Abdominal lymphadenopathy in children with Gaucher disease: Relation to disease severity and glucosylsphingosine.

Few case reports and series reported abdominal lymphadenopathy (ALN) in people with Gaucher disease (GD). However, it's prevalence among Gaucher population, clinical implications and potential biomarkers are unknown. Hence this study aims to assess the prevalence of ALN among children with GD & to correlate it to neutrophil-lymphocytic-ratio (NLR), platelet-lymphocytic-ratio (PLR) and glucosylsphingosine (Lyso-GL1). Fifty children with GD (14 type-1 and 36 type-3) on enzyme-replacement therapy (ERT) were compared to 50 matched healthy controls, focusing on history of pressure manifestations by ALN (diarrhea, constipation, abdominal pain, intestinal obstruction), and history of splenectomy, with calculation of severity scoring index (SSI). NLR, PLR and Lyso-GL1 were measured. Abdominal-ultrasound was done with assessment of liver and spleen volumes and ALN. CT-scan was done for those having significant lymphadenopathy. Twenty-six children with GD had ALN (52%). The most common presentations were abdominal-pain (22%) & constipation (18%), with intestinal-obstruction in 3 children (6%). Children with GD had significantly higher NLR (p < .001) and decreased PLR (p = .024) compared to controls. Interestingly, children with GD having ALN had significantly higher SSI (.012), Lyso-GL1 (p = .002) and NLR (p = .001) than those without ALN. Multivariate-logistic regression showed that ALN was independently related to Lyso-GL1 (p = .027), NLR (p = .023) and SSI (p = .032). Thus, ALN is a prevalent GD morbidity with wide clinical-spectrum ranging from asymptomatic cases to intestinal obstruction. ALN is related to SSI, NLR and Lyso-GL1 in children with GD.HighlightsChildren with GD had significantly higher NLR and lower PLR compared to controls.Children with GD having ALN had significantly higher SSI, Lyso-GL1 and NLR than those without ALN.ALN was independently related to Lyso-GL1, NLR and SSI in children with GD.

Few case reports and series reported

    abdominal lymphadenopathy (ALN)
    DIAGNOSIS

 in people with

    Gaucher disease (GD)
    DIAGNOSIS

. However, it's prevalence among

    Gaucher
    DIAGNOSIS

 population, clinical implications and potential biomarkers are unknown. Hence this study aims to assess the prevalence of

    ALN
    DIAGNOSIS

 among

    children
    AGE

 with

    GD
    DIAGNOSIS

 & to correlate it to

    neutrophil-lymphocytic-ratio (NLR), platelet-lymphocytic-ratio (PLR)
    BIOCHEMICAL

 and

    glucosylsphingosine (Lyso-GL1)
    BIOCHEMICAL

. Fifty

    children
    AGE

 with

    GD
    DIAGNOSIS

 (14

    type-1
    DIAGNOSIS

 and 36

    type-3)
    DIAGNOSIS

 on

    enzyme-replacement therapy (ERT)
    MEDICATION

 were compared to 50 matched healthy controls, focusing on history of

    pressure manifestations by ALN
    SYMPTOMS

 (

    diarrhea
    SYMPTOMS

,

    constipation
    SYMPTOMS

,

    abdominal pain
    SYMPTOMS

,

    intestinal obstruction
    SYMPTOMS

), and

    history of splenectomy
    MEDICATION

, with calculation of

    severity scoring index (SSI)
    PARACLINICAL

.

    NLR, PLR and Lyso-GL1
    BIOCHEMICAL

    were measured
    PARACLINICAL

.

    Abdominal-ultrasound
    PARACLINICAL

 was done with

    assessment of liver and spleen volumes
    PARACLINICAL

 and

    ALN
    PARACLINICAL

.

    CT-scan
    PARACLINICAL

 was done for those having

    significant lymphadenopathy
    SYMPTOMS

. Twenty-six

    children
    AGE

 with

    GD
    DIAGNOSIS

 had

    ALN
    DIAGNOSIS

 (52%). The most common presentations were

    abdominal-pain
    SYMPTOMS

 (22%) &

    constipation
    SYMPTOMS

 (18%), with

    intestinal-obstruction
    SYMPTOMS

 in 3

    children
    AGE

 (6%).

    Children
    AGE

 with

    GD
    DIAGNOSIS

 had significantly

    higher NLR
    BIOCHEMICAL

 (p < .001) and

    decreased PLR
    BIOCHEMICAL

 (p = .024) compared to controls. Interestingly,

    children
    AGE

 with

    GD
    DIAGNOSIS

 having

    ALN
    DIAGNOSIS

 had significantly

    higher SSI
    BIOCHEMICAL

 (.012)

    , Lyso-GL1
    BIOCHEMICAL

 (p = .002)

    and NLR
    BIOCHEMICAL

 (p = .001) than those without

    ALN
    DIAGNOSIS

.

    Multivariate-logistic regression
    PARACLINICAL

 showed that

    ALN
    DIAGNOSIS

 was independently related to

    Lyso-GL1
    BIOCHEMICAL

 (p = .027),

    NLR
    BIOCHEMICAL

 (p = .023) and

    SSI
    SYMPTOMS

 (p = .032). Thus,

    ALN
    DIAGNOSIS

 is a prevalent

    GD morbidity
    DIAGNOSIS

 with wide clinical-spectrum ranging from

    asymptomatic cases
    SYMPTOMS

 to

    intestinal obstruction
    SYMPTOMS

.

    ALN
    DIAGNOSIS

 is related to

    SSI
    BIOCHEMICAL

,

    NLR and Lyso-GL1
    BIOCHEMICAL

 in

    children
    AGE

 with GD.HighlightsChildren with

    GD
    DIAGNOSIS

 had

    significantly higher NLR and lower PLR
    BIOCHEMICAL

 compared to controls.

    Children
    AGE

 with

    GD
    DIAGNOSIS

 having

    ALN
    DIAGNOSIS

 had significantly

    higher SSI, Lyso-GL1 and NLR
    BIOCHEMICAL

 than those without ALN.ALN was independently related to

    Lyso-GL1, NLR
    BIOCHEMICAL

 and

    SSI
    BIOCHEMICAL

 in

    children
    AGE

 with

    GD
    DIAGNOSIS

.

abdominal lymphadenopathy (ALN)
Gaucher disease (GD)
Gaucher
ALN
GD
GD
type-1
type-3)
GD
ALN
GD
GD
ALN
ALN
ALN
ALN
GD morbidity
ALN
GD
GD
ALN
GD

enzyme-replacement therapy (ERT)
history of splenectomy

pressure manifestations by ALN
diarrhea
constipation
abdominal pain
intestinal obstruction
significant lymphadenopathy
abdominal-pain
constipation
intestinal-obstruction
SSI
asymptomatic cases
intestinal obstruction


Gaucher's Disease in an Adult Female: A Rare Entity.

Gaucher's disease is a rare inborn error of metabolism with an autosomal recessive pattern of inheritance. With over 26 million births occurring per annum, extrapolation of this figure would give us an estimated burden of 17,000 babies born with lysosomal storage disorder (LSD). Given the large population of India and the high rates of consanguineous marriage that takes place in the subcontinent, LSD might not be as rare as we perceive it to be. We report a rare occurrence of type-1 Gaucher's disease in an adult female patient born of a non-consanguineous marriage, belonging to the tropical area of Chhattisgarh, India where there is a predominance of malaria, thalassemia, and sickling. The diagnosis was challenging in this case since we needed to work out all the differential diagnoses of pancytopenia with hepatomegaly and massive splenomegaly. The key part was her medical history where there was documentation of her elder brother's death due to some mental illness of undiagnosed etiology. Being a difficult time due to coronavirus disease 2019 ( COVID-19), we were able to diagnose the patient with a bone marrow biopsy followed by glucocerebrosidase enzyme level suggestive of Gaucher's disease.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare inborn error of metabolism
    DIAGNOSIS

 with an

    autosomal recessive pattern of inheritance
    GENETICS

. With over 26 million births occurring per annum, extrapolation of this figure would give us an estimated burden of 17,000 babies born with

    lysosomal storage disorder (LSD)
    DIAGNOSIS

. Given the large population of

    India
    ETHNICITY

 and the high rates of

    consanguineous marriage
    GENETICS

 that takes place in the subcontinent,

    LSD
    DIAGNOSIS

 might not be as rare as we perceive it to be. We report a rare occurrence of

    type-1 Gaucher's disease
    DIAGNOSIS

 in an

    adult
    AGE

    female
    GENDER

 patient

    born of a non-consanguineous marriage
    FAMILY

, belonging to the tropical area of

    Chhattisgarh
    ETHNICITY

,

    India
    ETHNICITY

 where there is a predominance of

    malaria
    SYMPTOMS

,

    thalassemia
    DIAGNOSIS

, and

    sickling
    SYMPTOMS

. The diagnosis was challenging in this case since we needed to work out all the

    differential diagnoses
    PARACLINICAL

 of

    pancytopenia
    BIOCHEMICAL

 with

    hepatomegaly
    SYMPTOMS

 and

    massive splenomegaly
    SYMPTOMS

. The key part was

    her
    GENDER

 medical history where there was documentation of

    her elder brother's death due to some mental illness of undiagnosed etiology
    FAMILY

. Being a difficult time due to coronavirus disease 2019 ( COVID-19), we were able to diagnose the patient with a

    bone marrow biopsy
    PARACLINICAL

 followed by

    glucocerebrosidase enzyme level
    PARACLINICAL

 suggestive of

    Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease
rare inborn error of metabolism
lysosomal storage disorder (LSD)
LSD
type-1 Gaucher's disease
thalassemia
Gaucher's disease

malaria
sickling
hepatomegaly
massive splenomegaly


Gaucher disease type 1: the first experience of enzyme replacement therapy in pediatric practice in Moldova - case report.

We report on a case of a little girl patient diagnosed with Gaucher disease (GD) type 1 in her early childhood and our first experience with enzyme replacement therapy (ERT). She was first diagnosed accidentally with enlarged spleen during a pediatric examination when she was three years old, but the family ignored investigations; she was hospitalized for diagnosis at six years old. The GD was confirmed based on: clinical manifestations of left abdominal flank pain, multiple bruising, general weakness, bone pain, low appetite, failure to thrive <5th percentile, minor hepato- and severe splenomegaly, enlarged submaxillary lymph nodes, associated by anemia with normal platelets; low activity of beta-Glucosidase, two found mutations in GBA gene, Gaucher cells in bone marrow. The ERT was initiated with Imiglucerase (54 UI/kg/2 wks) two years later after diagnosis, avoiding the splenectomy. Subsequently, the platelets showed the first a promising result, gradually increasing their number every 2 weeks and maintaining it in good parameters till the reported moment (2.5 yrs from the start). The hemoglobin level was appreciated within normal ranges 3 months after ERT start and stabilized completely after 6 months. On the other hand, the red blood count normalized within 20 months of applied therapy. The Lyso-GL-1 decreased by 30% after three months of therapy, no antibodies to Imiglucerase were found. The initial spleen volume (1178.19 cm3) decreased by almost 60% in 6 months of ERT, reaching absolutely normal dimensions after 9 months. The ERT with Imiglucerase was tolerated very well by the patient, showing a clear improvement of clinical symptoms after 4-6 months of therapy, hematological picture and splenomegaly solving. Even if the little patient had to come every 2 weeks for infusion, her quality of life improved a lot, being a totally happy child, going to school and having friends. The ERT should be initiated immediately after diagnosis to prevent the multisystem complications.

We report on a case of a

    little
    AGE

    girl
    GENDER

 patient diagnosed with

    Gaucher disease (GD) type 1
    DIAGNOSIS

 in

    her early childhood
    AGE

 and our first experience with

    enzyme replacement therapy (ERT)
    MEDICATION

.

    She
    GENDER

 was first diagnosed accidentally with

    enlarged spleen
    SYMPTOMS

 during a pediatric examination when

    she
    GENDER

    was three years old
    AGE

, but the

    family ignored investigations
    NEG_FINDINGS

;

    she
    GENDER

 was hospitalized for diagnosis at

    six years old
    AGE

. The

    GD
    DIAGNOSIS

 was confirmed based on: clinical manifestations of

    left abdominal flank pain
    SYMPTOMS

,

    multiple bruising
    SYMPTOMS

,

    general weakness
    SYMPTOMS

,

    bone pain
    SYMPTOMS

,

    low appetite
    SYMPTOMS

,

    failure to thrive <5th percentile
    SYMPTOMS

,

    minor hepato- and severe splenomegaly
    SYMPTOMS

,

    enlarged submaxillary lymph nodes
    SYMPTOMS

, associated by

    anemia
    BIOCHEMICAL

 with

    normal platelets
    BIOCHEMICAL

;

    low activity of beta-Glucosidase
    BIOCHEMICAL

,

    two found mutations in GBA gene
    GENETICS

,

    Gaucher cells in bone marrow
    MICROSCOPIC

. The

    ERT
    MEDICATION

 was

    initiated with Imiglucerase (54 UI/kg/2 wks)
    MEDICATION

 two years later after diagnosis,

    avoiding the splenectomy
    NEG_FINDINGS

. Subsequently, the

    platelets showed the first a promising result
    BIOCHEMICAL

,

    gradually increasing their number every 2 weeks
    BIOCHEMICAL

 and

    maintaining it in good parameters
    BIOCHEMICAL

 till the reported moment (2.5 yrs from the start). The

    hemoglobin level was appreciated within normal ranges
    BIOCHEMICAL

 3 months after

    ERT start
    MEDICATION

 and

    stabilized completely after 6 months
    BIOCHEMICAL

. On the other hand,

    the red blood count normalized
    BIOCHEMICAL

 within

    20 months of applied therapy
    MEDICATION

. The

    Lyso-GL-1 decreased by 30%
    BIOCHEMICAL

 after

    three months of therapy
    MEDICATION

,

    no antibodies to Imiglucerase were found
    NEG_FINDINGS

. The

    initial spleen volume (1178.19 cm3) decreased by almost 60%
    SYMPTOMS

 in 6

    months of ERT
    MEDICATION

,

    reaching absolutely normal dimensions
    SYMPTOMS

 after 9

    months
    SYMPTOMS

. The

    ERT with Imiglucerase
    MEDICATION

 was tolerated very well by the patient, showing a

    clear improvement of clinical symptoms
    SYMPTOMS

 after

    4-6 months of therapy
    MEDICATION

,

    hematological picture
    BIOCHEMICAL

 and

    splenomegaly solving
    SYMPTOMS

. Even if the little patient had to come every 2 weeks for infusion,

    her
    GENDER

 quality of life improved a lot, being a totally happy child, going to school and having friends. The

    ERT
    MEDICATION

 should be initiated immediately after diagnosis to prevent the

    multisystem complications
    SYMPTOMS

.


Pediatric Gaucher disease with intermediate type 2-3 phenotype associated with parkinsonian features and levodopa responsiveness.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid β-glucosidase encoded by the GBA gene. In patients with GD, childhood onset parkinsonian features have been rarely described.

Twin siblings with GD are described, including clinical follow-up and treatment response. Bone marrow, enzyme activity studies and genotyping were performed.

By age 9 months, symptoms at onset were thrombocytopenia and splenomegaly. By age 2, hypokinesia, bradykinesia and oculomotor apraxia were observed. By age 5 a complete rigid hypokinetic syndrome was stablished in both patients, including bradykinesia, tremor and rigidity. Treatment with imiglucerase, miglustat, ambroxol and levodopa were performed. Levodopa showed a good response with improvement in motor and non-motor skills. Foamy cells were found in the bone marrow study. Glucocerebrosidase activity was 28% and 26%. Sanger sequencing analysis identified a missense mutation and a complex allele (NP_000148: p.[(Asp448His)]; [(Leu422Profs*4)]) in compound heterozygosity in GBA gene.

Two siblings with neuronopathic GD with an intermediate form between type 2 and 3, with a systemic and neurological phenotype are described. The complex neurological picture included a hypokinetic-rigid and tremor syndrome that improved with levodopa treatment. These conditions together have not been previously described in pediatric GD. We suggest that in children with parkinsonian features, lysosomal storage disorders must be considered, and a levodopa trial must be performed. Moreover, this report give support to the finding that GBA and parkinsonian features share biological pathways and highlight the importance of lysosomal mechanisms in parkinsonism pathogenesis, what might have therapeutic implications.

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of acid β-glucosidase encoded by the GBA gene
    BIOCHEMICAL

. In patients with

    GD
    DIAGNOSIS

,

    childhood onset parkinsonian features
    AGE

 have been rarely described.

    Twin siblings with GD
    FAMILY

 are described, including

    clinical follow-up
    PARACLINICAL

 and treatment response.

    Bone marrow, enzyme activity studies
    PARACLINICAL

 and

    genotyping
    PARACLINICAL

 were performed.

By

    age 9 months
    AGE

, symptoms at onset were

    thrombocytopenia
    BIOCHEMICAL

 and

    splenomegaly
    SYMPTOMS

. By

    age 2
    AGE

,

    hypokinesia
    SYMPTOMS

,

    bradykinesia
    SYMPTOMS

 and

    oculomotor apraxia
    SYMPTOMS

 were observed. By

    age 5
    AGE

 a

    complete rigid hypokinetic syndrome
    SYMPTOMS

 was stablished in both patients, including

    bradykinesia, tremor and rigidity
    SYMPTOMS

.

    Treatment with imiglucerase, miglustat, ambroxol and levodopa
    MEDICATION

 were performed.

    Levodopa
    MEDICATION

 showed a good response with

    improvement in motor and non-motor skills
    SYMPTOMS

.

    Foamy cells were found in the bone marrow study
    MICROSCOPIC

.

    Glucocerebrosidase activity was 28% and 26%
    BIOCHEMICAL

.

    Sanger sequencing analysis
    PARACLINICAL

 identified a

    missense mutation and a complex allele (NP_000148: p.[(Asp448His)]; [(Leu422Profs*4)]) in compound heterozygosity in GBA gene
    GENETICS

.

Two siblings with

    neuronopathic GD with an intermediate form between type 2 and 3
    DIAGNOSIS

, with a

    systemic and neurological phenotype
    SYMPTOMS

 are described. The

    complex neurological picture
    SYMPTOMS

 included a

    hypokinetic-rigid and tremor syndrome
    SYMPTOMS

 that improved with

    levodopa treatment
    MEDICATION

. These conditions together have not been previously described in

    pediatric
    AGE

    GD
    DIAGNOSIS

. We suggest that in

    children
    AGE

 with

    parkinsonian features
    SYMPTOMS

,

    lysosomal storage disorders
    DIAGNOSIS

 must be considered, and a

    levodopa trial
    MEDICATION

 must be performed. Moreover, this report give support to the finding that

    GBA
    MICROSCOPIC

 and

    parkinsonian features
    SYMPTOMS

 share

    biological pathways
    SYMPTOMS

 and highlight the importance of

    lysosomal mechanisms
    SYMPTOMS

 in

    parkinsonism
    DIAGNOSIS

 pathogenesis, what might have therapeutic implications.


A very rare cause of protein losing enteropathy: Gaucher disease.

Mesenteric lymphadenopathy is a rare manifestation of Gaucher disease (GD) in children and can be accompanied by protein losing enteropathy (PLE). PLE is a difficult-to-treat complication of GD. To date, only a few pediatric GD cases with PLE and massive mesenteric lymphadenopathies have been reported.

Here, we report a girl with chronic neuronopathic GD, whose disease course was complicated by massive mesenteric lymphadenopathies with resultant protein losing enteropathy despite a regular and appropriate enzyme replacement therapy of 60 IU/kg/biweekly until the development of mesenteric lymphadenopathies and 120 IU/kg/biweekly thereafter.

PLE is a devastating and life threatening complication of GD developing despite long term use of high dose ERT. Clinicians should be alert for this complication particularly in GD patients presenting with progressive abdominal distension, edema, ascites and diarrhea or in patients who have already developed mesenteric lymphadenopathies. Timely diagnosis may allow early intervention with previously suggested surgical or medical treatment options. Although there is no specific and effective treatment, surgical and aggressive medical interventions in addition to ERT were reported to relieve diarrhea and halt progression of mesenteric lymphadenopathies.

    Mesenteric lymphadenopathy
    SYMPTOMS

 is a rare manifestation of

    Gaucher disease (GD)
    DIAGNOSIS

 in

    children
    AGE

 and can be accompanied by

    protein losing enteropathy (PLE)
    BIOCHEMICAL

.

    PLE
    DIAGNOSIS

 is a difficult-to-treat complication of

    GD
    DIAGNOSIS

. To date, only a few

    pediatric
    AGE

    GD
    DIAGNOSIS

 cases with

    PLE
    SYMPTOMS

 and

    massive mesenteric lymphadenopathies
    SYMPTOMS

 have been reported.

Here, we report a

    girl
    GENDER

 with

    chronic neuronopathic GD
    DIAGNOSIS

, whose disease course was complicated by

    massive mesenteric lymphadenopathies
    SYMPTOMS

 with resultant

    protein losing enteropathy
    BIOCHEMICAL

    despite a regular and appropriate enzyme replacement therapy of 60 IU/kg/biweekly
    NEG_FINDINGS

 until the development of

    mesenteric lymphadenopathies
    SYMPTOMS

    and 120 IU/kg/biweekly thereafter
    MEDICATION

.

    PLE
    DIAGNOSIS

 is a devastating and life threatening complication of

    GD
    DIAGNOSIS

 developing

    despite long term use of high dose ERT
    NEG_FINDINGS

. Clinicians should be alert for this complication particularly in

    GD
    DIAGNOSIS

 patients presenting with

    progressive abdominal distension
    SYMPTOMS

,

    edema
    SYMPTOMS

,

    ascites
    SYMPTOMS

 and

    diarrhea
    SYMPTOMS

 or in patients who have already developed

    mesenteric lymphadenopathies
    SYMPTOMS

. Timely diagnosis may allow

    early intervention with previously suggested surgical or medical treatment options
    MEDICATION

. Although there is no specific and effective treatment,

    surgical and aggressive medical interventions in addition to ERT
    MEDICATION

 were reported to

    relieve diarrhea
    SYMPTOMS

 and

    halt progression of mesenteric lymphadenopathies
    SYMPTOMS

.

Gaucher disease (GD)
PLE
GD
GD
chronic neuronopathic GD
PLE
GD
GD

protein losing enteropathy (PLE)
protein losing enteropathy


Perinatal-lethal Gaucher disease presenting with blueberry muffin lesions.

"Blueberry muffin baby" is an expression applied to newborns displaying a generalized purpuric rash caused by dermal erythropoiesis. This presentation is typically associated with TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpesvirus) complex infections. However, alternative diagnoses should be considered, including other infections, neoplastic diseases, congenital vascular lesions, and metabolic diseases. We report a case of perinatal-lethal-type Gaucher disease presenting with cholestasis, hepatosplenomegaly, persistent thrombocytopenia, and blueberry muffin-like skin lesions.

"

    Blueberry muffin baby"
    SYMPTOMS

 is an expression applied to

    newborns
    AGE

 displaying a

    generalized purpuric rash caused by dermal erythropoiesis
    SYMPTOMS

. This presentation is typically associated with

    TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpesvirus) complex infections
    DIAGNOSIS

. However, alternative diagnoses should be considered, including

    other infections
    DIAGNOSIS

,

    neoplastic diseases
    DIAGNOSIS

,

    congenital vascular lesions
    SYMPTOMS

, and

    metabolic diseases
    DIAGNOSIS

. We report a case of

    perinatal-lethal-type Gaucher disease
    DIAGNOSIS

 presenting with

    cholestasis
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

,

    persistent thrombocytopenia
    BIOCHEMICAL

, and

    blueberry muffin-like skin lesions
    SYMPTOMS

.


An unusual case of T-cell acute lymphoblastic leukemia in a patient with BCR-ABL positive chronic myeloid leukemia and Gaucher disease.

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disease characterized by a massive overproduction of myeloid cells. It is associated with the Philadelphia chromosome [Ph1, t (9; 22) (q34; q11)] or BCR-ABL fusion gene. CML usually undergoes a triphasic clinical course ending in a blast crisis, an accelerated phase of blasts and promyelocyte production. Ten percent of CML patients reach the blast crisis phase, with 20-30% of leukemias belonging to B-cell lymphoid lineage. However, a transformation of CML into T-cell acute lymphoblastic leukemia (T-ALL) is rare.

We present a 56-year-old male patient, known case of hypertension and Ph1 CML of eight years with a family history of Gaucher disease who developed T-ALL. The patient presented with lymphadenopathy and severe anemia, needing packed RBC transfusion, neutropenia and thrombocytopenia at the admission. However, the monocytes and basophils percentage were high. The patient underwent a cervical lymph node core biopsy, and the immunohistochemistry stains showed an invasion of neoplastic cells positive for CD3, CD5, BCL2, CD34, TdT and focally positive for C-Kit and negative for CD20, CD56 and pan-CK. These histopathology features were consistent with T-cell acute lymphoblastic leukemia (T-ALL).

Blast crisis remain a challenge in CML management. It's of great importance to do a full proper workup including lymph nodes biopsies. The aim is to reverse blast crisis and restore the chronic phase.

    Chronic myelogenous leukemia (CML)
    DIAGNOSIS

 is a

    chronic myeloproliferative disease
    DIAGNOSIS

 characterized by a

    massive overproduction of myeloid cells
    MICROSCOPIC

. It is associated with the

    Philadelphia chromosome [Ph1, t (9; 22) (q34; q11)] or BCR-ABL fusion gene
    GENETICS

.

    CML
    DIAGNOSIS

 usually undergoes a

    triphasic
    DIAGNOSIS

 clinical course ending in a

    blast crisis
    DIAGNOSIS

, an

    accelerated phase of blasts and promyelocyte production
    MICROSCOPIC

. Ten percent of

    CML
    DIAGNOSIS

 patients reach the blast crisis phase, with 20-30% of

    leukemias
    DIAGNOSIS

 belonging to

    B-cell lymphoid lineage
    MICROSCOPIC

. However, a

    transformation of CML into T-cell acute lymphoblastic leukemia (T-ALL)
    DIAGNOSIS

 is rare.

We present a

    56-year-old
    AGE

    male
    GENDER

 patient,

    known case of hypertension
    FAMILY

 and

    Ph1 CML of eight years
    DIAGNOSIS

 with a

    family history of Gaucher disease
    FAMILY

 who developed

    T-ALL
    DIAGNOSIS

. The patient presented with

    lymphadenopathy
    SYMPTOMS

 and

    severe anemia
    BIOCHEMICAL

, needing

    packed RBC transfusion
    MEDICATION

,

    neutropenia
    BIOCHEMICAL

 and

    thrombocytopenia
    BIOCHEMICAL

 at the admission. However, the

    monocytes and basophils percentage were high
    BIOCHEMICAL

. The patient underwent a

    cervical lymph node core biopsy
    PARACLINICAL

, and the

    immunohistochemistry stains
    PARACLINICAL

 showed an

    invasion of neoplastic cells positive for CD3, CD5, BCL2, CD34, TdT and focally positive for C-Kit
    MICROSCOPIC

 and

    negative for CD20, CD56 and pan-CK
    NEG_FINDINGS

. These histopathology features were consistent with

    T-cell acute lymphoblastic leukemia (T-ALL)
    DIAGNOSIS

.

    Blast crisis
    DIAGNOSIS

 remain a challenge in

    CML
    DIAGNOSIS

 management. It's of great importance to do a full proper workup including

    lymph nodes biopsies
    PARACLINICAL

. The aim is to reverse

    blast crisis
    DIAGNOSIS

 and

    restore the chronic phase
    SYMPTOMS

.

lymphadenopathy
restore the chronic phase


[Perinatal lethal Gaucher disease. Case report].

The paper describes a case of a perinatal lethal Gaucher disease in a 29-week-old fetus with non-immune hydrops, facial dysmorphia, hepatosplenomegaly, and hypoplasia of cerebellum and pons. Gaucher cells were found in the lymph nodes, spleen, lungs, thymus, cerebellum, and bone marrow. No storage cells have been detected in the placenta. There was a significant placental weight increase due to swelling. The diagnosis of Gaucher disease was confirmed by biochemical analysis (deficiency of glucocerebrosidase activity and sharply increased hexanoylsphingosine concentration) and molecular genetic techniques (the presence of two mutations of the GBA gene). Our observation shows that characteristic histologic signs of disease can be detected at early stages of development.

The paper describes a case of a

    perinatal lethal Gaucher disease
    DIAGNOSIS

 in a

    29-week-old
    AGE

    fetus
    AGE

 with

    non-immune hydrops
    SYMPTOMS

,

    facial dysmorphia
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

, and

    hypoplasia of cerebellum and pons
    SYMPTOMS

.

    Gaucher cells were found in the lymph nodes, spleen, lungs, thymus, cerebellum, and bone marrow
    MICROSCOPIC

.

    No storage cells have been detected in the placenta
    NEG_FINDINGS

. There was a

    significant placental weight increase
    SYMPTOMS

 due to

    swelling
    SYMPTOMS

. The diagnosis of

    Gaucher disease
    DIAGNOSIS

 was confirmed by

    biochemical analysis
    PARACLINICAL

 (

    deficiency of glucocerebrosidase activity
    BIOCHEMICAL

 and

    sharply increased hexanoylsphingosine concentration
    BIOCHEMICAL

) and

    molecular genetic techniques
    PARACLINICAL

 (the

    presence of two mutations of the GBA gene
    GENETICS

). Our observation shows that

    characteristic histologic signs of disease
    SYMPTOMS

 can be detected at

    early stages of development
    AGE

.

perinatal lethal Gaucher disease
Gaucher disease


Case report: Gaucher disease in trepanobiopsy of 16yo woman examined for suspected myelodysplastic syndrome.

Gaucher disease is an autosomal recessive disease belonging to the so-called storage diseases. More than 300 mutations of the GBA1 gene encoding the β-glucocerebrosidase enzyme are known. It is a very rare disease in the Czech Republic. Currently 35 patients are treated. In our case report, we present the case of a 16 year old female patient attending the Clinic of Pediatric Medicine at the University Hospital in Ostrava. Since 2007, the patient has suffered prolonged thrombocytopenia, at the time with progression, and splenomegaly, which has not been further investigated. Trepanobiopsy was sent to the Department of Pathology with suspicion of myelodysplastic syndrome in May of 2018. In the biopsy examination, the individual bloodline did not show dysplastic features and the number of blasts was not increased. The marrow interstitium was 70% permeated with gaucher cells with intraplasmatic fibrous material. Cells were in the appearance of „crumpled paper“ and expressed CD68 in immunohistochemical stain and in histochemical examination of PAS and iron (Fe) staining. Based on a morphological finding, Gauchers disease was suspected. Repeated bone marrow aspirates were subsequently captured by gaucher cells, and a next biochemical examination showed a β-glucocerebrosidase enzyme decrease of activity. Gaucher disease is a progressive disease that requires early diagnosis with the onset of therapy.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal recessive disease
    GENETICS

 belonging to the so-called

    storage diseases
    DIAGNOSIS

. More than 300

    mutations of the GBA1 gene encoding the β-glucocerebrosidase enzyme
    GENETICS

 are known. It is a very rare disease in the

    Czech Republic
    ETHNICITY

. Currently 35 patients are treated. In our case report, we present the case of a

    16 year old
    AGE

    female
    GENDER

 patient attending the Clinic of Pediatric Medicine at the University Hospital in

    Ostrava
    ETHNICITY

. Since 2007, the patient has suffered

    prolonged thrombocytopenia
    BIOCHEMICAL

, at the time with progression, and

    splenomegaly
    SYMPTOMS

, which has

    not been further investigated
    NEG_FINDINGS

.

    Trepanobiopsy
    PARACLINICAL

 was sent to the

    Department of Pathology
    PARACLINICAL

 with suspicion of

    myelodysplastic syndrome
    DIAGNOSIS

 in May of 2018. In the

    biopsy examination
    PARACLINICAL

, the

    individual bloodline did not show dysplastic features
    NEG_FINDINGS

 and the

    number of blasts was not increased
    NEG_FINDINGS

.

    The marrow interstitium was 70% permeated with gaucher cells with intraplasmatic fibrous material
    MICROSCOPIC

.

    Cells were in the appearance of „crumpled paper“
    MICROSCOPIC

 and

    expressed CD68
    MICROSCOPIC

 in

    immunohistochemical stain
    PARACLINICAL

 and in

    histochemical examination of PAS and iron (Fe) staining
    PARACLINICAL

. Based on a morphological finding,

    Gauchers disease
    DIAGNOSIS

 was suspected.

    Repeated bone marrow aspirates
    PARACLINICAL

 were subsequently

    captured by gaucher cells
    MICROSCOPIC

, and a next

    biochemical examination
    PARACLINICAL

 showed a

    β-glucocerebrosidase enzyme decrease of activity
    BIOCHEMICAL

.

    Gaucher disease
    DIAGNOSIS

 is a

    progressive disease
    DIAGNOSIS

 that requires early diagnosis with the onset of therapy.

Gaucher disease
storage diseases
myelodysplastic syndrome
Gauchers disease
Gaucher disease
progressive disease


Restrictive cardiomyopathy: A rare presentation of gaucher disease.

Restrictive cardiomyopathy is an unusual form of cardiomyopathy accounting only for 2%-5% of all pediatric cardiomyopathies. It is mostly idiopathic. Gaucher disease in association with restrictive cardiomyopathy is extremely rare. We herein report a case of cardiac failure in an 8-year-old male child caused by restrictive cardiomyopathy. Pathogenesis of which was attributed to Gaucher disease. In any case of restrictive cardiomyopathy, Gaucher disease should be included in differential diagnosis and investigated accordingly.

    Restrictive cardiomyopathy
    DIAGNOSIS

 is an unusual form of

    cardiomyopathy
    DIAGNOSIS

 accounting only for 2%-5% of all pediatric

    cardiomyopathies
    DIAGNOSIS

. It is mostly

    idiopathic
    DIAGNOSIS

.

    Gaucher disease
    DIAGNOSIS

 in association with

    restrictive cardiomyopathy
    DIAGNOSIS

 is extremely rare. We herein report a case of

    cardiac failure
    SYMPTOMS

 in an

    8-year-old
    AGE

    male
    GENDER

    child
    AGE

 caused by

    restrictive cardiomyopathy
    DIAGNOSIS

. Pathogenesis of which was attributed to

    Gaucher disease
    DIAGNOSIS

. In any case of

    restrictive cardiomyopathy
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

 should be included in

    differential diagnosis
    PARACLINICAL

 and investigated accordingly.

Restrictive cardiomyopathy
cardiomyopathy
cardiomyopathies
idiopathic
Gaucher disease
restrictive cardiomyopathy
restrictive cardiomyopathy
Gaucher disease
restrictive cardiomyopathy
Gaucher disease


Novel manifestations of Farber disease mimicking neuronopathic Gaucher disease.

Diagnosis of rare disorders requires heightened clinical acumen. When such disorders present with atypical or novel features, it adds to the diagnostic challenge. A 9-month-old female infant who had received a diagnosis of neonatal hepatitis due to cytomegalovirus infection at 2 months of age presented to our institute with developmental delay, fever, vomiting, feeding difficulty, breathlessness and features of elevated intracranial pressure due to hydrocephalus. Key examination findings with cholestatic jaundice as an early manifestation led to suspicion of type 4 Farber disease. Observation of hydrocephalus, hypertension, bilateral pinguecula and Erlenmeyer flask deformity of the femur were unusual findings for Farber disease. The child had few features (pinguecula, Erlenmeyer flask deformity and hydrocephalus) overlapping with Gaucher disease. Alternatively, prosaposin deficiency (Farber disease type 7) was another differential diagnosis. Diagnosis of Farber disease was confirmed by detection of foamy macrophages on skin biopsy and two homozygous missense variants in ASAH1 gene.

Diagnosis of

    rare disorders
    DIAGNOSIS

 requires heightened clinical acumen. When such disorders present with atypical or novel features, it adds to the diagnostic challenge. A

    9-month-old
    AGE

    female
    GENDER

    infant
    AGE

 who had received a diagnosis of

    neonatal hepatitis due to cytomegalovirus infection
    DIAGNOSIS

    at 2 months of age
    AGE

 presented to our institute with

    developmental delay
    SYMPTOMS

,

    fever
    SYMPTOMS

,

    vomiting
    SYMPTOMS

,

    feeding difficulty
    SYMPTOMS

,

    breathlessness
    SYMPTOMS

 and

    features of elevated intracranial pressure due to hydrocephalus
    SYMPTOMS

. Key examination findings with

    cholestatic jaundice
    SYMPTOMS

 as an early manifestation led to suspicion of

    type 4 Farber disease
    DIAGNOSIS

. Observation of

    hydrocephalus
    SYMPTOMS

,

    hypertension
    SYMPTOMS

,

    bilateral pinguecula
    SYMPTOMS

 and

    Erlenmeyer flask deformity of the femur
    SYMPTOMS

 were unusual findings for

    Farber disease
    DIAGNOSIS

. The

    child
    AGE

 had

    few features (pinguecula, Erlenmeyer flask deformity
    SYMPTOMS

 and

    hydrocephalus
    SYMPTOMS

    ) overlapping with Gaucher disease
    SYMPTOMS

. Alternatively,

    prosaposin deficiency
    BIOCHEMICAL

 (

    Farber disease type 7)
    DIAGNOSIS

 was another differential diagnosis. Diagnosis of

    Farber disease
    DIAGNOSIS

 was confirmed by

    detection of foamy macrophages on skin biopsy
    MICROSCOPIC

 and

    two homozygous missense variants in ASAH1 gene
    GENETICS

.


Elevated holo-transcobalamin in Gaucher disease type II: A case report.

Gaucher disease (GD), one of the most common lysosomal disorders, is caused by deficiency of β-glucocerebrosidase. Based on the presence and severity of neurological complications, GD is classified into types I, II (the most severe form), and III. Abnormalities in systemic markers of vitamin B12 (B12) metabolism have been reported in GD type I patients, suggesting a higher prevalence of B12 deficiency in these patients. A 2-month-old male with GD type II was admitted to the hospital presenting jaundice, hepatosplenomegaly, and ichthyosis. At admission, cholestasis and ascites, abnormal liver function enzymes, prolonged prothrombin time, and high levels of B12 were confirmed. Analysis of biomarkers of B12 status revealed elevated B12 and holo-transcobalamin (holo-TC) levels. The B12 profile found in our patient is the opposite to what is described for GD type I patients. Holo-TC may increase in inflammatory states or due to liver diseases. In GD, the accumulation of glucocerebroside may be a trigger that initiates a systemic inflammatory reaction, characterized by macrophage activation. We suggest higher levels of holo-TC could be associated with a more severe (neuronopathic) GD, and be a biomarker of GD type II.

    Gaucher disease (GD)
    DIAGNOSIS

, one of the most common

    lysosomal disorders
    DIAGNOSIS

, is caused by

    deficiency of β-glucocerebrosidase
    BIOCHEMICAL

. Based on the presence and severity of

    neurological complications
    SYMPTOMS

,

    GD
    DIAGNOSIS

 is classified into

    types I, II
    DIAGNOSIS

 (the most severe form), and

    III
    DIAGNOSIS

.

    Abnormalities in systemic markers of vitamin B12 (B12) metabolism
    BIOCHEMICAL

 have been reported in

    GD type I
    DIAGNOSIS

 patients, suggesting a higher prevalence of

    B12 deficiency
    BIOCHEMICAL

 in these patients. A

    2-month-old
    AGE

    male
    GENDER

 with

    GD type II
    DIAGNOSIS

 was admitted to the hospital presenting

    jaundice
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

, and

    ichthyosis
    SYMPTOMS

. At admission,

    cholestasis
    SYMPTOMS

 and

    ascites
    SYMPTOMS

,

    abnormal liver function enzymes
    BIOCHEMICAL

,

    prolonged prothrombin time
    BIOCHEMICAL

, and

    high levels of B12
    BIOCHEMICAL

 were confirmed.

    Analysis of biomarkers of B12 status
    PARACLINICAL

 revealed

    elevated B12 and holo-transcobalamin (holo-TC) levels
    BIOCHEMICAL

. The

    B12 profile
    BIOCHEMICAL

 found in our patient is the opposite to what is described for

    GD type I
    DIAGNOSIS

 patients.

    Holo-TC may increase
    BIOCHEMICAL

 in inflammatory states or due to

    liver diseases
    DIAGNOSIS

. In

    GD
    DIAGNOSIS

, the

    accumulation of glucocerebroside
    MICROSCOPIC

 may be a trigger that initiates a

    systemic inflammatory reaction
    SYMPTOMS

, characterized by

    macrophage activation
    MICROSCOPIC

. We suggest

    higher levels of holo-TC
    BIOCHEMICAL

 could be associated with a more severe (

    neuronopathic) GD
    DIAGNOSIS

, and be a biomarker of

    GD type II
    DIAGNOSIS

.

Gaucher disease (GD)
lysosomal disorders
GD
types I, II
III
GD type I
GD type II
GD type I
liver diseases
GD
neuronopathic) GD
GD type II

neurological complications
jaundice
hepatosplenomegaly
ichthyosis
cholestasis
ascites
systemic inflammatory reaction


Early initiation of ambroxol treatment diminishes neurological manifestations of type 3 Gaucher disease: A long-term outcome of two siblings.

Gaucher disease type 3 (GD3) is a severely debilitating disorder characterized by multisystemic manifestations and neurodegeneration. Enzyme replacement therapy alleviates visceral signs and symptoms but has no effect on neurological features. Ambroxol has been suggested as an enzyme enhancement agent. Some studies have confirmed its effectiveness in preventing the progression of neurological manifestations of neuronopathic Gaucher disease. In this study, we report two GD3 siblings in whom ambroxol combined with enzyme replacement therapy was initiated at different stages of the disease. We demonstrate the enzyme enhancement effect of ambroxol on L444P/H225Q;D409H glucocerebrosidase activity through results of fibroblast studies and long-term clinical outcomes of the two patients. The sibling diagnosed at the age of four-and-a-half years with significant neurological involvement manifested relatively rapid improvement on ambroxol treatment, followed by stabilization of further course. The younger sibling, in whom the treatment was started at seven weeks, displayed attention deficit and low average cognitive functioning at the age of seven years, but did not manifest other neurological symptoms. The difference in neurological outcomes indicates that ambroxol delayed or even halted the evolution of neurological manifestations in the younger sibling. This observation suggests that early initiation of ambroxol treatment may arrest neurological involvement in some GD3 patients.

    Gaucher disease type 3 (GD3)
    DIAGNOSIS

 is a

    severely debilitating disorder
    DIAGNOSIS

 characterized by

    multisystemic manifestations
    SYMPTOMS

 and

    neurodegeneration
    SYMPTOMS

.

    Enzyme replacement therapy
    MEDICATION

    alleviates visceral signs and symptoms
    SYMPTOMS

 but has

    no effect on neurological features
    NEG_FINDINGS

.

    Ambroxol
    MEDICATION

 has been suggested as an

    enzyme enhancement agent
    MEDICATION

. Some studies have confirmed its effectiveness in preventing the

    progression of neurological manifestations
    SYMPTOMS

 of

    neuronopathic Gaucher disease
    DIAGNOSIS

. In this study, we report two

    GD3
    DIAGNOSIS

 siblings in whom

    ambroxol combined with enzyme replacement therapy
    MEDICATION

 was initiated at different stages of the disease. We demonstrate the

    enzyme enhancement
    BIOCHEMICAL

 effect of

    ambroxol
    MEDICATION

 on

    L444P/H225Q;D409H glucocerebrosidase activity
    GENETICS

 through results of

    fibroblast studies
    PARACLINICAL

 and long-term clinical outcomes of the two patients. The sibling diagnosed

    at the age of four-and-a-half years
    AGE

 with

    significant neurological involvement
    SYMPTOMS

 manifested

    relatively rapid improvement
    SYMPTOMS

 on

    ambroxol treatment
    MEDICATION

, followed by

    stabilization of further course
    SYMPTOMS

. The younger sibling, in whom the

    treatment was started at seven weeks
    MEDICATION

, displayed

    attention deficit
    SYMPTOMS

 and

    low average cognitive functioning
    SYMPTOMS

    at the age of seven years
    AGE

, but

    did not manifest other neurological symptoms
    NEG_FINDINGS

. The difference in neurological outcomes indicates that

    ambroxol
    MEDICATION

 delayed or even

    halted the evolution of neurological manifestations
    SYMPTOMS

 in the younger sibling. This observation suggests that

    early initiation of ambroxol treatment
    MEDICATION

 may

    arrest neurological involvement
    SYMPTOMS

 in some

    GD3
    DIAGNOSIS

 patients.


Successful Treatment of Gaucher Disease With Matched Sibling Hematopoietic Stem Cell Transplantation: A Case Report and Literature Review.

Gaucher disease (GD) is the most common lysosomal storage disease and requires long-term enzyme replacement therapy (ERT), which is costly and inconvenient for resource-limited countries such as Thailand. The authors present the case of a 1-year-old boy who was diagnosed with GD type 1 with a homozygous mutation at c.1448 T>C (L444P). He was treated with ERT and matched sibling hematopoietic stem cell transplantation (HSCT) was performed 6 months after the ERT was initiated. At a 3-year follow-up after the HSCT, he had full engraftment and the Lyso-GL1 levels were also at an acceptable level, which indicated disease remission. In conclusion, the authors suggest HSCT for long-term remission of GD in children.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most common

    lysosomal storage disease
    DIAGNOSIS

 and requires

    long-term enzyme replacement therapy (ERT)
    MEDICATION

, which is costly and inconvenient for resource-limited countries such as

    Thailand
    ETHNICITY

. The authors present the case of a

    1-year-old
    AGE

    boy
    GENDER

 who was diagnosed with

    GD type 1
    DIAGNOSIS

 with a

    homozygous mutation at c.1448 T>C (L444P)
    GENETICS

.

    He
    GENDER

 was treated with

    ERT
    MEDICATION

 and

    matched sibling hematopoietic stem cell transplantation (HSCT) was performed 6 months after the ERT was initiated
    MEDICATION

. At a 3

    -year follow-up
    PARACLINICAL

 after the

    HSCT
    MEDICATION

,

    he
    GENDER

 had

    full engraftment
    SYMPTOMS

 and the

    Lyso-GL1 levels were also at an acceptable level
    BIOCHEMICAL

, which indicated

    disease remission
    MEDICATION

. In conclusion, the authors suggest

    HSCT
    MEDICATION

 for

    long-term remission
    MEDICATION

    of GD
    DIAGNOSIS

 in

    children
    AGE

.

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


The role of glucosylsphingosine as an early indicator of disease progression in early symptomatic type 1 Gaucher disease.

Gaucher disease (GD), a lysosomal storage disorder caused by β-glucocerebrosidase deficiency, results in the accumulation of glucosylceramide and glucosylsphingosine. Glucosylsphingosine has emerged as a sensitive and specific biomarker for GD and treatment response. However, limited information exists on its role in guiding treatment decisions in pre-symptomatic patients identified at birth or due to a positive family history. We present two pediatric patients with GD1 and highlight the utility of glucosylsphingosine monitoring in guiding treatment initiation.

    Gaucher disease (GD)
    DIAGNOSIS

, a

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    β-glucocerebrosidase deficiency
    BIOCHEMICAL

, results in the

    accumulation of glucosylceramide and glucosylsphingosine
    MICROSCOPIC

.

    Glucosylsphingosine
    BIOCHEMICAL

 has emerged as a sensitive and specific biomarker for

    GD
    DIAGNOSIS

 and treatment response. However, limited information exists on its role in guiding treatment decisions in

    pre-symptomatic
    AGE

 patients identified at

    birth
    AGE

 or due to a

    positive family history
    FAMILY

. We present two

    pediatric
    AGE

 patients with

    GD1
    DIAGNOSIS

 and highlight the utility of

    glucosylsphingosine monitoring
    PARACLINICAL

 in guiding treatment initiation.

Gaucher disease (GD)
lysosomal storage disorder
GD
GD1


Successful treatment of Gaucher disease type 1 by enzyme replacement therapy over a 10-year duration in a Japanese pediatric patient: A case report.

The prevalence of Gaucher disease (GD) in Japan is much lower than that in Western countries; therefore, data on Japanese pediatric patients with GD type 1 are currently limited. The present study reports on the case of a Japanese pediatric patient with GD type 1 who was diagnosed when she presented with hepatosplenomegaly, thrombocytopenia and slight anemia at the age of 2 years. Serology tests revealed high levels of acid phosphatase (ACP) and angiotensin-converting enzyme (ACE). A bone marrow biopsy revealed the presence of Gaucher cells. Abdominal MRI indicated huge hepatosplenomegaly. Erlenmeyer flask deformity was observed on X-ray examination. MRI of the femora featured a high-intensity area within the diaphysis region. The enzymatic activity of leukocyte β-glucosidase, the measurement of which is necessary for a definitive diagnosis of GD, had decreased to 186.7 nmol/h/mg (reference range, 1,424.0-2,338.0 nmol/h/mg). Based on these results, the patient was clinically diagnosed with GD. Glucocerebrosidase gene analysis identified the compound heterozygote mutation of F213I (c.754T>A) on exon 7 and L444P (c.1448T>C) on exon 11. Enzyme replacement therapy (ERT) along with an intravenous infusion of 60 U/kg of imiglucerase every other week was initiated following diagnosis. Hemoglobin levels and the platelet count gradually improved and normalized after two years. ACP and ACE levels, biomarkers of the progression of GD, also improved. Abdominal MRI at six months after the initiation of ERT revealed a decrease in the size of the liver and spleen, which normalized after 1 year. Conversely, MRI of the femora indicated no improvement in the high-intensity area within the diaphysis region for 10 years.

The prevalence of

    Gaucher disease (GD)
    DIAGNOSIS

 in

    Japan
    ETHNICITY

 is much lower than that in Western countries; therefore, data on

    Japanese
    ETHNICITY

    pediatric
    AGE

 patients with

    GD type 1
    DIAGNOSIS

 are currently limited. The present study reports on the case of a

    Japanese
    ETHNICITY

    pediatric
    AGE

 patient with

    GD type 1
    DIAGNOSIS

 who was diagnosed when

    she
    GENDER

 presented with

    hepatosplenomegaly
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

 and

    slight anemia
    BIOCHEMICAL

 at the

    age of 2 years
    AGE

.

    Serology tests
    PARACLINICAL

 revealed

    high levels of acid phosphatase (ACP) and angiotensin-converting enzyme (ACE)
    BIOCHEMICAL

. A

    bone marrow biopsy
    PARACLINICAL

 revealed the

    presence of Gaucher cells
    MICROSCOPIC

.

    Abdominal MRI
    PARACLINICAL

 indicated

    huge hepatosplenomegaly
    SYMPTOMS

.

    Erlenmeyer flask deformity
    SYMPTOMS

 was observed on

    X-ray examination
    PARACLINICAL

.

    MRI of the femora
    PARACLINICAL

 featured a

    high-intensity area within the diaphysis region
    SYMPTOMS

. The

    enzymatic activity of leukocyte β-glucosidase
    BIOCHEMICAL

, the measurement of which is necessary for a definitive diagnosis of

    GD
    DIAGNOSIS

    , had decreased to 186.7 nmol/h/mg (reference range, 1,424.0-2,338.0 nmol/h/mg)
    BIOCHEMICAL

. Based on these results, the patient was clinically diagnosed with

    GD
    DIAGNOSIS

.

    Glucocerebrosidase gene analysis
    PARACLINICAL

 identified the

    compound heterozygote mutation of F213I (c.754T>A) on exon 7 and L444P (c.1448T>C) on exon 11
    GENETICS

.

    Enzyme replacement therapy (ERT) along with an intravenous infusion of 60 U/kg of imiglucerase every other week
    MEDICATION

 was initiated following diagnosis.

    Hemoglobin levels and the platelet count gradually improved
    BIOCHEMICAL

    and normalized
    BIOCHEMICAL

 after two

    years
    BIOCHEMICAL

.

    ACP and ACE levels
    BIOCHEMICAL

, biomarkers of the progression of

    GD
    DIAGNOSIS

, also

    improved
    BIOCHEMICAL

.

    Abdominal MRI
    PARACLINICAL

 at six months after the initiation

    of ERT
    MEDICATION

 revealed a

    decrease in the size of the liver and spleen, which normalized
    SYMPTOMS

 after 1 year. Conversely,

    MRI of the femora
    PARACLINICAL

 indicated

    no improvement in the high-intensity area within the diaphysis region for 10 years
    SYMPTOMS

.

Gaucher disease (GD)
GD type 1
GD type 1
GD
GD
GD


Gaucher disease type 1: Unexpected diagnosis in a 75-year old patient presenting with splenomegaly.

We present a 75-year old Korean female patient harboring novel hemizygous variant mutation in glucosidase beta acid (GBA) gene, who was diagnosed with splenic marginal zone cell lymphoma and Gaucher disease (GD) concurrently. Our case is significant in that (1) it delivers the message that GD can occur at any age regardless of ethnicity and (2) we report a novel variant of pathogenic GBA mutation, and the fact that the patient harbored hemizygous mutation.

We present a

    75-year old
    AGE

    Korean
    ETHNICITY

    female
    GENDER

 patient harboring

    novel hemizygous variant mutation in glucosidase beta acid (GBA) gene
    GENETICS

, who was diagnosed with

    splenic marginal zone cell lymphoma
    DIAGNOSIS

 and

    Gaucher disease (GD)
    DIAGNOSIS

 concurrently. Our case is significant in that (1) it delivers the message that

    GD
    DIAGNOSIS

 can occur at

    any age
    AGE

 regardless of ethnicity and (2) we report a

    novel variant of pathogenic GBA mutation
    GENETICS

, and the fact that the patient harbored

    hemizygous mutation
    GENETICS

.

splenic marginal zone cell lymphoma
Gaucher disease (GD)
GD


[Successful treatment with enzyme replacement therapy for pelvic fragile fracture in an elderly case of type I Gaucher's disease].

A 76-year-old male with lower-limb weakness was admitted to our hospital where thrombocytopenia and anemia were noticed. CT showed massive splenomegaly and multiple nodules inside the spleen. Bone marrow examination showed an increase of macrophages with large cytoplasm. Suspected of splenic lymphoma, the patient underwent splenectomy. Spleen specimens were histologically analyzed and suggested the probability of Gaucher's disease (GD). Leukocyte glucocerebrosidase (GBA) enzyme activity had decreased to 1.25 nmol/mg, and mutation analysis of GBA revealed two missense variants, p.D448H (D409H), p.L483P (L444P), which confirmed the diagnosis of type I GD. Fourteen months after splenectomy, he developed right buttock pain, and pelvic magnetic resonance imaging showed a fragile right pubic and pelvic fracture. We initiated injection of imiglucerase as enzyme replacement therapy (ERT) and administered bisphosphonate. His symptoms gradually improved without surgical treatment. In addition, thrombocytopenia and anemia also improved, and angiotensin-converting enzyme levels decreased. Type I GD should be considered a differential diagnosis of giant splenomegaly and thrombocytopenia, even in the elderly. ERT or substrate reduction therapy should be administrated to GD patients, while paying attention to the development of bone lesions.

A

    76-year-old
    AGE

    male
    GENDER

 with

    lower-limb weakness
    SYMPTOMS

 was admitted to our hospital where

    thrombocytopenia
    BIOCHEMICAL

 and

    anemia
    BIOCHEMICAL

 were noticed.

    CT
    PARACLINICAL

 showed

    massive splenomegaly
    SYMPTOMS

 and

    multiple nodules inside the spleen
    MICROSCOPIC

.

    Bone marrow examination
    PARACLINICAL

 showed an

    increase of macrophages with large cytoplasm
    MICROSCOPIC

. Suspected of

    splenic lymphoma
    DIAGNOSIS

, the patient underwent

    splenectomy
    MEDICATION

.

    Spleen specimens
    PARACLINICAL

 were

    histologically analyzed
    PARACLINICAL

 and suggested the probability of

    Gaucher's disease (GD)
    DIAGNOSIS

.

    Leukocyte glucocerebrosidase (GBA) enzyme activity had decreased to 1.25 nmol/mg
    BIOCHEMICAL

, and

    mutation analysis of GBA
    PARACLINICAL

 revealed

    two missense variants, p.D448H (D409H), p.L483P (L444P)
    GENETICS

, which confirmed the diagnosis of

    type I GD
    DIAGNOSIS

. Fourteen months after

    splenectomy
    MEDICATION

,

    he
    GENDER

 developed

    right buttock pain
    SYMPTOMS

, and

    pelvic magnetic resonance imaging
    PARACLINICAL

 showed a

    fragile right pubic and pelvic fracture
    SYMPTOMS

. We initiated

    injection of imiglucerase as enzyme replacement therapy (ERT)
    MEDICATION

 and

    administered bisphosphonate
    MEDICATION

. His

    symptoms gradually improved
    SYMPTOMS

    without surgical treatment
    NEG_FINDINGS

. In addition,

    thrombocytopenia and anemia also improved
    BIOCHEMICAL

, and

    angiotensin-converting enzyme levels decreased
    BIOCHEMICAL

.

    Type I GD
    DIAGNOSIS

 should be considered a

    differential diagnosis
    PARACLINICAL

 of

    giant splenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

, even in the

    elderly
    AGE

.

    ERT
    MEDICATION

 or

    substrate reduction therapy
    MEDICATION

 should be administrated to

    GD
    DIAGNOSIS

 patients, while paying attention to the development of

    bone lesions
    SYMPTOMS

.

lower-limb weakness
massive splenomegaly
right buttock pain
fragile right pubic and pelvic fracture
symptoms gradually improved
giant splenomegaly
bone lesions

splenic lymphoma
Gaucher's disease (GD)
type I GD
Type I GD
GD


A patient with Gaucher disease and plasma cell dyscrasia: bidirectional impact.

Patients with Gaucher disease (GD), a rare autosomal recessive glycosphingolipid storage disease, commonly present to hematologists with unexplained splenomegaly, thrombocytopenia, anemia, and bone symptoms. Patients with GD may develop other manifestations, such as autoimmune thrombocytopenia, monoclonal gammopathy, multiple myeloma, or, even more rarely, other hematological malignancies; sometimes they are first diagnosed during an assessment of those disorders. Although the diagnosis and management of patients with GD have significantly evolved over the last 30 years, some patients remain poor responders to GD-specific therapy, needing novel and investigational therapies. Ideally, patients with GD, like patients with other rare diseases, should be managed by a multidisciplinary team expert with the diverse clinical manifestations and potential GD-related or -unrelated comorbidities. The hematology community should be knowledgeable regarding the presentation and the variety of hematologic complications and comorbidities associated with Gaucher disease.

Patients with

    Gaucher disease (GD)
    DIAGNOSIS

, a

    rare autosomal recessive
    GENETICS

    glycosphingolipid storage disease
    DIAGNOSIS

, commonly present to

    hematologists
    PARACLINICAL

 with

    unexplained splenomegaly
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

, and

    bone symptoms
    SYMPTOMS

. Patients with

    GD
    DIAGNOSIS

 may develop other manifestations, such as

    autoimmune thrombocytopenia
    DIAGNOSIS

,

    monoclonal gammopathy
    DIAGNOSIS

,

    multiple myeloma
    DIAGNOSIS

, or, even more rarely, other

    hematological malignancies
    DIAGNOSIS

; sometimes they are first diagnosed during an assessment of those disorders. Although the diagnosis and management of patients with

    GD
    DIAGNOSIS

 have significantly evolved over the last 30 years, some patients remain

    poor responders to GD-specific therapy
    NEG_FINDINGS

, needing novel and investigational therapies. Ideally, patients with

    GD
    DIAGNOSIS

, like patients with other

    rare diseases
    DIAGNOSIS

, should be managed by a multidisciplinary team expert with the diverse clinical manifestations and potential GD-related or -unrelated comorbidities. The

    hematology community
    PARACLINICAL

 should be knowledgeable regarding the presentation and the variety of

    hematologic complications
    SYMPTOMS

 and comorbidities associated with

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease (GD)
glycosphingolipid storage disease
GD
autoimmune thrombocytopenia
monoclonal gammopathy
multiple myeloma
hematological malignancies
GD
GD
rare diseases
Gaucher disease

unexplained splenomegaly
bone symptoms
hematologic complications


Parkinsonism in Patients with Neuronopathic (Type 3) Gaucher Disease: A Case Series.

The link between Parkinson's disease (PD), the second most common neurodegenerative disorder, and nonneuronopathic Gaucher disease (GD) is well established. Currently, PD is primarily associated with nonneuronopathic GD; however, with currently available treatments, patients with chronic neuronopathic GD, who historically had a shortened life span, are now living well into their 50s and beyond.

We highlight 4 patients with chronic neuronopathic GD with parkinsonian features, describing their GD genotype and phenotype as well as the presentation and progression of their parkinsonism. Symptoms presented in their fourth or fifth decade of life, and include unilateral bradykinesia and/or tremor. Of the patients, 3 had cognitive impairment. The fourth patient has not shown cognitive decline 6 years after PD onset.

This small series highlights that PD is not exclusively associated with nonneuronopathic GD and that as the chronic neuronopathic GD population ages, the clinical spectrum and heterogeneity of neurological manifestations may include parkinsonism.

The link between

    Parkinson's disease (PD)
    DIAGNOSIS

, the second most common

    neurodegenerative disorder
    DIAGNOSIS

, and

    nonneuronopathic Gaucher disease (GD)
    DIAGNOSIS

 is well established. Currently,

    PD
    DIAGNOSIS

 is primarily associated with

    nonneuronopathic GD
    DIAGNOSIS

; however, with currently available treatments, patients with

    chronic neuronopathic GD
    DIAGNOSIS

, who historically had a shortened life span, are now living well

    into their 50s and beyond
    AGE

.

We highlight 4 patients with

    chronic neuronopathic GD
    DIAGNOSIS

 with

    parkinsonian features
    SYMPTOMS

, describing their

    GD
    DIAGNOSIS

 genotype and phenotype as well as the presentation and progression of their

    parkinsonism
    DIAGNOSIS

. Symptoms presented

    in their fourth or fifth decade of life
    AGE

, and include

    unilateral bradykinesia and/or tremor
    SYMPTOMS

. Of the patients, 3 had

    cognitive impairment
    SYMPTOMS

. The fourth patient has

    not shown cognitive decline 6 years after PD onset
    NEG_FINDINGS

.

This small series highlights that

    PD
    DIAGNOSIS

 is not exclusively associated with

    nonneuronopathic GD
    DIAGNOSIS

 and that as the

    chronic neuronopathic GD
    DIAGNOSIS

 population ages, the clinical spectrum and heterogeneity of

    neurological manifestations
    SYMPTOMS

 may include

    parkinsonism
    DIAGNOSIS

.

Parkinson's disease (PD)
neurodegenerative disorder
nonneuronopathic Gaucher disease (GD)
PD
nonneuronopathic GD
chronic neuronopathic GD
chronic neuronopathic GD
GD
parkinsonism
PD
nonneuronopathic GD
chronic neuronopathic GD
parkinsonism

parkinsonian features
unilateral bradykinesia and/or tremor
cognitive impairment
neurological manifestations


Vitreous Hemorrhage in Type 3 Gaucher Disease: An Angiographic and Pathologic Analysis.

To describe the case of a 12-year-old female with vitreoretinal manifestations of Type 3 Gaucher disease.

Retrospective case report including multimodal imaging and histologic examination of the vitreous.

A 12-year-old female with a history of Gaucher disease Type 3 was referred to the ophthalmology service for evaluation of vitreous deposits in both eyes. Funduscopic examination was notable for white vitreous opacities in both eyes. Ultra-widefield fluorescein angiography demonstrated areas of blockage associated with the deposits as well as focal areas of leakage. OCT angiography showed shadow artifact without intrinsic flow at these sites. Three years after presentation, she developed a right hemorrhagic posterior vitreous detachment, requiring pars plana vitrectomy with scleral buckle. A vitreous sample was sent to pathology, which demonstrated Gaucher cells.

Gaucher disease is a rare metabolic condition caused by an autosomal recessive deficiency of glucocerebrosidase. To our knowledge, this is the first report of hemorrhagic posterior vitreous detachment in Type 3 Gaucher disease, including ultra-widefield imaging, OCT angiography, and histopathology.

To describe the case of a

    12-year-old
    AGE

    female
    GENDER

 with

    vitreoretinal manifestations
    SYMPTOMS

 of

    Type 3 Gaucher disease
    DIAGNOSIS

.

Retrospective case report including

    multimodal imaging
    PARACLINICAL

 and

    histologic examination of the vitreous
    PARACLINICAL

.

A

    12-year-old
    AGE

    female
    GENDER

 with a history of

    Gaucher disease Type 3
    DIAGNOSIS

 was referred to the ophthalmology service for evaluation of

    vitreous deposits in both eyes
    SYMPTOMS

.

    Funduscopic examination
    PARACLINICAL

 was notable for

    white vitreous opacities in both eyes
    SYMPTOMS

.

    Ultra-widefield fluorescein angiography
    PARACLINICAL

 demonstrated

    areas of blockage associated with the deposits
    SYMPTOMS

 as well as

    focal areas of leakage
    SYMPTOMS

.

    OCT angiography
    PARACLINICAL

 showed

    shadow artifact without intrinsic flow at these sites
    SYMPTOMS

. Three years after presentation,

    she
    GENDER

 developed a

    right hemorrhagic posterior vitreous detachment
    SYMPTOMS

, requiring

    pars plana vitrectomy with scleral buckle
    MEDICATION

. A

    vitreous sample was sent to pathology
    PARACLINICAL

, which demonstrated

    Gaucher cells
    MICROSCOPIC

    .
    MICROSCOPIC

    Gaucher disease
    DIAGNOSIS

 is a

    rare metabolic condition
    GENETICS

 caused by an

    autosomal recessive
    GENETICS

    deficiency of glucocerebrosidase
    BIOCHEMICAL

. To our knowledge, this is the first report of

    hemorrhagic posterior vitreous detachment
    SYMPTOMS

 in

    Type 3 Gaucher disease
    DIAGNOSIS

, including

    ultra-widefield imaging
    PARACLINICAL

,

    OCT angiography
    PARACLINICAL

, and

    histopathology
    PARACLINICAL

.

Type 3 Gaucher disease
Gaucher disease Type 3
Gaucher disease
Type 3 Gaucher disease

rare metabolic condition
autosomal recessive


Consequences of treatment for hemophagocytic lymphohistiocytosis in a patient with undiagnosed Gaucher disease Type 1.

Gaucher disease, a lysosomal storage disorder and hemophagocytic lymphohistiocytosis (HLH), a disorder of the immune system, have several overlapping clinical features including cytopenias, elevated serum ferritin, and splenomegaly. Prior reports of acute infantile neuronopathic, Type 2 Gaucher disease manifesting with signs of HLH have been published. Here we describe an adult patient who was initially suspected of having HLH, and was treated with a 10-day course of etoposide and a 5-day course alemtuzumab for presumptive HLH, only to later to have his presentation be determined to be due to Type 1 Gaucher disease. HLH chemotherapy treatment appeared to trigger a severe Gaucher acute pain crisis and extensive bony disease including avascular necrosis. Prolonged immunosuppression, and recurrent infections further complicated a lengthy hospitalization. We discuss the clinical overlap between Gaucher and HLH and the iatrogenic consequences of HLH-directed therapy on underlying Type 1 Gaucher disease.

    Gaucher disease
    DIAGNOSIS

, a

    lysosomal storage disorder
    DIAGNOSIS

 and

    hemophagocytic lymphohistiocytosis (HLH)
    DIAGNOSIS

, a

    disorder of the immune system
    DIAGNOSIS

, have several overlapping clinical features including

    cytopenias
    BIOCHEMICAL

,

    elevated serum ferritin
    BIOCHEMICAL

, and

    splenomegaly
    SYMPTOMS

. Prior reports of

    acute infantile neuronopathic
    DIAGNOSIS

,

    Type 2 Gaucher disease
    DIAGNOSIS

 manifesting with

    signs of HLH
    SYMPTOMS

 have been published. Here we describe an

    adult
    AGE

 patient who was

    initially suspected of having HLH
    NEG_FINDINGS

, and was

    treated with a 10-day course of etoposide and a 5-day course alemtuzumab
    MEDICATION

 for presumptive

    HLH
    DIAGNOSIS

, only to later to have his presentation be determined to be due to

    Type 1 Gaucher disease
    DIAGNOSIS

.

    HLH chemotherapy treatment
    MEDICATION

 appeared to trigger a

    severe Gaucher acute pain crisis
    SYMPTOMS

 and

    extensive bony disease including avascular necrosis
    SYMPTOMS

.

    Prolonged immunosuppression
    MEDICATION

, and

    recurrent infections
    SYMPTOMS

 further complicated a

    lengthy hospitalization
    MEDICATION

. We discuss the clinical overlap between

    Gaucher
    DIAGNOSIS

 and

    HLH
    DIAGNOSIS

 and the iatrogenic consequences of

    HLH-directed therapy
    MEDICATION

 on underlying

    Type 1 Gaucher disease
    DIAGNOSIS

.


Development of a human iPSC line (SMBCi004-A) from a patient with Gaucher disease.

A human induced pluripotent stem cell (iPSC) line was generated from the urine cells of a 8-year-old female with Gaucher disease with the homozygous changes c.1448 T>C in the GBA gene. Reprogramming factors OCT4, SOX2, KLF4, and miR-302-367 were delivered using a non-integrative plasmid. Our iPSCs showed complete pluripotency, normal genetic stability, and the ability to differentiate into three germ layers.

A

    human induced pluripotent stem cell (iPSC) line
    MICROSCOPIC

 was generated from

    the urine cells
    MICROSCOPIC

 of a

    8-year-old
    AGE

    female
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 with the

    homozygous changes c.1448 T>C in the GBA gene
    GENETICS

.

    Reprogramming factors OCT4, SOX2, KLF4, and miR-302-367
    MEDICATION

 were delivered using a non-integrative plasmid. Our iPSCs showed

    complete pluripotency
    MICROSCOPIC

,

    normal genetic stability
    NEG_FINDINGS

, and the

    ability to differentiate into three germ layers
    MICROSCOPIC

.


Symmetric, bilateral upper and lower extremity lucent lesions in a patient with Gaucher's disease on enzyme replacement therapy.

We report a case of a 6-year old girl with known type 3 Gaucher's Disease on enzyme replacement therapy who developed bilateral, symmetric osteolytic lesions in her humeri and femurs. While this manifestation of Gaucher's disease has been previously documented, it is an exceedingly rare variation. We observe that this patient shares 2 commonalities with 3 other patients reported in the literature to present with this phenotype. First, the patient's L444P/L444P genotype, present in approximately 11% of all Gaucher's patients, was also seen in these other patients. Second, like the other patients, this patient was treated with enzyme replacement therapy. It is unknown whether there is a correlation between these 2 independent variables and this rare phenotype, and further investigation may be warranted.

We report a case of a

    6-year old
    AGE

    girl
    GENDER

 with known

    type 3 Gaucher's Disease
    DIAGNOSIS

 on

    enzyme replacement therapy
    MEDICATION

 who developed

    bilateral, symmetric osteolytic lesions in her humeri and femurs
    SYMPTOMS

. While this manifestation of

    Gaucher's disease
    DIAGNOSIS

 has been previously documented, it is an exceedingly rare variation. We observe that this patient shares 2 commonalities with 3 other patients reported in the literature to present with this phenotype. First, the patient's

    L444P/L444P genotype
    GENETICS

, present in approximately 11% of all

    Gaucher's
    DIAGNOSIS

 patients, was also seen in these other patients. Second, like the other patients, this patient was treated with

    enzyme replacement therapy
    MEDICATION

. It is unknown whether there is a correlation between these 2 independent variables and this rare phenotype, and further investigation may be warranted.

type 3 Gaucher's Disease
Gaucher's disease
Gaucher's

enzyme replacement therapy
enzyme replacement therapy


Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.

In GM1 gangliosidosis the lack of function of β-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce.

We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases.

This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.

In

    GM1 gangliosidosis
    DIAGNOSIS

 the

    lack of function of β-galactosidase
    BIOCHEMICAL

 results in an

    accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system
    MICROSCOPIC

, leading to

    severe disability
    SYMPTOMS

 and

    premature death
    SYMPTOMS

. In the

    type 2 form of the disease
    DIAGNOSIS

,

    early intervention
    MEDICATION

 would be important to avoid

    precocious complications
    SYMPTOMS

. To date, there are no effective therapeutic options in preventing

    progressive neurological deterioration
    SYMPTOMS

.

    Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase
    MEDICATION

, has been proposed for the treatment of several

    lysosomal storage disorders
    DIAGNOSIS

 such as

    Gaucher type 1
    DIAGNOSIS

 and

    Niemann Pick Type C diseases
    DIAGNOSIS

. However, data on

    Miglustat therapy
    MEDICATION

 in patients with

    GM1 gangliosidosis
    DIAGNOSIS

 are still scarce.

We report here the results of

    Miglustat administration
    MEDICATION

 in four

    Italian
    ETHNICITY

    children
    AGE

 (

    average age: 55 months, range 20-125)
    AGE

 affected by

    GM1 gangliosidosis type 2
    DIAGNOSIS

 treated in three different Italian pediatric hospitals specialized in

    metabolic diseases
    DIAGNOSIS

.

This treatment was safe and relatively well tolerated by all patients, with

    stabilization and/or slowing down of the neurological progression
    SYMPTOMS

 in three subjects.

GM1 gangliosidosis
type 2 form of the disease
lysosomal storage disorders
Gaucher type 1
Niemann Pick Type C diseases
GM1 gangliosidosis
GM1 gangliosidosis type 2
metabolic diseases


An uncommon cause of early infantile liver disease and raised chitotriosidase.

Our subject presented at 11 months of age, following a varicella zoster infection, with acute on chronic liver disease and was found to have raised serum chitotriosidase. White cell enzyme analysis for Gaucher, Niemann Pick A, B and lysosomal acid lipase deficiency were normal. Niemann Pick type C (NPC) disease was considered as a provisional diagnosis and liver transplantation assessment deferred until recovery from varicella and results of mutational analysis of NPC gene were available. Liver biopsy at a later date showed findings suggestive of glycogen storage disease (GSD) type IV but he was too unstable for an urgent liver transplantation and sadly passed away at the age of 13 months. The classic hepatic subtype of glycogen storage disorder type IV (GSD IV) is a rare metabolic cause of early-onset liver disease and raised chitotriosidase. There are very few reports of raised chito in GSD IV. Liver transplantation has a favourable outcome for the hepatic subtype of GSD IV and early diagnosis in our subject could have potentially altered the outcome.

Our subject presented at

    11 months of age
    AGE

, following a

    varicella zoster infection
    DIAGNOSIS

, with

    acute on chronic liver disease
    DIAGNOSIS

 and was found to have

    raised serum chitotriosidase
    BIOCHEMICAL

.

    White cell enzyme analysis for Gaucher, Niemann Pick A, B and lysosomal acid lipase deficiency were normal
    NEG_FINDINGS

.

    Niemann Pick type C (NPC) disease
    DIAGNOSIS

 was considered as a provisional diagnosis and

    liver transplantation
    MEDICATION

 assessment deferred until recovery from

    varicella
    DIAGNOSIS

 and results of

    mutational analysis of NPC gene
    PARACLINICAL

 were available.

    Liver biopsy
    PARACLINICAL

 at a later date showed findings suggestive of

    glycogen storage disease (GSD) type IV
    DIAGNOSIS

 but

    he
    GENDER

    was too unstable for an urgent liver transplantation
    NEG_FINDINGS

 and sadly

    passed away
    SYMPTOMS

    at the age of 13 months
    AGE

. The

    classic hepatic subtype of glycogen storage disorder type IV (GSD IV)
    DIAGNOSIS

 is a rare metabolic cause of

    early-onset liver disease
    DIAGNOSIS

 and

    raised chitotriosidase
    BIOCHEMICAL

. There are very few reports of

    raised chito
    BIOCHEMICAL

 in

    GSD IV
    DIAGNOSIS

.

    Liver transplantation
    MEDICATION

 has a favourable outcome for the

    hepatic subtype of GSD IV
    DIAGNOSIS

 and early diagnosis in our subject could have potentially altered the outcome.

raised serum chitotriosidase
raised chitotriosidase
raised chito

liver transplantation
Liver transplantation


99mTc-MDP Bone Scintigraphy in Gaucher Disease.

In this case report, we present the bone scintigraphic findings of a 9-year-old boy with Gaucher disease who has a history of fractures to evaluate the extent of his osseous lesions. Gaucher disease is a genetic deficiency of lysosomal enzyme glucocerebrosidase, which results in the accumulation of glucocerebroside in the macrophages in the reticuloendothelial cells of the spleen, liver, and bone marrow. Most patients with type 1 Gaucher disease present a clinical or radiographic evidence of infiltrative bone disease. Lipid-filled macrophages called Gaucher cells infiltrate the bone marrow, leading to medullary expansion, diffuse osteoporosis, ischemic necrosis, and fractures.

In this case report, we present the

    bone scintigraphic findings
    PARACLINICAL

 of a

    9-year-old
    AGE

    boy
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 who has a

    history of fractures
    SYMPTOMS

 to evaluate the extent of his

    osseous lesions
    SYMPTOMS

.

    Gaucher disease
    DIAGNOSIS

 is a

    genetic deficiency of lysosomal enzyme glucocerebrosidase
    GENETICS

, which results in the

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

. Most patients with

    type 1 Gaucher disease
    DIAGNOSIS

 present a

    clinical or radiographic evidence of infiltrative bone disease
    SYMPTOMS

.

    Lipid-filled macrophages called Gaucher cells infiltrate the bone marrow
    MICROSCOPIC

, leading to

    medullary expansion
    MICROSCOPIC

,

    diffuse osteoporosis
    SYMPTOMS

,

    ischemic necrosis
    SYMPTOMS

, and

    fractures
    SYMPTOMS

.

Gaucher disease
Gaucher disease
type 1 Gaucher disease


Impact on bone microarchitecture and failure load in a patient with type I Gaucher disease who switched from Imiglucerase to Eliglustat.

Gaucher disease (GD; OMIM 230800) is a lysosomal storage disorder caused by a deficiency in acid beta-glucosidase as a result of mutation in the GBA gene. Type 1 GD (GD1) is the most common form and its clinical manifestations include severe hematological, visceral and bone disease. The goal of disease-modifying treatments for GD1 is to reduce substrate storage and hence toxicity from the disease. The two common therapeutic routes for managing GD1 are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). These therapies have shown to improve hematological and visceral aspects of the disease. However, quantitative investigations into how these therapies may help prevent or improve the progression of bone disease is limited. This case involves a patient diagnosed with GD1 in childhood, who began ERT in young adulthood. Following over 20 years of treatment with ERT, the patient switched to SRT. This case report examined the novel application of high-resolution peripheral quantitative computed tomography (HR-pQCT) in a patient who switched from ERT to SRT. Using bone microarchitecture measurements from HR-pQCT, we applied finite element analysis techniques to calculate the failure load which estimates the resistance to fracture. Over the course of one year following the switch from ERT to SRT therapy, failure load improved in the patient's lower limb. In conclusion, failure load can be computed in the short term in a patient who made a switch from ERT to SRT. Further exploration of failure load in study design to look at interventions that impact bone quality in GD may be considered.

    Gaucher disease (GD
    DIAGNOSIS

;

    OMIM 230800
    GENETICS

    )
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency in acid beta-glucosidase
    BIOCHEMICAL

 as a result of

    mutation in the GBA gene
    GENETICS

.

    Type 1 GD (GD1)
    DIAGNOSIS

 is the most common form and its clinical manifestations include

    severe hematological, visceral and bone disease
    SYMPTOMS

. The goal of

    disease-modifying treatments
    MEDICATION

 for

    GD1
    DIAGNOSIS

 is to reduce

    substrate storage
    MICROSCOPIC

 and hence

    toxicity from the disease
    MICROSCOPIC

. The two common therapeutic routes for managing

    GD1
    DIAGNOSIS

 are

    enzyme replacement therapy (ERT)
    MEDICATION

 and

    substrate reduction therapy (SRT)
    MEDICATION

. These therapies have shown to

    improve hematological and visceral aspects of the disease
    SYMPTOMS

. However, quantitative investigations into how these therapies may help prevent or improve the progression of

    bone disease
    SYMPTOMS

 is limited. This case involves a patient diagnosed with

    GD1
    DIAGNOSIS

 in

    childhood
    AGE

, who

    began ERT
    MEDICATION

 in

    young adulthood
    AGE

.

    Following over 20 years of treatment with ERT
    MEDICATION

, the patient

    switched to SRT
    MEDICATION

. This case report examined the novel application of

    high-resolution peripheral quantitative computed tomography (HR-pQCT)
    PARACLINICAL

 in a patient who

    switched from ERT to SRT
    MEDICATION

. Using

    bone microarchitecture measurements from HR-pQCT
    PARACLINICAL

, we applied

    finite element analysis techniques
    PARACLINICAL

 to calculate the

    failure load
    SYMPTOMS

 which estimates the

    resistance to fracture
    SYMPTOMS

. Over the course of one year following the

    switch from ERT to SRT therapy
    MEDICATION

,

    failure load improved in the patient's lower limb
    SYMPTOMS

. In conclusion,

    failure load
    SYMPTOMS

 can be computed in the short term in a patient who made a

    switch from ERT to SRT
    MEDICATION

. Further exploration of

    failure load
    PARACLINICAL

 in study design to look at interventions that impact bone quality in

    GD
    DIAGNOSIS

 may be considered.


Niemann-Pick disease type-B: a unique case report with compound heterozygosity and complicated lipid management.

Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by deficient activity of acid sphingomyelinase.

We present a case of NPD type B with a unique compound heterozygosity for SMPD1 (NM_000543.4:c.[84delC];[96G > A]) in which both mutations that induce an early stop codon are located before the second in-frame initiation codon. The clinical presentation of the patient is compatible with NPD type B. She was initially diagnosed of Gaucher Disease, but her altered lipid profile led to a clinical suspicion of NPD. Combined high doses of atorvastatin and ezetimibe were given to treat the severe hypercholesterolemia.

The pharmacological management of the lipid profile in these patients is important. A unique compound mutation in SMPD1 gene is described.

    Niemann-Pick disease (NPD)
    DIAGNOSIS

 is a

    rare autosomal recessive hereditary disease
    GENETICS

 characterized by

    deficient activity of acid sphingomyelinase
    BIOCHEMICAL

.

We present a case of

    NPD type B
    DIAGNOSIS

 with a

    unique compound heterozygosity for SMPD1 (NM_000543.4:c.[84delC];[96G > A]) in which both mutations that induce an early stop codon are located before the second in-frame initiation codon
    GENETICS

. The clinical presentation of the patient is compatible with NPD type B.

    She
    GENDER

    was initially diagnosed of Gaucher Disease
    NEG_FINDINGS

, but

    her
    GENDER

    altered lipid profile
    BIOCHEMICAL

 led to a clinical suspicion of

    NPD
    DIAGNOSIS

.

    Combined high doses of atorvastatin and ezetimibe
    MEDICATION

 were given to treat the

    severe hypercholesterolemia
    BIOCHEMICAL

.

The

    pharmacological management of the lipid profile
    MEDICATION

 in these patients is important. A

    unique compound mutation in SMPD1 gene
    GENETICS

 is described.

Niemann-Pick disease (NPD)
NPD type B
NPD


Liver transplantation for Gaucher disease presenting as neonatal cholestasis: Case report and literature review.

We present a rare case of neonatal cholestasis in a female infant with Gaucher Disease (GD), who received liver transplantation. We review the relevant literature on similar disease presentations.

A chart review of the index case was performed. PubMed and Medline databases were searched to identify other cases.

A 4-day-old female was referred with conjugated hyperbilirubinemia. Physical examination revealed icterus with hepatosplenomegaly and normal neurologic examination. The diagnosis of GD was confirmed through liver biopsy, low glucocerebrosidase enzyme activity, and two pathogenic mutations in GBA gene. Despite early initiation of ERT, the patient had worsening of her liver failure and underwent a left lateral segment liver transplant from a living donor at 7 months of age. She experienced improvement of her liver enzymes and coagulation, but passed away at 8 months due to the late onset of neurologic involvement. Nine other cases of GD presenting with neonatal cholestasis have been reported. Forty-four percent (4/9) of cases received ERT and none were considered for transplant. Overall, the literature suggests a poor prognosis with death reported in 77% (7/9) cases.

Neonatal presentation of GD represents a poor prognosis despite early initiation of treatment. Diagnosis remains a challenge as the presentation is rare and multiple tests such as BM biopsy, liver biopsy with both light and electron microscopy, enzymology, and genetic testing may need to be completed to reach a diagnosis. Neurological sequelae may manifest later making the decision to proceed with liver transplantation a difficult one.

We present a rare case of

    neonatal
    AGE

    cholestasis
    DIAGNOSIS

 in a

    female
    GENDER

    infant
    AGE

 with

    Gaucher Disease (GD)
    DIAGNOSIS

, who

    received liver transplantation
    MEDICATION

. We review the relevant literature on similar disease presentations.

A

    4-day-old
    AGE

    female
    GENDER

 was referred with

    conjugated hyperbilirubinemia
    BIOCHEMICAL

.

    Physical examination
    PARACLINICAL

 revealed

    icterus with hepatosplenomegaly
    SYMPTOMS

 and

    normal neurologic examination
    NEG_FINDINGS

. The diagnosis of

    GD
    DIAGNOSIS

 was confirmed through

    liver biopsy
    PARACLINICAL

,

    low glucocerebrosidase enzyme activity
    BIOCHEMICAL

, and

    two pathogenic mutations in GBA gene
    GENETICS

.

    Despite early initiation of ERT
    NEG_FINDINGS

, the patient had

    worsening of her liver failure
    SYMPTOMS

 and

    underwent a left lateral segment liver transplant from a living donor
    MEDICATION

    at 7 months of age
    AGE

.

    She
    GENDER

 experienced

    improvement of her liver enzymes and coagulation
    BIOCHEMICAL

, but

    passed away
    SYMPTOMS

    at 8 months
    AGE

 due to the

    late onset of neurologic involvement
    SYMPTOMS

. Nine other cases of

    GD
    DIAGNOSIS

 presenting with

    neonatal
    AGE

    cholestasis
    DIAGNOSIS

 have been reported. Forty-four percent (4/9) of cases received

    ERT
    MEDICATION

 and none were considered for

    transplant
    MEDICATION

. Overall, the literature suggests a poor prognosis with

    death
    SYMPTOMS

 reported in 77% (7/9) cases.

    Neonatal
    AGE

 presentation of

    GD
    DIAGNOSIS

 represents a poor prognosis

    despite early initiation of treatment
    NEG_FINDINGS

. Diagnosis remains a challenge as the presentation is rare and multiple tests such as

    BM biopsy
    PARACLINICAL

,

    liver biopsy with both light and electron microscopy
    PARACLINICAL

,

    enzymology
    PARACLINICAL

, and

    genetic testing
    PARACLINICAL

 may need to be completed to reach a diagnosis.

    Neurological sequelae
    SYMPTOMS

 may manifest later making the decision to proceed with

    liver transplantation
    MEDICATION

 a difficult one.

cholestasis
Gaucher Disease (GD)
GD
GD
cholestasis
GD

icterus with hepatosplenomegaly
worsening of her liver failure
passed away
late onset of neurologic involvement
death
Neurological sequelae

normal neurologic examination
Despite early initiation of ERT
despite early initiation of treatment


Cognitive decline and depressive symptoms: early non-motor presentations of parkinsonism among Egyptian Gaucher patients.

Evidence about the link between glucocerebrosidase (GCase) and parkinsonism is growing. Parkinsonism was described in adult type 1 Gaucher disease (GD); few case reports described it in type 3GD. To assess the presence of parkinsonian features in a cohort of Egyptian GD patients and correlate these findings to their genotype, phenotype, severity scoring index (SSI), cognitive function, and the presence of depressive symptoms. Twenty-four GD patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history, neurological symptoms, depressive symptoms, and family history of parkinsonism. Anthropometric measures, complete neurological assessment, and SSI were examined. Neuropsychiatric evaluation included parts I, II, III, and V of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), and Wechsler Intelligence Scale for Children (WISC-children). Molecular analysis of the acid GBA gene was performed, and SSI was calculated. Sixteen GD patients (66.6%) had parkinsonian features with a male to female ratio of 1:1. Their mean age was 15.69 ± 5.62 (range, 12-26). They were all on enzyme replacement therapy (ERT) with a dose of 60 U/kg/2 weeks. Twelve GD patients were phenotypically type 3 (75%). Thirteen GD patients with parkinsonian features (81.25%) had L483P mutation. GD patients with parkinsonian features had higher SSI (P < 0.001), lower cognitive functions (P = 0.007), and more significant depressive symptoms (P = 0.031). Logistic regression analysis revealed that GD genotype (P = 0.003), GD type (P = 0.006), and cognitive functions (P = 0.03) were the only significant independent factors for the development of parkinsonian features among GD patients. With the increased life span and improved somatic manifestations of type 3GD on ERT, these patients can live to develop parkinsonism. Cognitive decline and depression can be early predictors of parkinsonism among GD population.

Evidence about the link between

    glucocerebrosidase (GCase)
    BIOCHEMICAL

 and

    parkinsonism
    DIAGNOSIS

 is growing.

    Parkinsonism
    DIAGNOSIS

 was described in

    adult
    AGE

    type 1 Gaucher disease (GD)
    DIAGNOSIS

; few case reports described it in

    type 3GD
    DIAGNOSIS

. To assess the presence of

    parkinsonian features
    SYMPTOMS

 in a cohort of

    Egyptian
    ETHNICITY

    GD
    DIAGNOSIS

 patients and correlate these findings to their genotype, phenotype,

    severity scoring index (SSI)
    PARACLINICAL

, cognitive function, and the presence of

    depressive symptoms
    SYMPTOMS

. Twenty-four

    GD
    DIAGNOSIS

 patients from the Pediatric Hematology Clinic, Ain Shams University, were assessed for medication history,

    neurological symptoms
    SYMPTOMS

,

    depressive symptoms
    SYMPTOMS

, and

    family history of parkinsonism
    FAMILY

.

    Anthropometric measures
    PARACLINICAL

,

    complete neurological assessment
    PARACLINICAL

, and

    SSI
    PARACLINICAL

 were examined.

    Neuropsychiatric evaluation included parts I, II, III, and V of the Unified Parkinson's Disease Rating Scale (UPDRS)
    PARACLINICAL

,

    Beck Depression Inventory (BDI)
    PARACLINICAL

, and

    Wechsler Intelligence Scale for Children (WISC-children)
    PARACLINICAL

.

    Molecular analysis of the acid GBA gene
    PARACLINICAL

 was performed, and

    SSI was calculated
    PARACLINICAL

. Sixteen

    GD
    DIAGNOSIS

 patients (66.6%) had

    parkinsonian features
    SYMPTOMS

 with a

    male
    GENDER

 to

    female
    GENDER

 ratio of 1:1. Their

    mean age was 15.69 ± 5.62 (range, 12-26)
    AGE

. They were all on

    enzyme replacement therapy (ERT) with a dose of 60 U/kg/2 weeks
    MEDICATION

. Twelve

    GD
    DIAGNOSIS

 patients were phenotypically

    type 3
    DIAGNOSIS

 (75%). Thirteen

    GD
    DIAGNOSIS

 patients with

    parkinsonian features
    SYMPTOMS

 (81.25%) had

    L483P mutation
    GENETICS

.

    GD
    DIAGNOSIS

 patients with

    parkinsonian features
    SYMPTOMS

 had

    higher SSI
    SYMPTOMS

 (P < 0.001),

    lower cognitive functions
    SYMPTOMS

 (P = 0.007), and

    more significant depressive symptoms
    SYMPTOMS

 (P = 0.031).

    Logistic regression analysis
    PARACLINICAL

 revealed that

    GD genotype
    GENETICS

 (P = 0.003),

    GD type
    DIAGNOSIS

 (P = 0.006), and

    cognitive functions
    SYMPTOMS

 (P = 0.03) were the only significant independent factors for the development of

    parkinsonian features
    SYMPTOMS

 among

    GD
    DIAGNOSIS

 patients. With the increased life span and improved somatic manifestations of

    type 3GD
    DIAGNOSIS

 on

    ERT
    MEDICATION

, these patients can live to develop

    parkinsonism
    DIAGNOSIS

.

    Cognitive decline
    SYMPTOMS

 and

    depression
    SYMPTOMS

 can be early predictors of

    parkinsonism
    DIAGNOSIS

 among

    GD
    DIAGNOSIS

 population.

parkinsonism
Parkinsonism
type 1 Gaucher disease (GD)
type 3GD
GD
GD
GD
GD
type 3
GD
GD
GD type
GD
type 3GD
parkinsonism
parkinsonism
GD

parkinsonian features
depressive symptoms
neurological symptoms
depressive symptoms
parkinsonian features
parkinsonian features
parkinsonian features
higher SSI
lower cognitive functions
more significant depressive symptoms
cognitive functions
parkinsonian features
Cognitive decline
depression