Propionic acidemia: an extremely rare cause of hemophagocytic lymphohistiocytosis in an infant.

Hemophagocytic lymphohystiocytosis (HLH) may be primary (inherited/familial) or secondary to infections, malignancies, rheumatologic disorders, immune deficiency syndromes and metabolic diseases. Cases including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis have previously been reported. It is unclear how the metabolites trigger HLH in metabolic diseases. A 2-month-old infant with lethargy, pallor, poor feeding, hepatosplenomegaly, fever and pancytopenia, was diagnosed with HLH and the HLH-2004 treatment protocol was initiated. Analysis for primary HLH gene mutations and metabolic screening tests were performed together; primary HLH gene mutations were negative, but hyperammonemia and elevated methyl citrate were detected. Propionic acidemia was diagnosed with tandem mass spectrometry in neonatal dried blood spot. We report this case of HLH secondary to propionic acidemia. Both metabolic disorder screening tests and gene mutation analysis may be performed simultaneously especially for early diagnosis in infants presenting with HLH.

    Hemophagocytic lymphohystiocytosis (HLH)
    DIAGNOSIS

 may be primary (

    inherited/familial)
    GENETICS

 or secondary to

    infections
    DIAGNOSIS

,

    malignancies
    DIAGNOSIS

,

    rheumatologic disorders
    DIAGNOSIS

,

    immune deficiency syndromes
    DIAGNOSIS

 and

    metabolic diseases
    DIAGNOSIS

. Cases including

    lysinuric protein intolerance
    DIAGNOSIS

,

    multiple sulfatase deficiency
    DIAGNOSIS

,

    galactosemia
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    Pearson syndrome
    DIAGNOSIS

, and

    galactosialidosis
    DIAGNOSIS

 have previously been reported. It is unclear how the metabolites trigger

    HLH
    DIAGNOSIS

 in

    metabolic diseases
    DIAGNOSIS

. A

    2-month-old
    AGE

    infant
    AGE

 with

    lethargy
    SYMPTOMS

,

    pallor
    SYMPTOMS

,

    poor feeding
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

,

    fever
    SYMPTOMS

 and

    pancytopenia
    BIOCHEMICAL

, was diagnosed with

    HLH
    DIAGNOSIS

 and the

    HLH-2004 treatment protocol
    MEDICATION

 was initiated.

    Analysis for primary HLH gene mutations
    PARACLINICAL

 and

    metabolic screening tests
    PARACLINICAL

 were performed together;

    primary HLH gene mutations were negative
    NEG_FINDINGS

, but

    hyperammonemia
    BIOCHEMICAL

 and

    elevated methyl citrate were detected
    BIOCHEMICAL

.

    Propionic acidemia
    BIOCHEMICAL

 was diagnosed with

    tandem mass spectrometry in neonatal dried blood spot
    PARACLINICAL

. We report this case of

    HLH
    DIAGNOSIS

 secondary to

    propionic acidemia
    DIAGNOSIS

. Both

    metabolic disorder screening tests
    PARACLINICAL

 and

    gene mutation analysis
    PARACLINICAL

 may be performed simultaneously especially for early diagnosis in

    infants
    AGE

 presenting with

    HLH
    DIAGNOSIS

.

lethargy
pallor
poor feeding
hepatosplenomegaly
fever

pancytopenia
hyperammonemia
elevated methyl citrate were detected
Propionic acidemia


Dual-action ambroxol in treatment of chronic pain in Gaucher Disease.

A significant number of patients with Gaucher disease (GD) suffer from chronic or acute pain that reduces their quality of life. A mutation in lysosomal enzyme β-glucosidase (GCase) leads to an accumulation of glucocerebroside in the macrophage-lineage cells, causing the development of clinical symptoms. Novel studies have revealed that ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol), the well-known mucolytic drug, acts as a chaperone for the mutant, misfolded enzyme. In addition, as has recently been shown, ambroxol is a Nav 1.8 channel blocker in Aβ, Aδ and unmyelinated C fibres, and therefore reduces the transmission of sensory stimuli from the primary afferent neurons to the dorsal spinal cord. In this way, it can act analgetically. Thus, in addition to broncholytic properties, ambroxol combines two other important functions: it enhances enzyme replacement therapy (ERT) and pain management in patients with GD. We present a 38-year-old female patient with type 3 GD who had reported permanent bone pain in the lumbar-sacral part of the spine for over a year without any pathology evidenced in the undertaken, recommended diagnostic tests. The pain was partly controlled with standard analgesics, that is, paracetamol and tramadol. Ambroxol was introduced at a dose of 150mg/d without a noticeable effect. However, when the dose was increased up to 450mg/d, the intensity of pain diminished and subsided within the following months. Two of three attempts to reduce the dose of ambroxol resulted in a pain relapse within a week, which subsided after resetting the previous, higher dose. This observation of the effects of ambroxol in a GD patient is worth considering for other GD patients with chronic pain.

A significant number of patients with

    Gaucher disease (GD)
    DIAGNOSIS

 suffer from

    chronic or acute pain
    SYMPTOMS

 that reduces their quality of life. A

    mutation in lysosomal enzyme β-glucosidase (GCase)
    GENETICS

 leads to an

    accumulation of glucocerebroside in the macrophage-lineage cells
    MICROSCOPIC

, causing the development of

    clinical symptoms
    SYMPTOMS

. Novel studies have revealed that

    ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol)
    MEDICATION

, the well-known

    mucolytic drug
    MEDICATION

, acts as a chaperone for the mutant, misfolded enzyme. In addition, as has recently been shown,

    ambroxol
    MEDICATION

 is a

    Nav 1.8 channel blocker in Aβ, Aδ and unmyelinated C fibres
    GENETICS

, and therefore

    reduces the transmission of sensory stimuli from the primary afferent neurons to the dorsal spinal cord
    SYMPTOMS

. In this way, it can act

    analgetically
    MEDICATION

. Thus, in addition to

    broncholytic properties
    MEDICATION

,

    ambroxol
    MEDICATION

 combines two other important functions: it

    enhances enzyme replacement therapy (ERT)
    MEDICATION

 and

    pain management
    MEDICATION

 in patients with

    GD
    DIAGNOSIS

. We present a

    38-year-old
    AGE

    female
    GENDER

 patient with

    type 3 GD
    DIAGNOSIS

 who had reported

    permanent bone pain in the lumbar-sacral part of the spine for over a year
    SYMPTOMS

    without any pathology evidenced in the undertaken, recommended diagnostic tests
    NEG_FINDINGS

. The

    pain was partly controlled with standard analgesics
    NEG_FINDINGS

    , that is, paracetamol and tramadol
    MEDICATION

.

    Ambroxol was introduced at a dose of 150mg/d without a noticeable effect
    MEDICATION

. However, when the

    dose was increased up to 450mg/d
    MEDICATION

,

    the intensity of pain diminished and subsided within the following months
    SYMPTOMS

. Two of three attempts

    to reduce the dose of ambroxol
    MEDICATION

 resulted in a

    pain relapse
    SYMPTOMS

 within a week, which subsided after

    resetting the previous, higher dose
    MEDICATION

. This observation of the effects of

    ambroxol
    MEDICATION

 in a

    GD
    DIAGNOSIS

 patient is worth considering for other

    GD
    DIAGNOSIS

 patients with

    chronic pain
    SYMPTOMS

.


A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease.

Mutations in the GBA gene that encodes the lysosomal enzyme acid β-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD.

The genomic DNA of the proband was screened for nine common mutations using Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All exons and exon-intron boundaries, and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing. RNA analysis was performed using standard procedures, and the abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced. The relevant intronic region was further sequenced by the Sanger method to identify the genetic variant.

A novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for GD. This mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon.

This study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions.

    Mutations in the GBA gene that encodes the lysosomal enzyme acid β-glucocerebrosidase
    GENETICS

 cause

    Gaucher disease (GD)
    DIAGNOSIS

, the most common

    lysosomal storage disorder
    DIAGNOSIS

. Most of the mutations are

    missense/nonsense
    GENETICS

, however, a few

    splicing mutations within or close to conserved consensus donor or acceptor splice sites
    GENETICS

 have also been described. The aim of the study was to identify the mutation(s) in a

    Cypriot
    ETHNICITY

 patient with

    type I GD
    DIAGNOSIS

.

    The genomic DNA of the proband
    PARACLINICAL

 was screened for

    nine common mutations
    GENETICS

 using

    Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis
    PARACLINICAL

.

    All exons and
    PARACLINICAL

 exon-intron boundaries

    , and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing
    PARACLINICAL

.

    RNA analysis
    PARACLINICAL

 was performed using standard procedures, and the

    abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced
    PARACLINICAL

.

    The relevant intronic region was further sequenced by the Sanger method
    PARACLINICAL

 to identify the genetic variant.

A

    novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene
    GENETICS

. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for

    GD
    DIAGNOSIS

. This

    mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon
    GENETICS

.

This study expands the mutation spectrum of

    GD
    DIAGNOSIS

 and highlights the importance of

    RNA sequencing
    PARACLINICAL

 for the molecular diagnosis of patients bearing

    mutations in nonexonic regions
    GENETICS

.

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


Berberoğlu-Ateş B, Varan A, Demir H, Akyüz C, Yüce A. Coexistence or a related condition: an infant with retinoblastoma and Gaucher disease. Turk J Pediatr 2019; 61: 449-452. Gaucher disease (GD) is the most prevalant lysosomal lipid storage disease that results from loss of function of acid β-glucosidase due to mutations in the glucocerebrosidase gene. Common features of all types of GD include hepatosplenomegaly, cytopenia, and various patterns of bone and lung involvement. Retinoblastoma is a malignant tumor of the developing retina that occurs in children, typically before the age of five. Retinoblastoma develops from cells that have cancer-predisposing variants in both copies of RB1. The association between GD and retinoblastoma has not been reported until now. Here we report the case that was diagnosed with, retinoblastoma at the age of 2 months and then GD at the age of 11 months. Although there are controversies concerning the association between GD and cancer; malignancies should be kept in mind during GD patients follow up.

Berberoğlu-Ateş B, Varan A, Demir H, Akyüz C, Yüce A. Coexistence or a related condition: an

    infant
    AGE

 with

    retinoblastoma
    DIAGNOSIS

 and

    Gaucher disease
    DIAGNOSIS

. Turk J Pediatr 2019; 61: 449-452.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most prevalant

    lysosomal lipid storage disease
    DIAGNOSIS

 that results from

    loss of function of acid β-glucosidase
    BIOCHEMICAL

 due to

    mutations in the glucocerebrosidase gene
    GENETICS

. Common features of all types of

    GD
    DIAGNOSIS

 include

    hepatosplenomegaly
    SYMPTOMS

,

    cytopenia
    BIOCHEMICAL

, and

    various patterns of bone and lung involvement
    SYMPTOMS

.

    Retinoblastoma
    DIAGNOSIS

 is a

    malignant tumor of the developing retina
    DIAGNOSIS

 that occurs in

    children
    AGE

, typically

    before the age of five
    AGE

.

    Retinoblastoma
    DIAGNOSIS

 develops from

    cells that have cancer-predisposing variants in both copies of RB1
    GENETICS

. The association between

    GD
    DIAGNOSIS

 and

    retinoblastoma
    DIAGNOSIS

 has not been reported until now. Here we report the case that was diagnosed with,

    retinoblastoma
    DIAGNOSIS

    at the age of 2 months
    AGE

 and then

    GD
    DIAGNOSIS

    at the age of 11 months
    AGE

. Although there are controversies concerning the association between

    GD and cancer
    DIAGNOSIS

;

    malignancies
    DIAGNOSIS

 should be kept in mind during

    GD
    DIAGNOSIS

 patients follow up.

loss of function of acid β-glucosidase
cytopenia


White vitreous opacities in five patients with Gaucher disease type 3.

Fundal abnormalities, including preretinal and retinal changes, are a rare finding in patients with the autosomal recessive lysosomal storage disorder Gaucher disease, most often described in patients with the chronic neuronopathic form (type 3). We evaluated whether these ophthalmological findings correlated with other manifestations of type 3 Gaucher disease. Reviewing the records of 40 patients with type 3 Gaucher disease, we identified five with white vitreous opacities and reviewed their clinical course in depth. Each of the patients described decreased visual acuity and "floaters" obstructing their vision. The development and/or progression of these fluffy-appearing white opacities in each patient were tracked longitudinally in the context of their neurological and other clinical findings. It was noted that all five patients shared genotype p.L483P/p.L483P (L444P/L444P) and had significant neurological, oculomotor and bone involvement and two had undergone splenectomy. Enzyme replacement therapy with recombinant glucocerebrosidase did not prevent the development or progression of these ocular opacities. Since preretinal findings, in addition to other neuro-ophthalmological findings, can be a feature of Gaucher disease, it is recommended that patients be monitored by regular eye examinations.

    Fundal abnormalities
    SYMPTOMS

, including

    preretinal and retinal changes
    SYMPTOMS

, are a rare finding in patients with the

    autosomal recessive
    GENETICS

    lysosomal storage disorder Gaucher disease
    DIAGNOSIS

, most often described in patients with the

    chronic neuronopathic form (type 3)
    DIAGNOSIS

. We evaluated whether these

    ophthalmological findings
    SYMPTOMS

 correlated with other manifestations of

    type 3 Gaucher disease
    DIAGNOSIS

. Reviewing the records of 40 patients with

    type 3 Gaucher disease
    DIAGNOSIS

, we identified five with

    white vitreous opacities
    SYMPTOMS

 and reviewed their clinical course in depth. Each of the patients described

    decreased visual acuity
    SYMPTOMS

 and

    "floaters" obstructing their vision
    SYMPTOMS

. The development and/or progression of these

    fluffy-appearing white opacities
    SYMPTOMS

 in each patient were tracked longitudinally in the context of their neurological and other clinical findings. It was noted that all five patients shared

    genotype p.L483P/p.L483P (L444P/L444P)
    GENETICS

 and had

    significant neurological, oculomotor and bone involvement
    SYMPTOMS

 and two had undergone

    splenectomy
    MEDICATION

.

    Enzyme replacement therapy with recombinant glucocerebrosidase
    MEDICATION

    did not prevent the development or progression of these ocular opacities
    NEG_FINDINGS

. Since

    preretinal findings
    SYMPTOMS

, in addition to other

    neuro-ophthalmological findings
    SYMPTOMS

, can be a feature of

    Gaucher disease
    DIAGNOSIS

, it is recommended that patients be monitored by

    regular eye examinations
    PARACLINICAL

.

autosomal recessive
genotype p.L483P/p.L483P (L444P/L444P)


A case of motor neuron involvement in Gaucher disease.

Gaucher disease (GD) is a genetic disorder characterized by an accumulation of glucosylceramide in cells in the monocyte-macrophage system. We describe a case of a 33-year-old man with a previous diagnosis of type 3 GD who displayed a progressive weakening of the limbs followed by upper motor neuron involvement. A diagnosis of definite Amyotrophic Lateral Sclerosis was made. This is the first reported case of concurrent Gaucher disease and the ALS phenotype in the same patient.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    genetic disorder
    GENETICS

 characterized by an

    accumulation of glucosylceramide in cells in the monocyte-macrophage system
    MICROSCOPIC

. We describe a case of a

    33-year-old
    AGE

    man
    GENDER

 with a previous diagnosis of

    type 3 GD
    DIAGNOSIS

 who displayed a

    progressive weakening of the limbs
    SYMPTOMS

 followed by

    upper motor neuron involvement
    SYMPTOMS

. A diagnosis of

    definite Amyotrophic Lateral Sclerosis
    DIAGNOSIS

 was made. This is the first reported case of

    concurrent Gaucher disease and the ALS phenotype
    DIAGNOSIS

 in the same patient.

progressive weakening of the limbs
upper motor neuron involvement


Ambroxol improves skeletal and hematological manifestations on a child with Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disease caused by the deficiency of glucocerebrosidase characterized by a broad spectrum of clinical manifestations including hepatosplenomegaly, bone infiltration, and cytopenia, and even central nervous system involvement. Bone manifestations are typical of the GD-I and partially responded to mainstay therapy. Ambroxol (ABX), an approved cough-suppressant, was identified as an enzyme-enhancement agent of the residual activity of glucocerebrosidase mutants derived from different misfolding-mutations in the GBA gene. Here, we describe the early beneficial effects of ABX on skeletal and hematological manifestations of a child suffering with progressive GD-I.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 caused by the

    deficiency of glucocerebrosidase
    BIOCHEMICAL

 characterized by a broad spectrum of clinical manifestations including

    hepatosplenomegaly
    SYMPTOMS

,

    bone infiltration
    SYMPTOMS

, and

    cytopenia
    BIOCHEMICAL

, and even

    central nervous system involvement
    SYMPTOMS

.

    Bone manifestations
    SYMPTOMS

 are typical of the

    GD-I
    DIAGNOSIS

 and partially responded to

    mainstay therapy
    MEDICATION

.

    Ambroxol (ABX), an approved cough-suppressant
    MEDICATION

, was identified as an

    enzyme-enhancement agent of the residual activity of glucocerebrosidase mutants
    MEDICATION

 derived from

    different misfolding-mutations in the GBA gene
    GENETICS

. Here, we describe the early beneficial effects of

    ABX
    MEDICATION

 on

    skeletal and hematological manifestations
    SYMPTOMS

 of a

    child
    AGE

 suffering with progressive GD-I.

Gaucher disease (GD)
lysosomal storage disease
GD-I

deficiency of glucocerebrosidase
cytopenia


Rare GBA1 genotype associated with severe bone disease in Gaucher disease type 1.

Gaucher disease (GD) type 1 is a lysosomal disease characterised by hepatosplenomegaly, anemia, thrombocytopenia, bone changes, and bone marrow infiltration. The disease is caused by biallelic pathogenic variants in GBA1 which codes for glucocerebrosidase, an enzyme involved in the catabolic pathway of complex lipids.

To report on the case of two sisters with GD type 1 who bear a genotype never reported in the literature.

Patient 1 is a 47-year-old female diagnosed at 42 years of age with chronic lumbar pain, mild splenomegaly, slightly reduced platelets and normal hemoglobin values, severe Bone Marrow Burden (BMB) score, high chitotriosidase activity, and low glucocerebrosidase. Patient 2 is a 50-year-old female, sister of patient 1, who was diagnosed after familial screening. At 45 years of age, she had osteonecrosis of the left femur and a total hysterectomy because of uncontrollable bleeding. At first evaluation, she had bone pain with a high BMB score, mild splenomegaly, normal hemoglobin, normal platelets count, elevated chitotriosidase activity, and low glucocerebrosidase activity. Both patients were found to be compound heterozygotes for the p.Glu388Lys and the p.Ser405Asn variants in GBA1.

This is the first family with GD and this combination of variants which causes a phenotype remarkable for severe bone disease with no or mild hematological manifestations.

    Gaucher disease (GD) type 1
    DIAGNOSIS

 is a

    lysosomal disease
    DIAGNOSIS

 characterised by

    hepatosplenomegaly
    SYMPTOMS

,

    anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

,

    bone changes
    SYMPTOMS

, and

    bone marrow infiltration
    MICROSCOPIC

. The disease is caused by

    biallelic pathogenic variants in GBA1 which codes for glucocerebrosidase
    GENETICS

, an enzyme involved in the

    catabolic pathway of complex lipids
    MICROSCOPIC

.

To report on the

    case of two sisters with GD type 1 who bear a genotype
    FAMILY

 never reported in the literature.

Patient 1 is a

    47-year-old
    AGE

    female
    GENDER

 diagnosed at

    42 years of age
    AGE

 with

    chronic lumbar pain
    SYMPTOMS

,

    mild splenomegaly
    SYMPTOMS

,

    slightly reduced platelets and normal hemoglobin values
    BIOCHEMICAL

,

    severe Bone Marrow Burden (BMB) score
    MICROSCOPIC

,

    high chitotriosidase activity
    BIOCHEMICAL

, and

    low glucocerebrosidase
    BIOCHEMICAL

. Patient 2 is a

    50-year-old
    AGE

    female
    GENDER

,

    sister of patient 1
    FAMILY

, who was diagnosed after

    familial screening
    PARACLINICAL

. At

    45 years of age
    AGE

,

    she
    GENDER

 had

    osteonecrosis of the left femur
    DIAGNOSIS

 and a

    total hysterectomy
    MEDICATION

 because of

    uncontrollable bleeding
    SYMPTOMS

. At first evaluation,

    she
    GENDER

 had

    bone pain with a high BMB score
    SYMPTOMS

,

    mild splenomegaly
    SYMPTOMS

,

    normal hemoglobin
    BIOCHEMICAL

,

    normal platelets count
    NEG_FINDINGS

,

    elevated chitotriosidase activity
    BIOCHEMICAL

, and

    low glucocerebrosidase activity
    BIOCHEMICAL

. Both patients were found to be

    compound heterozygotes for the p.Glu388Lys and the p.Ser405Asn variants in GBA1
    GENETICS

.

This is the first

    family with GD
    FAMILY

 and this

    combination of variants
    GENETICS

 which causes a

    phenotype remarkable for severe bone disease
    SYMPTOMS

 with

    no or mild hematological manifestations
    NEG_FINDINGS

.

Gaucher disease (GD) type 1
lysosomal disease
osteonecrosis of the left femur

normal platelets count
no or mild hematological manifestations


Reduction of large soft-tissue Gaucheromas with substrate reduction therapy.

Soft-tissue masses are rarely seen in Gaucher disease. We previously reported a case of a 30-year-old patient with Gaucher disease type 3, receiving β-glucocerebrosidase enzyme replacement therapy (ERT), who presented with slowly enlarging masses infiltrated with Gaucher cells along her back. Substrate reduction therapy introduced in addition to ERT, resulted in significant reduction of the large masses.

    Soft-tissue masses
    SYMPTOMS

 are rarely seen in

    Gaucher disease
    DIAGNOSIS

. We previously reported a case of a

    30-year-old
    AGE

 patient with

    Gaucher disease type 3
    DIAGNOSIS

,

    receiving β-glucocerebrosidase enzyme replacement therapy (ERT)
    MEDICATION

, who presented with

    slowly enlarging masses infiltrated with Gaucher cells along her back
    SYMPTOMS

.

    Substrate reduction therapy introduced in addition to ERT
    MEDICATION

, resulted in

    significant reduction of the large masses
    SYMPTOMS

.


Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex.

    Hereditary spastic paraplegia (HSP)
    DIAGNOSIS

 is a group of disorders with predominant symptoms of

    lower-extremity weakness
    SYMPTOMS

 and

    spasticity
    SYMPTOMS

. Despite the delineation of numerous genetic causes of

    HSP
    DIAGNOSIS

, a significant portion of individuals with

    HSP
    DIAGNOSIS

 remain molecularly undiagnosed. Through

    exome sequencing
    PARACLINICAL

, we identified five unrelated families with

    childhood-onset nonsyndromic HSP
    DIAGNOSIS

, all presenting with

    progressive spastic gait
    SYMPTOMS

,

    leg clonus
    SYMPTOMS

, and

    toe walking
    SYMPTOMS

    starting from 7 to 8 years old
    AGE

. A

    recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene
    GENETICS

 was found in four families, and a

    similar variant (c.475_476delTT, p.F159*)
    GENETICS

 was detected in a fifth family. The variant was confirmed

    to be de novo in two families and inherited from an affected parent in two other families
    GENETICS

.

    RNA studies performed in lymphocytes
    PARACLINICAL

 from one patient with the

    de novo c.426_427delGA variant
    GENETICS

 demonstrated

    escape of nonsense-mediated decay of the UBAP1 mutant transcript
    GENETICS

, suggesting the

    generation of a truncated protein
    GENETICS

. Both variants identified in this study are predicted to result in

    truncated proteins losing the capacity of binding to ubiquitinated proteins
    BIOCHEMICAL

, hence appearing to exhibit a

    dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex
    SYMPTOMS

.

Hereditary spastic paraplegia (HSP)
HSP
HSP
childhood-onset nonsyndromic HSP


Polyneuropathy in Gaucher disease type 1 and 3 - a descriptive case series.

Polyneuropathy (PNP) has been reported to be a possible phenotypic feature in Gaucher disease type 1 (GD1), while less is known about PNP in type 3 (GD3). We performed a cross-sectional study, exploring PNP in a Swedish GD cohort. Clinical assessment and blood biochemistry were carried out in 8 patients with GD1 and 11 patients with GD3. In patients with symptoms or clinical findings indicative of PNP, nerve conduction studies and quantitative sensory testing were performed. Assessments were compared to historic controls. A subclinical small fiber neuropathy (SFN) was demonstrated in 2 of 8 patients in the significantly (p = 0,021) older GD1 cohort. A large fiber PNP was evident in an additional 3 GD1 patients but could not be ascribed as disease manifestation. No GD3 patients exhibited neurophysiological evidence of small or large fiber PNP attributed to GD3. Compared to historic controls, no significant group differences were evident with regard to neuropathy rating scores. In summary, our study does not support large fiber PNP as a prevalent manifestation of GD. SFN is a possible feature in GD1, although small sample size limits definite conclusions. Our study provides novel data, arguing against clinically significant small or large fiber PNP in GD3.

    Polyneuropathy (PNP)
    DIAGNOSIS

 has been reported to be a possible phenotypic feature in

    Gaucher disease type 1 (GD1)
    DIAGNOSIS

, while less is known about

    PNP
    DIAGNOSIS

 in

    type 3 (GD3)
    DIAGNOSIS

. We performed a cross-sectional study, exploring

    PNP
    DIAGNOSIS

 in a

    Swedish
    ETHNICITY

    GD
    DIAGNOSIS

 cohort.

    Clinical assessment and blood biochemistry
    PARACLINICAL

 were carried out in 8 patients with

    GD1
    DIAGNOSIS

 and 11 patients with

    GD3
    DIAGNOSIS

. In patients with

    symptoms or clinical findings indicative of PNP
    SYMPTOMS

,

    nerve conduction studies
    PARACLINICAL

 and

    quantitative sensory testing
    PARACLINICAL

 were performed. Assessments were compared to historic controls. A

    subclinical small fiber neuropathy (SFN)
    SYMPTOMS

 was demonstrated in 2 of 8 patients in the significantly (p = 0,021) older

    GD1
    DIAGNOSIS

 cohort. A

    large fiber PNP
    SYMPTOMS

 was evident in an additional 3

    GD1
    DIAGNOSIS

 patients but could not be ascribed as disease manifestation. No

    GD3
    DIAGNOSIS

 patients exhibited

    neurophysiological evidence of small or large fiber PNP attributed to GD3
    NEG_FINDINGS

. Compared to historic controls,

    no
    NEG_FINDINGS

 significant group differences were evident with regard to

    neuropathy rating scores
    NEG_FINDINGS

. In summary, our study does not support

    large fiber PNP
    NEG_FINDINGS

 as a prevalent manifestation of

    GD
    DIAGNOSIS

.

    SFN
    DIAGNOSIS

 is a possible feature in

    GD1
    DIAGNOSIS

, although small sample size limits definite conclusions. Our study provides novel data, arguing

    against clinically significant small or large fiber PNP
    NEG_FINDINGS

 in

    GD3
    DIAGNOSIS

.


Synchronous multiple myeloma and Gaucher disease.

Pseudo-Gaucher cells can be found in multiple hematologic malignancies, hemoglobinopathies, infections, and multiple storage disorders upon bone marrow aspirate and biopsy; however, Gaucher disease (GD) should be ruled out, particularly when the cytoplasmic inclusions cannot be adequately characterized. It is well known that GD may be associated with monoclonal gammopathies; however, although enzyme replacement therapy (ERT) may result in an improvement in polyclonal gammopathies, its effect on the progression of monoclonal gammopathy of undetermined significance to multiple myeloma (MM) remains uncertain. ERT may improve patient's cytopenias and facilitate administration of anti-myeloma therapy in patients with concurrent GD and MM; however, the current paucity of data makes it challenging to determine its effect on response to anti-myeloma therapy or the risk of relapse. Hematologists should be familiar with the clinical presentation and diagnosis of GD and its association with monoclonal gammopathies. Here we present a case of synchronous smoldering MM and GD.

    Pseudo-Gaucher cells
    MICROSCOPIC

 can be found in

    multiple hematologic malignancies
    DIAGNOSIS

,

    hemoglobinopathies
    DIAGNOSIS

,

    infections
    DIAGNOSIS

, and

    multiple storage disorders
    DIAGNOSIS

 upon

    bone marrow aspirate and biopsy
    PARACLINICAL

; however,

    Gaucher disease (GD)
    DIAGNOSIS

 should be ruled out, particularly when the

    cytoplasmic inclusions
    MICROSCOPIC

 cannot be adequately characterized. It is well known that

    GD
    DIAGNOSIS

 may be associated with

    monoclonal gammopathies
    DIAGNOSIS

; however, although

    enzyme replacement therapy (ERT)
    MEDICATION

 may result in an

    improvement in polyclonal gammopathies
    BIOCHEMICAL

, its effect on the progression of

    monoclonal gammopathy of undetermined significance
    DIAGNOSIS

 to

    multiple myeloma (MM)
    DIAGNOSIS

 remains uncertain.

    ERT
    MEDICATION

 may improve patient's

    cytopenias
    BIOCHEMICAL

 and

    facilitate administration of anti-myeloma therapy
    MEDICATION

 in patients with

    concurrent GD and MM
    DIAGNOSIS

; however, the current paucity of data makes it challenging to determine its effect on response to

    anti-myeloma therapy
    MEDICATION

 or the risk of relapse.

    Hematologists
    PARACLINICAL

 should be familiar with the clinical presentation and diagnosis of

    GD
    DIAGNOSIS

 and its association with

    monoclonal gammopathies
    DIAGNOSIS

. Here we present a case of

    synchronous smoldering MM and GD
    DIAGNOSIS

.

improvement in polyclonal gammopathies
cytopenias


Huge Splenomegaly with Pancytopenia Due to Gaucher's Disease in a 22 Years Old Woman.

Gaucher's disease is one of the important storage disorders. It belongs to the lysosomal storage disorders group. There is defective activity of an enzyme named β-glucosidase which ultimately renders the cell of macrophage lineage loaded with glucocerebrosides. There is multi-organ involvement that manifests as hepatosplenomegaly, variable cytopenias, skeletal disorders, neurological features etc. When serum β-glucosidase level is below 15% of mean normal activity Gaucher's disease is confirmed. Enzyme replacement is the definitive treatment. Here we report a case of type 1 or non-neuropathic form Gauchers disease presented with feeling of a lump in left upper abdomen and progressive generalized weakness and hepatosplenomegaly. Her complete blood count revealed pancytopenia and bone trephine biopsy showed Gaucher's cells. Diagnosis and management may be delayed as this disease is rare. Clinical and bone marrow examination is the mainstay of diagnosis. So emphasis should be given in this regard.

    Gaucher's disease
    DIAGNOSIS

 is one of the important

    storage disorders
    DIAGNOSIS

. It belongs to the

    lysosomal storage disorders
    DIAGNOSIS

 group. There is

    defective activity of an enzyme named β-glucosidase
    BIOCHEMICAL

 which ultimately

    renders the cell of macrophage lineage loaded with glucocerebrosides
    MICROSCOPIC

. There is

    multi-organ involvement
    SYMPTOMS

 that manifests as

    hepatosplenomegaly
    SYMPTOMS

,

    variable cytopenias
    BIOCHEMICAL

,

    skeletal disorders
    SYMPTOMS

,

    neurological features
    SYMPTOMS

 etc. When

    serum β-glucosidase level is below 15% of mean normal activity
    BIOCHEMICAL

    Gaucher's disease
    DIAGNOSIS

 is confirmed.

    Enzyme replacement
    MEDICATION

 is the definitive treatment. Here we report a case of

    type 1 or non-neuropathic form Gauchers disease
    DIAGNOSIS

 presented with

    feeling of a lump in left upper abdomen
    SYMPTOMS

 and

    progressive generalized weakness
    SYMPTOMS

 and

    hepatosplenomegaly
    SYMPTOMS

.

    Her
    GENDER

    complete blood count
    PARACLINICAL

 revealed

    pancytopenia
    BIOCHEMICAL

 and

    bone trephine biopsy
    PARACLINICAL

 showed

    Gaucher's cells
    MICROSCOPIC

. Diagnosis and management may be delayed as this disease is rare.

    Clinical and bone marrow examination
    PARACLINICAL

 is the mainstay of diagnosis. So emphasis should be given in this regard.

multi-organ involvement
hepatosplenomegaly
skeletal disorders
neurological features
feeling of a lump in left upper abdomen
progressive generalized weakness
hepatosplenomegaly


A case of bony lytic lesions in a patient with Gaucher disease.

Gaucher disease is a clinically heterogeneous disorder of glucocerebroside metabolism and may present incidentally late in life with unexplained thrombocytopenia, splenomegaly, or bony lesions. Clinicians should be aware that patients with Gaucher disease appear to have an increased risk for developing hematolymphoid malignancies, particularly monoclonal gammopathies and plasma cell myeloma.

    Gaucher disease
    DIAGNOSIS

 is a

    clinically heterogeneous disorder of glucocerebroside metabolism
    DIAGNOSIS

 and may present incidentally

    late in life
    AGE

 with

    unexplained thrombocytopenia
    BIOCHEMICAL

,

    splenomegaly
    SYMPTOMS

, or

    bony lesions
    SYMPTOMS

. Clinicians should be aware that patients with

    Gaucher disease
    DIAGNOSIS

 appear to have an increased risk for developing

    hematolymphoid malignancies
    DIAGNOSIS

, particularly

    monoclonal gammopathies
    DIAGNOSIS

 and

    plasma cell myeloma
    DIAGNOSIS

.


Gaucher disease in Montenegro - genotype/phenotype correlations: Five cases report.

The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD.

Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient).

The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.

The most common

    lysosomal storage disorder
    DIAGNOSIS

 is

    Gaucher disease (GD)
    DIAGNOSIS

. It is a

    deficiency of lysosomal glucocerebrosidase (GBA)
    BIOCHEMICAL

 due to

    biallelic mutations in the GBA gene
    GENETICS

, characterized by the

    deposition of glucocerebroside in macrophage-monocyte system cells
    MICROSCOPIC

. The report targets clinical phenotypes of

    GD
    DIAGNOSIS

 in order to correlate them with

    GBA gene mutations
    GENETICS

, as well as to identify

    GBA gene mutation
    GENETICS

 in patients in

    Montenegro
    ETHNICITY

 that are diagnosed with

    GD
    DIAGNOSIS

.

Five patients (4

    male
    GENDER

, 1

    female
    GENDER

) of

    type 1 GD (GD1)
    DIAGNOSIS

 are reported. The

    age at diagnosis ranged from 7 to 40
    AGE

. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of

    splenomegaly
    SYMPTOMS

 and

    thrombocytopenia
    BIOCHEMICAL

, while other symptoms included

    bone pain
    SYMPTOMS

,

    hepatomegaly
    SYMPTOMS

,

    abdominal pain
    SYMPTOMS

 and

    fatigue
    SYMPTOMS

.

    Osteopenia
    SYMPTOMS

 was present in a majority of the patients: 4/5. All patients were found to have an

    asymptomatic Erlenmeyer flask deformity of the distal femur
    SYMPTOMS

. On

    enzyme replacement therapy (ERT)
    MEDICATION

, the

    hematological and visceral parameters showed significant improvement
    BIOCHEMICAL

, but

    no significant progression in bone mineral density was noticed
    NEG_FINDINGS

.

    GBA gene sequencing
    PARACLINICAL

 revealed

    homozygosity for the N370S mutation
    GENETICS

 in one patient. The genotypes of the other patients were

    N370S/55bp deletion, N370S/D409H
    GENETICS

 (2 patients), and

    H255Q/N370S
    GENETICS

 (1 patient).

The phenotypes of the

    GD1
    DIAGNOSIS

 encountered in

    Montenegro
    ETHNICITY

 were severe but all responded well to

    ERT
    MEDICATION

.

lysosomal storage disorder
Gaucher disease (GD)
GD
GD
type 1 GD (GD1)
GD1

biallelic mutations in the GBA gene
GBA gene mutations
GBA gene mutation
homozygosity for the N370S mutation
N370S/55bp deletion, N370S/D409H
H255Q/N370S


Very rare condition of multiple Gaucheroma: A case report and review of the literature.

This study presented a 3 years old boy with Gaucher disease (GD) who was treated with enzyme replacement therapy(ERT) for 19 months and developed multiple Gaucheroma. The literature was reviewed.

The medical chart and literature were reviewed. A boy presented at the age of 15 months with anemia, thrombocytopenia, and hepatosplenomegaly. Enzyme assay and gene mutations confirmed GD. ERT was administered. When the boy was 3 years old, multiple masses were discovered from abdominal MRI and biopsy revealed Gaucheroma. We reviewed 20 GD patients with Gaucheroma and Gaucher cell infiltrated lymphadenopathies.

Gaucheroma is a rare condition in regularly treated GD patients. This patient showed poor response to doubled ERT doses. The imaging studies are necessary for Gaucher patients to detect Gaucheroma and determine their malignancy. Regular checkups are recommended in all GD patients even with ERT treatment, due to the possibility of having a deteriorating change, like Gaucheroma.

This study presented a

    3 years old
    AGE

    boy
    GENDER

 with

    Gaucher disease (GD)
    DIAGNOSIS

 who was

    treated with enzyme replacement therapy(ERT) for 19 months
    MEDICATION

 and developed

    multiple Gaucheroma
    MICROSCOPIC

. The literature was reviewed.

The medical chart and literature were reviewed. A

    boy
    GENDER

 presented at the

    age of 15 months
    AGE

 with

    anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

, and

    hepatosplenomegaly
    SYMPTOMS

.

    Enzyme assay
    PARACLINICAL

 and

    gene mutations
    PARACLINICAL

 confirmed

    GD
    DIAGNOSIS

.

    ERT
    MEDICATION

 was administered. When the

    boy
    GENDER

 was

    3 years old
    AGE

,

    multiple masses
    SYMPTOMS

 were discovered from

    abdominal MRI
    PARACLINICAL

 and

    biopsy
    PARACLINICAL

 revealed

    Gaucheroma
    MICROSCOPIC

. We reviewed 20

    GD
    DIAGNOSIS

 patients with

    Gaucheroma
    MICROSCOPIC

 and

    Gaucher cell infiltrated lymphadenopathies
    MICROSCOPIC

.

    Gaucheroma
    DIAGNOSIS

 is a rare condition in regularly treated

    GD
    DIAGNOSIS

 patients. This patient showed

    poor response to doubled ERT doses
    NEG_FINDINGS

. The

    imaging studies
    PARACLINICAL

 are necessary for

    Gaucher
    DIAGNOSIS

 patients to detect

    Gaucheroma
    DIAGNOSIS

 and determine their malignancy.

    Regular checkups
    PARACLINICAL

 are recommended in all

    GD
    DIAGNOSIS

 patients even with

    ERT treatment
    MEDICATION

, due to the possibility of having a deteriorating change, like

    Gaucheroma
    DIAGNOSIS

.

Gaucher disease (GD)
GD
GD
Gaucheroma
GD
Gaucher
Gaucheroma
GD
Gaucheroma


Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.

Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants.

We report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation.

This is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.

    Gaucher disease type 1 (GD1)
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 rarely resulting in

    end stage pulmonary hypertension (PH)
    SYMPTOMS

 and

    interstitial lung disease
    DIAGNOSIS

. There have only been two previous case reports of patients with

    GD1
    DIAGNOSIS

 receiving

    lung transplants
    MEDICATION

.

We report a case of

    successful bilateral sequential lung transplantation
    MEDICATION

 in a patient with

    end-stage GD1-related PH
    DIAGNOSIS

. Prior to

    transplant
    MEDICATION

, the patient was on

    enzyme replacement therapy with imiglucerase
    MEDICATION

 and

    pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol
    MEDICATION

. The patient had

    pre-transplant comorbidities of prior splenectomy
    MEDICATION

 and

    osteopenia
    SYMPTOMS

.

    She
    GENDER

 underwent

    bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction
    MEDICATION

.

    Her
    GENDER

    explanted lungs
    PARACLINICAL

 demonstrated

    severe pulmonary arterial hypertensive changes
    SYMPTOMS

, but

    no Gaucher cells
    NEG_FINDINGS

.

    She
    GENDER

 was

    maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant
    MEDICATION

.

    Her
    GENDER

    post-transplant
    MEDICATION

 course was complicated by

    hemorrhagic shock
    SYMPTOMS

,

    prolonged support with extracorporeal membrane oxygenation
    MEDICATION

, and

    acute renal failure
    SYMPTOMS

    requiring dialysis
    MEDICATION

. Despite these complications, the patient was discharged and is doing well nine months post

    -transplantation
    MEDICATION

.

This is one of only three reported cases of

    lung transplantation
    MEDICATION

 in patients with

    GD1
    DIAGNOSIS

. Each case has involved

    previously splenectomised
    MEDICATION

,

    female
    GENDER

 patients with

    GD1
    DIAGNOSIS

. This is the first to report

    transplantation
    MEDICATION

 in a patient with

    severe PH
    SYMPTOMS

 and

    no pulmonary parenchymal disease
    NEG_FINDINGS

. As evidenced in our patient,

    long term treatment with imiglucerase
    MEDICATION

 may

    eliminate the Gaucher cells in the lungs
    MICROSCOPIC

. The

    PH
    SYMPTOMS

 in these patients is most consistent with

    pulmonary arterial hypertension
    SYMPTOMS

, raising the question of whether this should be reclassified as WHO

    Group 1 PH
    DIAGNOSIS

.

no Gaucher cells
no pulmonary parenchymal disease


Reversal of life-threatening hepatopulmonary syndrome in Gaucher disease by imiglucerase enzyme replacement therapy.

Advanced liver disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the disease can be ameliorated. We describe a splenectomized patient with Gaucher disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver disease. Our report suggests that Gaucher disease pathology involving advanced fibrosis and life-threatening complications can be reversed by imiglucerase enzyme therapy.

Effect of imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.

    Advanced liver disease
    DIAGNOSIS

 complicated by

    hepatopulmonary syndrome
    SYMPTOMS

 is a recognized complication of

    Gaucher disease
    DIAGNOSIS

.

    Macrophage-targeted, recombinant enzyme replacement therapy
    MEDICATION

 is effective in reversing clinical manifestations attributed to the

    accumulation of glycolipid-laden macrophages
    MICROSCOPIC

 but it is not known whether

    advanced fibrotic features of the disease
    MICROSCOPIC

 can be ameliorated. We describe a

    splenectomized
    MEDICATION

 patient with

    Gaucher disease
    DIAGNOSIS

 who developed

    massive hepatomegaly
    SYMPTOMS

,

    cirrhosis of the liver
    MICROSCOPIC

 and

    life-threatening hepatopulmonary syndrome
    SYMPTOMS

. Treatment with

    Imiglucerase enzyme replacement therapy
    MEDICATION

 resulted in

    dramatic reversal of hepatopulmonary syndrome and liver disease
    SYMPTOMS

. Our report suggests that

    Gaucher disease
    DIAGNOSIS

 pathology involving

    advanced fibrosis
    MICROSCOPIC

 and

    life-threatening complications
    SYMPTOMS

 can be reversed by

    imiglucerase enzyme therapy
    MEDICATION

.

Effect of

    imiglucerase enzyme replacement therapy
    MEDICATION

 on

    Hepatopulmonary Syndrome
    DIAGNOSIS

 in

    Gaucher Disease
    DIAGNOSIS

.

Advanced liver disease
Gaucher disease
Gaucher disease
Gaucher disease
Hepatopulmonary Syndrome
Gaucher Disease


[Gaucher Disease type 1 mimicking immune thrombocytopenia: Role of hyperferritinemia and hypergammaglobulinemia in the initial evaluation of an isolated thrombopenia].

Gaucher disease type 1 is a rare genetic disease. It can cause thrombocytopenia. Current guidelines do not support bone marrow examination in front of isolated thrombocytopenia if no evidence suggests malignant hemopathy. This strategy aiming at sparing unnecessary investigations makes such rare diseases more difficult to diagnose.

A 31-year-old woman was diagnosed with immune thrombocytopenia according to current guidelines. She presented later with mild splenomegaly. Bone marrow aspirate smears showed Gaucher cells. Gaucher disease was then confirmed. Looking backward, initial biological clues (hyperferritinemia, hypergammaglobulinemia) should have enabled to consider the diagnosis.

Gaucher disease type 1 can be responsible for apparently isolated thrombocytopenia. The disease must be looked for if the thrombocytopenia is associated with unexplained hypergammaglobulinemia or hyperferritinemia. Diagnosing immune thrombocytopenia without bone marrow sample requires to systematically pay attention to any clinical or biological abnormality, not to ignore rare differential diagnoses.

    Gaucher disease type 1
    DIAGNOSIS

 is a

    rare genetic disease
    GENETICS

. It can cause

    thrombocytopenia
    BIOCHEMICAL

. Current guidelines do not support

    bone marrow examination
    PARACLINICAL

 in front of

    isolated thrombocytopenia
    BIOCHEMICAL

 if

    no evidence suggests malignant hemopathy
    NEG_FINDINGS

. This strategy aiming at sparing unnecessary investigations makes such rare diseases more difficult to diagnose.

A

    31-year-old
    AGE

    woman
    GENDER

 was diagnosed with

    immune thrombocytopenia
    DIAGNOSIS

 according to current guidelines.

    She
    GENDER

 presented later with

    mild splenomegaly
    SYMPTOMS

.

    Bone marrow aspirate smears
    PARACLINICAL

 showed

    Gaucher cells
    MICROSCOPIC

.

    Gaucher disease
    DIAGNOSIS

 was then confirmed. Looking backward, initial biological clues (

    hyperferritinemia
    BIOCHEMICAL

,

    hypergammaglobulinemia
    BIOCHEMICAL

) should have enabled to consider the diagnosis.

    Gaucher disease type 1
    DIAGNOSIS

 can be responsible for apparently

    isolated thrombocytopenia
    BIOCHEMICAL

. The disease must be looked for if the

    thrombocytopenia
    BIOCHEMICAL

 is associated with

    unexplained hypergammaglobulinemia
    BIOCHEMICAL

 or

    hyperferritinemia
    BIOCHEMICAL

. Diagnosing

    immune thrombocytopenia
    DIAGNOSIS

    without bone marrow sample
    PARACLINICAL

 requires to systematically pay attention to any clinical or biological abnormality, not to ignore rare differential diagnoses.

Gaucher disease type 1
immune thrombocytopenia
Gaucher disease
Gaucher disease type 1
immune thrombocytopenia

thrombocytopenia
isolated thrombocytopenia
hyperferritinemia
hypergammaglobulinemia
isolated thrombocytopenia
thrombocytopenia
unexplained hypergammaglobulinemia
hyperferritinemia


This study presented a 3 years old boy with Gaucher disease (GD) who was treated with enzyme replacement therapy (ERT) for 19 months and then developed multiple Gaucheroma. Review of literature was performed simultaneously.

The medical chart and literature were reviewed. A boy presented at the age of 15 months with anemia, thrombocytopenia, and hepatosplenomegaly. GD was confirmed by enzyme assay and gene mutations. ERT was administered right after the diagnosis. When the boy was 3 years old, multiple masses were discovered during a regular checkup abdominal MRI and biopsy revealed Gaucheroma. We also reviewed 20 GD patients with Gaucheroma and Gaucher cell infiltrated lymphadenopathies.

Gaucheroma is a rare condition of regularly treated GD patients. This patient even showed poor response to doubled ERT doses. The imaging studies are necessary for Gaucher patients to detect Gaucheroma and determine their malignancy. Regular checkups are recommended in all GD patients even with regular treatment, due to the possibility of having deteriorating change, like Gaucheroma.

This study presented a

    3 years old
    AGE

    boy
    GENDER

 with

    Gaucher disease (GD)
    DIAGNOSIS

 who was

    treated with enzyme replacement therapy (ERT) for 19 months
    MEDICATION

 and then developed

    multiple Gaucheroma
    MICROSCOPIC

. Review of literature was performed simultaneously.

The medical chart and literature were reviewed. A

    boy
    GENDER

 presented at the

    age of 15 months
    AGE

 with

    anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

, and

    hepatosplenomegaly
    SYMPTOMS

.

    GD
    DIAGNOSIS

 was confirmed by

    enzyme assay
    PARACLINICAL

 and

    gene mutations
    PARACLINICAL

.

    ERT
    MEDICATION

 was administered right after the diagnosis. When the

    boy
    GENDER

 was

    3 years old
    AGE

,

    multiple masses
    SYMPTOMS

 were discovered during a regular checkup

    abdominal MRI
    PARACLINICAL

 and

    biopsy
    PARACLINICAL

 revealed

    Gaucheroma
    MICROSCOPIC

. We also reviewed 20

    GD
    DIAGNOSIS

 patients with

    Gaucheroma
    MICROSCOPIC

 and

    Gaucher cell infiltrated lymphadenopathies
    MICROSCOPIC

.

    Gaucheroma
    DIAGNOSIS

 is a rare condition of regularly treated

    GD
    DIAGNOSIS

 patients. This patient even showed

    poor response to doubled ERT doses
    NEG_FINDINGS

. The

    imaging studies
    PARACLINICAL

 are necessary for

    Gaucher
    DIAGNOSIS

 patients to detect

    Gaucheroma
    DIAGNOSIS

 and determine their malignancy.

    Regular checkups
    PARACLINICAL

 are recommended in all

    GD
    DIAGNOSIS

 patients even with

    regular treatment
    MEDICATION

, due to the possibility of having

    deteriorating change
    SYMPTOMS

, like

    Gaucheroma
    DIAGNOSIS

.

hepatosplenomegaly
multiple masses
deteriorating change


A Neonatal Case With Perinatal Lethal Gaucher Disease Associated With Missense G234E and H413P Heterozygous Mutations.

Perinatal lethal Gaucher disease (PLGD), a particular and serious form of type 2 Gaucher disease (GD), often causes lethality in utero or death within hours after birth. The typical clinical manifestations include non-immune hydrops fetalis (NIHF), premature birth, fetal growth restriction, fetal intrauterine death, or neonatal distress and rapid death after birth. Here, we present a premature neonate with GD whose main clinical manifestations included intrauterine growth retardation, anasarca, facial dysmorphia, ichthyosis, respiratory distress, hepatosplenomegaly, joint contractures, myoclonus, refractory thrombocytopenia, anemia, elevated levels of liver enzymes, bile acid and direct bilirubin, cholestasis, pulmonary hypoplasia, intracranial hemorrhage, and abnormal electroencephalogram. The activity of β- glucocerebrosidase was 0 in the peripheral white blood cells of the neonate. The sequencing analysis identified the presence of missense G234E and H413P heterozygous mutations in glucerebrosidase (GBA) exon 7 and 10, with the latter first observed to be associated with PLGD. This infant died at 73 days of age.

    Perinatal lethal Gaucher disease (PLGD)
    DIAGNOSIS

, a particular and serious form of

    type 2 Gaucher disease (GD)
    DIAGNOSIS

, often causes

    lethality
    SYMPTOMS

    in utero
    AGE

 or

    death
    SYMPTOMS

    within hours after birth
    AGE

. The typical clinical manifestations include

    non-immune hydrops fetalis (NIHF)
    SYMPTOMS

,

    premature birth
    SYMPTOMS

,

    fetal growth restriction
    SYMPTOMS

,

    fetal intrauterine death
    SYMPTOMS

, or

    neonatal distress
    SYMPTOMS

 and

    rapid death
    SYMPTOMS

    after birth
    AGE

. Here, we present a

    premature neonate
    AGE

 with

    GD
    DIAGNOSIS

 whose main clinical manifestations included

    intrauterine growth retardation
    SYMPTOMS

,

    anasarca
    SYMPTOMS

,

    facial dysmorphia
    SYMPTOMS

,

    ichthyosis
    SYMPTOMS

,

    respiratory distress
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

,

    joint contractures
    SYMPTOMS

,

    myoclonus
    SYMPTOMS

,

    refractory thrombocytopenia
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

,

    elevated levels of liver enzymes, bile acid and direct bilirubin
    BIOCHEMICAL

,

    cholestasis
    SYMPTOMS

,

    pulmonary hypoplasia
    SYMPTOMS

,

    intracranial hemorrhage
    SYMPTOMS

, and

    abnormal electroencephalogram
    SYMPTOMS

. The

    activity of β- glucocerebrosidase was 0 in the peripheral white blood cells
    BIOCHEMICAL

 of the

    neonate
    AGE

. The

    sequencing analysis
    PARACLINICAL

 identified the

    presence of missense G234E and H413P heterozygous mutations in glucerebrosidase (GBA) exon 7 and 10
    GENETICS

, with the latter first observed to be associated with

    PLGD
    DIAGNOSIS

. This

    infant
    AGE

    died
    SYMPTOMS

 at

    73 days of age
    AGE

.

Perinatal lethal Gaucher disease (PLGD)
type 2 Gaucher disease (GD)
GD
PLGD

lethality
death
non-immune hydrops fetalis (NIHF)
premature birth
fetal growth restriction
fetal intrauterine death
neonatal distress
rapid death
intrauterine growth retardation
anasarca
facial dysmorphia
ichthyosis
respiratory distress
hepatosplenomegaly
joint contractures
myoclonus
cholestasis
pulmonary hypoplasia
intracranial hemorrhage
abnormal electroencephalogram
died


Gaucher Disease Involving Virchow's Lymph Node: a Case Report.

Gaucher disease is a metabolic storage disorder caused by a mutation in the lysosomal enzyme B-glucocerebrosidase. This disease is usually manifested in new born infants, however, an exceptional case of this disease in adult has been recently reported. A 21-year-old Caucasian patient was diagnosed with Gaucher disease, demonstrating Virchow's lymphatic node enlargement and mild splenomegaly. A familial link to this disease was also found. Macrophage infiltration was observed in the aff ected Virchow's lymph node which is not a classic sign of Gaucher disease. DNA analysis and a whole blood count also suggested a manifestation of this disease. In summary, this is the first study to report such case of Gaucher disease in an adult female patient, which may suggest an asymptomatic characteristic of this condition and an importance of the presence of Gaucher cells in the enlarged Virchow's lymph node.

    Gaucher disease
    DIAGNOSIS

 is a

    metabolic storage disorder
    DIAGNOSIS

 caused by a

    mutation in the lysosomal enzyme B-glucocerebrosidase
    GENETICS

. This disease is usually manifested in

    new born infants
    AGE

, however, an exceptional case of this disease in

    adult
    AGE

 has been recently reported. A

    21-year-old
    AGE

    Caucasian
    ETHNICITY

 patient was diagnosed with

    Gaucher disease
    DIAGNOSIS

, demonstrating

    Virchow's lymphatic node enlargement
    SYMPTOMS

 and

    mild splenomegaly
    SYMPTOMS

.

    A familial link to this disease was also found
    FAMILY

.

    Macrophage infiltration was observed in the aff ected Virchow's lymph node
    MICROSCOPIC

 which is

    not a classic sign of Gaucher disease
    NEG_FINDINGS

.

    DNA analysis
    PARACLINICAL

 and a

    whole blood count
    PARACLINICAL

 also suggested a manifestation of this disease. In summary, this is the first study to report such case of

    Gaucher disease
    DIAGNOSIS

 in an

    adult
    AGE

    female
    GENDER

 patient, which may suggest an asymptomatic characteristic of this condition and an importance of the

    presence of Gaucher cells in the enlarged Virchow's lymph node
    MICROSCOPIC

.

Gaucher disease
metabolic storage disorder
Gaucher disease
Gaucher disease

Virchow's lymphatic node enlargement
mild splenomegaly


Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder.

Lysosomal storage disorders (LSDs) collectively constitute a significant public health burden in developing countries. Commoner LSDs include Gaucher, Fabry, and Niemann-Pick disease (NPD), but many cases remain undiagnosed. With the high incidence of consanguineous marriages, South East Asian countries are expected to have high prevalence of these LSDs. Here we report 4 cases of NPD type A/B in 3 families presenting with hepatosplenomegaly and cytopenias including one family with two sibs having hypertension and mitral valve prolapse. The diagnosis of NPD was proven by mutation analysis with identification of novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the SMPD1 gene. We also had two cases of NPD type C, confirmed on mutation analysis.

    Lysosomal storage disorders (LSDs)
    DIAGNOSIS

 collectively constitute a significant public health burden in developing countries. Commoner

    LSDs
    DIAGNOSIS

 include

    Gaucher
    DIAGNOSIS

,

    Fabry
    DIAGNOSIS

, and

    Niemann-Pick disease (NPD)
    DIAGNOSIS

, but many cases remain undiagnosed. With the high incidence of

    consanguineous marriages
    GENETICS

,

    South East Asian
    ETHNICITY

 countries are expected to have high prevalence of these

    LSDs
    DIAGNOSIS

. Here we report 4 cases of

    NPD type A/B
    DIAGNOSIS

 in 3 families presenting with

    hepatosplenomegaly
    SYMPTOMS

 and

    cytopenias
    BIOCHEMICAL

 including one

    family with two sibs having hypertension and mitral valve prolapse
    FAMILY

. The diagnosis of

    NPD
    DIAGNOSIS

 was proven by

    mutation analysis
    PARACLINICAL

 with identification of

    novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the SMPD1 gene
    GENETICS

. We also had two cases of

    NPD type C
    DIAGNOSIS

, confirmed on

    mutation analysis
    PARACLINICAL

.

Lysosomal storage disorders (LSDs)
LSDs
Gaucher
Fabry
Niemann-Pick disease (NPD)
LSDs
NPD type A/B
NPD
NPD type C


Gaucher disease type 3c: New patients with unique presentations and review of the literature.

Gaucher disease (GD) is the most prevalent lysosomal disorder caused by GBA mutations and abnormal glucocerebrosidase function, leading to glucocerebrosideaccumulation mainly in the liver, spleen, bone marrow, lungs, and occasionally in the central nervous system. Gaucher disease type 3c (GD3c) is a rare subtype of the subacute/chronic neuronopathic GD3, caused by homozygosity for the GBA p.Asp448His (D409H) mutation. GD3c is characterized mainly by cardiovascular and neuro-ophthalmological findings. In this paper, we describe four new GD3c patients exhibiting rare cardiovascular, pulmonary and psychiatric findings, as well as atypical disease courses. Review of the GD3c-related literature revealed clinical descriptions of 36 patients, presenting predominantly with cardiovascular calcifications; 15%, including Patient 1b in this study, had non-calcified lesions - fibrosis and atherosclerosis. Only 7.5% of patients have been described without heart disease, including Patient 3; however, Patient 2 had a fulminant coronary disease. Neurological findings in GD3c consist mainly of oculomotor apraxia (80%), which is absent in Patient 3, while other neurological findings are common (65%) but diverse. Patient 1b developed a psychiatric behavioral disorder, which has not been previously described in GD3c. Patient 1b also had interstitial lung disease, which was only described in one GD3c patient as pulmonary fibrosis. In view of these unique features, we recommend a revised surveillance protocol; however, further studies are required to establish the management of these patients and the role of GBA in the described pathologies.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most prevalent

    lysosomal disorder
    DIAGNOSIS

 caused by

    GBA mutations
    GENETICS

 and

    abnormal glucocerebrosidase function
    BIOCHEMICAL

, leading to

    glucocerebrosideaccumulation mainly in the liver, spleen, bone marrow, lungs, and occasionally in the central nervous system
    MICROSCOPIC

.

    Gaucher disease type 3c (GD3c)
    DIAGNOSIS

 is a rare subtype of the

    subacute/chronic neuronopathic GD3
    DIAGNOSIS

, caused by

    homozygosity for the GBA p.Asp448His (D409H) mutation
    GENETICS

.

    GD3c
    DIAGNOSIS

 is characterized mainly by

    cardiovascular and neuro-ophthalmological findings
    SYMPTOMS

. In this paper, we describe four new

    GD3c
    DIAGNOSIS

 patients exhibiting

    rare cardiovascular, pulmonary and psychiatric findings
    SYMPTOMS

, as well as

    atypical disease courses
    SYMPTOMS

. Review of the

    GD3c
    DIAGNOSIS

-related literature revealed clinical descriptions of 36 patients, presenting predominantly with

    cardiovascular calcifications
    SYMPTOMS

; 15%, including Patient 1b in this study, had

    non-calcified lesions - fibrosis and atherosclerosis
    SYMPTOMS

. Only 7.5% of patients have been described

    without heart disease
    NEG_FINDINGS

, including Patient 3; however, Patient 2 had a

    fulminant coronary disease
    DIAGNOSIS

.

    Neurological findings
    SYMPTOMS

 in

    GD3c
    DIAGNOSIS

 consist mainly of

    oculomotor apraxia
    SYMPTOMS

 (80%), which is absent in Patient 3, while other

    neurological findings
    SYMPTOMS

 are common (65%) but diverse. Patient 1b developed a

    psychiatric behavioral disorder
    DIAGNOSIS

, which has not been previously described in

    GD3c
    DIAGNOSIS

. Patient 1b also had

    interstitial lung disease
    DIAGNOSIS

, which was only described in one

    GD3c
    DIAGNOSIS

 patient as

    pulmonary fibrosis
    DIAGNOSIS

. In view of these unique features, we recommend a revised surveillance protocol; however, further studies are required to establish the management of these patients and the role of GBA in the described pathologies.


Differential radiological diagnosis of tuberculous sacroiliitis and bone involvement in Gaucher disease: a clinical case.

Differential diagnosis of bone involvement in patients with Gaucher disease can be challenging. Other diseases with similar radiological signs should be ruled out. Here we present a clinical case of tuberculous sacroiliitis in the patient with type I Gaucher disease. Advanced radiological methods of examination are described. Our case report proves the necessity of an individual approach to the management of such cohort of patients. Keywords: Gaucher disease, tuberculosis of bones and joints, differential diagnosis, comprehensive treatment.

    Differential diagnosis
    PARACLINICAL

 of

    bone involvement
    SYMPTOMS

 in patients with

    Gaucher disease
    DIAGNOSIS

 can be challenging. Other diseases with similar

    radiological signs
    SYMPTOMS

 should be ruled out. Here we present a clinical case of

    tuberculous sacroiliitis
    DIAGNOSIS

 in the patient with

    type I Gaucher disease
    DIAGNOSIS

.

    Advanced radiological methods of examination
    PARACLINICAL

 are described. Our case report proves the necessity of an individual approach to the management of such cohort of patients. Keywords:

    Gaucher disease
    DIAGNOSIS

,

    tuberculosis of bones and joints
    DIAGNOSIS

,

    differential diagnosis
    PARACLINICAL

,

    comprehensive treatment
    MEDICATION

.

Gaucher disease
tuberculous sacroiliitis
type I Gaucher disease
Gaucher disease
tuberculosis of bones and joints


Acute Gaucher Disease-Like Condition in an Indian Infant with a Novel Biallelic Mutation in the Prosaposin Gene.

This is the first reported case of prosaposin (PSAP) mutation from India manifesting as an acute neuronal Gaucher disease-like condition. A 2-month-old male baby presented with encephalopathy, resistant tonic-clonic seizures, moderate hepatosplenomegaly, hypotonia, and cherry red spot in the retinae. The child had anemia, thrombocytopenia, elevated chitotriosidase, and normal activity of acid sphingomyelinase and low normal activity of β-glucosidase 1 (β-glucocerebrosidase 1, GBA). The child succumbed in the fourth month of life due to persistent respiratory distress and refractory seizures. The clinical phenotype, cherry red spots, elevated chitotriosidase, and lysosomal assays led to the suspicion of Gaucher disease. Exome sequencing revealed a homozygous stop codon mutation in the PSAP gene (c.G1228T, p.Glu410ter). Prenatal diagnosis in the next pregnancy revealed a carrier fetus, who was unaffected postnatally. The diagnosis of specific activator deficiency such as saposin C and saposin D deficiency (in the current study) should be considered and tested for when Gaucher disease is suspected in an infant with partially deficient or near normal GBA activity.

This is the first reported case of

    prosaposin (PSAP) mutation
    GENETICS

 from

    India
    ETHNICITY

 manifesting as an

    acute neuronal Gaucher disease-like condition
    DIAGNOSIS

. A

    2-month-old
    AGE

    male
    GENDER

    baby
    AGE

 presented with

    encephalopathy
    SYMPTOMS

,

    resistant tonic-clonic seizures
    SYMPTOMS

,

    moderate hepatosplenomegaly
    SYMPTOMS

,

    hypotonia
    SYMPTOMS

, and

    cherry red spot in the retinae
    SYMPTOMS

. The

    child
    AGE

 had

    anemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

,

    elevated chitotriosidase
    BIOCHEMICAL

, and

    normal activity of acid sphingomyelinase
    NEG_FINDINGS

 and

    low normal activity of β-glucosidase 1 (β-glucocerebrosidase 1, GBA)
    NEG_FINDINGS

. The

    child
    AGE

    succumbed
    SYMPTOMS

    in the fourth month of life
    AGE

 due to

    persistent respiratory distress
    SYMPTOMS

 and

    refractory seizures
    SYMPTOMS

. The clinical phenotype,

    cherry red spots
    SYMPTOMS

,

    elevated chitotriosidase
    BIOCHEMICAL

, and

    lysosomal assays
    PARACLINICAL

 led to the suspicion of

    Gaucher disease
    DIAGNOSIS

.

    Exome sequencing
    PARACLINICAL

 revealed a

    homozygous stop codon mutation in the PSAP gene (c.G1228T, p.Glu410ter)
    GENETICS

.

    Prenatal diagnosis in the next pregnancy revealed a carrier fetus, who was unaffected postnatally
    FAMILY

. The diagnosis of

    specific activator deficiency such as saposin C and saposin D deficiency
    BIOCHEMICAL

 (in the current study) should be considered and tested for when

    Gaucher disease
    DIAGNOSIS

 is suspected in an

    infant
    AGE

 with

    partially deficient or near normal GBA activity
    BIOCHEMICAL

.

encephalopathy
resistant tonic-clonic seizures
moderate hepatosplenomegaly
hypotonia
cherry red spot in the retinae
succumbed
persistent respiratory distress
refractory seizures
cherry red spots


Two siblings with Gaucher type 3c: different clinical presentations.

Background Gaucher disease (GD) is a lysosomal storage disorder caused by autosomal recessive mutations in the glucocerebrosidase (GBA) gene, which encodes acid β-glucosidase. GD type 3c is a rare group characterised by cardiovascular involvement, and homozygous D448H is the most frequent mutation. Case presentation We describe two patients who had homozygous D448H mutations. The index patient had hepatosplenomegaly, liver insufficiency and cardiac involvement and her sister had severe cardiac involvement with cardiomyopathy and diffuse aortic calcification. The index case's liver was transplanted at the age of 6 months from a related donor and her sister who had severe cardiovascular disease died at the age of 12 years. Conclusions Our patients had clinical variability. We need to discuss whether liver involvement could be the initial signs in patients with GD type 3c.

Background

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    autosomal recessive mutations in the glucocerebrosidase (GBA) gene
    GENETICS

, which encodes

    acid β-glucosidase
    BIOCHEMICAL

.

    GD type 3c
    DIAGNOSIS

 is a rare group characterised by

    cardiovascular involvement
    SYMPTOMS

, and

    homozygous D448H is the most frequent mutation
    GENETICS

. Case presentation We describe two patients who had

    homozygous D448H mutations
    GENETICS

. The index patient had

    hepatosplenomegaly
    SYMPTOMS

,

    liver insufficiency
    SYMPTOMS

 and

    cardiac involvement
    SYMPTOMS

 and

    her
    GENDER

    sister had severe cardiac involvement with cardiomyopathy and diffuse aortic calcification
    FAMILY

. The index case's

    liver was transplanted at the age of 6 months
    MEDICATION

    from a related donor
    MEDICATION

 and

    her sister who had severe cardiovascular disease died at the age of 12 years
    FAMILY

. Conclusions Our patients had clinical variability. We need to discuss whether

    liver involvement
    SYMPTOMS

 could be the initial signs in patients with

    GD type 3c
    DIAGNOSIS

.

Gaucher disease (GD)
lysosomal storage disorder
GD type 3c
GD type 3c

cardiovascular involvement
hepatosplenomegaly
liver insufficiency
cardiac involvement
liver involvement


A 30-Year-Old Carrier of Gaucher Disease with Multiple Myeloma.

We are reporting a case of a 30-year-old male with no past medical history who presented with new onset of renal failure, anemia, and splenomegaly and was diagnosed with multiple myeloma. Given the splenomegaly and the patient's Jewish heritage, blood tests were done and the patient was found to be a Gaucher disease carrier. The association of Gaucher disease and multiple myeloma has previously been reported; however, we want to describe the case of a young Gaucher disease carrier who developed multiple myeloma and provide a review of the literature.

We are reporting a case of a

    30-year-old
    AGE

    male
    GENDER

    with no past medical history
    NEG_FINDINGS

 who presented with

    new onset of renal failure
    SYMPTOMS

,

    anemia
    BIOCHEMICAL

, and

    splenomegaly
    SYMPTOMS

 and was diagnosed with

    multiple myeloma
    DIAGNOSIS

. Given the

    splenomegaly
    SYMPTOMS

 and the patient's

    Jewish heritage
    ETHNICITY

,

    blood tests
    PARACLINICAL

 were done and the patient was found to be a

    Gaucher disease carrier
    DIAGNOSIS

. The association of

    Gaucher disease
    DIAGNOSIS

 and

    multiple myeloma
    DIAGNOSIS

 has previously been reported; however, we want to describe the case of a

    young
    AGE

    Gaucher disease
    DIAGNOSIS

 carrier who developed

    multiple myeloma
    DIAGNOSIS

 and provide a review of the literature.

new onset of renal failure
splenomegaly
splenomegaly

multiple myeloma
Gaucher disease carrier
Gaucher disease
multiple myeloma
Gaucher disease
multiple myeloma


Liver damage in a patient with Gaucher's disease type 1 and alpha-1 antitrypsin deficiency: a potential epigenetic effect?

Gaucher's disease and alpha-1 antitrypsin deficiency are genetic diseases that can cause different kinds of liver damage, but are rarely associated with cirrhosis. Here, we describe the case of a patient with both diseases who presented with cirrhosis, followed by liver failure and death. Although the interaction between these two diseases remains unclear, we suspect the involvement of an epigenetic factor in the evolution of the aggressive liver disease.

    Gaucher's disease
    DIAGNOSIS

 and

    alpha-1 antitrypsin deficiency
    BIOCHEMICAL

 are

    genetic diseases
    GENETICS

 that can cause different kinds of

    liver damage
    SYMPTOMS

, but are rarely associated with

    cirrhosis
    DIAGNOSIS

. Here, we describe the case of a patient with both diseases who presented with

    cirrhosis
    DIAGNOSIS

, followed by

    liver failure
    SYMPTOMS

 and

    death
    SYMPTOMS

. Although the interaction between these two diseases remains unclear, we suspect the involvement of an

    epigenetic factor
    GENETICS

 in the evolution of the

    aggressive liver disease
    DIAGNOSIS

.

Gaucher's disease
cirrhosis
cirrhosis
aggressive liver disease


Splenic Artery Aneurysms, A Rare Complication of Type 1 Gaucher Disease: Report of Five Cases.

Type 1 Gaucher disease is a rare genetic lysosomal disorder due to acid betaglucosidase deficiency. The main features are thrombocytopenia, anemia, hepatosplenomegaly and complex skeletal disease. Complications include pulmonary hypertension, cirrhosis and splenic infarction; comorbidities, such as autoimmune phenomena, B-cell malignancies and Parkinson disease also occur. Visceral aneurysms have been only rarely noted in Gaucher disease. We report the retrospective data from patients with Gaucher disease type 1 and splenic arterial aneurysm. We describe the different outcomes of a giant splenic arterial aneurysm in five patients with type 1 Gaucher disease and discuss the main possible pathophysiological explanations. Aneurysms of the splenic artery are rare in Gaucher disease but are probably greatly under-reported.

    Type 1 Gaucher disease
    DIAGNOSIS

 is a

    rare genetic lysosomal disorder
    GENETICS

 due to

    acid betaglucosidase deficiency
    BIOCHEMICAL

. The main features are

    thrombocytopenia
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

,

    hepatosplenomegaly
    SYMPTOMS

 and

    complex skeletal disease
    SYMPTOMS

. Complications include

    pulmonary hypertension
    SYMPTOMS

,

    cirrhosis
    SYMPTOMS

 and

    splenic infarction
    SYMPTOMS

; comorbidities, such as

    autoimmune phenomena
    SYMPTOMS

,

    B-cell malignancies
    MICROSCOPIC

 and

    Parkinson disease
    DIAGNOSIS

 also occur.

    Visceral aneurysms
    SYMPTOMS

 have been only rarely noted in

    Gaucher disease
    DIAGNOSIS

. We report the retrospective data from patients with

    Gaucher disease type 1
    DIAGNOSIS

 and

    splenic arterial aneurysm
    SYMPTOMS

. We describe the different outcomes of a

    giant splenic arterial aneurysm
    SYMPTOMS

 in five patients with

    type 1 Gaucher disease
    DIAGNOSIS

 and discuss the main possible pathophysiological explanations.

    Aneurysms of the splenic artery
    SYMPTOMS

 are rare in

    Gaucher disease
    DIAGNOSIS

 but are probably greatly under-reported.

Type 1 Gaucher disease
Parkinson disease
Gaucher disease
Gaucher disease type 1
type 1 Gaucher disease
Gaucher disease

acid betaglucosidase deficiency
thrombocytopenia
anemia

hepatosplenomegaly
complex skeletal disease
pulmonary hypertension
cirrhosis
splenic infarction
autoimmune phenomena
Visceral aneurysms
splenic arterial aneurysm
giant splenic arterial aneurysm
Aneurysms of the splenic artery


Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene.

Impairment of saposin B causes rare atypical metachromatic leukodystrophy (MLD). It is encoded (together with saposin A, C, and D) by the PSAP gene. Only ten pathogenic variants were described in the PSAP gene in MLD patients to date. We report on two novel variants in the PSAP gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11 in a patient with MLD. We discuss the fact, that variants resulting in PSAP null allele can be shared in patients with the deficit of other saposins (A-D) or whole prosaposin. The patient's phenotype depends then on the nature of the second allele - atypical Gaucher disease in case of saposin A, MLD in case of saposin B, and Krabbe disease in case of saposin C impairing mutations. The clinically most severe prosaposin deficit is caused by the presence of two PSAP null alleles. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with PSAP mutations.

    Impairment of saposin B
    BIOCHEMICAL

 causes

    rare atypical metachromatic leukodystrophy (MLD)
    SYMPTOMS

. It is encoded (together with saposin A, C, and D) by the

    PSAP gene
    GENETICS

. Only ten pathogenic variants were described in the

    PSAP gene
    GENETICS

 in

    MLD
    DIAGNOSIS

 patients to date. We report on

    two novel variants in the PSAP gene - c.679_681delAAG in the saposin B encoding exon 6 and c.1268delT in the saposin D encoding exon 11
    GENETICS

 in a patient with

    MLD
    DIAGNOSIS

. We discuss the fact, that

    variants resulting in PSAP null allele
    GENETICS

 can be shared in patients with the

    deficit of other saposins (A-D) or whole prosaposin
    BIOCHEMICAL

. The patient's phenotype depends then on the nature of the second allele -

    atypical Gaucher disease
    DIAGNOSIS

 in case of

    saposin A
    BIOCHEMICAL

,

    MLD
    DIAGNOSIS

 in case of

    saposin B
    BIOCHEMICAL

, and

    Krabbe disease
    DIAGNOSIS

 in case of

    saposin C impairing mutations
    BIOCHEMICAL

. The clinically most severe

    prosaposin deficit
    BIOCHEMICAL

 is caused by the

    presence of two PSAP null alleles
    GENETICS

. Thus, the assessment of a variant impact is needed to prevent delayed diagnosis or misdiagnosis in patients with

    PSAP mutations
    GENETICS

.

MLD
MLD
atypical Gaucher disease
MLD
Krabbe disease


Three cases of multi-generational Gaucher disease and colon cancer from an Ashkenazi Jewish family: A lesson for cascade screening.

Gaucher disease (GD) is one of the commonest lysosomal storage diseases that is inherited in an autosomal recessive manner and affects 1 in 50,000 to 100,000 people in the general population. The frequency is much higher (1 in 500 to 1000) in people of Ashkenazi Jewish heritage due to a founder effect. GD is caused by decreased or absent activity of β-glucosidase with subsequent accumulation of the substrate glucosylceramide in macrophages due to genetic alterations in the GBA gene. These often accumulate in the spleen, liver and bone marrow. Three types exist, with type 1 being the most common, also referred to as non-neuronopathic GD. A broad clinical spectrum exists; patients of any age may manifest with hepatosplenomegaly, anaemia, thrombocytopenia, lung disease, bone abnormalities or may remain asymptomatic throughout their lifespan. Multi-generational disease does not usually occur because the risk of disease with each pregnancy, presuming both parents are carriers of the condition, is 25%. Herein, we report an Ashkenazi Jewish family with multi-generational GD type 1 and multigenerational colon cancer in the same three individuals, and reinforce the importance of cascade screening in families with genetic conditions.

    Gaucher disease (GD)
    DIAGNOSIS

 is one of the commonest

    lysosomal storage diseases
    DIAGNOSIS

 that is

    inherited in an autosomal recessive manner
    GENETICS

 and affects 1 in 50,000 to 100,000 people in the general population. The frequency is much higher (1 in 500 to 1000) in people of

    Ashkenazi Jewish heritage
    ETHNICITY

 due to a

    founder effect
    GENETICS

.

    GD
    DIAGNOSIS

 is caused by

    decreased or absent activity of β-glucosidase
    BIOCHEMICAL

 with subsequent

    accumulation of the substrate glucosylceramide in macrophages
    MICROSCOPIC

 due to

    genetic alterations in the GBA gene
    GENETICS

.

    These often accumulate in the spleen, liver and bone marrow
    MICROSCOPIC

. Three types exist, with

    type 1
    DIAGNOSIS

 being the most common, also referred to as

    non-neuronopathic GD
    DIAGNOSIS

. A broad clinical spectrum exists; patients of

    any age
    AGE

 may manifest with

    hepatosplenomegaly
    SYMPTOMS

,

    anaemia
    BIOCHEMICAL

,

    thrombocytopenia
    BIOCHEMICAL

,

    lung disease
    SYMPTOMS

,

    bone abnormalities
    SYMPTOMS

 or

    may remain asymptomatic
    NEG_FINDINGS

 throughout their

    lifespan
    NEG_FINDINGS

.

    Multi-generational disease
    DIAGNOSIS

 does not usually occur because the risk of disease with each

    pregnancy
    DIAGNOSIS

, presuming

    both parents are carriers of the condition
    FAMILY

, is 25%. Herein, we report an

    Ashkenazi Jewish
    ETHNICITY

    family with multi-generational GD type 1 and multigenerational colon cancer in the same three individuals
    FAMILY

, and reinforce the importance of

    cascade screening
    PARACLINICAL

 in

    families with genetic conditions
    FAMILY

.

Gaucher disease (GD)
lysosomal storage diseases
GD
type 1
non-neuronopathic GD
Multi-generational disease
pregnancy

Ashkenazi Jewish heritage
Ashkenazi Jewish

hepatosplenomegaly
lung disease
bone abnormalities


Small Bowel Mucosal Involvement and Mesenteric Mass Formation in a Young Female with Type 3 Gaucher Disease. A Case Report.

Gaucher Disease arises due to a deficiency in the enzyme glucocerebrosidase and is the most common lysosomal storage disease. This enzyme deficiency leads to the accumulation of glucocerebroside within macrophages (Gaucher cells) and the resulting infiltration of these cells into organs can cause clinical symptoms. There are three types of Gaucher Disease that differ based on the clinical course and the presence or absence of neurological involvement, but classically, Gaucher cell infiltrates impact a patient's spleen, liver, bone marrow and cortex. In this report, we present a case of Type 3 Gaucher Disease involving small bowel mucosa with a mesenteric mass formation. These unusual sites of Gaucher cell deposition likely led directly to uncommonly seen clinical symptoms, including small bowel obstruction and lower gastrointestinal hemorrhage.

    Gaucher Disease
    DIAGNOSIS

 arises due to a

    deficiency in the enzyme glucocerebrosidase
    BIOCHEMICAL

 and is the most common

    lysosomal storage disease
    DIAGNOSIS

. This

    enzyme deficiency
    BIOCHEMICAL

 leads to the

    accumulation of glucocerebroside within macrophages (Gaucher cells)
    MICROSCOPIC

 and the resulting

    infiltration of these cells into organs
    MICROSCOPIC

 can cause

    clinical symptoms
    SYMPTOMS

. There are three types of

    Gaucher Disease
    DIAGNOSIS

 that differ based on the clinical course and the presence or absence of

    neurological involvement
    SYMPTOMS

, but classically,

    Gaucher cell infiltrates impact a patient's spleen, liver, bone marrow and cortex
    MICROSCOPIC

. In this report, we present a case of

    Type 3 Gaucher Disease
    MICROSCOPIC

 involving

    small bowel mucosa
    SYMPTOMS

 with a

    mesenteric mass formation
    SYMPTOMS

. These

    unusual sites of Gaucher cell deposition
    MICROSCOPIC

 likely led directly to

    uncommonly seen clinical symptoms
    SYMPTOMS

, including

    small bowel obstruction
    SYMPTOMS

 and

    lower gastrointestinal hemorrhage
    SYMPTOMS

.

Gaucher Disease
lysosomal storage disease
Gaucher Disease

clinical symptoms
neurological involvement
small bowel mucosa
mesenteric mass formation
uncommonly seen clinical symptoms
small bowel obstruction
lower gastrointestinal hemorrhage


[Cavernoma complicated with biliopatia secondary to type 1 Gaucher disease: report of a Peruvian case].

Gaucher disease is an autosomal recessive lysosomal storage disorder characterized by deficiency of beta-glucosidase that would lead to the accumulation of glucosylceramide mainly in cells of the mononuclear phagocytic system causing systemic effectations. We present a patient of twenty years who is suffering from chronic pain in the left hypochondrium with episodes of bleeding for 3 years and sensation of thermal rise, physical examination revealed jaundice and massive splenomegaly, without neurological involvement. Severe osteoporosis, pancytopenia, and the presence of portal vein thrombosis with cavernomatous transformation complicated by portal biliopathy simulating a klatskin tumor, marrow and enzymatic studies were compatible with Gaucher disease, were shown as unexpected findings. he received treatment with imiglucerase, following up. It is a rare case, of great interest, heterogeneity in its clinical manifestations and unpublished by its complication, constituting a challenge to reach its diagnosis of this orphan disease.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 characterized by

    deficiency of beta-glucosidase
    BIOCHEMICAL

 that would lead to the

    accumulation of glucosylceramide mainly in cells of the mononuclear phagocytic system
    MICROSCOPIC

 causing

    systemic effectations
    SYMPTOMS

. We present a patient of

    twenty years
    AGE

 who is suffering from

    chronic pain in the left hypochondrium with episodes of bleeding for 3 years
    SYMPTOMS

 and

    sensation of thermal rise
    SYMPTOMS

, physical examination revealed

    jaundice
    SYMPTOMS

 and

    massive splenomegaly
    SYMPTOMS

,

    without neurological involvement
    NEG_FINDINGS

.

    Severe osteoporosis
    SYMPTOMS

,

    pancytopenia
    BIOCHEMICAL

, and the

    presence of portal vein thrombosis with cavernomatous transformation
    SYMPTOMS

 complicated by

    portal biliopathy simulating a klatskin tumor
    SYMPTOMS

,

    marrow and enzymatic studies
    PARACLINICAL

 were compatible with

    Gaucher disease
    DIAGNOSIS

, were shown as unexpected findings.

    he
    GENDER

 received

    treatment with imiglucerase
    MEDICATION

, following up. It is a rare case, of great interest, heterogeneity in its clinical manifestations and unpublished by its complication, constituting a challenge to reach its diagnosis of this

    orphan disease
    DIAGNOSIS

.

Gaucher disease
lysosomal storage disorder
Gaucher disease
orphan disease

deficiency of beta-glucosidase
pancytopenia


Coexistence of Gaucher Disease and severe congenital neutropenia.

Gaucher Disease (GD) is the most common lysosomal storage disorder has traditionally been classified into three clinical phenotypes. Type 3 GD is characterized by neurological involvement but neurological symptoms generally appear later in life than in type 2 disease. Neutropenia is much rarer than other hematological manifestations in GD and has not been scrutinized adequately. Severe congenital neutropenia (SCN) is a rare disease entity which is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. We report a patient who presented in the first year of life with visceral involvement and severe neutropenia in whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1. In contrast to his expired siblings he had experienced no severe infections. These clinical observations suggest that enzyme replacement therapy may display a modulating factor with respect to the clinical course of SCN. SYNOPSIS: Our patient is the only report of the combination of Gaucher Disease and Kostmann Syndrome in the literature. The clinical course of our patient is not severe when comparing with exitus siblings and other Kostmann Syndrome patients. But when considering the patient's only clinical difference is ERT, this case is very important to emphasise the role of enzyme replacement therapy in bone marrow.

    Gaucher Disease (GD)
    DIAGNOSIS

 is the most common

    lysosomal storage disorder
    DIAGNOSIS

 has traditionally been classified into three clinical phenotypes.

    Type 3 GD
    DIAGNOSIS

 is characterized by

    neurological involvement
    SYMPTOMS

 but

    neurological symptoms
    SYMPTOMS

 generally appear later in life than in

    type 2 disease
    DIAGNOSIS

.

    Neutropenia
    BIOCHEMICAL

 is much rarer than other

    hematological manifestations
    BIOCHEMICAL

 in

    GD
    DIAGNOSIS

 and has not been scrutinized adequately.

    Severe congenital neutropenia (SCN)
    DIAGNOSIS

 is a rare disease entity which is characterized by a

    paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage
    BIOCHEMICAL

 and consequent

    increased susceptibility to severe and recurrent infections
    SYMPTOMS

. We report a patient who presented in the

    first year of life
    AGE

 with

    visceral involvement
    SYMPTOMS

 and

    severe neutropenia
    BIOCHEMICAL

 in

    whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1
    FAMILY

.

    In contrast to his expired siblings
    FAMILY

 he had experienced

    no severe infections
    NEG_FINDINGS

. These clinical observations suggest that

    enzyme replacement therapy
    MEDICATION

 may display a modulating factor with respect to the clinical course of

    SCN
    DIAGNOSIS

. SYNOPSIS: Our patient is the only report of the

    combination of Gaucher Disease and Kostmann Syndrome
    DIAGNOSIS

 in the literature.

    The clinical course of our patient is not severe when comparing with exitus siblings
    FAMILY

 and other

    Kostmann Syndrome
    DIAGNOSIS

 patients. But when considering the patient's only clinical difference is

    ERT
    MEDICATION

, this case is very important to emphasise the role of

    enzyme replacement therapy in bone marrow
    MEDICATION

.