucher disease (NGD)
    DIAGNOSIS

.

    Systemic disease
    DIAGNOSIS

 can now be treated by

    enzyme replacement therapy (ERT)
    MEDICATION

, but its efficacy in

    NGD
    DIAGNOSIS

 is limited. Two

    infants
    AGE

 who presented with

    bulbar palsy
    SYMPTOMS

 and

    failure to thrive
    SYMPTOMS

 were enzymatically diagnosed

    at 8 months
    AGE

 with

    NGD
    DIAGNOSIS

. They were started on

    high-dose ERT (120 IU/kg every 2 weeks)
    MEDICATION

. Both underwent

    serial oculomotor assessment
    PARACLINICAL

 and an

    audiological battery
    PARACLINICAL

, including

    visual reinforcement audiometry, otoacoustic emissions, and the auditory brain stem response (ABR)
    PARACLINICAL

.

    Biochemical markers
    PARACLINICAL

 showed an

    incomplete systemic response to ERT
    BIOCHEMICAL

, but

    neurological deterioration was relentless
    SYMPTOMS

, leading to

    death
    SYMPTOMS

    at 16 and 25 months
    AGE

.

    Oculomotor testing
    PARACLINICAL

 revealed a

    complete absence of saccadic eye movements
    SYMPTOMS

 and

    progressive bilateral sixth nerve palsy
    SYMPTOMS

 in one.

    Audiological assessment
    PARACLINICAL

 revealed

    progressive deterioration of ABRs
    SYMPTOMS

, but

    with normal peripheral hearing and otoacoustic emissions
    NEG_FINDINGS

. Both

    infants
    AGE

 showed

    neurological deterioration
    SYMPTOMS

    in spite of high-dose ERT
    NEG_FINDINGS

. The

    audiological
    PARACLINICAL

 findings suggested a

    loss of inner hair cell pathway function
    SYMPTOMS

 with

    preserved outer hair function
    NEG_FINDINGS

, similar to what is seen in

    auditory neuropathy
    DIAGNOSIS

. The

    unusual pattern of audiological and oculomotor abnormalities
    SYMPTOMS

 is consistent with an

    excitotoxic mechanism predisposing nerve cells to glucocerebroside toxicity
    SYMPTOMS

. Such

    excitotoxic damage
    SYMPTOMS

 may be amenable to

    direct therapeutic intervention
    MEDICATION

.

Gaucher disease (GD)
lysosomal disorder
systemic disease
type I)
type II)
type III)
Types II and III
neuronopathic Gaucher disease (NGD)
Systemic disease
NGD
NGD
auditory neuropathy

enzyme replacement therapy (ERT)
high-dose ERT (120 IU/kg every 2 weeks)
direct therapeutic intervention


Cauda equina syndrome due to an intra-dural sacral cyst in type-1 Gaucher disease.

The authors report a rare case of type-1 Gaucher disease with neurological and haematological involvement. The first onset was epilepsy, the diagnosis of GD1 was then confirmed and the patient experienced parkinsonism. The biological analysis revealed monoclonal gammapathy and factor-II mutation. The patient's condition worsened due to cauda equina syndrome. Magnetic resonance imaging and surgery revealed an intra-thecal sacral cyst which, to our knowledge, has not been reported previously; therefore, when confronted with the fractures commonly observed in GD1, other unusual causes of spinal cord and root compression should not be overlooked.

The authors report a rare case of

    type-1 Gaucher disease
    DIAGNOSIS

 with

    neurological and haematological involvement
    SYMPTOMS

. The first onset was

    epilepsy
    SYMPTOMS

, the diagnosis of

    GD1
    DIAGNOSIS

 was then confirmed and the patient experienced

    parkinsonism
    DIAGNOSIS

. The

    biological analysis
    PARACLINICAL

 revealed

    monoclonal gammapathy
    BIOCHEMICAL

 and

    factor-II mutation
    GENETICS

. The patient's condition worsened due to

    cauda equina syndrome
    DIAGNOSIS

.

    Magnetic resonance imaging and surgery
    PARACLINICAL

 revealed an

    intra-thecal sacral cyst
    SYMPTOMS

 which, to our knowledge, has not been reported previously; therefore, when confronted with the fractures commonly observed in

    GD1
    DIAGNOSIS

, other

    unusual causes of spinal cord and root compression
    SYMPTOMS

 should not be overlooked.


Gaucher disease and brucella: just a mere coincidence?

Gaucher disease type I and brucellosis are chronic diseases with similar symptoms and physical signs though the former is the most common lysosomal storage disease and the latter is an infectious disease. The similarities between these diseases make differential diagnosis difficult. Immunodeficiency is a feature of Gaucher disease type I and increases the susceptibility towards infections. A Gaucher disease type I patient with brucellosis is presented with improvement after treatment of brucellosis.

    Gaucher disease type I
    DIAGNOSIS

 and

    brucellosis
    DIAGNOSIS

 are

    chronic diseases
    DIAGNOSIS

 with

    similar symptoms and physical signs
    SYMPTOMS

 though the former is the most common

    lysosomal storage disease
    DIAGNOSIS

 and the latter is an

    infectious disease
    DIAGNOSIS

. The similarities between these diseases make

    differential diagnosis
    PARACLINICAL

 difficult.

    Immunodeficiency
    SYMPTOMS

 is a feature of

    Gaucher disease type I
    DIAGNOSIS

 and increases the susceptibility towards

    infections
    SYMPTOMS

. A

    Gaucher disease type I
    DIAGNOSIS

 patient with

    brucellosis
    DIAGNOSIS

 is presented with improvement after

    treatment of brucellosis
    MEDICATION

.

Gaucher disease type I
brucellosis
chronic diseases
lysosomal storage disease
infectious disease
Gaucher disease type I
Gaucher disease type I
brucellosis

similar symptoms and physical signs
Immunodeficiency
infections


Amyloidosis and gastric bleeding in a patient with Gaucher disease.

To describe the clinical course of a patient with Gaucher disease who subsequently developed amyloidosis.

We present a case of a splenectomized patient with Gaucher disease who developed portal hypertension secondary to an enlarged, cirrhotic-like liver, and recurrent life-threatening upper gastrointestinal bleeding.

Despite repeated diagnostic biopsies, amyloidosis was only ascertained after death.

Albeit very rare, there are four other similar cases in the literature, but unlike these previous reports of concurrence of Gaucher disease and amyloidosis, in this patient the gastrointestinal symptoms were life-threatening but there was no evidence of gammopathy or renal disease. Also, this is the first patient who was treated with enzyme replacement therapy for 5 years prior to manifestation of amyloidosis.

Coexistence of apparently unrelated diseases with Gaucher disease demands a greater awareness of abnormalities at the biochemical and/or molecular level to adequately manage patients with Gaucher disease, regardless of concurrent enzyme replacement therapy.

To describe the clinical course of a patient with

    Gaucher disease
    DIAGNOSIS

 who subsequently developed

    amyloidosis
    DIAGNOSIS

.

We present a case of a

    splenectomized
    MEDICATION

 patient with

    Gaucher disease
    DIAGNOSIS

 who developed

    portal hypertension
    SYMPTOMS

 secondary to an

    enlarged, cirrhotic-like liver
    SYMPTOMS

, and

    recurrent life-threatening upper gastrointestinal bleeding
    SYMPTOMS

.

    Despite repeated diagnostic biopsies
    NEG_FINDINGS

,

    amyloidosis
    DIAGNOSIS

 was only ascertained after

    death
    SYMPTOMS

.

Albeit very rare, there are four other similar cases in the literature, but unlike these previous reports of

    concurrence of Gaucher disease and amyloidosis
    DIAGNOSIS

, in this patient the

    gastrointestinal symptoms were life-threatening
    SYMPTOMS

 but there was

    no evidence of gammopathy or renal disease
    NEG_FINDINGS

. Also, this is the first patient who was

    treated with enzyme replacement therapy for 5 years
    MEDICATION

 prior to manifestation of

    amyloidosis
    DIAGNOSIS

.

    Coexistence of apparently unrelated diseases with Gaucher disease
    DIAGNOSIS

 demands a greater awareness of abnormalities at the biochemical and/or molecular level to adequately manage patients with

    Gaucher disease
    DIAGNOSIS

,

    regardless of concurrent enzyme replacement therapy
    NEG_FINDINGS

.


[Type I Gaucher's disease--a rare genetic metabolic disease].

Morbus Gaucher is a rare disease. It occurs once in 40,000 to 65,000 persons in the whole world. This is the most frequent lysosome disease in the clinics. This is the first lysosome disease used in perinatal diagnostics and the first one where enzyme therapy was implemented. Case of gaucher disease morbus type I was found in girl of age 14 in Cantonal hospital "Dr. Irfan Ljubijankić" in Bihać. The clinical investigations were carried out at the same hospital, and samples necessary for the further detailed biochemical analysis were taken together with all other relevant data for this disease. In this case, taking into account rules of distribution of certain genes responsible for transfer of characteristics and processes, and following genealogical series, it could be concluded that parents of our patient are heterozygotes (healthy) and carriers of Gaucher gene, and that 1/4 of their children are dominant homozygotes (healthy), 2/4 are heterozygotes (healthy) and carriers of Gaucher gene, and 1/4 of children, together with the patient, are recessive homozygotes, and carriers of Gaucher gene with expression of the type I of this disease. For therapy of Gaucher disease there are in the market two enzyme. Aglucerosis obtained from human placenta and imiglucerasis obtained from cells of ovarian of hamster. The second preparation is cheaper and it is in wide use. There are no differences in the activity, as well as in creation of antibodies--the enzyme entered in use for the first time in 1989, and since 1991 is in wide use. In Bosnia and Herzegovina, therapy is not possible due to the financial restrictions.

    Morbus Gaucher
    DIAGNOSIS

 is a

    rare disease
    DIAGNOSIS

. It occurs once in 40,000 to 65,000 persons in the whole world. This is the most frequent

    lysosome disease
    DIAGNOSIS

 in the clinics. This is the first

    lysosome disease
    DIAGNOSIS

 used in

    perinatal diagnostics
    PARACLINICAL

 and the first one where

    enzyme therapy
    MEDICATION

 was implemented. Case of

    gaucher disease morbus type I
    DIAGNOSIS

 was found in

    girl
    GENDER

    of age 14
    AGE

 in Cantonal hospital "Dr. Irfan Ljubijankić" in Bihać. The

    clinical investigations
    PARACLINICAL

 were carried out at the same hospital, and samples necessary for the further detailed

    biochemical analysis
    PARACLINICAL

 were taken together with all other relevant data for this disease. In this case, taking into account rules of

    distribution of certain genes responsible for transfer of characteristics and processes
    GENETICS

, and following genealogical series, it could be concluded that

    parents of
    FAMILY

 our patient

    are heterozygotes (healthy) and carriers of Gaucher gene
    FAMILY

, and that 1/4

    of their children are dominant homozygotes (healthy)
    FAMILY

, 2/4 are

    heterozygotes (healthy) and carriers of Gaucher gene
    GENETICS

, and 1/4 of children, together with the patient, are

    recessive homozygotes
    GENETICS

, and

    carriers of Gaucher gene
    GENETICS

 with expression of the

    type I of this disease
    DIAGNOSIS

. For therapy of

    Gaucher disease
    DIAGNOSIS

 there are in the market two

    enzyme. Aglucerosis obtained from human placenta
    MEDICATION

 and

    imiglucerasis obtained from cells of ovarian of hamster
    MICROSCOPIC

. The second preparation is cheaper and it is in wide use. There are no differences in the activity, as well as in creation

    of antibodies
    NEG_FINDINGS

--the enzyme entered in use for the first time in 1989, and since 1991 is in wide use. In

    Bosnia and Herzegovina
    ETHNICITY

,

    therapy is not
    NEG_FINDINGS

 possible due to the financial restrictions.

Morbus Gaucher
rare disease
lysosome disease
lysosome disease
gaucher disease morbus type I
type I of this disease
Gaucher disease


Gaucher's disease with Parkinson's disease: clinical and pathological aspects.

The association between type 1 Gaucher disease and PD has been reported in the literature. The clinical picture is characterized by the predominance of bilateral akinetic-rigid signs and poor response to levodopa therapy. The authors describe four patients (two siblings) with type 1 Gaucher disease presenting with the following signs of typical PD: asymmetric onset of rigidity, resting tremor, bradykinesia, and a favorable response to Parkinson therapies.

The

    association between type 1 Gaucher disease
    DIAGNOSIS

 and

    PD
    DIAGNOSIS

 has been reported in the literature. The clinical picture is characterized by the

    predominance of bilateral akinetic-rigid signs
    SYMPTOMS

 and

    poor response to levodopa therapy
    NEG_FINDINGS

. The authors describe four patients (two siblings) with

    type 1 Gaucher disease
    DIAGNOSIS

 presenting with the following

    signs of typical PD
    SYMPTOMS

:

    asymmetric onset of rigidity
    SYMPTOMS

,

    resting tremor
    SYMPTOMS

,

    bradykinesia
    SYMPTOMS

, and a

    favorable response to Parkinson therapies
    NEG_FINDINGS

.


Marked clinical and histologic improvement in a patient with type-1 Gaucher's disease following long-term glucocerebroside substitution. A case report and review of current diagnosis and management.

Type-1 Gaucher's disease represents the most common lysosomal storage disorder. With the introduction of enzyme replacement therapy, many of the clinical manifestations can be controlled. The functional deficiency of the lysosomal beta-glucocerebrosidase leads to deposition of glycosylceramide in the liver, spleen, and bone marrow. We report the clinical and pathologic presentation of a patient with a florid type-1 Gaucher's disease who received long-term enzyme replacement therapy, which led to marked clinical improvement. A repeat liver biopsy performed at the time of a cholecystectomy several years after initiation of enzyme replacement therapy revealed complete resolution of Gaucher cells.

    Type-1 Gaucher's disease
    DIAGNOSIS

 represents the most common

    lysosomal storage disorder
    DIAGNOSIS

. With the introduction of

    enzyme replacement therapy
    MEDICATION

, many of the clinical manifestations can be controlled. The

    functional deficiency of the lysosomal beta-glucocerebrosidase
    BIOCHEMICAL

 leads to

    deposition of glycosylceramide in the liver, spleen, and bone marrow
    MICROSCOPIC

. We report the clinical and pathologic presentation of a patient with a

    florid type-1 Gaucher's disease
    DIAGNOSIS

 who received

    long-term enzyme replacement therapy
    MEDICATION

, which led to

    marked clinical improvement
    SYMPTOMS

. A

    repeat liver biopsy
    PARACLINICAL

 performed at the time of a

    cholecystectomy
    MEDICATION

 several years after

    initiation of enzyme replacement therapy
    MEDICATION

 revealed

    complete resolution of Gaucher cells
    MICROSCOPIC

.

Type-1 Gaucher's disease
lysosomal storage disorder
florid type-1 Gaucher's disease


Type I Gaucher's disease with homozygous R463C mutation without neurological involvement.

Gaucher's disease is an inherited glycolipid storage disorder, caused by a deficiency of the catabolic enzyme glucocerebrosidase. Frequently, N370S and L444P of mutations are observed. R463C (i.e., 1504C-->T) mutation may predict neurological involvement in Gaucher's disease. We report a 36-year-old Turkish man with type I Gaucher's disease with homozygous R463C mutation without neurological involvement.

    Gaucher's disease
    DIAGNOSIS

 is an

    inherited glycolipid storage disorder
    GENETICS

, caused by a

    deficiency of the catabolic enzyme glucocerebrosidase
    BIOCHEMICAL

. Frequently,

    N370S and L444P of mutations
    GENETICS

 are observed.

    R463C (i.e., 1504C-->T) mutation
    GENETICS

 may predict

    neurological involvement
    SYMPTOMS

 in

    Gaucher's disease
    DIAGNOSIS

. We report a

    36-year-old
    AGE

    Turkish
    ETHNICITY

    man
    GENDER

 with

    type I Gaucher's disease
    DIAGNOSIS

 with

    homozygous R463C mutation
    GENETICS

    without neurological involvement
    NEG_FINDINGS

.

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

inherited glycolipid storage disorder
N370S and L444P of mutations
R463C (i.e., 1504C-->T) mutation
homozygous R463C mutation


Gaucher's disease: identification of novel mutant alleles and genotype-phenotype relationships.

A sequencing protocol for the acid beta-glucosidase (GCase) gene (GBA) was developed using a long-range PCR template. This protocol has an advantage of greater DNA yields over similar strategies. Seven Gaucher's disease patients had four novel and five other rare alleles. A non-pseudogene in-frame deletion (g.2600-2602delTAC) and a new complex mutation (null allele) were identified in Gaucher's disease type 1, i.e. the g.2600-2602delTAC deletion is associated with the non-neuronopathic variant. An F251L allele was found in a baby with the collodion skin phenotype. Three mutant alleles were identified in a single primary family with type 3. The patients' father at 45 years is healthy and is heteroallelic for the G202R and E326K alleles. Family studies indicated that E326K is in trans to G202R and L444P, and that isolated E326K is non-pathogenic in this family. A rare mutation R257Q was identified in a type 2 patient, providing an association with neuronopathic disease. A genotype L444P/L444P was noted in a 22-year-old non-neuronopathic patient. Complete gene sequencing showed a new complex allele consisting of L444P and g.7741T > C in the 3' UTR. Three additional complex alleles also involved the 3' UTR. Complete gene characterization in Gaucher's disease should allow greater insights into the correlation of specific alleles with phenotype.

A

    sequencing protocol for the acid beta-glucosidase (GCase) gene (GBA)
    PARACLINICAL

 was developed using a

    long-range PCR template
    PARACLINICAL

. This protocol has an advantage of greater DNA yields over similar strategies. Seven

    Gaucher's disease
    DIAGNOSIS

 patients had

    four novel and five other rare alleles
    GENETICS

. A

    non-pseudogene in-frame deletion (g.2600-2602delTAC)
    GENETICS

 and a

    new complex mutation (null allele)
    GENETICS

 were identified in

    Gaucher's disease type 1
    DIAGNOSIS

, i.e. the

    g.2600-2602delTAC deletion is associated with the non-neuronopathic variant
    GENETICS

. An

    F251L allele
    GENETICS

 was found in a

    baby
    AGE

 with the

    collodion skin phenotype
    SYMPTOMS

.

    Three mutant alleles
    GENETICS

 were identified in a

    single primary family with type 3
    FAMILY

. The patients'

    father at 45 years is healthy and is heteroallelic for the G202R and E326K alleles
    FAMILY

.

    Family studies
    PARACLINICAL

 indicated that

    E326K is in trans to G202R and L444P
    GENETICS

, and that

    isolated E326K is non-pathogenic
    GENETICS

    in this family
    FAMILY

. A

    rare mutation R257Q
    GENETICS

 was identified in a

    type 2
    DIAGNOSIS

 patient, providing an association with

    neuronopathic disease
    DIAGNOSIS

. A

    genotype L444P/L444P
    GENETICS

 was noted in a

    22-year-old
    AGE

    non-neuronopathic
    NEG_FINDINGS

 patient.

    Complete gene sequencing
    PARACLINICAL

 showed a

    new complex allele consisting of L444P and g.7741T > C in the 3' UTR
    GENETICS

.

    Three additional complex alleles also involved the 3' UTR
    GENETICS

.

    Complete gene characterization
    PARACLINICAL

 in

    Gaucher's disease
    DIAGNOSIS

 should allow greater insights into the correlation of specific alleles with phenotype.

Gaucher's disease
Gaucher's disease type 1
type 2
neuronopathic disease
Gaucher's disease


Adult-onset neuronopathic form of Gaucher's disease: a case report.

We report a patient with Gaucher's disease (GD) developing prominent neurological abnormalities in adult life confirming the existence of an adult neuronopathic form of GD. In this adult-onset form, an akinetic-rigid syndrome poorly responsive to dopatherapy, supranuclear gaze palsy, myoclonic jerks, seizures, cerebellar ataxia, cognitive and psychotic disturbances are frequent manifestations. The widely used clinical classification seems inadequate since it does not consider this rare form of GD. Until further understanding of the pathogenesis of the disease is achieved it is not possible to predict accurately which patients will or will not have late-onset nervous system involvement.

We report a patient with

    Gaucher's disease (GD)
    DIAGNOSIS

 developing

    prominent neurological abnormalities
    SYMPTOMS

 in

    adult life
    AGE

 confirming the existence of an

    adult neuronopathic form of GD
    DIAGNOSIS

. In this

    adult-onset
    AGE

 form, an

    akinetic-rigid syndrome
    SYMPTOMS

    poorly responsive to dopatherapy
    NEG_FINDINGS

,

    supranuclear gaze palsy
    SYMPTOMS

,

    myoclonic jerks
    SYMPTOMS

,

    seizures
    SYMPTOMS

,

    cerebellar ataxia
    SYMPTOMS

,

    cognitive and psychotic disturbances
    SYMPTOMS

 are frequent manifestations. The widely used clinical classification seems inadequate since it does not consider this rare form of

    GD
    DIAGNOSIS

. Until further understanding of the pathogenesis of the disease is achieved it is not possible to predict accurately which patients will or will not have

    late-onset nervous system involvement
    SYMPTOMS

.

Gaucher's disease (GD)
adult neuronopathic form of GD
GD

prominent neurological abnormalities
akinetic-rigid syndrome
supranuclear gaze palsy
myoclonic jerks
seizures
cerebellar ataxia
cognitive and psychotic disturbances
late-onset nervous system involvement