Fabry's disease with familial lymphedema of the lower limbs. Case report and family study.

The case of a 49-year-old man with Fabry's disease (FD), confirmed by histopathological findings of kidney and skin biopsies and enzymatic studies, is reported. Clinical symptoms mainly consisted in severe neurological involvement, and in conspicuous lymphedema of the lower limbs. Two decreased brothers of the patient were also affected with symptons strongly suggesting FD, as well as the lymphedema of the lower limbs. On the basis of these data, the association of FD with familial lymphedema of the lower limbs is discussed: a lipid accumulation in the lymphatic as well as the blood vessel wall is proposed as a possible explanation; the hypothesis of an inborn error in the development of the lymphatic system, controlled by a gene closedly associated with the FD gene on the same chromosome can also be advanced.

The case of a

    49-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease (FD)
    DIAGNOSIS

, confirmed by

    histopathological findings of kidney and skin biopsies
    PARACLINICAL

 and

    enzymatic studies
    PARACLINICAL

, is reported. Clinical symptoms mainly consisted in

    severe neurological involvement
    SYMPTOMS

, and in

    conspicuous lymphedema of the lower limbs
    SYMPTOMS

.

    Two decreased brothers of the patient were also affected with symptons strongly suggesting FD
    FAMILY

, as well as the

    lymphedema of the lower limbs
    SYMPTOMS

. On the basis of these data, the association of

    FD
    DIAGNOSIS

 with

    familial lymphedema of the lower limbs
    SYMPTOMS

 is discussed: a

    lipid accumulation in the lymphatic as well as the blood vessel wall
    MICROSCOPIC

 is proposed as a possible explanation; the hypothesis of an

    inborn error in the development of the lymphatic system, controlled by a gene closedly associated with the FD gene on the same chromosome
    GENETICS

 can also be advanced.


Histopathology and electron and immunofluorescence microscopy of gingivitis granulomatosa associated with glossitis and cheilitis in a case of Anderson-Fabry disease.

A 17-year-old white boy with signs, symptoms, and family history of angiokeratoma corporis diffusum universale, Anderson-Fabry disease (AFD), developed recurrent and then persistent swelling of both lips, erythematous hyperplastic gingivae, and a pebbled tongue. Positive blood findings were raised serum IgE, decreased T-cell level, and increased B-cell level. Histopathology of the gingiva showed noncaseating granulomas with multinucleate giant cells containing Schaumann bodies and large plasma-cell infiltrates in which immunofluorescence demonstrated immune globulins of several classes. Electron microscopy and histochemistry demonstrated ceramide in the vasculature. No glycolipid was found in the macrophages or giant cells of the granulomas which, in contrast, resembled sarcoid reactions. Plasma cells with Russell bodies and immune reaction-induced degranulation of mast cells were also identified. The pathogenesis of the oral findings possibly relates to altered immune reactivity associated with damage to the microvasculature analogous to that in Melkersson-Rosenthal syndrome.

A

    17-year-old
    AGE

    white
    ETHNICITY

    boy
    GENDER

 with signs, symptoms, and

    family history of angiokeratoma corporis diffusum universale
    FAMILY

,

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

, developed

    recurrent and then persistent swelling of both lips
    SYMPTOMS

,

    erythematous hyperplastic gingivae
    SYMPTOMS

, and a

    pebbled tongue
    SYMPTOMS

. Positive blood findings were

    raised serum IgE
    BIOCHEMICAL

,

    decreased T-cell level
    BIOCHEMICAL

, and

    increased B-cell level
    BIOCHEMICAL

.

    Histopathology of the gingiva
    PARACLINICAL

 showed

    noncaseating granulomas with multinucleate giant cells containing Schaumann bodies
    MICROSCOPIC

 and

    large plasma-cell infiltrates
    MICROSCOPIC

 in which

    immunofluorescence demonstrated immune globulins of several classes
    BIOCHEMICAL

.

    Electron microscopy
    PARACLINICAL

 and

    histochemistry
    PARACLINICAL

 demonstrated

    ceramide in the vasculature
    MICROSCOPIC

.

    No glycolipid was found in the macrophages or giant cells of the granulomas
    NEG_FINDINGS

 which, in contrast, resembled

    sarcoid reactions
    NEG_FINDINGS

.

    Plasma cells with Russell bodies
    MICROSCOPIC

 and

    immune reaction-induced degranulation of mast cells
    MICROSCOPIC

 were also identified. The pathogenesis of the

    oral findings
    SYMPTOMS

 possibly relates to

    altered immune reactivity
    BIOCHEMICAL

 associated with

    damage to the microvasculature
    SYMPTOMS

 analogous to that in

    Melkersson-Rosenthal syndrome
    DIAGNOSIS

.

Anderson-Fabry disease (AFD)
Melkersson-Rosenthal syndrome


Eye findings in the diagnosis of Fabry's disease. Patients with renal failure.

Two patients underwent renal transplantation for what was thought to be glomerulonephritis and chronic pyelonephritis. The diagnosis of Fabry's disease was made as an incidental finding during an ophthalmologic consultation for evaluation of blurred vision. These two cases illustrate the usefulness of an eye examination in the correct diagnosis in patients with the multisystem complaints of Fabry's disease. The correct diagnosis was extremely important in understanding the other manifestations of this disease in the affected patient and in the genetic counseling of the family.

Two patients underwent

    renal transplantation
    MEDICATION

 for what was thought to be

    glomerulonephritis
    DIAGNOSIS

 and

    chronic pyelonephritis
    DIAGNOSIS

. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 was made as an incidental finding during an

    ophthalmologic consultation
    PARACLINICAL

 for evaluation of

    blurred vision
    SYMPTOMS

. These two cases illustrate the usefulness of an

    eye examination
    PARACLINICAL

 in the correct diagnosis in patients with the

    multisystem complaints
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

. The correct diagnosis was extremely important in understanding the other manifestations of this disease in the affected patient and in the genetic counseling of the family.

glomerulonephritis
chronic pyelonephritis
Fabry's disease
Fabry's disease


Accelerated atrioventricular conduction in Fabry's disease: a case report.

Three unrelated men with Fabry's disease (angiokeratoma corporis diffusum universale) and accelerated atrioventricular conduction are described. AQn His bundle electrogram in one patient who reported episodes of tachycardia demonstrated a prolonged deflection preceding the ventricular complex. This deflection is thought to represent an abnormal His bundle potential, possible resulting from glycolipid deposition. In the second patient the PR interval decreased from 0.18 to 0.11 second during 10 years, and in the third patient it decreased from 0.12 to 0.10 seconds during 13 years. Accelerated atrioventricular conduction may develop in Fabry's disease.

Three unrelated

    men
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum universale)
    DIAGNOSIS

 and

    accelerated atrioventricular conduction
    SYMPTOMS

 are described.

    AQn His bundle electrogram
    PARACLINICAL

 in one patient who reported

    episodes of tachycardia
    SYMPTOMS

 demonstrated a

    prolonged deflection preceding the ventricular complex
    SYMPTOMS

. This deflection is thought to represent an

    abnormal His bundle potential
    SYMPTOMS

, possible resulting from

    glycolipid deposition
    MICROSCOPIC

. In the second patient the

    PR interval decreased from 0.18 to 0.11 second during 10 years
    SYMPTOMS

, and in the third patient

    it decreased from 0.12 to 0.10 seconds during 13 years
    SYMPTOMS

.

    Accelerated atrioventricular conduction
    SYMPTOMS

 may develop in

    Fabry's disease
    DIAGNOSIS

.


Involvement of peripheral nerve and muscle in Fabry's disease. Histologic, ultrastructural, and morphometric studies.

Light microscopic and ultrastructural studies of biopsy specimens from the sural nerve and the gastrocnemius muscle in a patient with Fabry's disease showed accumulation of lipids in endothelial and perithelial cells of the vessel walls. In addition, the peripheral nerve exhibited deposition of lipids in the perineurial cells, occasionally in unmyelinated and myelinated axons, and infrequently in Schwann cell cytoplasm. In the muscle biopsy specimen, stored lipid was found in the sarcoplasm. Quantitative histologic studies showed loss of large unmyelinated and thin myelinated nerve fibers. Excruciating pain and loss of sweating, characteristic of this disorder, may result from loss of these fiber categories. The peripheral neuropathy is probably secondary to perikaryal deposition of lipid as described previously in the literature.

    Light microscopic and ultrastructural studies of biopsy specimens from the sural nerve and the gastrocnemius muscle
    PARACLINICAL

 in a patient with

    Fabry's disease
    DIAGNOSIS

 showed

    accumulation of lipids in endothelial and perithelial cells of the vessel walls
    MICROSCOPIC

. In addition,

    the peripheral nerve
    MICROSCOPIC

 exhibited

    deposition of lipids in the perineurial cells, occasionally in unmyelinated and myelinated axons, and infrequently in Schwann cell cytoplasm
    MICROSCOPIC

. In the

    muscle biopsy specimen
    PARACLINICAL

,

    stored lipid was found in the sarcoplasm
    MICROSCOPIC

.

    Quantitative histologic studies
    PARACLINICAL

 showed

    loss of large unmyelinated and thin myelinated nerve fibers
    SYMPTOMS

.

    Excruciating pain
    SYMPTOMS

 and

    loss of sweating
    SYMPTOMS

, characteristic of this disorder, may result from

    loss of these fiber categories
    SYMPTOMS

. The

    peripheral neuropathy
    DIAGNOSIS

 is probably secondary to

    perikaryal deposition of lipid
    MICROSCOPIC

 as described previously in the literature.


Central retinal artery occlusion complicating Fabry's disease.

A 16-year-old boy had a central retinal artery occlusion and was subsequently diagnosed as a hemizygote with Fabry's disease. The typical ocular manifestations in males with this inborn error of glycosphingolipid metabolism include whorl-like corneal epithelial infiltrates, retinal and conjunctival vessel tortuosity, and lenticular changes. The present case represents the first report of a retinal artery occlusion as an ocular complication of Fabry's disease.

A

    16-year-old
    AGE

    boy
    GENDER

 had a

    central retinal artery occlusion
    SYMPTOMS

 and was subsequently diagnosed as a

    hemizygote with Fabry's disease
    FAMILY

. The typical

    ocular manifestations
    SYMPTOMS

 in

    males
    GENDER

 with this

    inborn error of glycosphingolipid metabolism
    GENETICS

 include

    whorl-like corneal epithelial infiltrates
    SYMPTOMS

,

    retinal and conjunctival vessel tortuosity
    SYMPTOMS

, and

    lenticular changes
    SYMPTOMS

. The present case represents the first report of a

    retinal artery occlusion
    SYMPTOMS

 as an

    ocular complication
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

.


Detection of Fabry's disease heterozygotes by hair root analysis.

The alpha-galactosidase/beta-hexosaminidase ratio was measured for individual hair roots as a method for heterozygote detection in Fabry's disease. Hair root analysis in control individuals revealed no striking sex difference in alpha-galactosidase/beta-hexosaminidase ratio when five males and five females were compared. The values for the ratio X 100, calculating both enzyme activities in nmol of product per min per microliter of hair extract, ranged from 0.8 to 9 for controls and from less than 0.1 to 0.4 for two hemizygous males. Hair root analysis in four heterozygotes with clinical evidence of disease gave values for each individual in the control range, in the range for hemizygotes and in an intermediate range. The experience using hair root analysis for heterozygote detection in the X-linked Lesch-Nyhan syndrome suggests that this approch will be a sensitive heterozygote detection method which takes advantage of the occurrence of hairs with a deficient phenotype on the basis of Lyonization. We observed an affected male who was born to a female without clinical or biochemical evidence (examination included extensive hair root analysis) of Fabry's disease, thus documenting a likely instance of new mutation.

The

    alpha-galactosidase/beta-hexosaminidase ratio
    BIOCHEMICAL

 was

    measured for individual hair roots
    PARACLINICAL

 as a method for heterozygote detection in

    Fabry's disease
    DIAGNOSIS

.

    Hair root analysis
    PARACLINICAL

 in control individuals revealed

    no striking sex difference
    NEG_FINDINGS

 in

    alpha-galactosidase/beta-hexosaminidase ratio
    BIOCHEMICAL

 when five

    males
    GENDER

 and five

    females
    GENDER

 were compared. The values for the ratio X 100, calculating

    both enzyme activities in nmol of product per min per microliter of hair extract
    BIOCHEMICAL

, ranged from

    0.8 to 9
    BIOCHEMICAL

 for controls and from

    less than 0.1 to 0.4
    BIOCHEMICAL

 for two

    hemizygous males
    GENETICS

.

    Hair root analysis
    PARACLINICAL

 in four

    heterozygotes
    GENETICS

 with

    clinical evidence of disease
    SYMPTOMS

 gave values for each individual in the control range, in the range for

    hemizygotes
    GENETICS

 and in an intermediate range. The experience using

    hair root analysis
    PARACLINICAL

 for heterozygote detection in the

    X-linked
    GENETICS

    Lesch-Nyhan syndrome
    DIAGNOSIS

 suggests that this approch will be a sensitive heterozygote detection method which takes advantage of the occurrence of

    hairs with a deficient phenotype
    MICROSCOPIC

 on the basis of Lyonization. We observed an affected

    male
    GENDER

    who was born to a female
    FAMILY

    without clinical or biochemical evidence
    NEG_FINDINGS

 (examination included

    extensive hair root analysis
    PARACLINICAL

)

    of Fabry's disease
    NEG_FINDINGS

, thus documenting a likely instance of

    new mutation
    GENETICS

.

hemizygous males
heterozygotes
hemizygotes
X-linked
new mutation


Corneal ultrastructural changes in Fabry's disease.

A case of Fabry's disease is reported. The findings of the corneal alterations with the light microscope as well as with the electron microscope are described. The diffuse corneal haziness seems to be due to small intracellular osmiophilic inclusions of the epithelium. There seems also to be a relation between the giant inclusions in the corneal epithelium, not yet described, and the clinical presence of punctiform grey opacities. The pathogenesis of the whorl-like opacities remains unsolved.

A case of

    Fabry's disease
    DIAGNOSIS

 is reported. The findings of the

    corneal alterations
    SYMPTOMS

 with the

    light microscope
    PARACLINICAL

 as well as with the

    electron microscope
    PARACLINICAL

 are described. The

    diffuse corneal haziness
    SYMPTOMS

 seems to be due to

    small intracellular osmiophilic inclusions of the epithelium
    MICROSCOPIC

. There seems also to be a relation between the

    giant inclusions in the corneal epithelium
    MICROSCOPIC

, not yet described, and the clinical presence of

    punctiform grey opacities
    SYMPTOMS

. The pathogenesis of the

    whorl-like opacities
    SYMPTOMS

 remains unsolved.

corneal alterations
diffuse corneal haziness
punctiform grey opacities
whorl-like opacities


[Vascular lesions of Fabry's disease. Optical, histochemical and ultrastructural studies].

On the basis of a new case of Fabry's disease and the various cases published in the literature, the authors analyse the vascular lesions of this angiodysplasia related to an error in lipid metabolism. They emphasise the involvement of lymph vessels (in particular those of the small bowel), and the ultrastructural characteristics and the mode of formation of deposits within the endothelial cells of the vascular walls.

On the basis of a new case of

    Fabry's disease
    DIAGNOSIS

 and the various cases published in the literature, the authors analyse the

    vascular lesions
    SYMPTOMS

 of this

    angiodysplasia
    DIAGNOSIS

 related to an

    error in lipid metabolism
    BIOCHEMICAL

. They emphasise the

    involvement of lymph vessels (in particular those of the small bowel)
    SYMPTOMS

, and the ultrastructural characteristics and the

    mode of formation of deposits within the endothelial cells of the vascular walls
    MICROSCOPIC

.


[Fabry's disease. Carbamazepine therapy in acrodyniform syndrome].

A 19 year old male affected with Fabry's disease suffered from severe nervous manifestations. Despite very peculiar pains of the extremities, the diagnosis has been missed for a long time and was painted out at this age because of sharp reconstitution of the family history. Fabry's disease was confirmed by discovering typical corneal lesion, a low leucocyte (W.B.C.) alpha-galactosidase activity and foam cells in renal glomerular epithelium. The importance of an early diagnosis is obvious in this case: 10 Instead of degrading narcotic therapy, Carbamazepin brought forward normal social and school living. 20 Familial investigations show up that all the siblings were affected (three boys including the propositus)--several symptoms were found in the heterozygous conductor mother. Despite the rarety of Fabry's disease, the authors emphasize the easiness of diagnosis on simple clinical and biochemical grounds. The authors insist on the symptomatic and therapeutic action of Carbamazepin or Diphenytoin in order to prevent painfull symptoms which often appear during initial course of the disease.

A

    19 year old
    AGE

    male
    GENDER

 affected with

    Fabry's disease
    DIAGNOSIS

 suffered from

    severe nervous manifestations
    SYMPTOMS

. Despite

    very peculiar pains of the extremities
    SYMPTOMS

, the diagnosis has been missed for a long time and was painted out at this age because of sharp reconstitution

    of the family history
    FAMILY

.

    Fabry's disease
    DIAGNOSIS

 was confirmed by discovering

    typical corneal lesion
    SYMPTOMS

, a

    low leucocyte (W.B.C.) alpha-galactosidase activity
    BIOCHEMICAL

 and

    foam cells in renal glomerular epithelium
    MICROSCOPIC

. The importance of an early diagnosis is obvious in this case: 10

    Instead of degrading narcotic therapy
    NEG_FINDINGS

,

    Carbamazepin
    MEDICATION

 brought forward

    normal social and school living
    MEDICATION

. 20

    Familial investigations
    PARACLINICAL

 show up

    that all the siblings were affected (three boys including the propositus)--several symptoms were found in the heterozygous conductor mother
    FAMILY

. Despite the rarety of

    Fabry's disease
    DIAGNOSIS

, the authors emphasize the easiness of diagnosis on simple clinical and biochemical grounds. The authors insist on the

    symptomatic and therapeutic action of Carbamazepin or Diphenytoin
    MEDICATION

 in order to prevent

    painfull symptoms
    SYMPTOMS

 which often appear during initial course of the disease.

Fabry's disease
Fabry's disease
Fabry's disease

severe nervous manifestations
very peculiar pains of the extremities
typical corneal lesion
painfull symptoms


Clinical, histopathological, and biochemical findings in Fabry's disease. A case report and family study.

An extensive enzymatic and morphological study was performed in a 38-year-old patient with Fabry's disease (FD). The quantitative evaluation of the enzyme alpha-galactosidase was shown to be important in identifying the genetic distribution of FD in the family tree of the patient under study. An enzymatic activity less than 0.5 nanomole/hr/10(6) cells and ranging from 2.2 to 1.1 nanomoles/hr/10(6) cells was found in the affected males and the heterozygous females, respectively. alpha-galactosidase activity in the patient's leukocytes correlates well with the histopathological findings of the kidney and skin biopsy specimens, thus demonstrating the need for both of these special examinations for a correct diagnosis of FD.

An

    extensive enzymatic and morphological study
    PARACLINICAL

 was performed in a

    38-year-old
    AGE

 patient with

    Fabry's disease (FD)
    DIAGNOSIS

. The

    quantitative evaluation of the enzyme alpha-galactosidase
    PARACLINICAL

 was shown to be important in identifying the

    genetic distribution of FD in the family tree
    FAMILY

 of the patient under study.

    An enzymatic activity less than 0.5 nanomole/hr/10(6) cells and ranging from 2.2 to 1.1 nanomoles/hr/10(6) cells
    BIOCHEMICAL

 was found in the affected

    males
    GENDER

 and the

    heterozygous
    GENETICS

    females
    GENDER

, respectively.

    alpha-galactosidase activity in the patient's leukocytes
    BIOCHEMICAL

 correlates well with the

    histopathological findings of the kidney and skin biopsy specimens
    PARACLINICAL

, thus demonstrating the need for both of these special examinations for a correct diagnosis of

    FD
    DIAGNOSIS

.


Cardiac manifestations of Fabry's disease. Report of a case with pulmonary regurgitation diagnosed on the basis of endomyocardial biopsy findings.

A case of Fabry's disease with pulmonary regurgitation is reported, and the cause of valvular involvement, the electrophysiological mechanism of the short PR interval, and the usefulness of the endomyocardial biopsy method in an attempt to establish the diagnosis in Fabry's disease have been discussed.

A case of

    Fabry's disease
    DIAGNOSIS

 with

    pulmonary regurgitation
    SYMPTOMS

 is reported, and the cause of

    valvular involvement
    SYMPTOMS

, the electrophysiological mechanism of

    the short PR interval
    SYMPTOMS

, and the usefulness of the

    endomyocardial biopsy method
    PARACLINICAL

 in an attempt to establish the diagnosis in

    Fabry's disease
    DIAGNOSIS

 have been discussed.

pulmonary regurgitation
valvular involvement
the short PR interval


Ultrastructure of muscle and sensory nerve in Fabry's disease.

A study of a muscle biopsy has provided evidence of storage involvement of the skeletal muscle fibres in Fabry's disease. In the endothelial cells of the capillaries, the inclusions were more abundant and pleomorphic. Muscle satellite cells were spared. In the sensory nerve biopsy, the perineurial and endothelial cells contained lamillar bodies, but not the Schwann cells. There was a slight reduction of the number of the small myelinated fibres and of the unmyelinated fibres. An electron microscopic study of a muscle biopsy can be helpful in the diagnosis of the disease. The physiopathology of the pain attacks is still a matter for discussion.

A

    study of a muscle biopsy
    PARACLINICAL

 has provided evidence of

    storage involvement of the skeletal muscle fibres
    MICROSCOPIC

 in

    Fabry's disease
    DIAGNOSIS

.

    In the endothelial cells of the capillaries, the inclusions were more abundant and pleomorphic
    MICROSCOPIC

.

    Muscle satellite cells were spared
    NEG_FINDINGS

. In the

    sensory nerve biopsy
    PARACLINICAL

,

    the perineurial and endothelial cells contained lamillar bodies, but not the Schwann cells
    MICROSCOPIC

. There was a

    slight reduction of the number of the small myelinated fibres and of the unmyelinated fibres
    SYMPTOMS

. An

    electron microscopic study of a muscle biopsy
    PARACLINICAL

 can be helpful in the diagnosis of the disease. The physiopathology of the

    pain attacks
    SYMPTOMS

 is still a matter for discussion.


Enzymic detection of metachromatic leukodystrophy patients and heterozygotes.

Two unrelated families with metachromatic leukodystrophy have been examined for the leukocyte enzyme arylsufatase A. The enzyme activities clearly reflect an autosomal recessive mode of inherence. All four parents showed heterozygote enzyme levels 40-60 percent of the control range while the two affected children had less than 20 percent normal activity. The two sibs of one affected child were shown to be heterozygote carriers. A simple screening method for sulfatase activity in tears has been developed which distinguished between metachromatic leukodystrophy patients and a control population which included other neurological disorders. Enzyme screening on tears may also be used to detect other lysosomal storage diseases including Tay-Sachs and Fabry disease.

Two unrelated families with

    metachromatic leukodystrophy
    SYMPTOMS

 have been examined for the leukocyte enzyme arylsufatase A. The

    enzyme activities
    BIOCHEMICAL

 clearly reflect an

    autosomal recessive mode of inherence
    GENETICS

.

    All four parents showed heterozygote enzyme levels 40-60 percent of the control range
    FAMILY

 while the two affected children had

    less than 20 percent normal activity
    BIOCHEMICAL

.

    The two sibs of one affected child were shown to be heterozygote carriers
    FAMILY

. A simple screening method for

    sulfatase activity in tears
    BIOCHEMICAL

 has been developed which distinguished between

    metachromatic leukodystrophy
    DIAGNOSIS

 patients and a control population which included other

    neurological disorders
    DIAGNOSIS

.

    Enzyme screening on tears
    PARACLINICAL

 may also be used to detect other

    lysosomal storage diseases
    DIAGNOSIS

 including

    Tay-Sachs
    DIAGNOSIS

 and

    Fabry disease
    DIAGNOSIS

.

enzyme activities
less than 20 percent normal activity
sulfatase activity in tears

metachromatic leukodystrophy
neurological disorders
lysosomal storage diseases
Tay-Sachs
Fabry disease


Pseudo-clinical Fabry's disease without alpha galactosidase deficiency.

The authors describe two cases of clinical Fabry's disease. The first patient presents a deficiency of alpha galactosidase and a urinary excretion of ceramide trihexosides and dihexosides ; the second patient had a normal alpha galactosidase and normal excretion of urinary lipids. In this latter case the Km and the activity of the enzyme measured at different pH were similar to those of normal enzyme. The other lysosomal enzymes, beta galactosidase, beta glucosidase, hexosaminidases A and B, alpha fucosidase, arylsulfatases, phosphatase acids were also measured in patient 2 and all have normal activities. There is no urinary excretion of glycolipids or mucopolysaccharides. Yet this patient has an accumulation of material in his fibroblasts and renal cells. The authors also present a genetic study.

The authors describe two cases of clinical

    Fabry's disease
    DIAGNOSIS

. The first patient presents a

    deficiency of alpha galactosidase
    BIOCHEMICAL

 and a

    urinary excretion of ceramide trihexosides and dihexosides
    BIOCHEMICAL

 ; the second patient had a

    normal alpha galactosidase
    NEG_FINDINGS

 and

    normal excretion of urinary lipids
    NEG_FINDINGS

. In this latter case the

    Km and the activity of the enzyme measured at different pH were similar to those of normal enzyme
    BIOCHEMICAL

. The other

    lysosomal enzymes, beta galactosidase, beta glucosidase, hexosaminidases A and B, alpha fucosidase
    BIOCHEMICAL

,

    arylsulfatases
    BIOCHEMICAL

,

    phosphatase acids
    BIOCHEMICAL

 were also measured in patient 2 and

    all have normal activities
    NEG_FINDINGS

. There is

    no urinary excretion of glycolipids or mucopolysaccharides
    NEG_FINDINGS

. Yet this patient has an

    accumulation of material in his fibroblasts and renal cells
    MICROSCOPIC

. The authors also present a

    genetic study
    PARACLINICAL

.


Fucosidosis.

Disseminated angiokeratomas can be seen in patients with an inherited deficiency of alpha-l-fucosidase as well as in patients with classic Fabry's disease. Patients with deficiency of this lysosomal enzyme, or fucosidosis, have spasticity, mental retardation, and retardation of growth in addition to angiokeratomas. We herein report three new cases of this rare syndrome.

    Disseminated angiokeratomas
    SYMPTOMS

 can be seen in patients with an

    inherited deficiency of alpha-l-fucosidase
    GENETICS

 as well as in patients with classic

    Fabry's disease
    DIAGNOSIS

. Patients with

    deficiency of this lysosomal enzyme
    BIOCHEMICAL

, or

    fucosidosis
    DIAGNOSIS

, have

    spasticity
    SYMPTOMS

,

    mental retardation
    SYMPTOMS

, and

    retardation of growth
    SYMPTOMS

 in addition to

    angiokeratomas
    SYMPTOMS

. We herein report three new cases of this rare syndrome.

Disseminated angiokeratomas
spasticity
mental retardation
retardation of growth
angiokeratomas


Study on a family with anderson--Fabry's disease and associated familial spastic paraplegia.

A family in the north-east of England with Anderson--Fabry's disease is presented. Alpha-galactosidase activity in plasma and white cells was significantly reduced in three adult male members of the family. One of them had an abnormal chromosome karyotype pattern with an extra Y chromosome (47,XYY) and he was clinically less severely affected than his brothers. Coincidentally five other members of the family suffered from a form of familial spastic paraplegia.

A

    family
    FAMILY

 in the

    north-east of England
    ETHNICITY

 with

    Anderson--Fabry's disease
    DIAGNOSIS

 is presented.

    Alpha-galactosidase activity in plasma and white cells was significantly reduced
    BIOCHEMICAL

 in three

    adult
    AGE

    male
    GENDER

 members of the family. One of them had an

    abnormal chromosome karyotype pattern with an extra Y chromosome (47,XYY)
    GENETICS

 and

    he
    GENDER

    was clinically less severely affected than his brothers
    FAMILY

. Coincidentally

    five other members of the family suffered from a form of familial spastic paraplegia
    FAMILY

.


[Iconographic aspects of ocular involvement in Fabry's disease].

An illustration of the ocular involvement seen in Fabry's disease: cornea verticilata, vascular conjunctival lesions, dyschromatopsia was observed in two brothers who were carriers of the condition.

An illustration of the

    ocular involvement
    SYMPTOMS

 seen in

    Fabry's disease
    DIAGNOSIS

:

    cornea verticilata
    SYMPTOMS

,

    vascular conjunctival lesions
    SYMPTOMS

,

    dyschromatopsia
    SYMPTOMS

 was observed in

    two brothers who were carriers of the condition
    FAMILY

.

ocular involvement
cornea verticilata
vascular conjunctival lesions
dyschromatopsia


Hearing loss in patients with dialysis and renal transplants.

Hearing loss in renal dialysis and renal transplant patients occurs quite frequently. An assessment of the likely etiological factors is nearly impossible in a retrospective analysis of any one patient because many factors exist simultaneously. In a prospective study of a large series of patients an identification of factors contributing to the hearing loss was possible in the majority of patients. During the study it became increasingly apparent that what was observed at any one time was the combined effect of many factors. Although one factor seemed to precipitate the hearing loss it was inadvisable to attribute total responsibility to that agent or circumstance. Further, this combined effect was not a simple addition of effects but potentiation. The serious implications of this phenomenon are discussed.

    Hearing loss
    SYMPTOMS

 in

    renal dialysis
    MEDICATION

 and

    renal transplant
    MEDICATION

 patients occurs quite frequently. An assessment of the likely etiological factors is nearly impossible in a retrospective analysis of any one patient because many factors exist simultaneously. In a prospective study of a large series of patients an identification of factors contributing to the

    hearing loss
    SYMPTOMS

 was possible in the majority of patients. During the study it became increasingly apparent that what was observed at any one time was the combined effect of many factors. Although one factor seemed to precipitate the

    hearing loss
    SYMPTOMS

 it was

    inadvisable to attribute total
    NEG_FINDINGS

 responsibility to that agent or circumstance. Further, this combined effect was not a simple addition of effects but

    potentiation
    SYMPTOMS

. The serious implications of this phenomenon are discussed.

Hearing loss
hearing loss
hearing loss
potentiation


Cardiac valvular anomalies in Fabry disease. Clinical, morphologic, and biochemical studies.

The cardiovascular abnormalities were investigated in two unrelated hemizygous males with Fabry disease who had clinical mitral insufficiency. Postmortem examination of their hearts revelaed anatomic, ultrastructural and biochemical abnormalities resulting from defective activity of the lysosomal enzyme, alpha-galactosidase A. The ultrastructural and biochemical studies demonstrated the marked accumulation of the major glycosphingolipd substrate, trihexosyl ceramide, in the lyosomes of all the cardiac tissues examined; the greatest concentrations were found in the mitral valve and elft ventricular myocardium. Intriguingly, digalactosyl ceramide, a glycosphingolipid substrate not detectable in normal lung, vessel or cardiac tissues, was found increased only in the lung and right heart tissues. Morphologic and chemical examination of cardiac and systemic vessels demonstrated accumulation of trihexosyl ceramide in lysosomes of the vascular endothelium. These studies demonstrate that the progressive accumulation of trihexosyl ceramide in the lysosomes of the cardiac structures and vascular system leads to the multiple cardiovascular manfiestation of Fabry disease.

The

    cardiovascular abnormalities
    SYMPTOMS

 were investigated in two unrelated

    hemizygous males
    FAMILY

 with

    Fabry disease
    DIAGNOSIS

 who had

    clinical mitral insufficiency
    SYMPTOMS

.

    Postmortem examination of their hearts
    PARACLINICAL

 revelaed

    anatomic, ultrastructural and biochemical abnormalities
    SYMPTOMS

 resulting from defective activity of the lysosomal enzyme, alpha-galactosidase A. The

    ultrastructural and biochemical studies
    PARACLINICAL

 demonstrated the

    marked accumulation of the major glycosphingolipd substrate, trihexosyl ceramide, in the lyosomes of all the cardiac tissues examined
    MICROSCOPIC

; the

    greatest concentrations were found in the mitral valve and elft ventricular myocardium
    MICROSCOPIC

. Intriguingly,

    digalactosyl ceramide, a glycosphingolipid substrate not detectable in normal lung, vessel or cardiac tissues
    MICROSCOPIC

,

    was found increased only in the lung and right heart tissues
    MICROSCOPIC

.

    Morphologic and chemical examination of cardiac and systemic vessels
    PARACLINICAL

 demonstrated

    accumulation of trihexosyl ceramide in lysosomes of the vascular endothelium
    MICROSCOPIC

. These studies demonstrate that the

    progressive accumulation of trihexosyl ceramide in the lysosomes of the cardiac structures and vascular system
    MICROSCOPIC

 leads to the

    multiple cardiovascular manfiestation
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

.


Angiokeratoma corporis diffusum (Fabry disease). A lysosomal disease.

Angiokeratoma corporis diffusum (Fabry disease) is an X-linked recessive disease. We had an opportunity to examine a heterozygous female patient with angiokeratoma and cornea verticillata. The patient's serum alpha-galactosidase activity was reported to be about 50% of normal. Skin lesion biopsy specimens were stained with electron microscopic acid phsophatase (ACP), with proper controls. Acid phosphatase activity was demonstrable within membrane-bound inclusions of cutaneous vascular endothelial cells. This suggested that the accumulation of abnormal glycolipids in the vascular cells occurs in the lysosomes.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 (

    Fabry disease)
    DIAGNOSIS

 is an

    X-linked recessive disease
    GENETICS

. We had an opportunity to examine a

    heterozygous
    GENETICS

    female
    GENDER

 patient with

    angiokeratoma
    SYMPTOMS

 and

    cornea verticillata
    SYMPTOMS

. The patient's

    serum alpha-galactosidase activity was reported to be about 50% of normal
    BIOCHEMICAL

.

    Skin lesion biopsy specimens
    PARACLINICAL

 were

    stained with electron microscopic acid phsophatase (ACP)
    PARACLINICAL

, with proper controls.

    Acid phosphatase activity was demonstrable within membrane-bound inclusions of cutaneous vascular endothelial cells
    MICROSCOPIC

. This suggested that the

    accumulation of abnormal glycolipids in the vascular cells occurs in the lysosomes
    MICROSCOPIC

.

Angiokeratoma corporis diffusum
angiokeratoma
cornea verticillata


Oral lesions in fucosidosis.

The oral lesions in two previously reported cases of fucosidosis are discussed. The patients have coarse facies, severe mental retardation, spondyloepiphyseal dysplasia, deficiency of a-L-fucosidase, and red punctate lesions of the skin and oral mucosa. Gingival biopsy specimens showed that these lesions were identical to the angiokeratoma corporis diffusum reported in Fabry's disease, but had different locations. Because of the slowly progressing psychomotor retardation and recurrent upper respiratory tract infections that the prognosis for patients with this disease is poor. Treatment appears to be aimed at early diagnosis through amniocentesis.

The

    oral lesions
    SYMPTOMS

 in two previously reported cases of

    fucosidosis
    DIAGNOSIS

 are discussed. The patients have

    coarse facies
    SYMPTOMS

,

    severe mental retardation
    SYMPTOMS

,

    spondyloepiphyseal dysplasia
    DIAGNOSIS

,

    deficiency of a-L-fucosidase
    BIOCHEMICAL

, and

    red punctate lesions of the skin and oral mucosa
    SYMPTOMS

.

    Gingival biopsy specimens
    PARACLINICAL

 showed that these

    lesions were identical to the angiokeratoma corporis diffusum
    SYMPTOMS

 reported in

    Fabry's disease
    MICROSCOPIC

, but had different locations. Because of the

    slowly progressing psychomotor retardation
    SYMPTOMS

 and

    recurrent upper respiratory tract infections
    SYMPTOMS

 that the prognosis for patients with this disease is poor. Treatment appears to be aimed at early diagnosis through

    amniocentesis
    PARACLINICAL

.


Fucosidosis type 2.

Two siblings, 9 and 4 1/2 years old, had alpha-L-fucosidase deficiency, angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facila features, and dysostosis multiplex. It appears that genetic heterogeneity is present in fucosidosis; there are at least two types. In type 1, patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. In type 2, patients have angiokeratoma, milder psychomotor retardation and neurologic signs, longer survival, and normal salinity in the sweat. Quantitative studies on erythrocytes and in saliva disclosed severely increased expressions of Lea and Leb. Biopsies of skin and gingiva showed alterations as seen in angiokeratoma. There was also evidence of lysosomal storage in vascular endothelium, eccrine sweat gland epithelium, and fibroblasts of the skin.

    Two siblings, 9 and 4 1/2 years old
    FAMILY

, had

    alpha-L-fucosidase deficiency
    BIOCHEMICAL

,

    angiokeratoma
    SYMPTOMS

,

    progressive psychomotor retardation
    SYMPTOMS

,

    neurologic signs
    SYMPTOMS

,

    coarse facila features
    SYMPTOMS

, and

    dysostosis multiplex
    DIAGNOSIS

. It appears that

    genetic heterogeneity
    GENETICS

 is present in

    fucosidosis
    DIAGNOSIS

; there are at least two types. In type 1, patients have

    no vascular lesions
    NEG_FINDINGS

, but have

    rapid psychomotor regression
    SYMPTOMS

,

    severe and rapidly progressing neurologic signs
    SYMPTOMS

,

    elevated sodium and chloride excretion in the sweat
    BIOCHEMICAL

, and

    fatal outcome
    SYMPTOMS

    before the sixth year
    AGE

. In

    type 2
    DIAGNOSIS

, patients have

    angiokeratoma
    SYMPTOMS

,

    milder psychomotor retardation
    SYMPTOMS

    and neurologic signs
    SYMPTOMS

,

    longer survival
    SYMPTOMS

, and

    normal salinity in the sweat
    NEG_FINDINGS

.

    Quantitative studies on erythrocytes and in saliva
    PARACLINICAL

 disclosed

    severely increased expressions of Lea and Leb
    BIOCHEMICAL

.

    Biopsies of skin and gingiva
    PARACLINICAL

 showed

    alterations as seen in angiokeratoma
    SYMPTOMS

. There was also

    evidence of lysosomal storage in vascular endothelium, eccrine sweat gland epithelium, and fibroblasts of the skin
    MICROSCOPIC

.

no vascular lesions
normal salinity in the sweat


B.C.P. Jansen Institute, University of Amsterdam, Amsterdam, The Netherlands.

In a patient with Fabry's disease who had undergone kidney transplantation to correct uremia, the neutral glycosphingolipids and alpha-galactosidase activity have been measured in plasma and urine and, 9 months later, after the death of the patient, in autopsy material. After transplantation, there was no significant increase in alpha-galactosidase activity in plasma; the activity found never exceeded 3% of the mean control value. A striking parallelism was found during the follow-up period in the increase and decrease of trihexosylceramide and globoside and also of glucosylceramide and dihexosylceramide. The alpha-galactosidase activity in spleen and liver was as low as that observed in untreated Fabry hemizygotes. These data and those obtained from autopsy material provide evidence that renal transplantation does not lead to a specific enzymic breakdown of trihexosylceramide in Fabry patients. However, no trihexosylceramide accumulation was observed in the transplanted kidney.

In a patient with

    Fabry's disease
    DIAGNOSIS

 who had undergone

    kidney transplantation
    MEDICATION

 to correct

    uremia
    DIAGNOSIS

, the

    neutral glycosphingolipids and alpha-galactosidase activity
    BIOCHEMICAL

 have been

    measured in plasma and urine
    BIOCHEMICAL

 and, 9 months later, after the death of the patient, in

    autopsy material
    PARACLINICAL

. After

    transplantation
    MEDICATION

, there was

    no significant increase in alpha-galactosidase activity in plasma
    NEG_FINDINGS

;

    the activity found never exceeded 3% of the mean control value
    BIOCHEMICAL

. A striking parallelism was found during the follow-up period in the

    increase and decrease of trihexosylceramide and globoside
    BIOCHEMICAL

 and also

    of glucosylceramide and dihexosylceramide
    MICROSCOPIC

.

    The alpha-galactosidase activity in spleen and liver was as low as that observed in untreated Fabry hemizygotes
    BIOCHEMICAL

. These data and those obtained from autopsy material provide evidence that

    renal transplantation
    MEDICATION

 does not lead to a

    specific enzymic breakdown of trihexosylceramide
    NEG_FINDINGS

 in

    Fabry
    DIAGNOSIS

 patients. However,

    no trihexosylceramide accumulation was observed in the transplanted kidney
    NEG_FINDINGS

.

kidney transplantation
transplantation
renal transplantation


[Fabry-Anderson's disease].

Fabry's disease was originally considered a skin disease. Mainly affected are epidermis, kidney, heart and vessels. Newer studies show that the disease is an inherited defect of metabolism with abnormal accumulation of "Zeramid-Tri- or-Dihexoside" in different organs. The main clinical symptoms are epidermal changes, cornea verticillata and kidney changes. The diagnosis is verified by kidney biopsy or biochemical analysis of blood and urine. The activity of alpha-galactosidase in the blood is reduced, the secretion of Zeramid-Trihexoside in urine is increased. Causal therapy still does not exist, different methodes of treatment are discussed but still in the experimental stage. A case report is given.

    Fabry's disease
    DIAGNOSIS

 was originally considered a

    skin disease
    DIAGNOSIS

. Mainly affected are

    epidermis, kidney, heart and vessels
    SYMPTOMS

. Newer studies show that the disease is an

    inherited defect of metabolism
    GENETICS

 with

    abnormal accumulation of "Zeramid-Tri- or-Dihexoside" in different organs
    MICROSCOPIC

. The main clinical symptoms are

    epidermal changes
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

 and

    kidney changes
    SYMPTOMS

. The diagnosis is verified by

    kidney biopsy
    PARACLINICAL

 or

    biochemical analysis of blood and urine
    PARACLINICAL

. The

    activity of alpha-galactosidase in the blood is reduced
    BIOCHEMICAL

, the

    secretion of Zeramid-Trihexoside in urine is increased
    MICROSCOPIC

. Causal therapy still does not exist, different methodes of treatment are discussed but still in the experimental stage. A case report is given.

epidermis, kidney, heart and vessels
epidermal changes
cornea verticillata
kidney changes


Cardiac manifestations of Fabry's disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction.

The light and electron microscopic findings in the heart of a patient with Fabry's disease are described. The study revealed that all cardiac tissues, including the conducting tissues and the valves, were involved. The latter finding was of particular interest since the patient was known to have mitral insufficiency. The findings of diffuse ballooning of the mitral valve with localized "overshoot" and massive glycolipid storage in the valve substance suggest that the abnormal storage process was itself responsible for the valvular insufficiency. The widespread involvement of the myocardium and conducting tissues is consistent with the elelctrocardiographic changes indicating infarction, although myocardial necrosis was not observed. The findings in this case suggest that the cardiac manifestations in Fabry's disease can be either primary, that is, directly related to the enzyme deficiency, or secondary, that is, evolving with time as a consequence of the disease.

The

    light and electron microscopic findings in the heart
    PARACLINICAL

 of a patient with

    Fabry's disease
    DIAGNOSIS

 are described. The study revealed that

    all cardiac tissues, including the conducting tissues and the valves, were involved
    SYMPTOMS

. The latter finding was of particular interest since the patient was known to have

    mitral insufficiency
    SYMPTOMS

. The findings of

    diffuse ballooning of the mitral valve with localized "overshoot"
    SYMPTOMS

 and

    massive glycolipid storage in the valve substance
    MICROSCOPIC

 suggest that the

    abnormal storage process
    MICROSCOPIC

 was itself responsible for the

    valvular insufficiency
    SYMPTOMS

. The

    widespread involvement of the myocardium and conducting tissues
    SYMPTOMS

 is consistent with the

    elelctrocardiographic changes indicating infarction
    SYMPTOMS

, although

    myocardial necrosis was not observed
    NEG_FINDINGS

. The findings in this case suggest that the

    cardiac manifestations
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 can be either primary, that is, directly related to the

    enzyme deficiency
    BIOCHEMICAL

, or secondary, that is, evolving with time as a consequence of the disease.


Metabolism of neutral glycosphingolipids in plasma of a normal human and a patient with Fabry's disease.

[6-2H2]Glucose was used as a tracer for a comparative study on the metabolism of the neutral glycosylceramides in plasma of a control subject and a patient with Fabry's disease. The incorporation of the tracer into the glucosyl and galactosyl moieties of the glycosphingolipids was measured by gas chromatography-mass spectrometry of the tetra-0-acetyl methyl glycoside derivatives. Experiments on the precision and accuracy for measurements of [6,6-2H2]hexose in a sample demonstrated that incorporation of 0.2% or more of [6,6-2H2]glucose could be detected with a 95% confidence limit of +/-0.16%. The labeled substrate (35g) was infused into each subject with a 5-g priming dose and the remainder administered at a constant rate of 3 g/hour over a 10-hour period. During the infusion, the plasma glucose of each subject attained a concentration of about 30% [6,6-2H2]glucose which diminished rapidly after the administration of substrate was complete. A concentration of 0.8% [6,6-2H2]glucose was observed in glucosylceramide (GL-la) from plasma of both subjects between 48 and 72 hours after the infusion began. The label disappeared from this lipid at a logarithmic rate and 0.2% or less of the molecules were labeled 9 days after the experiment began. In contrast to the results with GL-la, the maximum incorporation of [6,6-2H2]hexose into lactosylceramide (galactosyl-(beta1 leads to 4)-glucosylceramide) was 2-fold higher in the Fabry patient (1.6%) than in the control (0.8%). The trihexosylceramide (galactosyl-(alpha1 leads to 4)-galactosyl-(beta1 leads to 4)-glucosylceramide, GL-3a) from plasma of the control reached a maximum of 0.4% [6,6-2H2]hexose in both the glucosyl and galactosyl moieties whereas the GL-3a from the Fabry patient was not significantly labeled. The maximal labeling of the GL-4a fraction (N-acetyl-galactosaminyl-galactosyl-galactosyl-glucosylceramide) was slightly depressed in the Fabry patient (0.4%) as compared to the control (0.7%). Turnover times for the glycosphingolipids of plasma were calculated to be from 4 to 8 days and the turnover rates were from 1 to 6 mumol/day.

[

    6-2H2]Glucose
    PARACLINICAL

 was used as a tracer for a comparative study on the

    metabolism of the neutral glycosylceramides in plasma
    MICROSCOPIC

 of a control subject and a patient with

    Fabry's disease
    DIAGNOSIS

. The

    incorporation of the tracer into the glucosyl and galactosyl moieties of the glycosphingolipids
    MICROSCOPIC

 was measured by

    gas chromatography-mass spectrometry of the tetra-0-acetyl methyl glycoside derivatives
    PARACLINICAL

. Experiments on the precision and accuracy for measurements of [6,6-2H2]hexose in a sample demonstrated that

    incorporation of 0.2% or more of [6,6-2H2]glucose
    MICROSCOPIC

 could be detected with a 95% confidence limit of +/-0.16%. The

    labeled substrate (35g)
    PARACLINICAL

 was infused into each subject

    with a 5-g priming dose and the remainder administered at a constant rate of 3 g/hour over a 10-hour period
    MEDICATION

. During the infusion,

    the plasma glucose of
    BIOCHEMICAL

 each subject

    attained a concentration of about 30% [6,6-2H2]glucose which diminished
    BIOCHEMICAL

 rapidly after the administration of substrate was complete. A

    concentration of 0.8% [6,6-2H2]glucose was observed in glucosylceramide (GL-la) from plasma
    MICROSCOPIC

 of both subjects between 48 and 72 hours after the infusion began.

    The label disappeared from this lipid at a logarithmic rate
    MICROSCOPIC

 and

    0.2% or less of the molecules were labeled
    MICROSCOPIC

 9 days after the experiment began. In contrast to the results with

    GL-la
    MICROSCOPIC

, the

    maximum incorporation of [6,6-2H2]hexose into lactosylceramide (galactosyl-(beta1 leads to 4)-glucosylceramide)
    MICROSCOPIC

 was 2-fold higher in the

    Fabry
    DIAGNOSIS

 patient (

    1.6%
    MICROSCOPIC

) than in the control (0.8%).

    The trihexosylceramide (galactosyl-(alpha1 leads to 4)-galactosyl-(beta1 leads to 4)-glucosylceramide, GL-3a) from plasma
    MICROSCOPIC

 of the control

    reached a maximum of 0.4% [6,6-2H2]hexose in both the glucosyl and galactosyl moieties
    MICROSCOPIC

 whereas the

    GL-3a
    MICROSCOPIC

 from the

    Fabry
    DIAGNOSIS

 patient

    was not significantly labeled
    NEG_FINDINGS

. The

    maximal labeling of the GL-4a fraction (N-acetyl-galactosaminyl-galactosyl-galactosyl-glucosylceramide) was slightly depressed
    MICROSCOPIC

 in the

    Fabry
    DIAGNOSIS

 patient

    (0.4%)
    BIOCHEMICAL

 as compared to the control (

    0.7%
    BIOCHEMICAL

).

    Turnover times for the glycosphingolipids of plasma
    BIOCHEMICAL

 were calculated to be from 4 to 8 days and the

    turnover rates were from 1 to 6 mumol/
    BIOCHEMICAL

day.


[Renal transplantation in patients suffering from Fabry's disease. Kidney transplantation from an heterozygote subject to a subject without Fabry's disease].

We report the case of a renal transplantation performed with the kidney of an asymptomatic female carrier of Fabry's disease. The recipient, her daughter, had normal alpha-galactosidase levels. Eight years after transplantation, the characteristic lesions of the glomerular epithelial cells, noted as early as 11 days after transplantation, are unchanged on the successive biopsies. This observation suggests that 1) some heterozygotes (perhaps all of them) have glomerular changes, 2) the glomerular changes are not modified if the kidney is placed in a normal enzymatic "environment".

We report the case of a

    renal transplantation performed with the kidney
    MEDICATION

 of an

    asymptomatic
    NEG_FINDINGS

    female
    GENDER

    carrier of Fabry's disease
    FAMILY

. The recipient, her daughter, had

    normal alpha-galactosidase levels
    NEG_FINDINGS

. Eight years after

    transplantation
    MEDICATION

, the

    characteristic lesions of the glomerular epithelial cells
    MICROSCOPIC

, noted as early as 11 days after

    transplantation
    MEDICATION

, are unchanged on the

    successive biopsies
    PARACLINICAL

. This observation suggests that 1) some

    heterozygotes
    GENETICS

 (perhaps all of them) have

    glomerular changes
    SYMPTOMS

, 2) the

    glomerular changes are not modified
    NEG_FINDINGS

 if the kidney is placed in a

    normal enzymatic "environment"
    NEG_FINDINGS

.

asymptomatic
normal alpha-galactosidase levels
glomerular changes are not modified
normal enzymatic "environment"


Case 11, Part 2. Angiokeratoma corporis diffusum (Fabry's disease).

A case of Fabry's disease is reported. The patient had multiple supernumerary, impacted, and unerupted teeth and other developmental abnormalities of the facial skeleton. The patient tolerated surgical removal of impacted and unerupted teeth without complications. However, this did not relieve the facial pain. The expected prognosis of this patient will be a continued vascular and renal degeneration with death probable before the age of 50 years if the disease is untreated. Currently, the patient is being considered as a possible candidate for renal transplantation.

A case of

    Fabry's disease
    DIAGNOSIS

 is reported. The patient had

    multiple supernumerary, impacted, and unerupted teeth
    SYMPTOMS

 and other

    developmental abnormalities of the facial skeleton
    SYMPTOMS

. The patient tolerated

    surgical removal of impacted and unerupted teeth
    MEDICATION

    without complications
    NEG_FINDINGS

. However, this

    did not relieve the facial pain
    NEG_FINDINGS

. The expected prognosis of this patient will be a

    continued vascular and renal degeneration
    SYMPTOMS

 with

    death
    SYMPTOMS

 probable

    before the age of 50 years
    AGE

 if the disease is untreated. Currently, the patient is being considered as a possible candidate for

    renal transplantation
    MEDICATION

.

without complications
did not relieve the facial pain


[Angiokeratoma corporis diffusum (Fabry's disease). Biochemical diagnosis in plasma].

In a 35-year-old man with the full picture of Fabry's disease there was an almost fourfold increase of trihexosylceramide concentration in plasma and a decrease in the alpha-galactosidase activity to 13 percent as compared with the values from a control group. Using the same biochemical methods it could be shown that two nephews of the patient are hemizygote carriers and that two sisters and the mother of the patient are heterozygote carriers. Causative treatment of the disease is unknown. In this patient the attacks of pain could be permanently improved with phenytoin and carbamazepin.

In a

    35-year-old
    AGE

    man
    GENDER

 with the full picture of

    Fabry's disease
    DIAGNOSIS

 there was an

    almost fourfold increase of trihexosylceramide concentration in plasma
    BIOCHEMICAL

 and a

    decrease in the alpha-galactosidase activity to 13 percent
    BIOCHEMICAL

 as compared with the values from a control group. Using the same biochemical methods it could be shown that

    two nephews of the patient are hemizygote carriers and that two sisters and the mother of the patient are heterozygote carriers
    FAMILY

. Causative treatment of the disease is unknown. In this patient the

    attacks of pain
    SYMPTOMS

 could be

    permanently improved
    SYMPTOMS

 with

    phenytoin and carbamazepin
    MEDICATION

.


On the diagnosis of Fabry's disease.

Fabry's disease is a recessive X-linked inborn error of metabolism due to deficiency of the lysosomal enzyme alpha-galactosidase. The large variety of symptoms may make the diagnosis difficult. A severely afflicted female patient is presented. For several years she had been treated under the diagnosis polyarteritis nodosa until the characteristic cutaneous lesions of Fabry's disease were recognized. Enzymatic studies and electronmicroscopic examinations confirmed the diagnosis. A symptomatic effect of corticosteroid treatment was proven. The grave prognosis, the recent attempts at enzyme substitution therapy and the possibility of preventing new cases by prenatal diagnosis should stimulate the efforts of the clinician to diagnose the disease.

    Fabry's disease
    DIAGNOSIS

 is a

    recessive X-linked inborn error of metabolism
    GENETICS

 due to

    deficiency of the lysosomal enzyme alpha-galactosidase
    BIOCHEMICAL

. The large variety of symptoms may make the diagnosis difficult. A severely afflicted

    female
    GENDER

 patient is presented. For several years

    she
    GENDER

 had been treated under the diagnosis

    polyarteritis nodosa
    DIAGNOSIS

 until the

    characteristic cutaneous lesions of Fabry's disease
    SYMPTOMS

 were recognized.

    Enzymatic studies
    PARACLINICAL

 and

    electronmicroscopic examinations
    PARACLINICAL

 confirmed the diagnosis. A symptomatic effect of

    corticosteroid treatment
    MEDICATION

 was proven. The grave prognosis, the recent attempts at

    enzyme substitution therapy
    MEDICATION

 and the possibility of preventing new cases by prenatal diagnosis should stimulate the efforts of the clinician to diagnose the disease.

corticosteroid treatment
enzyme substitution therapy


Large Mesenteric Gaucheroma Responds to Substrate Reduction Therapy: A New Management of Gaucheromas.

Gaucheromas, which are pseudotumors consisting of a cluster of Gaucher cells, are rare complications in Gaucher's disease (GD) and reported in patients treated with enzyme replacement therapy (ERT). Gaucheromas commonly develop in the lymph nodes in the mesenteric and mediastinal regions and can cause serious complications including protein-losing enteropathy. A large mesenteric Gaucheroma showed a significant reduction in size after initiation of substrate reduction therapy (SRT) with eliglustat in an adult patient with GD type 3. Combination therapy with ERT and SRT should be considered to prevent Gaucheromas in patients with GD.

    Gaucheromas
    MICROSCOPIC

, which are

    pseudotumors consisting of a cluster of Gaucher cells
    MICROSCOPIC

, are rare complications in

    Gaucher's disease (GD)
    DIAGNOSIS

 and reported in patients treated with

    enzyme replacement therapy (ERT)
    MEDICATION

.

    Gaucheromas
    MICROSCOPIC

 commonly develop in the

    lymph nodes in the mesenteric and mediastinal regions
    MICROSCOPIC

 and can cause serious complications including

    protein-losing enteropathy
    BIOCHEMICAL

. A

    large mesenteric Gaucheroma
    MICROSCOPIC

    showed a significant reduction in size
    SYMPTOMS

 after

    initiation of substrate reduction therapy (SRT) with eliglustat
    MEDICATION

 in an

    adult
    AGE

 patient with

    GD type 3
    DIAGNOSIS

.

    Combination therapy with ERT and SRT
    MEDICATION

 should be considered to prevent

    Gaucheromas
    MICROSCOPIC

 in patients with

    GD
    DIAGNOSIS

.


Gaucher disease: A cause of massive splenomegaly in a 15-year-old black African male.

Patients with Gaucher disease (GD), a rare autosomal recessive lysosomal storage disease, commonly present to paediatricians with massive splenomegaly. While the diagnosis and management of patients with this chronic multisystem disorder has evolved significantly in recent years, the initial diagnosis represents a challenge. We describe the case of a 15-year-old black African male who presented with abdominal distension, delayed growth and fatigue. Initial laboratory studies revealed severe anaemia (haemoglobin concentration 8 g/dL) and moderate thrombocytopenia (platelet count 80 × 109/L). A computed tomography scan of the abdomen showed an enlarged liver of 173 mm and massive splenomegaly of 27 mm. The diagnosis of GD was confirmed by reduced beta-glucocerebrosidase activity and heterozygous mutations in the GBA1 gene. The patient was managed at a dedicated paediatric haematology unit with enzyme replacement therapy and regular clinical, biochemical and radiological monitoring.

Patients with

    Gaucher disease (GD)
    DIAGNOSIS

, a

    rare autosomal recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

, commonly present to

    paediatricians
    PARACLINICAL

 with

    massive splenomegaly
    SYMPTOMS

. While the diagnosis and management of patients with this

    chronic multisystem disorder
    DIAGNOSIS

 has evolved significantly in recent years, the initial diagnosis represents a challenge. We describe the case of a

    15-year-old
    AGE

    black African
    ETHNICITY

    male
    GENDER

 who presented with

    abdominal distension
    SYMPTOMS

,

    delayed growth
    SYMPTOMS

 and

    fatigue
    SYMPTOMS

. Initial

    laboratory studies
    PARACLINICAL

 revealed

    severe anaemia (haemoglobin concentration 8 g/dL)
    BIOCHEMICAL

 and

    moderate thrombocytopenia (platelet count 80 × 109/L)
    BIOCHEMICAL

. A

    computed tomography scan of the abdomen
    PARACLINICAL

 showed an

    enlarged liver of 173 mm
    SYMPTOMS

 and

    massive splenomegaly of 27 mm
    SYMPTOMS

. The diagnosis of

    GD
    DIAGNOSIS

 was confirmed by

    reduced beta-glucocerebrosidase activity
    BIOCHEMICAL

 and

    heterozygous mutations in the GBA1 gene
    GENETICS

. The patient was managed at a

    dedicated paediatric haematology unit
    MEDICATION

 with

    enzyme replacement therapy
    MEDICATION

 and

    regular clinical, biochemical and radiological monitoring
    PARACLINICAL

.

Gaucher disease (GD)
lysosomal storage disease
chronic multisystem disorder
GD

rare autosomal recessive
heterozygous mutations in the GBA1 gene

massive splenomegaly
abdominal distension
delayed growth
fatigue
enlarged liver of 173 mm
massive splenomegaly of 27 mm

dedicated paediatric haematology unit
enzyme replacement therapy


Long-term efficacy of low-dose perampanel for progressive myoclonus epilepsy in a patient with Gaucher disease type 3.

We report the case of a patient with progressive myoclon epilepsy due to Gaucher disease type 3 whose seizures and ability to perform activities of daily living were significantly improved after starting low-dose perampanel therapy.

Our patient's generalized tonic-clonic seizures and myoclonus did not improve despite the administration of multiple antiseizure medications and enzyme replacement therapy. The myoclonus reduced following pharmacological chaperone therapy, but this effect was temporary, and the generalized tonic-clonic seizures continued to occur. However, the generalized tonic-clonic seizures disappeared following treatment with 2 mg/day of perampanel. In addition, the decrease in myoclonus dramatically improved motor function such as talking, eating, and walking and stabilized the patient's mental status. These effects have been sustained for more than 4 years.

Perampanel is expected to be effective in the treatment of progressive myoclon epilepsy associated with Gaucher disease type 3 and should be considered the drug of choice for this condition.

We report the case of a patient with

    progressive myoclon epilepsy
    SYMPTOMS

 due to

    Gaucher disease type 3
    DIAGNOSIS

 whose

    seizures and ability to perform activities of daily living were significantly improved
    SYMPTOMS

 after starting

    low-dose perampanel therapy
    MEDICATION

.

Our patient's

    generalized tonic-clonic seizures
    SYMPTOMS

 and

    myoclonus
    SYMPTOMS

    did not improve despite the administration of multiple antiseizure medications and enzyme replacement therapy
    NEG_FINDINGS

. The

    myoclonus reduced
    SYMPTOMS

 following

    pharmacological chaperone therapy
    MEDICATION

, but this effect was temporary, and the

    generalized tonic-clonic seizures continued to occur
    SYMPTOMS

. However, the

    generalized tonic-clonic seizures
    SYMPTOMS

 disappeared following

    treatment with 2 mg/day of perampanel
    MEDICATION

. In addition, the

    decrease in myoclonus
    SYMPTOMS

 dramatically

    improved motor function such as talking, eating, and walking
    SYMPTOMS

 and

    stabilized the patient's mental status
    SYMPTOMS

. These effects have been sustained for more than 4 years.

    Perampanel
    MEDICATION

 is expected to be effective in the treatment of

    progressive myoclon epilepsy
    DIAGNOSIS

    associated with Gaucher disease type 3
    DIAGNOSIS

 and should be considered the drug of choice for this condition.

Gaucher disease type 3
progressive myoclon epilepsy
associated with Gaucher disease type 3

low-dose perampanel therapy
pharmacological chaperone therapy
treatment with 2 mg/day of perampanel
Perampanel


Novel Management and Screening Approaches for Haematological Complications of Gaucher's Disease.

Gaucher disease (GD) is the most common lysosomal storage disorder. The principal manifestations for its diagnosis and further monitoring include haematological manifestations such as anaemia, thrombocytopaenia, spleen enlargement, and bleeding disorders, among others. This review aims to summarise and update the role of haematological complications in GD diagnosis and follow-up, describe their management strategies, and to use these indicators as part of the diagnostic approach.

A systematic review following the recommendations of PRISMA-P 2020 was carried out. Publications indexed in the databases PubMed, Embase, Science Open, Mendeley, and Web of Science were electronically searched by three independent reviewers, and publications up to June 2021 were accessed. A total of 246 publications were initially listed, of which 129 were included for further review and analysis. Case reports were considered if they were representative of a relevant hematologic complication.

From the first review dated in 1974 to the latest publication in 2021, including different populations confirmed that the haematological manifestations such as thrombocytopaenia and splenomegaly at diagnosis of GD type 1 are the most frequent features of the disease. The incorporation of haematological parameters to diagnosis strategies increases their cost-effectiveness. Hematologic parameters are part of the scoring system for disease assessment and the evaluation of therapeutic outcomes, providing reliable and accessible data to improve the management of GD. However, cytopaenia, underlying coagulation disorders, and platelet dysfunction need to be addressed, especially during pregnancy or surgery. Long-term haematological complications include the risk of neoplasia and immune impairment, an area of unmet need that is currently under research.

Haematological features are key for GD suspicion, diagnosis, and management. Normalization of hematological parameters is achieved with the treatment; however, there are unmet needs such as the underlying inflammatory status and the long-term risk of hematologic neoplasia.

    Gaucher disease (GD)
    DIAGNOSIS

 is the most common

    lysosomal storage disorder
    DIAGNOSIS

. The principal manifestations for its diagnosis and further monitoring include

    haematological manifestations
    SYMPTOMS

 such as

    anaemia
    BIOCHEMICAL

,

    thrombocytopaenia
    BIOCHEMICAL

,

    spleen enlargement
    SYMPTOMS

, and

    bleeding disorders
    SYMPTOMS

, among others. This review aims to summarise and update the role of

    haematological complications
    BIOCHEMICAL

 in

    GD
    DIAGNOSIS

 diagnosis and follow-up, describe their management strategies, and to use these indicators as part of the diagnostic approach.

A systematic review following the recommendations of PRISMA-P 2020 was carried out. Publications indexed in the databases PubMed, Embase, Science Open, Mendeley, and Web of Science were electronically searched by three independent reviewers, and publications up to June 2021 were accessed. A total of 246 publications were initially listed, of which 129 were included for further review and analysis. Case reports were considered if they were representative of a relevant

    hematologic complication
    DIAGNOSIS

.

From the first review dated in 1974 to the latest publication in 2021, including different populations confirmed that the

    haematological manifestations
    SYMPTOMS

 such as

    thrombocytopaenia
    BIOCHEMICAL

 and

    splenomegaly
    SYMPTOMS

 at diagnosis of

    GD type 1
    DIAGNOSIS

 are the most frequent features of the disease. The incorporation of

    haematological parameters
    PARACLINICAL

 to diagnosis strategies increases their cost-effectiveness.

    Hematologic parameters
    PARACLINICAL

 are part of the scoring system for disease assessment and the evaluation of therapeutic outcomes, providing reliable and accessible data to improve the management of

    GD
    DIAGNOSIS

. However,

    cytopaenia
    BIOCHEMICAL

,

    underlying coagulation disorders
    BIOCHEMICAL

, and

    platelet dysfunction
    BIOCHEMICAL

 need to be addressed, especially during

    pregnancy
    MEDICATION

 or

    surgery
    MEDICATION

.

    Long-term haematological complications
    SYMPTOMS

 include the risk of

    neoplasia
    SYMPTOMS

 and

    immune impairment
    SYMPTOMS

, an area of unmet need that is currently under research.

    Haematological features
    PARACLINICAL

 are key for

    GD
    DIAGNOSIS

 suspicion, diagnosis, and management.

    Normalization of hematological parameters
    BIOCHEMICAL

 is achieved with the treatment; however, there are unmet needs such as the underlying inflammatory status and the long-term risk of

    hematologic neoplasia
    DIAGNOSIS

.

Gaucher disease (GD)
lysosomal storage disorder
GD
hematologic complication
GD type 1
GD
GD
hematologic neoplasia

haematological manifestations
spleen enlargement
bleeding disorders
haematological manifestations
splenomegaly
Long-term haematological complications
neoplasia
immune impairment


Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan.

Gaucher disease (GD) is caused by reduced lysosomal enzyme β-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD. METHODS: All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed. RESULTS: In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results. CONCLUSION: PMS data from patients with types 1-3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan.

NCT03625882 registered July 2014.

    Gaucher disease (GD)
    DIAGNOSIS

 is caused by

    reduced lysosomal enzyme β-glucocerebrosidase activity
    BIOCHEMICAL

. Heterogeneous genotypes and phenotypes have been observed within

    GD
    DIAGNOSIS

 types and across ethnicities.

    Enzyme replacement therapy
    MEDICATION

 is generally recommended for patients with

    type 1 GD
    DIAGNOSIS

, the least severe form of

    GD
    DIAGNOSIS

. In

    Japan
    ETHNICITY

,

    velaglucerase alfa
    MEDICATION

 has a broad indication covering

    type 1, 2 or 3 GD
    DIAGNOSIS

. METHODS: All patients with

    type 1, 2, or 3 GD
    DIAGNOSIS

 administered

    velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion
    MEDICATION

 after its launch date in

    Japan
    ETHNICITY

 in 2014, were enrolled in a non-interventional,

    observational post-marketing surveillance (PMS)
    PARACLINICAL

. Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of

    infusion-related reactions (IRRs)
    SYMPTOMS

, the safety of

    velaglucerase alfa
    MEDICATION

 in patients with

    types 2 and 3 GD
    DIAGNOSIS

, from patients

    under one year of age
    AGE

 to

    elderly
    AGE

 patients (

    ≥ 65 years of age
    AGE

). Long-term efficacy was also assessed. RESULTS: In total, 53 patients with

    GD
    DIAGNOSIS

 were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen

    adverse drug reactions (ADRs)
    SYMPTOMS

 were reported in seven patients. All reported

    ADRs
    SYMPTOMS

 occurred in patients with

    type 2 GD
    DIAGNOSIS

.

    ADRs
    SYMPTOMS

 were reported by 63.6% (7/11) of patients with

    type 2 GD
    DIAGNOSIS

. Ten

    ADRs
    SYMPTOMS

 were reported in five patients

    aged < 4 years
    AGE

.

    No elderly patients experienced any ADR
    NEG_FINDINGS

 during the surveillance period. Five

    ADRs
    SYMPTOMS

 occurring in three (10.0%) patients were classified as

    IRRs
    SYMPTOMS

, with one case of

    vomiting (moderate severity)
    SYMPTOMS

 resulting in

    treatment discontinuation
    MEDICATION

. Ten

    serious adverse events
    SYMPTOMS

 were reported in five (16.7%) patients. Three

    fatal events were considered to be unrelated to treatment with velaglucerase alfa
    SYMPTOMS

.

    Platelet counts increased
    BIOCHEMICAL

 after the

    administration of velaglucerase alfa
    MEDICATION

    and were generally maintained within the normal range over the administration period
    BIOCHEMICAL

. Among eleven patients tested for

    neutralizing anti-velaglucerase alfa antibodies
    BIOCHEMICAL

, two (18.2%) were assessed as positive results. CONCLUSION: PMS data from patients with

    types 1-3 GD
    DIAGNOSIS

 in

    Japan
    ETHNICITY

 indicate that

    long-term treatment with velaglucerase alfa
    MEDICATION

 was well-tolerated and associated with

    increased platelet counts
    BIOCHEMICAL

, which is consistent with observations made in studies outside of

    Japan
    ETHNICITY

.

    NCT03625882
    MEDICATION

 registered July 2014.

Gaucher disease (GD)
GD
type 1 GD
GD
type 1, 2 or 3 GD
type 1, 2, or 3 GD
types 2 and 3 GD
GD
type 2 GD
type 2 GD
types 1-3 GD


Multiple de novo gene variations in a progeroid phenotype case report: haploinsufficiency mechanisms.

We are presenting the case of a 6-year-old male patient with progeroid phenotype and severe developmental delay referred to Genetic clinic. Given the complex phenotype an extensive metabolic and genetic evaluation was performed including a whole exome sequencing analysis that showed genetic variants in TTR, RELN, MYH6, PHIP, and SYNE2 genes. Patients' mother and brother were analyzed for the genetic variants in MYH6, PHIP and RELN. Both had same variants on PHIP and RELN as our patient, with no apparent phenotypical consequences. Physical examination was remarkable for dysmorphism including plagiocephaly, low set and abnormally shaped ears, up slanted palpebral fissures, hypoplastic alae nasi, and a head circumference two standard deviations below the 3rd percentile (microcephaly). Other characteristics include wrinkled skin, a broad forehead, sparse eyelashes in lower eyelid, short palpebral fissures, upturned nares, thick lips, right occipital plagiocephaly, overfolded helix and prominent anti-helix, protuberant chest, scaphoid abdomen, digitalized thumbs, and kyphosis due to low muscle tone. The patient presented abnormal EEG with evidence of epileptic discharges. A temporal bone CT showed plagiocephaly with flattening of the right occipital bone. Brain MRI showed callosal agenesis with bilateral colpocephaly with temporal horn dilatation, parahippocampal atrophy, lissencephaly and midbrain hypoplasia. The combination of de novo gene variants mentioned above has never been reported nor correlated as the result of haploinsufficiency mechanisms. Thus, we propose haploinsufficiency and loss of heterozygosity as etiological reasons for this patient phenotype. Further proteomic studies are needed to allocate the extense of genetic influence within the clinical manifestations.

We are presenting the case of a

    6-year-old
    AGE

    male
    GENDER

 patient with

    progeroid phenotype
    SYMPTOMS

 and

    severe developmental delay
    SYMPTOMS

 referred to

    Genetic clinic
    PARACLINICAL

. Given the complex phenotype an

    extensive metabolic and genetic evaluation
    PARACLINICAL

 was performed including a

    whole exome sequencing analysis
    PARACLINICAL

 that showed

    genetic variants in TTR, RELN, MYH6, PHIP, and SYNE2 genes
    GENETICS

. Patients'

    mother and brother were analyzed for the genetic variants in MYH6, PHIP and RELN
    FAMILY

.

    Both had same variants on PHIP and RELN
    FAMILY

 as our patient, with

    no apparent phenotypical consequences
    NEG_FINDINGS

.

    Physical examination
    PARACLINICAL

 was remarkable for

    dysmorphism
    SYMPTOMS

 including

    plagiocephaly
    SYMPTOMS

,

    low set and abnormally shaped ears
    SYMPTOMS

,

    up slanted palpebral fissures
    SYMPTOMS

,

    hypoplastic alae nasi
    SYMPTOMS

, and a

    head circumference two standard deviations below the 3rd percentile (microcephaly)
    SYMPTOMS

. Other characteristics include

    wrinkled skin
    SYMPTOMS

, a

    broad forehead
    SYMPTOMS

,

    sparse eyelashes in lower eyelid
    SYMPTOMS

,

    short palpebral fissures
    SYMPTOMS

,

    upturned nares
    SYMPTOMS

,

    thick lips
    SYMPTOMS

,

    right occipital plagiocephaly
    SYMPTOMS

,

    overfolded helix and prominent anti-helix
    SYMPTOMS

,

    protuberant chest
    SYMPTOMS

,

    scaphoid abdomen
    SYMPTOMS

,

    digitalized thumbs
    SYMPTOMS

, and

    kyphosis due to low muscle tone
    SYMPTOMS

. The patient presented

    abnormal EEG
    SYMPTOMS

 with

    evidence of epileptic discharges
    SYMPTOMS

. A

    temporal bone CT
    PARACLINICAL

 showed

    plagiocephaly with flattening of the right occipital bone
    SYMPTOMS

.

    Brain MRI
    PARACLINICAL

 showed

    callosal agenesis with bilateral colpocephaly with temporal horn dilatation
    SYMPTOMS

,

    parahippocampal atrophy
    SYMPTOMS

,

    lissencephaly
    SYMPTOMS

 and

    midbrain hypoplasia
    SYMPTOMS

. The

    combination of de novo gene variants
    GENETICS

 mentioned above has never been reported nor correlated as the result of

    haploinsufficiency mechanisms
    GENETICS

. Thus, we propose

    haploinsufficiency
    GENETICS

 and

    loss of heterozygosity
    GENETICS

 as etiological reasons for this patient phenotype. Further proteomic studies are needed to allocate the extense of genetic influence within the clinical manifestations.


Ambroxol chaperone therapy for Gaucher disease type I-associated liver cirrhosis and portal hypertension: a case report.

Gaucher disease (GD) is a rare autosomal recessive inherited disease caused by the deficiency of glucocerebrosidase and characterized by a broad spectrum of clinical manifestations, including hepatosplenomegaly, bone infiltration, and cytopenia. Moreover, it is even involved in the central nervous system. GD is classified into three phenotypes on the ground of neurologic involvement: type 1 (GD1), the commonly adult-onset, non-neuropathic variant; type 2 (GD2), the acute neuropathic form; and type 3 (GD3), the severe chronic neuro-visceral form. Recently, several studies have shown a promising outcome of ambroxol chaperone therapy for the treatment of GD, but its therapeutic role in GD1-associated liver cirrhosis and portal hypertension was not verified.

A 36-year-old male patient was admitted for esophageal varices lasting for one year with a 34-year history of liver and spleen enlargement. The patient was diagnosed with GD1 with cirrhosis and portal hypertension based on the identification of Gaucher cells and advanced fibrosis in the liver biopsy tissue and two known pathogenic mutations on the glucocerebrosidase (GBA) gene. The patient received 660 mg/d of ambroxol for up to two years. At his six-month follow-up, the patient exhibited a remarkable increase in GBA activity (+35.5%) and decrease in liver stiffness (-19.5%) and portal vein diameter (-41.2%) as examined by ultrasound elastography and computer tomography, respectively. At two-year follow-up, the liver stiffness was further reduced (-55.5%) in comparison with untreated patients.

This case report suggests that long-term treatment with high dose ambroxol may play a role in the reduction of hepatic fibrosis in GD1.

    Gaucher disease (GD)
    DIAGNOSIS

 is a

    rare autosomal recessive inherited disease
    GENETICS

 caused by the

    deficiency of glucocerebrosidase
    BIOCHEMICAL

 and characterized by a broad spectrum of clinical manifestations, including

    hepatosplenomegaly
    SYMPTOMS

,

    bone infiltration
    SYMPTOMS

, and

    cytopenia
    BIOCHEMICAL

. Moreover, it is even involved in the

    central nervous system
    SYMPTOMS

.

    GD
    DIAGNOSIS

 is classified into three phenotypes on the ground of

    neurologic involvement
    SYMPTOMS

:

    type 1 (GD1)
    DIAGNOSIS

, the commonly

    adult-onset, non-neuropathic variant
    DIAGNOSIS

;

    type 2 (GD2), the acute neuropathic form
    DIAGNOSIS

; and

    type 3 (GD3)
    DIAGNOSIS

, the

    severe chronic neuro-visceral form
    DIAGNOSIS

. Recently, several studies have shown a promising outcome of

    ambroxol chaperone therapy
    MEDICATION

 for the treatment of

    GD
    DIAGNOSIS

, but its therapeutic role in

    GD1-associated liver cirrhosis
    DIAGNOSIS

 and

    portal hypertension
    SYMPTOMS

 was not verified.

A

    36-year-old
    AGE

    male
    GENDER

 patient was admitted for

    esophageal varices lasting for one year
    SYMPTOMS

 with a

    34-year history of liver and spleen enlargement
    SYMPTOMS

. The patient was diagnosed with

    GD1
    DIAGNOSIS

 with

    cirrhosis
    DIAGNOSIS

 and

    portal hypertension
    SYMPTOMS

 based on the

    identification of Gaucher cells and advanced fibrosis in the liver biopsy tissue
    MICROSCOPIC

 and

    two known pathogenic mutations on the glucocerebrosidase (GBA) gene
    GENETICS

. The patient

    received 660 mg/d of ambroxol for up to two years
    MEDICATION

. At his

    six-month follow-up
    PARACLINICAL

, the patient exhibited a

    remarkable increase in GBA activity (+35.5%)
    BIOCHEMICAL

 and

    decrease in liver stiffness (-19.5%) and portal vein diameter (-41.2%)
    SYMPTOMS

 as examined by

    ultrasound elastography and computer tomography
    PARACLINICAL

, respectively. At

    two-year follow-up
    PARACLINICAL

, the

    liver stiffness was further reduced (-55.5%)
    SYMPTOMS

 in comparison with untreated patients.

This case report suggests that

    long-term treatment with high dose ambroxol
    MEDICATION

 may play a role in the reduction of

    hepatic fibrosis
    MICROSCOPIC

 in

    GD1
    DIAGNOSIS

.


Jaw involvement in Gaucher disease: a not-so-uncommon feature of a rare disease.

Gaucher disease is an inborn error of metabolism resulting from the deficiency of the enzyme glucocerebrosidase and consequent accumulation of glucocerebroside within the lysosomes of macrophages. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease, and results from the progressive infiltration of lipid-laden cells in various organs. Common manifestations of Gaucher disease include enlarged liver and/or spleen (hepatosplenomegaly), bone marrow disease (pancytopenia) and bone abnormalities, which are extremely variable and can affect multiple skeletal sites. While bone involvement of long bones and vertebrae is a well-recognised feature of Gaucher disease, jawbone involvement is less commonly noted. Here, we describe a case of a 63-year-old patient with type 1 Gaucher disease with a history of long-term use of bisphosphonates and who had presented with dental pain, with subsequent investigations confirming the radiological features of jaw involvement in Gaucher disease, including periodontal disease.

    Gaucher disease
    DIAGNOSIS

 is an

    inborn error of metabolism
    GENETICS

 resulting from the

    deficiency of the enzyme glucocerebrosidase
    BIOCHEMICAL

 and consequent

    accumulation of glucocerebroside within the lysosomes of macrophages
    MICROSCOPIC

. The clinical presentation is very diverse, depending on the age of onset and the severity of the disease, and results from the

    progressive infiltration of lipid-laden cells in various organs
    MICROSCOPIC

. Common manifestations of

    Gaucher disease
    DIAGNOSIS

 include

    enlarged liver and/or spleen
    SYMPTOMS

 (

    hepatosplenomegaly
    SYMPTOMS

),

    bone marrow disease
    MICROSCOPIC

 (

    pancytopenia
    BIOCHEMICAL

) and

    bone abnormalities
    SYMPTOMS

, which are extremely variable and can affect

    multiple skeletal sites
    SYMPTOMS

. While

    bone involvement of long bones and vertebrae
    SYMPTOMS

 is a well-recognised feature of

    Gaucher disease
    DIAGNOSIS

,

    jawbone involvement
    SYMPTOMS

 is less commonly noted. Here, we describe a case of a

    63-year-old
    AGE

 patient with

    type 1 Gaucher disease
    DIAGNOSIS

 with a

    history of long-term use of bisphosphonates
    MEDICATION

 and who had presented with

    dental pain
    SYMPTOMS

, with subsequent investigations confirming the

    radiological features of jaw involvement
    SYMPTOMS

 in

    Gaucher disease
    DIAGNOSIS

, including

    periodontal disease
    DIAGNOSIS

.

Gaucher disease
Gaucher disease
Gaucher disease
type 1 Gaucher disease
Gaucher disease
periodontal disease


Renal involvement in a patient with the chronic visceral subtype of acid sphingomyelinase deficiency resembles Fabry disease.

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease (LSD) in which sphingomyelin accumulates due to deficient acid sphingomyelinase. In the chronic visceral subtype, organ manifestations are generally limited to the spleen, liver, and lungs. We report a male patient with the chronic visceral subtype who developed proteinuria and renal insufficiency at the age of 49. In renal tissue, foam cells were observed in the glomeruli as well as sphingomyelin accumulation within podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Although macrophages are the primary storage cells in both ASMD and Gaucher disease, comparison to the histopathological findings in Gaucher and Fabry disease revealed a diffuse storage pattern in multiple renal cell types, closer resembling the pattern found in Fabry disease.

    Acid sphingomyelinase deficiency (ASMD)
    BIOCHEMICAL

 is a

    lysosomal storage disease (LSD)
    DIAGNOSIS

 in which

    sphingomyelin accumulates
    MICROSCOPIC

 due to

    deficient acid sphingomyelinase
    BIOCHEMICAL

. In the

    chronic visceral subtype
    DIAGNOSIS

,

    organ manifestations
    SYMPTOMS

 are generally

    limited to the spleen, liver, and lungs
    SYMPTOMS

. We report a

    male
    GENDER

 patient with the

    chronic visceral subtype
    DIAGNOSIS

 who developed

    proteinuria
    BIOCHEMICAL

 and

    renal insufficiency
    SYMPTOMS

 at the

    age of 49
    AGE

.

    In renal tissue
    MICROSCOPIC

,

    foam cells were observed in the glomeruli
    MICROSCOPIC

 as well as

    sphingomyelin accumulation within podocytes, mesangial cells, endothelial cells, and tubular epithelial cells
    MICROSCOPIC

. Although

    macrophages are the primary storage cells
    MICROSCOPIC

 in both

    ASMD
    DIAGNOSIS

 and

    Gaucher disease
    DIAGNOSIS

, comparison to the histopathological findings in

    Gaucher
    MICROSCOPIC

 and

    Fabry disease
    DIAGNOSIS

 revealed a

    diffuse storage pattern in multiple renal cell types, closer resembling the pattern found in Fabry disease
    MICROSCOPIC

.

Acid sphingomyelinase deficiency (ASMD)
deficient acid sphingomyelinase
proteinuria

lysosomal storage disease (LSD)
chronic visceral subtype
chronic visceral subtype
ASMD
Gaucher disease
Fabry disease

organ manifestations
limited to the spleen, liver, and lungs
renal insufficiency


A Japanese Patient with Gaucher Disease Treated with the Oral Drug Eliglustat as Substrate Reducing Therapy.

Gaucher disease is a rare genetic disorder caused by the deficiency of acid β-glucosidase to effectively catalyze the degradation of glucosylceramide to glucose and ceramide. We report here the case of a 31-year-old male Japanese patient with Gaucher disease who switched from enzyme replacement therapy (ERT) to substrate reducing therapy (SRT). Liver dysfunction was identified at a routine medical checkup, and the patient was referred to our hospital with "idiopathic liver disease." Clinical laboratory tests indicated thrombocytopenia and splenomegaly, which are characteristic symptoms of Gaucher disease. To definitively diagnose Gaucher disease, a bone marrow biopsy and acid β-glucosidase activity measurement were conducted; the results supported a diagnosis of Gaucher disease. This case emphasizes that it is possible for periodic medical checkups in adults to lead to the diagnosis of rare genetic disorders. The patient underwent ERT treatment with imiglucerase for 5 years; the platelet count rapidly increased and the spleen size rapidly decreased, indicating a good response to the drug. However, the patient increasingly felt the burden of visiting the hospital for 2 h of infusion ERT every 2 weeks. Consequently, it was jointly decided that he should switch from ERT to SRT with an oral drug. This switch was successful with no deterioration of laboratory data. This case report is the first to describe a Japanese Gaucher disease patient treated with eliglustat for >2 years. We showed that SRT is a well-tolerated and effective option for the treatment of Gaucher disease.

    Gaucher disease
    DIAGNOSIS

 is a

    rare genetic disorder
    GENETICS

 caused by the

    deficiency of acid β-glucosidase
    BIOCHEMICAL

 to

    effectively catalyze the degradation of glucosylceramide to glucose and ceramide
    BIOCHEMICAL

. We report here the case of a

    31-year-old
    AGE

    male
    GENDER

    Japanese
    ETHNICITY

 patient with

    Gaucher disease
    DIAGNOSIS

 who

    switched from enzyme replacement therapy (ERT) to substrate reducing therapy (SRT)
    MEDICATION

.

    Liver dysfunction
    SYMPTOMS

 was identified at a

    routine medical checkup
    PARACLINICAL

, and the patient was referred to our hospital with "

    idiopathic liver disease
    DIAGNOSIS

."

    Clinical laboratory tests
    PARACLINICAL

 indicated

    thrombocytopenia
    BIOCHEMICAL

 and

    splenomegaly
    SYMPTOMS

, which are characteristic symptoms of

    Gaucher disease
    DIAGNOSIS

. To definitively diagnose

    Gaucher disease
    DIAGNOSIS

, a

    bone marrow biopsy
    PARACLINICAL

 and

    acid β-glucosidase activity measurement
    PARACLINICAL

 were conducted; the results supported a diagnosis of

    Gaucher disease
    DIAGNOSIS

. This case emphasizes that it is possible for periodic medical checkups in

    adults
    AGE

 to lead to the diagnosis of

    rare genetic disorders
    DIAGNOSIS

. The patient underwent

    ERT treatment with imiglucerase for 5 years
    MEDICATION

; the

    platelet count rapidly increased
    BIOCHEMICAL

 and the

    spleen size rapidly decreased
    SYMPTOMS

, indicating a good response to the drug. However, the patient increasingly felt the burden of

    visiting the hospital for 2 h of infusion ERT every 2 weeks
    MEDICATION

. Consequently, it was jointly decided that

    he
    GENDER

 should

    switch from ERT to SRT with an oral drug
    MEDICATION

. This switch was successful with

    no deterioration of laboratory data
    NEG_FINDINGS

. This case report is the first to describe a

    Japanese
    ETHNICITY

    Gaucher disease
    DIAGNOSIS

 patient

    treated with eliglustat for >2 years
    MEDICATION

. We showed that

    SRT
    MEDICATION

 is a well-tolerated and effective option for the treatment of

    Gaucher disease
    DIAGNOSIS

.

Gaucher disease
Gaucher disease
idiopathic liver disease
Gaucher disease
Gaucher disease
Gaucher disease
rare genetic disorders
Gaucher disease
Gaucher disease

Liver dysfunction
splenomegaly
spleen size rapidly decreased