Mandibular and dental manifestations of Gaucher disease.

Gaucher disease is a systemic lysosomal storage disorder with a high prevalence among Ashkenazi Jews. It is caused by an inherited deficiency of the lysosomal enzyme glucocerebrosidase. Common signs and symptoms include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal involvement. Oral and dental manifestations are less commonly seen. These manifestations are often asymptomatic, although they may be detected by routine dental x-rays. There are several case reports and a few larger series published describing patients with Gaucher disease who have mandibulo-maxillofacial involvement. This review aims to examine the oral manifestations observed in Gaucher disease and to suggest practical guidelines for dealing with these often worrisome signs. Among the critical issues are the benign nature of Gaucher cell infiltration of the mandible and the critical importance of being prepared for postprocedure bleeding and/or infections. Therefore, it is essential that dental practitioners be aware of the possible oral and dental complications of Gaucher disease, as well as the available treatment modalities.

    Gaucher disease
    DIAGNOSIS

 is a

    systemic lysosomal storage disorder
    DIAGNOSIS

 with a high prevalence among

    Ashkenazi Jews
    ETHNICITY

. It is caused by an

    inherited deficiency of the lysosomal enzyme glucocerebrosidase
    GENETICS

. Common signs and symptoms include

    hepatosplenomegaly
    SYMPTOMS

,

    anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

, and

    skeletal involvement
    SYMPTOMS

.

    Oral and dental manifestations
    SYMPTOMS

 are less commonly seen. These manifestations are often

    asymptomatic
    NEG_FINDINGS

, although they may be detected by routine

    dental x-rays
    PARACLINICAL

. There are several case reports and a few larger series published describing patients with

    Gaucher disease
    DIAGNOSIS

 who have

    mandibulo-maxillofacial involvement
    SYMPTOMS

. This review aims to examine the

    oral manifestations
    SYMPTOMS

 observed in

    Gaucher disease
    DIAGNOSIS

 and to suggest practical guidelines for dealing with these often worrisome signs. Among the critical issues are the

    benign nature of Gaucher cell infiltration of the mandible
    NEG_FINDINGS

 and the critical importance of being prepared for

    postprocedure bleeding
    SYMPTOMS

 and/or

    infections
    SYMPTOMS

. Therefore, it is essential that dental practitioners be aware of the possible

    oral and dental complications
    SYMPTOMS

 of

    Gaucher disease
    DIAGNOSIS

, as well as the available treatment modalities.

Gaucher disease
systemic lysosomal storage disorder
Gaucher disease
Gaucher disease
Gaucher disease

hepatosplenomegaly
skeletal involvement
Oral and dental manifestations
mandibulo-maxillofacial involvement
oral manifestations
postprocedure bleeding
infections
oral and dental complications


[Clinical outcomes of 2 pediatric patients with Gaucher's disease in enzyme replacement therapy for 9 years].

We report two cases of type 1 Gaucher's disease in childhood and their outcomes after 9 years of enzyme replacement therapy. The first case concerns a 6-year-old boy who was diagnosed with Gaucher's disease after developing petechial exanthema, thrombocytopenia, anemia and hepatosplenomegaly, coinciding with chickenpox. The second case involves a 9-year-old girl who was referred to our unit. She had hepatosplenomegaly since 4-month-old and subsequently developed thrombocytopenia. Both patients have the N370S/L444P mutation. Enzyme replacement therapy was started with 60 U/kg imiglucerase every 2 weeks at the age of 6 and 9 years, respectively. In both patients, the therapeutic goals were achieved and maintained throughout treatment with a dose of 30 U/kg.

We report two cases of

    type 1 Gaucher's disease
    DIAGNOSIS

 in

    childhood
    AGE

 and their outcomes after

    9 years of enzyme replacement therapy
    MEDICATION

. The first case concerns a

    6-year-old
    AGE

    boy
    GENDER

 who was diagnosed with

    Gaucher's disease
    DIAGNOSIS

 after developing

    petechial exanthema
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

 and

    hepatosplenomegaly
    SYMPTOMS

, coinciding with

    chickenpox
    DIAGNOSIS

. The second case involves a

    9-year-old
    AGE

    girl
    GENDER

 who was referred to our unit.

    She
    GENDER

 had

    hepatosplenomegaly
    SYMPTOMS

    since 4-month-old
    AGE

 and subsequently developed

    thrombocytopenia
    BIOCHEMICAL

. Both patients have the

    N370S/L444P mutation
    GENETICS

.

    Enzyme replacement therapy was started with 60 U/kg imiglucerase every 2 weeks
    MEDICATION

 at the

    age of 6 and 9 years
    AGE

, respectively. In both patients, the therapeutic goals were achieved and maintained throughout treatment with a dose of 30 U/kg.

type 1 Gaucher's disease
Gaucher's disease
chickenpox

petechial exanthema
hepatosplenomegaly
hepatosplenomegaly


[Safety of use of velaglucerase in 2 patients with type 1 Gaucher's disease].

The incidence of immunologic reactions in patients with Gaucher's disease (GD) on enzymatic replacement therapy with imiglucerase is about 17% and related with the presence of non-neutralizing immunoglobulin G antibodies. The clinical trials with a new enzyme obtained in human cells (GA-GCB-velaglucerase) have demonstrated absence of immune reactions and no antibodies against the enzyme in spite of some patients had previous developed antibodies against imiglucerase. We present 2 clinical cases of patients diagnosed with EG in childhood and who developed antibodies and important imiglucerase immunoallergic adverse reaction during the imiglucerase perfusion, indicating systematic administration of steroids and antihistamines prior to each perfusion and perfusion time > 4h.

The incidence of

    immunologic reactions
    SYMPTOMS

 in patients with

    Gaucher's disease (GD)
    DIAGNOSIS

 on

    enzymatic replacement therapy with imiglucerase
    MEDICATION

 is about 17% and related with the

    presence of non-neutralizing immunoglobulin G antibodies
    BIOCHEMICAL

. The clinical trials with a

    new enzyme obtained in human cells (GA-GCB-velaglucerase)
    MEDICATION

 have demonstrated

    absence of immune reactions
    NEG_FINDINGS

 and

    no antibodies against the enzyme
    NEG_FINDINGS

 in spite of some patients had

    previous developed antibodies against imiglucerase
    NEG_FINDINGS

. We present 2 clinical cases of patients diagnosed with

    EG
    DIAGNOSIS

 in

    childhood
    AGE

 and who developed

    antibodies and important imiglucerase immunoallergic adverse reaction
    SYMPTOMS

 during the

    imiglucerase perfusion
    MEDICATION

, indicating

    systematic administration of steroids and antihistamines prior to each perfusion
    MEDICATION

 and

    perfusion time > 4h
    MEDICATION

.


Adult Gaucher disease in southern Tunisia: report of three cases.

Gaucher disease (GD) is the most frequent lysosomal storage disorder; type 1 is by far the most common form. It is characterized by variability in age of onset, clinical signs and progression. It is usually diagnosed in the first or second decade of life with the appearance of bone pains, splenomegaly and thrombocytopenia, but the disease may be diagnosed at any age between 1 and 73 years. In the present study, we report 3 cases with late onset of GD in whom the disease was a surprise finding including one patient with Parkinson disease. This late onset is described as an adult form of Gaucher disease.

Molecular investigation showed mutational homogeneity in Tunisian adult patients suffering from GD. Indeed, all patients carry the p.N370S mutation: two patients at a homozygous state and one patient at compound heterozygous state.

The p.N370S mutation presents a large variability in the onset of the disease and its clinical manifestation supporting the view that GD should be considered as a continuum phenotype rather than a predefined classification.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most frequent

    lysosomal storage disorder
    DIAGNOSIS

;

    type 1
    DIAGNOSIS

 is by far the most common form. It is characterized by variability in age of onset, clinical signs and progression. It is usually diagnosed

    in the first or second decade of life
    AGE

 with the appearance of

    bone pains
    SYMPTOMS

,

    splenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

, but the disease may be diagnosed at

    any age between 1 and 73 years
    AGE

. In the present study, we report 3 cases with

    late onset of GD
    DIAGNOSIS

 in whom the disease was a surprise finding including one patient with

    Parkinson disease
    DIAGNOSIS

. This

    late onset
    DIAGNOSIS

 is described as an

    adult
    AGE

 form of

    Gaucher disease
    DIAGNOSIS

.

    Molecular investigation
    PARACLINICAL

 showed

    mutational homogeneity
    GENETICS

 in

    Tunisian
    ETHNICITY

    adult
    AGE

 patients suffering from

    GD
    DIAGNOSIS

. Indeed, all patients carry the

    p.N370S mutation
    GENETICS

: two patients at

    a homozygous state
    GENETICS

 and one patient at

    compound heterozygous state
    GENETICS

.

The

    p.N370S mutation
    GENETICS

 presents a large variability in the onset of the disease and its clinical manifestation supporting the view that

    GD
    DIAGNOSIS

 should be considered as a continuum phenotype rather than a predefined classification.

Gaucher disease (GD)
lysosomal storage disorder
type 1
late onset of GD
Parkinson disease
late onset
Gaucher disease
GD
GD

mutational homogeneity
p.N370S mutation
a homozygous state
compound heterozygous state
p.N370S mutation


Progressive mesenteric lymphadenopathy with protein-losing enteropathy; a devastating complication in Gaucher disease.

Mesenteric lymphadenopathy has been rarely reported in pediatric patients with Gaucher disease, developing despite the enzyme replacement therapy. The clinical implication of this condition is undetermined, with no consensus on treatment strategies. However, this condition can reflect the progression of Gaucher disease. Moreover, it can be accompanied by the serious complication, protein-losing enteropathy. Our experience underlines the importance of careful monitoring and early intervention for mesenteric lymphadenopathy, especially in pediatric patients with neuronopathic Gaucher disease.

    Mesenteric lymphadenopathy
    SYMPTOMS

 has been rarely reported in

    pediatric
    AGE

 patients with

    Gaucher disease
    DIAGNOSIS

, developing

    despite the enzyme replacement therapy
    NEG_FINDINGS

. The clinical implication of this condition is undetermined, with no consensus on treatment strategies. However, this condition can reflect the progression of

    Gaucher disease
    DIAGNOSIS

. Moreover, it can be accompanied by the serious complication,

    protein-losing enteropathy
    BIOCHEMICAL

. Our experience underlines the importance of careful monitoring and

    early intervention
    MEDICATION

 for

    mesenteric lymphadenopathy
    SYMPTOMS

, especially in

    pediatric
    AGE

 patients with

    neuronopathic Gaucher disease
    DIAGNOSIS

.

Mesenteric lymphadenopathy
mesenteric lymphadenopathy

Gaucher disease
Gaucher disease
neuronopathic Gaucher disease


Synchronous presentation of Gaucher disease and solitary plasmacytoma with progression to multiple myeloma.

A 37-year-old Polish immigrant presented with unilateral hip pain and difficulty weight-bearing. Plain radiography and magnetic resonance imaging (MRI) revealed a lytic lesion in the acetabulum, with abnormal serum electrophoresis and bone marrow biopsy. The patient was diagnosed with two rare conditions presenting synchronously - Gaucher disease and plasmacytoma. He was treated with enzyme therapy and radiotherapy, but subsequently developed a recurrence of plasmacytoma in the right femur, confirmed with bone marrow biopsy. This was also treated with radiotherapy, followed by a retrograde femoral nail to reduce the risk of pathological fracture. The patient went on to develop multiple lytic lesions in the ribs and vertebra, seen on MRI. Further bone marrow biopsy confirmed dissemination of the plasmacytoma into multiple myeloma, for which he was treated with systemic chemotherapy. In patients presenting with refractory bone or joint pain, haematological and histological investigations should be considered to exclude less common diagnoses.

A

    37-year-old
    AGE

    Polish
    ETHNICITY

    immigrant
    GENDER

 presented with

    unilateral hip pain
    SYMPTOMS

 and

    difficulty weight-bearing
    NEG_FINDINGS

.

    Plain radiography
    PARACLINICAL

 and

    magnetic resonance imaging (MRI)
    PARACLINICAL

 revealed a

    lytic lesion in the acetabulum
    SYMPTOMS

, with

    abnormal serum electrophoresis
    BIOCHEMICAL

 and

    bone marrow biopsy
    PARACLINICAL

. The patient was diagnosed with two rare conditions presenting synchronously -

    Gaucher disease
    DIAGNOSIS

 and

    plasmacytoma
    DIAGNOSIS

.

    He
    GENDER

 was treated with

    enzyme therapy and radiotherapy
    MEDICATION

, but subsequently developed a

    recurrence of plasmacytoma in the right femur
    MICROSCOPIC

, confirmed with

    bone marrow biopsy
    PARACLINICAL

. This was also treated with

    radiotherapy, followed by a retrograde femoral nail to reduce the risk of pathological fracture
    MEDICATION

. The patient went on to develop

    multiple lytic lesions in the ribs and vertebra
    SYMPTOMS

, seen on

    MRI
    PARACLINICAL

. Further

    bone marrow biopsy
    PARACLINICAL

 confirmed

    dissemination of the plasmacytoma into multiple myeloma
    MICROSCOPIC

, for which

    he
    GENDER

 was treated with

    systemic chemotherapy
    MEDICATION

. In patients presenting with

    refractory bone or joint pain
    SYMPTOMS

,

    haematological and histological investigations
    PARACLINICAL

 should be considered to exclude less common diagnoses.


Gauchers disease presenting with portal hypertension.

Gauchers disease is a rare lysosomal storage disorder characterized by abnormal accumulation of lipid-laden macrophages in different organs. Though hepatosplenomegaly is commonly found, symptomatic presentation with portal hypertension is rare. We report a child with liver cirrhosis and bleeding esophageal varices who was diagnosed with Gaucher's disease.

    Gauchers disease
    DIAGNOSIS

 is a

    rare lysosomal storage disorder
    DIAGNOSIS

 characterized by

    abnormal accumulation of lipid-laden macrophages in different organs
    MICROSCOPIC

. Though

    hepatosplenomegaly
    SYMPTOMS

 is commonly found, symptomatic presentation with

    portal hypertension
    SYMPTOMS

 is rare. We report a

    child
    AGE

 with

    liver cirrhosis
    DIAGNOSIS

 and

    bleeding esophageal varices
    SYMPTOMS

 who was diagnosed with

    Gaucher's disease
    DIAGNOSIS

.

Gauchers disease
rare lysosomal storage disorder
liver cirrhosis
Gaucher's disease

hepatosplenomegaly
portal hypertension
bleeding esophageal varices


Recombinant macrophage targeted enzyme replacement therapy for Gaucher disease in India.

Gaucher disease in India has been reported only in a few case reports from India. The aim of the study was to assess the response to enzyme replacement therapy in Indian patients with Gaucher disease.

Retrospective analysis of patients receiving CHO-derived recombinant macrophage-targetted glucocorebrosidase.

Five centers from India with experience in treating lysosomal storage disorders.

The diagnosis of Gaucher disease was confirmed by low glucocerebrosidase levels, though it was first made on splenectomy in 8 and on bone marrow examination in 9 patients. Twenty five of 52 patients diagnosed with Gaucher disease (17 Type I, 8 mild Type III) received treatment for >6 months. Indications for treatment included symptomatic anemia, thrombo-cytopenia, organomegaly, bone disease or mild neurological symptoms leading to impairment of quality of life. Patients with significant neurological involvement were excluded. The drug infusions were given intravenously every 15 days.

Hemoglobin, platelet counts, liver and spleen volumes and growth parameters.

22 of the 25 children who survived were analyzed. After 6 months of treatment, the mean (range) increase in hemoglobin was 1.5 (-3.4 to 6.1) g/dL (P=0.01) and in platelet count was 32 x 10(9)/L (-98.5 x 109 to 145.5 x10(9))/L (P=0.02). The mean (range) increase in weight was 3 kg (-5.6 to 10.5) (P=0.04) and in height was 7.1 cm (0 to 26.5) (P=0.0003). Liver size decreased by a mean (range) of 38.5% (- 5.5 to 86.7) (P=0.0003) and the spleen size by 34.8% (0 to 91.7) (P=0.004). All patients had improvement in bone pains and in 2 patients, neurological symptoms improved with others remaining static.

This is the first reported cohort of patients in India reporting our experience with imiglucerase enzyme replacement therapy for treatment of Gaucher Disease in India.

    Gaucher disease
    DIAGNOSIS

 in

    India
    ETHNICITY

 has been reported only in a few case reports from

    India
    ETHNICITY

. The aim of the study was to assess the response to

    enzyme replacement therapy
    MEDICATION

 in

    Indian
    ETHNICITY

 patients with

    Gaucher disease
    DIAGNOSIS

.

Retrospective analysis of patients receiving

    CHO-derived recombinant macrophage-targetted glucocorebrosidase
    MEDICATION

.

Five centers from

    India
    ETHNICITY

 with experience in treating

    lysosomal storage disorders
    DIAGNOSIS

.

The diagnosis of

    Gaucher disease
    DIAGNOSIS

 was confirmed by

    low glucocerebrosidase levels
    BIOCHEMICAL

, though it was first made on

    splenectomy
    MEDICATION

 in 8 and on

    bone marrow examination
    PARACLINICAL

 in 9 patients. Twenty five of 52 patients diagnosed with

    Gaucher disease
    DIAGNOSIS

 (17

    Type I
    DIAGNOSIS

, 8

    mild Type III
    DIAGNOSIS

) received

    treatment for >6 months
    MEDICATION

. Indications for treatment included

    symptomatic anemia
    BIOCHEMICAL

,

    thrombo-cytopenia
    BIOCHEMICAL

,

    organomegaly
    SYMPTOMS

,

    bone disease
    SYMPTOMS

 or

    mild neurological symptoms
    SYMPTOMS

 leading to

    impairment of quality of life
    SYMPTOMS

. Patients with

    significant neurological involvement
    SYMPTOMS

 were excluded. The

    drug infusions were given intravenously every 15 days
    MEDICATION

.

    Hemoglobin, platelet counts
    BIOCHEMICAL

,

    liver and spleen volumes
    SYMPTOMS

 and

    growth parameters
    SYMPTOMS

.

22 of the 25

    children
    AGE

 who survived were analyzed.

    After 6 months of treatment
    MEDICATION

, the

    mean (range) increase in hemoglobin was 1.5 (-3.4 to 6.1) g/dL
    BIOCHEMICAL

 (P=0.01)

    and in platelet count was 32 x 10(9)/L (-98.5 x 109 to 145.5 x10(9))/L
    BIOCHEMICAL

 (P=0.02). The mean (range)

    increase in weight was 3 kg (-5.6 to 10.5)
    SYMPTOMS

 (P=0.04) and

    in height was 7.1 cm (0 to 26.5)
    SYMPTOMS

 (P=0.0003).

    Liver size decreased by a mean (range) of 38.5% (- 5.5 to 86.7)
    SYMPTOMS

 (P=0.0003) and

    the spleen size by 34.8% (0 to 91.7)
    SYMPTOMS

 (P=0.004). All patients had

    improvement in bone pains
    SYMPTOMS

 and in 2 patients,

    neurological symptoms improved
    SYMPTOMS

 with

    others remaining static
    SYMPTOMS

.

This is the first reported cohort of patients in

    India
    ETHNICITY

 reporting our experience with

    imiglucerase enzyme replacement therapy
    MEDICATION

 for treatment of

    Gaucher Disease
    DIAGNOSIS

 in

    India
    ETHNICITY

.

Gaucher disease
Gaucher disease
lysosomal storage disorders
Gaucher disease
Gaucher disease
Type I
mild Type III
Gaucher Disease


Coxarthritis as the presenting symptom of Gaucher disease type 1.

Gaucher disease (GD) type 1 is the most common lysosomal storage disorder due to beta glucocerebrosidase deficiency leading to an abnormal accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system. The disease presentation is usually characterized by signs and symptoms related to hypersplenism, such as splenomegaly, anaemia, thrombocytopenia and leucopenia. Skeletal disease may occur later for the infiltration of bone marrow by macrophages infiltration and bone resorption: bone involvement may be heterogeneously manifested by symptoms ranging from bone crisis to avascular necrosis, osteoporosis and defect in remodeling of long bones. Herein, we report a patient in whom the osteoarticular involvement has been the only symptom of the disease stressing that this unusual presentation of GD has prompted a wide differential diagnosis with more common forms of coxitis.

    Gaucher disease (GD) type 1
    DIAGNOSIS

 is the most common

    lysosomal storage disorder
    DIAGNOSIS

 due to

    beta glucocerebrosidase deficiency
    BIOCHEMICAL

 leading to an

    abnormal accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system
    MICROSCOPIC

. The disease presentation is usually characterized by signs and symptoms related to

    hypersplenism
    BIOCHEMICAL

, such as

    splenomegaly
    BIOCHEMICAL

,

    anaemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

 and

    leucopenia
    BIOCHEMICAL

.

    Skeletal disease
    DIAGNOSIS

 may occur later for the

    infiltration of bone marrow by macrophages infiltration
    MICROSCOPIC

 and

    bone resorption
    MICROSCOPIC

:

    bone involvement
    SYMPTOMS

 may be heterogeneously manifested by symptoms ranging from

    bone crisis
    SYMPTOMS

 to

    avascular necrosis
    SYMPTOMS

,

    osteoporosis
    SYMPTOMS

 and

    defect in remodeling of long bones
    SYMPTOMS

. Herein, we report a patient in whom the

    osteoarticular involvement
    SYMPTOMS

 has been the only symptom of the disease stressing that this unusual presentation of

    GD
    DIAGNOSIS

 has prompted a wide differential diagnosis with more common forms of

    coxitis
    DIAGNOSIS

.

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

beta glucocerebrosidase deficiency
hypersplenism
splenomegaly
anaemia
thrombocytopenia
leucopenia

bone involvement
bone crisis
avascular necrosis
osteoporosis
defect in remodeling of long bones
osteoarticular involvement


Iliopsoas hematoma in Gaucher's disease.

Gaucher's disease is an autosomal recessive inherited disease characterized by oraganomegaly, cytopenia and bone destruction. Clotting disorders and platelet dysfunctions are described. We report the case of a 22-year-old man who presented subacute groin pain due to spontaneous iliopsoas hematoma. Laboratory investigations found moderate thrombocytopenia, normal coagulation factor activities and unspecific platelet function test disturbances. His spleen was moderately enlarged and no significant bone lesions were found. Iliopsoas hematoma is a rare complication in Gaucher's disease and should be included in the differential diagnosis of pain localized to the groin-hip area, which could rather evoke hip osteonecrosis in this context.

    Gaucher's disease
    DIAGNOSIS

 is an

    autosomal recessive inherited disease
    GENETICS

 characterized by

    oraganomegaly
    SYMPTOMS

,

    cytopenia
    BIOCHEMICAL

 and

    bone destruction
    SYMPTOMS

.

    Clotting disorders
    BIOCHEMICAL

 and

    platelet dysfunctions
    BIOCHEMICAL

 are described. We report the case of a

    22-year-old
    AGE

    man
    GENDER

 who presented

    subacute groin pain
    SYMPTOMS

 due to

    spontaneous iliopsoas hematoma
    SYMPTOMS

.

    Laboratory investigations
    PARACLINICAL

 found

    moderate thrombocytopenia
    BIOCHEMICAL

,

    normal coagulation factor activities
    NEG_FINDINGS

 and

    unspecific platelet function test disturbances
    NEG_FINDINGS

. His

    spleen was moderately enlarged
    SYMPTOMS

 and

    no significant bone lesions were found
    NEG_FINDINGS

.

    Iliopsoas hematoma
    SYMPTOMS

 is a rare complication in

    Gaucher's disease
    DIAGNOSIS

 and should be included in the

    differential diagnosis
    PARACLINICAL

 of

    pain localized to the groin-hip area
    SYMPTOMS

, which could rather evoke

    hip osteonecrosis
    DIAGNOSIS

 in this context.

Gaucher's disease
Gaucher's disease
hip osteonecrosis

oraganomegaly
bone destruction
subacute groin pain
spontaneous iliopsoas hematoma
spleen was moderately enlarged
Iliopsoas hematoma
pain localized to the groin-hip area

cytopenia
Clotting disorders
platelet dysfunctions
moderate thrombocytopenia


Gaucher disease due to saposin C deficiency, previously described as non-neuronopathic form--no positive effects after 2-years of miglustat therapy.

Gaucher disease occurs mainly as a result of a deficiency of the lysosomal enzyme beta-glucocerebrosidase activity. A rare variant form of Gaucher disease is known in which saposin C required for glucosylceramide degradation is deficient. In an earlier paper we described the first cases of two siblings with the non-neuronopathic form of Gaucher disease caused by saposin C deficiency [Tylki-Szymańska et al., 2007]. In this article, we present a follow up of clinical and biochemical findings in one patient who has been treated with miglustat for two years. We observed that administration of miglustat failed to exert any favorable effect on the clinical condition, haematological parameters and glucosylceramide level in the serum. In two individuals (described in this article) very slow deterioration of the peripheral and central nervous systems was observed.

    Gaucher disease
    DIAGNOSIS

 occurs mainly as a result of a

    deficiency of the lysosomal enzyme beta-glucocerebrosidase activity
    BIOCHEMICAL

. A rare variant form of

    Gaucher disease
    DIAGNOSIS

 is known in which

    saposin C required for glucosylceramide degradation is deficient
    BIOCHEMICAL

. In an earlier paper we described the first cases of

    two siblings with the non-neuronopathic form of Gaucher disease
    FAMILY

 caused by

    saposin C deficiency
    BIOCHEMICAL

 [Tylki-Szymańska et al., 2007]. In this article, we present a follow up of clinical and biochemical findings in one patient who has been

    treated with miglustat for two years
    MEDICATION

. We observed that

    administration of miglustat failed to exert any favorable effect on the clinical condition, haematological parameters and glucosylceramide level in the serum
    NEG_FINDINGS

. In two individuals (described in this article)

    very slow deterioration of the peripheral and central nervous systems
    SYMPTOMS

 was observed.


Secondary hemophagocytosis in 3 patients with organic acidemia involving propionate metabolism.

Hemophagocytic lymphohistiocytosis (HLH) may develop secondary to infections, malignancies, immune deficiency syndromes, and rheumatologic and metabolic disorders. Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature. In this report the authors present 3 children with disorders of propionate metabolism--1 with methylmalonic acidemia and 2 with propionic acidemia--who developed secondary HLH during their metabolic attacks. All patients fulfilled the 5 HLH criteria of the Histiocyte Society. Familial HLH was ruled out by molecular analysis. Plasma exchange was performed for 2 of them. Unfortunately 1 died of multiorgan failure despite intensive therapy. This is the first report of such an association.

    Hemophagocytic lymphohistiocytosis (HLH)
    DIAGNOSIS

 may develop secondary to

    infections
    SYMPTOMS

,

    malignancies
    DIAGNOSIS

,

    immune deficiency syndromes
    DIAGNOSIS

, and

    rheumatologic and metabolic disorders
    DIAGNOSIS

. Associations between

    HLH
    DIAGNOSIS

 and

    inborn errors of metabolism
    DIAGNOSIS

, including

    lysinuric protein intolerance
    DIAGNOSIS

,

    multiple sulfatase deficiency
    DIAGNOSIS

,

    galactosemia
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    Pearson syndrome
    DIAGNOSIS

, and

    galactosialidosis
    DIAGNOSIS

, have previously been reported in the literature. In this report the authors present 3

    children
    AGE

 with disorders of propionate metabolism--1 with

    methylmalonic acidemia
    DIAGNOSIS

 and 2 with

    propionic acidemia
    DIAGNOSIS

--who developed

    secondary HLH
    DIAGNOSIS

 during their

    metabolic attacks
    SYMPTOMS

. All patients fulfilled the 5 HLH criteria of the Histiocyte Society.

    Familial HLH was ruled out by molecular analysis
    NEG_FINDINGS

.

    Plasma exchange
    MEDICATION

 was performed for 2 of them. Unfortunately 1

    died of multiorgan failure
    SYMPTOMS

    despite intensive therapy
    NEG_FINDINGS

. This is the first report of such an association.

infections
metabolic attacks
died of multiorgan failure


Bilateral symmetrical cortical osteolytic lesions in two patients with Gaucher disease.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder characterized by the reduced or absent activity of glucocerebrosidase. The disease is split into three types. Type 3, or chronic neuronopathic GD, manifests with heterogeneous clinical presentations. Skeletal manifestations of GD can include abnormal bone remodeling resulting in the characteristic Erlenmeyer flask deformities, painful bone crises, osteopenia, and an increased frequency of fractures. Osteolytic lesions can also occur but are rare and tend to be large, expanding intramedullary lesions with cortical thinning. We present two adolescent patients with type 3 GD who developed bilateral symmetrical cortical osteolytic lesions. The lesions in both cases demonstrate predominant cortical scalloping with fairly indolent growth. Neither patient manifests some of the more common bony manifestations of GD--bone crises or osteonecrosis. These atypical and unique skeletal findings in two unrelated probands with type 3 GD further expand the extent of phenotypic variation encountered in this single gene disorder.

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 characterized by the

    reduced or absent activity of glucocerebrosidase
    BIOCHEMICAL

. The disease is split into three types.

    Type 3,
    DIAGNOSIS

 or

    chronic neuronopathic GD
    DIAGNOSIS

, manifests with heterogeneous clinical presentations.

    Skeletal manifestations
    SYMPTOMS

 of

    GD
    DIAGNOSIS

 can include

    abnormal bone remodeling
    SYMPTOMS

 resulting in the

    characteristic Erlenmeyer flask deformities
    SYMPTOMS

,

    painful bone crises
    SYMPTOMS

,

    osteopenia
    SYMPTOMS

, and an

    increased frequency of fractures
    SYMPTOMS

.

    Osteolytic lesions
    SYMPTOMS

 can also occur but are rare and tend to be

    large, expanding intramedullary lesions with cortical thinning
    SYMPTOMS

. We present two

    adolescent
    AGE

 patients with

    type 3 GD
    DIAGNOSIS

 who developed

    bilateral symmetrical cortical osteolytic lesions
    SYMPTOMS

. The lesions in both cases demonstrate

    predominant cortical scalloping with fairly indolent growth
    SYMPTOMS

. Neither patient manifests some of the more common

    bony manifestations of GD
    SYMPTOMS

--

    bone crises
    SYMPTOMS

 or

    osteonecrosis
    NEG_FINDINGS

. These

    atypical and unique skeletal findings
    SYMPTOMS

 in two unrelated probands with

    type 3 GD
    DIAGNOSIS

 further expand the extent of phenotypic variation encountered in this

    single gene disorder
    GENETICS

.

Gaucher disease (GD)
lysosomal storage disorder
Type 3,
chronic neuronopathic GD
GD
type 3 GD
type 3 GD

autosomal recessive
single gene disorder


Unusual presentation of adult Gaucher's disease: A long and difficult road to diagnosis.

Gaucher's disease is the most frequent sphingolipid storage disease. We present a case of type 1 non-neuropathic type of adult Gaucher's disease patient with atypical presentation.

    Gaucher's disease
    DIAGNOSIS

 is the most frequent

    sphingolipid storage disease
    DIAGNOSIS

. We present a case of

    type 1 non-neuropathic type of adult Gaucher's disease
    DIAGNOSIS

 patient with

    atypical presentation
    SYMPTOMS

.


A newborn case with perinatal-lethal Gaucher disease due to R463H homozygosity complicated by C677T homozygosity in the MTHFR gene.

Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis, in utero fetal demise and neonatal distress. In some cases without hydrops, neurological signs occur in the first week of life and lead to death within 3 months. Less common signs of the disease are hepatosplenomegaly, ichthyosis, arthrogryposis and facial dysmorphy. We describe a preterm neonate with Gaucher disease homozygous for R463H mutation in GBA gene who showed severe neurologic signs in addition to refractory thrombocytopenia, hepatosplenomagaly, direct hyperbilirubinemia, facial dysmorphy and ichthyosiform skin abnormalities in addition to having thrombosis in portal and splenic veins possibly due to homozygosity for C677T mutation in MTHFR gene. To the best of our knowledge, this is the first case homozygous for the GBA R463H mutation resulting in Gaucher disease with a concomitant homozygous MTHFR C677T mutation.

    Perinatal-lethal Gaucher disease
    DIAGNOSIS

 is very rare and is considered a variant of

    type 2 Gaucher disease
    DIAGNOSIS

 that occurs in the

    neonatal
    AGE

    period
    AGE

. The most distinct features of

    perinatal-lethal Gaucher disease
    DIAGNOSIS

 are

    non-immune hydrops fetalis
    DIAGNOSIS

,

    in utero fetal demise
    SYMPTOMS

 and

    neonatal distress
    SYMPTOMS

. In some cases

    without hydrops
    NEG_FINDINGS

,

    neurological signs
    SYMPTOMS

 occur

    in the first week of life
    AGE

 and lead to

    death
    SYMPTOMS

    within 3 months
    AGE

. Less common signs of the disease are

    hepatosplenomegaly
    SYMPTOMS

,

    ichthyosis
    SYMPTOMS

,

    arthrogryposis
    SYMPTOMS

 and

    facial dysmorphy
    SYMPTOMS

. We describe a

    preterm
    AGE

    neonate
    AGE

 with

    Gaucher disease
    DIAGNOSIS

    homozygous for R463H mutation in GBA gene
    GENETICS

 who showed

    severe neurologic signs
    SYMPTOMS

 in addition to

    refractory thrombocytopenia
    BIOCHEMICAL

,

    hepatosplenomagaly
    SYMPTOMS

,

    direct hyperbilirubinemia
    BIOCHEMICAL

,

    facial dysmorphy
    SYMPTOMS

 and

    ichthyosiform skin abnormalities
    SYMPTOMS

 in addition to having

    thrombosis in portal and splenic veins
    SYMPTOMS

 possibly due to

    homozygosity for C677T mutation in MTHFR gene
    GENETICS

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

    homozygous for the GBA R463H mutation
    GENETICS

 resulting in

    Gaucher disease
    DIAGNOSIS

 with a concomitant

    homozygous MTHFR C677T mutation
    GENETICS

.

Perinatal-lethal Gaucher disease
type 2 Gaucher disease
perinatal-lethal Gaucher disease
non-immune hydrops fetalis
Gaucher disease
Gaucher disease

in utero fetal demise
neonatal distress
neurological signs
death
hepatosplenomegaly
ichthyosis
arthrogryposis
facial dysmorphy
severe neurologic signs
hepatosplenomagaly
facial dysmorphy
ichthyosiform skin abnormalities
thrombosis in portal and splenic veins

refractory thrombocytopenia
direct hyperbilirubinemia


Gaucher disease.

A 14 months old boy of consanguineous parent presented with hepatosplenomegaly with delayed mile stones of development. He is till unable to walk. He was moderately anemic. Moderately wasted and stunted. Neurological examination was normal except subnormal intelligence. This subnormal intelligence and delayed milestone possibly may be due to secondary effect of growth retardation. Musculo-skeletal system examination revealed no abnormality. Diagnosis was supported by typical bone involvement in X-ray film (Thin cortex in Limb bone) and Gaucher cell in the splenic aspiration. There are three sub-types Type I: Non neuropathic form. Type II: Acute neuropathic form. Type III: Chronic neuropathic form. However, some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited. So, this patient more or less correlates with Gaucher disease type I. Treatment option for type I and III include medicine and enzyme replacement therapy, which is usually very effective.

A

    14 months old
    AGE

    boy
    GENDER

 of

    consanguineous parent
    FAMILY

 presented with

    hepatosplenomegaly
    SYMPTOMS

 with

    delayed mile stones of development
    SYMPTOMS

.

    He
    GENDER

 is till

    unable to walk
    NEG_FINDINGS

.

    He
    GENDER

 was

    moderately anemic
    BIOCHEMICAL

.

    Moderately wasted
    SYMPTOMS

 and

    stunted
    SYMPTOMS

.

    Neurological examination was normal
    NEG_FINDINGS

 except

    subnormal intelligence
    SYMPTOMS

. This

    subnormal intelligence
    SYMPTOMS

 and

    delayed milestone
    SYMPTOMS

 possibly may be due to secondary effect of

    growth retardation
    SYMPTOMS

.

    Musculo-skeletal system examination
    PARACLINICAL

 revealed

    no abnormality
    NEG_FINDINGS

. Diagnosis was supported by

    typical bone involvement in X-ray film (Thin cortex in Limb bone)
    SYMPTOMS

 and

    Gaucher cell in the splenic aspiration
    MICROSCOPIC

. There are three sub-types

    Type I: Non neuropathic form
    DIAGNOSIS

.

    Type II: Acute neuropathic form
    DIAGNOSIS

.

    Type III
    DIAGNOSIS

:

    Chronic neuropathic form
    DIAGNOSIS

. However, some cases do not fit precisely into one of these categories. All forms of

    Gaucher disease
    DIAGNOSIS

 are

    autosomal recessively inherited
    GENETICS

. So, this patient more or less correlates with Gaucher disease type I. Treatment option for

    type I and III
    DIAGNOSIS

 include

    medicine
    MEDICATION

 and

    enzyme replacement therapy
    MEDICATION

, which is usually very effective.

unable to walk
Neurological examination was normal
no abnormality

Type I: Non neuropathic form
Type II: Acute neuropathic form
Type III
Chronic neuropathic form
Gaucher disease
type I and III


A mutation in SCARB2 is a modifier in Gaucher disease.

Lysosomal integral membrane protein type 2 (LIMP-2) is responsible for proper sorting and lysosomal targeting of glucocerebrosidase, the enzyme deficient in Gaucher disease (GD). Mutations in the gene for LIMP-2, SCARB2, are implicated in inherited forms of myoclonic epilepsy, and myoclonic epilepsy is part of the phenotypic spectrum associated with GD. We investigated whether SCARB2 mutations impact the Gaucher phenotype focusing on patients with myoclonic epilepsy, including a pair of siblings with GD who were discordant for myoclonic seizures. Sequencing of SCARB2 genomic and cDNA identified a heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy, absent from his sibling and controls. Glucocerebrosidase activity, Western blots, real-time PCR, and immunofluorescence studies demonstrated markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2, and diminished glucocerebrosidase in lysosomes. The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase. Sequencing of SCARB2 in 13 other subjects with GD and myoclonic epilepsy and 40 controls failed to identify additional mutations. The study provides further evidence for the association of LIMP-2 and myoclonic epilepsy, explains the drastically different phenotypes encountered in the siblings, and demonstrates that LIMP-2 can serve as a modifier in GD.

    Lysosomal integral membrane protein type 2 (LIMP-2)
    GENETICS

 is responsible for proper sorting and

    lysosomal targeting of glucocerebrosidase
    BIOCHEMICAL

, the

    enzyme deficient
    BIOCHEMICAL

 in

    Gaucher disease (GD)
    DIAGNOSIS

.

    Mutations in the gene for LIMP-2, SCARB2
    GENETICS

, are implicated in

    inherited
    GENETICS

 forms of

    myoclonic epilepsy
    DIAGNOSIS

, and

    myoclonic epilepsy
    DIAGNOSIS

 is part of the phenotypic spectrum associated with

    GD
    DIAGNOSIS

. We investigated whether

    SCARB2 mutations
    GENETICS

 impact the

    Gaucher
    DIAGNOSIS

 phenotype focusing on patients with

    myoclonic epilepsy
    DIAGNOSIS

, including a

    pair of siblings with GD who were discordant for myoclonic seizures
    FAMILY

.

    Sequencing of SCARB2 genomic and cDNA
    PARACLINICAL

 identified a

    heterozygous, maternally inherited novel mutation, c.1412A>G (p.Glu471Gly), in the brother with GD and myoclonic epilepsy
    GENETICS

,

    absent from his sibling
    FAMILY

 and controls.

    Glucocerebrosidase activity
    BIOCHEMICAL

,

    Western blots
    PARACLINICAL

,

    real-time PCR
    PARACLINICAL

, and

    immunofluorescence studies
    PARACLINICAL

 demonstrated

    markedly decreased LIMP-2 and glucocerebrosidase in cells from the sibling with (p.Glu471Gly) LIMP-2
    MICROSCOPIC

, and

    diminished glucocerebrosidase in lysosomes
    MICROSCOPIC

.

    The cells secreted highly glycosylated enzyme and showed mistrafficking of glucocerebrosidase
    MICROSCOPIC

.

    Sequencing of SCARB2
    PARACLINICAL

 in 13 other subjects with

    GD
    DIAGNOSIS

 and

    myoclonic epilepsy
    DIAGNOSIS

 and 40 controls

    failed to identify additional mutations
    NEG_FINDINGS

. The study provides further evidence for the association of

    LIMP-2
    DIAGNOSIS

 and

    myoclonic epilepsy
    DIAGNOSIS

, explains the

    drastically different phenotypes encountered in the siblings
    FAMILY

, and demonstrates that

    LIMP-2
    GENETICS

 can serve as a modifier in

    GD
    DIAGNOSIS

.

Gaucher disease (GD)
myoclonic epilepsy
myoclonic epilepsy
GD
Gaucher
myoclonic epilepsy
GD
myoclonic epilepsy
LIMP-2
myoclonic epilepsy
GD


Parkinsonism associated with glucocerebrosidase mutation.

Gaucher's disease is an autosomal recessive, lysosomal storage disease caused by mutations of the β-glucocerebrosidase gene (GBA). There is increasing evidence that GBA mutations are a genetic risk factor for the development of Parkinson's disease (PD). We report herein a family of Koreans exhibiting parkinsonism-associated GBA mutations.

A 44-year-old woman suffering from slowness and paresthesia of the left arm for the previous 1.5years, visited our hospital to manage known invasive ductal carcinoma. During a preoperative evaluation, she was diagnosed with Gaucher's disease and double mutations of S271G and R359X in GBA. Parkinsonian features including low amplitude postural tremors, rigidity, bradykinesia and shuffling gait were observed. Genetic analysis also revealed that her older sister, who had also been diagnosed with PD and had been taking dopaminergic drugs for 8-years, also possessed a heterozygote R359X mutation in GBA. (18)F-fluoropropylcarbomethoxyiodophenylnortropane positron-emission tomography in these patients revealed decreased uptake of dopamine transporter in the posterior portion of the bilateral putamen.

This case study demonstrates Korean familial cases of PD with heterozygote mutation of GBA, further supporting the association between PD and GBA mutation.

    Gaucher's disease
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

,

    lysosomal storage disease
    DIAGNOSIS

 caused by

    mutations of the β-glucocerebrosidase gene (GBA)
    GENETICS

. There is increasing evidence that

    GBA mutations
    GENETICS

 are a genetic risk factor for the development of

    Parkinson's disease (PD)
    DIAGNOSIS

. We report herein a family of Koreans exhibiting

    parkinsonism-associated GBA mutations
    GENETICS

.

A

    44-year-old
    AGE

    woman
    GENDER

 suffering from

    slowness and paresthesia of the left arm for the previous 1.5years
    SYMPTOMS

, visited our hospital to manage known

    invasive ductal carcinoma
    DIAGNOSIS

. During a preoperative evaluation,

    she
    GENDER

 was diagnosed with

    Gaucher's disease
    DIAGNOSIS

 and

    double mutations of S271G and R359X in GBA
    GENETICS

.

    Parkinsonian features
    SYMPTOMS

 including

    low amplitude postural tremors
    SYMPTOMS

,

    rigidity
    SYMPTOMS

,

    bradykinesia
    SYMPTOMS

 and

    shuffling gait
    SYMPTOMS

 were observed.

    Genetic analysis
    PARACLINICAL

 also revealed that

    her
    GENDER

    older sister, who had also been diagnosed with PD and had been taking dopaminergic drugs for 8-years
    FAMILY

    , also possessed a heterozygote R359X mutation in GBA
    FAMILY

.

    (18)F-fluoropropylcarbomethoxyiodophenylnortropane positron-emission tomography
    PARACLINICAL

 in these patients revealed

    decreased uptake of dopamine transporter in the posterior portion of the bilateral putamen
    MICROSCOPIC

.

This case study demonstrates

    Korean
    ETHNICITY

    familial cases of PD
    FAMILY

 with

    heterozygote mutation of GBA
    GENETICS

, further supporting the association between

    PD
    DIAGNOSIS

 and

    GBA mutation
    GENETICS

.

Gaucher's disease
lysosomal storage disease
Parkinson's disease (PD)
invasive ductal carcinoma
Gaucher's disease
PD


Gaucher disease diagnosed after bone marrow trephine biopsy - a report of two cases.

The hematologist is at the forefront of specialists to whom patients with Gaucher disease present because of cytopenia and hepatosplenomegaly. Usually, patients with such symptoms have undergone trephine biopsy. We present the cases of two patients in whom Gaucher disease was suspected because of the discovery of Gaucher cells in trephine biopsy, and subsequently confirmed via enzymatic and molecular investigations.

The

    hematologist
    PARACLINICAL

 is at the forefront of specialists to whom patients with

    Gaucher disease
    DIAGNOSIS

 present because of

    cytopenia
    BIOCHEMICAL

 and

    hepatosplenomegaly
    SYMPTOMS

. Usually, patients with such symptoms have undergone

    trephine biopsy
    PARACLINICAL

. We present the cases of two patients in whom

    Gaucher disease
    DIAGNOSIS

 was suspected because of the

    discovery of Gaucher cells in trephine biopsy
    MICROSCOPIC

, and subsequently confirmed via

    enzymatic and molecular investigations
    PARACLINICAL

.


Cor pulmonale in a case of infantile Gaucher's disease.

Infantile Gaucher's disease presenting as cor pulmonale is rarely reported in pediatric literature. We report a 3.3 year old boy with infantile Gaucher's disease who presented to us as interstitial lung disease, pulmonary hypertension along with features of cor pulmonale. The high resolution CT findings were typical of interstitial and airspace disease. Cor pulmonale in this patient was a result of severe pulmonary hypertension.

    Infantile Gaucher's disease
    DIAGNOSIS

 presenting as

    cor pulmonale
    DIAGNOSIS

 is rarely reported in

    pediatric
    AGE

 literature. We report a

    3.3 year old
    AGE

    boy
    GENDER

 with

    infantile Gaucher's disease
    DIAGNOSIS

 who presented to us as

    interstitial lung disease
    DIAGNOSIS

,

    pulmonary hypertension
    SYMPTOMS

 along with

    features of cor pulmonale
    SYMPTOMS

. The

    high resolution CT findings
    PARACLINICAL

 were typical of

    interstitial and airspace disease
    MICROSCOPIC

.

    Cor pulmonale
    SYMPTOMS

 in this patient was a result of

    severe pulmonary hypertension
    SYMPTOMS

.

Infantile Gaucher's disease
cor pulmonale
infantile Gaucher's disease
interstitial lung disease

pulmonary hypertension
features of cor pulmonale
Cor pulmonale
severe pulmonary hypertension


Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond.

Parkinson's disease is associated with mutations in the glucocerebrosidase gene, which result in the enzyme deficiency causing Gaucher disease, the most common lysosomal storage disorder. We have performed an exhaustive literature search and found that additional lysosomal storage disorders might be associated with Parkinson's disease, based on case reports, the appearance of pathological features such as α-synuclein deposits in the brain, and substantia nigra pathology. Our findings suggest that the search for biochemical and cellular pathways that link Parkinson's disease with lysosomal storage disorders should not be limited exclusively to changes that occur in Gaucher disease, such as changes in glucocerebrosidase activity or in glucosylceramide levels, but rather include changes that might be common to a wide variety of lysosomal storage disorders. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of mutations in genes encoding lysosomal proteins in patients displaying Parkinson's symptoms.

    Parkinson's disease
    DIAGNOSIS

 is associated with

    mutations in the glucocerebrosidase gene
    GENETICS

, which result in the

    enzyme deficiency
    BIOCHEMICAL

 causing

    Gaucher disease
    DIAGNOSIS

, the most common

    lysosomal storage disorder
    DIAGNOSIS

. We have performed an exhaustive literature search and found that additional

    lysosomal storage disorders
    DIAGNOSIS

 might be associated with

    Parkinson's disease
    DIAGNOSIS

, based on case reports, the appearance of pathological features such as

    α-synuclein deposits in the brain
    MICROSCOPIC

, and

    substantia nigra pathology
    MICROSCOPIC

. Our findings suggest that the search for biochemical and cellular pathways that link

    Parkinson's disease
    DIAGNOSIS

 with

    lysosomal storage disorders
    DIAGNOSIS

 should not be limited exclusively to changes that occur in

    Gaucher disease
    DIAGNOSIS

, such as

    changes in glucocerebrosidase activity or in glucosylceramide levels
    BIOCHEMICAL

, but rather include changes that might be common to a wide variety of

    lysosomal storage disorders
    DIAGNOSIS

. Moreover, we propose that additional genetic, epidemiological, and clinical studies should be performed to check the precise incidence of

    mutations in genes encoding lysosomal proteins
    GENETICS

 in patients displaying

    Parkinson's symptoms
    SYMPTOMS

.

Parkinson's disease
Gaucher disease
lysosomal storage disorder
lysosomal storage disorders
Parkinson's disease
Parkinson's disease
lysosomal storage disorders
Gaucher disease
lysosomal storage disorders


Congenital ichthyosis in severe type II Gaucher disease with a homozygous null mutation.

This paper describes a neonate with type II Gaucher disease. The phenotype was unusually severe with congenital ichthyosis, hepatosplenomegaly, muscular hypotonia, myoclonus and respiratory failure. Electron microscopy of the skin revealed lamellar body contents in the stratum corneum interstices, appearances considered to be typical of type II Gaucher disease. The baby died from respiratory failure 1 month postpartum having made no neurological progress. Molecular analysis identified a previously not reported homozygous null mutation, c.1505G→A of the β-glucocerebrosidase gene.

This paper describes a

    neonate
    AGE

 with

    type II Gaucher disease
    DIAGNOSIS

. The phenotype was unusually severe with

    congenital ichthyosis
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

,

    muscular hypotonia
    SYMPTOMS

,

    myoclonus
    SYMPTOMS

 and

    respiratory failure
    SYMPTOMS

.

    Electron microscopy of the skin
    PARACLINICAL

 revealed

    lamellar body contents in the stratum corneum interstices
    MICROSCOPIC

, appearances considered to be typical of

    type II Gaucher disease
    MICROSCOPIC

. The

    baby
    AGE

    died
    SYMPTOMS

 from

    respiratory failure
    SYMPTOMS

    1 month postpartum
    AGE

 having

    made no neurological progress
    NEG_FINDINGS

.

    Molecular analysis
    PARACLINICAL

 identified a previously not reported

    homozygous null mutation, c.1505G→A of the β-glucocerebrosidase gene.
    GENETICS

congenital ichthyosis
hepatosplenomegaly
muscular hypotonia
myoclonus
respiratory failure
died
respiratory failure


Gaucher disease: when molecular testing and clinical presentation disagree -the novel c.1226A>G(p.N370S)--RecNcil allele.

We report a 31 year old woman who had prenatal carrier screening for Ashkenazi Jewish (AJ) genetic diseases and was found to have two acid ß-glucosidase (GBA) mutations, c.1226A>G(p.N370S) and c.1448T>C(p.L444P), consistent with the diagnosis of Type 1 Gaucher disease (GD1). This genotype typically manifests in late-adolescence with hepatosplenomegaly and early-onset bone involvement. The Proband had a normal physical examination, no organomegaly, and normal blood counts, skeletal survey, and bone density. Leukocyte acid ß-glucosidase and plasma chitotriosidase activities were normal. To investigate these unexpected results, her GBA alleles were RT-PCR amplified and sequenced. Five RT-PCR clones were negative for both mutations, while five clones had the c.1226A>G(p.N370S) and c.1448T>C(p.L444P) mutations, along with c.1483G>C(p.A456P), and c.1497G>C(p.V460V) mutations, the latter three lesions composing the rare GBA pseudogene-derived RecNcil allele. Genetic testing misdiagnosed the asymptomatic Proband as affected with Type 1 Gaucher disease; however, molecular studies revealed a novel allele with the two common GBA mutations on the RecNcil background. This allele presumably arose by crossing-over between a c.1226A>G allele and the pseudogene, gene conversion, or a new c.1226A>G mutation on the RecNcil background. This novel complex allele highlights a limitation of carrier screening for GD.

We report a

    31 year old
    AGE

    woman
    GENDER

 who had

    prenatal carrier screening
    PARACLINICAL

 for

    Ashkenazi Jewish (AJ) genetic diseases
    ETHNICITY

 and was found to have

    two acid ß-glucosidase (GBA) mutations, c.1226A>G(p.N370S) and c.1448T>C(p.L444P)
    GENETICS

, consistent with the diagnosis of

    Type 1 Gaucher disease (GD1)
    DIAGNOSIS

. This genotype typically manifests in

    late-adolescence
    AGE

 with

    hepatosplenomegaly
    SYMPTOMS

 and

    early-onset bone involvement
    SYMPTOMS

. The

    Proband
    GENDER

 had a

    normal physical examination
    NEG_FINDINGS

,

    no organomegaly
    NEG_FINDINGS

, and

    normal blood counts, skeletal survey, and bone density
    NEG_FINDINGS

.

    Leukocyte acid ß-glucosidase and plasma chitotriosidase activities were normal
    NEG_FINDINGS

. To investigate these unexpected results,

    her
    GENDER

    GBA alleles were RT-PCR amplified and sequenced
    PARACLINICAL

. Five

    RT-PCR clones
    PARACLINICAL

 were

    negative for both mutations
    NEG_FINDINGS

, while five clones had the

    c.1226A>G(p.N370S) and c.1448T>C(p.L444P) mutations, along with c.1483G>C(p.A456P), and c.1497G>C(p.V460V) mutations, the latter three lesions composing the rare GBA pseudogene-derived RecNcil allele
    GENETICS

.

    Genetic testing
    PARACLINICAL

    misdiagnosed the asymptomatic Proband as affected with Type 1 Gaucher disease
    NEG_FINDINGS

; however,

    molecular studies
    PARACLINICAL

 revealed a

    novel allele with the two common GBA mutations on the RecNcil background
    GENETICS

. This allele presumably arose by

    crossing-over between a c.1226A>G allele and the pseudogene, gene conversion, or a new c.1226A>G mutation on the RecNcil background
    GENETICS

. This

    novel complex allele
    GENETICS

 highlights a limitation of

    carrier screening
    PARACLINICAL

 for

    GD
    DIAGNOSIS

.

hepatosplenomegaly
early-onset bone involvement


[Bone manifestations of Gaucher's disease in Mexican patients].

Gaucher's disease (GD) is the most common of the lysosomal storage diseases (LSDs) that have been defined so far. Its incidence rate is quite low, but its organ involvement profile is disrupting as it results in a considerable morbidity and mortality rate, as well as in high health care costs and poor quality of life. It is a recessive and autosomal genetic disease associated with the insufficiency of the enzyme glucocerebrosidase. The storage of the substrate produces considerable organ deterioration in the skeleton, liver, kidneys, lungs, spleen, brain and bone marrow. This report presents several clinical cases of Mexican patients characterized by bone damage with the purpose of disseminating among orthopedic surgeons the typical findings and course of the disease. The particularities of the patients are discussed, as well as their response to enzyme replacement therapy (ERT) and the results of their clinical follow-up with the latest therapeutic resources.

    Gaucher's disease (GD)
    DIAGNOSIS

 is the most common of the

    lysosomal storage diseases (LSDs)
    DIAGNOSIS

 that have been defined so far. Its incidence rate is quite low, but its

    organ involvement
    SYMPTOMS

 profile is disrupting as it results in a considerable morbidity and mortality rate, as well as in high health care costs and

    poor quality of life
    SYMPTOMS

. It is a

    recessive and autosomal genetic disease
    GENETICS

 associated with the

    insufficiency of the enzyme glucocerebrosidase
    BIOCHEMICAL

. The

    storage of the substrate
    MICROSCOPIC

 produces

    considerable organ deterioration in the skeleton, liver, kidneys, lungs, spleen, brain and bone marrow
    MICROSCOPIC

. This report presents several clinical cases of

    Mexican
    ETHNICITY

 patients characterized by

    bone damage
    SYMPTOMS

 with the purpose of disseminating among orthopedic surgeons the typical findings and course of the disease. The particularities of the patients are discussed, as well as their response to

    enzyme replacement therapy (ERT)
    MEDICATION

 and the results of their clinical follow-up with the latest therapeutic resources.

Gaucher's disease (GD)
lysosomal storage diseases (LSDs)

organ involvement
poor quality of life
bone damage


[Difficult transitions from paediatric to adult care in type 1 Gaucher disease].

Gaucher disease is the most frequent lysosomal storage disease. It is a progressive chronic disease that can lead to substantial bone and joint damage and hematological cytopenias. This progressive disease severely worsens the patients' quality of life. Over the past 20 years, enzymatic treatment has considerably improved both symptoms and quality of life. Yet, bone and joint damage may be irreversible. This emphasizes the importance of rigorous follow-up so as to begin uninterrupted treatment before lesion onset. The transition from pediatric to adult care is a major concern for chronic patients. This step is often associated with follow-up problems and may lead to disease worsening. We present three cases of patients who were lost to follow-up during the transition phase. For all 3 patients, the disease notably worsened because follow-up was interrupted during this period.

    Gaucher disease
    DIAGNOSIS

 is the most frequent

    lysosomal storage disease
    DIAGNOSIS

. It is a

    progressive chronic disease
    DIAGNOSIS

 that can lead to

    substantial bone and joint damage
    SYMPTOMS

 and

    hematological cytopenias
    BIOCHEMICAL

. This

    progressive disease
    DIAGNOSIS

 severely worsens the patients' quality of life. Over the past 20 years,

    enzymatic treatment
    MEDICATION

 has considerably improved both symptoms and

    quality of life
    SYMPTOMS

. Yet,

    bone and joint damage
    SYMPTOMS

 may be irreversible. This emphasizes the importance of rigorous follow-up so as to begin

    uninterrupted treatment
    MEDICATION

 before lesion onset. The

    transition from pediatric to adult care
    MEDICATION

 is a major concern for chronic patients. This step is often associated with follow-up problems and may lead to

    disease worsening
    SYMPTOMS

. We present three cases of patients who were

    lost to follow-up
    NEG_FINDINGS

 during the transition phase. For all 3 patients, the

    disease notably worsened
    SYMPTOMS

 because

    follow-up
    MEDICATION

 was interrupted during this period.

Gaucher disease
lysosomal storage disease
progressive chronic disease
progressive disease

substantial bone and joint damage
quality of life
bone and joint damage
disease worsening
disease notably worsened

enzymatic treatment
uninterrupted treatment
transition from pediatric to adult care
follow-up


Homozygous N396T mutation in Gaucher disease: Portuguese sisters with markedly different phenotypes.

Gaucher disease (GD) is characterized by reduced activity of glucocerebrosidase leading to complications in the reticuloendothelial system. N396T, a rarer mutation of the glucocerebrosidase gene, has been encountered in Portuguese populations and has generally been associated with milder phenotypes. This report presents brief histories of two Portuguese sisters, both with homozygous N396T mutations. These patients are phenotypically very different despite the fact that in both patients residual enzyme activity is very low. The case of patient 1 is complicated by comorbid diabetes mellitus and human immunodeficiency virus (HIV) infection. Enzyme replacement therapy (ERT) improved this patient's clinical picture sufficiently to enable antiretroviral treatment to proceed for the HIV. This report demonstrates the poor correlation of clinical GD with genotype as well as with residual enzyme activity. It further illustrates how treatment of the underlying GD with ERT improved symptoms allowing for antiretroviral therapy thereby improving both the GD and HIV.

    Gaucher disease (GD)
    DIAGNOSIS

 is characterized by

    reduced activity of glucocerebrosidase
    BIOCHEMICAL

 leading to

    complications in the reticuloendothelial system
    SYMPTOMS

.

    N396T, a rarer mutation of the glucocerebrosidase gene
    GENETICS

, has been encountered in

    Portuguese
    ETHNICITY

 populations and has generally been associated with milder phenotypes. This report presents brief histories of two

    Portuguese
    ETHNICITY

    sisters, both with homozygous N396T mutations
    FAMILY

. These patients are phenotypically very different despite the fact that in both patients

    residual enzyme activity is very low
    BIOCHEMICAL

. The case of patient 1 is complicated by

    comorbid diabetes mellitus
    DIAGNOSIS

 and

    human immunodeficiency virus (HIV) infection
    DIAGNOSIS

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 improved this patient's clinical picture sufficiently to enable

    antiretroviral treatment to proceed for the HIV
    MEDICATION

. This report demonstrates the

    poor correlation of clinical GD
    NEG_FINDINGS

 with genotype as well as with

    residual enzyme activity
    NEG_FINDINGS

. It further illustrates how treatment of the underlying

    GD
    DIAGNOSIS

 with

    ERT
    MEDICATION

 improved symptoms allowing for

    antiretroviral therapy
    MEDICATION

 thereby improving both the

    GD
    DIAGNOSIS

 and

    HIV
    DIAGNOSIS

.

reduced activity of glucocerebrosidase
residual enzyme activity is very low

poor correlation of clinical GD
residual enzyme activity


Splenomegaly, cardiomegaly, and osteoporosis in a child with Gaucher disease.

A 15-month-old girl, born to the consanguineous parents, was referred with the sign of massive splenomegaly associated with thrombocytopenia and anemia. Plasma Chitotriosidase estimation was carried out as a screening test and was found to be normal with reduced activity of β-glucosidase in leucocytes suggestive of Gaucher disease. At the age of 4 years, severe osteoporosis and cardiomegaly with pulmonary congestion were observed in the child. Molecular analysis for GBA gene has revealed homozygous status for L444P (c.1448C) in the proband, whereas parents and two elder sisters were found to be heterozygote. Prenatal study during the fourth pregnancy was carried out from cultured chorionic villi for β-glucosidase, which was in the carrier range. Further confirmation of the carrier status was carried out from amniotic fluid DNA and was found to be heterozygous for L444P (c.1448C) in the GBA gene. This case demonstrates that children with the sign of splenomegaly with anemia and thrombocytopenia need to be screened for Gaucher disease, and molecular study can further help to confirm the heterozygous status, where prenatal study by enzyme investigation demonstrate heterozygous condition.

A

    15-month-old
    AGE

    girl
    GENDER

,

    born to the consanguineous parents
    FAMILY

, was referred with the sign of

    massive splenomegaly
    SYMPTOMS

 associated with

    thrombocytopenia
    BIOCHEMICAL

 and

    anemia
    BIOCHEMICAL

.

    Plasma Chitotriosidase estimation
    NEG_FINDINGS

 was carried out as a screening test and was found to

    be normal
    NEG_FINDINGS

 with

    reduced activity of β-glucosidase in leucocytes
    BIOCHEMICAL

 suggestive of

    Gaucher disease
    DIAGNOSIS

. At the

    age of 4 years
    AGE

,

    severe osteoporosis
    SYMPTOMS

 and

    cardiomegaly
    SYMPTOMS

 with

    pulmonary congestion
    SYMPTOMS

 were observed in the

    child
    AGE

.

    Molecular analysis for GBA gene
    PARACLINICAL

 has revealed

    homozygous status for L444P (c.1448C) in the proband
    GENETICS

,

    whereas parents and two elder sisters were found to be heterozygote
    FAMILY

.

    Prenatal study during the fourth pregnancy
    PARACLINICAL

 was carried out from

    cultured chorionic villi for β-glucosidase
    PARACLINICAL

, which was in the carrier range. Further confirmation of the carrier status was carried out from

    amniotic fluid DNA
    PARACLINICAL

 and was found to be

    heterozygous for L444P (c.1448C) in the GBA gene
    GENETICS

. This case demonstrates that

    children
    AGE

 with the sign of

    splenomegaly
    SYMPTOMS

 with

    anemia
    BIOCHEMICAL

 and

    thrombocytopenia
    BIOCHEMICAL

 need to be screened for

    Gaucher disease
    DIAGNOSIS

, and

    molecular study
    PARACLINICAL

 can further help to confirm the heterozygous status, where

    prenatal study by enzyme investigation
    PARACLINICAL

 demonstrate

    heterozygous condition
    GENETICS

.

massive splenomegaly
severe osteoporosis
cardiomegaly
pulmonary congestion
splenomegaly

Plasma Chitotriosidase estimation
be normal


[Experience in the management of pediatric patients with Gaucher disease].

Among lysosomal storage diseases, Gaucher disease depicts the highest rate of incidence, according with the international epidemiological reports. Gaucher disease is due to an impairing of the acid beta-glucosidase enzyme, since its lack promotes accumulation of the sphingolipid glucosylceramide at macrophages, leading to heterogeneous multiorganic damage (visceral, skeletal, and central nervous system affectation). This paper portrays a series of clinical cases of Gaucher disease with patients treated at the same city (Monterrey, Nuevo León), at the Paediatric Haematology Department of the Specialties General Hospital, UMAE 25, in Monterrey of the Instituto Mexicano del Seguro Social. Gaucher disease is symptomatic since early childhood in a good proportion of patients. The patients in this serie was treated with enzyme replacement therapy, and share the typical overall features of the disease.

Among

    lysosomal storage diseases
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

 depicts the highest rate of incidence, according with the international epidemiological reports.

    Gaucher disease
    DIAGNOSIS

 is due to an

    impairing of the acid beta-glucosidase enzyme
    BIOCHEMICAL

, since its

    lack
    BIOCHEMICAL

 promotes

    accumulation of the sphingolipid glucosylceramide at macrophages
    MICROSCOPIC

, leading to

    heterogeneous multiorganic damage (visceral, skeletal, and central nervous system affectation)
    SYMPTOMS

. This paper portrays a series of clinical cases of

    Gaucher disease
    DIAGNOSIS

 with patients treated at the same city (

    Monterrey
    ETHNICITY

,

    Nuevo León
    ETHNICITY

), at the

    Paediatric Haematology
    PARACLINICAL

 Department of the Specialties General Hospital,

    UMAE 25
    MEDICATION

, in

    Monterrey
    ETHNICITY

 of the

    Instituto Mexicano del Seguro Social
    ETHNICITY

.

    Gaucher disease
    DIAGNOSIS

 is symptomatic

    since early childhood
    AGE

 in a good proportion of patients. The patients in this serie was treated with

    enzyme replacement therapy
    MEDICATION

, and share the typical overall features of the disease.

lysosomal storage diseases
Gaucher disease
Gaucher disease
Gaucher disease
Gaucher disease

Monterrey
Nuevo León
Monterrey
Instituto Mexicano del Seguro Social


Successful pregnancy and lactation outcome in a patient with Gaucher disease receiving enzyme replacement therapy, and the subsequent distribution and excretion of imiglucerase in human breast milk.

Enzyme replacement therapy (ERT) with imiglucerase is a well-established, effective treatment for Gaucher disease. However, there have been no published reports regarding the excretion of imiglucerase into human breast milk and its effects on the nursing infant.

This letter reports on the successful pregnancy and lactation of a patient with Gaucher disease receiving treatment with imiglucerase, and the subsequent distribution and excretion of imiglucerase in human breast milk.

A 39-year-old Japanese female (height, 164 cm; weight, 55 kg) with Gaucher disease had 2 successful pregnancies and continued ERT through both. The study was conducted 6 months after the first delivery. She was administered a 1-hour infusion of imiglucerase 60 U/kg that coincided with her regular every-2-week regimen. Serum and breast-milk samples were obtained before and up to 24 hours after administration. Breast-milk samples were also obtained from 10 nursing mothers with galactorrhea as controls.

The preinfusion level of breast-milk β-glucocerebrosidase was 0.008 nmol/h/mL. The peak of serum β-glucocerebrosidase activity (0.119 nmol/h/mL) was obtained at the end of the 1-hour infusion period. Slightly increased enzymatic activity (0.016 nmol/h/mL) was observed in the first breast milk sampled after imiglucerase infusion.

We report a case of successful pregnancy and breastfeeding in a Japanese patient with Gaucher disease. A small amount of imiglucerase was found to be excreted into human breast milk, but only in the first milk produced after infusion.

    Enzyme replacement therapy (ERT) with imiglucerase
    MEDICATION

 is a well-established, effective treatment for

    Gaucher disease
    DIAGNOSIS

. However, there have been no published reports regarding the

    excretion of imiglucerase into human breast milk
    BIOCHEMICAL

 and its effects on the

    nursing infant
    AGE

.

This letter reports on the

    successful pregnancy and lactation
    MEDICATION

 of a patient with

    Gaucher disease
    DIAGNOSIS

 receiving

    treatment with imiglucerase
    MEDICATION

, and the subsequent distribution and

    excretion of imiglucerase in human breast milk
    MICROSCOPIC

.

A

    39-year-old
    AGE

    Japanese
    ETHNICITY

    female
    GENDER

 (height, 164 cm; weight, 55 kg) with

    Gaucher disease
    DIAGNOSIS

 had

    2 successful pregnancies
    MEDICATION

 and

    continued ERT through both
    MEDICATION

. The study was conducted 6 months after the first delivery.

    She
    GENDER

 was

    administered a 1-hour infusion of imiglucerase 60 U/kg that coincided with her regular every-2-week regimen
    MEDICATION

.

    Serum and breast-milk samples were obtained before and up to 24 hours after administration
    PARACLINICAL

.

    Breast-milk samples
    PARACLINICAL

 were also obtained from 10 nursing mothers with

    galactorrhea
    NEG_FINDINGS

 as controls.

The preinfusion level of breast-milk β-glucocerebrosidase was 0.008 nmol/h/mL. The

    peak of serum β-glucocerebrosidase activity (0.119 nmol/h/mL)
    BIOCHEMICAL

 was obtained at the end of the 1-hour infusion period.

    Slightly increased enzymatic activity (0.016 nmol/h/mL) was observed in the first breast milk sampled after imiglucerase infusion
    BIOCHEMICAL

.

We report a case of

    successful pregnancy and breastfeeding
    MEDICATION

 in a

    Japanese
    ETHNICITY

 patient with

    Gaucher disease
    DIAGNOSIS

. A

    small amount of imiglucerase was found to be excreted into human breast milk, but only in the first milk produced after infusion
    MICROSCOPIC

.

Gaucher disease
Gaucher disease
Gaucher disease
Gaucher disease


Gaucher disease with foamy transformed macrophages and erythrophagocytic activity.

Foamy transformation of macrophages is typically seen in lysosomal storage disorders in patients with Niemann-Pick disease, but foamy Gaucher cells (GC) were previously reported only once, in the autopsy report. Although the majority of stored glucocerebroside in GC is of erythrocyte origin, apparent erythrophagocytosis by GC in bone marrow is an unusual finding. Here, we describe the case of an adult non-Jewish Caucasian male with a heterozygous Gaucher disease type 1 (mutations c.1226A>G and c.1448T>C in the GBA1 gene) who presented with atypical morphology of GC on bone marrow examination. Approximately 15% of his GC showed a notable erythrophagocytic activity or unusual appearance of foamy transformed macrophages with a great number of vacuoles and erythrocyte rests in the cytoplasm. This report highlights the fact that morphological examination of cells and tissue specimens is very helpful in the diagnosis of a storage disorder but that confirmatory testing for specific diseases should always follow. Moreover, it is now clear that Gaucher disease should be a part of the differential diagnosis of foamy transformed macrophages.

    Foamy transformation of macrophages
    MICROSCOPIC

 is typically seen in

    lysosomal storage disorders
    DIAGNOSIS

 in patients with

    Niemann-Pick disease
    DIAGNOSIS

, but

    foamy Gaucher cells (GC)
    MICROSCOPIC

 were previously reported only once, in the autopsy report. Although the

    majority of stored glucocerebroside in GC is of erythrocyte origin
    MICROSCOPIC

,

    apparent erythrophagocytosis by GC in bone marrow
    MICROSCOPIC

 is an unusual finding. Here, we describe the case of an

    adult
    AGE

    non-Jewish Caucasian
    ETHNICITY

    male
    GENDER

 with a

    heterozygous Gaucher disease type 1 (mutations c.1226A>G and c.1448T>C in the GBA1 gene)
    GENETICS

 who presented with

    atypical morphology of GC
    MICROSCOPIC

 on

    bone marrow examination
    PARACLINICAL

.

    Approximately 15% of his GC showed a notable erythrophagocytic activity or unusual appearance of foamy transformed macrophages with a great number of vacuoles and erythrocyte rests in the cytoplasm
    MICROSCOPIC

. This report highlights the fact that

    morphological examination of cells and tissue specimens
    PARACLINICAL

 is very helpful in the diagnosis of a

    storage disorder
    DIAGNOSIS

 but that confirmatory testing for specific diseases should always follow. Moreover, it is now clear that

    Gaucher disease
    DIAGNOSIS

 should be a part of the

    differential diagnosis
    PARACLINICAL

 of

    foamy transformed macrophages
    MICROSCOPIC

.

lysosomal storage disorders
Niemann-Pick disease
storage disorder
Gaucher disease


Characterization of the c.(-203)A>G variant in the glucocerebrosidase gene and its association with phenotype in Gaucher disease.

Gaucher disease (GD) is a rare autosomal recessive disorder caused mainly by mutations in the glucocerebrosidase (GBA) gene. Great phenotypic variability has been observed among patients with the same genotype, suggesting other factors, such as polymorphic variants, might influence GD phenotypes. We previously reported the c.(-203)A>G (g.1256A>G) variant in exon 1 of the GBA gene in Spanish GD patients.

We analyzed the frequency and transcriptional activity of the promoter carrying the G-allele using restriction isotyping, electrophoretic mobility shift assay, cell culture, transfection, and luciferase assays.

We found the variant is present at a similar frequency to the control group. In our patients, the G-allele was always found in combination with another mutation in the same allele, and patients carrying the c.(-203)A>G variant showed a more severe GD phenotype. The promoter containing the G-allele showed a 35% reduction in promoter activity when transfected into HepG2 cells.

The c.(-203)A>G variant seems to be a polymorphism resulting in a decrease in activity of the GBA promoter. The change, per se, is not enough to elicit a GD phenotype, but it may produce a more severe phenotype in GD patients when combined with an already defective GBA protein.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    rare autosomal recessive disorder
    GENETICS

 caused mainly by

    mutations in the glucocerebrosidase (GBA) gene
    GENETICS

. Great phenotypic variability has been observed among patients with the same genotype, suggesting other factors, such as

    polymorphic variants
    GENETICS

, might influence

    GD
    DIAGNOSIS

 phenotypes. We previously reported the

    c.(-203)A>G (g.1256A>G) variant in exon 1 of the GBA gene
    GENETICS

 in

    Spanish
    ETHNICITY

    GD
    DIAGNOSIS

 patients.

We analyzed the frequency and

    transcriptional activity of the promoter carrying the G-allele
    GENETICS

 using

    restriction isotyping
    PARACLINICAL

,

    electrophoretic mobility shift assay
    PARACLINICAL

,

    cell culture
    PARACLINICAL

,

    transfection
    PARACLINICAL

, and

    luciferase assays
    PARACLINICAL

.

We found the variant is present at a similar frequency to the control group. In our patients,

    the G-allele was always found in combination with another mutation in the same allele
    GENETICS

, and patients carrying the

    c.(-203)A>G variant
    GENETICS

 showed a

    more severe GD phenotype
    SYMPTOMS

. The

    promoter containing the G-allele showed a 35% reduction in promoter activity
    GENETICS

 when transfected into

    HepG2 cells
    MICROSCOPIC

.

    The c.(-203)A>G variant seems to be a polymorphism resulting in a decrease in activity of the GBA promoter
    GENETICS

. The change, per se, is not enough to elicit a

    GD
    DIAGNOSIS

 phenotype, but it may produce a more severe phenotype in

    GD
    DIAGNOSIS

 patients when combined with an already

    defective GBA protein
    BIOCHEMICAL

.


A monozygotic twin pair with highly discordant Gaucher phenotypes.

We describe monozygotic twin sisters, born to consanguineous Moroccan parents, who are highly discordant for the manifestations of Gaucher disease. Both carry Gaucher genotype N188S/N188S. One has severe visceral involvement, epilepsy, and a cerebellar syndrome. Her twin does not manifest any symptoms or signs of Gaucher disease but suffers from type 1 diabetes mellitus. The concurrence of a mild Gaucher mutation with a severe phenotype, as well as the occurrence of highly discordant phenotypes in a pair of monozygotic twins, is discussed.

We describe

    monozygotic twin sisters, born to consanguineous Moroccan parents
    FAMILY

,

    who are highly discordant for the manifestations of Gaucher disease
    FAMILY

. Both carry Gaucher genotype N188S/N188S. One has

    severe visceral involvement
    SYMPTOMS

,

    epilepsy
    SYMPTOMS

, and a

    cerebellar syndrome
    SYMPTOMS

.

    Her
    GENDER

    twin does not manifest any symptoms or signs of Gaucher disease
    FAMILY

 but suffers from

    type 1 diabetes mellitus
    DIAGNOSIS

. The

    concurrence of a mild Gaucher mutation with a severe phenotype
    FAMILY

, as well as the occurrence of

    highly discordant phenotypes in a pair of monozygotic twins
    FAMILY

, is discussed.

severe visceral involvement
epilepsy
cerebellar syndrome


Avascular necrosis of the capitate.

Although a large portion of the capitate is supplied by a single nutrient vessel, avascular necrosis of the capitatum is a rare condition. Its etiology is not clear, but a number of factors are linked to its pathogenesis including: repetitive trauma, dorsal instability of the carpus, Gaucher disease, systemic lupus erythematosus, gout, and steroid use. A 24-year-old woman presented with right wrist pain of 12 months duration. She reported no major trauma and reported that her pain had begun during the third month of her pregnancy. She had a history of hyperemesis gravidarum treated with 2 to 4 mg/daily of prednisone during her pregnancy for 6 weeks. She had 70° extension and 45° flexion of her wrist. Radiographs showed a hypodense area at the capitate head and midcarpal joint arthritis. Magnetic resonance imaging demonstrated avascular necrosis of the capitate and midcarpal collapse at the lunocapitate joint. Lunocapitate fusion with a partial scaphoidectomy was performed. At final follow-up 28 months postoperatively, she had 60° of volar flexion, and 50° of dorsiflexion. She was pain free in the majority of her activities of daily living. A small dose of steroid use during pregnancy, even in a short period of time, is a potential risk for avascular necrosis of the capitate and patients with a gradual onset of wrist pain during pregnancy may need to be investigated further if symptoms are not resolved with basic nonoperative measures within a reasonable time frame.

Although a large portion

    of the capitate
    SYMPTOMS

 is supplied by a

    single nutrient vessel
    SYMPTOMS

,

    avascular necrosis of the capitatum
    DIAGNOSIS

 is a rare condition. Its etiology is not clear, but a number of factors are linked to its pathogenesis including:

    repetitive trauma
    SYMPTOMS

,

    dorsal instability of the carpus
    SYMPTOMS

,

    Gaucher disease
    DIAGNOSIS

,

    systemic lupus erythematosus
    DIAGNOSIS

,

    gout
    DIAGNOSIS

, and

    steroid use
    MEDICATION

. A

    24-year-old
    AGE

    woman
    GENDER

 presented with

    right wrist pain of 12 months duration
    SYMPTOMS

.

    She
    GENDER

 reported

    no major trauma
    NEG_FINDINGS

 and reported that

    her
    GENDER

 pain had begun during the

    third month of her pregnancy
    AGE

.

    She
    GENDER

 had a history of

    hyperemesis gravidarum
    DIAGNOSIS

    treated with 2 to 4 mg/daily of prednisone during her pregnancy for 6 weeks
    MEDICATION

.

    She
    GENDER

 had

    70° extension and 45° flexion of her wrist
    SYMPTOMS

.

    Radiographs
    PARACLINICAL

 showed a

    hypodense area at the capitate head
    SYMPTOMS

 and

    midcarpal joint arthritis
    SYMPTOMS

.

    Magnetic resonance imaging
    PARACLINICAL

 demonstrated

    avascular necrosis of the capitate and midcarpal collapse at the lunocapitate joint
    SYMPTOMS

.

    Lunocapitate fusion with a partial scaphoidectomy
    MEDICATION

 was performed. At

    final follow-up
    PARACLINICAL

 28 months postoperatively,

    she
    GENDER

 had

    60° of volar flexion, and 50° of dorsiflexion
    SYMPTOMS

.

    She
    GENDER

 was

    pain free in the majority of her activities of daily living
    NEG_FINDINGS

. A

    small dose of steroid use
    MEDICATION

 during

    pregnancy
    DIAGNOSIS

, even in a short period of time, is a potential risk for

    avascular necrosis of the capitate
    DIAGNOSIS

 and patients with a

    gradual onset of wrist pain
    SYMPTOMS

 during

    pregnancy
    DIAGNOSIS

 may need to be investigated further if

    symptoms are not resolved with basic nonoperative measures
    NEG_FINDINGS

 within a reasonable time frame.

avascular necrosis of the capitatum
Gaucher disease
systemic lupus erythematosus
gout
hyperemesis gravidarum
pregnancy
avascular necrosis of the capitate
pregnancy


Molecular characterization of a new deletion of the GBA1 gene due to an inter Alu recombination event.

Gaucher disease is the most frequent lysosomal storage disorder due to the autosomal recessive deficiency of acid β-glucosidase. More than 300 mutations in the GBA1 gene have been described. However only one large deletion of the GBA1 gene has been reported to date. Here, using a combination of different experimental approaches including PCR, sequencing and Southern blot analysis, we describe the identification and characterization of a new large deletion of the GBA1 gene due to an inter Alu recombination event.

    Gaucher disease
    DIAGNOSIS

 is the most frequent

    lysosomal storage disorder
    DIAGNOSIS

 due to the

    autosomal recessive
    GENETICS

    deficiency of acid β-glucosidase
    BIOCHEMICAL

. More than 300

    mutations in the GBA1 gene
    GENETICS

 have been described. However only one

    large deletion of the GBA1 gene
    GENETICS

 has been reported to date. Here, using a combination of different experimental approaches including

    PCR, sequencing
    PARACLINICAL

 and

    Southern blot analysis
    PARACLINICAL

, we describe the identification and characterization of a

    new large deletion of the GBA1 gene due to an inter Alu recombination event
    GENETICS

.

Gaucher disease
lysosomal storage disorder


Vitrectomy for vitreous opacities and macular pucker in Gaucher disease.

To report significant surgical results in an uncommon ophthalmologic complication of a rare disease.

Interventional case report.

A 16-year-old girl with type III Gaucher disease experienced visual loss in both eyes. Ophthalmologic examination revealed dense whitish vitreous opacities and macular pucker OU. Visual acuity (VA) OD was 20/63 and OS was 20/25. She underwent 25-gauge vitrectomy with removal of the vitreous core, posterior vitreous cortex, and indocyanine green?stained internal limiting membrane OD. Visual acuity improved, reaching 20/25 1 year after surgery despite the appearance of small preretinal flecks. Visual acuity OS decreased some time later and vitrectomy was performed when VA OS was 20/100. Three years after surgery, BCVA was 20/25 OD and 20/20 OS 1 year after surgery.

We describe a young patient with Gaucher disease with severe bilateral vitreous opacities and macular pucker. After surgery, vitreous opacities partially and progressively recurred, but the overall favorable outcome strongly supports a surgical approach in cases of this kind.

To report significant surgical results in an uncommon

    ophthalmologic complication
    SYMPTOMS

 of a

    rare disease
    DIAGNOSIS

.

    Interventional case report
    MEDICATION

.

A

    16-year-old
    AGE

    girl
    GENDER

 with

    type III Gaucher disease
    DIAGNOSIS

 experienced

    visual loss in both eyes
    SYMPTOMS

.

    Ophthalmologic examination
    PARACLINICAL

 revealed

    dense whitish vitreous opacities
    SYMPTOMS

 and

    macular pucker OU
    SYMPTOMS

.

    Visual acuity (VA) OD was 20/63 and OS was 20/25
    SYMPTOMS

.

    She
    GENDER

 underwent

    25-gauge vitrectomy with removal of the vitreous core, posterior vitreous cortex, and indocyanine green?stained internal limiting membrane OD
    MEDICATION

.

    Visual acuity improved, reaching 20/25
    SYMPTOMS

 1 year after

    surgery
    MEDICATION

    despite the appearance of small preretinal flecks
    NEG_FINDINGS

.

    Visual acuity OS decreased
    SYMPTOMS

 some time later and

    vitrectomy
    MEDICATION

 was performed when

    VA OS was 20/100
    SYMPTOMS

. Three years after

    surgery
    MEDICATION

,

    BCVA was 20/25 OD and 20/20 OS
    SYMPTOMS

 1 year after

    surgery
    MEDICATION

.

We describe a

    young
    AGE

 patient with

    Gaucher disease
    DIAGNOSIS

 with

    severe bilateral vitreous opacities
    SYMPTOMS

 and

    macular pucker
    SYMPTOMS

. After

    surgery
    MEDICATION

,

    vitreous opacities partially and progressively recurred
    SYMPTOMS

, but the overall favorable outcome strongly supports a

    surgical approach
    MEDICATION

 in cases of this kind.

rare disease
type III Gaucher disease
Gaucher disease


Gaucher disease with prenatal onset and perinatal death due to compound heterozygosity for the missense R131C and null Rec Nci I GBA mutations.

Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45). Three clinical forms of Gaucher disease have been described: type 1, nonneuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic (OMIM 230800, 230900, 231000). Over the past decade, recognition of a distinct, perinatal lethal form of Gaucher disease (PLGD) has led researchers and clinicians to evaluate Gaucher disease in the differential diagnosis of congenital ichthyosis and nonimmune hydrops fetalis. To date, more than 30 cases of PLGD have been genotyped and reported. It has been observed that homozygosity for recombinant GBA alleles, which are fundamentally null alleles, leads to early lethality, usually in utero or during the 1st few days of life, whereas genotypes involving a recombinant allele and a missense mutation may be less detrimental. Here, we report a case of Gaucher disease with prenatal onset and death within hours of birth, likely due to compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation. In view of the patient's severe clinical course, and based on reviews of other PLGD cases, we postulate that a missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele, may result in early lethality in patients with PLGD. We also speculate that R131C is an extremely severe mutation that has occurred more than once in different populations and, in either the homozygous form or heterozygous with another severe mutation, will result in a poor prognosis.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal recessive disorder
    GENETICS

 resulting from

    deficient activity of the lysosomal enzyme glucocerebrosidase (GBA
    BIOCHEMICAL

, E.C.3.2.1.45). Three clinical forms of

    Gaucher disease
    DIAGNOSIS

 have been described:

    type 1, nonneuronopathic
    DIAGNOSIS

;

    type 2, acute neuronopathic
    DIAGNOSIS

; and

    type 3, subacute neuronopathic
    DIAGNOSIS

 (

    OMIM 230800
    GENETICS

, 230900, 231000). Over the past decade, recognition of a distinct,

    perinatal lethal form of Gaucher disease (PLGD)
    DIAGNOSIS

 has led researchers and clinicians to evaluate

    Gaucher disease
    DIAGNOSIS

 in the

    differential diagnosis
    PARACLINICAL

 of

    congenital ichthyosis
    DIAGNOSIS

 and

    nonimmune hydrops fetalis
    DIAGNOSIS

. To date, more than 30 cases of

    PLGD
    DIAGNOSIS

 have been genotyped and reported. It has been observed that

    homozygosity for recombinant GBA alleles, which are fundamentally null alleles
    GENETICS

, leads to

    early lethality
    SYMPTOMS

, usually

    in utero or during the 1st few days of life
    AGE

, whereas

    genotypes involving a recombinant allele and a missense mutation
    GENETICS

 may be less detrimental. Here, we report a case of

    Gaucher disease
    DIAGNOSIS

 with

    prenatal onset
    SYMPTOMS

 and

    death
    SYMPTOMS

    within hours of birth
    AGE

, likely due to

    compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation
    GENETICS

. In view of the patient's severe clinical course, and based on reviews of other

    PLGD
    DIAGNOSIS

 cases, we postulate that a

    missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele
    GENETICS

, may result in

    early lethality
    SYMPTOMS

 in patients with

    PLGD
    DIAGNOSIS

. We also speculate that

    R131C
    GENETICS

 is an

    extremely severe mutation
    GENETICS

 that has occurred more than once in different populations and, in either the

    homozygous form or heterozygous with another severe mutation
    GENETICS

, will result in a poor prognosis.

early lethality
prenatal onset
death
early lethality


Perinatal lethal Gaucher disease.

Perinatal Lethal Gaucher Disease (PLGD) is a rare form of Gaucher disease and is often considered a distinct form of type 2 Gaucher disease. The authors report on an infant who presented with progressive hepatosplenomegaly, ichthyosis, generalized skin edema and neonatal encephalopathy and died at 6 h of age. Autopsy revealed massive hepatosplenomegaly, ichthyosis, a diffuse collodion picture and histological evidence of infiltration by Gaucher cells in the liver, spleen, lung, thymus, lymph node and bone marrow. Genetic testing of the parents revealed both to be carriers of Gaucher disease.

    Perinatal Lethal Gaucher Disease (PLGD)
    DIAGNOSIS

 is a

    rare form of Gaucher disease
    DIAGNOSIS

 and is often considered a distinct form of

    type 2 Gaucher disease
    DIAGNOSIS

. The authors report on an

    infant
    AGE

 who presented with

    progressive hepatosplenomegaly
    SYMPTOMS

,

    ichthyosis
    SYMPTOMS

,

    generalized skin edema
    SYMPTOMS

 and

    neonatal encephalopathy
    SYMPTOMS

 and

    died
    SYMPTOMS

    at 6 h of age
    AGE

.

    Autopsy
    PARACLINICAL

 revealed

    massive hepatosplenomegaly
    SYMPTOMS

,

    ichthyosis
    SYMPTOMS

, a

    diffuse collodion picture
    SYMPTOMS

 and

    histological evidence of infiltration by Gaucher cells in the liver, spleen, lung, thymus, lymph node and bone marrow
    MICROSCOPIC

.

    Genetic testing of the parents revealed both to be carriers of Gaucher disease
    FAMILY

.

Perinatal Lethal Gaucher Disease (PLGD)
rare form of Gaucher disease
type 2 Gaucher disease

progressive hepatosplenomegaly
ichthyosis
generalized skin edema
neonatal encephalopathy
died
massive hepatosplenomegaly
ichthyosis
diffuse collodion picture