Two novel mutations in glucocerebrosidase, C23W and IVS7-1 G>A, identified in Type 1 Gaucher patients heterozygous for N370S.

Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from deficient glucocerebrosidase activity. There have been nearly 300 mutations described to date. Novel mutations can potentially provide insight into the biochemical basis of the disease. Two novel mutations are described in two Type 1 Gaucher patients with N370S compound heterozygosity; a point mutation that causes an amino acid substitution at cysteine residue 23 for tryptophan, and a second point mutation within the splicing element at the 3' end of intron 7. Both mutations were identified by PCR amplification and sequence analysis of patient glucocerebrosidase genomic DNA. Restriction fragment length polymorphism analysis was established for both novel mutations for efficient identification in future patients. Past literature suggests that mutations affecting cysteine residues involved in disulfide bridges, as well as mutations affecting splicing patterns of the glucocerebrosidase transcript, are detrimental to enzyme activity. However, compound heterozygosity with N370S, a mild mutation, will lead to a mild phenotype. The cases reported here support these past findings.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from

    deficient glucocerebrosidase activity
    BIOCHEMICAL

. There have been nearly 300 mutations described to date. Novel mutations can potentially provide insight into the biochemical basis of the disease. Two novel mutations are described in two

    Type 1 Gaucher
    DIAGNOSIS

 patients with

    N370S compound heterozygosity
    GENETICS

; a

    point mutation that causes an amino acid substitution at cysteine residue 23 for tryptophan
    GENETICS

, and a

    second point mutation within the splicing element at the 3' end of intron 7
    GENETICS

. Both mutations were identified by

    PCR amplification and sequence analysis of patient glucocerebrosidase genomic DNA
    PARACLINICAL

.

    Restriction fragment length polymorphism analysis
    PARACLINICAL

 was established for both novel mutations for efficient identification in future patients. Past literature suggests that

    mutations affecting cysteine residues involved in disulfide bridges
    GENETICS

, as well as

    mutations affecting splicing patterns of the glucocerebrosidase transcript
    GENETICS

, are detrimental to

    enzyme activity
    BIOCHEMICAL

. However,

    compound heterozygosity with N370S, a mild mutation
    GENETICS

, will lead to a mild phenotype. The cases reported here support these past findings.

Gaucher disease
lysosomal storage disorder
Type 1 Gaucher

deficient glucocerebrosidase activity
enzyme activity


A Rare Case of Hemoglobin E Hemoglobinopathy with Gaucher's Disease.

Hemoglobin (Hb) E mutation is common in north-east part of our country. The natural history of Hb E thalassemia is highly variable. The phenotype, for patients with similar mutations, can range from asymptomatic to transfusion dependent. Our patient presented at 2 years of age with failure to thrive and hepatosplenomegaly. Routine work up revealed microcytic, hypochromic red blood cells. Hb E homozygous was indicated on electrophoresis and hemoglobin HPLC. Evaluation of parents revealed Haemoglobin E trait in both. Therapeutic splenectomy revealed Gaucher-like cells. β-Glucocerebrosidase levels were low. Presence of Gaucher-like cells with normal β-glucocerebrosidase (pseudo-Gaucher cells) are known in leukemia, multiple myeloma, thalassemia and mycobacterial infections. Co-existence of Gaucher's disease with Hb E mutation is not reported to the best of our knowledge.

    Hemoglobin (Hb) E mutation
    GENETICS

 is common in north-east part of our country. The natural history of

    Hb E thalassemia
    DIAGNOSIS

 is highly variable. The phenotype, for patients with similar mutations, can range from

    asymptomatic
    NEG_FINDINGS

 to

    transfusion dependent
    BIOCHEMICAL

. Our patient presented at

    2 years of age
    AGE

 with

    failure to thrive
    SYMPTOMS

 and

    hepatosplenomegaly
    SYMPTOMS

.

    Routine work up
    PARACLINICAL

 revealed

    microcytic, hypochromic red blood cells
    MICROSCOPIC

.

    Hb E homozygous
    GENETICS

 was indicated on

    electrophoresis and hemoglobin HPLC
    PARACLINICAL

.

    Evaluation of parents revealed Haemoglobin E trait in both
    FAMILY

.

    Therapeutic splenectomy
    MEDICATION

 revealed

    Gaucher-like cells
    MICROSCOPIC

.

    β-Glucocerebrosidase levels were low
    BIOCHEMICAL

.

    Presence of Gaucher-like cells
    MICROSCOPIC

 with

    normal β-glucocerebrosidase
    NEG_FINDINGS

 (

    pseudo-Gaucher cells)
    MICROSCOPIC

 are known in

    leukemia
    DIAGNOSIS

,

    multiple myeloma
    DIAGNOSIS

,

    thalassemia
    DIAGNOSIS

 and

    mycobacterial infections
    DIAGNOSIS

.

    Co-existence of Gaucher's disease with Hb E mutation
    DIAGNOSIS

 is not reported to the best of our knowledge.

Hemoglobin (Hb) E mutation
Hb E homozygous

transfusion dependent
β-Glucocerebrosidase levels were low


Pathological fracture and pyogenic osteomyelitis in a patient with type 2 Gaucher disease.

In Gaucher disease (GD), enzyme replacement therapy (ERT) results in the alleviation of hematological abnormalities and visceral infiltration as well as improvement in quality of life and life-span. However, several years may be required for skeletal manifestations, which are usually observed in type 1 and 3 GD, to respond to ERT. Infants with type 2 GD rarely present skeletal manifestations because most of these patients die within the first 2 years of life before they develop skeletal involvement. The use of ERT may prolong the lifespan of these patients and influence the natural history of the disease. The present study reports a new natural history of treated GD in which a 2-year and 7-month-old girl with type 2 GD who was receiving ERT developed valproate-induced Fanconi syndrome, pathological fractures, and pyogenic osteomyelitis. In conclusion, skeletal disease may occur in any type of GD, and Fanconi syndrome may lead to severe skeletal complications in patients with GD.

In

    Gaucher disease (GD)
    DIAGNOSIS

,

    enzyme replacement therapy (ERT)
    MEDICATION

 results in the

    alleviation of hematological abnormalities
    SYMPTOMS

 and

    visceral infiltration
    SYMPTOMS

 as well as

    improvement in quality of life
    SYMPTOMS

 and life-span. However, several years may be required for

    skeletal manifestations
    SYMPTOMS

, which are usually observed in

    type 1 and 3 GD
    DIAGNOSIS

, to respond to

    ERT
    MEDICATION

.

    Infants
    AGE

 with

    type 2 GD
    DIAGNOSIS

 rarely present

    skeletal manifestations
    SYMPTOMS

 because most of these patients die

    within the first 2 years of life
    AGE

 before they develop

    skeletal involvement
    SYMPTOMS

. The use of

    ERT
    MEDICATION

 may prolong the lifespan of these patients and influence the natural history of the disease. The present study reports a new natural history of

    treated GD
    DIAGNOSIS

 in which a

    2-year and 7-month-old
    AGE

    girl
    GENDER

 with

    type 2 GD
    DIAGNOSIS

 who was receiving

    ERT
    MEDICATION

 developed

    valproate-induced Fanconi syndrome
    DIAGNOSIS

,

    pathological fractures
    SYMPTOMS

, and

    pyogenic osteomyelitis
    SYMPTOMS

. In conclusion,

    skeletal disease
    DIAGNOSIS

 may occur in any type of

    GD
    DIAGNOSIS

, and

    Fanconi syndrome
    DIAGNOSIS

 may lead to

    severe skeletal complications
    SYMPTOMS

 in patients with

    GD
    DIAGNOSIS

.

Gaucher disease (GD)
type 1 and 3 GD
type 2 GD
treated GD
type 2 GD
valproate-induced Fanconi syndrome
skeletal disease
GD
Fanconi syndrome
GD

enzyme replacement therapy (ERT)
ERT
ERT
ERT


Peripheral autonomic nervous system involvement in Gaucher-related parkinsonism.

The pathological process affects the peripheral autonomic nervous system in the vast majority of sporadic PD patients. Recent reports have shown that patients with a familial form of the disease caused by mutation of the gene encoding LRRK2 and alpha-synuclein also display autonomic abnormalities, especially cardiac sympathetic denervation. In the present report, we have studied the involvement of the peripheral autonomic system in a patient with Gaucher disease-associated parkinsonism. Using colonic biopsies and quantitative 123I-MIBG scintigraphy respectively, we show that both Lewy pathology and cardiac denervation were present in this case of Gaucher-associated Parkinsonism. We discuss the consequence of these findings on the pathophysiology of the disease.

The pathological process

    affects the peripheral autonomic nervous system
    SYMPTOMS

 in the vast majority of

    sporadic PD
    DIAGNOSIS

 patients. Recent reports have shown that patients with a

    familial form of the disease
    GENETICS

 caused by

    mutation of the gene encoding LRRK2 and alpha-synuclein
    GENETICS

 also display

    autonomic abnormalities
    SYMPTOMS

, especially

    cardiac sympathetic denervation
    SYMPTOMS

. In the present report, we have studied the

    involvement of the peripheral autonomic system
    SYMPTOMS

 in a patient with

    Gaucher disease-associated parkinsonism
    DIAGNOSIS

. Using

    colonic biopsies
    PARACLINICAL

 and

    quantitative 123I-MIBG scintigraphy
    PARACLINICAL

 respectively, we show that

    both Lewy pathology
    MICROSCOPIC

 and

    cardiac denervation
    SYMPTOMS

 were present in this case of

    Gaucher-associated Parkinsonism
    DIAGNOSIS

. We discuss the consequence of these findings on the pathophysiology of the disease.

sporadic PD
Gaucher disease-associated parkinsonism
Gaucher-associated Parkinsonism


Middle-ear involvement in type I Gaucher's disease - a unique case.

Gaucher's disease is a rare autosomal recessive lysosomal storage disease. We describe a unique case of middle-ear involvement presenting with hearing loss.

A five-year-old boy with known Gaucher's disease presented with bilateral hearing impairment and conductive hearing loss on pure tone audiometry with flat tympanometry traces.

Exploratory Tympanomastoidectomy revealed inflammatory material filling the mastoid and the middle ear. Histological analysis confirmed Gaucher cell infiltrates.

This is the first detailed report in the english language literature of Gaucher's disease affecting the middle ear and the mastoid. We discuss the disease process and suggest future management options.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare autosomal recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

. We describe a unique case of

    middle-ear involvement
    SYMPTOMS

 presenting with

    hearing loss
    SYMPTOMS

.

A

    five-year-old
    AGE

    boy
    GENDER

 with known

    Gaucher's disease
    DIAGNOSIS

 presented with

    bilateral hearing impairment
    SYMPTOMS

 and

    conductive hearing loss
    SYMPTOMS

 on

    pure tone audiometry
    PARACLINICAL

 with

    flat tympanometry traces
    SYMPTOMS

.

    Exploratory Tympanomastoidectomy
    MEDICATION

 revealed

    inflammatory material filling the mastoid and the middle ear
    MICROSCOPIC

.

    Histological analysis
    PARACLINICAL

 confirmed

    Gaucher cell infiltrates
    MICROSCOPIC

.

This is the first detailed report in the english language literature of

    Gaucher's disease affecting the middle ear and the mastoid
    DIAGNOSIS

. We discuss the disease process and suggest future management options.

middle-ear involvement
hearing loss
bilateral hearing impairment
conductive hearing loss
flat tympanometry traces


Acquired von Willebrand syndrome in patients with Gaucher disease.

Although various coagulation abnormalities occur in patients with Gaucher disease (GD), von Willebrand factor (vWF) deficiency has rarely been reported. A retrospective review of six treatment naïve cases with GD and concomitant vWF deficiency over a 12-year-period in a single center is presented. All patients had a personal history of prior hemorrhages. Based on both reduced level of vWF antigen (vWF:Ag, range 14-56%) and ristocetin cofactor activity (vWF:RCo, range 12-53%), with a vWF:RCo/Ag ratio >0.7, the diagnosis of type 1 von Willebrand disease was made in all six cases. During enzyme replacement therapy (ERT) of a 2-year duration all patients normalized their vWF:Ag levels. Based on the positive ERT effect on vWF:Ag levels, vWF deficiency was assumed to be acquired. It should be noted that beside vWF deficiency four patients with GD exhibited mild thrombocytopenia (range 81-131×10(9)/L) and three had additional hemostatic defects (reduced collagen platelet aggregation, FV, FXI and FXII deficiencies).

Although various

    coagulation abnormalities
    BIOCHEMICAL

 occur in patients with

    Gaucher disease (GD)
    DIAGNOSIS

,

    von Willebrand factor (vWF) deficiency
    BIOCHEMICAL

 has rarely been reported. A retrospective review of six

    treatment naïve
    MEDICATION

 cases with

    GD
    DIAGNOSIS

 and

    concomitant vWF deficiency
    BIOCHEMICAL

 over a 12-year-period in a single center is presented. All patients had a

    personal history of prior hemorrhages
    SYMPTOMS

. Based on both

    reduced level of vWF antigen (vWF:Ag, range 14-56%) and ristocetin cofactor activity (vWF:RCo, range 12-53%)
    BIOCHEMICAL

, with a

    vWF:RCo/Ag ratio >0.7
    BIOCHEMICAL

, the diagnosis of

    type 1 von Willebrand disease
    DIAGNOSIS

 was made in all six cases. During

    enzyme replacement therapy (ERT) of a 2-year duration
    MEDICATION

 all patients

    normalized their vWF:Ag levels
    BIOCHEMICAL

. Based on the

    positive ERT effect on vWF:Ag levels
    BIOCHEMICAL

,

    vWF deficiency
    BIOCHEMICAL

 was assumed to be

    acquired
    DIAGNOSIS

. It should be noted that beside

    vWF deficiency
    BIOCHEMICAL

 four patients with

    GD
    DIAGNOSIS

 exhibited

    mild thrombocytopenia (range 81-131×10(9)/L)
    BIOCHEMICAL

 and three had additional

    hemostatic defects
    BIOCHEMICAL

 (

    reduced collagen platelet aggregation, FV, FXI and FXII deficiencies)
    BIOCHEMICAL

.

Gaucher disease (GD)
GD
type 1 von Willebrand disease
acquired
GD


Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease.

The clinical presentation of Gaucher disease (GD), an inherited lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, is highly variable, and three clinical types are distinguished based upon the presence of neurologic symptoms. Thrombocytopenia, anemia, hepatosplenomegaly, and bone manifestations are the most typical signs of GD type 1 (GD1).

We present the case of an unsplenectomized man suffering from heterozygous GD1 with mutations of c.1226A>G (N370S) and RecNci I (L444P, A456P, and V460V) in the GBA1 gene, who developed recurrent pulmonary aspergillosis caused by Aspergillus fumigatus and a mycobacterial infection caused by Mycobacterium avium. Despite long-lasting therapy of both aspergillosis (including antifungal drugs and surgery), and the mycobacterial infection (triple therapy with rifampicin, ethambutol, and clarithromycin), recurrent positivity for M. avium and A. fumigatus was detected.

Symptomatic lung involvement and an increased susceptibility to pulmonary infections are uncommon in GD and, if present, are often associated with more severe disease manifestations. To our knowledge, this is the first published report on the association of GD and pulmonary aspergillosis and mycobacterial infection. It illustrates the increased susceptibility of untreated GD patients to opportunistic pulmonary infections and ineffective eradication of these infections despite adequate therapy.

The clinical presentation of

    Gaucher disease (GD)
    DIAGNOSIS

, an

    inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by the

    deficient activity of the lysosomal enzyme glucocerebrosidase
    BIOCHEMICAL

, is highly variable, and three clinical types are distinguished based upon the presence of

    neurologic symptoms
    SYMPTOMS

.

    Thrombocytopenia
    BIOCHEMICAL

,

    anemia
    BIOCHEMICAL

,

    hepatosplenomegaly
    SYMPTOMS

, and

    bone manifestations
    SYMPTOMS

 are the most typical signs of

    GD type 1 (GD1)
    DIAGNOSIS

.

We present the case of an

    unsplenectomized
    MEDICATION

    man
    GENDER

 suffering from

    heterozygous GD1
    GENETICS

 with

    mutations of c.1226A>G (N370S) and RecNci I (L444P, A456P, and V460V) in the GBA1 gene
    GENETICS

, who developed

    recurrent pulmonary aspergillosis caused by Aspergillus fumigatus
    DIAGNOSIS

 and a

    mycobacterial infection caused by Mycobacterium avium
    DIAGNOSIS

.

    Despite long-lasting therapy of both aspergillosis (including antifungal drugs and surgery), and the mycobacterial infection
    NEG_FINDINGS

 (

    triple therapy with rifampicin, ethambutol, and clarithromycin)
    MEDICATION

,

    recurrent positivity for M. avium and A. fumigatus
    MICROSCOPIC

 was detected.

    Symptomatic lung involvement
    SYMPTOMS

 and an

    increased susceptibility to pulmonary infections
    SYMPTOMS

 are uncommon in

    GD
    DIAGNOSIS

 and, if present, are often associated with more severe disease manifestations. To our knowledge, this is the first published report on the association of

    GD
    DIAGNOSIS

 and

    pulmonary aspergillosis and mycobacterial infection
    DIAGNOSIS

. It illustrates the increased susceptibility of untreated

    GD
    DIAGNOSIS

 patients to

    opportunistic pulmonary infections
    DIAGNOSIS

 and

    ineffective eradication of these infections
    NEG_FINDINGS

    despite adequate therapy
    NEG_FINDINGS

.


Parkinsonism syndrome in heterozygotes for Niemann-Pick C1.

Niemann-Pick C (NPC) disease is a rare autosomal recessive lipid storage disorder. We report here the unique occurrence of three adult heterozygous carriers of mutations in the NPC1 gene who also have a parkinsonism syndrome. This suggests the possibility that mutations in NPC1 could be a risk factor for Parkinson's disease similar to the phenomenon that is now recognized with Gaucher disease and the glucocerebrosidase (GBA) gene. This report should be a stimulus for larger more detailed epidemiological studies.

    Niemann-Pick C (NPC) disease
    DIAGNOSIS

 is a

    rare autosomal recessive
    GENETICS

    lipid storage disorder
    DIAGNOSIS

. We report here the unique occurrence of three

    adult
    AGE

    heterozygous carriers of mutations in the NPC1 gene
    GENETICS

 who also have a

    parkinsonism syndrome
    DIAGNOSIS

. This suggests the possibility that

    mutations in NPC1
    GENETICS

 could be a risk factor for

    Parkinson's disease
    DIAGNOSIS

 similar to the phenomenon that is now recognized with

    Gaucher disease
    DIAGNOSIS

 and the

    glucocerebrosidase
    BIOCHEMICAL

 (GBA) gene. This report should be a stimulus for larger more detailed epidemiological studies.

Niemann-Pick C (NPC) disease
lipid storage disorder
parkinsonism syndrome
Parkinson's disease
Gaucher disease


A case of adult type 1 Gaucher disease complicated by temporal intestinal hemorrhage.

A 21-year-old man with a history of sudden rectal hemorrhage was referred to our hospital. Examination disclosed thrombocytopenia and hepatosplenomegaly. A liver biopsy specimen demonstrated Gaucher cells in Glisson's capsule. Additional investigations revealed a low level of leukocyte β-glucosidase activity and common mutations of the glucocerebrosidase gene, L444P/D409H. We diagnosed the patient with Gaucher disease type 1. He underwent enzyme replacement therapy. Thrombocytopenia and hepatosplenomegaly improved at a rate of approximately 50 and 20%, respectively, within 6 months. This case suggests that we must pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia.

A

    21-year-old
    AGE

    man
    GENDER

 with a history of

    sudden rectal hemorrhage
    SYMPTOMS

 was referred to our hospital. Examination disclosed

    thrombocytopenia
    BIOCHEMICAL

 and

    hepatosplenomegaly
    SYMPTOMS

. A

    liver biopsy specimen
    PARACLINICAL

 demonstrated

    Gaucher cells in Glisson's capsule
    MICROSCOPIC

. Additional investigations revealed a

    low level of leukocyte β-glucosidase activity
    BIOCHEMICAL

 and common mutations of the glucocerebrosidase gene, L444P/D409H. We diagnosed the patient with

    Gaucher disease type 1
    DIAGNOSIS

.

    He
    GENDER

 underwent

    enzyme replacement therapy
    MEDICATION

.

    Thrombocytopenia
    BIOCHEMICAL

 and

    hepatosplenomegaly
    SYMPTOMS

 improved at a rate of approximately 50 and 20%, respectively, within 6 months. This case suggests that we must pay attention to

    adult Gaucher disease
    DIAGNOSIS

 as a

    differential diagnosis
    PARACLINICAL

 for

    cryptogenic thrombocytopenia
    BIOCHEMICAL

.

sudden rectal hemorrhage
hepatosplenomegaly
hepatosplenomegaly

Gaucher disease type 1
adult Gaucher disease


Gaucher disease with pathological femoral neck fracture.

Fractures of the femoral neck are rare and usually result from serious and high-energy trauma in the skeleton in young adults. Gaucher's disease (GD) is a lysosomal storage disorder that has progressive course and is rarely seen. Research has shown that a pathological femoral neck fracture with GD mostly emerges in childhood. But in adults, there are no reports of pathological femoral neck fractures with GD. We present a unique case of GD with a pathological femoral neck fracture in a 54-year-old woman who did not undergo surgery because of haematological problems including thrombocytopaenia.

    Fractures of the femoral neck
    SYMPTOMS

 are rare and usually result from

    serious and high-energy trauma in the skeleton
    SYMPTOMS

 in

    young adults
    AGE

.

    Gaucher's disease (GD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 that has progressive course and is rarely seen. Research has shown that a

    pathological femoral neck fracture
    SYMPTOMS

 with

    GD
    DIAGNOSIS

 mostly emerges in

    childhood
    AGE

. But in

    adults
    AGE

, there are no reports of

    pathological femoral neck fractures
    SYMPTOMS

 with

    GD
    DIAGNOSIS

. We present a unique case of

    GD
    DIAGNOSIS

 with a

    pathological femoral neck fracture
    SYMPTOMS

 in a

    54-year-old
    AGE

    woman
    GENDER

 who

    did not undergo surgery because of haematological problems
    NEG_FINDINGS

 including

    thrombocytopaenia
    BIOCHEMICAL

.

Gaucher's disease (GD)
lysosomal storage disorder
GD
GD
GD


[Neuropathic Gaucher disease treated with long enzyme replacement therapy. Two clinical cases].

Gaucher disease (GD) is the most common of all inherited lipid storage diseases. It is an autosomal recessive disorder portraying catabolism and cerebroside deposit in the lysosomes, which is due to a lack of glucocerebrosidase enzyme. Though GD shows a panethnic pattern of presentation, it particularly affects the Ashkenazi Jewish population. Several mutations have been defined among GD patients, and some genotypes related to neurologic affection have been described (L444P--most common mutation for neuropathic GD--188S, V394L and G377S). Lipid material storage or deposit exerts multiorganic affection. Enzyme replacement therapy (ERT) has demonstrable efficacy in reversing organic damage related to GD, though its capability to stop neurologic affection is currently under controversy and particular research. This paper portrays two GD cases of Mexican children treated with ERT at general zone hospitals of the Instituto Mexicano del Seguro Social in recent years, both of them depicting characteristic type 3 GD mutations, and comparing their clinical evolution with and without neurological features.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most common of all

    inherited lipid storage diseases
    GENETICS

. It is an

    autosomal recessive disorder
    GENETICS

 portraying

    catabolism and cerebroside deposit in the lysosomes
    MICROSCOPIC

, which is due to a

    lack of glucocerebrosidase enzyme
    BIOCHEMICAL

. Though

    GD
    DIAGNOSIS

 shows a panethnic pattern of presentation, it particularly affects the

    Ashkenazi Jewish
    ETHNICITY

 population. Several mutations have been defined among

    GD
    DIAGNOSIS

 patients, and some genotypes related to

    neurologic affection
    SYMPTOMS

 have been described (

    L444P--most common mutation for neuropathic GD--188S, V394L and G377S)
    GENETICS

.

    Lipid material storage or deposit
    MICROSCOPIC

 exerts

    multiorganic affection
    SYMPTOMS

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 has demonstrable efficacy in

    reversing organic damage related to GD
    SYMPTOMS

, though its capability to

    stop neurologic affection
    SYMPTOMS

 is currently under controversy and particular research. This paper portrays two

    GD
    DIAGNOSIS

 cases of

    Mexican
    ETHNICITY

    children
    AGE

 treated with

    ERT
    MEDICATION

 at

    general zone hospitals
    MEDICATION

 of the

    Instituto Mexicano del Seguro
    DIAGNOSIS

 Social in recent years, both of them depicting characteristic

    type 3 GD mutations
    GENETICS

, and comparing their clinical evolution with and without

    neurological features
    SYMPTOMS

.

Gaucher disease (GD)
GD
GD
GD
Instituto Mexicano del Seguro

neurologic affection
multiorganic affection
reversing organic damage related to GD
stop neurologic affection
neurological features

Enzyme replacement therapy (ERT)
ERT
general zone hospitals


An unusual presentation of Gaucher disease in an infant with progressive dyspnea.

The most common lysosomal storage disorder, Gaucher disease, represents a collection of 3 clinical syndromes associated with disrupted glucocerebroside catabolism. Despite the common occurrence of dyspnea in advanced Gaucher, dyspnea is rarely reported as a presenting symptom of the disease.

A 10-month-old male was referred to the Otolaryngology Clinic for evaluation of progressive dyspnea. Physical examination was significant for cervical adenopathy, inspiratory stridor, and developmental delay. A complete evaluation for failure to thrive and lymphadenopathy was performed, with subsequent lymph node biopsy and enzyme assay confirming the presence of Gaucher disease.

A high level of suspicion is required to make an early diagnosis of Gaucher disease, but it should be considered in patients presenting with failure to thrive, generalized lymphadenopathy, and respiratory or neurologic findings. Initiation of early treatment is paramount for the prevention of irreversible disease.

The most common

    lysosomal storage disorder
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

, represents a collection of 3 clinical syndromes associated with

    disrupted glucocerebroside catabolism
    BIOCHEMICAL

. Despite the common occurrence of

    dyspnea
    SYMPTOMS

 in

    advanced Gaucher
    DIAGNOSIS

,

    dyspnea
    SYMPTOMS

 is rarely reported as a presenting symptom of the disease.

A

    10-month-old
    AGE

    male
    GENDER

 was referred to the

    Otolaryngology
    PARACLINICAL

 Clinic for evaluation of

    progressive dyspnea
    SYMPTOMS

.

    Physical examination
    PARACLINICAL

 was significant for

    cervical adenopathy
    SYMPTOMS

,

    inspiratory stridor
    SYMPTOMS

, and

    developmental delay
    SYMPTOMS

. A complete evaluation for

    failure to thrive
    SYMPTOMS

 and

    lymphadenopathy
    SYMPTOMS

 was performed, with subsequent

    lymph node biopsy
    PARACLINICAL

 and

    enzyme assay
    PARACLINICAL

 confirming the presence of

    Gaucher disease
    DIAGNOSIS

.

A high level of suspicion is required to make an early diagnosis of

    Gaucher disease
    DIAGNOSIS

, but it should be considered in patients presenting with

    failure to thrive
    SYMPTOMS

,

    generalized lymphadenopathy
    SYMPTOMS

, and

    respiratory or neurologic findings
    SYMPTOMS

. Initiation of

    early treatment
    MEDICATION

 is paramount for the prevention of

    irreversible disease
    SYMPTOMS

.

lysosomal storage disorder
Gaucher disease
advanced Gaucher
Gaucher disease
Gaucher disease

dyspnea
dyspnea
progressive dyspnea
cervical adenopathy
inspiratory stridor
developmental delay
failure to thrive
lymphadenopathy
failure to thrive
generalized lymphadenopathy
respiratory or neurologic findings
irreversible disease


Non-specific symptomatogy presenting in a patient with Gaucher's disease creating a challenging diagnosis: a case report.

Gaucher's disease is the most common of the lysosomal storage diseases; however, with a current worldwide incidence of 1/75,000, it is still a rare occurrence. We present a case of Gaucher's disease type 1 in a Hispanic patient, the first incidence of this specific subtype of Gaucher's disease to be reported in Puerto Rico. Due to the patient's uncharacteristic presentation of negative initial bone marrow biopsy followed by the findings of Gaucher cells on splenic tissue examination, we investigate the specificity and sensitivity of various diagnostic methods to the disease as evidenced in the current literature. Physician awareness of an effective diagnostic approach as illustrated by this report is critical for the early diagnosis of Gaucher's disease so as to prevent disease progression and increased patient morbidity.

    Gaucher's disease
    DIAGNOSIS

 is the most common of the

    lysosomal storage diseases
    DIAGNOSIS

; however, with a current worldwide incidence of 1/75,000, it is still a rare occurrence. We present a case of

    Gaucher's disease type 1
    DIAGNOSIS

 in a

    Hispanic
    ETHNICITY

 patient, the first incidence of this specific

    subtype of Gaucher's disease
    DIAGNOSIS

 to be reported in

    Puerto Rico
    ETHNICITY

. Due to the patient's uncharacteristic presentation of

    negative initial bone marrow biopsy
    NEG_FINDINGS

 followed by the findings of

    Gaucher cells on splenic tissue examination
    MICROSCOPIC

, we investigate the specificity and sensitivity of various diagnostic methods to the disease as evidenced in the current literature. Physician awareness of an effective diagnostic approach as illustrated by this report is critical for the early diagnosis of

    Gaucher's disease
    DIAGNOSIS

 so as to prevent disease progression and increased patient morbidity.

Gaucher's disease
lysosomal storage diseases
Gaucher's disease type 1
subtype of Gaucher's disease
Gaucher's disease


A case of Gaucher's disease progressing to liver cirrhosis.

We are going to present a 17 year old female with Gaucher's disease. The patient presented with fever, cough, respiratory distress & abdominal heaviness. There was mild pallor, redness of palm of hands & raised temperature. Liver was hugely enlarged along with splenomegaly. X-ray chest showed non specific bronchiectatic change in both lungs. Ultrasonography of abdomen revealed marked hepatosplenomegaly with no ascites. Bone marrow examination showed cellular marrow with plenty of megakaryocytes. Most of the cells were smear cells & there was histiocytes proliferation & infiltration of bone marrow by small atypical cells. Histologically, lipid was found in hepatocytes in moderate amount. The portal areas showed high lipid contents in macrophages. Different clinical findings & incidental diagnosis of lipid storage disease submerged us in diagnostic dilemma. We give conservative treatment with antibiotic cefuroxime, syrup lactulose & vitamins and this patient was improved.

We are going to present a

    17 year old
    AGE

    female
    GENDER

 with

    Gaucher's disease
    DIAGNOSIS

. The patient presented with

    fever
    SYMPTOMS

,

    cough
    SYMPTOMS

,

    respiratory distress
    SYMPTOMS

 &

    abdominal heaviness
    SYMPTOMS

. There was

    mild pallor
    SYMPTOMS

,

    redness of palm of hands
    SYMPTOMS

 &

    raised temperature
    SYMPTOMS

.

    Liver was hugely enlarged
    SYMPTOMS

 along with

    splenomegaly
    SYMPTOMS

.

    X-ray chest
    PARACLINICAL

 showed

    non specific bronchiectatic change in both lungs
    SYMPTOMS

.

    Ultrasonography of abdomen
    PARACLINICAL

 revealed

    marked hepatosplenomegaly
    SYMPTOMS

 with

    no ascites
    NEG_FINDINGS

.

    Bone marrow examination
    PARACLINICAL

 showed

    cellular marrow with plenty of megakaryocytes
    MICROSCOPIC

.

    Most of the cells were smear cells
    MICROSCOPIC

 & there was

    histiocytes proliferation
    MICROSCOPIC

 &

    infiltration of bone marrow by small atypical cells
    MICROSCOPIC

. Histologically,

    lipid was found in hepatocytes in moderate amount
    MICROSCOPIC

. The

    portal areas showed high lipid contents in macrophages
    MICROSCOPIC

. Different clinical findings & incidental diagnosis of

    lipid storage disease
    DIAGNOSIS

 submerged us in diagnostic dilemma. We give

    conservative treatment with antibiotic cefuroxime, syrup lactulose & vitamins
    MEDICATION

 and this patient was improved.


Corneal manifestations and in vivo confocal microscopy of Gaucher disease.

To report corneal abnormalities and confocal microscopy findings in a patient with a variant of Gaucher disease (GD).

Case report with slit-lamp photography, confocal microscopy, and molecular analysis of the glucocerebrosidase gene.

Ophthalmic evaluation in a 57-year-old white patient demonstrated corneal opacities scattered throughout the cornea. Confocal microscopy revealed a completely distorted stromal architecture. The anterior part showed keratocytes with an abnormal morphology intermingled with minute white dots. In the posterior part, normal keratocytes were virtually absent and replaced by hyperreflective rod-like structures. Analysis of the glucocerebrosidase gene disclosed a heterozygous F216Y/L444P mutation. The patient's old records revealed that these corneal abnormalities were already present at the age of 16 years, almost 15 years before the diagnosis of GD was made. His 2 siblings known with the same disorder and mutations also showed abnormal visual acuity and increased central corneal thickness. The confocal microscopy demonstrated some subclinical abnormalities, but otherwise normal corneas.

Our patient had an unusual mutation responsible for his GD. Although corneal opacities are virtually unknown in GD, except in the D409H homozygous cardiovascular subtype, this patient had marked corneal stromal abnormalities.

To report

    corneal abnormalities
    SYMPTOMS

 and

    confocal microscopy findings
    PARACLINICAL

 in a patient with a

    variant of Gaucher disease (GD)
    DIAGNOSIS

.

Case report with

    slit-lamp photography
    PARACLINICAL

,

    confocal microscopy
    PARACLINICAL

, and

    molecular analysis of the glucocerebrosidase gene
    PARACLINICAL

.

    Ophthalmic evaluation
    PARACLINICAL

 in a

    57-year-old
    AGE

    white
    ETHNICITY

 patient demonstrated

    corneal opacities scattered throughout the cornea
    SYMPTOMS

.

    Confocal microscopy
    PARACLINICAL

 revealed a

    completely distorted stromal architecture
    SYMPTOMS

. The

    anterior part showed keratocytes with an abnormal morphology intermingled with minute white dots
    MICROSCOPIC

.

    In the posterior part, normal keratocytes were virtually absent and replaced by hyperreflective rod-like structures
    MICROSCOPIC

.

    Analysis of the glucocerebrosidase gene
    PARACLINICAL

 disclosed a

    heterozygous F216Y/L444P mutation
    GENETICS

. The patient's old records revealed that these

    corneal abnormalities
    SYMPTOMS

 were already present at the

    age of 16 years
    AGE

, almost 15 years before the diagnosis of

    GD
    DIAGNOSIS

 was made.

    His 2 siblings known with the same disorder and mutations
    FAMILY

 also showed

    abnormal visual acuity
    SYMPTOMS

 and

    increased central corneal thickness
    SYMPTOMS

. The

    confocal microscopy
    PARACLINICAL

 demonstrated some

    subclinical abnormalities
    SYMPTOMS

, but

    otherwise normal corneas
    NEG_FINDINGS

.

Our patient had an

    unusual mutation responsible for his GD
    GENETICS

. Although

    corneal opacities
    SYMPTOMS

 are virtually unknown in

    GD
    DIAGNOSIS

, except in the

    D409H homozygous cardiovascular subtype
    GENETICS

, this patient had

    marked corneal stromal abnormalities
    SYMPTOMS

.

heterozygous F216Y/L444P mutation
unusual mutation responsible for his GD
D409H homozygous cardiovascular subtype


Malignancies and monoclonal gammopathy in Gaucher disease; a systematic review of the literature.

Gaucher disease is an autosomal, recessively inherited, lysosomal storage disease, which has been associated with gammopathies and malignancies. This report represents the results of a systematic review of the literature on the prevalence of monoclonal gammopathies and malignancies in Gaucher disease. A PubMed search identified 365 studies, of which 80 reported on concomitant Gaucher disease and malignancies and/or gammopathies (15 cohort/cross sectional studies, and 65 case reports/series). Based on these studies, we conclude that compared to the general population, Gaucher patients have an increased risk of cancer in general [pooled relative risk of 1·70 (95% confidence interval 1·27-2·31)], and multiple myeloma and haematological malignancies in particular (estimated risk between 25·0 and 51·1 and 3·5 and 12·7, respectively). In addition, an increased risk has been reported for hepatocellular carcinoma and renal cell carcinoma. Several factors have been hypothesized to play a role in the pathophysiology. These include: splenectomy, immune dysregulation, endoplasmic reticulum stress, genetic modifiers, altered iron metabolism and insulin resistance.

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal, recessively inherited
    GENETICS

,

    lysosomal storage disease
    DIAGNOSIS

, which has been associated with

    gammopathies
    DIAGNOSIS

 and

    malignancies
    DIAGNOSIS

. This report represents the results of a systematic review of the literature on the prevalence of

    monoclonal gammopathies
    DIAGNOSIS

 and

    malignancies
    DIAGNOSIS

 in

    Gaucher disease
    DIAGNOSIS

. A PubMed search identified 365 studies, of which 80 reported on

    concomitant Gaucher disease and malignancies and/or gammopathies
    DIAGNOSIS

 (15 cohort/cross sectional studies, and 65 case reports/series). Based on these studies, we conclude that compared to the general population,

    Gaucher
    DIAGNOSIS

 patients have an increased risk of

    cancer
    DIAGNOSIS

 in general [pooled relative risk of 1·70 (95% confidence interval 1·27-2·31)], and

    multiple myeloma
    DIAGNOSIS

 and

    haematological malignancies
    DIAGNOSIS

 in particular (estimated risk between 25·0 and 51·1 and 3·5 and 12·7, respectively). In addition, an increased risk has been reported for

    hepatocellular carcinoma
    DIAGNOSIS

 and

    renal cell carcinoma
    DIAGNOSIS

. Several factors have been hypothesized to play a role in the pathophysiology. These include:

    splenectomy
    MEDICATION

,

    immune dysregulation
    SYMPTOMS

,

    endoplasmic reticulum stress
    SYMPTOMS

,

    genetic modifiers
    GENETICS

,

    altered iron metabolism
    SYMPTOMS

 and

    insulin resistance
    SYMPTOMS

.

autosomal, recessively inherited
genetic modifiers

immune dysregulation
endoplasmic reticulum stress
altered iron metabolism
insulin resistance


[Pregnancy in Gaucher disease].

Gaucher disease is a lysosomal storage disorder due to deficiency of glucocerebrosidase. The association with pregnancy exposes the worsening of the disease and complications of pregnancy and puerperium. We report a case of pregnancy in a woman of 35 years, suffering from Gaucher disease type 1. Pregnancy had a favorable outcome. Complications occurred. They were kept under control. The outcome was favorable. The authors discuss the evolution of the disease during pregnancy and management of complications. They can occur during pregnancy, post-partum and breastfeeding. Support begins with preconception consultation. It involves finding and correcting the biological problems and deficiencies, and management of complications. Genetic counseling is important, it helps prevent inbreeding.

    Gaucher disease
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 due to

    deficiency of glucocerebrosidase
    BIOCHEMICAL

. The association with

    pregnancy
    DIAGNOSIS

 exposes the worsening of the disease and

    complications of pregnancy
    SYMPTOMS

 and

    puerperium
    SYMPTOMS

. We report a case of

    pregnancy
    DIAGNOSIS

 in a

    woman
    GENDER

 of

    35 years
    AGE

, suffering from

    Gaucher disease type 1
    DIAGNOSIS

.

    Pregnancy
    SYMPTOMS

 had a favorable outcome.

    Complications
    SYMPTOMS

 occurred. They were kept under control. The outcome was favorable. The authors discuss the evolution of the disease during

    pregnancy
    DIAGNOSIS

 and management of complications. They can occur during

    pregnancy
    AGE

,

    post-partum
    AGE

 and

    breastfeeding
    MEDICATION

. Support begins with

    preconception consultation
    MEDICATION

. It involves finding and correcting the biological problems and deficiencies, and management of complications.

    Genetic counseling
    MEDICATION

 is important, it helps prevent

    inbreeding
    SYMPTOMS

.

Gaucher disease
lysosomal storage disorder
pregnancy
pregnancy
Gaucher disease type 1
pregnancy

complications of pregnancy
puerperium
Pregnancy
Complications
inbreeding

breastfeeding
preconception consultation
Genetic counseling


Enzyme Replacement Therapy in a Patient with Gaucher Disease Type III: A Paradigmatic Case Showing Severe Adverse Reactions Started a Long Time After the Beginning of Treatment.

There are three recombinant enzymes available for the treatment of Gaucher disease (GD): imiglucerase, velaglucerase alfa, and taliglucerase alfa.

A male GD type III patient, 14 years old, genotype p.L444P/L444, diagnosed at 2 years old. He had been treated with imiglucerase for 9 years since the diagnosis. In 2008, however, he presented a severe adverse reaction to imiglucerase, characterized by cough, laryngeal stridor, and periorbital edema. The infusions were suspended for 3 months when imiglucerase was restarted with premedication and a slower infusion rate. After 5 months, he presented a new adverse reaction with vomiting, tachypnea, cough, and periorbital edema. Intradermal testing confirmed IgE-mediated reaction but serological tests were negative. After 2 years and 10 months with no specific treatment and a significant worsening of the clinical picture, taliglucerase alfa was prescribed, with premedication and a slower infusion rate. At the first infusion, he presented moderate adverse reaction and the infusions were suspended. After 2 months, velaglucerase alfa was initiated uneventfully. He maintains day-hospital infusions without premedication and shows improvement of clinical and laboratory parameters.

This is the first report of the use of velaglucerase alfa in patients with GD type III. The use of recombinant enzymes is safe for the majority of GD patients, but severe reactions may occur even many years after the beginning of the treatment. Premedication and slower infusion rate reduce the incidence of adverse reactions but may not solve the problem. This case report further demonstrates the different safety profile among all the recombinant enzymes available for the treatment of GD.

There are three

    recombinant enzymes
    MEDICATION

 available for the treatment of Gaucher disease (GD):

    imiglucerase, velaglucerase alfa
    MEDICATION

, and

    taliglucerase alfa
    MEDICATION

.

A

    male
    GENDER

    GD type III
    DIAGNOSIS

 patient,

    14 years old
    AGE

,

    genotype p.L444P/L444
    GENETICS

, diagnosed at

    2 years old
    AGE

.

    He
    GENDER

 had been

    treated with imiglucerase for 9 years
    MEDICATION

 since the diagnosis. In 2008, however,

    he
    GENDER

 presented a

    severe adverse reaction to imiglucerase
    SYMPTOMS

, characterized by

    cough
    SYMPTOMS

,

    laryngeal stridor
    SYMPTOMS

, and

    periorbital edema
    SYMPTOMS

. The

    infusions were suspended for 3 months
    MEDICATION

 when

    imiglucerase was restarted with premedication and a slower infusion rate
    MEDICATION

. After 5 months,

    he
    GENDER

 presented a

    new adverse reaction
    SYMPTOMS

 with

    vomiting
    SYMPTOMS

,

    tachypnea
    SYMPTOMS

,

    cough
    SYMPTOMS

, and

    periorbital edema
    SYMPTOMS

.

    Intradermal testing
    PARACLINICAL

 confirmed

    IgE-mediated reaction
    BIOCHEMICAL

 but

    serological tests were negative
    NEG_FINDINGS

. After

    2 years and 10 months
    MEDICATION

 with

    no specific treatment
    NEG_FINDINGS

 and a

    significant worsening of the clinical picture
    SYMPTOMS

,

    taliglucerase alfa was prescribed, with premedication and a slower infusion rate
    MEDICATION

. At the first infusion, he presented

    moderate adverse reaction
    SYMPTOMS

 and the

    infusions were suspended
    MEDICATION

. After 2 months,

    velaglucerase alfa was initiated uneventfully
    MEDICATION

. He

    maintains day-hospital infusions
    MEDICATION

    without premedication
    NEG_FINDINGS

 and shows

    improvement of clinical and laboratory parameters
    SYMPTOMS

.

This is the first report of the use of

    velaglucerase alfa
    MEDICATION

 in patients with

    GD type III
    DIAGNOSIS

. The use of

    recombinant enzymes
    MEDICATION

 is safe for the majority of

    GD
    DIAGNOSIS

 patients, but

    severe reactions
    SYMPTOMS

 may occur even many years after the beginning of the treatment.

    Premedication
    MEDICATION

 and

    slower infusion rate
    MEDICATION

 reduce the incidence of

    adverse reactions
    SYMPTOMS

 but may not solve the problem. This case report further demonstrates the different safety profile among all the

    recombinant enzymes
    MEDICATION

 available for the treatment of

    GD
    DIAGNOSIS

.

serological tests were negative
no specific treatment
without premedication


Jaws features in Type 1 Gaucher disease.

Our aims were to present 2 new cases of Gaucher disease involving the jaws and to review the literature.

Two new cases and the literature from 1982-2011 were reviewed.

Ten articles describing 35 cases (for a total of 37 with 2 new cases presented) were analyzed. The mandible and maxilla were affected in 97.3% and 24.3% of the reported cases, respectively. Generalized rarefaction of bone (osteopenia) was present in 83.8%, and well-defined radiolucent lesions in 40.5%. The effects on the surrounding structures included loss of cortication of the mandibular canal (56.7%), cortical bone thinning (27%), expansion, root resorption (24.3%), mandibular canal displacement (18.9%), cortical perforation, maxillary sinus obliteration, and tooth displacement (10.8%).

Two distinct bone abnormalities with separate pathophysiologies, radiographic presentation, and effects on the surrounding structures are suggested: 1) generalized mandibular/maxillary osteopenia and 2) a well-defined radiolucent lesion, which appears only in the mandible. This review refutes 2 accepted assumptions; according to the results, 1) the most common manifestation is generalized osteopenia (and the resulting mandibular canal changes), whereas the well-defined radiolucent lesion is the next most common, and 2) cortical bone thinning/perforations and lamina dura thinning are not uncommon in these patients.

Our aims were to present 2 new cases of

    Gaucher disease involving the jaws
    DIAGNOSIS

 and to review the literature.

Ten articles describing 35 cases (for a total of 37 with 2 new cases presented) were analyzed. The mandible and maxilla were affected in 97.3% and 24.3% of the reported cases, respectively.

    Generalized rarefaction of bone (osteopenia)
    SYMPTOMS

 was present in 83.8%, and

    well-defined radiolucent lesions
    SYMPTOMS

 in 40.5%. The

    effects on the surrounding structures
    SYMPTOMS

 included

    loss of cortication of the mandibular canal
    SYMPTOMS

 (56.7%),

    cortical bone thinning
    SYMPTOMS

 (27%),

    expansion, root resorption
    SYMPTOMS

 (24.3%),

    mandibular canal displacement
    SYMPTOMS

 (18.9%),

    cortical perforation
    SYMPTOMS

,

    maxillary sinus obliteration
    SYMPTOMS

, and

    tooth displacement
    SYMPTOMS

 (10.8%).

Two distinct

    bone abnormalities
    SYMPTOMS

 with separate pathophysiologies, radiographic presentation, and

    effects on the surrounding structures
    SYMPTOMS

 are suggested: 1)

    generalized mandibular/maxillary osteopenia
    SYMPTOMS

 and 2) a

    well-defined radiolucent lesion, which appears only in the mandible
    SYMPTOMS

. This review refutes 2 accepted assumptions; according to the results, 1) the most common manifestation is

    generalized osteopenia (and the resulting mandibular canal changes
    SYMPTOMS

), whereas the

    well-defined radiolucent lesion
    SYMPTOMS

 is the next most common, and 2)

    cortical bone thinning/perforations
    SYMPTOMS

 and

    lamina dura thinning
    SYMPTOMS

 are not uncommon in these patients.


Minimal intervention dentistry: part 4. Detection and diagnosis of initial caries lesions.

The detection of carious lesions is focused on the identification of early mineral changes to allow the demineralisation process to be managed by non-invasive interventions. The methods recommended for clinical diagnosis of initial carious lesions are discussed and illustrated. These include the early detection of lesions, evaluation of the extent of the lesion and its state of activity and the establishment of appropriate monitoring. The place of modern tools, including those based on fluorescence, is discussed. These can help inform patients. They are also potentially useful in regular control visits to monitor the progression or regression of early lesions. A rigorous and systematic approach to caries diagnosis is essential to establish a care plan for the disease and to identify preventive measures based on more precise diagnosis and to reduce reliance on restorative measures.

The detection of

    carious lesions
    SYMPTOMS

 is focused on the identification of

    early mineral changes
    SYMPTOMS

 to allow the

    demineralisation
    SYMPTOMS

 process to be managed by

    non-invasive interventions
    MEDICATION

. The methods recommended for clinical diagnosis of

    initial carious lesions
    SYMPTOMS

 are discussed and illustrated. These include the early detection of lesions, evaluation of the extent of the lesion and its state of activity and the establishment of appropriate monitoring. The place of modern tools, including those based on

    fluorescence
    PARACLINICAL

, is discussed. These can help inform patients. They are also potentially useful in regular control visits to monitor the progression or regression of

    early lesions
    SYMPTOMS

. A rigorous and systematic approach to caries diagnosis is essential to establish a care plan for the disease and to identify preventive measures based on more precise diagnosis and to

    reduce reliance on restorative measures
    NEG_FINDINGS

.

carious lesions
early mineral changes
demineralisation
initial carious lesions
early lesions


Idiopathic avascular necrosis of the femoral heads in five members of a Moroccan family.

Avascular necrosis (AVN) is idiopathic in about 40% of cases. The pathophysiology of avascular necrosis remains incompletely elucidated. Here, we report a case that underlines the role for inherited factors in AVN of the femoral heads. Idiopathic AVN of the femoral heads occurred in five members of the same family (a woman, her two paternal aunts, her male paternal cousin and her female paternal cousin) at a mean age of 42.4 years (range, 33-58 years). Standard pelvic radiographs showed Arlet and Ficat stage 4 AVN in three patients and stage 3 in two patients. None of the patients had a history of glucocorticoid therapy, alcohol abuse, or trauma. All five patients underwent investigations for a cause, including blood cell counts, a lipid profile, coagulation tests, testing for antinuclear antibodies, hemoglobin electrophoresis, ultrasonography of the abdomen, and standard radiographs of the long limb bones. The results were normal or negative, ruling out known hereditary causes of AVN such as sickle cell anemia and Gaucher disease. Many cases of familial AVN of the femoral head have been described in patients with sickle cell anemia or Gaucher disease. However, only five families with idiopathic familial AVN of the femoral heads have been reported (three in the US and two in Taiwan). All the patients in these families had isolated bilateral AVN of the femoral heads without AVN at other sites.

    Avascular necrosis (AVN)
    DIAGNOSIS

 is

    idiopathic
    DIAGNOSIS

 in about 40% of cases. The pathophysiology of

    avascular necrosis
    DIAGNOSIS

 remains incompletely elucidated. Here, we report a case that underlines the role for

    inherited factors
    GENETICS

 in

    AVN of the femoral heads
    DIAGNOSIS

.

    Idiopathic AVN of the femoral heads
    DIAGNOSIS

 occurred in

    five members of the same family (a woman
    FAMILY

    , her two paternal aunts, her male paternal cousin and her female paternal cousin)
    FAMILY

 at a

    mean age of 42.4 years (range, 33-58 years)
    AGE

.

    Standard pelvic radiographs
    PARACLINICAL

 showed

    Arlet and Ficat stage 4 AVN
    DIAGNOSIS

 in three patients and

    stage 3
    DIAGNOSIS

 in two patients.

    None
    NEG_FINDINGS

 of the patients

    had a history of glucocorticoid therapy, alcohol abuse
    NEG_FINDINGS

,

    or trauma
    NEG_FINDINGS

. All five patients underwent investigations for a cause, including

    blood cell counts, a lipid profile
    PARACLINICAL

,

    coagulation tests
    PARACLINICAL

,

    testing for antinuclear antibodies
    PARACLINICAL

,

    hemoglobin electrophoresis
    PARACLINICAL

,

    ultrasonography of the abdomen
    PARACLINICAL

, and

    standard radiographs of the long limb bones
    PARACLINICAL

.

    The results were normal or negative
    NEG_FINDINGS

,

    ruling out known hereditary causes of AVN such as sickle cell anemia and Gaucher disease
    NEG_FINDINGS

. Many cases of

    familial AVN of the femoral head
    DIAGNOSIS

 have been described in patients with

    sickle cell anemia
    DIAGNOSIS

 or

    Gaucher disease
    DIAGNOSIS

. However, only five families with

    idiopathic familial AVN of the femoral heads
    DIAGNOSIS

 have been reported (three in the US and two in

    Taiwan
    ETHNICITY

). All the patients in these families had

    isolated bilateral AVN of the femoral heads
    SYMPTOMS

    without AVN at other sites
    NEG_FINDINGS

.


Recent trends in human Brucella canis infection.

There is little information in the literature regarding the clinical progress of brucellosis in patients affected by other diseases. We report Brucella canis human infection link to Gaucher's disease and Guillain Barré syndrome and discuss complications observed in a case with infective endocarditis. The three cases described came from areas of socio-economic deprivation and scarce epidemiological information where the healthcare personnel did not even consider such diagnosis. The growth of large urban populations deprived from basic services has created a new set of global health challenges. Changes in the urban environment due to slum communities' expansion have resulted in increased dog populations in the peridomiciliary environment. Eleven laboratory employees working with the strains found and their identification were examined. Sanitary authorities should focus on the zoonotic aspect of B. canis considering the dramatic increase of canine roamers near urban centers.

There is little information in the literature regarding the clinical progress of

    brucellosis
    DIAGNOSIS

 in patients affected by other diseases. We report

    Brucella canis human infection
    DIAGNOSIS

 link to

    Gaucher's disease
    DIAGNOSIS

 and

    Guillain Barré syndrome
    DIAGNOSIS

 and discuss complications observed in a case with

    infective endocarditis
    DIAGNOSIS

. The three cases described came from areas of

    socio-economic deprivation
    SYMPTOMS

 and scarce epidemiological information where the healthcare personnel did not even consider such diagnosis. The growth of large urban populations deprived from basic services has created a new set of global health challenges. Changes in the urban environment due to slum communities' expansion have resulted in increased dog populations in the

    peridomiciliary
    MICROSCOPIC

 environment.

    Eleven laboratory employees
    PARACLINICAL

 working with the strains found and their identification were examined. Sanitary authorities should focus on the zoonotic aspect of

    B. canis
    DIAGNOSIS

 considering the dramatic increase of canine roamers near urban centers.

brucellosis
Brucella canis human infection
Gaucher's disease
Guillain Barré syndrome
infective endocarditis
B. canis


Successful desensitization to imiglucerase of an adult patient diagnosed with type I Gaucher disease.

Gaucher disease is the most common lysosomal storage disorder, and enzyme replacement therapy, such as administration of imiglucerase, is the standard therapy. Anaphylaxis to imiglucerase is rarely reported. Here, we report a 26-year-old female who was diagnosed with type 1 Gaucher disease and referred to our Allergy Outpatient Clinic because of an anaphylactic reaction due to imiglucerase enzyme therapy. A desensitization protocol was administered with two different dilutions with an increasing rate of administration delivered in 10 consecutive steps by intravenous infusion in an intensive care setting. No reactions occurred during the procedure, and the total final dose of 2,000 U was successfully administered. To our knowledge, this is the first adult case with successful desensitization to imiglucerase. Desensitization protocols to drugs in chronic disease patients for whom no alternative therapies are available can be lifesaving.

    Gaucher disease
    DIAGNOSIS

 is the most common

    lysosomal storage disorder
    DIAGNOSIS

, and

    enzyme replacement therapy, such as administration of imiglucerase
    MEDICATION

, is the standard therapy.

    Anaphylaxis to imiglucerase
    NEG_FINDINGS

 is rarely reported. Here, we report a

    26-year-old
    AGE

    female
    GENDER

 who was diagnosed with

    type 1 Gaucher disease
    DIAGNOSIS

 and referred to our Allergy Outpatient Clinic because of an

    anaphylactic reaction
    SYMPTOMS

 due to

    imiglucerase enzyme therapy
    MEDICATION

. A

    desensitization protocol
    MEDICATION

 was administered with two different dilutions with an increasing rate of administration delivered in 10 consecutive steps

    by intravenous infusion in an intensive care setting
    MEDICATION

.

    No reactions occurred during the procedure
    NEG_FINDINGS

, and

    the total final dose of 2,000 U was successfully administered
    MEDICATION

. To our knowledge, this is the first

    adult
    AGE

 case with

    successful desensitization to imiglucerase
    MEDICATION

.

    Desensitization protocols to drugs
    MEDICATION

 in

    chronic disease
    DIAGNOSIS

 patients for whom

    no alternative therapies
    NEG_FINDINGS

 are available can be lifesaving.

Gaucher disease
lysosomal storage disorder
type 1 Gaucher disease
chronic disease


Fast protocol for the diagnosis of lysosomal diseases in nonimmune hydrops fetalis.

Nonimmune hydrops fetalis (NIHF) is defined by the excessive fluid accumulation in more than one foetal compartments and body cavities because of nonimmune reasons. It has been described that 14 lysosomal diseases may be causative of NIHF. The aim of this study was to design a fast protocol to investigate the most frequent lysosomal diseases that are reported that may cause NIHF.

We analysed the glycosaminoglycans excretion in the amniotic fluid supernatant and four different lysosomal enzymatic activities in the amniotic cultured cells of the different NIHF amniotic fluids we received.

We investigated 30 NIHF cases, using this fast protocol. We detected two cases of NIHF because of lysosomal diseases, which represent 6.6%. We diagnosed one case of mucopolysaccharidosis type VII and one case of Gaucher disease.

The fast protocol we designed analyses seven of the most frequent lysosomal pathologies that have been described that may cause NIHF, with only five different determinations, which make the analysis of NIHF fast, cost-effective and without need of too much amniotic fluid. We believe this protocol may be useful for the analysis of lysosomal diseases in NIHF.

    Nonimmune hydrops fetalis (NIHF)
    DIAGNOSIS

 is defined by the

    excessive fluid accumulation in more than one foetal compartments and body cavities
    MICROSCOPIC

 because of

    nonimmune reasons
    NEG_FINDINGS

. It has been described that 14

    lysosomal diseases
    DIAGNOSIS

 may be causative of

    NIHF
    DIAGNOSIS

. The aim of this study was to design a fast protocol to investigate the most frequent

    lysosomal diseases
    DIAGNOSIS

 that are reported that may cause

    NIHF
    DIAGNOSIS

.

We

    analysed the glycosaminoglycans excretion in the amniotic fluid supernatant
    BIOCHEMICAL

 and

    four different lysosomal enzymatic activities in the amniotic cultured cells of the different NIHF amniotic fluids
    MICROSCOPIC

 we received.

We investigated 30

    NIHF
    DIAGNOSIS

 cases, using this fast protocol. We detected two cases of

    NIHF
    DIAGNOSIS

 because of

    lysosomal diseases
    DIAGNOSIS

, which represent 6.6%. We diagnosed one case of

    mucopolysaccharidosis type VII
    DIAGNOSIS

 and one case of

    Gaucher disease
    DIAGNOSIS

.

The fast protocol we designed analyses seven of the most frequent

    lysosomal pathologies
    DIAGNOSIS

 that have been described that may cause

    NIHF
    DIAGNOSIS

, with only five different determinations, which make the

    analysis of NIHF
    PARACLINICAL

 fast, cost-effective and

    without need of too much amniotic fluid
    NEG_FINDINGS

. We believe this protocol may be useful for the analysis of

    lysosomal diseases
    DIAGNOSIS

 in

    NIHF
    DIAGNOSIS

.

Nonimmune hydrops fetalis (NIHF)
lysosomal diseases
NIHF
lysosomal diseases
NIHF
NIHF
NIHF
lysosomal diseases
mucopolysaccharidosis type VII
Gaucher disease
lysosomal pathologies
NIHF
lysosomal diseases
NIHF

nonimmune reasons
without need of too much amniotic fluid


Simultaneous detection of Gaucher's disease and renal involvement of non-Hodgkin's lymphoma: the first Asian case report and a review of literature.

Gaucher's disease (GD) is a rare autosomal recessive (AR) disorder characterized by a deficiency of glucocerebrosidase (glucosylceramidase, acid β-glucosidase). This enzyme deficiency results in an accumulation of sphingolipids in the cells of GD patients, which may contribute to the dysregulation of the immune system, B-cell dysfunction and expression of specific cytokines such as interleukin (IL) -1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF). Accumulated substrate may directly affect the patient's immunity and pose a higher risk for cancer, especially hematologic malignancies. However, recent large-scale studies suggest that the relative risks of GD and hematologic malignancies are not statistically significant and, therefore, their association with each other remains controversial. In this report, we present the first Asian GD case where the patient was simultaneously diagnosed with a non-Hodgkin's lymphoma. A renal biopsy confirmed that the patient had diffuse large B-cell lymphoma (DLBCL). A bone marrow study during lymphoma staging revealed Gaucher cells with abundant fibrillary, blue-gray cytoplasm and a wrinkled, tissue paper-like appearance. Subsequently, an acid β-glucosidase (GbA) gene mutation study demonstrating two heterozygote mutations, G202R (c.721G>A; p.G241R), a known pathogenic mutation, and a novel mutation R277C (c.946C>T; p.R316C) prompted the diagnosis of GD. Previous case reports have demonstrated concurrent GD and lymphoma in type 1 GD patients, with 40% of patients diagnosed with GD when a lymphoma is detected during disease evaluation. In Korea, GD cases with the G202R gene mutation have been reported in neuropathic patients with a very low frequency. To our knowledge, this case represents the first observation of the G202R mutation in a type 1 GD patient associated with lymphoma. Furthermore, this report is the first patient with DLBCL with kidney involvement along with GD.

    Gaucher's disease (GD)
    DIAGNOSIS

 is a

    rare autosomal recessive (AR) disorder
    GENETICS

 characterized by a

    deficiency of glucocerebrosidase (glucosylceramidase, acid β-glucosidase)
    BIOCHEMICAL

. This

    enzyme deficiency
    BIOCHEMICAL

 results in an

    accumulation of sphingolipids in the cells of GD
    MICROSCOPIC

 patients, which may contribute to the

    dysregulation of the immune system
    BIOCHEMICAL

,

    B-cell dysfunction
    BIOCHEMICAL

 and

    expression of specific cytokines such as interleukin (IL) -1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)
    BIOCHEMICAL

.

    Accumulated substrate
    MICROSCOPIC

 may directly affect the patient's immunity and pose a higher risk for

    cancer
    DIAGNOSIS

, especially

    hematologic malignancies
    DIAGNOSIS

. However, recent large-scale studies suggest that the relative risks of

    GD
    DIAGNOSIS

 and

    hematologic malignancies
    DIAGNOSIS

 are not statistically significant and, therefore, their association with each other remains controversial. In this report, we present the first

    Asian
    ETHNICITY

    GD
    DIAGNOSIS

 case where the patient was simultaneously diagnosed with a

    non-Hodgkin's lymphoma
    DIAGNOSIS

. A

    renal biopsy
    PARACLINICAL

 confirmed that the patient had

    diffuse large B-cell lymphoma (DLBCL)
    DIAGNOSIS

. A

    bone marrow study
    PARACLINICAL

 during

    lymphoma staging
    PARACLINICAL

 revealed

    Gaucher cells with abundant fibrillary, blue-gray cytoplasm and a wrinkled, tissue paper-like appearance
    MICROSCOPIC

. Subsequently, an

    acid β-glucosidase (GbA) gene mutation study
    PARACLINICAL

 demonstrating

    two heterozygote mutations, G202R (c.721G>A; p.G241R), a known pathogenic mutation, and a novel mutation R277C (c.946C>T; p.R316C)
    GENETICS

 prompted the diagnosis of

    GD
    DIAGNOSIS

. Previous case reports have demonstrated

    concurrent GD and lymphoma
    DIAGNOSIS

 in

    type 1 GD
    DIAGNOSIS

 patients, with 40% of patients diagnosed with

    GD
    DIAGNOSIS

 when a

    lymphoma
    DIAGNOSIS

 is detected during disease evaluation. In

    Korea
    ETHNICITY

,

    GD
    DIAGNOSIS

 cases with the

    G202R gene mutation
    GENETICS

 have been reported in

    neuropathic
    DIAGNOSIS

 patients with a very low frequency. To our knowledge, this case represents the first observation of the

    G202R mutation
    GENETICS

 in a

    type 1 GD patient associated with lymphoma
    DIAGNOSIS

. Furthermore, this report is the first patient with

    DLBCL
    DIAGNOSIS

 with

    kidney involvement
    SYMPTOMS

 along with

    GD
    DIAGNOSIS

.


Analysis of the pre-retinal opacities in Gaucher Disease using spectral domain optical coherent tomography.

Fundal opacities have been reported in patients with Gaucher disease, a rare autosomal recessive lysosomal storage disease, prior to the advent of optical coherent tomography. This report provides a detailed analysis of the fundal opacities in a 14-year-old girl with genetically proven Gaucher disease using spectral domain optical coherent tomography. It illustrates clearly that these opacities were pre-retinal opacities located at the vitreo-retinal interface associated with localized posterior vitreous detachments, rather than vitreous opacities as previously suggested in the literature.

    Fundal opacities
    SYMPTOMS

 have been reported in patients with

    Gaucher disease
    DIAGNOSIS

, a

    rare autosomal recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

, prior to the advent of

    optical coherent tomography
    PARACLINICAL

. This report provides a detailed analysis of the

    fundal opacities
    SYMPTOMS

 in a

    14-year-old
    AGE

    girl
    GENDER

 with genetically proven

    Gaucher disease
    DIAGNOSIS

 using

    spectral domain optical coherent tomography
    PARACLINICAL

. It illustrates clearly that these

    opacities
    SYMPTOMS

 were

    pre-retinal opacities located at the vitreo-retinal interface associated with localized posterior vitreous detachments
    SYMPTOMS

, rather than

    vitreous opacities
    SYMPTOMS

 as previously suggested in the literature.

Gaucher disease
lysosomal storage disease
Gaucher disease


Tracheal involvement in ulcerative colitis: clinical presentation and potential interest of 2-deoxy-2[¹⁸F]fluoro-D-glucose positron emission tomography (¹⁸F-FDG PET) for the management.

Ulcerative colitis (UC) is an inflammatory bowel disease that can on rare occasions affect the respiratory tract. We report the case of a 32-year-old woman suffering from UC, for whom 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography ((18)F-FDG PET) was useful, both for diagnosis and management of tracheal involvement. She presented with severe cough and fever, and bronchoscopy revealed inflammation of the trachea. Infection, vasculitis and relapsing chondritis were first ruled out. Lymphoma was then suspected, and (18)F-FDG PET was performed, but revealed only a moderately increased uptake on the posterior wall of the trachea. Histological findings revealed non-specific inflammation. Systemic corticosteroids were prescribed and symptoms improved rapidly. After 3 months, bronchoscopy showed a significant reduction of the local inflammation, and (18)F-FDG PET did not reveal the previous abnormal tracheal (18)F-FDG uptake. Management of tracheal involvement of UC requires close monitoring. However, repeated bronchoscopies can be harmful in these inflammatory situations, and non-invasive techniques could be useful. (18)F-FDG PET is used for the follow-up of digestive involvement of UC, but extra-intestinal locations have not been evaluated. Our case highlights the potential interest of (18)F-FDG PET for tracheal involvement of UC, allowing a non-invasive assessment of local inflammation.

    Ulcerative colitis (UC)
    DIAGNOSIS

 is an

    inflammatory bowel disease
    DIAGNOSIS

 that can on rare occasions

    affect the respiratory tract
    SYMPTOMS

. We report the case of a

    32-year-old
    AGE

    woman
    GENDER

 suffering from

    UC
    DIAGNOSIS

, for whom

    2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography ((18)F-FDG PET)
    PARACLINICAL

 was useful, both for diagnosis and management of

    tracheal involvement
    SYMPTOMS

.

    She
    GENDER

 presented with

    severe cough
    SYMPTOMS

 and

    fever
    SYMPTOMS

, and

    bronchoscopy
    PARACLINICAL

 revealed

    inflammation of the trachea
    SYMPTOMS

.

    Infection, vasculitis and relapsing chondritis were first ruled out
    NEG_FINDINGS

.

    Lymphoma
    NEG_FINDINGS

 was then suspected, and

    (18)F-FDG PET
    PARACLINICAL

 was performed, but revealed

    only a moderately increased uptake on the posterior wall of the trachea
    SYMPTOMS

.

    Histological findings
    PARACLINICAL

 revealed

    non-specific inflammation
    NEG_FINDINGS

.

    Systemic corticosteroids
    MEDICATION

 were prescribed and

    symptoms improved
    SYMPTOMS

 rapidly. After 3 months,

    bronchoscopy
    PARACLINICAL

 showed a

    significant reduction of the local inflammation
    SYMPTOMS

, and

    (18)F-FDG PET
    PARACLINICAL

    did not reveal the previous abnormal tracheal (18)F-FDG uptake
    NEG_FINDINGS

. Management of

    tracheal involvement
    SYMPTOMS

    of UC
    DIAGNOSIS

 requires close monitoring. However,

    repeated bronchoscopies
    PARACLINICAL

 can be harmful in these inflammatory situations, and non-invasive techniques could be useful.

    (18)F-FDG PET
    PARACLINICAL

 is used for the

    follow-up
    PARACLINICAL

 of

    digestive involvement
    SYMPTOMS

    of UC
    DIAGNOSIS

, but extra-intestinal locations have not been evaluated. Our case highlights the potential interest of

    (18)F-FDG PET
    PARACLINICAL

 for

    tracheal involvement
    SYMPTOMS

    of UC
    DIAGNOSIS

, allowing a

    non-invasive assessment of local inflammation
    PARACLINICAL

.

Ulcerative colitis (UC)
inflammatory bowel disease
UC
of UC
of UC
of UC


Gaucher's disease: rare presentation of a rare disease.

Gaucher's disease is a rare lysosymal storage disorder characterized by deposition of glucocerebroside in cells of the macrophage monocyte system. Gaucher's disease has 3 types-non-neuronopathic (type I), acute neuronopathic (type II), and chronic neuronopathic (type III). It generally presents with delayed milestones, seizures, bony deformities, or massive organomegaly. The acute neuronoapthic variety is the rarer type that predominantly presents with neurological features. The authors present a case of the acute neuronopathic variety of Gaucher's disease where the child presented with only abnormal head position.

    Gaucher's disease
    DIAGNOSIS

 is a

    rare lysosymal storage disorder
    DIAGNOSIS

 characterized by

    deposition of glucocerebroside in cells of the macrophage monocyte system
    MICROSCOPIC

.

    Gaucher's disease
    DIAGNOSIS

 has 3 types-

    non-neuronopathic (type I)
    DIAGNOSIS

,

    acute neuronopathic (type II)
    DIAGNOSIS

, and

    chronic neuronopathic (type III)
    DIAGNOSIS

. It generally presents with

    delayed milestones
    SYMPTOMS

,

    seizures
    SYMPTOMS

,

    bony deformities
    SYMPTOMS

, or

    massive organomegaly
    SYMPTOMS

. The

    acute neuronoapthic variety
    DIAGNOSIS

 is the rarer type that predominantly presents with

    neurological features
    SYMPTOMS

. The authors present a case of the

    acute neuronopathic variety of Gaucher's disease
    DIAGNOSIS

 where the

    child
    AGE

 presented with

    only abnormal head position
    SYMPTOMS

.

delayed milestones
seizures
bony deformities
massive organomegaly
neurological features
only abnormal head position


Abundant hepatic Gaucher-like cells following chemotherapy and bone marrow transplantation for hematologic malignancy: report of two cases.

Cells with a resemblance to Gaucher cells, sometimes called pseudo-Gaucher cells, are seen in the bone marrow of some patients with hematologic malignancy or anemia. These cells are derived from cells of the monocytic lineage but do not show the characteristic inclusions of true Gaucher cells when examined by electron microscopy. Large numbers of Gaucher-like cells were found in the livers at autopsy of 2 patients with hematologic malignancy treated with chemotherapy and bone marrow transplant. Knowledge of this phenomenon may be useful in the interpretation of liver biopsy done on a patient with bone marrow transplant.

    Cells with a resemblance to Gaucher cells
    MICROSCOPIC

, sometimes called

    pseudo-Gaucher cells
    MICROSCOPIC

, are seen

    in the bone marrow
    MICROSCOPIC

 of some patients with

    hematologic malignancy
    DIAGNOSIS

 or

    anemia
    DIAGNOSIS

. These cells are derived from

    cells of the monocytic lineage
    MICROSCOPIC

 but

    do not show the characteristic inclusions of true Gaucher cells
    NEG_FINDINGS

 when examined by

    electron microscopy
    PARACLINICAL

.

    Large numbers of Gaucher-like cells
    MICROSCOPIC

 were

    found in the livers
    MICROSCOPIC

 at

    autopsy
    PARACLINICAL

 of 2 patients with

    hematologic malignancy
    DIAGNOSIS

 treated with

    chemotherapy and bone marrow transplant
    MEDICATION

. Knowledge of this phenomenon may be useful in the interpretation of

    liver biopsy
    PARACLINICAL

 done on a patient with

    bone marrow transplant
    MEDICATION

.

hematologic malignancy
anemia
hematologic malignancy

chemotherapy and bone marrow transplant
bone marrow transplant


Novel frameshift mutation (Pro171fsX21) in neonatal type 2 Gaucher's disease.

Gaucher's disease is caused by a deficiency of glucocerebrosidase (GBA) and results in the accumulation of glucocerebroside within macrophages. We report on a 33(+2) gestational week premature infant whose family history was significant for a previously undiagnosed premature sibling with similar clinical features, including severe hydrops fetalis, hepatosplenomegaly, skin lesions at birth followed by death. The diagnosis of Gaucher's disease type 2 in the present case was based on postmortem pathological findings and a subsequent gene analysis that indicated a heterozygous condition for the novel deletion mutation at GBA cDNA nucleotide position 630 resulting in the frameshift (Pro171fsX21) in exon 6 and a G→A transition mutation at GBA cDNA nucleotide position 887 (Arg257Gln) in exon 7.

    Gaucher's disease
    DIAGNOSIS

 is caused by a

    deficiency of glucocerebrosidase (GBA)
    BIOCHEMICAL

 and results in the

    accumulation of glucocerebroside within macrophages
    MICROSCOPIC

. We report on a

    33(+2) gestational week premature infant
    AGE

 whose

    family history was significant for a previously undiagnosed premature sibling with similar clinical features
    FAMILY

, including

    severe hydrops fetalis
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

,

    skin lesions at birth
    SYMPTOMS

 followed by

    death
    SYMPTOMS

. The diagnosis of

    Gaucher's disease type 2
    DIAGNOSIS

 in the present case was based on

    postmortem pathological findings
    PARACLINICAL

 and a subsequent

    gene analysis
    PARACLINICAL

 that indicated a

    heterozygous condition for the novel deletion mutation at GBA cDNA nucleotide position 630 resulting in the frameshift (Pro171fsX21) in exon 6 and a G→A transition mutation at GBA cDNA nucleotide position 887 (Arg257Gln) in exon 7.
    GENETICS

Gaucher's disease
Gaucher's disease type 2

severe hydrops fetalis
hepatosplenomegaly
skin lesions at birth
death


A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders.

Gaucher disease (GD) is an autosomal recessive storage disorder that most commonly results from the inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent. Here, we report two cases of type 2 GD resulting from the inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation. Germline mutations or mosiacism are not generally associated with autosomal recessive disorders. The probands from the two unrelated families had the same maternal mutation, leu444pro, that we propose resulted from a de novo maternal germline mutation occurring at this known 'hotspot' for mutation. This first report of a germline mutation for a common point mutation leu444pro (c.1448 T>C;p.leu483pro) in GD has significant implications for molecular diagnostics and genetic counseling in recessive disorders.

    Gaucher disease (GD)
    DIAGNOSIS

 is an

    autosomal recessive storage disorder
    DIAGNOSIS

 that most commonly results from the

    inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent
    GENETICS

. Here, we report two cases of

    type 2 GD
    DIAGNOSIS

 resulting from the

    inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation
    GENETICS

.

    Germline mutations
    GENETICS

 or

    mosiacism
    GENETICS

 are not generally associated with

    autosomal recessive disorders
    GENETICS

. The

    probands from the two unrelated families had the same maternal mutation, leu444pro, that
    FAMILY

 we propose resulted from

    a de novo maternal germline mutation occurring at this known 'hotspot' for mutation
    GENETICS

. This first report of a

    germline mutation for a common point mutation leu444pro (c.1448 T>C;p.leu483pro)
    GENETICS

 in

    GD
    DIAGNOSIS

 has significant implications for

    molecular diagnostics
    PARACLINICAL

 and

    genetic counseling
    MEDICATION

 in

    recessive disorders
    DIAGNOSIS

.

Gaucher disease (GD)
autosomal recessive storage disorder
type 2 GD
GD
recessive disorders


Gaucher disease: successful treatment of myoclonic status epilepticus with levetiracetam.

We present the first reported case of a rapid clinical and electroencephalographic response to intravenous levetiracetam infusion of myoclonic status epilepticus in a patient with progressive myoclonus epilepsy due to Gaucher disease. Under continuous video-EEG monitoring, the clinical myoclonic status and the electrographic ictal discharges resolved within 10 minutes after the infusion was initiated. The patient tolerated the treatment well without any reported side effects. This case suggests that levetiracetam may be a safe, effective, and well tolerated intravenous drug in patients with metabolic myoclonic status epilepticus such as Gaucher disease.

We present the first reported case of a

    rapid clinical and electroencephalographic response
    SYMPTOMS

 to

    intravenous levetiracetam infusion
    MEDICATION

 of

    myoclonic status epilepticus
    DIAGNOSIS

 in a patient with

    progressive myoclonus epilepsy
    DIAGNOSIS

 due to

    Gaucher disease
    DIAGNOSIS

. Under

    continuous video-EEG monitoring
    PARACLINICAL

, the

    clinical myoclonic status
    SYMPTOMS

 and the

    electrographic ictal discharges resolved
    SYMPTOMS

 within 10 minutes after the infusion was initiated. The patient tolerated the treatment well

    without any reported side effects
    NEG_FINDINGS

. This case suggests that

    levetiracetam
    MEDICATION

 may be a safe, effective, and well tolerated

    intravenous drug
    MEDICATION

 in patients with

    metabolic myoclonic status epilepticus
    DIAGNOSIS

 such as

    Gaucher disease
    DIAGNOSIS

.

intravenous levetiracetam infusion
levetiracetam
intravenous drug

myoclonic status epilepticus
progressive myoclonus epilepsy
Gaucher disease
metabolic myoclonic status epilepticus
Gaucher disease


Unexpected cure from cutaneous leukocytoclastic vasculitis in a patient treated with N-butyldeoxynojirimycin (miglustat) for Gaucher disease.

Cutaneous leukocytoclastic vasculitis (CLV) is a necrotizing inflammation of the small vessels in the dermis. We report the case of a Swedish man with an untreated N370S/L444P Gaucher disease who developed CLV at the age of 79 years. The patient has been treated for CLV with topical and oral corticosteroids, moisturizing agents, and periodically with antibiotics for 3 years without improvement. Administration of miglustat (N-butyldeoxynojirimycin; Zavesca®) because of progress of Gaucher disease resulted in a prompt and durable cure of the CLV.

    Cutaneous leukocytoclastic vasculitis (CLV)
    DIAGNOSIS

 is a

    necrotizing inflammation of the small vessels in the dermis
    MICROSCOPIC

. We report the case of a

    Swedish
    ETHNICITY

    man
    GENDER

 with an

    untreated N370S/L444P Gaucher disease
    GENETICS

 who developed

    CLV
    DIAGNOSIS

 at the

    age of 79 years
    AGE

. The patient has been treated for

    CLV
    DIAGNOSIS

 with

    topical and oral corticosteroids, moisturizing agents, and periodically with antibiotics for 3 years
    MEDICATION

    without improvement
    NEG_FINDINGS

.

    Administration of miglustat (N-butyldeoxynojirimycin; Zavesca®)
    MEDICATION

 because of progress of

    Gaucher disease
    DIAGNOSIS

 resulted in a prompt and

    durable cure of the CLV
    SYMPTOMS

.


Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.

Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

    Gaucher disease (GD)
    DIAGNOSIS

, an

    inherited macrophage glycosphingolipidosis
    GENETICS

, manifests with an extraordinary variety of phenotypes that show imperfect correlation with

    mutations in the GBA gene
    GENETICS

. In addition to the classic manifestations, patients suffer from increased susceptibility to

    hematologic and nonhematologic malignancies
    DIAGNOSIS

. The mechanism(s) underlying

    malignancy
    DIAGNOSIS

 in

    GD
    DIAGNOSIS

 is not known, but is postulated to be secondary to

    macrophage dysfunction
    MICROSCOPIC

 and

    immune dysregulation
    SYMPTOMS

 arising from

    lysosomal accumulation of glucocerebroside
    MICROSCOPIC

. However, there is weak correlation between

    GD/cancer
    DIAGNOSIS

 phenotype and the

    systemic burden of glucocerebroside-laden macrophages
    MICROSCOPIC

. Therefore, we hypothesized that

    genetic modifier(s)
    GENETICS

 may underlie the

    GD/cancer
    DIAGNOSIS

 phenotype. In the present study, the genetic basis of

    GD/T-cell acute lymphoblastic lymphoma
    DIAGNOSIS

 in 2 affected siblings was deciphered through

    genomic analysis
    PARACLINICAL

.

    GBA gene sequencing
    PARACLINICAL

 revealed homozygosity for a novel mutation, D137N.

    Whole-exome capture and massively parallel sequencing combined with homozygosity mapping
    PARACLINICAL

 identified a

    homozygous novel mutation in the MSH6 gene
    GENETICS

 that leads to

    constitutional mismatch repair deficiency syndrome
    GENETICS

 and

    increased cancer risk
    SYMPTOMS

.

    Enzyme studies
    PARACLINICAL

 demonstrated that the

    D137N mutation in GBA is a pathogenic mutation
    GENETICS

, and

    immunohistochemistry
    PARACLINICAL

 confirmed the

    absence of the MSH6 protein
    BIOCHEMICAL

. Therefore, precise phenotype annotation followed by

    individual genome analysis
    PARACLINICAL

 has the potential to identify genetic modifiers of

    GD
    DIAGNOSIS

, facilitate personalized management, and provide novel insights into disease pathophysiology.

immune dysregulation
increased cancer risk


Pulmonary involvement in siblings with Gaucher disease type III.

Pulmonary involvement has been described in all types of Gaucher disease (GD) but it is considered as relatively rare manifestation. There are reports suggesting that homozygosity for L444P mutation in GBA gene is associated with a substantial risk for developing primary pulmonary disease in GD.

We reported sisters with pulmonary involvement in GD type III. Respiratory failure with fatal outcome at 3 years and 4 months of age occurred in K.K. due to pulmonary complications of GD. At the time enzyme replacement therapy (ERT) was not available in Serbia. J.K., homozygous for L444P mutation, developed asymptomatic pulmonary involvement at the age of 6 after 2.5 years of ERT. Pulmonary disease in J.K. was verified by high resolution computerized tomography, cytology of bronchoalveolar lavage fluid and histopathology of transbronchial lung biopsy.

Primary lung disease in children homoallelic for L444P mutation in GBA gene emerges as a significant clinical manifestation of GD with unclear response to ERT.

    Pulmonary involvement
    SYMPTOMS

 has been described in all types of

    Gaucher disease (GD)
    DIAGNOSIS

 but it is considered as relatively rare manifestation. There are reports suggesting that

    homozygosity for L444P mutation in GBA gene
    GENETICS

 is associated with a substantial risk for developing

    primary pulmonary disease
    DIAGNOSIS

 in

    GD
    DIAGNOSIS

.

We reported

    sisters with pulmonary involvement
    FAMILY

 in

    GD type III
    DIAGNOSIS

.

    Respiratory failure
    SYMPTOMS

 with

    fatal outcome
    SYMPTOMS

    at 3 years and 4 months of age
    AGE

 occurred in K.K. due to

    pulmonary complications
    SYMPTOMS

 of

    GD
    DIAGNOSIS

. At the time

    enzyme replacement therapy (ERT) was not available
    NEG_FINDINGS

 in

    Serbia
    ETHNICITY

. J.K.,

    homozygous for L444P mutation
    GENETICS

, developed

    asymptomatic pulmonary involvement
    SYMPTOMS

 at the

    age of 6
    AGE

 after

    2.5 years of ERT
    MEDICATION

.

    Pulmonary disease
    DIAGNOSIS

 in J.K. was verified by

    high resolution computerized tomography
    PARACLINICAL

,

    cytology of bronchoalveolar lavage fluid
    PARACLINICAL

 and

    histopathology of transbronchial lung biopsy
    PARACLINICAL

.

    Primary lung disease
    DIAGNOSIS

 in

    children
    AGE

    homoallelic for L444P mutation in GBA gene
    GENETICS

 emerges as a significant clinical manifestation of

    GD
    DIAGNOSIS

 with

    unclear response to ERT
    NEG_FINDINGS

.

Pulmonary involvement
Respiratory failure
fatal outcome
pulmonary complications
asymptomatic pulmonary involvement

Gaucher disease (GD)
primary pulmonary disease
GD
GD type III
GD
Pulmonary disease
Primary lung disease
GD


[Enzyme replacement therapy for Gaucher disease introduced in late adulthood].

Gaucher disease is the most prevalent lysosomal storage disorder caused by recessive mutation of the beta-glucocerebrosidase gene, which leads to massive lysosomal accumulation of glucocerebrosids especially in macrophages of bone marrow, liver and spleen. The most common presenting signs and symptoms are hepatosplenomegaly, bone pain, pathologic fractures, fatigue, bleeding tendency and recurrent infections. Regular enzyme replacement therapy which is available since 1992 in Hungary successfully reverses the symptoms of the disorder, including hematological abnormalities, bone infiltration and hepatosplenomegaly. Authors present here two cases diagnosed in late adulthood to emphasize the importance of early diagnosis and treatment.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    recessive mutation of the beta-glucocerebrosidase gene
    GENETICS

, which leads to

    massive lysosomal accumulation of glucocerebrosids especially in macrophages of bone marrow, liver and spleen
    MICROSCOPIC

. The most common presenting signs and symptoms are

    hepatosplenomegaly
    SYMPTOMS

,

    bone pain
    SYMPTOMS

,

    pathologic fractures
    SYMPTOMS

,

    fatigue
    SYMPTOMS

,

    bleeding tendency
    SYMPTOMS

 and

    recurrent infections
    SYMPTOMS

.

    Regular enzyme replacement therapy
    MEDICATION

 which is available since 1992 in

    Hungary
    ETHNICITY

 successfully reverses the symptoms of the disorder, including

    hematological abnormalities
    BIOCHEMICAL

,

    bone infiltration
    MICROSCOPIC

 and

    hepatosplenomegaly
    SYMPTOMS

. Authors present here two cases diagnosed in

    late adulthood
    AGE

 to emphasize the importance of early diagnosis and treatment.

Gaucher disease
lysosomal storage disorder

hepatosplenomegaly
bone pain
pathologic fractures
fatigue
bleeding tendency
recurrent infections
hepatosplenomegaly


[Hepatopulmonary syndrome: a complication of type 1 Gaucher disease].

Gaucher's disease is a not exceptional lysosomial disease in Tunisia. Type 1 is by far the most common one. Pulmonary involvement is considered to be rare in type 1 Gaucher's disease. Pulmonary hypertension, infiltration of the lungs with Gaucher cells, and severe hypoxemia due to intrapulmonary arterial-venous shunts, have been described in case reports and small case series. We reported the case of hepatopulmonary syndrome in a 14-year-old boy with type 1 Gaucher disease. The diagnosis of Gaucher disease was established, at 2 years age, by enzyme assay of leucocyte β-glucosidase. The patient presented dyspnoea, digital clubbing and cyanosis of the lips. The arterial blood gas found severe hypoxaemia with PaO(2) at 56.9 mmHg. The diagnosis of hepatopulmonary syndrome, in our patient, was confirmed by demonstration of the intrapulmonary shunting using contrast-enhanced echocardiography and the technetium-99m-labeled macroaggregated albumin. The patient was treated by symptomatic measure, long term oxygen therapy because the insufficiency of the enzyme replacement therapy. Screening for hypoxemia in children with liver disease should be considered.

    Gaucher's disease
    DIAGNOSIS

 is a not exceptional

    lysosomial disease
    DIAGNOSIS

 in

    Tunisia
    ETHNICITY

.

    Type 1
    DIAGNOSIS

 is by far the most common one.

    Pulmonary involvement
    SYMPTOMS

 is considered to be rare in

    type 1 Gaucher's disease
    DIAGNOSIS

.

    Pulmonary hypertension
    SYMPTOMS

,

    infiltration of the lungs with Gaucher cells
    MICROSCOPIC

, and

    severe hypoxemia
    SYMPTOMS

 due to

    intrapulmonary arterial-venous shunts
    SYMPTOMS

, have been described in case reports and small case series. We reported the case of

    hepatopulmonary syndrome
    DIAGNOSIS

 in a

    14-year-old
    AGE

    boy
    GENDER

 with

    type 1 Gaucher disease
    DIAGNOSIS

. The diagnosis of

    Gaucher disease
    DIAGNOSIS

 was established,

    at 2 years age
    AGE

, by

    enzyme assay of leucocyte β-glucosidase
    PARACLINICAL

. The patient presented

    dyspnoea
    SYMPTOMS

,

    digital clubbing
    SYMPTOMS

 and

    cyanosis of the lips
    SYMPTOMS

. The

    arterial blood gas
    PARACLINICAL

 found

    severe hypoxaemia
    BIOCHEMICAL

 with

    PaO(2) at 56.9 mmHg
    BIOCHEMICAL

. The diagnosis of

    hepatopulmonary syndrome
    DIAGNOSIS

, in our patient, was confirmed by demonstration of the

    intrapulmonary shunting
    SYMPTOMS

 using

    contrast-enhanced echocardiography
    PARACLINICAL

 and the

    technetium-99m-labeled macroaggregated albumin
    PARACLINICAL

. The patient was treated by

    symptomatic measure
    MEDICATION

,

    long term oxygen therapy
    MEDICATION

 because the insufficiency of the

    enzyme replacement therapy
    MEDICATION

. Screening for

    hypoxemia
    DIAGNOSIS

 in

    children
    AGE

 with

    liver disease
    DIAGNOSIS

 should be considered.

Gaucher's disease
lysosomial disease
Type 1
type 1 Gaucher's disease
hepatopulmonary syndrome
type 1 Gaucher disease
Gaucher disease
hepatopulmonary syndrome
hypoxemia
liver disease

Pulmonary involvement
Pulmonary hypertension
severe hypoxemia
intrapulmonary arterial-venous shunts
dyspnoea
digital clubbing
cyanosis of the lips
intrapulmonary shunting

symptomatic measure
long term oxygen therapy
enzyme replacement therapy