Mild thrombocytopenia as presenting symptom of type 1 Gauchers's disease.

A young woman was examined for a mild thrombocytopenia which was present for some months. No signs of bleeding had so far occurred. Physical examination was normal except for a moderately enlarged spleen. Laboratory investigations showed a low platelet count. There was no evidence of an autoimmune or hematologic disease. Bone narrow aspirate indicated Gaucher's-like cells raising the suspicion of Gaucher's disease. This was further supported by electron microscopic demonstration of Gaucher's bodies in crista biopsy specimens. However, the definitive diagnosis was obtained by verifying deficient lysosomal glucosylceramide-beta-D-glucosidase activity in peripheral blood leukocytes. Upon the absence of neurologic involvement the patient was typical for the adult-onset or type 1 form of Gaucher's disease.

A

    young
    AGE

    woman
    GENDER

 was examined for a

    mild thrombocytopenia
    BIOCHEMICAL

 which was present for some months.

    No signs of bleeding had so far occurred
    NEG_FINDINGS

.

    Physical examination was normal
    NEG_FINDINGS

 except for a

    moderately enlarged spleen
    SYMPTOMS

.

    Laboratory investigations
    PARACLINICAL

 showed a

    low platelet count
    BIOCHEMICAL

. There was

    no evidence of an autoimmune or hematologic disease
    NEG_FINDINGS

.

    Bone narrow aspirate
    PARACLINICAL

 indicated

    Gaucher's-like cells
    MICROSCOPIC

 raising the suspicion of

    Gaucher's disease
    DIAGNOSIS

. This was further supported by

    electron microscopic demonstration of Gaucher's bodies in crista biopsy specimens
    PARACLINICAL

. However, the definitive diagnosis was obtained by verifying

    deficient lysosomal glucosylceramide-beta-D-glucosidase activity in peripheral blood leukocytes
    BIOCHEMICAL

. Upon the

    absence of neurologic involvement
    NEG_FINDINGS

 the patient was typical for the

    adult-onset or type 1 form of Gaucher's disease
    DIAGNOSIS

.


Severe valvular and aortic arch calcification in a patient with Gaucher's disease homozygous for the D409H mutation.

Gaucher's disease is an autosomal recessive inherited defect of the lysosomal enzyme glucocerebrosidase, which leads to glucocerebroside accumulation in the reticuloendothelial system. Homozygosity for the D409H mutation has been associated with cardiovascular valvular disease. We present a case of a 17-year-old Palestinian patient who presented with severe aortic and mitral valvular calcification, as well as calcification of the ascending aorta, the aortic arch and the ostia of his coronary arteries. The patient was confirmed to be homozygous for the D409H mutation in the glucocerebrosidase gene. The patient's enzyme assay for glucocerebrosidase activity was 5 nm/h/mg protein (normal 13-22 nm/h/mg). The patient presented with symptoms of dyspnea and chest pain. He had a 6-year history of documented aortic valve calcification by echocardiogram after two of his older brothers died of congestive heart failure and severe valvular calcification. Cardiac catheterization showed a severely calcified aorta with almost no motion of the aortic valve leaflets and severe calcification of the mitral valve and the mitral valvular apparatus. The patient underwent extensive cardiac surgery with aortic and mitral valve replacements and intraoperative findings confirmed calcification of the entire aortic root. Electron microscopy of the valves confirmed the presence of Gaucher's cells. Enzyme therapy with imiglucerase was initiated. The patient is in stable condition, 20 months post-operatively.

    Gaucher's disease
    DIAGNOSIS

 is an

    autosomal recessive inherited
    GENETICS

    defect of the lysosomal enzyme glucocerebrosidase
    BIOCHEMICAL

, which leads to

    glucocerebroside accumulation in the reticuloendothelial system
    MICROSCOPIC

.

    Homozygosity for the D409H mutation
    GENETICS

 has been associated with

    cardiovascular valvular disease
    DIAGNOSIS

. We present a case of a

    17-year-old
    AGE

    Palestinian
    ETHNICITY

 patient who presented with

    severe aortic and mitral valvular calcification
    SYMPTOMS

, as well as

    calcification of the ascending aorta, the aortic arch and the ostia of his coronary arteries
    SYMPTOMS

. The patient was confirmed to be

    homozygous for the D409H mutation in the glucocerebrosidase gene
    GENETICS

. The patient's

    enzyme assay for glucocerebrosidase activity was 5 nm/h/mg protein (normal 13-22 nm/h/mg)
    BIOCHEMICAL

. The patient presented with symptoms of

    dyspnea
    SYMPTOMS

 and

    chest pain
    SYMPTOMS

.

    He
    GENDER

 had a 6-year history of

    documented aortic valve calcification
    SYMPTOMS

 by

    echocardiogram
    PARACLINICAL

    after two of his older brothers died of congestive heart failure
    FAMILY

 and

    severe valvular calcification
    SYMPTOMS

.

    Cardiac catheterization
    PARACLINICAL

 showed a

    severely calcified aorta with almost no motion of the aortic valve leaflets
    SYMPTOMS

 and

    severe calcification of the mitral valve and the mitral valvular apparatus
    SYMPTOMS

. The patient underwent

    extensive cardiac surgery with aortic and mitral valve replacements
    MEDICATION

 and

    intraoperative findings
    PARACLINICAL

 confirmed

    calcification of the entire aortic root
    SYMPTOMS

.

    Electron microscopy of the valves
    PARACLINICAL

 confirmed the

    presence of Gaucher's cells
    MICROSCOPIC

.

    Enzyme therapy with imiglucerase
    MEDICATION

 was initiated. The patient is in stable condition, 20 months post-operatively.

Gaucher's disease
cardiovascular valvular disease


Improvement of splenomegaly and pancytopenia by enzyme replacement therapy against type 1 Gaucher disease: a report of sibling cases.

Gaucher disease is a genetic lipid storage disease and represents a potentially serious health problem. It arises from a deficiency of glucocerebrosidase activity with secondary accumulation of large quantities of glucocerebroside. Symptoms are usually multisystemic, often debilitating or disabling, and sometimes disfiguring, and they can lead to death. We report objective clinical response's to repeated infusion of human placental and recombinant glucocerebrosidase in 2 patients with type 1 Gaucher disease and increased hemoglobin levels and platelet counts. Splenic volume decreased during the period of enzyme administration. Enzyme replacement therapy has improved the treatment of type 1 Gaucher disease by safely and effectively arresting, decreasing, or normalizing many of its major signs and symptoms. Consideration by physicians must be given to Gaucher disease, and appropriate treatments must be given when confronted with cryptogenic pancytopenia or hepatosplenomegaly.

    Gaucher disease
    DIAGNOSIS

 is a

    genetic lipid storage disease
    DIAGNOSIS

 and represents a potentially serious health problem. It arises from a

    deficiency of glucocerebrosidase activity
    BIOCHEMICAL

 with secondary

    accumulation of large quantities of glucocerebroside
    MICROSCOPIC

. Symptoms are usually

    multisystemic
    SYMPTOMS

, often

    debilitating or disabling
    SYMPTOMS

, and sometimes

    disfiguring
    SYMPTOMS

, and they can lead to

    death
    SYMPTOMS

. We report objective clinical response's to

    repeated infusion of human placental and recombinant glucocerebrosidase
    MEDICATION

 in 2 patients with

    type 1 Gaucher disease
    DIAGNOSIS

 and

    increased hemoglobin levels and platelet counts
    BIOCHEMICAL

.

    Splenic volume decreased
    MICROSCOPIC

 during the period of

    enzyme administration
    MEDICATION

.

    Enzyme replacement therapy
    MEDICATION

 has improved the treatment of

    type 1 Gaucher disease
    DIAGNOSIS

 by

    safely and effectively arresting, decreasing, or normalizing many of its major signs and symptoms
    SYMPTOMS

. Consideration by physicians must be given to

    Gaucher disease
    DIAGNOSIS

, and appropriate treatments must be given when confronted with

    cryptogenic pancytopenia
    BIOCHEMICAL

 or

    hepatosplenomegaly
    SYMPTOMS

.

Gaucher disease
genetic lipid storage disease
type 1 Gaucher disease
type 1 Gaucher disease
Gaucher disease


Type II Gaucher disease: compound heterozygote with RecNciI and L444P mutations.

We report the phenotype and genotype of an Indonesian Chinese boy with type II Gaucher disease. He had a unique presentation of recurrent cyanosis from laryngospasm. He was compound heterozygous for L444P/L444P + A456P + V460V. There have been few reports of this heterozygosity and its phenoptype. This genotype-phenotype correlation will be important for physicians in genetic counselling. Type II Gaucher disease in Southeast Asia may not be as rare as was perceived, but may be a condition that is under-reported. The success of our technique together with the results have made it possible for us to perform prenatal diagnosis and carrier detection for the family.

We report the phenotype and genotype of an

    Indonesian
    ETHNICITY

    Chinese
    ETHNICITY

    boy
    GENDER

 with

    type II Gaucher disease
    DIAGNOSIS

.

    He
    GENDER

 had a unique presentation of

    recurrent cyanosis from laryngospasm
    SYMPTOMS

.

    He
    GENDER

 was compound heterozygous for L444P/L444P + A456P + V460V. There have been few reports of this heterozygosity and its phenoptype. This genotype-phenotype correlation will be important for physicians in genetic counselling.

    Type II Gaucher disease
    DIAGNOSIS

 in

    Southeast Asia
    ETHNICITY

 may not be as rare as was perceived, but may be a condition that is under-reported. The success of our technique together with the results have made it possible for us to perform

    prenatal diagnosis
    PARACLINICAL

 and carrier detection for the family.

type II Gaucher disease
Type II Gaucher disease


High-grade lymphoma mimicking bone crisis in Gaucher's disease.

A 33-year-old woman with type 1 Gaucher's disease developed painful swelling of her right tibia. Initial diagnostics suggested a typical bone crisis. However, clinical course and subsequent imaging pointed to malignant disease, which was specified as high-grade lymphoma. Chemotherapy was applied together with enzyme replacement and resulted in complete remission of the lymphoma. We conclude that osseous lesions, although suggestive of common manifestations of Gaucher's disease, should be discriminated very carefully from neoplastic infiltration to maintain curative treatment options.

A

    33-year-old
    AGE

    woman
    GENDER

 with

    type 1 Gaucher's disease
    DIAGNOSIS

 developed

    painful swelling of her right tibia
    SYMPTOMS

. Initial diagnostics suggested a

    typical bone crisis
    NEG_FINDINGS

. However, clinical course and subsequent

    imaging
    PARACLINICAL

 pointed to

    malignant disease
    DIAGNOSIS

, which was specified as

    high-grade lymphoma
    DIAGNOSIS

.

    Chemotherapy
    MEDICATION

 was applied

    together with enzyme replacement
    MEDICATION

 and resulted in

    complete remission of the lymphoma
    SYMPTOMS

. We conclude that

    osseous lesions
    SYMPTOMS

, although suggestive of common manifestations of

    Gaucher's disease
    DIAGNOSIS

, should be discriminated very carefully from

    neoplastic infiltration
    DIAGNOSIS

 to maintain curative treatment options.

type 1 Gaucher's disease
malignant disease
high-grade lymphoma
Gaucher's disease
neoplastic infiltration

painful swelling of her right tibia
complete remission of the lymphoma
osseous lesions

Chemotherapy
together with enzyme replacement


A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation.

A fatal infantile storage disorder with hepatosplenomegaly and severe neurological disease is described. Sphingolipids, including monohexosylceramides (mainly glucosylceramide), dihexosylceramides (mainly lactosylceramide), globotriaosyl ceramide, sulphatides, ceramides and globotetraosyl ceramide, were stored in the tissues. In general, cholesterol and sphingomyelin levels were unaltered. The storage process was generalized and affected a number of cell types, with histiocytes, which infiltrated a number of visceral organs and the brain, especially involved. The ultrastructure of the storage lysosomes was membranous with oligolamellar, mainly vesicular, profiles. Infrequently, there were Gaucher-like lysosomes in histiocytes. The neuropathology was severe and featured neuronal storage and loss with a massive depopulation of cortical neurons and pronounced fibrillary astrocytosis. There was a paucity of myelin and stainable axons in the white matter with signs of active demyelination. Immunohistochemical investigations indicated that saposins A, B, C and D were all deficient. The patient was homozygous for a 1 bp deletion (c.803delG) within the SAP-B domain of the prosaposin gene which leads to a frameshift and premature stop codon. In the heterozygous parents, mutant cDNA was detected by amplification refractory mutation analysis in the nuclear, but not the cytoplasmic, fraction of fibroblast RNA, indicating that the mutant mRNA was rapidly degraded. The storage process in the proband resembled that of a published case from an unrelated family. Saposins were also deficient in this case, leading to its reclassification as prosaposin deficiency, and her mother was found to be a carrier for the same c.803delG mutation. Both of the investigated families came from the same district of eastern Slovakia.

A

    fatal infantile storage disorder
    DIAGNOSIS

 with

    hepatosplenomegaly
    SYMPTOMS

 and

    severe neurological disease
    SYMPTOMS

 is described.

    Sphingolipids, including monohexosylceramides (mainly glucosylceramide), dihexosylceramides (mainly lactosylceramide), globotriaosyl ceramide, sulphatides, ceramides and globotetraosyl ceramide, were stored in the tissues
    MICROSCOPIC

. In general,

    cholesterol and sphingomyelin levels were unaltered
    NEG_FINDINGS

.

    The storage process was generalized and affected a number of cell types, with histiocytes, which infiltrated a number of visceral organs and the brain, especially involved
    MICROSCOPIC

. The

    ultrastructure of the storage lysosomes was membranous with oligolamellar, mainly vesicular, profiles
    MICROSCOPIC

.

    Infrequently, there were Gaucher-like lysosomes in histiocytes
    MICROSCOPIC

. The

    neuropathology
    SYMPTOMS

 was severe and featured

    neuronal storage and loss
    SYMPTOMS

 with a

    massive depopulation of cortical neurons
    SYMPTOMS

 and

    pronounced fibrillary astrocytosis
    MICROSCOPIC

. There was a

    paucity of myelin and stainable axons in the white matter
    MICROSCOPIC

 with

    signs of active demyelination
    SYMPTOMS

.

    Immunohistochemical investigations
    PARACLINICAL

 indicated that

    saposins A, B, C and D were all deficient
    BIOCHEMICAL

. The patient was

    homozygous for a 1 bp deletion (c.803delG) within the SAP-B domain of the prosaposin gene which leads to a frameshift and premature stop codon
    GENETICS

.

    In the heterozygous parents
    FAMILY

,

    mutant cDNA was
    GENETICS

 detected by

    amplification refractory mutation analysis
    PARACLINICAL

    in the nuclear, but not the cytoplasmic, fraction of fibroblast RNA
    MICROSCOPIC

, indicating that

    the mutant mRNA was rapidly degraded
    GENETICS

. The

    storage process
    MICROSCOPIC

 in the proband resembled that of a published case

    from an unrelated family
    FAMILY

.

    Saposins were also deficient
    BIOCHEMICAL

 in this case, leading to its reclassification as

    prosaposin deficiency
    BIOCHEMICAL

, and

    her
    GENDER

    mother was found to be a carrier for the same c.803delG mutation
    FAMILY

.

    Both of the investigated families came from the same
    FAMILY

 district of

    eastern Slovakia
    ETHNICITY

.


[Gaucher's disease with D409H/D409H genotype. evolution with enzyme replacement therapy].

Gaucher's disease is caused by mutations in the gene encoding glucocerebrosidase. The D409H mutation is the third most frequent mutation in Spain and has been associated with a particular phenotype, including oculomotor apraxia and cardiac valvular calcifications in late childhood. We report a 4-year-old patient, homozygous for the D409H mutation, who was diagnosed with Gaucher's disease at the age of 45days. Enzyme replacement therapy was started at the age of 2months. We report the patient's evolution after 4years of treatment.

    Gaucher's disease
    DIAGNOSIS

 is caused by

    mutations in the gene encoding glucocerebrosidase
    GENETICS

. The

    D409H mutation
    GENETICS

 is the third most frequent mutation in

    Spain
    ETHNICITY

 and has been associated with a particular phenotype, including

    oculomotor apraxia
    SYMPTOMS

 and

    cardiac valvular calcifications
    SYMPTOMS

 in

    late childhood
    AGE

. We report a

    4-year-old
    AGE

 patient,

    homozygous for the D409H mutation
    GENETICS

, who was diagnosed with

    Gaucher's disease
    DIAGNOSIS

 at the

    age of 45days
    AGE

.

    Enzyme replacement therapy was started at the age of 2months
    MEDICATION

. We report the patient's evolution after

    4years of treatment
    MEDICATION

.

oculomotor apraxia
cardiac valvular calcifications


Glucocerebrosidase mutations among African-American patients with type 1 Gaucher disease.

While the inherited deficiency of the enzyme glucocerebrosidase (Gaucher disease) is panethnic in its distribution, there have not been studies of the mutations encountered in specific ethnic groups in the United States, other than those on Ashkenazi Jews. We present the clinical descriptions and genotypes of seven patients of African-American ancestry with type 1 Gaucher disease, and summarize the published literature regarding the genotypes encountered in this population. All seven of the patients had moderate-to-severe manifestations of the disease, and all developed symptoms by adolescence. Genotypic analyses revealed that no two probands shared the same genotype. The common mutations N370S, c.84-85insG, IVS2+1 G-->A, and R463C were not seen. Mutation L444P was present on one allele in each of the patients; but the same mutation was encountered as a single point mutation in three of the patients, and as part of a recombinant allele in four of the patients. Southern blot analyses revealed a glucocerebrosidase fusion allele in one patient, and a duplication resulting from recombination in the region downstream from the glucocerebrosidase gene in three of the patients. Five different point mutations (A90T, R48W, N117D, R170C, and V352L), one deletion mutation (c.222-224 delTAC), and one insertion mutation (c.153-154 insTACAGC) were encountered. Our results demonstrate that there is significant genotypic heterogeneity among African-American patients with type 1 Gaucher disease, and that recombinations in the glucocerebrosidase gene locus are particularly common in this patient group. Published 2001 Wiley-Liss, Inc.

While the

    inherited deficiency of the enzyme glucocerebrosidase
    GENETICS

    (Gaucher disease)
    DIAGNOSIS

 is panethnic in its distribution, there have not been studies of the mutations encountered in specific ethnic groups in the United States, other than those on

    Ashkenazi Jews
    ETHNICITY

. We present the clinical descriptions and genotypes of seven patients of

    African-American
    ETHNICITY

 ancestry with

    type 1 Gaucher disease
    DIAGNOSIS

, and summarize the published literature regarding the genotypes encountered in this population. All seven of the patients had

    moderate-to-severe manifestations of the disease
    SYMPTOMS

, and all developed symptoms by

    adolescence
    AGE

.

    Genotypic analyses
    PARACLINICAL

 revealed that

    no two probands shared the same genotype
    FAMILY

. The

    common mutations N370S, c.84-85insG, IVS2+1 G-->A, and R463C
    GENETICS

 were not seen.

    Mutation L444P was present on one allele
    GENETICS

 in each of the patients; but the

    same mutation was encountered as a single point mutation
    GENETICS

 in three of the patients,

    and as part of a recombinant allele
    GENETICS

 in four of the patients.

    Southern blot analyses
    PARACLINICAL

 revealed a

    glucocerebrosidase fusion allele
    GENETICS

 in one patient, and a

    duplication resulting from recombination in the region downstream from the glucocerebrosidase gene
    GENETICS

 in three of the patients.

    Five different point mutations (A90T, R48W, N117D, R170C, and V352L)
    GENETICS

,

    one deletion mutation (c.222-224 delTAC)
    GENETICS

, and one

    insertion mutation (c.153-154 insTACAGC)
    GENETICS

 were encountered. Our results demonstrate that there is significant genotypic heterogeneity among

    African-American
    ETHNICITY

 patients with

    type 1 Gaucher disease
    DIAGNOSIS

, and that

    recombinations in the glucocerebrosidase gene locus
    GENETICS

 are particularly common in this patient group. Published 2001 Wiley-Liss, Inc.

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

Ashkenazi Jews
African-American
African-American


Neurological features in Gaucher's disease during enzyme replacement therapy.

This report describes two patients with Gaucher's disease who had unusual clinical symptoms during enzyme replacement therapy. One patient was a female with type 3 Gaucher's disease. She developed a pericardial effusion at 7 y of age, which contained many Gaucher cells despite enzyme replacement therapy. She died from neurological deterioration during enzyme replacement therapy, despite an improvement in her visceral manifestations. The other patient is a male with type 2 Gaucher's disease, who has achieved long-term survival after being supported by mechanical ventilation and enzyme replacement therapy. While on enzyme replacement therapy at the age of 4 y, he suffered a generalized cutaneous disease which was clinically diagnosed as ichthyosis.

These cases suggest that ordinary enzyme replacement therapy is insufficient for some of the non-neurological manifestations of severe types of Gaucher's disease.

This report describes two patients with

    Gaucher's disease
    DIAGNOSIS

 who had

    unusual clinical symptoms
    SYMPTOMS

 during

    enzyme replacement therapy
    MEDICATION

. One patient was a

    female
    GENDER

 with

    type 3 Gaucher's disease
    DIAGNOSIS

.

    She
    GENDER

 developed a

    pericardial effusion
    SYMPTOMS

 at

    7 y of age
    AGE

, which

    contained many Gaucher cells
    MICROSCOPIC

    despite enzyme replacement therapy
    NEG_FINDINGS

.

    She
    GENDER

    died
    SYMPTOMS

 from

    neurological deterioration
    SYMPTOMS

 during

    enzyme replacement therapy
    MEDICATION

,

    despite an improvement in her visceral manifestations
    NEG_FINDINGS

. The other patient is a

    male
    GENDER

 with

    type 2 Gaucher's disease
    DIAGNOSIS

, who has achieved

    long-term survival
    MEDICATION

 after being

    supported by mechanical ventilation
    MEDICATION

 and

    enzyme replacement therapy
    MEDICATION

. While

    on enzyme replacement therapy
    MEDICATION

 at the

    age of 4 y
    AGE

,

    he
    GENDER

 suffered a

    generalized cutaneous disease
    SYMPTOMS

 which was clinically diagnosed as

    ichthyosis
    DIAGNOSIS

.

These cases suggest that

    ordinary enzyme replacement therapy is insufficient for
    NEG_FINDINGS

 some of the non-neurological manifestations of severe types of

    Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease
type 3 Gaucher's disease
type 2 Gaucher's disease
ichthyosis
Gaucher's disease

unusual clinical symptoms
pericardial effusion
died
neurological deterioration
generalized cutaneous disease

enzyme replacement therapy
enzyme replacement therapy
long-term survival
supported by mechanical ventilation
enzyme replacement therapy
on enzyme replacement therapy


Improvement of neurological symptoms by enzyme replacement therapy for Gaucher disease type IIIb.

Enzyme replacement therapy might improve chronic liver dysfunction and contribute to the resolution of basal ganglia lesions in patients with type 3b Gaucher disease.

    Enzyme replacement therapy
    MEDICATION

 might improve

    chronic liver dysfunction
    SYMPTOMS

 and contribute to the

    resolution of basal ganglia lesions
    SYMPTOMS

 in patients with

    type 3b Gaucher disease
    DIAGNOSIS

.

chronic liver dysfunction
resolution of basal ganglia lesions


Pregnancy after avascular necrosis of the femur complicating Gaucher's disease.

A patient with type I Gaucher's disease had avascular necrosis of the right femoral head that resulted in an altered bony pelvis and marked restriction of right hip abduction. Enzyme replacement therapy with alglucerase prevented further deterioration and improved thrombocytopenia. Vaginal delivery was achieved with the patient in the left lateral position with exaggerated flexion at the contralateral hip.

A patient with

    type I Gaucher's disease
    DIAGNOSIS

 had

    avascular necrosis of the right femoral head
    SYMPTOMS

 that resulted in an

    altered bony pelvis
    SYMPTOMS

 and

    marked restriction of right hip abduction
    SYMPTOMS

.

    Enzyme replacement therapy with alglucerase
    MEDICATION

    prevented further deterioration
    SYMPTOMS

 and

    improved thrombocytopenia
    BIOCHEMICAL

.

    Vaginal delivery
    MEDICATION

 was achieved with the patient in the left lateral position with

    exaggerated flexion at the contralateral hip
    SYMPTOMS

.


Adult Gaucher disease in association with primary malignant bone tumors.

Malignant neoplastic disorders are more common in patients with Gaucher disease (GD) than in the general population. Very few cases of primary malignant bone tumors in association with GD have been reported to date. Thus, the recommendations for an adequate therapy are often based on limited professional experience. To their knowledge, the authors report the first case of a leiomyosarcoma of the bone in a patient with GD and report another patient with GD and an anaplastic large cell non-Hodgkin lymphoma with localized osseous manifestation. A review of the literature is included.

The clinical, radiologic, and histologic data of the authors' two patients who had GD and primary malignant bone tumor are presented. Epidemiologic data, clinical data, and treatment results from published reports of 18 patients who had GD and various malignancies and the authors' 2 patients were compared and evaluated.

Radiographic examination showed a destructive osteolytic lesion in a case of a leiomyosarcoma of the bone and in a case of anaplastic, large-cell, non-Hodgkin lymphoma. In both cases, the bone marrow architecture was partially effaced by sheets of large histiocytic cells with striated or fibrillary cytoplasm. In both patients, chemotherapy was performed. Whereas the patient who had the leiomyosarcoma showed poor recovery of the bone marrow that necessitated withdrawal of aggressive chemotherapy, the patient who had non-Hodgkin lymphoma and enzyme therapy tolerated the chemotherapy well. In spite of local control after preoperative radiotherapy and hemipelvectomy, the first patient developed lung metastases and finally died. The second patient was continuously free of disease at a follow-up examination 32 months after chemotherapy and radiotherapy. In a total of 20 patients who had malignant disorders and GD, the numbers of males and females were equivalent, and the mean age was 55 years. Approximately 33% presented with a cancer originating in the bone. In 16 patients, follow-up data were available. Of these, after a mean follow-up of 36 months (range, few days-108 mos), only 2 patients were continuously free of disease, and one patient was alive with disease. The other patients had died of disease or hemorrhagic complications of GD.

Because there is a relatively high incidence of malignant disorders of the bone, the study suggested that malignant disorders have to be included in the differential diagnosis of painful lytic lesions in patients who have GD. Evaluation of the expense and value of enzyme therapy to patients who have GD should be undertaken with regard to the incidence of malignant disorders and patient survival.

    Malignant neoplastic disorders
    DIAGNOSIS

 are more common in patients with

    Gaucher disease (GD)
    DIAGNOSIS

 than in the general population. Very few cases of

    primary malignant bone tumors
    DIAGNOSIS

 in association with

    GD
    DIAGNOSIS

 have been reported to date. Thus, the recommendations for an adequate therapy are often based on limited professional experience. To their knowledge, the authors report the first case of a

    leiomyosarcoma of the bone
    DIAGNOSIS

 in a patient with

    GD
    DIAGNOSIS

 and report another patient with

    GD
    DIAGNOSIS

 and an

    anaplastic large cell non-Hodgkin lymphoma
    DIAGNOSIS

 with

    localized osseous manifestation
    SYMPTOMS

. A review of the literature is included.

The clinical, radiologic, and histologic data of the authors' two patients who had

    GD
    DIAGNOSIS

 and

    primary malignant bone tumor
    DIAGNOSIS

 are presented. Epidemiologic data, clinical data, and treatment results from published reports of 18 patients who had

    GD
    DIAGNOSIS

 and

    various malignancies
    DIAGNOSIS

 and the authors' 2 patients were compared and evaluated.

    Radiographic examination
    PARACLINICAL

 showed a

    destructive osteolytic lesion
    SYMPTOMS

 in a case of a

    leiomyosarcoma of the bone
    DIAGNOSIS

 and in a case of

    anaplastic, large-cell, non-Hodgkin lymphoma
    DIAGNOSIS

. In both cases,

    the bone marrow architecture was partially effaced by sheets of large histiocytic cells with striated or fibrillary cytoplasm
    MICROSCOPIC

. In both patients,

    chemotherapy
    MEDICATION

 was performed. Whereas the patient who had the

    leiomyosarcoma
    DIAGNOSIS

 showed

    poor recovery of the bone marrow that necessitated withdrawal of aggressive chemotherapy
    NEG_FINDINGS

, the patient who had

    non-Hodgkin lymphoma
    DIAGNOSIS

 and

    enzyme therapy
    MEDICATION

 tolerated

    the chemotherapy
    MEDICATION

 well. In

    spite of local control
    NEG_FINDINGS

 after

    preoperative radiotherapy
    MEDICATION

 and

    hemipelvectomy
    MEDICATION

, the first patient developed

    lung metastases
    SYMPTOMS

 and finally

    died
    SYMPTOMS

. The second patient was

    continuously free of disease
    NEG_FINDINGS

 at a

    follow-up examination
    PARACLINICAL

 32 months after

    chemotherapy and radiotherapy
    MEDICATION

. In a total of 20 patients who had

    malignant disorders
    DIAGNOSIS

 and

    GD
    DIAGNOSIS

, the numbers of

    males
    GENDER

 and

    females
    GENDER

 were equivalent, and the mean

    age was 55 years
    AGE

. Approximately 33% presented with a

    cancer originating in the bone
    DIAGNOSIS

. In 16 patients, follow-up data were available. Of these, after a mean follow-up of 36 months (range, few days-108 mos), only 2 patients were continuously

    free of disease
    NEG_FINDINGS

, and one patient was alive with disease. The other patients had

    died of disease or hemorrhagic complications of GD
    SYMPTOMS

.

Because there is a relatively high incidence of

    malignant disorders of the bone
    DIAGNOSIS

, the study suggested that

    malignant disorders
    DIAGNOSIS

 have to be included in the

    differential diagnosis
    PARACLINICAL

 of

    painful lytic lesions
    SYMPTOMS

 in patients who have

    GD
    DIAGNOSIS

. Evaluation of the expense and value of

    enzyme therapy
    MEDICATION

 to patients who have

    GD
    DIAGNOSIS

 should be undertaken with regard to the incidence of

    malignant disorders
    DIAGNOSIS

 and patient survival.

chemotherapy
enzyme therapy
the chemotherapy
preoperative radiotherapy
hemipelvectomy
chemotherapy and radiotherapy
enzyme therapy


Three Gaucher-disease-producing mutations in a patient with Gaucher disease: mechanism and diagnostic implications.

As Gaucher disease is an autosomal recessive disorder, most patients are either homozygotes or compound heterozygotes for glucocerebrosidase mutations. We have encountered a patient with three mutations, two c.1226A-->G (1226G, N370S) and one c.1448 T-->C (1448C, L444P). This was shown to be due to a gene conversion event in which the sequence of the glucocerebrosidase pseudogene that includes the 1448C mutation had been imposed on a glucocerebrosidase gene that already had the 1226G mutation. The patient had relatively mild disease which had been discovered after an attack of infectious mononucleosis, a relationship that has been observed previously. If it had not been recognized that this patient had the 1226G/1226G,1448C genotype, prenatal testing might have falsely identified a 1226G,1448C/wt (wild type) fetus as having Gaucher disease.

As

    Gaucher disease
    DIAGNOSIS

 is an

    autosomal recessive disorder
    GENETICS

, most patients are either

    homozygotes or compound heterozygotes for glucocerebrosidase mutations
    GENETICS

. We have encountered a patient with

    three mutations, two c.1226A-->G (1226G, N370S) and one c.1448 T-->C (1448C, L444P)
    GENETICS

. This was shown to be due to a

    gene conversion event in which the sequence of the glucocerebrosidase pseudogene that includes the 1448C mutation had been imposed on a glucocerebrosidase gene that already had the 1226G mutation
    GENETICS

. The patient had

    relatively mild disease
    SYMPTOMS

 which had been discovered after an

    attack of infectious mononucleosis
    DIAGNOSIS

, a relationship that has been observed previously. If it had not been recognized that this patient had the

    1226G/1226G,1448C genotype
    GENETICS

,

    prenatal testing
    PARACLINICAL

 might have falsely identified a

    1226G,1448C/wt (wild type) fetus
    GENETICS

 as having

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
attack of infectious mononucleosis
Gaucher disease


A new variant neuropathic type of Gaucher's disease characterized by hydrocephalus, corneal opacities, deformed toes, and fibrous thickening of spleen and liver capsules.

We report a new variant type of Gaucher's disease characterized by hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules. This patient had 1 D409H allele. He differed from other reported cases with a 1342G to C (D409H) homozygous mutation (onset at 4 months, no cardiac involvement until the age of 12 years, and massive hepatosplenomegaly with fibrous thickening of spleen and liver capsules). Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement.

We report a new

    variant type of Gaucher's disease
    DIAGNOSIS

 characterized by

    hydrocephalus
    SYMPTOMS

,

    corneal opacities
    SYMPTOMS

,

    deformed toes
    SYMPTOMS

,

    gastroesophageal reflux
    SYMPTOMS

, and

    fibrous thickening of splenic and hepatic capsules
    SYMPTOMS

. This patient had

    1 D409H allele
    GENETICS

.

    He
    GENDER

 differed from other reported cases with a

    1342G to C (D409H) homozygous mutation
    GENETICS

 (

    onset at 4 months
    AGE

,

    no cardiac involvement
    NEG_FINDINGS

    until the age of 12 years
    AGE

, and

    massive hepatosplenomegaly with fibrous thickening of spleen and liver capsules
    SYMPTOMS

).

    Enzyme replacement therapy was given for 4 years
    MEDICATION

, resulting in an

    improvement of visceral and hematologic abnormalities
    SYMPTOMS

 but

    no neurologic improvement
    NEG_FINDINGS

.

1 D409H allele
1342G to C (D409H) homozygous mutation

no cardiac involvement
no neurologic improvement


Coincidence of Gaucher's disease due to a 1226G/1448C mutation and of an immunoglobulin G lambda multiple myeloma with Bence-Jones proteinuria.

We report about a 58-year-old female with coexisting type-I Gaucher's disease (GD) and multiple myeloma (MM). The diagnosis of GD was made in early childhood by means of bone marrow biopsy and was recently confirmed by analysis of the patient's genomic DNA for the underlying glucocerebrosidase mutations and the identification of the 1226G/1448C genotype. At the age of 24 years, the patient developed massive splenomegaly. Therefore, a splenectomy was performed. No further therapy was necessary for the next 34 years until 1999 when progressive anemia and thrombocytopenia occurred. Additional laboratory analysis revealed high serum protein and immunoglobulin (Ig) G levels and evidence of monoclonal gammopathy and lambda light-chain proteinuria, indicating plasma cell dyscrasia. This diagnosis was confirmed by the detection of osteolytic lesions in skeletal X-rays and a bone marrow biopsy showing an extensive infiltration with Gaucher cells and an increase of plasma cells, which expressed lambda light chains. When examined by means of electron microscopy, typical Gaucher cells, i.e., histiocytes containing tubular-structured cytoplasmatic material and spots of plasma cells with an increase of the endoplasmic reticulum, were found. GD associated with acquired MM has been described 13 times in the literature from 1968 to 1997. Only three of the patients were suffering from IgG myeloma. This distribution of the monoclonal component is in contrast to that of patients suffering from MM alone.

We report about a

    58-year-old
    AGE

    female
    GENDER

 with

    coexisting type-I Gaucher's disease (GD) and multiple myeloma (MM)
    DIAGNOSIS

. The diagnosis of

    GD
    DIAGNOSIS

 was made in

    early childhood
    AGE

 by means of

    bone marrow biopsy
    PARACLINICAL

 and was recently confirmed by

    analysis of the patient's genomic DNA for the underlying glucocerebrosidase mutations
    PARACLINICAL

 and the

    identification of the 1226G/1448C genotype
    GENETICS

. At the

    age of 24 years
    AGE

, the patient developed

    massive splenomegaly
    SYMPTOMS

. Therefore, a

    splenectomy
    MEDICATION

 was performed.

    No further therapy was necessary for the next 34 years
    NEG_FINDINGS

 until 1999 when

    progressive anemia
    BIOCHEMICAL

 and

    thrombocytopenia
    BIOCHEMICAL

 occurred. Additional

    laboratory analysis
    PARACLINICAL

 revealed

    high serum protein and immunoglobulin (Ig) G levels
    BIOCHEMICAL

 and

    evidence of monoclonal gammopathy
    BIOCHEMICAL

 and

    lambda light-chain proteinuria
    BIOCHEMICAL

, indicating

    plasma cell dyscrasia
    DIAGNOSIS

. This diagnosis was confirmed by the detection of

    osteolytic lesions in skeletal X-rays
    SYMPTOMS

 and a

    bone marrow biopsy
    PARACLINICAL

 showing an

    extensive infiltration with Gaucher cells and an increase of plasma cells, which expressed lambda light chains
    MICROSCOPIC

. When examined by means of

    electron microscopy
    PARACLINICAL

,

    typical Gaucher cells, i.e., histiocytes containing tubular-structured cytoplasmatic material and spots of plasma cells with an increase of the endoplasmic reticulum, were found
    MICROSCOPIC

.

    GD associated with acquired MM
    DIAGNOSIS

 has been described 13 times in the literature from 1968 to 1997. Only three of the patients were suffering from

    IgG myeloma
    DIAGNOSIS

. This distribution of the monoclonal component is in contrast to that of patients suffering from

    MM
    DIAGNOSIS

 alone.

massive splenomegaly
osteolytic lesions in skeletal X-rays


A new gene-pseudogene fusion allele due to a recombination in intron 2 of the glucocerebrosidase gene causes Gaucher disease.

Gaucher disease is the most prevalent sphingolipid storage disorder in humans caused by a recessively inherited deficiency of the enzyme glucocerebrosidase. More than 100 mutations have been described in the glucocerebrosidase gene causing Gaucher disease. Some of them are complex alleles with several mutations due to recombination events between the gene and its highly homologous pseudogene. The generation of these recombinant alleles involves, in most cases, a crossover in the 3' end of the gene, beyond exon 8. However, in a few cases recombination took place in a more upstream location. Here we describe the analysis of a patient with type I Gaucher disease who bears a new complex allele. This allele was originated by a crossover between the gene and the pseudogene at intron 2, the most upstream recombination site described so far, which gave rise to a fusion gene. The patient was first diagnosed as homozygous for the c.1226 A --> G (N370S) mutation but the early onset of the disease prompted us to perform parental DNA analysis which showed that the mother was not a N370S carrier, suggesting deletion of at least part of the gene. Molecular analysis of the complex allele was carried out by Southern blot, PCR, and sequencing. We were able to close down the region of the recombination event to an interval of 18 nucleotides, corresponding to the last 15 nucleotides of intron 2 and the first 3 nucleotides of exon 3 of the gene. These 18 nucleotides are identical between the gene and pseudogene making any further refinement impossible. An exhaustive list of published glucocerebrosidase complex alleles, describing their recombination points, is included for comparison.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    sphingolipid storage disorder
    DIAGNOSIS

 in humans caused by a

    recessively inherited
    GENETICS

    deficiency of the enzyme glucocerebrosidase
    BIOCHEMICAL

. More than 100 mutations have been described in the

    glucocerebrosidase gene
    GENETICS

 causing

    Gaucher disease
    DIAGNOSIS

. Some of them are

    complex alleles
    GENETICS

 with

    several mutations
    GENETICS

 due to

    recombination events between the gene and its highly homologous pseudogene
    GENETICS

. The generation of these

    recombinant alleles
    GENETICS

 involves, in most cases, a

    crossover in the 3' end of the gene, beyond exon 8
    GENETICS

. However, in a few cases recombination took place in a more upstream location. Here we describe the analysis of a patient with

    type I Gaucher disease
    DIAGNOSIS

 who bears a

    new complex allele
    GENETICS

. This allele was originated by a

    crossover between the gene and the pseudogene at intron 2, the most upstream recombination
    GENETICS

 site described so far, which gave rise to a

    fusion gene
    GENETICS

. The patient was first diagnosed as

    homozygous for the c.1226 A --> G (N370S) mutation
    GENETICS

 but the early onset of the disease prompted us to perform

    parental DNA analysis
    PARACLINICAL

 which showed that

    the mother was not a N370S carrier
    FAMILY

, suggesting

    deletion of at least part of the gene
    GENETICS

.

    Molecular analysis of the complex allele
    PARACLINICAL

 was carried out by

    Southern blot, PCR, and sequencing
    PARACLINICAL

. We were able to close down the region of the recombination event to an

    interval of 18 nucleotides, corresponding to the last 15 nucleotides of intron 2 and the first 3 nucleotides of exon 3 of the gene
    GENETICS

. These

    18 nucleotides are identical between the gene and pseudogene
    GENETICS

 making any further refinement impossible. An exhaustive list of published

    glucocerebrosidase complex alleles
    GENETICS

, describing their recombination points, is included for comparison.

Gaucher disease
sphingolipid storage disorder
Gaucher disease
type I Gaucher disease


Niemann-Pick disease type C: two cases and an update.

We describe two patients with juvenile-onset Niemann-Pick disease type C (NPC) to illustrate the variable neurologic features of this condition. One presented with hypersplenism at age 10 and was misdiagnosed with Gaucher disease. He developed complex partial seizures in his teens but remained otherwise neurologically asymptomatic until his mid 30s. At age 45, he had mild dementia and dysarthria, vertical supranuclear ophthalmoplegia, axonal sensorimotor polyneuropathy, and cerebellar ataxia. The second patient presented with rapidly progressive dystonia at age 8, and mild hepatosplenomegaly, vertical supranuclear ophthalmoplegia, severe behavioral disorder, and dementia by age 14. The diagnosis of NPC was based on deficient cholesterol esterification and excessive lysosomal filipin staining in cultured skin fibroblasts. Current notions about diagnosis and pathogenesis of NPC are reviewed.

We describe two patients with

    juvenile-onset Niemann-Pick disease type C (NPC)
    DIAGNOSIS

 to illustrate the variable neurologic features of this condition. One presented with

    hypersplenism
    BIOCHEMICAL

 at

    age 10
    AGE

 and was

    misdiagnosed with Gaucher disease
    NEG_FINDINGS

.

    He
    GENDER

 developed

    complex partial seizures
    SYMPTOMS

    in his teens
    AGE

 but

    remained otherwise neurologically asymptomatic
    NEG_FINDINGS

 until

    his mid 30s
    AGE

. At

    age 45
    AGE

,

    he
    GENDER

 had

    mild dementia
    SYMPTOMS

 and

    dysarthria
    SYMPTOMS

,

    vertical supranuclear ophthalmoplegia
    SYMPTOMS

,

    axonal sensorimotor polyneuropathy
    DIAGNOSIS

, and

    cerebellar ataxia
    SYMPTOMS

. The second patient presented with

    rapidly progressive dystonia
    SYMPTOMS

 at

    age 8
    AGE

, and

    mild hepatosplenomegaly
    SYMPTOMS

,

    vertical supranuclear ophthalmoplegia
    SYMPTOMS

,

    severe behavioral disorder
    SYMPTOMS

, and

    dementia
    SYMPTOMS

 by

    age 14
    AGE

. The diagnosis of

    NPC
    DIAGNOSIS

 was based on

    deficient cholesterol esterification
    BIOCHEMICAL

 and

    excessive lysosomal filipin staining in cultured skin fibroblasts
    MICROSCOPIC

. Current notions about diagnosis and pathogenesis of

    NPC
    DIAGNOSIS

 are reviewed.

hypersplenism
deficient cholesterol esterification

complex partial seizures
mild dementia
dysarthria
vertical supranuclear ophthalmoplegia
cerebellar ataxia
rapidly progressive dystonia
mild hepatosplenomegaly
vertical supranuclear ophthalmoplegia
severe behavioral disorder
dementia


Mutation analysis of Gaucher disease using dot-blood samples on FTA filter paper.

FTA((R)) filter papers were used as an effective means of blood cell collection, genomic DNA processing, and delivery. Minute blood samples (<1 microL) were collected onto the filters via a simple lateral prick to the patient's finger, circumventing the need for intravenous blood puncture. Collected samples, which are stable at room temperature for several years, were subsequently sent through the postal system to the diagnostic laboratory, bypassing the stringent requirements of courier delivery. Using this method, we performed restriction fragment length polymorphism (RFLP) and nucleotide sequence analysis on prevalent mutations among Canadian and Chinese Gaucher disease patients. Of the 12 alleles (six patients) analyzed, 42% (5/12) have the N370S mutation and 58% (7/12) the L444P mutation, the two most common alleles found among Jewish and non-Jewish Gaucher disease patients. Uniquely, a Chinese Gaucher disease patient was found to have an N370S mutation. Although the presence of the N370S mutation is regarded as common in other ethnic groups, previous to this report it had not been noted in an individual of Asian descent. PvuII polymorphism analysis showed that the N370S mutation found in the Chinese patient was linked to the Pv1.1(-) polymorphism, as has been previously seen in the Jewish population. The use of FTA((R)) filter paper facilitates access of samples to diagnostic centers, and therefore provides an effective means of performing population-based mutational analysis of Gaucher disease internationally.

    FTA((R)) filter papers
    MEDICATION

 were used as an effective means of

    blood cell collection
    PARACLINICAL

,

    genomic DNA processing
    PARACLINICAL

, and delivery.

    Minute blood samples
    PARACLINICAL

 (<1 microL) were collected onto the filters via a

    simple lateral prick to the patient's finger
    PARACLINICAL

, circumventing the need for

    intravenous blood puncture
    PARACLINICAL

. Collected samples, which are stable at room temperature for several years, were subsequently sent through the postal system to the diagnostic laboratory, bypassing the stringent requirements of courier delivery. Using this method, we performed

    restriction fragment length polymorphism (RFLP) and nucleotide sequence analysis
    PARACLINICAL

 on prevalent mutations among

    Canadian
    ETHNICITY

 and

    Chinese
    ETHNICITY

    Gaucher disease
    DIAGNOSIS

 patients. Of the 12 alleles (six patients) analyzed, 42% (5/12) have the

    N370S mutation
    GENETICS

 and 58% (7/12) the

    L444P mutation
    GENETICS

, the two most common alleles found among

    Jewish
    ETHNICITY

 and

    non-Jewish
    ETHNICITY

    Gaucher disease
    DIAGNOSIS

 patients. Uniquely, a

    Chinese
    ETHNICITY

    Gaucher disease
    DIAGNOSIS

 patient was found to have an

    N370S mutation
    GENETICS

. Although the presence of the

    N370S mutation
    GENETICS

 is regarded as common in other ethnic groups, previous to this report it had not been noted in an individual of

    Asian descent
    ETHNICITY

.

    PvuII polymorphism analysis
    PARACLINICAL

 showed that the

    N370S mutation
    GENETICS

 found in the

    Chinese
    ETHNICITY

 patient

    was linked to the Pv1.1(-) polymorphism
    GENETICS

, as has been previously seen in the

    Jewish
    ETHNICITY

 population. The use of

    FTA((R)) filter paper
    PARACLINICAL

 facilitates access of samples to diagnostic centers, and therefore provides an effective means of performing population-based

    mutational analysis
    PARACLINICAL

 of

    Gaucher disease
    DIAGNOSIS

 internationally.

Canadian
Chinese
Jewish
non-Jewish
Chinese
Asian descent
Chinese
Jewish

Gaucher disease
Gaucher disease
Gaucher disease
Gaucher disease

N370S mutation
L444P mutation
N370S mutation
N370S mutation
N370S mutation
was linked to the Pv1.1(-) polymorphism


Extraosseous manifestation of Gaucher's disease type I: MR and histological appearance.

Gaucher's disease type I is the most prevalent lysosomal storage disorder caused by an autosomal-recessive inherited deficiency of glucocerebrosidase activity with secondary accumulation of glucocerebrosides within the lysosomes of macrophages. The storage disorder produces a multisystem disease characterized by progressive visceral enlargement and gradual replacement of bone marrow with lipid-laden macrophages. Skeletal disease is a major source of disability in Gaucher's disease. Extraosseous extension of Gaucher cells is an extremely rare manifestation of skeletal Gaucher's disease. This is a report on the MRI and histopathological findings of an extraosseous Gaucher-cell extension into the midface in a patient with Gaucher's disease.

    Gaucher's disease type I
    DIAGNOSIS

 is the most prevalent

    lysosomal storage disorder
    DIAGNOSIS

 caused by an

    autosomal-recessive inherited
    GENETICS

    deficiency of glucocerebrosidase activity
    BIOCHEMICAL

 with

    secondary accumulation of glucocerebrosides within the lysosomes of macrophages
    MICROSCOPIC

. The

    storage disorder
    DIAGNOSIS

 produces a

    multisystem disease
    DIAGNOSIS

 characterized by

    progressive visceral enlargement
    SYMPTOMS

 and

    gradual replacement of bone marrow with lipid-laden macrophages
    MICROSCOPIC

.

    Skeletal disease
    SYMPTOMS

 is a major source of disability in

    Gaucher's disease
    DIAGNOSIS

.

    Extraosseous extension of Gaucher cells
    MICROSCOPIC

 is an extremely rare manifestation of

    skeletal Gaucher's disease
    MICROSCOPIC

. This is a report on the

    MRI
    PARACLINICAL

 and histopathological findings of an

    extraosseous Gaucher-cell extension into the midface
    MICROSCOPIC

 in a patient with

    Gaucher's disease
    DIAGNOSIS

.

Gaucher's disease type I
lysosomal storage disorder
storage disorder
multisystem disease
Gaucher's disease
Gaucher's disease

progressive visceral enlargement
Skeletal disease


Identification of a novel recombinant allele in three unrelated Italian Gaucher patients: implications for prognosis and genetic counseling.

Gaucher disease (GD) results from deleterious mutations in the glucocerebrosidase gene. The relatively high frequency of some of these, especially at cDNA nucleotide 1226G (N370S) and at cDNA nucleotide 1448C (L444P), has led to the development of rapid screening techniques that can sometimes be misleading. In this report, we describe a novel rearrangement between the glucocerebrosidase gene and its pseudogene, identified as a consequence of a discrepancy between the genotype, homozygous for the common 1226G mutation, of an Italian patient with type 1 Gaucher disease, and the absence of the 1226G allele in her daughter. Additional investigations went on to reveal a novel recombinant allele beginning in intron 6 and extending through the rest of the coding sequence. Italian GD patients found homozygous for a specific mutation or with one or both alleles still unknown were further investigated and the novel recombinant allele was identified in an adult type 1 patient previously genotyped 1226G/1226G and in a young patient with an unknown genotype. The detection of this allele in three unrelated GD patients originating from the same geographic area in central Italy suggested a founder effect. This study emphasizes the implications of an accurate genotyping for the prognostic value of glucocerebrosidase genotype and reliable genetic counseling.

    Gaucher disease (GD)
    DIAGNOSIS

 results from

    deleterious mutations in the glucocerebrosidase gene
    GENETICS

. The relatively high frequency of some of these, especially at

    cDNA nucleotide 1226G (N370S) and at cDNA nucleotide 1448C (L444P)
    GENETICS

, has led to the development of rapid screening techniques that can sometimes be misleading. In this report, we describe a

    novel rearrangement between the glucocerebrosidase gene and its pseudogene
    GENETICS

, identified as a consequence of a discrepancy between the genotype,

    homozygous for the common 1226G mutation
    GENETICS

, of an

    Italian
    ETHNICITY

 patient with

    type 1 Gaucher disease
    DIAGNOSIS

, and the

    absence of the 1226G allele in her daughter
    FAMILY

. Additional investigations went on to reveal a

    novel recombinant allele beginning in intron 6 and extending through the rest of the coding sequence
    GENETICS

.

    Italian
    ETHNICITY

    GD
    DIAGNOSIS

 patients found

    homozygous for a specific mutation
    GENETICS

 or with one

    or both alleles still unknown
    GENETICS

 were further investigated and the

    novel recombinant allele
    GENETICS

 was identified in an

    adult
    AGE

    type 1
    DIAGNOSIS

 patient previously

    genotyped 1226G/1226G
    GENETICS

 and in a

    young
    AGE

 patient with an unknown genotype. The detection of this allele in three unrelated

    GD
    DIAGNOSIS

 patients originating from the same geographic area in

    central Italy
    ETHNICITY

 suggested a

    founder effect
    GENETICS

. This study emphasizes the implications of an accurate genotyping for the prognostic value of

    glucocerebrosidase genotype
    PARACLINICAL

 and

    reliable genetic counseling
    MEDICATION

.

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


Perinatal lethal form of Gaucher's disease presenting with hemosiderosis.

A term infant with hydrops fetalis presented with hypotonia, massive splenomegaly, renal failure, and severe hyperferritinemia. Multiple organ failure, myoclonus, and opisthotonus ensued and she died at 15 days of age. High rounded forehead, large open fontanel, and a small recessed chin led to initial premortem diagnosis of Zellweger syndrome, but her plasma profile of long chain fatty acid was normal. Her subsequent clinical course and findings of postmortem examinations were consistent with perinatal lethal form of Gaucher's disease (PLGD). The diagnosis was confirmed by deficiency of enzyme beta-glucocerebrosidase in white blood cells and in cultured fibroblasts. In addition to the crossover features of Zellweger phenotype, this infant exhibited a number of unusual features including, severe hyperferritinemia, rapid progression of splenomegaly, and absence of icthyosis.

A

    term infant
    AGE

 with

    hydrops fetalis
    DIAGNOSIS

 presented with

    hypotonia
    SYMPTOMS

,

    massive splenomegaly
    SYMPTOMS

,

    renal failure
    SYMPTOMS

, and

    severe hyperferritinemia
    BIOCHEMICAL

.

    Multiple organ failure
    SYMPTOMS

,

    myoclonus
    SYMPTOMS

, and

    opisthotonus
    SYMPTOMS

 ensued and

    she
    GENDER

    died
    SYMPTOMS

    at 15 days of age
    AGE

.

    High rounded forehead
    SYMPTOMS

,

    large open fontanel
    SYMPTOMS

, and a

    small recessed chin
    SYMPTOMS

 led to initial premortem diagnosis of

    Zellweger syndrome
    DIAGNOSIS

, but

    her
    GENDER

    plasma profile of long chain fatty acid was normal
    NEG_FINDINGS

.

    Her
    GENDER

 subsequent clinical course and findings of

    postmortem examinations
    PARACLINICAL

 were consistent with

    perinatal lethal form of Gaucher's disease (PLGD)
    DIAGNOSIS

. The diagnosis was confirmed by

    deficiency of enzyme beta-glucocerebrosidase in white blood cells and in cultured fibroblasts
    BIOCHEMICAL

. In addition to the

    crossover features of Zellweger phenotype
    SYMPTOMS

, this

    infant
    AGE

 exhibited a number of unusual features including,

    severe hyperferritinemia
    BIOCHEMICAL

,

    rapid progression of splenomegaly
    SYMPTOMS

, and

    absence of icthyosis
    NEG_FINDINGS

.


Longterm follow-up of electroencephalographic and clinical findings of a case with Gaucher's disease type 3a.

Among three recognised clinical phenotypes, type 3a Gaucher's disease is characterised by mild to severe systemic disease, neurological manifestations and myoclonic seizures. We report the long term clinical and electrophysiological follow-up of a 27-year old man with a diagnosis of type 3a Gaucher's disease, which was confirmed by bone marrow biopsy examination and leukocyte glucocerebrosidase level measurement. His neurological examination was normal throughout the follow-up period. EEG examination, recorded five days after the first seizure, revealed generalised nonrhythmic paroxysmal rapid spikes with occipital predominance increased by photic stimulation and normal background activity. The frequency of seizures increased from 3-4/year to 1-2/month within a follow-up period of 12 years and a repeat EEG examination on the eight year of diagnosis revealed additional background slowing. A giant potential was obtained in somatosensory evoked potential (SEP) examination. EEG findings of this case demonstrate a specific pattern with rapid spike activity, photosensitivity, eye closure sensitivity and gradual background slowing.

Among three recognised clinical phenotypes,

    type 3a Gaucher's disease
    DIAGNOSIS

 is characterised by

    mild to severe systemic disease
    SYMPTOMS

,

    neurological manifestations
    SYMPTOMS

 and

    myoclonic seizures
    SYMPTOMS

. We report the long term clinical

    and electrophysiological follow-up
    PARACLINICAL

 of a

    27-year old
    AGE

    man
    GENDER

 with a diagnosis of

    type 3a Gaucher's disease
    DIAGNOSIS

, which was confirmed by

    bone marrow biopsy examination
    PARACLINICAL

 and

    leukocyte glucocerebrosidase level measurement
    BIOCHEMICAL

.

    His
    GENDER

    neurological examination was normal throughout the follow-up period
    NEG_FINDINGS

.

    EEG examination
    PARACLINICAL

, recorded five days after the first

    seizure
    SYMPTOMS

, revealed

    generalised nonrhythmic paroxysmal rapid spikes with occipital predominance increased by photic stimulation
    SYMPTOMS

 and

    normal background activity
    NEG_FINDINGS

. The frequency of

    seizures increased from 3-4/year to 1-2
    SYMPTOMS

/month within a follow-up period of 12 years and a

    repeat EEG examination
    PARACLINICAL

 on the eight year of diagnosis revealed

    additional background slowing
    SYMPTOMS

. A giant potential was obtained in

    somatosensory evoked potential (SEP) examination
    PARACLINICAL

. EEG findings of this case demonstrate a

    specific pattern with rapid spike activity
    SYMPTOMS

,

    photosensitivity
    SYMPTOMS

,

    eye closure sensitivity
    SYMPTOMS

 and

    gradual background slowing
    SYMPTOMS

.

type 3a Gaucher's disease
type 3a Gaucher's disease


Functional characterization of the novel mutation IVS 8 (-11delC) (-14T>A) in the intron 8 of the glucocerebrosidase gene of two Italian siblings with Gaucher disease type I.

Gaucher disease, the most common glycolipid storage disease, can be caused by a large variety of mutations. We report here the identification and characterization of a novel mutation in the human glucocerebrosidase gene, IVS 8 (-11delC) (-14T>A), in two siblings with Gaucher disease type I which occurs within the 3' end of intron 8. Both siblings were compound heterozygotes for the IVS 8 (-11delC) (-14T>A) mutation and for the c.626 G>C (R170P) substitution within exon 6. No mRNA species carrying the IVS 8 (-11delC) (-14T>A) mutation were detected by RT-PCR analysis of the RNA extracted from the patients' fibroblasts. To study the possible effects of the IVS 8 (-11delC) (-14T>A) sequence alteration on the splicing of the proximal exon 9, we have established an in vitro system generating a minigene carrying the genomic region of human glucocerebrosidase spanning from exon 8 to exon 10. Transfections into the human Hep3B cell line of the wild-type construct resulted in the expression of mRNA with the glucocerebrosidase exons correctly spliced. On the contrary, transfections of the construct carrying the IVS 8 (-11delC) (-14T>A) mutation resulted in the expression of mRNA with an 11-bp insertion located between the end of exon 8 and the beginning of exon 9. These results indicated that the 5243T>A substitution created a new 3' splice site 11 bp upstream of the wild-type one, leading to the incorporation into the mRNA of these extra 11 bases. Moreover, the new 3' splice site created by this 5243T>A transversion was preferred over the wild-type one in 100% of cases. The in vitro studies suggest that, in the patients, the 11-bp inclusion causes a shift in the reading frame with the generation of a stop codon after codon 388 which undergoes early degradation.

    Gaucher disease
    DIAGNOSIS

, the most common

    glycolipid storage disease
    DIAGNOSIS

, can be caused by a large variety of mutations. We report here the identification and characterization of a

    novel mutation in the human glucocerebrosidase gene, IVS 8 (-11delC) (-14T>A),
    GENETICS

 in two

    siblings with Gaucher disease type I
    FAMILY

 which occurs

    within the 3' end of intron 8
    GENETICS

.

    Both siblings were compound heterozygotes for the IVS 8 (-11delC) (-14T>A) mutation and for the c.626 G>C (R170P) substitution within exon 6
    FAMILY

.

    No mRNA species carrying the IVS 8 (-11delC) (-14T>A) mutation
    NEG_FINDINGS

 were detected by

    RT-PCR analysis of the RNA extracted from the patients' fibroblasts
    PARACLINICAL

. To study the possible effects of the

    IVS 8 (-11delC) (-14T>A) sequence alteration
    GENETICS

 on the

    splicing of the proximal exon 9
    GENETICS

, we have established an in vitro system generating a

    minigene carrying the genomic region of human glucocerebrosidase spanning from exon 8 to exon 10
    PARACLINICAL

.

    Transfections into the human Hep3B cell line
    MICROSCOPIC

 of the wild-type construct resulted in the expression of

    mRNA with the glucocerebrosidase exons correctly spliced
    MICROSCOPIC

. On the contrary, transfections of the construct carrying

    the IVS 8 (-11delC) (-14T>A) mutation
    GENETICS

 resulted in the expression of

    mRNA with an 11-bp insertion located between the end of exon 8 and the beginning of exon 9
    GENETICS

. These results indicated that the

    5243T>A substitution created a new 3' splice site 11 bp upstream of the wild-type one, leading to the incorporation into the mRNA of these extra 11 bases
    GENETICS

. Moreover,

    the new 3' splice site created by this 5243T>A transversion was preferred over the wild-type one
    GENETICS

 in 100% of cases. The in vitro studies suggest that, in the patients, the

    11-bp inclusion causes a shift in the reading frame with the generation of a stop codon after codon 388 which undergoes early degradation
    GENETICS

.

Gaucher disease
glycolipid storage disease


Macular changes in type I Gaucher's disease.

The authors illustrate the spectrum of Gaucher's disease involving the eye in the case of a 51-year-old man suffering from Type I Gaucher's disease who presented with unusual macular changes. This is the first report of chronic adult non-neuronopathic disease (Type I) with a plaque-like mass at the fovea. Our hypothesis is that the lesion at the fovea is probably an aggregation of Gaucher's cells.

The authors illustrate the spectrum of

    Gaucher's disease involving the eye
    DIAGNOSIS

 in the case of a

    51-year-old
    AGE

    man
    GENDER

 suffering from

    Type I Gaucher's disease
    DIAGNOSIS

 who presented with

    unusual macular changes
    SYMPTOMS

. This is the first report of

    chronic adult non-neuronopathic disease (Type I)
    DIAGNOSIS

 with a

    plaque-like mass at the fovea
    SYMPTOMS

. Our hypothesis is that the

    lesion at the fovea
    SYMPTOMS

 is probably an

    aggregation of Gaucher's cells
    MICROSCOPIC

.

unusual macular changes
plaque-like mass at the fovea
lesion at the fovea


Identification of Gaucher cells in the chorionic villi associated with recurrent hydrops fetalis.

Recurrent non-immune hydrops fetalis has rarely been reported. In order to detect the risk of recurrence in a subsequent pregnancy, one should carefully consider the possibility of an inborn error of metabolism. In such cases, placental examination may be useful in detecting such metabolic storage disorders in the fetus, which usually present as vacuolization of placental cells. We describe a rare case of recurrent hydrops that was detected by placental examination. Through light microscopy, electron microscope (EM) studies and beta-glucocerebrosidase activity the disease was identified as Gaucher's disease.

    Recurrent non-immune hydrops fetalis
    DIAGNOSIS

 has rarely been reported. In order to detect the risk of recurrence in a subsequent pregnancy, one should carefully consider the possibility of an

    inborn error of metabolism
    GENETICS

. In such cases,

    placental examination
    PARACLINICAL

 may be useful in detecting such

    metabolic storage disorders
    DIAGNOSIS

    in the fetus
    MICROSCOPIC

, which usually present as

    vacuolization of placental cells
    MICROSCOPIC

. We describe a rare case of

    recurrent hydrops
    DIAGNOSIS

 that was detected by

    placental examination
    PARACLINICAL

. Through

    light microscopy
    PARACLINICAL

,

    electron microscope (EM) studies
    PARACLINICAL

 and

    beta-glucocerebrosidase activity
    BIOCHEMICAL

 the disease was identified as

    Gaucher's disease
    DIAGNOSIS

.

Recurrent non-immune hydrops fetalis
metabolic storage disorders
recurrent hydrops
Gaucher's disease


Surgical management of spinal involvement in children and adolescents with Gaucher's disease.

Gaucher's disease is an uncommon hereditary glycolipid storage disorder characterized by the accumulation of glucocerebroside in the lysosomes of macrophages of the reticuloendothelial system. Skeletal manifestations are variable in severity and typically involve the long bones. Vertebral involvement is less well characterized, particularly in children and adolescents. We report on the surgical management of spinal involvement in four children and adolescents with Gaucher's disease; two for kyphotic deformity and two for kyphotic deformity associated with neurologic compromise. We recommend anterior spinal release with fusion and posterior spinal fusion with segmental instrumentation in cases of kyphotic deformity. In cases of spinal cord compromise at the apex of the kyphotic deformity with retropulsion of involved bone, anterior decompression also should be performed. Routine surveillance for spinal deformity in patients with Gaucher's disease is necessary to allow early intervention before the development of severe deformity and neurologic compromise.

    Gaucher's disease
    DIAGNOSIS

 is an

    uncommon hereditary
    GENETICS

    glycolipid storage disorder
    DIAGNOSIS

 characterized by the

    accumulation of glucocerebroside in the lysosomes of macrophages of the reticuloendothelial system
    MICROSCOPIC

.

    Skeletal manifestations
    SYMPTOMS

 are variable in severity and typically

    involve the long bones
    SYMPTOMS

.

    Vertebral involvement
    SYMPTOMS

 is less well characterized, particularly in

    children
    AGE

 and

    adolescents
    AGE

. We report on the

    surgical management of spinal involvement
    MEDICATION

 in four

    children
    AGE

 and

    adolescents
    AGE

 with

    Gaucher's disease
    DIAGNOSIS

; two for

    kyphotic deformity
    MEDICATION

 and two for

    kyphotic deformity associated with neurologic compromise
    SYMPTOMS

. We recommend

    anterior spinal release with fusion
    MEDICATION

 and

    posterior spinal fusion with segmental instrumentation
    MEDICATION

 in cases of

    kyphotic deformity
    MEDICATION

. In cases of

    spinal cord compromise at the apex of the kyphotic deformity
    SYMPTOMS

 with

    retropulsion of involved bone
    SYMPTOMS

,

    anterior decompression
    MEDICATION

 also should be performed.

    Routine surveillance for spinal deformity
    PARACLINICAL

 in patients with

    Gaucher's disease
    DIAGNOSIS

 is necessary to allow

    early intervention
    MEDICATION

 before the development of

    severe deformity
    SYMPTOMS

 and

    neurologic compromise
    SYMPTOMS

.

Gaucher's disease
glycolipid storage disorder
Gaucher's disease
Gaucher's disease


Gaucher disease of the spleen: CT and MR findings.

We present a 26-year-old male patient with Gaucher disease who presented with epigastric pain and a palpable mass in the left abdomen. Ultrasound, abdominal computed tomography, and magnetic resonance imaging showed massive splenomegaly with multiple splenic nodules up to 7 cm in diameter. Splenic nodules should be included in the differential diagnosis of splenic masses. Follow-up is necessary because of the increased incidence of hematologic malignancies in Gaucher disease.

We present a

    26-year-old
    AGE

    male
    GENDER

 patient with

    Gaucher disease
    DIAGNOSIS

 who presented with

    epigastric pain
    SYMPTOMS

 and a

    palpable mass in the left abdomen
    SYMPTOMS

.

    Ultrasound
    PARACLINICAL

,

    abdominal computed tomography
    PARACLINICAL

, and

    magnetic resonance imaging
    PARACLINICAL

 showed

    massive splenomegaly
    SYMPTOMS

 with

    multiple splenic nodules up to 7 cm in diameter
    SYMPTOMS

.

    Splenic nodules
    DIAGNOSIS

 should be included in the

    differential diagnosis
    PARACLINICAL

 of

    splenic masses
    SYMPTOMS

.

    Follow-up
    PARACLINICAL

 is necessary because of the increased incidence of

    hematologic malignancies
    DIAGNOSIS

 in

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
Splenic nodules
hematologic malignancies
Gaucher disease


Life-threatening splenic hemorrhage in two patients with Gaucher disease.

Massive splenomegaly is a frequent finding in patients with Gaucher disease, the most common of the sphingolipidoses. Even so, the risk for splenic rupture and intracapsular hemorrhage has not been emphasized due to the rarity of this occurrence and the fibrotic, rubbery consistency of splenic tissue in these patients. We report two adult patients with type 1 Gaucher disease who suffered life-threatening splenic bleeds that were not acutely diagnosed. Both patients ultimately required emergent splenectomies. Factors complicating the diagnosis of splenic hemorrhage in patients with Gaucher disease are discussed. Published 2000 Wiley-Liss, Inc.

    Massive splenomegaly
    SYMPTOMS

 is a frequent finding in patients with

    Gaucher disease
    DIAGNOSIS

, the most common of the

    sphingolipidoses
    DIAGNOSIS

. Even so, the risk for

    splenic rupture
    SYMPTOMS

 and

    intracapsular hemorrhage
    SYMPTOMS

 has not been emphasized due to the rarity of this occurrence and the

    fibrotic, rubbery consistency of splenic tissue
    SYMPTOMS

 in these patients. We report two

    adult
    AGE

 patients with

    type 1 Gaucher disease
    DIAGNOSIS

 who suffered

    life-threatening splenic bleeds
    SYMPTOMS

 that were

    not acutely diagnosed
    NEG_FINDINGS

. Both patients ultimately required

    emergent splenectomies
    MEDICATION

. Factors complicating the diagnosis of

    splenic hemorrhage
    SYMPTOMS

 in patients with

    Gaucher disease
    DIAGNOSIS

 are discussed. Published 2000 Wiley-Liss, Inc.

Gaucher disease
sphingolipidoses
type 1 Gaucher disease
Gaucher disease


Extraordinary bone involvement in a gaucher disease type I patient.

We report on a 63-year-old patient with Gaucher disease type I who developed severe bone involvement with destructive lesions and huge soft tissue extension in both humeri that appeared to evolve slowly. The clinical course and histopathological findings in our patient suggested a progressive extraosseous extension of the storage cells into the soft tissue, accompanied by a striking increase of fibrotic tissue and resulting in an impressive deformity. The extraordinary bone involvement in this patient expands our knowledge on the most severe skeletal complications of untreated Gaucher disease.

We report on a

    63-year-old
    AGE

 patient with

    Gaucher disease type I
    DIAGNOSIS

 who developed

    severe bone involvement
    SYMPTOMS

    with destructive lesions
    SYMPTOMS

 and

    huge soft tissue extension in both humeri
    SYMPTOMS

 that appeared to evolve slowly. The clinical course and

    histopathological findings
    PARACLINICAL

 in our patient suggested a

    progressive extraosseous extension of the storage cells into the soft tissue
    MICROSCOPIC

, accompanied by a

    striking increase of fibrotic tissue
    MICROSCOPIC

 and resulting in an

    impressive deformity
    SYMPTOMS

. The

    extraordinary bone involvement
    SYMPTOMS

 in this patient expands our knowledge on the most severe

    skeletal complications
    SYMPTOMS

 of

    untreated Gaucher disease
    DIAGNOSIS

.

Gaucher disease type I
untreated Gaucher disease


Massive hepatic fibrosis in Gaucher's disease: clinico-pathological and radiological features.

Hepatomegaly is frequent in patients with type 1 Gaucher's disease and is associated with infiltration of the liver with pathological macrophages. Most patients suffer no significant clinical consequences, but a few develop portal hypertension which may progress to parenchymal liver failure. We describe four patients with Gaucher's disease who have developed portal hypertension. We have reviewed their clinical histories and all available histological and radiological material. All had severe Gaucher's disease with multi-organ involvement, and had undergone splenectomy in childhood. Histologically, this advanced liver disease was characterized by a picture of extreme and advanced confluent fibrosis occupying the central region of the liver. This massive fibrosis is associated with characteristic radiological appearances. The liver histology in these cases is highly unusual and virtually unknown in other conditions. Our studies indicate that without specific treatment the liver disease is progressive and rapidly fatal. However, institution of enzyme replacement therapy with imiglucerase may have beneficial effects even when the condition is far advanced.

    Hepatomegaly
    SYMPTOMS

 is frequent in patients with

    type 1 Gaucher's disease
    DIAGNOSIS

 and is associated with

    infiltration of the liver with pathological macrophages
    MICROSCOPIC

. Most patients suffer

    no significant clinical consequences
    NEG_FINDINGS

, but a few develop

    portal hypertension
    SYMPTOMS

 which may progress to

    parenchymal liver failure
    SYMPTOMS

. We describe four patients with

    Gaucher's disease
    DIAGNOSIS

 who have developed

    portal hypertension
    SYMPTOMS

. We have reviewed their clinical histories and all available

    histological and radiological material
    PARACLINICAL

. All had

    severe Gaucher's disease
    DIAGNOSIS

 with

    multi-organ involvement
    SYMPTOMS

, and had undergone

    splenectomy
    MEDICATION

 in

    childhood
    AGE

. Histologically, this

    advanced liver disease
    DIAGNOSIS

 was characterized by a picture of

    extreme and advanced confluent fibrosis occupying the central region of the liver
    MICROSCOPIC

. This

    massive fibrosis
    SYMPTOMS

 is associated with

    characteristic radiological appearances
    SYMPTOMS

. The

    liver histology
    DIAGNOSIS

 in these cases is highly unusual and virtually unknown in other conditions. Our studies indicate that

    without specific treatment
    NEG_FINDINGS

 the

    liver disease
    DIAGNOSIS

 is progressive and

    rapidly fatal
    SYMPTOMS

. However, institution of

    enzyme replacement therapy with imiglucerase
    MEDICATION

 may have beneficial effects even when the condition is far advanced.

Hepatomegaly
portal hypertension
parenchymal liver failure
portal hypertension
multi-organ involvement
massive fibrosis
characteristic radiological appearances
rapidly fatal

type 1 Gaucher's disease
Gaucher's disease
severe Gaucher's disease
advanced liver disease
liver histology
liver disease

no significant clinical consequences
without specific treatment


[An adult form of type-I. Gaucher's disease].

A young woman with no previous history of any diseases was admitted for further evaluation of a mild thrombocytopenia she has had for some months. No signs of bleeding have so far occurred. Physical examination was normal except for a moderately enlarged spleen. Routine investigations showed lower platelet count. There was no laboratory evidence of disease conditions with autoimmune/inflammatory or hematologic origin. Bone marrow aspirate indicated Gaucher's-like cells raising the suspicion of Gaucher's disease. This was further supported by electron microscopic demonstration of Gaucher's bodies (with the characteristic tubular structures) in crista biopsy specimens. However, definitive diagnosis was obtained by verifying deficient lysosomal glucosylceramide-beta-D-glucosidase activity in peripheral blood leukocytes. Upon the absence of neurologic involvement the patient was typical for the adult form or type-1 Gaucher's disease.

A

    young
    AGE

    woman
    GENDER

    with no previous history of any diseases
    NEG_FINDINGS

 was admitted for further evaluation of a

    mild thrombocytopenia she
    BIOCHEMICAL

 has had

    for some months
    SYMPTOMS

.

    No signs of bleeding
    NEG_FINDINGS

 have so far occurred.

    Physical examination was normal
    NEG_FINDINGS

 except for a

    moderately enlarged spleen
    SYMPTOMS

.

    Routine investigations
    PARACLINICAL

 showed

    lower platelet count
    BIOCHEMICAL

. There was

    no laboratory evidence of disease conditions with autoimmune/inflammatory or hematologic origin
    NEG_FINDINGS

.

    Bone marrow aspirate
    PARACLINICAL

 indicated

    Gaucher's-like cells
    MICROSCOPIC

 raising the suspicion of

    Gaucher's disease
    DIAGNOSIS

. This was further supported by

    electron microscopic demonstration of Gaucher's bodies (with the characteristic tubular structures) in crista biopsy specimens
    PARACLINICAL

. However, definitive diagnosis was obtained by verifying

    deficient lysosomal glucosylceramide-beta-D-glucosidase activity in peripheral blood leukocytes
    BIOCHEMICAL

. Upon the

    absence of neurologic involvement
    NEG_FINDINGS

 the patient was typical for the

    adult form
    DIAGNOSIS

 or

    type-1 Gaucher's disease
    DIAGNOSIS

.

for some months
moderately enlarged spleen

Gaucher's disease
adult form
type-1 Gaucher's disease


Severe type II Gaucher disease with ichthyosis, arthrogryposis and neuronal apoptosis: molecular and pathological analyses.

Severe infantile Gaucher disease associated with ichthyosis and neonatal death is a rare subgroup of Type II Gaucher disease. This group of infants has little, if any, detectable beta-glucocerebrosidase activity, and prior genetic analyses have been limited in detecting the mutations responsible for this phenotype. We document an Hispanic infant succumbing with arthrogryposis and collodion membrane covering the skin who had no detectable beta-glucocerebrosidase activity in tissue samples and who was homozygous for a rare recombinant allele, RecNciI. Microscopic evaluation demonstrated accumulation of Gaucher cells in visceral organs and extensive loss of neurons in the anterior horns, brainstem, and cortex of the nervous system. The apoptosis of neuronal cells from the anterior horns and brainstem are a reasonable explanation for the arthrogryposis and neonatal death, respectively.

    Severe infantile Gaucher disease
    DIAGNOSIS

 associated with

    ichthyosis
    SYMPTOMS

 and

    neonatal
    AGE

    death
    SYMPTOMS

 is a rare subgroup of

    Type II Gaucher disease
    DIAGNOSIS

. This group of

    infants
    AGE

 has

    little, if any, detectable beta-glucocerebrosidase activity
    NEG_FINDINGS

, and prior genetic analyses have been limited in detecting the mutations responsible for this phenotype. We document an

    Hispanic
    ETHNICITY

    infant
    AGE

    succumbing
    SYMPTOMS

 with

    arthrogryposis
    SYMPTOMS

 and

    collodion membrane covering the skin
    SYMPTOMS

 who had

    no detectable beta-glucocerebrosidase activity in tissue samples
    NEG_FINDINGS

 and who was homozygous for a rare recombinant allele, RecNciI.

    Microscopic evaluation
    PARACLINICAL

 demonstrated

    accumulation of Gaucher cells in visceral organs
    MICROSCOPIC

 and

    extensive loss of neurons in the anterior horns, brainstem, and cortex of the nervous system
    SYMPTOMS

. The

    apoptosis of neuronal cells from the anterior horns and brainstem
    MICROSCOPIC

 are a reasonable explanation for the

    arthrogryposis
    SYMPTOMS

 and

    neonatal death
    SYMPTOMS

, respectively.

Severe infantile Gaucher disease
Type II Gaucher disease


Prenatal diagnosis of Gaucher's disease type 2. Ultrasonographic, biochemical and histological aspects.

We report on the early prenatal diagnosis of fetal Gaucher disease type 2 by ultrasound examination and beta-glucosidase activity assay on amniocytes from a fetus of 15 weeks' gestation whose first sibling fetus had previously been affected with hydrops fetalis. These cases emphasize the importance of the pathological examination of all fetuses presenting with hydrops fetalis and also stress that minimal and precocious echographic signs can be suggestive of such a lysosomal storage disease.

We report on the early prenatal diagnosis of

    fetal Gaucher disease type 2
    DIAGNOSIS

 by

    ultrasound examination
    PARACLINICAL

 and

    beta-glucosidase activity assay on amniocytes
    PARACLINICAL

 from a

    fetus of 15 weeks' gestation
    AGE

    whose first sibling fetus had previously been affected with hydrops fetalis
    FAMILY

. These cases emphasize the importance of the

    pathological examination
    PARACLINICAL

 of all

    fetuses
    AGE

 presenting with

    hydrops fetalis
    DIAGNOSIS

 and also stress that

    minimal and precocious echographic signs
    SYMPTOMS

 can be suggestive of such a

    lysosomal storage disease
    DIAGNOSIS

.

fetal Gaucher disease type 2
hydrops fetalis
lysosomal storage disease


Communicating hydrocephalus in a patient with Gaucher's disease type 3.

The case of a 3-year-old male with type 3 Gaucher's disease, whose genotype for the beta-glucosidase gene was D409H/unknown mutation, is presented. After the onset of visceral and neurologic signs during infancy, a radiologic investigation at 3 years of age revealed communicating hydrocephalus, an unusual complication of Gaucher's disease. A ventriculoperitoneal shunt operation led to clinical and radiologic improvement. The possibility of this complication should be considered in the treatment of patients with Gaucher's disease.

The case of a

    3-year-old
    AGE

    male
    GENDER

 with

    type 3 Gaucher's disease
    DIAGNOSIS

, whose

    genotype for the beta-glucosidase gene was D409H/unknown mutation
    GENETICS

, is presented. After the onset of

    visceral and neurologic signs
    SYMPTOMS

 during

    infancy
    AGE

, a

    radiologic investigation
    PARACLINICAL

 at

    3 years of age
    AGE

 revealed

    communicating hydrocephalus
    SYMPTOMS

, an unusual complication of

    Gaucher's disease
    DIAGNOSIS

. A

    ventriculoperitoneal shunt operation
    MEDICATION

 led to

    clinical and radiologic improvement
    SYMPTOMS

. The possibility of this complication should be considered in the treatment of patients with

    Gaucher's disease
    DIAGNOSIS

.

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

visceral and neurologic signs
communicating hydrocephalus
clinical and radiologic improvement


Avascular necrosis. A case history and literature review.

We describe a patient with avascular necrosis in both shoulders. Confirmatory testing in making the diagnosis included plain radiography, bone scan, and magnetic resonance imaging. The pathogenesis and staging of the disease by radiography are presented in the article. Treatment options include a conservative regimen of shoulder range of motion exercises and nonsteroidal anti-inflammatory agents or surgery (arthroplasty or core decompression). The patient's risk factors include long-term corticosteroid use, smoking, and alcohol consumption. Other known risk factors include sickle cell disease, Gaucher disease, chemotherapy, lymphoma, dysbaric conditions, and trauma. This literature search shows that prevention and early diagnosis lend the best outcomes for the diagnosis of avascular necrosis.

We describe a patient with

    avascular necrosis in both shoulders
    SYMPTOMS

. Confirmatory testing in making the diagnosis included

    plain radiography
    PARACLINICAL

,

    bone scan
    PARACLINICAL

, and

    magnetic resonance imaging
    PARACLINICAL

. The pathogenesis and staging of the disease by

    radiography
    PARACLINICAL

 are presented in the article. Treatment options include a

    conservative regimen of shoulder range of motion exercises
    MEDICATION

 and

    nonsteroidal anti-inflammatory agents
    MEDICATION

 or

    surgery (arthroplasty or core decompression)
    MEDICATION

. The patient's risk factors include

    long-term corticosteroid use
    MEDICATION

,

    smoking
    MEDICATION

, and

    alcohol consumption
    MEDICATION

. Other known risk factors include

    sickle cell disease
    DIAGNOSIS

,

    Gaucher disease
    DIAGNOSIS

,

    chemotherapy
    MEDICATION

,

    lymphoma
    DIAGNOSIS

,

    dysbaric conditions
    DIAGNOSIS

, and

    trauma
    SYMPTOMS

. This literature search shows that prevention and early diagnosis lend the best outcomes for the diagnosis of

    avascular necrosis
    DIAGNOSIS

.

avascular necrosis in both shoulders
trauma

sickle cell disease
Gaucher disease
lymphoma
dysbaric conditions
avascular necrosis


Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease.

To describe a case with a new genetic variant of type 3 Gaucher disease presenting with stimulus-sensitive and action myoclonus in the presence of selective dentate abnormalities.

Clinical, pathologic, and molecular genetic studies.

Medical school departments.

A 6-year-old girl with type 3 Gaucher disease experienced progressively crippling generalized stimulus-sensitive and action myoclonus. Repeated electroencephalographic examination did not show cortical activity associated with the myoclonus, suggesting its subcortical origin. Neuropathological examination revealed selective degeneration of the cerebellar dentate nucleus and dentatorubrothalamic pathway in the face of essentially complete lack of storage in the brain. Mutation analysis identified the following 2 mutant alleles: one with a V394L mutation and the other with the lesion RecTL (D409H + L444P + A456P + V460V), which resulted from a recombination event, with the pseudogene located 16 kilobases downstream from the structural gene.

Given the restricted abnormalities, this genetically unique case provides insight into the pathogenesis of myoclonus and suggests a prominent role for the cerebellar dentate nucleus in its genesis.

To describe a case with a

    new genetic variant of type 3 Gaucher disease
    GENETICS

 presenting with

    stimulus-sensitive and action myoclonus
    SYMPTOMS

 in the presence of

    selective dentate abnormalities
    SYMPTOMS

.

    Clinical, pathologic, and molecular genetic studies
    PARACLINICAL

.

    Medical school departments
    PARACLINICAL

.

A

    6-year-old
    AGE

    girl
    GENDER

 with

    type 3 Gaucher disease
    DIAGNOSIS

 experienced

    progressively crippling generalized stimulus-sensitive and action myoclonus
    SYMPTOMS

.

    Repeated electroencephalographic examination
    PARACLINICAL

    did not show cortical activity associated with the myoclonus
    NEG_FINDINGS

, suggesting its subcortical origin.

    Neuropathological examination
    PARACLINICAL

 revealed

    selective degeneration of the cerebellar dentate nucleus and dentatorubrothalamic pathway
    SYMPTOMS

 in the face of

    essentially complete lack of storage in the brain
    NEG_FINDINGS

.

    Mutation analysis
    PARACLINICAL

 identified the following

    2 mutant alleles: one with a V394L mutation and the other with the lesion RecTL (D409H + L444P + A456P + V460V), which resulted from a recombination event, with the pseudogene located 16 kilobases downstream from the structural gene
    GENETICS

.

Given the

    restricted abnormalities
    SYMPTOMS

, this genetically unique case provides insight into the pathogenesis of

    myoclonus
    SYMPTOMS

 and suggests a prominent role for the

    cerebellar dentate nucleus
    SYMPTOMS

 in its genesis.


Pseudo-Gaucher cells in myelodysplasia.

A case of myelodysplastic syndrome is reported, in which the bone marrow contained many cells with the typical light microscopic morphology of Gaucher cells. In the absence of any evidence of inherited Gaucher's disease, these cells are considered to be pseudo-Gaucher cells, which have been described previously in association with other haematological diseases. This is the first report of their occurrence in myelodysplastic syndrome.

A case of

    myelodysplastic syndrome
    DIAGNOSIS

 is reported, in which

    the bone marrow contained many cells with the typical light microscopic morphology of Gaucher cells
    MICROSCOPIC

. In the

    absence of any evidence of inherited Gaucher's disease
    NEG_FINDINGS

, these cells are considered to be

    pseudo-Gaucher cells
    MICROSCOPIC

, which have been described previously in association with other

    haematological diseases
    DIAGNOSIS

. This is the first report of their occurrence in

    myelodysplastic syndrome
    DIAGNOSIS

.

myelodysplastic syndrome
haematological diseases
myelodysplastic syndrome


Novel point mutation (W184R) in neonatal type 2 Gaucher disease.

Gaucher disease is the most prevalent inherited sphingolipidosis and results from deficient glucocerebrosidase activity. Three clinical forms of Gaucher disease have been described: type 1, or non-neuronopathic; type 2, or acute neuronopathic; and type 3, or subacute neuronopathic. We have identified a novel mutation in a patient of Russian-British descent who died of type 2 Gaucher disease a few hours after birth. A heterozygous T --> C transition mutation in exon 6, cDNA nucleotide position 667, results in the substitution of tryptophan by arginine at amino acid residue 184 (W184R) of glucocerebrosidase. This mutation creates a new cleavage site for the restriction endonuclease Hinf1. We developed a method that utilizes Hinf1 restriction endonuclease analysis to confirm the presence of the mutation and test family members. The second mutation identified in the other glucocerebrosidase allele of the patient is mutation L444P, a severe mutation frequent in type 2 and 3 Gaucher disease. Since the patient died very shortly after birth, we postulate that the W184R/L444P genotype may result in little or no detectable glucocerebrosidase activity and thus a poor prognosis.

    Gaucher disease
    DIAGNOSIS

 is the most prevalent

    inherited sphingolipidosis
    GENETICS

 and results from

    deficient glucocerebrosidase activity
    BIOCHEMICAL

. Three clinical forms of

    Gaucher disease
    DIAGNOSIS

 have been described:

    type 1, or non-neuronopathic
    DIAGNOSIS

;

    type 2, or acute neuronopathic
    DIAGNOSIS

; and

    type 3, or subacute neuronopathic
    DIAGNOSIS

. We have identified a

    novel mutation
    GENETICS

 in a patient of

    Russian-British descent
    ETHNICITY

 who

    died
    SYMPTOMS

 of

    type 2 Gaucher disease
    DIAGNOSIS

 a few hours

    after birth
    AGE

. A

    heterozygous T --> C transition mutation in exon 6, cDNA nucleotide position 667, results in the substitution of tryptophan by arginine at amino acid residue 184 (W184R) of glucocerebrosidase
    GENETICS

. This mutation creates a new cleavage site for the restriction endonuclease

    Hinf1
    GENETICS

. We developed a method that utilizes

    Hinf1 restriction endonuclease analysis
    PARACLINICAL

 to confirm the presence of the mutation and

    test family members
    PARACLINICAL

. The

    second mutation identified in the other glucocerebrosidase allele of the patient is mutation L444P, a severe mutation frequent in type 2 and 3 Gaucher disease
    GENETICS

. Since the patient

    died
    SYMPTOMS

 very

    shortly after birth
    AGE

, we postulate that the

    W184R/L444P genotype
    GENETICS

 may result in

    little or no detectable glucocerebrosidase activity
    NEG_FINDINGS

 and thus a poor prognosis.

Gaucher disease
Gaucher disease
type 1, or non-neuronopathic
type 2, or acute neuronopathic
type 3, or subacute neuronopathic
type 2 Gaucher disease


Type 2 Gaucher disease: the collodion baby phenotype revisited.

The association of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 Gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 Gaucher disease. Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.

The association of

    Gaucher disease
    DIAGNOSIS

, the

    inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45)
    GENETICS

, and

    congenital ichthyosis
    SYMPTOMS

 was first noted a decade ago. Subsequently, a

    null allele type 2 Gaucher
    GENETICS

 mouse was generated that also exhibited

    ichthyotic skin
    SYMPTOMS

, confirming that the

    skin disorder
    SYMPTOMS

 and

    enzyme deficiency
    BIOCHEMICAL

 were directly related. This paper details the clinical and molecular characterisation of 6 cases of

    type 2 Gaucher disease
    DIAGNOSIS

 presenting with the

    collodion baby phenotype
    SYMPTOMS

. The identified

    mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q)
    GENETICS

, as well as

    alleles resulting from recombination with the nearby glucocerebrosidase pseudogene
    GENETICS

. There is significant genotypic heterogeneity in this rare subset of patients with

    type 2 Gaucher disease
    DIAGNOSIS

.

    Gaucher disease
    DIAGNOSIS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 of

    congenital ichthyosis
    SYMPTOMS

    in the newborn period
    AGE

.

Gaucher disease
type 2 Gaucher disease
type 2 Gaucher disease
Gaucher disease

congenital ichthyosis
ichthyotic skin
skin disorder
collodion baby phenotype
congenital ichthyosis