Guillain-Barré Syndrome Associated With Zika Virus Infection in Martinique in 2016: A Prospective Study.

Guillain-Barré syndrome (GBS) has been reported to be associated with Zika virus (ZIKV) infection in case reports and retrospective studies, mostly on the basis of serological tests, with the problematic cross-reacting antibodies of the Flavivirus genus. Some GBS cases do not exhibit a high level of diagnostic certainty. This prospective study aimed to describe the clinical profiles and the frequency of GBS associated with ZIKV during the ZIKV outbreak in Martinique in 2016.

We recorded prospective data from GBS meeting levels 1 or 2 of diagnostic certainty for the Brighton Collaboration, with proof of recent ZIKV infection and negative screening for etiologies of GBS.

Of the sample of 34 patients with suspected GBS during the outbreak, 30 had a proven presence of GBS, and 23 had a recent ZIKV infection. The estimated GBS incidence rate ratio (2016 vs 2006-2015) was 4.52 (95% confidence interval, 2.80-7.64; P = .0001). Recent ZIKV infection was confirmed by urine reverse-transcription polymerase chain reaction (RT-PCR) analysis in 17 cases and by serology in 6 cases. Patients, 65% of whom were male, had a median age of 61 years (interquartile range, 56-71 years) and experienced severe GBS. Electrophysiological tests were consistent with the primary demyelinating form of the disease.

ZIKV infection is usually benign, when symptomatic, but in countries at risk of ZIKV epidemics, adequate intensive care bed capacity is required for management of severe GBS cases. Arbovirus RNA detection by RT-PCR should be part of the management of GBS cases.

    Guillain-Barré syndrome (GBS)
    DIAGNOSIS

 has been reported to be associated with

    Zika virus (ZIKV) infection
    DIAGNOSIS

 in case reports and retrospective studies, mostly on the basis of

    serological tests
    PARACLINICAL

, with the

    problematic cross-reacting antibodies of the Flavivirus genus
    BIOCHEMICAL

. Some

    GBS
    DIAGNOSIS

 cases

    do not exhibit a high level of diagnostic certainty
    NEG_FINDINGS

. This prospective study aimed to describe the clinical profiles and the frequency of

    GBS associated with ZIKV
    DIAGNOSIS

 during the

    ZIKV
    DIAGNOSIS

 outbreak in

    Martinique
    ETHNICITY

 in 2016.

We recorded prospective data from

    GBS
    DIAGNOSIS

 meeting levels 1 or 2 of diagnostic certainty for the Brighton Collaboration, with

    proof of recent ZIKV infection
    BIOCHEMICAL

 and

    negative screening for etiologies of GBS
    NEG_FINDINGS

.

Of the sample of 34 patients with suspected

    GBS
    DIAGNOSIS

 during the outbreak, 30 had a proven presence of

    GBS
    DIAGNOSIS

, and 23 had a recent

    ZIKV infection
    DIAGNOSIS

. The estimated

    GBS
    DIAGNOSIS

 incidence rate ratio (2016 vs 2006-2015) was 4.52 (95% confidence interval, 2.80-7.64; P = .0001). Recent

    ZIKV infection
    DIAGNOSIS

 was confirmed by

    urine reverse-transcription polymerase chain reaction (RT-PCR) analysis
    PARACLINICAL

 in 17 cases and by

    serology
    PARACLINICAL

 in 6 cases. Patients, 65% of whom were

    male
    GENDER

, had a

    median age of 61 years (interquartile range, 56-71 years)
    AGE

 and experienced

    severe GBS
    DIAGNOSIS

.

    Electrophysiological tests
    PARACLINICAL

 were consistent with the

    primary demyelinating form of the disease
    SYMPTOMS

.

    ZIKV infection
    DIAGNOSIS

 is usually

    benign
    NEG_FINDINGS

, when symptomatic, but in countries at risk of

    ZIKV
    SYMPTOMS

 epidemics,

    adequate intensive care bed capacity
    MEDICATION

 is required for management of

    severe GBS
    DIAGNOSIS

 cases.

    Arbovirus RNA detection by RT-PCR
    PARACLINICAL

 should be part of the management of

    GBS
    DIAGNOSIS

 cases.

Guillain-Barré syndrome (GBS)
Zika virus (ZIKV) infection
GBS
GBS associated with ZIKV
ZIKV
GBS
GBS
GBS
ZIKV infection
GBS
ZIKV infection
severe GBS
ZIKV infection
severe GBS
GBS


Intrathecal Baclofen Pump Implantation for Type 2 Gaucher Disease.

Gaucher disease (GD) is the most common type of lysosomal storage disease, with type 2 being the most severe subtype. Type 2 GD patients suffer significant progressive neurological impairment, including spasticity, opisthotonus, seizure, and apnea. The recently developed enzyme replacement therapy (ERT) has shown therapeutic benefit for GD. However, as the enzymes do not cross the blood-brain barrier, ERT does not ameliorate neurological impairment in GD. Intrathecal baclofen therapy (IBT) is indicated for spastic neurological diseases, such as cerebral palsy, and studies have shown its therapeutic benefit in improving several manifestations of GD, such as scoliosis caused by muscle spasticity and respiratory function. To date, the potential benefits of IBT for treating lysosomal storage diseases such as GD have not been examined. Here we provide the first report of a patient with type 2 GD treated with IBT, and demonstrate its therapeutic benefit in ameliorating the neurological aspects of this disease.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most common type of

    lysosomal storage disease
    DIAGNOSIS

, with

    type 2
    DIAGNOSIS

 being the most severe subtype.

    Type 2 GD
    DIAGNOSIS

 patients suffer

    significant progressive neurological impairment
    SYMPTOMS

, including

    spasticity
    SYMPTOMS

,

    opisthotonus
    SYMPTOMS

,

    seizure
    SYMPTOMS

, and

    apnea
    SYMPTOMS

. The recently developed

    enzyme replacement therapy (ERT)
    MEDICATION

 has shown therapeutic benefit for

    GD
    DIAGNOSIS

. However, as

    the enzymes do not cross the blood-brain barrier
    NEG_FINDINGS

,

    ERT does not ameliorate neurological impairment in GD
    NEG_FINDINGS

.

    Intrathecal baclofen therapy (IBT)
    MEDICATION

 is indicated for

    spastic neurological diseases
    DIAGNOSIS

, such as

    cerebral palsy
    DIAGNOSIS

, and studies have shown its therapeutic benefit in

    improving several manifestations of GD
    SYMPTOMS

, such as

    scoliosis caused by muscle spasticity
    SYMPTOMS

 and

    respiratory function
    SYMPTOMS

. To date, the potential benefits of

    IBT
    MEDICATION

 for treating

    lysosomal storage diseases
    DIAGNOSIS

 such as

    GD
    DIAGNOSIS

 have not been examined. Here we provide the first report of a patient with

    type 2 GD
    DIAGNOSIS

 treated with

    IBT
    MEDICATION

, and demonstrate its therapeutic benefit in

    ameliorating the neurological aspects
    SYMPTOMS

 of this disease.

Gaucher disease (GD)
lysosomal storage disease
type 2
Type 2 GD
GD
spastic neurological diseases
cerebral palsy
lysosomal storage diseases
GD
type 2 GD

enzyme replacement therapy (ERT)
Intrathecal baclofen therapy (IBT)
IBT
IBT


Treatment of profound thrombocytopenia in a patient with Gaucher disease type 1: Is there a role for substrate reduction therapy.

The availability of three enzyme replacement therapy (ERT) drugs and two substrate reduction therapy (SRT) drugs to treat Gaucher disease provides an opportunity to tailor therapies to a patient's specific clinical concerns. However, there is a gap in the literature regarding individual drug effectiveness in treating particular symptoms and the potential benefits of combination treatment. This report details treatment of a patient with Gaucher disease type 1 whose main clinical concern was profound thrombocytopenia (around 20 × 109/L, normal range: 150-450 × 109/L) with several episodes of bleeding with minimal trauma and bruises. The patient was treated with ERT at doses up to 60 units/kg weekly, with no improvement in platelet levels for 6 years. Subsequently, the patient transitioned to SRT and platelet levels increased almost two fold within the first month, and have remained stable at safe levels (30-60 × 109/L) for almost 2.5 years at the time of publication. This report demonstrates a possible therapeutic benefit of SRT in individual patients who do not meet therapeutic goals in terms of thrombocytopenia after a considerable period on first-line ERT treatment. Oral administration of SRT also improved this patient's quality of life allowing discontinuation of weekly ERT infusions, which better accommodated her demanding career and busy lifestyle.

The availability of three

    enzyme replacement therapy (ERT) drugs
    MEDICATION

 and two

    substrate reduction therapy (SRT) drugs
    MEDICATION

 to treat

    Gaucher disease
    DIAGNOSIS

 provides an opportunity to tailor therapies to a patient's specific clinical concerns. However, there is a gap in the literature regarding individual drug effectiveness in treating particular symptoms and the potential benefits of

    combination treatment
    MEDICATION

. This report details treatment of a patient with

    Gaucher disease type 1
    DIAGNOSIS

 whose main clinical concern was

    profound thrombocytopenia (around 20 × 109/L, normal range: 150-450 × 109/L)
    BIOCHEMICAL

 with

    several episodes of bleeding with minimal trauma and bruises
    SYMPTOMS

. The patient was

    treated with ERT at doses up to 60 units/kg weekly
    MEDICATION

    , with no improvement in platelet levels for 6 years
    NEG_FINDINGS

. Subsequently, the patient

    transitioned to SRT
    MEDICATION

 and

    platelet levels increased almost two fold within the first month, and have remained stable at safe levels (30-60 × 109/L) for almost 2.5 years
    BIOCHEMICAL

 at the time of publication. This report demonstrates a possible therapeutic benefit of

    SRT
    MEDICATION

 in individual patients who

    do not meet therapeutic goals in terms of thrombocytopenia after a considerable period on first-line ERT treatment
    NEG_FINDINGS

.

    Oral administration of SRT
    MEDICATION

 also improved this patient's quality of life allowing

    discontinuation of weekly ERT infusions
    MEDICATION

, which better accommodated

    her
    GENDER

 demanding career and busy lifestyle.


Torsion of a wandering spleen in an adolescent with Gaucher disease.

A wandering spleen is a rare condition characterized by the malposition of the spleen due to laxity or absence of its supporting ligaments. Although Gaucher disease generally presents with massive splenomegaly, which one of the predisposing causes of a wandering spleen, literature shows only one report of a wandering spleen in a child with Gaucher disease. In this case presentation, a 13-year-oldadolescent with Gaucher disease on enzyme replacement treatment was presented, who was detected having an abdominal mass on a routine visit and diagnosed with partial torsion of a wandering spleen associated with left lobe hypoplasia of the liver.

A

    wandering spleen
    SYMPTOMS

 is a rare condition characterized by the

    malposition of the spleen due to laxity or absence of its supporting ligaments
    SYMPTOMS

. Although

    Gaucher disease
    DIAGNOSIS

 generally presents with

    massive splenomegaly
    SYMPTOMS

, which one of the predisposing causes of a

    wandering spleen
    SYMPTOMS

, literature shows only one report of a

    wandering spleen
    SYMPTOMS

 in a

    child
    AGE

 with

    Gaucher disease
    DIAGNOSIS

. In this case presentation, a

    13-year-oldadolescent
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 on

    enzyme replacement treatment
    MEDICATION

 was presented, who was detected having an

    abdominal mass
    SYMPTOMS

 on a routine visit and diagnosed with

    partial torsion of a wandering spleen associated with left lobe hypoplasia of the liver
    SYMPTOMS

.

Gaucher disease
Gaucher disease
Gaucher disease


A case of improved hearing with cochlear implantation in Gaucher disease type 1.

Gaucher disease is a lysosomal storage disorder that is caused by congenital defective function of the enzyme glucocerebrosidase. Glucocerebroside that is not hydrolyzed by glucocerebrosidase mainly accumulates in the reticular tissue. We describe a Japanese boy with Gaucher disease type 1 who developed bilateral profound sensorineural hearing loss within approximately 4years. We performed cochlear implantation initially on his right ear and again on his left ear 5 months later. The cochlear implants were successfully utilized with a speech discrimination score of 95% on a Japanese sentence recognition test. There are many reports of central hearing loss in Gaucher disease type 2 or 3. However, to the best of our knowledge, this is the first report of profound inner ear hearing loss with Gaucher disease. It also appears to be the first record of cochlear implantation for Gaucher disease. Cochlear implants may be useful for sensorineural hearing loss in patients with Gaucher disease without neurological symptoms other than hearing loss.

    Gaucher disease
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 that is caused by congenital

    defective function of the enzyme glucocerebrosidase
    BIOCHEMICAL

.

    Glucocerebroside that is not hydrolyzed by glucocerebrosidase mainly accumulates in the reticular tissue
    MICROSCOPIC

. We describe a

    Japanese
    ETHNICITY

    boy
    GENDER

 with

    Gaucher disease type 1
    DIAGNOSIS

 who developed

    bilateral profound sensorineural hearing loss
    SYMPTOMS

 within approximately 4years. We performed

    cochlear implantation
    MEDICATION

 initially on his right ear and again on his left ear 5 months later. The

    cochlear implants
    MEDICATION

 were successfully utilized with a

    speech discrimination score of 95% on a Japanese sentence recognition test
    PARACLINICAL

. There are many reports of

    central hearing loss
    SYMPTOMS

 in

    Gaucher disease type 2 or 3
    DIAGNOSIS

. However, to the best of our knowledge, this is the first report of

    profound inner ear hearing loss
    SYMPTOMS

 with

    Gaucher disease
    DIAGNOSIS

. It also appears to be the first record of

    cochlear implantation
    MEDICATION

 for

    Gaucher disease
    DIAGNOSIS

.

    Cochlear implants
    MEDICATION

 may be useful for

    sensorineural hearing loss
    SYMPTOMS

 in patients with

    Gaucher disease
    DIAGNOSIS

    without neurological symptoms
    NEG_FINDINGS

 other than

    hearing loss
    SYMPTOMS

.

Gaucher disease
lysosomal storage disorder
Gaucher disease type 1
Gaucher disease type 2 or 3
Gaucher disease
Gaucher disease
Gaucher disease

cochlear implantation
cochlear implants
cochlear implantation
Cochlear implants


Parkinson disease in Gaucher disease.

Gaucher disease (GD) is an inborn error of metabolism caused by mutations in the gene (GBA) coding for glucocerebrosidase (GCase), inherited in an autosomal recessive pattern. GD patients have up to 9% risk of developing PD.

We report two patients with GD that developed PD at different disease stages.

We reviewed the literature on the coexistence of PD and GD and speculate that the severity of symptoms may be related to the type of GBA mutation inherited.

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    inborn error of metabolism
    GENETICS

 caused by

    mutations in the gene (GBA) coding for glucocerebrosidase (GCase)
    GENETICS

,

    inherited in an autosomal recessive pattern
    GENETICS

.

    GD
    DIAGNOSIS

 patients have up to 9% risk of developing

    PD
    DIAGNOSIS

.

We report two patients with

    GD
    DIAGNOSIS

 that developed

    PD
    DIAGNOSIS

 at different disease stages.

We reviewed the literature on the

    coexistence of PD and GD
    DIAGNOSIS

 and speculate that the severity of symptoms may be related to the

    type of GBA mutation inherited
    GENETICS

.

Gaucher disease (GD)
GD
PD
GD
PD
coexistence of PD and GD


Gaucher Disease Presenting in an Adult with Intracerebral Bleed.

Gaucher disease (GD) is the most common lysosomal storage disorder, caused by deficiency of acid beta glucosidase. GD usually presents in children but occasional cases can present in adulthood. Here we report a case of type I GD in a 37 year old female who presented with intracerebral bleed due to long standing thrombocytopenia. She underwent splenectomy in view of limited resources for enzyme replacement therapy. With splenectomy her platelet counts normalised and neurological status also improved.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most common

    lysosomal storage disorder
    DIAGNOSIS

, caused by

    deficiency of acid beta glucosidase
    BIOCHEMICAL

.

    GD
    DIAGNOSIS

 usually presents in

    children
    AGE

 but occasional cases can present in

    adulthood
    AGE

. Here we report a case of

    type I GD
    DIAGNOSIS

 in a

    37 year old
    AGE

    female
    GENDER

 who presented with

    intracerebral bleed
    SYMPTOMS

 due to

    long standing thrombocytopenia
    BIOCHEMICAL

.

    She
    GENDER

 underwent

    splenectomy
    MEDICATION

 in view of limited resources for

    enzyme replacement therapy
    MEDICATION

. With

    splenectomy
    MEDICATION

 her

    platelet counts normalised
    BIOCHEMICAL

 and

    neurological status also improved
    SYMPTOMS

.

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

deficiency of acid beta glucosidase
long standing thrombocytopenia
platelet counts normalised

intracerebral bleed
neurological status also improved

splenectomy
enzyme replacement therapy
splenectomy


Case report of unexpected gastrointestinal involvement in type 1 Gaucher disease: comparison of eliglustat tartrate treatment and enzyme replacement therapy.

Gastrointestinal involvement in Gaucher disease is very rare, and appears to be unresponsive to enzyme replacement therapy (ERT).

Here, we describe identical twin, splenectomized, non-neuronopathic Gaucher patients on long-term ERT for 9 years, who complained of epigastric discomfort due to Gaucher cell infiltration of the gastroduodenal mucosa. Rare compound heterozygous mutations (p.Arg48Trp and p.Arg257Gln) of the GBA gene were found in both. Improvement in the gastroduodenal infiltration and reduced chitotriosidase levels were observed in one who switched to eliglustat tartrate for 1 year, whereas the other one who maintained ERT showed no improvement of chitotriosidase level and persistent duodenal lesions.

This shows that eliglustat might be an effective treatment for Gaucher disease patients having lesions resistant to ERT.

    Gastrointestinal involvement
    SYMPTOMS

 in

    Gaucher disease
    DIAGNOSIS

 is very rare, and appears to be

    unresponsive to enzyme replacement therapy (ERT)
    NEG_FINDINGS

.

Here, we describe identical twin,

    splenectomized
    MEDICATION

,

    non-neuronopathic
    NEG_FINDINGS

    Gaucher
    DIAGNOSIS

 patients

    on long-term ERT for 9 years
    MEDICATION

, who complained of

    epigastric discomfort
    SYMPTOMS

 due to

    Gaucher cell infiltration of the gastroduodenal mucosa
    MICROSCOPIC

.

    Rare compound heterozygous mutations (p.Arg48Trp and p.Arg257Gln) of the GBA gene
    GENETICS

 were found in both.

    Improvement in the gastroduodenal infiltration
    MICROSCOPIC

 and

    reduced chitotriosidase levels
    BIOCHEMICAL

 were observed in one who

    switched to eliglustat tartrate for 1 year
    MEDICATION

, whereas the other one who

    maintained ERT
    MEDICATION

 showed

    no improvement of chitotriosidase level
    NEG_FINDINGS

 and

    persistent duodenal lesions
    SYMPTOMS

.

This shows that

    eliglustat
    MEDICATION

 might be an effective treatment for

    Gaucher disease
    DIAGNOSIS

 patients having

    lesions resistant to ERT
    NEG_FINDINGS

.

Gastrointestinal involvement
epigastric discomfort
persistent duodenal lesions


A rare form of Gaucher disease resulting from saposin C deficiency.

Gaucher disease is mainly caused by the deficiency of lysosomal acid β-glucosidase. Gaucher disease caused by the deficiency of saposin C is rare. Here we report a patient mainly presenting with hepatosplenomegaly, thrombocytopenia and anemia. EEG examination revealed increased theta waves. Gaucher cells identified in his bone marrow and the highly elevated plasma chitotriosidase activity and glucosylsphingosine supported a diagnosis of Gaucher disease. However, the leukocyte β-glucosidase activity was in a normal range. Sanger sequencing revealed a novel maternal exonic mutation c.1133C>G (p.Pro378Arg) in exon 10 of the PSAP gene, which codes the Sap C domain of PSAP protein. To search for other underlying mutations in this patient, whole genome sequencing was applied and revealed a deletion involving exon 2 to 7 of PSAP gene. The deletion appears as a de novo event on paternal chromosome. We concluded that biallelic mutations of PSAP gene were the cause of this patient's Gaucher disease. Our finding expands the mutation spectrum of Gaucher disease with saposin C deficiency.

    Gaucher disease
    DIAGNOSIS

 is mainly caused by the

    deficiency of lysosomal acid β-glucosidase
    BIOCHEMICAL

.

    Gaucher disease
    DIAGNOSIS

 caused by the

    deficiency of saposin C
    BIOCHEMICAL

 is rare. Here we report a patient mainly presenting with

    hepatosplenomegaly
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

 and

    anemia
    BIOCHEMICAL

.

    EEG examination
    PARACLINICAL

 revealed

    increased theta waves
    SYMPTOMS

.

    Gaucher cells identified in his bone marrow
    MICROSCOPIC

 and the

    highly elevated plasma chitotriosidase activity and glucosylsphingosine
    BIOCHEMICAL

 supported a diagnosis of

    Gaucher disease
    DIAGNOSIS

. However, the

    leukocyte β-glucosidase activity was in a normal range
    NEG_FINDINGS

.

    Sanger sequencing
    PARACLINICAL

 revealed a

    novel maternal exonic mutation c.1133C>G (p.Pro378Arg) in exon 10 of the PSAP gene, which codes the Sap C domain of PSAP protein
    GENETICS

. To search for other underlying mutations in this patient,

    whole genome sequencing
    PARACLINICAL

 was applied and revealed a

    deletion involving exon 2 to 7 of PSAP gene
    GENETICS

.

    The deletion appears as a de novo event on paternal chromosome
    GENETICS

. We concluded that

    biallelic mutations of PSAP gene
    GENETICS

 were the cause of this patient's

    Gaucher disease
    DIAGNOSIS

. Our finding expands the mutation spectrum of

    Gaucher disease
    DIAGNOSIS

 with

    saposin C deficiency
    BIOCHEMICAL

.

Gaucher disease
Gaucher disease
Gaucher disease
Gaucher disease
Gaucher disease

hepatosplenomegaly
increased theta waves


Long-term response in biochemical markers of bone turnover during enzyme replacement therapy in a case-series of patients with Gaucher disease type I from Northern Greece.

Gaucher disease (GD) is a lysosomal storage disorder characterized by severe skeletal complications. Bone complications are an important cause of morbidity of GD and are thought to result from imbalance in bone remodeling. The objective of this case series was to analyze the long-term effect of enzyme replacement therapy on chemokines MIP-1a and MIP-1b, cytokines IL-3, IL-6, IL-10, and IL-12, osteoprotegerin (OPG) and osteocalcin (BGP), chitotriosidase, quantitative ultrasound sonography (QUS), bone magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) in patients with GD in Northern Greece. In addition, the study aimed in investigating possible relationship between the above mentioned parameters.

Seven patients with GD type I (three males and four females) were included in the study. Mean age was 26.29 ± 15.34 years (range 7-47 years). Six patients were receiving enzyme replacement therapy (ERT), with 40-60 IU/kg of imiglucerase weekly, for a mean period of 36 months prior to study initiation. One patient started ERT after his inclusion in the study. The levels of MIP-1a, MIP-1b, IL-3, IL-6, IL-10, IL-12, OPG, BGP, chitotriosidase, bone imaging parameters assessed with two different techniques (QUS and DXA) and MRI data were estimated at baseline (T0) and after two years on ERT.

Chitotriosidase, MIP-1a, and IL-6 levels decreased in all patients after two years of ERT (p =0.05). In contrast, OPG and BGP levels increased (p =0.04 and p =0.02, respectively). Bone mineral density (BMD) demonstrated a progressive improvement with regards to the Z-score in all patients (p =0.05). The decrease in the plasma levels of MIP-1a strongly correlated with a decrease in the plasma levels of chitotriosidase. Additionally, decreased plasma levels of IL-6 were correlated with increased Z-score both at baseline (T0) as well as two years later, in all patients. There was no correlation between MRI findings and any inflammatory biomarker.

Measurement of serum markers in patients with GD under ERT could be used as an auxiliary tool in the monitoring of bone involvement, in combination with MRI imaging and BMD. However, larger studies involving higher numbers of GD patients are needed to confirm these conclusions. Hippokratia 2016, 20(2): 153-159.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 characterized by

    severe skeletal complications
    SYMPTOMS

.

    Bone complications
    SYMPTOMS

 are an important cause of morbidity of

    GD
    DIAGNOSIS

 and are thought to result from

    imbalance in bone remodeling
    SYMPTOMS

. The objective of this case series was to analyze the long-term effect of

    enzyme replacement therapy
    MEDICATION

 on

    chemokines MIP-1a and MIP-1b
    BIOCHEMICAL

,

    cytokines IL-3, IL-6, IL-10, and IL-12
    BIOCHEMICAL

,

    osteoprotegerin (OPG) and osteocalcin (BGP)
    BIOCHEMICAL

,

    chitotriosidase
    BIOCHEMICAL

,

    quantitative ultrasound sonography (QUS)
    PARACLINICAL

,

    bone magnetic resonance imaging (MRI)
    PARACLINICAL

 and

    dual-energy X-ray absorptiometry (DXA)
    PARACLINICAL

 in patients with

    GD
    DIAGNOSIS

 in

    Northern Greece
    ETHNICITY

. In addition, the study aimed in investigating possible relationship between the above mentioned parameters.

Seven patients with

    GD type I
    DIAGNOSIS

 (three

    males
    GENDER

 and four

    females
    GENDER

) were included in the study.

    Mean age was 26.29 ± 15.34 years (range 7-47 years)
    AGE

. Six patients were

    receiving enzyme replacement therapy (ERT), with 40-60 IU/kg of imiglucerase weekly, for a mean period of 36 months
    MEDICATION

 prior to study initiation. One patient started

    ERT
    MEDICATION

 after

    his
    GENDER

 inclusion in the study. The

    levels of MIP-1a, MIP-1b, IL-3, IL-6, IL-10, IL-12, OPG, BGP, chitotriosidase
    BIOCHEMICAL

,

    bone imaging parameters
    SYMPTOMS

    assessed with two different techniques (QUS and DXA)
    PARACLINICAL

 and

    MRI data were estimated at baseline (T0) and after two years
    PARACLINICAL

 on

    ERT
    MEDICATION

.

    Chitotriosidase, MIP-1a, and IL-6 levels decreased
    BIOCHEMICAL

 in all patients

    after two years of ERT
    MEDICATION

 (p =0.05). In contrast,

    OPG and BGP levels increased
    BIOCHEMICAL

 (p =0.04 and p =0.02, respectively).

    Bone mineral density (BMD) demonstrated a progressive improvement
    SYMPTOMS

 with regards to the Z-score in all patients (p =0.05). The

    decrease in the plasma levels of MIP-1a
    BIOCHEMICAL

 strongly correlated with a

    decrease in the plasma levels of chitotriosidase
    BIOCHEMICAL

. Additionally,

    decreased plasma levels of IL-6
    BIOCHEMICAL

 were correlated with increased Z-score both at baseline (T0) as well as two years later, in all patients. There was

    no correlation between MRI findings and any inflammatory biomarker
    NEG_FINDINGS

.

    Measurement of serum markers
    PARACLINICAL

 in patients with

    GD
    DIAGNOSIS

 under

    ERT
    MEDICATION

 could be used as an auxiliary tool in the

    monitoring of bone involvement
    PARACLINICAL

, in combination with

    MRI imaging
    PARACLINICAL

 and

    BMD
    PARACLINICAL

. However, larger studies involving higher numbers of

    GD
    DIAGNOSIS

 patients are needed to confirm these conclusions. Hippokratia 2016, 20(2): 153-159.

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


Severe cardiac involvement in Gaucher type IIIC: a case report and review of the literature.

Gaucher disease is an autosomal-recessive lysosomal storage disease characterised by the accumulation of glucocerebroside in macrophages; it is caused by mutations in glucocerebrosidase gene-1 in many organ tissues such as the liver, spleen, and bone marrow. Its different clinical subtypes, according to the presence and severity of neurological symptoms, are as follows: type I, non-neuronopathic (95%); type II, acute neuronopathic; and type III, chronic neuronopathic. Type IIIC is a rare subgroup characterised by cardiovascular involvement as well as eye-movement disorders and late-onset neurological symptoms. In such cases, homozygous D409H is the most frequently detected mutation. In this article, we report the case of a patient, aged 15 years and 8 months, with complaints of syncope and a diagnosis of type IIIC Gaucher disease.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal-recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 characterised by the

    accumulation of glucocerebroside in macrophages
    MICROSCOPIC

; it is caused by

    mutations in glucocerebrosidase gene-1 in many organ tissues such as the liver, spleen, and bone marrow
    GENETICS

. Its different clinical subtypes, according to the presence and severity of

    neurological symptoms
    SYMPTOMS

, are as follows:

    type I, non-neuronopathic
    DIAGNOSIS

 (95%);

    type II, acute neuronopathic
    DIAGNOSIS

; and

    type III, chronic neuronopathic
    DIAGNOSIS

.

    Type IIIC
    DIAGNOSIS

 is a rare subgroup characterised by

    cardiovascular involvement
    SYMPTOMS

 as well as

    eye-movement disorders
    SYMPTOMS

 and

    late-onset neurological symptoms
    SYMPTOMS

. In such cases,

    homozygous D409H is the
    GENETICS

 most frequently detected

    mutation
    GENETICS

. In this article, we report the case of a patient,

    aged 15 years and 8 months
    AGE

, with

    complaints of syncope
    SYMPTOMS

 and a diagnosis of

    type IIIC Gaucher disease
    DIAGNOSIS

.

Gaucher disease
lysosomal storage disease
type I, non-neuronopathic
type II, acute neuronopathic
type III, chronic neuronopathic
Type IIIC
type IIIC Gaucher disease

neurological symptoms
cardiovascular involvement
eye-movement disorders
late-onset neurological symptoms
complaints of syncope


Rare disease heralded by pulmonary manifestations: Avoiding pitfalls of an "asthma" label.

Pulmonary manifestations are seldom recognized as symptoms of storage disorders. The report describes the diagnostic journey in a 30-month-old male infant, born of a third-degree consanguineous marriage referred to our institute as severe persistent asthma. History revealed that the child had progressively worsening breathlessness and persistent dry cough not associated with fever but accompanied by weight loss. On physical examination, there was growth failure, respiratory distress, clubbing, hepatosplenomegaly, and occasional rhonchi. Blood gas revealed hypoxemia which improved with oxygen administration. Plain X-rays and high-resolution computed tomography of the chest showed perihilar alveolar infiltrates and patchy consolidation. The clinicoradiological features did not support a diagnosis of asthma but favored interstitial lung disease (ILD). Bronchoalveolar lavage was performed as a first-tier investigation. It showed periodic acid-Schiff-negative foamy macrophages. The clues of consanguinity, visceromegaly, ILD, and foamy macrophages in the bronchoalveolar fluid prompted consideration of lysosomal storage disorders as the likely etiology. Gaucher disease and Niemann-Pick disease A/B were ruled out by enzyme estimation. Niemann-Pick disease type C was suspected and confirmed by detecting a homozygous mutation in the NPC2 gene. This case serves to caution physicians against labeling breathlessness in every toddler as asthma. It emphasizes the importance of searching for tell-tale signs such as clubbing and extrapulmonary clues which point to a systemic disease such as lysosomal storage disorders as a primary etiology of chronic respiratory symptoms.

    Pulmonary manifestations
    SYMPTOMS

 are seldom recognized as symptoms of

    storage disorders
    DIAGNOSIS

. The report describes the diagnostic journey in a

    30-month-old
    AGE

    male
    GENDER

    infant
    AGE

, born of a

    third-degree consanguineous marriage
    FAMILY

 referred to our institute as

    severe persistent asthma
    DIAGNOSIS

. History revealed that the

    child
    AGE

 had

    progressively worsening breathlessness
    SYMPTOMS

 and

    persistent dry cough
    SYMPTOMS

    not associated with fever
    NEG_FINDINGS

 but accompanied by

    weight loss
    SYMPTOMS

. On physical examination, there was

    growth failure
    SYMPTOMS

,

    respiratory distress
    SYMPTOMS

,

    clubbing
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

, and

    occasional rhonchi
    SYMPTOMS

.

    Blood gas
    PARACLINICAL

 revealed

    hypoxemia
    BIOCHEMICAL

 which improved with

    oxygen administration
    MEDICATION

.

    Plain X-rays and high-resolution computed tomography of the chest
    PARACLINICAL

 showed

    perihilar alveolar infiltrates
    SYMPTOMS

 and

    patchy consolidation
    SYMPTOMS

. The clinicoradiological features

    did not support a diagnosis of asthma
    NEG_FINDINGS

 but favored

    interstitial lung disease (ILD)
    DIAGNOSIS

.

    Bronchoalveolar lavage
    PARACLINICAL

 was performed as a first-tier investigation. It showed

    periodic acid-Schiff-negative foamy macrophages
    MICROSCOPIC

. The clues of

    consanguinity
    FAMILY

,

    visceromegaly
    SYMPTOMS

,

    ILD
    DIAGNOSIS

, and

    foamy macrophages in the bronchoalveolar fluid
    MICROSCOPIC

 prompted consideration of

    lysosomal storage disorders
    DIAGNOSIS

 as the likely etiology.

    Gaucher disease and Niemann-Pick disease A/B were ruled out by enzyme estimation
    NEG_FINDINGS

.

    Niemann-Pick disease type C
    DIAGNOSIS

 was suspected and confirmed by detecting a

    homozygous mutation in the NPC2 gene
    GENETICS

. This case serves to

    caution physicians against labeling breathlessness in every toddler as asthma
    NEG_FINDINGS

. It emphasizes the importance of searching for tell-tale signs such as

    clubbing
    SYMPTOMS

 and

    extrapulmonary clues
    SYMPTOMS

 which point to a systemic disease such as

    lysosomal storage disorders
    DIAGNOSIS

 as a primary etiology of

    chronic respiratory symptoms
    SYMPTOMS

.

Pulmonary manifestations
progressively worsening breathlessness
persistent dry cough
weight loss
growth failure
respiratory distress
clubbing
hepatosplenomegaly
occasional rhonchi
perihilar alveolar infiltrates
patchy consolidation
visceromegaly
clubbing
extrapulmonary clues
chronic respiratory symptoms

storage disorders
severe persistent asthma
interstitial lung disease (ILD)
ILD
lysosomal storage disorders
Niemann-Pick disease type C
lysosomal storage disorders


Gaucher disease in the liver on hepatocyte specific contrast agent enhanced MR imaging.

Gaucher disease is a hereditary lipid storage disorder that affects the enzyme beta glucocerebrosidase, causing accumulation of glucocerebroside in macrophages of the reticuloendothelial system. Accumulation can occur in the liver and spleen, manifesting as hepatosplenomegaly, as well as within the bone marrow. Hepatic involvement is usually diffuse but can occasionally manifest as focal liver lesions. We present a case of a 2-year-old boy with Gaucher disease and an infiltrating liver lesion detected on imaging, which was pathologically shown to be focal changes related to the disease. Imaging characteristics of this lesion using hepatocyte specific contrast agent enhanced MRI, which have not been previously discussed in the literature, are described.

    Gaucher disease
    DIAGNOSIS

 is a

    hereditary
    GENETICS

    lipid storage disorder
    DIAGNOSIS

 that affects the

    enzyme beta glucocerebrosidase
    BIOCHEMICAL

, causing

    accumulation of glucocerebroside in macrophages of the reticuloendothelial system
    MICROSCOPIC

. Accumulation can occur in the liver and spleen, manifesting as

    hepatosplenomegaly
    SYMPTOMS

, as well as within the bone marrow.

    Hepatic involvement
    SYMPTOMS

 is usually diffuse but can occasionally manifest as

    focal liver lesions
    SYMPTOMS

. We present a case of a

    2-year-old
    AGE

    boy
    GENDER

 with

    Gaucher disease
    DIAGNOSIS

 and an

    infiltrating liver lesion
    SYMPTOMS

 detected on

    imaging
    PARACLINICAL

, which was pathologically shown to be focal changes related to the disease. Imaging characteristics of this lesion using

    hepatocyte specific contrast agent enhanced MRI
    PARACLINICAL

, which have not been previously discussed in the literature, are described.

Gaucher disease
lipid storage disorder
Gaucher disease

hepatosplenomegaly
Hepatic involvement
focal liver lesions
infiltrating liver lesion


Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report.

The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease.

We report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment.

This case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

The variants of

    neuronopathic Gaucher disease
    DIAGNOSIS

 may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The

    chronic neuronopathic form of Gaucher disease
    DIAGNOSIS

 is characterized by a

    later onset of neurological symptoms
    SYMPTOMS

 and

    protracted neurological and visceral involvement
    SYMPTOMS

. The first-choice treatment for

    nonneuronopathic Gaucher disease
    DIAGNOSIS

 is

    enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase
    MEDICATION

.

    Enzyme replacement therapy
    MEDICATION

 has been shown to

    improve hematological and bone manifestations associated with Gaucher disease
    SYMPTOMS

, but, as with most proteins,

    recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations
    NEG_FINDINGS

.

    Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin)
    MEDICATION

    inhibits glucosylceramide synthase
    BIOCHEMICAL

, which catalyzes the first step in

    glycosphingolipid synthesis
    BIOCHEMICAL

. Because

    miglustat
    MEDICATION

 can cross the blood-brain barrier, it has been suggested that,

    combined with enzyme replacement therapy
    MEDICATION

, it might be effective in treating

    neurological symptoms
    SYMPTOMS

 in patients with

    neuronopathic Gaucher disease
    DIAGNOSIS

.

We report observed effects of

    combined enzyme replacement therapy and substrate reduction therapy
    MEDICATION

 in a

    7-year-old
    AGE

    Caucasian
    ETHNICITY

    boy
    GENDER

 with

    neuronopathic Gaucher disease
    DIAGNOSIS

 who was

    homozygous for L444P mutations
    GENETICS

.

    He
    GENDER

 had

    received enzyme replacement therapy from the age of 18 months
    MEDICATION

, and

    concomitant miglustat treatment
    MEDICATION

 was commenced, with dosing according to body surface area uptitrated over 1 month with

    dietary modifications
    MEDICATION

 when he reached the

    age of 30 months
    AGE

.

    He
    GENDER

 experienced

    mild diarrhea
    SYMPTOMS

 after commencing

    miglustat therapy
    MEDICATION

, which decreased in frequency/severity over time. His

    splenomegaly was reduced
    SYMPTOMS

, and his

    hematological values and plasma angiotensin-converting enzyme activity normalized
    BIOCHEMICAL

.

    Plasma chitotriosidase also showed substantial and sustained decreases
    BIOCHEMICAL

. After

    5 years of combination therapy
    MEDICATION

, the patient showed

    no signs of neurological impairment
    NEG_FINDINGS

.

This case supports the concept that

    oral miglustat in combination with intravenous enzyme replacement therapy
    MEDICATION

 may be beneficial in preventing

    neurological signs
    SYMPTOMS

 in patients with

    chronic neuronopathic Gaucher disease
    DIAGNOSIS

. The importance of

    dietary modifications
    MEDICATION

 has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of

    combined treatment
    MEDICATION

 in this

    Gaucher disease subtype
    DIAGNOSIS

.


Massive Mesenteric Lymphadenopathy Causing Protein-losing Enteropathy in Gaucher Disease.

Protein-losing enteropathy due to massive mesenteric lymphadenopathy is a rare complication of Gaucher disease which is generally refractory to treatment with enzyme replacement and substrate reduction therapies. It is postulated that lymph nodes may act as a "sanctuary site" into which these treatments cannot penetrate. We present the case of a male child with Gaucher disease who developed massive mesenteric lymph nodes despite otherwise successful treatment with enzyme replacement therapy, and subsequently developed protein-losing enteropathy. The sonographic and magnetic resonance appearances of this complication are shown. Large volume lymphadenopathy inevitably provokes concern about the possibility of malignancy, but in a patient with Gaucher disease-particularly with significant ascites and clinical features of protein-losing enteropathy-this rare complication should be considered.

    Protein-losing enteropathy
    BIOCHEMICAL

 due to

    massive mesenteric lymphadenopathy
    SYMPTOMS

 is a rare complication of

    Gaucher disease
    DIAGNOSIS

 which is generally refractory to treatment with

    enzyme replacement and substrate reduction therapies
    MEDICATION

. It is postulated that lymph nodes may act as a "sanctuary site" into which these

    treatments cannot penetrate
    NEG_FINDINGS

. We present the case of a

    male
    GENDER

    child
    AGE

 with

    Gaucher disease
    DIAGNOSIS

 who developed

    massive mesenteric lymph nodes
    SYMPTOMS

 despite

    otherwise successful treatment with enzyme replacement therapy
    MEDICATION

, and subsequently developed

    protein-losing enteropathy
    BIOCHEMICAL

. The

    sonographic and magnetic resonance
    PARACLINICAL

 appearances of this complication are shown.

    Large volume lymphadenopathy
    SYMPTOMS

 inevitably provokes concern about the possibility of

    malignancy
    DIAGNOSIS

, but in a patient with

    Gaucher disease
    DIAGNOSIS

-particularly with

    significant ascites
    SYMPTOMS

 and

    clinical features of protein-losing enteropathy
    SYMPTOMS

-this rare complication should be considered.

Protein-losing enteropathy
protein-losing enteropathy

Gaucher disease
Gaucher disease
malignancy
Gaucher disease


Norrbottnian clinical variant of Gaucher disease in Southern Italy.

The Norrbottnian type of Gaucher disease (GD), as described many years ago, is due to a unique neuronopathic variant (c.1448T>G; L444P) that may have appeared during or before the sixteenth century in northern Sweden. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular, Norrbottnian patients described in Sweden and Poland seem to share identical clinical histories characterized by the early onset of significant hepatosplenomegaly, often requiring splenectomy at an early age. Neurological involvement generally appears during the first or second decade of life, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment. Osteopenia occurs primarily in the spine, causing a severe and progressive thoracic kyphosis, although the involvement of other skeletal sites cannot be excluded. Here, we report on four Gaucher type 3 patients with Southern Italian ancestry presenting with clinical features and disease progression comparable to those of the 'Norrbottnian' Swedish phenotype, particularly regarding skeletal involvement with poor responsiveness to any therapeutical approach. Although a common ancestry among Southern Italian and Swedish Norrbottnian GD patients could not be investigated, the genotype [L444P]+[L444P] is the most frequently encountered in Southern Italy.

The

    Norrbottnian type of Gaucher disease (GD)
    DIAGNOSIS

, as described many years ago, is due to a

    unique neuronopathic variant (c.1448T>G; L444P)
    GENETICS

 that may have appeared during or before the sixteenth century in

    northern Sweden
    ETHNICITY

. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular,

    Norrbottnian
    ETHNICITY

 patients described in

    Sweden
    ETHNICITY

 and

    Poland
    ETHNICITY

 seem to share identical clinical histories characterized by the

    early onset of significant hepatosplenomegaly
    SYMPTOMS

, often requiring

    splenectomy
    MEDICATION

 at an

    early age
    AGE

.

    Neurological involvement
    SYMPTOMS

 generally appears

    during the first or second decade of life
    AGE

, and includes

    horizontal gaze palsy
    SYMPTOMS

,

    epilepsy
    SYMPTOMS

,

    myoclonic movements
    SYMPTOMS

,

    ataxia
    SYMPTOMS

,

    dementia
    SYMPTOMS

 and

    cognitive impairment
    SYMPTOMS

.

    Osteopenia occurs primarily in the spine
    SYMPTOMS

, causing a

    severe and progressive thoracic kyphosis
    SYMPTOMS

, although the

    involvement of other skeletal sites
    SYMPTOMS

 cannot be excluded. Here, we report on four

    Gaucher type 3
    DIAGNOSIS

 patients with

    Southern Italian
    ETHNICITY

 ancestry presenting with

    clinical features and disease progression comparable to those of the 'Norrbottnian' Swedish phenotype
    SYMPTOMS

, particularly regarding

    skeletal involvement
    SYMPTOMS

 with

    poor responsiveness to any therapeutical approach
    NEG_FINDINGS

. Although a common ancestry among

    Southern Italian
    ETHNICITY

 and

    Swedish Norrbottnian
    ETHNICITY

    GD
    DIAGNOSIS

 patients could not be investigated, the

    genotype [L444P]+[L444P]
    GENETICS

 is the most frequently encountered in

    Southern Italy
    ETHNICITY

.

northern Sweden
Norrbottnian
Sweden
Poland
Southern Italian
Southern Italian
Swedish Norrbottnian
Southern Italy


Invasive group G streptococcal infection in a paediatric patient.

We present a paediatric case of group G streptococcal bacteraemia and vertebral osteomyelitis. The patient is a 14-year-old girl with Gaucher disease type 1 who presented with severe thoracolumbar pain. She was treated with a 4-week course of antibiotics for presumed osteomyelitis with clinical improvement.

We present a

    paediatric
    AGE

 case of

    group G streptococcal bacteraemia
    DIAGNOSIS

 and

    vertebral osteomyelitis
    DIAGNOSIS

. The patient is a

    14-year-old
    AGE

    girl
    GENDER

 with

    Gaucher disease type 1
    DIAGNOSIS

 who presented with

    severe thoracolumbar pain
    SYMPTOMS

.

    She
    GENDER

 was treated with a

    4-week course of antibiotics
    MEDICATION

 for

    presumed osteomyelitis
    DIAGNOSIS

 with

    clinical improvement
    SYMPTOMS

.

group G streptococcal bacteraemia
vertebral osteomyelitis
Gaucher disease type 1
presumed osteomyelitis

severe thoracolumbar pain
clinical improvement


Hemophagocytic lymphohistiocytosis triggered by Gaucher disease in a preterm neonate.

To present the diagnostic workup in an extremely low birth weight infant patient with signs of both sepsis and hemophagocytosis.

A preterm infant presented with clinical and laboratory signs of early-onset sepsis including hepatosplenomegaly, thrombocytopenia, direct hyperbilirubinemia, and elevated liver enzymes.

Despite extensive septic workup, no underlying infection was detected. Additional hyperferritinemia and other elevated inflammatory parameters raised the suspicion of a primary or secondary hemophagocytic lymphohistiocytosis (HLH).

However, further metabolic analysis yielded a positive result for Gaucher disease (GD) type 2, a rare, but possible trigger of HLH.

Our case shows that GD may lead to the picture of a secondary HLH and that a metabolic workup should always be performed in patients in whom primary HLH has been excluded.

To present the diagnostic workup in an

    extremely low birth weight
    SYMPTOMS

    infant
    AGE

 patient with

    signs of both sepsis and hemophagocytosis
    SYMPTOMS

.

A

    preterm infant
    AGE

 presented with

    clinical and laboratory signs of early-onset sepsis
    SYMPTOMS

 including

    hepatosplenomegaly
    SYMPTOMS

,

    thrombocytopenia
    BIOCHEMICAL

,

    direct hyperbilirubinemia
    BIOCHEMICAL

, and

    elevated liver enzymes
    BIOCHEMICAL

.

Despite

    extensive septic workup
    PARACLINICAL

,

    no underlying infection was detected
    NEG_FINDINGS

. Additional

    hyperferritinemia
    BIOCHEMICAL

 and other

    elevated inflammatory parameters
    BIOCHEMICAL

 raised the suspicion of a

    primary or secondary hemophagocytic lymphohistiocytosis (HLH)
    DIAGNOSIS

.

However, further

    metabolic analysis
    PARACLINICAL

 yielded a positive result for

    Gaucher disease (GD) type 2
    DIAGNOSIS

, a rare, but possible trigger of

    HLH
    DIAGNOSIS

.

Our case shows that

    GD
    DIAGNOSIS

 may lead to the picture of a

    secondary HLH
    DIAGNOSIS

 and that a

    metabolic workup
    PARACLINICAL

 should always be performed in patients in whom

    primary HLH has been excluded
    NEG_FINDINGS

.

thrombocytopenia
direct hyperbilirubinemia
elevated liver enzymes
hyperferritinemia
elevated inflammatory parameters

no underlying infection was detected
primary HLH has been excluded


Case report of cholelithiasis in a patient with type 1 Gaucher disease.

Patients with type 1 Gaucher disease have been reported to be more likely to have cholelithiasis.

A case of cholelithiasis in a patient with type 1 Gaucher disease; which is very intriguing to show this comorbidity. The case was the only known case with this pathology in time of diagnosis in our country (Kosovo). The patient is a 21-year old girl a known case of type 1 Gaucher disease, at the age of 8 years. The patient underwent elective laparoscopic cholecystectomy. Chronic inflammatory changes and adhesions were obvious during surgery.

Type 1 Gaucher disease patients have several risk factors for gallstone formation: increased biliary excretion of glucosylceramide, advanced liver disease and cirrhosis, splenomegaly, inborn error of metabolism, chronic systemic inflammation, T cell dysfunction, and insulin resistance" to risk factors.

Gallstones and cholecystitis should be considered when abdominal symptoms and liver dysfunctions are seen in these patients. More studies are needed in especially Kosovo.

Patients with

    type 1 Gaucher disease
    DIAGNOSIS

 have been reported to be more likely to have

    cholelithiasis
    DIAGNOSIS

.

A case of

    cholelithiasis
    DIAGNOSIS

 in a patient with

    type 1 Gaucher disease
    DIAGNOSIS

; which is very intriguing to show this comorbidity. The case was the only known case with this pathology in time of diagnosis in our country (

    Kosovo
    ETHNICITY

). The patient is a

    21-year old
    AGE

    girl
    GENDER

 a known case of

    type 1 Gaucher disease
    DIAGNOSIS

,

    at the age of 8 years
    AGE

. The patient underwent

    elective laparoscopic cholecystectomy
    MEDICATION

.

    Chronic inflammatory changes
    SYMPTOMS

 and

    adhesions
    SYMPTOMS

 were obvious during

    surgery
    MEDICATION

.

    Type 1 Gaucher disease
    DIAGNOSIS

 patients have several

    risk factors for gallstone formation
    SYMPTOMS

:

    increased biliary excretion of glucosylceramide
    BIOCHEMICAL

,

    advanced liver disease and cirrhosis
    SYMPTOMS

,

    splenomegaly
    SYMPTOMS

,

    inborn error of metabolism
    GENETICS

,

    chronic systemic inflammation
    SYMPTOMS

,

    T cell dysfunction
    BIOCHEMICAL

, and

    insulin resistance
    SYMPTOMS

" to risk factors.

    Gallstones
    DIAGNOSIS

 and

    cholecystitis
    DIAGNOSIS

 should be considered when

    abdominal symptoms
    SYMPTOMS

 and

    liver dysfunctions
    SYMPTOMS

 are seen in these patients. More studies are needed in especially

    Kosovo
    ETHNICITY

.

type 1 Gaucher disease
cholelithiasis
cholelithiasis
type 1 Gaucher disease
type 1 Gaucher disease
Type 1 Gaucher disease
Gallstones
cholecystitis

elective laparoscopic cholecystectomy
surgery

Chronic inflammatory changes
adhesions
risk factors for gallstone formation
advanced liver disease and cirrhosis
splenomegaly
chronic systemic inflammation
insulin resistance
abdominal symptoms
liver dysfunctions


The unusual association between Neuroblastoma and Gaucher Disease: Case report and review of the literature.

Gaucher disease (GD) patients have an increased risk of cancer, in particular of hematological origin, while the association between GD and Neuroblastoma (NBL) has never been described. Here we report the case of an adolescent diagnosed with NBL, also presenting splenomegaly and persistent thrombocytopenia. The association with GD, suggested by the histological findings on bone marrow biopsy, was confirmed by enzymatic and genetic tests. The possible pathogenetic mechanisms are briefly reviewed. The evidence of this new association supports the necessity of further studies on GD comorbidities and the need of systematic data collection and analysis, potentially through an international registry. A greater attention for GD in the hemato-oncological field is needed, in order to avoid underdiagnosis and to optimize treatment strategies.

    Gaucher disease (GD)
    DIAGNOSIS

 patients have an increased risk of

    cancer
    DIAGNOSIS

, in particular of

    hematological
    DIAGNOSIS

 origin, while the association between

    GD
    DIAGNOSIS

 and

    Neuroblastoma (NBL)
    DIAGNOSIS

 has never been described. Here we report the case of an

    adolescent
    AGE

 diagnosed with

    NBL
    DIAGNOSIS

, also presenting

    splenomegaly
    SYMPTOMS

 and

    persistent thrombocytopenia
    BIOCHEMICAL

. The association with

    GD
    DIAGNOSIS

, suggested by the histological findings on

    bone marrow biopsy
    PARACLINICAL

, was confirmed by

    enzymatic and genetic tests
    PARACLINICAL

. The possible pathogenetic mechanisms are briefly reviewed. The evidence of this new association supports the necessity of further studies on

    GD comorbidities
    DIAGNOSIS

 and the need of systematic data collection and analysis, potentially through an international registry. A greater attention for

    GD
    DIAGNOSIS

 in the hemato-oncological field is needed, in order to avoid underdiagnosis and to optimize treatment strategies.

Gaucher disease (GD)
cancer
hematological
GD
Neuroblastoma (NBL)
NBL
GD
GD comorbidities
GD


Lysosomal acid lipase deficiency: Expanding differential diagnosis.

The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal acid lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia. Evidence suggests LAL-D may be substantially underdiagnosed or misdiagnosed, which is critical given that disease progression can be unpredictable, with liver failure and/or accelerated atherosclerosis potentially contributing to early mortality. However, given the development of a simple diagnostic test and recently approved treatment, LAL-D should be incorporated into the differential diagnosis in relevant clinical settings. LAL-D can be diagnosed using an LAL enzyme-based biochemical test, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including diet, lipid-lowering medication, and treatment with sebelipase alfa, a recombinant enzyme replacement therapy shown to provide clinical benefit and improve disease-relevant markers in clinical trials. To illustrate the complexity of diagnosing LAL-D, this manuscript will describe the path to diagnosing LAL-D in a series of patient cases in which LAL-D was diagnosed as well as in patients where other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected.

The

    differential diagnoses
    PARACLINICAL

 for

    metabolic liver diseases
    DIAGNOSIS

 may be challenging in clinical settings, which represents a critical issue for disorders such as

    lysosomal acid lipase deficiency (LAL-D)
    DIAGNOSIS

.

    LAL-D
    DIAGNOSIS

 is caused by

    deficient activity of the LAL enzyme
    BIOCHEMICAL

, resulting in the

    accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls
    MICROSCOPIC

.

    LAL-D
    DIAGNOSIS

 is a

    progressive, multi-organ disease
    DIAGNOSIS

 with

    early mortality
    SYMPTOMS

 and significant morbidity characterized by a combination of

    hepatic dysfunction
    SYMPTOMS

 and

    dyslipidemia
    SYMPTOMS

. Evidence suggests

    LAL-D
    DIAGNOSIS

 may be substantially

    underdiagnosed or misdiagnosed
    NEG_FINDINGS

, which is critical given that disease progression can be unpredictable, with

    liver failure
    SYMPTOMS

 and/or

    accelerated atherosclerosis
    SYMPTOMS

 potentially contributing to

    early mortality
    SYMPTOMS

. However, given the development of a simple diagnostic test and recently approved treatment,

    LAL-D
    DIAGNOSIS

 should be incorporated into the

    differential diagnosis
    PARACLINICAL

 in relevant clinical settings.

    LAL-D
    DIAGNOSIS

 can be diagnosed using an

    LAL enzyme-based biochemical test
    PARACLINICAL

, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including

    diet
    MEDICATION

,

    lipid-lowering medication
    MEDICATION

, and

    treatment with sebelipase alfa, a recombinant enzyme replacement therapy
    MEDICATION

 shown to provide clinical benefit and

    improve disease-relevant markers
    SYMPTOMS

 in clinical trials. To illustrate the complexity of diagnosing

    LAL-D
    DIAGNOSIS

, this manuscript will describe the path to diagnosing

    LAL-D
    DIAGNOSIS

 in a series of patient cases in which

    LAL-D
    DIAGNOSIS

 was diagnosed as well as in patients where

    other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected
    NEG_FINDINGS

.

early mortality
hepatic dysfunction
dyslipidemia
liver failure
accelerated atherosclerosis
early mortality
improve disease-relevant markers


Histological characterisation of visceral changes in a patient with type 2 Gaucher disease treated with enzyme replacement therapy.

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase and accumulation of glucocerebroside. Three major sub-types have been described, type 2 is an acute neurological form that exhibits serious general symptoms and poor prognosis, compared with the other types. This case was a girl diagnosed with type 2 Gaucher disease at 12months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder. Enzyme replacement therapy (ERT) was administered, but she had frequent myoclonus and developmental regression. She needed artificial ventilation because of respiratory failure. She died at 11years of age. An autopsy demonstrated infiltrating CD68-positive large cells containing abundant lipids in alveoli, while in the liver, kidney and bone marrow CD68-positive cells were small and round. In the bone marrow, myelodysplastic changes were present without Gaucher cells. The infiltration of Gaucher cells in alveoli was marked, suggesting that ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar. Additional treatments are necessary to improve the neurological and pulmonary prognosis of type 2Gaucher disease.

    Gaucher disease
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 caused by

    deficiency of glucocerebrosidase
    BIOCHEMICAL

 and

    accumulation of glucocerebroside
    MICROSCOPIC

. Three major sub-types have been described,

    type 2
    DIAGNOSIS

 is an

    acute neurological form
    DIAGNOSIS

 that exhibits

    serious general symptoms
    SYMPTOMS

 and poor prognosis, compared with the other types. This case was a

    girl
    GENDER

 diagnosed with

    type 2 Gaucher disease
    DIAGNOSIS

 at

    12months of age
    AGE

 who presented with

    poor weight gain
    SYMPTOMS

    from infancy
    AGE

,

    stridor
    SYMPTOMS

,

    hypertonia
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

,

    trismus
    SYMPTOMS

 and an

    eye movement disorder
    SYMPTOMS

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 was administered, but

    she
    GENDER

 had frequent

    myoclonus
    SYMPTOMS

 and

    developmental regression
    SYMPTOMS

.

    She
    GENDER

 needed

    artificial ventilation
    MEDICATION

 because of

    respiratory failure
    SYMPTOMS

.

    She
    GENDER

    died
    SYMPTOMS

 at

    11years of age
    AGE

. An

    autopsy
    PARACLINICAL

 demonstrated

    infiltrating CD68-positive large cells containing abundant lipids in alveoli
    MICROSCOPIC

,

    while in the liver, kidney and bone marrow CD68-positive cells were small and round
    MICROSCOPIC

.

    In the bone marrow, myelodysplastic changes were present
    MICROSCOPIC

    without Gaucher cells
    NEG_FINDINGS

. The

    infiltration of Gaucher cells in alveoli was marked
    MICROSCOPIC

, suggesting that

    ERT was relatively ineffective in pulmonary involvement, particularly intra-alveolar
    NEG_FINDINGS

. Additional treatments are necessary to improve the neurological and pulmonary prognosis of

    type 2Gaucher disease
    DIAGNOSIS

.

Gaucher disease
lysosomal storage disease
type 2
acute neurological form
type 2 Gaucher disease
type 2Gaucher disease

serious general symptoms
poor weight gain
stridor
hypertonia
hepatosplenomegaly
trismus
eye movement disorder
myoclonus
developmental regression
respiratory failure
died

Enzyme replacement therapy (ERT)
artificial ventilation


Gaucheromas: When macrophages promote tumor formation and dissemination.

Deficiency of the lysosomal enzyme, β-glucocerebrosidase, and accumulation of its substrate in cells of the reticuloendothelial system affects multiple organ systems in patients with Gaucher disease (GD). Lipid laden macrophages turn into Gaucher cells (GC) which are the pathological characteristic of GD. GC focally accumulate in the liver, spleen and at extraosseous sites to form benign lesions called Gaucheromas. Gaucheromas pose diagnostic and therapeutic challenges. We studied the pathophysiology of extraosseous Gaucheroma formation in a cohort of patients with GD. Among 63 patients followed at a single center, 3 patients with genotypes L444P/L444P and N370S/N370S, were diagnosed with extraosseous Gaucheromas. Flow cytometry revealed a higher expression of CD16+/CCR4+ non-classical monocytes in blood of GD patients who have developed Gaucheromas. A biopsy showed infiltration of GC, which reactivity against CD163, CD68 and VEGF. The cell proliferative marker Ki67 and CCL2, a factor anti-tumor activity, were negative. Our study indicates that extraosseous Gaucheromas are comprised of cellular elements with characteristics of tumor-associated macrophages, the major players in cancer related inflammation. The occurrence of non-classical CD16+/CCR4+ monocytes reflect the underlying cause for the accumulation of the macrophages capable of migrating to distant sites outside the reticuloendotheial system, and giving rise to tumor-like Gaucheromas.

    Deficiency of the lysosomal enzyme, β-glucocerebrosidase
    BIOCHEMICAL

, and

    accumulation of its substrate in cells of the reticuloendothelial system affects multiple organ systems
    MICROSCOPIC

 in patients with

    Gaucher disease (GD)
    DIAGNOSIS

.

    Lipid laden macrophages turn into Gaucher cells (GC)
    MICROSCOPIC

 which are the pathological characteristic of

    GD
    DIAGNOSIS

.

    GC focally accumulate in the liver, spleen and at extraosseous sites to form benign lesions called Gaucheromas
    MICROSCOPIC

.

    Gaucheromas
    MICROSCOPIC

 pose diagnostic and therapeutic challenges. We studied the pathophysiology of

    extraosseous Gaucheroma formation
    MICROSCOPIC

 in a cohort of patients with

    GD
    DIAGNOSIS

. Among 63 patients followed at a single center, 3 patients with

    genotypes L444P/L444P and N370S/N370S
    GENETICS

, were diagnosed with

    extraosseous Gaucheromas
    MICROSCOPIC

.

    Flow cytometry
    PARACLINICAL

 revealed a

    higher expression of CD16+/CCR4+ non-classical monocytes in blood
    GENETICS

 of

    GD
    DIAGNOSIS

 patients who have developed

    Gaucheromas
    MICROSCOPIC

. A

    biopsy
    PARACLINICAL

 showed

    infiltration of GC
    MICROSCOPIC

, which

    reactivity against CD163, CD68 and VEGF
    BIOCHEMICAL

.

    The cell proliferative marker Ki67 and CCL2, a factor anti-tumor activity, were negative
    NEG_FINDINGS

. Our study indicates that

    extraosseous Gaucheromas
    MICROSCOPIC

 are comprised of

    cellular elements with characteristics of tumor-associated macrophages
    MICROSCOPIC

, the major players in

    cancer related inflammation
    MICROSCOPIC

. The occurrence of

    non-classical CD16+/CCR4+ monocytes
    GENETICS

 reflect the underlying cause for the

    accumulation of the macrophages capable of migrating to distant sites
    MICROSCOPIC

 outside the reticuloendotheial system, and giving rise to

    tumor-like Gaucheromas
    MICROSCOPIC

.


Successful switch from enzyme replacement therapy to miglustat in an adult patient with type 1 Gaucher disease: a case report.

Gaucher disease is one of the most common lipid-storage disorders, affecting approximately 1 in 75,000 births. Enzyme replacement therapy with recombinant glucocerebrosidase is currently considered the first-line treatment choice for patients with symptomatic Gaucher disease type 1. Oral substrate reduction therapy is generally considered a second-line treatment option for adult patients with mild to moderate Gaucher disease type 1 who are unable or unwilling to receive lifelong intravenous enzyme infusions. The efficacy and safety of the oral substrate reduction therapy miglustat (Zavesca®) in patients with Gaucher disease type 1 have been established in both short-term clinical trials and long-term, open-label extension studies. Published data indicate that miglustat can be used as maintenance therapy in patients with stable Gaucher disease type 1 switched from previous enzyme replacement therapy.

We report a case of a 44-year-old Caucasian man with Gaucher disease type 1 who was initially treated with enzyme replacement therapy but, owing to repeated cutaneous allergic reactions, had to be switched to miglustat after several attempts with enzyme replacement therapy. Despite many attempts, desensitization treatment did not result in improved toleration of imiglucerase infusions, and the patient became unwilling to continue with any intravenous enzyme replacement therapy. He subsequently agreed to switch to oral substrate reduction therapy with miglustat 100 mg twice daily titrated up to 100 mg three times daily over a short period. Long-term miglustat treatment maintained both hemoglobin and platelet levels within acceptable ranges over 8 years. The patient's spleen volume decreased, his plasma chitotriosidase levels stayed at reduced levels, and his bone mineral density findings have remained stable throughout follow-up. The patient's quality of life has remained satisfactory. Miglustat showed good gastrointestinal tolerability in this patient, and no adverse events have been reported.

Oral miglustat therapy proved to be a valid alternative treatment to intravenous enzyme replacement therapy for long-term maintenance in this patient with Gaucher disease type 1, who showed persistent allergic intolerance to imiglucerase infusions. This report exemplifies the type of patient with Gaucher disease type 1 who can benefit from switching from enzyme replacement therapy to substrate reduction therapy.

    Gaucher disease
    DIAGNOSIS

 is one of the most common

    lipid-storage disorders
    DIAGNOSIS

, affecting approximately 1 in 75,000 births.

    Enzyme replacement therapy with recombinant glucocerebrosidase
    MEDICATION

 is currently considered the first-line treatment choice for patients with

    symptomatic Gaucher disease type 1
    DIAGNOSIS

.

    Oral substrate reduction therapy
    MEDICATION

 is generally considered a second-line treatment option for

    adult
    AGE

 patients with

    mild to moderate Gaucher disease type 1
    DIAGNOSIS

 who are

    unable or unwilling to receive lifelong intravenous enzyme infusions
    NEG_FINDINGS

. The efficacy and safety of the

    oral substrate reduction therapy miglustat (Zavesca®)
    MEDICATION

 in patients with

    Gaucher disease type 1
    DIAGNOSIS

 have been established in both short-term clinical trials and long-term, open-label extension studies. Published data indicate that

    miglustat
    MEDICATION

 can be used as

    maintenance therapy
    MEDICATION

 in patients with

    stable Gaucher disease type 1
    DIAGNOSIS

    switched from previous enzyme replacement therapy
    MEDICATION

.

We report a case of a

    44-year-old
    AGE

    Caucasian
    ETHNICITY

    man
    GENDER

 with

    Gaucher disease type 1
    DIAGNOSIS

 who was

    initially treated with enzyme replacement therapy
    NEG_FINDINGS

 but, owing to

    repeated cutaneous allergic reactions, had to be switched to miglustat after several attempts with enzyme replacement therapy
    NEG_FINDINGS

. Despite many attempts,

    desensitization treatment did not result in improved toleration of imiglucerase infusions
    NEG_FINDINGS

, and the patient

    became unwilling to continue with any intravenous enzyme replacement therapy
    NEG_FINDINGS

.

    He
    GENDER

 subsequently agreed to

    switch to oral substrate reduction therapy with miglustat 100 mg twice daily titrated up to 100 mg three times daily over a short period
    MEDICATION

.

    Long-term miglustat treatment
    MEDICATION

    maintained both hemoglobin and platelet levels within acceptable ranges over 8 years
    BIOCHEMICAL

. The patient's

    spleen volume decreased
    PARACLINICAL

, his

    plasma chitotriosidase levels stayed at reduced levels
    BIOCHEMICAL

, and his

    bone mineral density findings have remained stable
    SYMPTOMS

 throughout

    follow-up
    PARACLINICAL

. The patient's

    quality of life has remained satisfactory
    SYMPTOMS

.

    Miglustat
    MEDICATION

 showed

    good gastrointestinal tolerability
    SYMPTOMS

 in this patient, and

    no adverse events
    NEG_FINDINGS

 have been reported.

    Oral miglustat therapy
    MEDICATION

 proved to be a valid

    alternative treatment to intravenous enzyme replacement therapy for long-term maintenance
    MEDICATION

 in this patient with

    Gaucher disease type 1
    DIAGNOSIS

, who showed

    persistent allergic intolerance to imiglucerase infusions
    NEG_FINDINGS

. This report exemplifies the type of patient with

    Gaucher disease type 1
    DIAGNOSIS

 who can benefit from

    switching from enzyme replacement therapy to substrate reduction therapy
    MEDICATION

.

Gaucher disease
lipid-storage disorders
symptomatic Gaucher disease type 1
mild to moderate Gaucher disease type 1
Gaucher disease type 1
stable Gaucher disease type 1
Gaucher disease type 1
Gaucher disease type 1
Gaucher disease type 1


An Unusual Case of LCHAD Deficiency Presenting With a Clinical Picture of Hemophagocytic Lymphohistiocytosis: Secondary HLH or Coincidence?

There are published reports stating that some of the congenital metabolic diseases, such as lysinuric protein intolerance, multiple sulphatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, might lead to secondary hemophagocytic lymphohistiocytosis (HLH). However, to date, to our knowledge, the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency has never been investigated among patients with HLH. Here, we report on a patient who was referred to our institution for a differential diagnosis of pancytopenia, liver failure, and rhabdomyolysis. The patient was diagnosed with HLH. Further investigation revealed an underlying diagnosis of the LCHAD deficiency. Our case was reported to contribute to the literature, as well as the HLH clinic, emphasizing the consideration of LCHAD deficiency, especially in 1 to 6 months' old infants with laboratory findings of hypoglycemia, metabolic acidosis, and elevated creatine kinase.

There are published reports stating that some of the

    congenital metabolic diseases
    GENETICS

, such as

    lysinuric protein intolerance
    DIAGNOSIS

,

    multiple sulphatase deficiency
    DIAGNOSIS

,

    galactosemia
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    Pearson syndrome
    DIAGNOSIS

, and

    galactosialidosis
    DIAGNOSIS

, might lead to

    secondary hemophagocytic lymphohistiocytosis (HLH)
    DIAGNOSIS

. However, to date, to our knowledge, the

    long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
    BIOCHEMICAL

 has never been investigated among patients with

    HLH
    DIAGNOSIS

. Here, we report on a patient who was referred to our institution for a

    differential diagnosis
    PARACLINICAL

 of

    pancytopenia
    BIOCHEMICAL

,

    liver failure
    SYMPTOMS

, and

    rhabdomyolysis
    SYMPTOMS

. The patient was diagnosed with

    HLH
    DIAGNOSIS

. Further investigation revealed an underlying diagnosis of the

    LCHAD deficiency
    BIOCHEMICAL

. Our case was reported to contribute to the literature, as well as the

    HLH
    DIAGNOSIS

 clinic, emphasizing the consideration of

    LCHAD deficiency
    BIOCHEMICAL

, especially in

    1 to 6 months' old
    AGE

    infants
    AGE

 with laboratory findings of

    hypoglycemia
    BIOCHEMICAL

,

    metabolic acidosis
    BIOCHEMICAL

, and

    elevated creatine kinase
    BIOCHEMICAL

.


[Late diagnosis of Gaucher's disease - care reports].

Gaucher's disease if one of the most frequent, among extremely rare, lysosomal storage diseases. It is the autosomal recessive inherited metabolic disorder, which can present in three main clinical forms. Type 1 - the most benign, in a not-neuropathic form, and types 2 and 3, both in neuropathic form, which manifest serious neurological symptoms.

The aim of the study was to draw attention to the late diagnosing of Gaucher's disease in the Polish population and to popularize the knowledge about this ultra-rare disease.

Having analyzed the cases of our patients, we have concluded that the diagnosis of Gaucher's disease type 1 is often made with a time delay of up to several years. The lack of deeper knowledge about the disease and its symptoms among the physicians was found a main reason for this time lag. The disease is usually not taken into consideration in difference diagnosis due to its "ultra-rare" character. Furthermore, the course of the disease is usually occult with no spectacular symptoms, whereas the frequently occurring chronic weakness and bone pains are not treated as serious pathology.

Early diagnosis of the Gaucher's disease gives patients the chance of an appropriate, effective substitutive therapy, as well as recovery of organ disturbances.

    Gaucher's disease
    DIAGNOSIS

 if one of the most frequent, among extremely rare,

    lysosomal storage diseases
    DIAGNOSIS

. It is the

    autosomal recessive inherited
    GENETICS

    metabolic disorder
    DIAGNOSIS

, which can present in three main clinical forms.

    Type 1 - the most benign, in a not-neuropathic form
    DIAGNOSIS

, and

    types 2 and 3, both in neuropathic form
    DIAGNOSIS

, which manifest

    serious neurological symptoms
    SYMPTOMS

.

The aim of the study was to draw attention to the late diagnosing of

    Gaucher's disease
    DIAGNOSIS

 in the

    Polish
    ETHNICITY

 population and to popularize the knowledge about this ultra-rare disease.

Having analyzed the cases of our patients, we have concluded that the diagnosis of

    Gaucher's disease type 1
    DIAGNOSIS

 is often made with a time delay of up to several years. The lack of deeper knowledge about the disease and its symptoms among the physicians was found a main reason for this time lag. The disease is usually not taken into consideration in difference diagnosis due to its "ultra-rare" character. Furthermore, the course of the disease is usually occult with

    no spectacular symptoms
    NEG_FINDINGS

, whereas the frequently occurring

    chronic weakness
    SYMPTOMS

 and

    bone pains
    SYMPTOMS

 are not treated as serious pathology.

Early diagnosis of the

    Gaucher's disease
    DIAGNOSIS

 gives patients the chance of an appropriate,

    effective substitutive therapy
    MEDICATION

, as well as

    recovery of organ disturbances
    SYMPTOMS

.

serious neurological symptoms
chronic weakness
bone pains
recovery of organ disturbances


Appendiceal involvement in a patient with Gaucher disease.

Almost any anatomical compartment may be involved in Gaucher disease (GD). Abdominal lymphadenopathy occurred during enzyme replacement therapy in more than a dozen children with GD so far. A fourteen-year-old boy from Serbia developed clinical signs of acute appendicitis six years after the onset of GD type 3 related abdominal lymphadenopathy. Ultrasound examination showed diffuse thickening of the intestinal wall in the ileocoecal region with periappendicular infiltration. An appendectomy was performed four months after conservative treatment with antibiotics. Histopathology revealed macrophages with cytological characteristics of Gaucher cells densely crammed in mesoappendiceal adipose tissue. Also the multifocal replacement of subserosal tissue by Gaucher cells and their infiltration to a variable depth of muscularis propria of the appendix were verified. Frank infiltration of the vermiform appendix with Gaucher cells represents a novel observation in a wide spectrum of manifestations reported in GD. A possible causative relationship of this infiltration with appendicitis is considered.

Almost any anatomical compartment may be involved in

    Gaucher disease (GD)
    DIAGNOSIS

.

    Abdominal lymphadenopathy
    SYMPTOMS

 occurred during

    enzyme replacement therapy
    MEDICATION

 in more than a dozen

    children
    AGE

 with

    GD
    DIAGNOSIS

 so far. A

    fourteen-year-old
    AGE

    boy
    GENDER

 from

    Serbia
    ETHNICITY

 developed

    clinical signs of acute appendicitis
    SYMPTOMS

 six years after the onset of

    GD type 3
    DIAGNOSIS

 related

    abdominal lymphadenopathy
    SYMPTOMS

.

    Ultrasound examination
    PARACLINICAL

 showed

    diffuse thickening of the intestinal wall in the ileocoecal region
    SYMPTOMS

 with

    periappendicular infiltration
    MICROSCOPIC

. An

    appendectomy
    MEDICATION

 was performed four months after

    conservative treatment with antibiotics
    MEDICATION

.

    Histopathology
    PARACLINICAL

 revealed

    macrophages with cytological characteristics of Gaucher cells densely crammed in mesoappendiceal adipose tissue
    MICROSCOPIC

. Also the

    multifocal replacement of subserosal tissue by Gaucher cells and their infiltration to a variable depth of muscularis propria of the appendix
    MICROSCOPIC

 were verified.

    Frank infiltration of the vermiform appendix with Gaucher cells
    MICROSCOPIC

 represents a novel observation in a wide spectrum of manifestations reported in

    GD
    DIAGNOSIS

. A possible causative relationship of this infiltration with

    appendicitis
    DIAGNOSIS

 is considered.

Gaucher disease (GD)
GD
GD type 3
GD
appendicitis

enzyme replacement therapy
appendectomy
conservative treatment with antibiotics


Large soft-tissue masses in an adult patient with Gaucher disease.

Extra-osseous masses are rarely seen in Gaucher disease. Here we present a case of a 30-year-old patient with Gaucher disease type 3, receiving β-glucocerebrosidase enzyme replacement therapy, who presented with slowly enlarging masses along her back. There was no osseous extension seen on imaging. Biopsy of the mass ultimately showed extensive soft tissue infiltration by Gaucher cells. No other cases of soft-tissue masses of this extent have been described in the literature, and therefore management remains unclear.

    Extra-osseous masses
    SYMPTOMS

 are rarely seen in

    Gaucher disease
    DIAGNOSIS

. Here we present a case of a

    30-year-old
    AGE

 patient with

    Gaucher disease type 3
    DIAGNOSIS

,

    receiving β-glucocerebrosidase enzyme replacement therapy
    MEDICATION

, who presented with

    slowly enlarging masses along her back
    SYMPTOMS

. There was

    no osseous extension
    NEG_FINDINGS

 seen on

    imaging
    PARACLINICAL

.

    Biopsy of the mass
    PARACLINICAL

 ultimately showed

    extensive soft tissue infiltration by Gaucher cells
    MICROSCOPIC

. No other cases of

    soft-tissue masses
    SYMPTOMS

 of this extent have been described in the literature, and therefore management remains unclear.

Extra-osseous masses
slowly enlarging masses along her back
soft-tissue masses


A case of traction retinal detachment in a patient with Gaucher disease.

This is the first report of vitreous surgery for traction retinal detachment in a patient with type III Gaucher disease with multiple vitreous opacities.

A 16-year-old boy who was diagnosed with Gaucher disease at age two and was undergoing enzyme replacement therapy presented with numerous white opacities of varying sizes in the vitreous bodies of both eyes. Visual acuity was 20/40 in the right eye and 20/2000 in the left eye. The retina of the left eye was completely detached, and vitreous surgery was performed.

Liquefaction of the vitreous body was advanced, and the central part of the vitreous cavity contained almost no vitreous humor. The macular region was successfully aspirated with a vitreous cutter to form a posterior vitreous detachment. From the optic disk to the nasal side, however, posterior vitreous detachment formation was prevented by strong adhesions between the retina and the vitreous body. The traction retinal detachment of the posterior fundus improved after vitreous body resection alone.

Traction retinal detachment may occur as a result of severe vitreous liquefaction in cases of Gaucher disease with numerous vitreous opacities.

This is the first report of

    vitreous surgery
    MEDICATION

 for

    traction retinal detachment
    SYMPTOMS

 in a patient with

    type III Gaucher disease
    DIAGNOSIS

 with

    multiple vitreous opacities
    SYMPTOMS

.

A

    16-year-old
    AGE

    boy
    GENDER

 who was diagnosed with

    Gaucher disease
    DIAGNOSIS

 at

    age two
    AGE

 and was undergoing

    enzyme replacement therapy
    MEDICATION

 presented with

    numerous white opacities of varying sizes in the vitreous bodies of both eyes
    SYMPTOMS

.

    Visual acuity was 20/40 in the right eye and 20/2000 in the left eye
    SYMPTOMS

.

    The retina of the left eye was completely detached
    SYMPTOMS

, and

    vitreous surgery
    MEDICATION

 was performed.

    Liquefaction of the vitreous body was advanced
    SYMPTOMS

, and

    the central part of the vitreous cavity contained almost no vitreous humor
    SYMPTOMS

.

    The macular region was successfully aspirated with a vitreous cutter to form a posterior vitreous detachment
    MEDICATION

.

    From the optic disk to the nasal side, however, posterior vitreous detachment formation was prevented by strong adhesions between the retina and the vitreous body
    NEG_FINDINGS

. The

    traction retinal detachment of the posterior fundus improved
    SYMPTOMS

 after

    vitreous body resection alone
    MEDICATION

.

    Traction retinal detachment
    SYMPTOMS

 may occur as a result of

    severe vitreous liquefaction
    SYMPTOMS

 in cases of

    Gaucher disease
    DIAGNOSIS

 with

    numerous vitreous opacities
    SYMPTOMS

.

type III Gaucher disease
Gaucher disease
Gaucher disease


A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease.

Gaucher's disease (GD) is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase (glucocerebrosidase [GBA]) that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease.

Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene. Sequence alignments of mammalian β-GBA (GCase) and three-dimensional protein structure prediction of the mutation were made. A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro.

GCase is relatively conserved at p.T219A. This novel mutation differs from its wild-type in structure. Moreover, it also causes a reduction in GCase enzyme activity.

This novel mutation (c.655A>G, p.T219A) is a pathogenic missense mutation, which contributes to GD.

    Gaucher's disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive disorder
    GENETICS

 caused by a

    deficiency of acid β-glucosidase (glucocerebrosidase [GBA])
    BIOCHEMICAL

 that results in the

    accumulation of glucocerebroside within macrophages
    MICROSCOPIC

. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease.

    Genomic DNA was obtained from peripheral blood leukocytes
    PARACLINICAL

 of the patient and

    Sanger sequencing is used to sequence GBA gene
    PARACLINICAL

.

    Sequence alignments of mammalian β-GBA (GCase)
    PARACLINICAL

 and

    three-dimensional protein structure prediction of the mutation
    PARACLINICAL

 were made. A construct of this mutant and its compound heterozygous counterpart were used to

    measure GCase in vitro
    PARACLINICAL

.

    GCase is relatively conserved at p.T219A.
    GENETICS

 This

    novel mutation differs from its wild-type in structure
    GENETICS

. Moreover, it also causes a

    reduction in GCase enzyme activity
    BIOCHEMICAL

.

This

    novel mutation (c.655A>G, p.T219A) is a pathogenic missense mutation
    GENETICS

, which contributes to

    GD
    DIAGNOSIS

.


The appearance of newly identified intraocular lesions in Gaucher disease type 3 despite long-term glucocerebrosidase replacement therapy.

Background Gaucher disease (GD) is an autosomal recessive lipid storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase. The presence of central nervous system disease is a hallmark of the neuronopathic forms of GD (types 2 and 3). Intraocular lesions (e.g. corneal clouding, retinal lesions, and vitreous opacities) have been infrequently reported in GD type 3 (GD3). Moreover, there are virtually no published data on the occurrence and natural course of intraocular lesions in GD3 patients treated with enzyme replacement therapy (ERT). Case presentation We describe the case of a 26-year-old Polish male with L444P homozygous GD3 (mutation c.1448T > C in the GBA1 gene) who developed fundus lesions despite 10 years of ERT. At the age of 23 years, a spectral domain optical coherence tomography (OCT) examination was performed which disclosed the presence of discrete lesions located preretinally, intraretinally in the nerve fiber layer, and in the vitreous body. A 3-year follow-up OCT examination has not shown any significant progression of the fundus lesions. Conclusions To the best of our knowledge, this is the first published report describing the occurrence of newly identified retinal and preretinal lesions occurring during long-term ERT in GD3. We recommend that a careful ophthalmic assessment, including a dilated fundus examination, should be included as part of annual follow-up in patients with GD3. Further studies are needed to understand the nature and clinical course of these changes and whether or not these intraocular findings have any predictive value in the context of neurologic and skeletal progression in GD3.

Background

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lipid storage disorder
    DIAGNOSIS

 caused by the

    deficient activity of the lysosomal enzyme glucocerebrosidase
    BIOCHEMICAL

. The presence of

    central nervous system disease
    SYMPTOMS

 is a hallmark of the

    neuronopathic forms of GD (types 2 and 3)
    DIAGNOSIS

.

    Intraocular lesions
    SYMPTOMS

 (e.g.

    corneal clouding
    SYMPTOMS

,

    retinal lesions
    SYMPTOMS

, and

    vitreous opacities
    SYMPTOMS

) have been infrequently reported in

    GD type 3 (GD3)
    DIAGNOSIS

. Moreover, there are virtually no published data on the occurrence and natural course of

    intraocular lesions
    SYMPTOMS

 in

    GD3
    DIAGNOSIS

 patients treated with

    enzyme replacement therapy (ERT)
    MEDICATION

. Case presentation We describe the case of a

    26-year-old
    AGE

    Polish
    ETHNICITY

    male
    GENDER

 with

    L444P homozygous GD3
    GENETICS

    (mutation c.1448T > C in the GBA1 gene)
    GENETICS

 who developed

    fundus lesions
    SYMPTOMS

    despite 10 years of ERT
    NEG_FINDINGS

. At the

    age of 23 years
    AGE

, a

    spectral domain optical coherence tomography (OCT) examination
    PARACLINICAL

 was performed which disclosed the

    presence of discrete lesions located preretinally, intraretinally in the nerve fiber layer, and in the vitreous body
    SYMPTOMS

. A

    3-year follow-up OCT examination
    PARACLINICAL

 has

    not shown any significant progression of the fundus lesions
    NEG_FINDINGS

. Conclusions To the best of our knowledge, this is the first published report describing the occurrence of

    newly identified retinal and preretinal lesions
    SYMPTOMS

 occurring during

    long-term ERT
    MEDICATION

 in

    GD3
    DIAGNOSIS

. We recommend that a

    careful ophthalmic assessment
    PARACLINICAL

, including a

    dilated fundus examination
    PARACLINICAL

, should be included as part of

    annual follow-up
    PARACLINICAL

 in patients with

    GD3
    DIAGNOSIS

. Further studies are needed to understand the nature and clinical course of these changes and whether or not these

    intraocular findings
    SYMPTOMS

 have any predictive value in the context of

    neurologic and skeletal progression
    SYMPTOMS

 in

    GD3
    DIAGNOSIS

.

autosomal recessive
L444P homozygous GD3
(mutation c.1448T > C in the GBA1 gene)

enzyme replacement therapy (ERT)
long-term ERT


Neonatal Jaundice with Splenomegaly: Not a Common Pick.

The most common conditions causing cholestatic jaundice in infants are biliary atresia, neonatal hepatitis, and Alagille syndrome. In these disorders, the clinical presentation includes jaundice, pale stools, dark urine and hepatomegaly. Splenomegaly is not an early feature since it is due to portal hypertension, a later event. The finding of cholestatic jaundice and a large spleen usually raises the suspicion of Niemann-Pick type C disease (NP-C), a lysosomal storage disorder. We present and discuss here a case of an infant with liver disease and splenomegaly that were not ascribed to NP-C, but to Gaucher disease type 2. Liver biopsy, enzymatic studies and whole exome sequencing allowed to make the diagnosis. Although rare, Gaucher disease can cause neonatal hepatitis. A prompt recognition is advocated.

The most common conditions causing

    cholestatic jaundice
    DIAGNOSIS

 in

    infants
    AGE

 are

    biliary atresia
    DIAGNOSIS

,

    neonatal hepatitis
    DIAGNOSIS

, and

    Alagille syndrome
    DIAGNOSIS

. In these disorders, the clinical presentation includes

    jaundice
    SYMPTOMS

,

    pale stools
    SYMPTOMS

,

    dark urine
    SYMPTOMS

 and

    hepatomegaly
    SYMPTOMS

.

    Splenomegaly
    SYMPTOMS

 is not an early feature since it is due to

    portal hypertension
    SYMPTOMS

, a later event. The finding of

    cholestatic jaundice
    SYMPTOMS

 and a

    large spleen
    SYMPTOMS

 usually raises the suspicion of

    Niemann-Pick type C disease (NP-C)
    DIAGNOSIS

, a

    lysosomal storage disorder
    DIAGNOSIS

. We present and discuss here a case of an

    infant
    AGE

 with

    liver disease
    SYMPTOMS

 and

    splenomegaly
    SYMPTOMS

 that were

    not ascribed to NP-C
    NEG_FINDINGS

, but to

    Gaucher disease type 2
    DIAGNOSIS

.

    Liver biopsy
    PARACLINICAL

,

    enzymatic studies
    PARACLINICAL

 and

    whole exome sequencing
    PARACLINICAL

 allowed to make the diagnosis. Although rare,

    Gaucher disease
    DIAGNOSIS

 can cause

    neonatal
    AGE

    hepatitis
    DIAGNOSIS

. A prompt recognition is advocated.

cholestatic jaundice
biliary atresia
neonatal hepatitis
Alagille syndrome
Niemann-Pick type C disease (NP-C)
lysosomal storage disorder
Gaucher disease type 2
Gaucher disease
hepatitis

jaundice
pale stools
dark urine
hepatomegaly
Splenomegaly
portal hypertension
cholestatic jaundice
large spleen
liver disease
splenomegaly