Psychiatric disorders in patients with Fabry's disease.

To determine the frequency and etiology of psychiatric complications in patients with Fabry's disease. Method-Retrospective analysis and review of the records of thirty-three patients with confirmed Fabry's disease.

Six patients (18%) developed psychiatric disorders. Five patients suffered depression and two of these patients committed suicide. One patient developed an acute confusional episode with subsequent development of behavioral changes as a complication of cerebrovascular disease.

Psychiatric disorders, most commonly depression, complicate Fabry's disease and contribute to the morbidity and mortality of this disease.

To determine the frequency and etiology of

    psychiatric complications
    SYMPTOMS

 in patients with

    Fabry's disease
    DIAGNOSIS

. Method-Retrospective analysis and review of the records of thirty-three patients with confirmed

    Fabry's disease
    DIAGNOSIS

.

Six patients (18%) developed

    psychiatric disorders
    DIAGNOSIS

. Five patients suffered

    depression
    DIAGNOSIS

 and two of these patients

    committed suicide
    SYMPTOMS

. One patient developed an

    acute confusional episode
    SYMPTOMS

 with subsequent

    development of behavioral changes
    SYMPTOMS

 as a complication of

    cerebrovascular disease
    DIAGNOSIS

.

    Psychiatric disorders
    DIAGNOSIS

, most commonly

    depression
    DIAGNOSIS

, complicate

    Fabry's disease
    DIAGNOSIS

 and contribute to the morbidity and mortality of this disease.

psychiatric complications
committed suicide
acute confusional episode
development of behavioral changes

Fabry's disease
Fabry's disease
psychiatric disorders
depression
cerebrovascular disease
Psychiatric disorders
depression
Fabry's disease


Displaced fracture of the lunate in a child.

This is a report of an additional case of transverse fracture of the lunate with marked displacement, requiring open reduction and osteosynthesis. The lunate became necrotic with all features of Kienböck's disease.

This is a report of an additional case of

    transverse fracture of the lunate with marked displacement
    SYMPTOMS

, requiring

    open reduction and osteosynthesis
    MEDICATION

.

    The lunate became necrotic with all features of Kienböck's disease
    SYMPTOMS

.


Joint manifestations of Fabry's disease.

We describe 2 patients with Fabry's disease with disabling crises of burning pain in hands and feet. These crises were accompanied by fever and an elevation of the erythrocyte sedimentation which often led to erroneous diagnosis of other rheumatic conditions. Fabry's disease should be considered on the different diagnoses of intermittent rheumatic syndromes.

We describe 2 patients with

    Fabry's disease
    DIAGNOSIS

 with

    disabling crises of burning pain in hands and feet
    SYMPTOMS

. These

    crises
    SYMPTOMS

 were accompanied by

    fever
    BIOCHEMICAL

 and an

    elevation of the erythrocyte sedimentation
    BIOCHEMICAL

 which often led to

    erroneous diagnosis of other rheumatic conditions
    NEG_FINDINGS

.

    Fabry's disease
    DIAGNOSIS

 should be considered on the different diagnoses of

    intermittent rheumatic syndromes
    DIAGNOSIS

.

Fabry's disease
Fabry's disease
intermittent rheumatic syndromes


[Present possibilities of prenatal diagnosis of Fabry's disease].

Fabry's disease (angiokeratoma corporis diffusum universale) is an inborn error of metabolism, which is based on a shortage in the cumulation of glycosphingolipids in endothelial and epithelial cells of glomeruli, vascular endothelia and in ganglion cells with subsequent severe organ damage. Heredity is X-linked recessive. In the submitted paper the authors present a case-history of a family where three men were affected and carriership was confirmed in five women. During the first pregnancy one of them a successful prenatal diagnosis was made from cultivated amniotic fluid cells. Chromosomal examination revealed female sex and the levels of the alpha-galactosidase A were established in cultivated cells. A healthy girl was delivered.

    Fabry's disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum universale)
    DIAGNOSIS

 is an

    inborn error of metabolism
    DIAGNOSIS

, which is based on a

    shortage in the cumulation of glycosphingolipids in endothelial and epithelial cells of glomeruli, vascular endothelia and in ganglion cells
    MICROSCOPIC

 with subsequent

    severe organ damage
    SYMPTOMS

.

    Heredity is X-linked recessive
    GENETICS

. In the submitted paper the authors present a

    case-history of a family where three men were affected
    FAMILY

 and

    carriership was confirmed in five women
    FAMILY

. During the first

    pregnancy
    MEDICATION

 one of them a successful

    prenatal diagnosis
    PARACLINICAL

 was made from

    cultivated amniotic fluid cells
    PARACLINICAL

.

    Chromosomal examination
    PARACLINICAL

 revealed

    female sex
    GENETICS

 and the

    levels of the alpha-galactosidase A were established in cultivated cells
    BIOCHEMICAL

. A healthy

    girl
    GENDER

 was delivered.

Heredity is X-linked recessive
female sex


[A case of Fabry's disease associated with lupus nephritis].

A 36-year-old woman was hospitalized because of nephrotic syndrome. On admission, laboratory studies revealed total protein 5.9g/dl, total cholesterol 381mg/dl, urine protein 2-4g/day, C3 68mg/dl(90-185mg/dl) and the immunological tests showed that antinuclear factor, anti-DNA antibodies and the LE cell phenomenon were positive. Renal function was within normal range. After admission, renal biopsy was done. Light microscopic finding showed diffuse membranous glomerulonephritis, and vacuolization of epithelial cells. Immunofluorescent microscopic finding showed a granular specific staining for IgG, IgM, C3 and C1q along the capillary loops. Electron microscopic finding showed subepithelial and subendothelial dense deposits, and visceral epithelial cell cytoplasm containing osmiophilic multilamellar lipoid bodies. In the studies of the enzyme activities, the patient's fibroblast extract demonstrated a partial deficiency of alpha-galactosidase, and urine ceramide trihexoside was positive. But the patient's leukocyte extract did not demonstrate a deficiency of alpha-galactosidase. So Fabry's disease associated with lupus nephritis was diagnosed. It seems that the case of Fabry's disease which is an X-linked disorder caused by deficiency of the lysosomal enzyme alpha-galactosidase, associated with lupus nephritis, is extremely rare.

A

    36-year-old
    AGE

    woman
    GENDER

 was hospitalized because of

    nephrotic syndrome
    DIAGNOSIS

. On admission,

    laboratory studies
    PARACLINICAL

 revealed

    total protein 5.9g/dl
    BIOCHEMICAL

,

    total cholesterol 381mg/dl
    BIOCHEMICAL

,

    urine protein 2-4g/day, C3 68mg/dl(90-185mg/dl)
    BIOCHEMICAL

 and the

    immunological tests
    PARACLINICAL

 showed that

    antinuclear factor, anti-DNA antibodies and the LE cell phenomenon were positive
    BIOCHEMICAL

.

    Renal function was within normal range
    NEG_FINDINGS

. After admission,

    renal biopsy
    PARACLINICAL

 was done.

    Light microscopic
    PARACLINICAL

 finding showed

    diffuse membranous glomerulonephritis
    MICROSCOPIC

, and

    vacuolization of epithelial cells
    MICROSCOPIC

.

    Immunofluorescent microscopic finding
    PARACLINICAL

 showed a

    granular specific staining for IgG, IgM, C3 and C1q along the capillary loops
    MICROSCOPIC

.

    Electron microscopic finding
    PARACLINICAL

 showed

    subepithelial and subendothelial dense deposits
    MICROSCOPIC

, and

    visceral epithelial cell cytoplasm containing osmiophilic multilamellar lipoid bodies
    MICROSCOPIC

. In the studies of the

    enzyme activities
    BIOCHEMICAL

, the patient's

    fibroblast extract demonstrated a partial deficiency of alpha-galactosidase
    BIOCHEMICAL

, and

    urine ceramide trihexoside was positive
    BIOCHEMICAL

. But the patient's

    leukocyte extract did not demonstrate a deficiency of alpha-galactosidase
    NEG_FINDINGS

. So

    Fabry's disease associated with lupus nephritis
    DIAGNOSIS

 was diagnosed. It seems that the case of

    Fabry's disease
    DIAGNOSIS

 which is an

    X-linked disorder
    GENETICS

 caused by

    deficiency of the lysosomal enzyme alpha-galactosidase
    BIOCHEMICAL

, associated with

    lupus nephritis
    DIAGNOSIS

, is extremely rare.


Relative hypoxia of the extremities in Fabry disease.

A purine degradation study, thermography and near infrared spectroscopy of the extremities were performed on 2 young males with Fabry disease and 2 healthy controls. Two-minute semi-ischemic forearm exercise caused a distinct increase in lactate in all subjects, but venous hypoxanthine and ammonia were greatly increased only in the Fabry patients, suggesting a relatively hypoxic state of the extremities. Limb thermograms of the patients revealed glove and stocking type disturbance at rest. Poor recovery of the skin temperature of the hands and forearms after exercise was observed in the patients, but the sharp increase in oxygenated hemoglobin after total ischemia was found to be normal or near infrared spectroscopy. Neurotropin showed an analgesic effect, i.e. a strong and selective heat-productive action on the painful lesions, and suppressed the hypoxanthine level after exercise in 1 patient. Although the pathophysiology of the pain in Fabry disease has not been clearly elucidated, a relatively hypoxic state with peripheral hypothermia might play an important role in triggering of a painful attack or chronic burning paresthesia.

A

    purine degradation study
    PARACLINICAL

,

    thermography
    PARACLINICAL

 and

    near infrared spectroscopy of the extremities
    PARACLINICAL

 were performed on 2

    young
    AGE

    males
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 and 2 healthy controls.

    Two-minute semi-ischemic forearm exercise
    PARACLINICAL

 caused a

    distinct increase in lactate
    BIOCHEMICAL

 in all subjects, but

    venous hypoxanthine and ammonia were greatly increased
    BIOCHEMICAL

 only in the

    Fabry
    DIAGNOSIS

 patients, suggesting a

    relatively hypoxic state of the extremities
    SYMPTOMS

.

    Limb thermograms
    PARACLINICAL

 of the patients revealed

    glove and stocking type disturbance at rest
    SYMPTOMS

.

    Poor recovery of the skin temperature of the hands and forearms after exercise
    SYMPTOMS

 was observed in the patients, but the

    sharp increase in oxygenated hemoglobin after total ischemia
    BIOCHEMICAL

    was found to be normal or near infrared spectroscopy
    NEG_FINDINGS

.

    Neurotropin
    MEDICATION

 showed an

    analgesic effect, i.e. a strong and selective heat-productive action on the painful lesions
    SYMPTOMS

, and

    suppressed the hypoxanthine level after exercise
    BIOCHEMICAL

 in 1 patient. Although the pathophysiology of the

    pain
    DIAGNOSIS

 in

    Fabry disease
    DIAGNOSIS

 has not been clearly elucidated, a

    relatively hypoxic state
    SYMPTOMS

 with

    peripheral hypothermia
    SYMPTOMS

 might play an important role in triggering of a

    painful attack
    SYMPTOMS

 or

    chronic burning paresthesia
    SYMPTOMS

.


Fabry's disease with complete atrioventricular block: histological evidence of involvement of the conduction system.

A 63 year old man with complete atrioventricular block was diagnosed as having Fabry's disease. A short PR interval is a common electrocardiographic finding in Fabry's disease, but complete atrioventricular block is a very rare complication. Necropsy indicated that lipid accumulation in the atrioventricular conduction system was the probable cause of this patient's atrioventricular block.

A

    63 year old
    AGE

    man
    GENDER

 with

    complete atrioventricular block
    SYMPTOMS

 was diagnosed as having

    Fabry's disease
    DIAGNOSIS

. A

    short PR interval
    SYMPTOMS

 is a common electrocardiographic finding in

    Fabry's disease
    DIAGNOSIS

, but

    complete atrioventricular block
    SYMPTOMS

 is a very rare complication.

    Necropsy
    PARACLINICAL

 indicated that

    lipid accumulation in the atrioventricular conduction system
    MICROSCOPIC

 was the probable cause of this patient's

    atrioventricular block
    SYMPTOMS

.

complete atrioventricular block
short PR interval
complete atrioventricular block
atrioventricular block


Two cases of Fabry's disease: a hemizygote with a point mutation in the alpha-galactosidase A gene and his relative.

A 34-year-old Japanese male had leg pain, edema of the legs, hypohidrosis, whorl-like opacities of the bilateral cornea, bilateral subcapsular cataracts, and chest discomfort on exercise. He had no characteristic angiokeratomas but did have telangiectases. The electrocardiogram revealed high voltage. The echocardiogram revealed mild mitral regurgitation. The alpha-galactosidase A activity in cultured lymphoblasts was deficient (0.5 nmol/h/mg protein). Electron microscopic examination of the skin revealed lamellar cytoplasmic inclusions in the endothelial cells, pericytes, and fibroblasts. He had a G--> A transition at nucleotide 982 in the coding sequence of the alpha-galactosidase A gene which resulted in a glycine to arginine amino acid substitution at residue 328. His uncle also had leg pain, edema of the legs, hypohidrosis, and chest pain on exercise. He had no characteristic angiokeratomas but did have telangiectases. Cardiovascular examination revealed hypertrophic cardiomyopathy and stenoses of coronary arteries. Electron microscopic examination of the skin revealed lamellar cytoplasmic inclusions in the endothelial cells, pericytes, and fibroblasts.

A

    34-year-old
    AGE

    Japanese
    ETHNICITY

    male
    GENDER

 had

    leg pain
    SYMPTOMS

,

    edema of the legs
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    whorl-like opacities of the bilateral cornea
    SYMPTOMS

,

    bilateral subcapsular cataracts
    SYMPTOMS

, and

    chest discomfort on exercise
    SYMPTOMS

.

    He
    GENDER

 had

    no characteristic angiokeratomas
    NEG_FINDINGS

 but did have

    telangiectases
    SYMPTOMS

. The

    electrocardiogram
    PARACLINICAL

 revealed

    high voltage
    SYMPTOMS

. The

    echocardiogram
    PARACLINICAL

 revealed

    mild mitral regurgitation
    SYMPTOMS

.

    The alpha-galactosidase A activity in cultured lymphoblasts was deficient (0.5 nmol/h/mg protein)
    BIOCHEMICAL

.

    Electron microscopic examination of the skin
    PARACLINICAL

 revealed

    lamellar cytoplasmic inclusions in the endothelial cells, pericytes, and fibroblasts
    MICROSCOPIC

.

    He
    GENDER

 had a

    G--> A transition at nucleotide 982 in the coding sequence of the alpha-galactosidase A gene which resulted in a glycine to arginine amino acid substitution at residue 328
    GENETICS

.

    His
    GENDER

    uncle also had leg pain
    FAMILY

,

    edema of the legs
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

, and

    chest pain on exercise
    SYMPTOMS

.

    He
    GENDER

 had

    no characteristic angiokeratomas
    NEG_FINDINGS

 but did have

    telangiectases
    SYMPTOMS

.

    Cardiovascular examination
    PARACLINICAL

 revealed

    hypertrophic cardiomyopathy
    SYMPTOMS

 and

    stenoses of coronary arteries
    SYMPTOMS

.

    Electron microscopic examination of the skin
    PARACLINICAL

 revealed

    lamellar cytoplasmic inclusions in the endothelial cells, pericytes, and fibroblasts
    MICROSCOPIC

.

no characteristic angiokeratomas
no characteristic angiokeratomas


Fabry's disease without angiokeratomas showing unusual eccrine gland vacuolation.

An unusual case of Anderson-Fabry's disease with renal damage and bilateral corneal deposits but without angiokeratomas is presented. Diagnosis was made by renal biopsy. Typical foamy transformation of endothelium, mesangium, tubular epithelial cells, vascular smooth muscle, and fibroblasts of kidney biopsy and similar changes of myoepithelial, perineural, and endothelial cells on the skin biopsy were observed. At electron microscopy, 'fingerprint-like' myelin figures were seen. The epithelial cells of eccrine sweat glands showed striking vacuolation but myelin figures were not seen. We suggest that electron microscopic study of skin biopsies is indicated in the evaluation of patients clinically suspected of having Fabry's disease.

An unusual case of

    Anderson-Fabry's disease
    DIAGNOSIS

 with

    renal damage
    SYMPTOMS

 and

    bilateral corneal deposits
    SYMPTOMS

 but

    without angiokeratomas
    NEG_FINDINGS

 is presented. Diagnosis was made by

    renal biopsy
    PARACLINICAL

.

    Typical foamy transformation of endothelium, mesangium, tubular epithelial cells, vascular smooth muscle, and fibroblasts of kidney biopsy
    MICROSCOPIC

 and

    similar changes of myoepithelial, perineural, and endothelial cells on the skin biopsy
    MICROSCOPIC

 were observed. At

    electron microscopy
    PARACLINICAL

,

    'fingerprint-like' myelin figures were seen
    MICROSCOPIC

.

    The epithelial cells of eccrine sweat glands showed striking vacuolation
    MICROSCOPIC

 but

    myelin figures were not seen
    NEG_FINDINGS

. We suggest that

    electron microscopic study of skin biopsies
    PARACLINICAL

 is indicated in the evaluation of patients clinically suspected of having

    Fabry's disease
    DIAGNOSIS

.

Anderson-Fabry's disease
Fabry's disease

without angiokeratomas
myelin figures were not seen


Fabry's disease.

A 20-year-old man presented with generalized acquired anhidrosis and heat intolerance which was confirmed by a sweat test. Other clinical features included severe pain of the extremities and cutaneous angiokeratomas. On electronmicroscopy, granules specific for Fabry's disease were observed in the endothelial cells. Biochemical examination revealed a decreased level of serum alpha-galactosidase A. These findings confirmed the diagnosis of Fabry's disease.

A

    20-year-old
    AGE

    man
    GENDER

 presented with

    generalized acquired anhidrosis
    SYMPTOMS

 and

    heat intolerance
    SYMPTOMS

 which was confirmed by a

    sweat test
    PARACLINICAL

. Other clinical features included

    severe pain of the extremities
    SYMPTOMS

 and

    cutaneous angiokeratomas
    SYMPTOMS

. On

    electronmicroscopy
    PARACLINICAL

,

    granules specific for Fabry's disease were observed in the endothelial cells
    MICROSCOPIC

.

    Biochemical examination
    PARACLINICAL

 revealed a decreased level of serum alpha-galactosidase A. These findings confirmed the diagnosis of

    Fabry's disease
    DIAGNOSIS

.

generalized acquired anhidrosis
heat intolerance
severe pain of the extremities
cutaneous angiokeratomas


Fabry disease: immunocytochemical characterization of neuronal involvement.

Fabry disease is an X-linked glycosphingolipid storage disease caused by deficiency of alpha-galactosidase. Storage of globotriaosylceramide, also known as ceramide trihexoside, is maximal in blood vessels but also occurs in neurons. We performed neuropathological histochemical studies on the brains and spinal cords of 2 patients with confirmed Fabry disease. Luxol fast blue-positive deposits were found in blood vessels throughout the central and peripheral nervous system and within selected neurons in spinal cord and ganglia, brainstem, amygdala, hypothalamus, and entorhinal cortex. Regions adjacent to involved neuronal groups, including nucleus basalis, striatum, globus pallidus, and thalamus, were spared. Electron microscopy showed lamellar cytoplasmic neuronal inclusion bodies. Using a monoclonal antibody reactive with ceramide trihexoside, we found more extensive neuronal deposition than evident by Luxol-fast blue staining and new areas of neuronal storage in the spinal cord and cerebral cortex. Blood vessels throughout the nervous system were strongly immunoreactive. The highly selective pattern of neuronal involvement we found suggests that glycosphingolipid exposure, uptake, or catabolism varies greatly with respect to neuronal morphology and distribution. The degree of toxicity to neurons and the clinical significance of this neuronal storage remains to be defined.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    glycosphingolipid storage disease
    DIAGNOSIS

 caused by

    deficiency of alpha-galactosidase
    BIOCHEMICAL

.

    Storage of globotriaosylceramide, also known as ceramide trihexoside, is maximal in blood vessels but also occurs in neurons
    MICROSCOPIC

. We performed

    neuropathological histochemical studies on the brains and spinal cords
    PARACLINICAL

 of 2 patients with confirmed

    Fabry disease
    DIAGNOSIS

.

    Luxol fast blue-positive deposits were found in blood vessels throughout the central and peripheral nervous system and within selected neurons in spinal cord and ganglia, brainstem, amygdala, hypothalamus, and entorhinal cortex
    MICROSCOPIC

.

    Regions adjacent to involved neuronal groups, including nucleus basalis, striatum, globus pallidus, and thalamus, were spared
    NEG_FINDINGS

.

    Electron microscopy
    PARACLINICAL

 showed

    lamellar cytoplasmic neuronal inclusion bodies
    MICROSCOPIC

. Using a

    monoclonal antibody reactive with ceramide trihexoside
    BIOCHEMICAL

, we found

    more extensive neuronal deposition
    MICROSCOPIC

 than evident by

    Luxol-fast blue staining
    PARACLINICAL

 and

    new areas of neuronal storage in the spinal cord and cerebral cortex
    MICROSCOPIC

.

    Blood vessels throughout the nervous system
    SYMPTOMS

 were

    strongly immunoreactive
    MICROSCOPIC

. The

    highly selective pattern of neuronal involvement
    SYMPTOMS

 we found suggests that

    glycosphingolipid
    MICROSCOPIC

 exposure, uptake, or catabolism varies greatly with respect to neuronal morphology and distribution. The degree of

    toxicity to neurons
    SYMPTOMS

 and the clinical significance of this

    neuronal storage
    MICROSCOPIC

 remains to be defined.

Fabry disease
glycosphingolipid storage disease
Fabry disease


Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease.

Single point mutations in the upstream region of exon 6 of the alpha-galactosidase A gene were found in two Japanese cases of the cardiac form of Fabry disease; 301Arg----Gln (902G----A) in a case that has already been published and 279Gln----Glu (835C----G) in a new case. They both expressed markedly low, but significant, amounts of residual activity in COS-1 cells. In contrast, two unrelated cases with classic Fabry disease were found to have different point mutations, which showed a complete loss of enzyme activity in a transient expression assay; 328Gly----Arg (982G----A) in the downstream region of exon 6 in one case and two combined mutations, 66Glu----Gln (196G----C)/112Arg----Cys (334C----T), in exon 2 in the other. We conclude, on the basis of the results recorded in this study and those in previous reports, that the pathogenesis of atypical Fabry disease is closely associated with point mutations in the upstream region of exon 6 of the alpha-galactosidase A gene.

    Single point mutations in the upstream region of exon 6 of the alpha-galactosidase A gene
    GENETICS

 were found in two

    Japanese
    ETHNICITY

 cases of the

    cardiac form of Fabry disease
    DIAGNOSIS

;

    301Arg----Gln (902G----A)
    GENETICS

 in a case that has already been published and

    279Gln----Glu (835C----G)
    GENETICS

 in a new case. They both expressed

    markedly low, but significant, amounts of residual activity in COS-1 cells
    BIOCHEMICAL

. In contrast, two unrelated cases with

    classic Fabry disease
    DIAGNOSIS

 were found to have

    different point mutations
    GENETICS

, which showed a

    complete loss of enzyme activity
    BIOCHEMICAL

 in a

    transient expression assay
    PARACLINICAL

;

    328Gly----Arg (982G----A) in the downstream region of exon 6
    GENETICS

 in one case and

    two combined mutations, 66Glu----Gln (196G----C)/112Arg----Cys (334C----T), in exon 2
    GENETICS

 in the other. We conclude, on the basis of the results recorded in this study and those in previous reports, that the pathogenesis of

    atypical Fabry disease
    DIAGNOSIS

 is closely associated with

    point mutations in the upstream region of exon 6 of the alpha-galactosidase A gene
    GENETICS

.

cardiac form of Fabry disease
classic Fabry disease
atypical Fabry disease


Cerebrovascular manifestations in a female carrier of Fabry's disease.

A female carrier of Fabry's disease with neurological manifestations is presented. An elective ophthalmological examination revealed a whorl keratopathy suggesting that the patient may be a carrier of Fabry's disease. She subsequently suffered two brainstem ischemic events. Cranial MRI examination performed revealed evidence of multiple subcortical strokes and diffuse white matter disease in her frontal lobes. Biochemical analysis confirmed that this patient was a carrier of Fabry's disease. The cerebrovascular manifestations may be secondary to tissue variability of mutant enzyme activity.

A

    female
    GENDER

 carrier of

    Fabry's disease
    DIAGNOSIS

 with

    neurological manifestations
    SYMPTOMS

 is presented. An

    elective ophthalmological examination
    PARACLINICAL

 revealed a

    whorl keratopathy
    SYMPTOMS

 suggesting that the patient may be a carrier of

    Fabry's disease
    DIAGNOSIS

.

    She
    GENDER

 subsequently suffered

    two brainstem ischemic events
    SYMPTOMS

.

    Cranial MRI examination
    PARACLINICAL

 performed revealed

    evidence of multiple subcortical strokes
    SYMPTOMS

 and

    diffuse white matter disease in her frontal lobes
    SYMPTOMS

.

    Biochemical analysis
    PARACLINICAL

 confirmed that this patient was a carrier of

    Fabry's disease
    DIAGNOSIS

. The

    cerebrovascular manifestations
    SYMPTOMS

 may be secondary to

    tissue variability of mutant enzyme activity
    BIOCHEMICAL

.

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


Ischemic optic neuropathy in a female carrier with Fabry's disease.

We report ocular findings of a patient with anterior ischemic optic neuropathy (AION) and cilioretinal artery occlusion in a female carrier of Fabry's disease. Fluorescein angiography revealed delayed filling of the upper and temporal part of peripapillary choroidal vessels and capillaries of the right optic disk and late filling of the cilioretinal artery. CT scanning was performed several times in early stages and demonstrated thickening of the intraorbital optic nerve due to ischemic edema. About 5 months later, the fellow eye showed optic disk edema, an early sign of AION, and was treated by systemic corticosteroid and urokinase whereby AION did not progress.

We report ocular findings of a patient with

    anterior ischemic optic neuropathy (AION)
    SYMPTOMS

 and

    cilioretinal artery occlusion
    SYMPTOMS

 in a

    female
    GENDER

 carrier of

    Fabry's disease
    DIAGNOSIS

.

    Fluorescein angiography
    PARACLINICAL

 revealed

    delayed filling of the upper and temporal part of peripapillary choroidal vessels and capillaries of the right optic disk
    SYMPTOMS

 and

    late filling of the cilioretinal artery
    SYMPTOMS

.

    CT scanning
    PARACLINICAL

 was performed several times in early stages and demonstrated

    thickening of the intraorbital optic nerve
    SYMPTOMS

 due to

    ischemic edema
    SYMPTOMS

. About 5 months later, the fellow eye showed

    optic disk edema
    SYMPTOMS

, an early sign of

    AION
    SYMPTOMS

, and was treated by

    systemic corticosteroid and urokinase
    MEDICATION

 whereby

    AION did not progress
    NEG_FINDINGS

.


Angiokeratoma corporis diffusum in a patient with normal enzyme activities and Turner's syndrome.

A case of angiokeratoma corporis diffusum (ACD) involving the skin of a 26-year-old patient with Turner's syndrome presenting with normal physical and mental development is reported. The unusual nature of this association confirms the theory that ACD presenting with skin lesions alone is a rare but specific clinical entity which differs from the hereditary sphingolipidoses like Fabry's disease.

A case of

    angiokeratoma corporis diffusum (ACD) involving the skin
    SYMPTOMS

 of a

    26-year-old
    AGE

 patient with

    Turner's syndrome
    DIAGNOSIS

 presenting with

    normal physical and mental development
    NEG_FINDINGS

 is reported. The unusual nature of this association confirms the theory that

    ACD
    DIAGNOSIS

 presenting with

    skin lesions
    SYMPTOMS

 alone is a rare but specific clinical entity which differs from the

    hereditary sphingolipidoses
    DIAGNOSIS

 like

    Fabry's disease
    DIAGNOSIS

.

Turner's syndrome
ACD
hereditary sphingolipidoses
Fabry's disease


Fabry's disease presenting with stroke.

An atypical patient with Fabry's disease is presented. This patient developed a left internal capsule lacunar stroke at the age of 25. The etiology of the stroke was unclear. At the age of 29 he was discovered to have corneal lesions suggestive of Fabry's disease but had no other clinical features typical of Fabry's disease. The diagnosis of Fabry's disease was confirmed biochemically. Fabry's disease should be included in the differential diagnosis of stroke of unclear etiology in young male patients.

An atypical patient with

    Fabry's disease
    DIAGNOSIS

 is presented. This patient developed a

    left internal capsule lacunar stroke
    SYMPTOMS

 at the

    age of 25
    AGE

. The etiology of the

    stroke
    SYMPTOMS

    was unclear
    NEG_FINDINGS

. At the

    age of 29
    AGE

    he
    GENDER

 was discovered to have

    corneal lesions suggestive of Fabry's disease
    SYMPTOMS

 but had

    no other clinical features typical of Fabry's disease
    NEG_FINDINGS

. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 was confirmed biochemically.

    Fabry's disease
    DIAGNOSIS

 should be included in the

    differential diagnosis
    PARACLINICAL

 of

    stroke of unclear etiology
    SYMPTOMS

 in

    young
    AGE

    male
    GENDER

 patients.


[Nephropathy in a case of Fabry's disease].

The present communication describes a 22 year-old male with clinical, biochemical and histopathological signs of Fabry's disease (FD). This is the second case of FD reported in Mexico. The main clinical manifestations of this patient were during puberty: intermittent weakness, acroparesthesias and hypohidrosis. At age 21 he developed heavy proteinuria (7-12 g/day) systemic hypertension and moderate renal failure. The kidney biopsy showed the typical alterations described in FD. On light microscopy, the renal pathology showed numerous vacuolated epithelial cells in the glomerular wall, giving them a "foamy" appearance; vacuolization was due to the presence of lipid material within these cells and in the interstitium. In electron microscopy, dense, irregularly shaped osmiophilic, laminated bodies with myelinlike configuration, were seen within the glomerular epithelial cells and in the urinary spaces. The low alfa-galactosidase activity in serum (0.18 nmol/h/mL normal values: 12.8) confirmed the diagnosis. Our findings in this case indicate that patients with FD may start with renal symptoms alone, which were full blown nephrotic syndrome, hypertension and moderate renal failure.

The present communication describes a

    22 year-old
    AGE

    male
    GENDER

 with clinical, biochemical and histopathological signs of

    Fabry's disease (FD)
    DIAGNOSIS

. This is the second case of

    FD
    DIAGNOSIS

 reported in

    Mexico
    ETHNICITY

. The main clinical manifestations of this patient were during

    puberty
    AGE

:

    intermittent weakness
    SYMPTOMS

,

    acroparesthesias
    SYMPTOMS

 and

    hypohidrosis
    SYMPTOMS

. At

    age 21
    AGE

    he
    GENDER

 developed

    heavy proteinuria (7-12 g/day)
    BIOCHEMICAL

 systemic

    hypertension
    SYMPTOMS

 and

    moderate renal failure
    SYMPTOMS

. The

    kidney biopsy
    PARACLINICAL

 showed the

    typical alterations described in FD
    MICROSCOPIC

. On

    light microscopy
    PARACLINICAL

, the

    renal pathology
    PARACLINICAL

 showed

    numerous vacuolated epithelial cells in the glomerular wall, giving them a "foamy" appearance
    MICROSCOPIC

;

    vacuolization was due to the presence of lipid material within these cells and in the interstitium
    MICROSCOPIC

. In

    electron microscopy
    PARACLINICAL

,

    dense, irregularly shaped osmiophilic, laminated bodies with myelinlike configuration, were seen within the glomerular epithelial cells and in the urinary spaces
    MICROSCOPIC

. The

    low alfa-galactosidase activity in serum (0.18 nmol/h/mL normal values: 12.8)
    BIOCHEMICAL

 confirmed the diagnosis. Our findings in this case indicate that patients with

    FD
    DIAGNOSIS

 may start with

    renal symptoms
    SYMPTOMS

 alone, which were

    full blown nephrotic syndrome
    SYMPTOMS

,

    hypertension
    SYMPTOMS

 and

    moderate renal failure
    SYMPTOMS

.

intermittent weakness
acroparesthesias
hypohidrosis
hypertension
moderate renal failure
renal symptoms
full blown nephrotic syndrome
hypertension
moderate renal failure


A 3' splice site consensus sequence mutation in the intron 3 of the alpha-galactosidase A gene in a patient with Fabry disease.

Fabry disease is an X-linked disorder accompanied with accumulation of glycosphingolipids resulting from the deficient activity of the lysosomal hydrolase, alpha-galactosidase A (alpha-GalA). In the present study, mRNA for alpha-GalA in fibroblasts from an 11-year-old Japanese patient with Fabry disease was examined using the reverse transcriptase-polymerase chain reaction (PCR). The shorter message of alpha-GalA was demonstrated in this patient when compared with the normal control. The complete deletion of exon 4 in the mRNA for alpha-GalA in the patient was disclosed by analysis of cDNA with restriction enzyme digestion and asymmetrical PCR sequencing. The direct sequencing of the genomic DNA demonstrated a single base substitution (G----A) at the 3' end of the consensus sequence of intron 3. This mutation destroyed a splice site in the alpha-GalA, which produced a mutant allele. It was also shown that the mother of the patient had this mutant as well as normal alleles as a heterozygote.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

 accompanied with

    accumulation of glycosphingolipids
    MICROSCOPIC

 resulting from the

    deficient activity of the lysosomal hydrolase, alpha-galactosidase A (alpha-GalA)
    BIOCHEMICAL

. In the present study,

    mRNA for alpha-GalA
    BIOCHEMICAL

    in fibroblasts
    MICROSCOPIC

 from an

    11-year-old
    AGE

    Japanese
    ETHNICITY

 patient with

    Fabry disease
    DIAGNOSIS

 was examined using the

    reverse transcriptase-polymerase chain reaction (PCR)
    PARACLINICAL

. The

    shorter message of alpha-GalA
    BIOCHEMICAL

 was demonstrated in this patient when compared with the normal control. The

    complete deletion of exon 4 in the mRNA for alpha-GalA
    GENETICS

 in the patient was disclosed by

    analysis of cDNA with restriction enzyme digestion
    PARACLINICAL

 and

    asymmetrical PCR sequencing
    PARACLINICAL

. The

    direct sequencing of the genomic DNA
    PARACLINICAL

 demonstrated a

    single base substitution (G----A) at the 3' end of the consensus sequence of intron 3
    GENETICS

. This

    mutation destroyed a splice site in the alpha-GalA, which produced a mutant allele
    GENETICS

. It was also shown that

    the mother of the patient had this mutant as well as normal alleles as a heterozygote
    FAMILY

.


Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.

Recently a novel case of angiokeratoma corporis diffusum with glycoaminoaciduria was described in a 46-yr-old Japanese woman. Known causes of the cutaneous manifestation were eliminated by enzyme analyses, and further characterization of the accumulated urinary O-linked sialopeptides revealed identity to those excreted by patients with an infantile neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. Investigation of the alpha-N-acetylgalactosaminidase activity and protein in the proband revealed less than 2% of normal activity and the absence of detectable immunoreactive enzyme protein, findings comparable to those in the patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. In addition, the proband's unaffected offspring had half-normal levels of alpha-N-acetylgalactosaminidase activity, consistent with this enzymatic deficiency being the primary metabolic defect in this autosomal recessive trait. Ultrastructural examination of skin and blood cells from the adult proband revealed the presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, these morphologic findings were not observed in the nonneural tissues from patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. These studies document the occurrence of two forms of alpha-N-acetylgalactosaminidase deficiency and sialopeptiduria, a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions and an adult-onset form characterized by angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides and the absence of detectable neurologic involvement.

Recently a novel case of

    angiokeratoma corporis diffusum
    SYMPTOMS

 with

    glycoaminoaciduria
    BIOCHEMICAL

 was described in a

    46-yr-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

.

    Known causes of the cutaneous manifestation
    NEG_FINDINGS

    were eliminated by enzyme analyses
    NEG_FINDINGS

, and further characterization of the

    accumulated urinary O-linked sialopeptides revealed identity to those excreted
    MICROSCOPIC

 by patients with an

    infantile neuroaxonal dystrophy
    DIAGNOSIS

 due to

    lysosomal alpha-N-acetylgalactosaminidase deficiency
    BIOCHEMICAL

. Investigation of the alpha-N-acetylgalactosaminidase activity

    and protein in the proband revealed less than 2% of normal activity
    BIOCHEMICAL

 and the

    absence of detectable immunoreactive enzyme protein
    BIOCHEMICAL

, findings comparable to those in the patients with

    infantile neuroaxonal dystrophy
    DIAGNOSIS

 and

    alpha-N-acetylgalactosaminidase deficiency
    BIOCHEMICAL

. In addition,

    the proband's unaffected offspring had half-normal levels of alpha-N-acetylgalactosaminidase activity
    FAMILY

, consistent with this

    enzymatic deficiency
    BIOCHEMICAL

 being the primary

    metabolic defect in this autosomal recessive trait
    GENETICS

.

    Ultrastructural examination of skin and blood cells
    PARACLINICAL

 from the

    adult
    AGE

 proband revealed the

    presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material
    MICROSCOPIC

. In contrast, these morphologic findings were

    not observed in the nonneural tissues
    NEG_FINDINGS

 from patients with

    infantile neuroaxonal dystrophy
    DIAGNOSIS

 and

    alpha-N-acetylgalactosaminidase deficiency
    NEG_FINDINGS

. These studies document the occurrence of two forms of

    alpha-N-acetylgalactosaminidase deficiency
    BIOCHEMICAL

 and

    sialopeptiduria
    BIOCHEMICAL

, a

    severe infantile-onset form of neuroaxonal dystrophy
    DIAGNOSIS

    without angiokeratoma or visceral lysosomal inclusions
    NEG_FINDINGS

 and an

    adult-onset
    AGE

 form characterized by

    angiokeratoma
    SYMPTOMS

,

    extensive lysosomal accumulation of sialoglycopeptides
    MICROSCOPIC

 and the

    absence of detectable neurologic involvement
    NEG_FINDINGS

.

angiokeratoma corporis diffusum
angiokeratoma


Chemical diagnosis of Fabry's disease by fluorometric assay and fast atom bombardment/mass spectrometry.

We report the results of a fluorometric assay for alpha-galactosidase A (EC.3.2.1.22) in plasma and leukocytes, and fast atom bombardment/mass spectrometry (FAB/MS) analysis of glycosphingolipids in urine sediments from a patient with Fabry's disease. In plasma, this patient had only 5.0% of the normal amount of alpha-galactosidase A, and his brother and mother had 11.0% and 25.0%, respectively. In leukocytes, the activities were below 8.0%. Glycosphingolipids from urine sediments were partially purified using a Sep-Pack C18 cartridge. The chemical diagnosis of Fabry's disease can be made more rapidly and accurately using fluorometric and FAB/MS analyses.

We report the results of a

    fluorometric assay for alpha-galactosidase A (EC.3.2.1.22) in plasma and leukocytes
    PARACLINICAL

, and

    fast atom bombardment/mass spectrometry (FAB/MS) analysis of glycosphingolipids in urine sediments
    PARACLINICAL

 from a patient with

    Fabry's disease
    DIAGNOSIS

.

    In plasma
    BIOCHEMICAL

, this patient

    had only 5.0% of the normal amount of alpha-galactosidase A
    BIOCHEMICAL

, and

    his
    GENDER

    brother and mother had 11.0% and 25.0%, respectively
    FAMILY

.

    In leukocytes, the activities were below 8.0%
    BIOCHEMICAL

.

    Glycosphingolipids from urine sediments
    MICROSCOPIC

 were

    partially purified using a Sep-Pack C18 cartridge
    MICROSCOPIC

. The chemical diagnosis of

    Fabry's disease
    DIAGNOSIS

 can be made more rapidly and accurately using

    fluorometric and FAB/MS analyses
    PARACLINICAL

.


Colonic involvement in Fabry's disease.

The case of a 54 year old man with Fabry's disease and extensive jejunal and colonic diverticulosis causing colonic stricture is presented. Histological examination of the resected colon revealed evidence of ceramide trihexose deposition in the myenteric nerve plexus. Colonic involvement in Fabry's disease has not been reported before.

The case of a

    54 year old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 and

    extensive jejunal and colonic diverticulosis
    SYMPTOMS

 causing

    colonic stricture
    SYMPTOMS

 is presented.

    Histological examination of the resected colon
    PARACLINICAL

 revealed

    evidence of ceramide trihexose deposition in the myenteric nerve plexus
    MICROSCOPIC

.

    Colonic involvement
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 has not been reported before.


[Value of the ophthalmologic examination in diagnosing patients with Anderson-Fabry disease and in heterozygote detection].

A 45-year-old man with Fabry's disease is presented. 27 relatives are examined. Among the different examinations (serum activity of alpha-galactosidase, urinary excretion of trihexosyl ceramide, renal function, ocular examination) ocular examination remains the easiest and cheapest test for detection of heterozygotes. The ocular manifestations of this enzymatic defect are reviewed.

A

    45-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 is presented. 27 relatives are examined. Among the different examinations (

    serum activity of alpha-galactosidase
    BIOCHEMICAL

,

    urinary excretion of trihexosyl ceramide
    BIOCHEMICAL

,

    renal function
    PARACLINICAL

,

    ocular examination
    PARACLINICAL

)

    ocular examination
    PARACLINICAL

 remains the easiest and cheapest test for detection of

    heterozygotes
    GENETICS

. The

    ocular manifestations
    SYMPTOMS

 of this

    enzymatic defect
    DIAGNOSIS

 are reviewed.


Fabry disease: detection of 13-bp deletion in alpha-galactosidase A gene and its application to gene diagnosis of heterozygotes.

Polymerase chain reaction amplification of reverse-transcribed messenger RNA from a patient with Fabry disease revealed a 13-base pair deletion in the 5' region (exon 1) of alpha-galactosidase A complementary DNA. This gene rearrangement was not detected by Southern or Northern analysis. Short direct repeats were present around the breakpoints, and considered to be of pathogenetic significance. Gene diagnosis of the mother and a female cousin was successfully achieved by polymerase chain reaction amplification of genomic DNA; the former as a Fabry disease heterozygote and the latter as a normal homozygote.

    Polymerase chain reaction amplification of reverse-transcribed messenger RNA from
    PARACLINICAL

 a patient with

    Fabry disease
    DIAGNOSIS

 revealed a

    13-base pair deletion in the 5' region (exon 1) of alpha-galactosidase A complementary DNA
    GENETICS

. This

    gene rearrangement
    GENETICS

 was

    not detected by Southern or Northern analysis
    NEG_FINDINGS

.

    Short direct repeats were present around the breakpoints
    GENETICS

, and considered to be of pathogenetic significance.

    Gene diagnosis of the mother and a female cousin
    FAMILY

 was successfully achieved by

    polymerase chain reaction amplification of genomic DNA
    PARACLINICAL

; the former as a

    Fabry disease heterozygote
    DIAGNOSIS

 and the latter as a

    normal homozygote
    GENETICS

.

Fabry disease
Fabry disease heterozygote


Recurrence of Fabry's disease in a renal allograft eleven years after successful renal transplantation.

A case of Fabry's disease in a renal transplant recipient with a follow-up period of 11 years is reported. The patient suffered from renal, skin, peripheral nerve lesions, and asymptomatic cardiomegaly. Fabry's disease symptoms disappeared after transplantation. Improvement of renal function was rapidly observed, and it remained satisfactory during the whole posttransplantation period. The patient died of a severe, uncontrolled infection and of biliary peritonitis. Autopsy showed a polyvisceral accumulation of sphingolipids deposits. The engrafted kidney was histologically free of disease. Ultrastructurally, it revealed numerous sphingolipid inclusions in the endothelial cells of capillaries. The explanation of this complication could be attributed to: (1) high circulating levels of plasma substrates locally overwhelming the enzymatic capability of the graft endothelial cells; and (2) the endothelial cells originated from the recipient but not from the donor, an occurrence that has been described after transplantation. Rejection and the newly formed deposits in the endothelial cells may lead to the loss of the engrafted organ. As a consequence of the increasing possibility of organ transplantation, this complication should be detected by studying the blood vessels ultrastructurally in order to evaluate the condition of the transplant.

A case of

    Fabry's disease
    DIAGNOSIS

 in a

    renal transplant recipient
    MEDICATION

 with a follow-up period of 11 years is reported. The patient suffered from

    renal, skin, peripheral nerve lesions
    SYMPTOMS

, and

    asymptomatic cardiomegaly
    SYMPTOMS

.

    Fabry's disease symptoms
    SYMPTOMS

 disappeared after

    transplantation
    MEDICATION

.

    Improvement of renal function
    SYMPTOMS

 was rapidly observed, and it remained satisfactory during the whole posttransplantation period. The patient

    died
    SYMPTOMS

 of a

    severe, uncontrolled infection
    SYMPTOMS

 and of

    biliary peritonitis
    DIAGNOSIS

.

    Autopsy
    PARACLINICAL

 showed a

    polyvisceral accumulation of sphingolipids deposits
    MICROSCOPIC

. The

    engrafted kidney was histologically free of disease
    NEG_FINDINGS

.

    Ultrastructurally
    PARACLINICAL

, it revealed

    numerous sphingolipid inclusions in the endothelial cells of capillaries
    MICROSCOPIC

. The explanation of this complication could be attributed to: (1)

    high circulating levels of plasma substrates locally overwhelming the enzymatic capability of the graft endothelial cells
    BIOCHEMICAL

; and (2) the endothelial cells originated from the recipient but not from the donor, an occurrence that has been described after

    transplantation
    MEDICATION

.

    Rejection
    SYMPTOMS

 and the

    newly formed deposits in the endothelial cells
    MICROSCOPIC

 may lead to the

    loss of the engrafted organ
    MICROSCOPIC

. As a consequence of the increasing possibility of

    organ transplantation
    MEDICATION

, this complication should be detected by

    studying the blood vessels
    PARACLINICAL

 ultrastructurally in order to evaluate the condition of the transplant.

renal transplant recipient
transplantation
transplantation
organ transplantation

renal, skin, peripheral nerve lesions
asymptomatic cardiomegaly
Fabry's disease symptoms
Improvement of renal function
died
severe, uncontrolled infection
Rejection


Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of alpha-galactosidase A.

A new variant form of Fabry disease with hypertrophic cardiomyopathy of late onset is reported. Two unrelated male hemizygotes of this disease first presented with signs and symptoms of cardiomyopathy after 50 years of age. Cultured lymphoblastoid cells showed significantly higher residual alpha-galactosidase A activities than in the patients with classical phenotypic expressions.

A new variant form of

    Fabry disease
    DIAGNOSIS

 with

    hypertrophic cardiomyopathy of late onset
    SYMPTOMS

 is reported. Two unrelated

    male
    GENDER

    hemizygotes of this disease
    FAMILY

 first presented with

    signs and symptoms of cardiomyopathy
    SYMPTOMS

    after 50 years of age
    AGE

.

    Cultured lymphoblastoid cells
    MICROSCOPIC

 showed

    significantly higher residual alpha-galactosidase A activities
    BIOCHEMICAL

 than in the patients with classical phenotypic expressions.


[Early acroparesthesia in females: a sign disclosing heterozygote Fabry disease].

Heterozygous Fabry's disease has an inconstant expression and very few complications. The theory of X-chromosome inactivation which, according to Lyon, occurs hazardly, is illustrated by the fact that the disease is expressed even in hemizygous women. Ophthalmic manifestations, as detected by the slit lamp method, are almost constant, 80 p. 100 of women with the disease having a verticillate cornea. Angiokeratoma is present in 20 p. 100 of the cases. Episodes of paraesthesia of the hands and feet are less common; in most cases they are attributed to the disease retrospectively, during family investigations. In two girls aged 10 and 11 years respectively and without history of Fabry's disease the only symptom suggestive of the diagnosis was paroxysmal acroparaesthesia. In one of the girls acroparaesthesia was associated with acrocyanosis, livedo and acro-osteolysis, but concordance was the only argument in favour of a link with Fabry's disease. Alterations of the extremities have been reported in this disease, including palmar erythema and a bluish discoloration of the palms due to dilatation of the superficial veins. Only two cases of livedo have been published. Acrosteolysis has never been documented in Fabry's disease, and its presence must be confirmed in further cases. The diagnosis of heterozygous Fabry's disease in these 2 girls was confirmed by the finding of ceramide trihexoside in urine and by leucocyte alpha-galactosidase levels that were 25 to 30 p. 100 of values obtained in controls. A study of the family of one of the girls showed that the father was involved; this hemizygous type of the disease with a 10 p. 100 alphagalactosidase level was totally asymptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)

    Heterozygous Fabry's disease
    DIAGNOSIS

 has an inconstant expression and very few complications. The theory of

    X-chromosome inactivation
    GENETICS

 which, according to Lyon, occurs hazardly, is illustrated by the fact that the disease is expressed even in

    hemizygous women
    GENETICS

.

    Ophthalmic manifestations
    SYMPTOMS

, as detected by the

    slit lamp method
    PARACLINICAL

, are almost constant, 80 p. 100 of

    women
    GENDER

 with the disease having a

    verticillate cornea
    SYMPTOMS

.

    Angiokeratoma
    SYMPTOMS

 is present in 20 p. 100 of the cases.

    Episodes of paraesthesia of the hands and feet
    SYMPTOMS

 are less common; in most cases they are attributed to the disease retrospectively, during

    family investigations
    PARACLINICAL

. In two

    girls
    GENDER

    aged 10 and 11 years
    AGE

 respectively and

    without history of Fabry's disease
    NEG_FINDINGS

 the only symptom suggestive of the diagnosis was

    paroxysmal acroparaesthesia
    SYMPTOMS

. In one of the

    girls
    GENDER

    acroparaesthesia
    SYMPTOMS

 was associated with

    acrocyanosis
    SYMPTOMS

,

    livedo
    SYMPTOMS

 and

    acro-osteolysis
    SYMPTOMS

, but concordance was the only argument in favour of a link with

    Fabry's disease
    DIAGNOSIS

.

    Alterations of the extremities
    SYMPTOMS

 have been reported in this disease, including

    palmar erythema
    SYMPTOMS

 and a

    bluish discoloration of the palms due to dilatation of the superficial veins
    SYMPTOMS

. Only two cases of

    livedo
    SYMPTOMS

 have been published.

    Acrosteolysis
    SYMPTOMS

 has never been documented in

    Fabry's disease
    DIAGNOSIS

, and its presence must be confirmed in further cases. The diagnosis of

    heterozygous Fabry's disease
    DIAGNOSIS

 in these 2

    girls
    GENDER

 was confirmed by the finding of

    ceramide trihexoside in urine
    BIOCHEMICAL

 and by

    leucocyte alpha-galactosidase levels that were 25 to 30 p. 100 of values obtained in controls
    BIOCHEMICAL

. A

    study of the family
    PARACLINICAL

 of one of the

    girls
    GENDER

 showed that

    the father was involved
    FAMILY

; this

    hemizygous type of the disease
    GENETICS

 with a

    10 p. 100 alphagalactosidase level
    BIOCHEMICAL

 was totally asymptomatic.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterozygous Fabry's disease
Fabry's disease
Fabry's disease
heterozygous Fabry's disease

X-chromosome inactivation
hemizygous women
hemizygous type of the disease


Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry's disease.

Immunohistochemical and biochemical analyses of several tissues were performed in two unusual cases of Fabry's disease which showed accumulation of globotriaosylceramide (Gal alpha 1-4Gal beta 1-4 Glc-Cer, Gb3Cer) only in the hearts, but no clinical signs of the disease. Immunohistochemical study revealed that the hearts from our cases (cases no. 1 and 2) contained large amounts of anti-Gb3Cer antibody-positive granules in cytoplasms as in typical Fabry's disease. The contents of accumulated Gb3Cer in the hearts from case no. 1, case no. 2, and a typical Fabry's disease case were approximately 100, 340, and 100 times higher than those from normal controls, respectively. While typical Fabry's diseased kidney and liver contained approximately 40 and 50 times higher amounts of Gb3Cer than did controls, no accumulation of Gb3Cer was observed in kidney and liver of our cases. The only exception was a slight increase of Gb3Cer in kidney of case no. 2 (about two times higher than controls), in which epithelial cells of the glomeruli but not of other types of cells were positively stained by anti-Gb3Cer antibody. Case no. 1 kidney and liver were not stained by the antibody. The glomerular endothelium and epithelium, tubular epithelium, smooth muscle of renal arteries, and several hepatocytes were Gb3Cer-positive in the typical Fabry's disease case. The involvements of our cases differed distinctly from the typical Fabry's disease case.

    Immunohistochemical and biochemical analyses of several tissues
    PARACLINICAL

 were performed in two unusual cases of

    Fabry's disease
    DIAGNOSIS

 which showed

    accumulation of globotriaosylceramide (Gal alpha 1-4Gal beta 1-4 Glc-Cer, Gb3Cer) only in the hearts
    MICROSCOPIC

, but

    no clinical signs of the disease
    NEG_FINDINGS

.

    Immunohistochemical study
    PARACLINICAL

 revealed that

    the hearts
    MICROSCOPIC

 from our cases (cases no. 1 and 2)

    contained large amounts of anti-Gb3Cer antibody-positive granules in cytoplasms as in typical Fabry's disease
    MICROSCOPIC

. The

    contents of accumulated Gb3Cer in the hearts
    MICROSCOPIC

 from case no. 1, case no. 2, and a

    typical Fabry's disease
    DIAGNOSIS

 case were approximately 100, 340, and 100

    times higher
    MICROSCOPIC

 than those from normal controls, respectively. While

    typical Fabry's diseased kidney and liver contained approximately 40 and 50 times higher amounts of Gb3Cer
    MICROSCOPIC

 than did controls,

    no accumulation of Gb3Cer was observed in kidney and liver
    NEG_FINDINGS

 of our cases. The only exception was a

    slight increase of Gb3Cer in kidney of
    MICROSCOPIC

 case no. 2

    (about two times higher than controls
    MICROSCOPIC

), in which

    epithelial cells of the glomeruli but not of other types of cells were positively stained by anti-Gb3Cer antibody
    MICROSCOPIC

.

    Case no. 1 kidney and liver were not stained by the antibody
    NEG_FINDINGS

.

    The glomerular endothelium and epithelium, tubular epithelium, smooth muscle of renal arteries, and several hepatocytes were Gb3Cer-positive
    MICROSCOPIC

 in the

    typical Fabry's disease
    DIAGNOSIS

 case. The involvements of our cases differed distinctly from the typical

    Fabry's disease
    DIAGNOSIS

 case.

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


Angiocheratoma corporis diffusum with normal enzyme activities.

A female case of angiokeratoma corporis diffusum without systemic involvement, with alpha-galactosidase A activity in the normal range, alpha-L-fucosidase in the lower levels of the normal range, and a few amount of urinary sialic acid is reported. Some problem about differential diagnosis with inherited disorders as Fabry's disease, fucosidosis, sialidosis is discussed. Although cases of angiokeratoma corporis diffusum without any underlying enzyme defect have been reported, we believe that angiokeratoma corporis diffusum is always related to known or unknown enzymatic defect, which activities could result in the normal range probably in relation to enzymatic polymorphism.

A

    female
    GENDER

 case of

    angiokeratoma corporis diffusum
    SYMPTOMS

    without systemic involvement
    NEG_FINDINGS

, with

    alpha-galactosidase A activity in the normal range
    BIOCHEMICAL

,

    alpha-L-fucosidase in the lower levels of the normal range
    BIOCHEMICAL

, and a

    few amount of urinary sialic acid
    BIOCHEMICAL

 is reported. Some problem about

    differential diagnosis
    PARACLINICAL

 with

    inherited disorders
    GENETICS

 as

    Fabry's disease
    DIAGNOSIS

,

    fucosidosis
    DIAGNOSIS

,

    sialidosis
    DIAGNOSIS

 is discussed. Although cases of

    angiokeratoma corporis diffusum
    SYMPTOMS

    without any underlying enzyme defect
    NEG_FINDINGS

 have been reported, we believe that

    angiokeratoma corporis diffusum
    SYMPTOMS

 is always related to known or unknown

    enzymatic defect
    BIOCHEMICAL

, which

    activities could result in the normal range
    BIOCHEMICAL

 probably in relation to enzymatic polymorphism.

angiokeratoma corporis diffusum
angiokeratoma corporis diffusum
angiokeratoma corporis diffusum

without systemic involvement
without any underlying enzyme defect


[A case of Fabry's disease detected by renal biopsy findings].

A 39 year-old man was found to have mild proteinuria by urinary examination since one year ago. He was for the first time diagnosed as having Fabry's disease by histopathological and electronmicroscopic findings of the renal biopsy specimens, which showed the presence of numerous vacuolated cells and electron dense bodies inside the cells. The level of WBC alpha-galactosidase was significantly lower than normal level. The pedigree of this patient showed a familial history of various types of renal disease. One of the patient's brothers also showed decreased level of WBC alpha-galactosidase, who has been treated by maintenance hemodialysis for 2 years. It is concluded that early diagnosis of this disease through renal biopsy and WBC alpha-galactosidase level is important to manage the future course of patients with Fabry's disease.

A

    39 year-old
    AGE

    man
    GENDER

 was found to have

    mild proteinuria
    BIOCHEMICAL

 by

    urinary examination
    PARACLINICAL

 since one year ago.

    He
    GENDER

 was for the first time diagnosed as having

    Fabry's disease
    DIAGNOSIS

 by

    histopathological and electronmicroscopic findings of the renal biopsy specimens
    PARACLINICAL

, which showed the

    presence of numerous vacuolated cells and electron dense bodies inside the cells
    MICROSCOPIC

. The

    level of WBC alpha-galactosidase was significantly lower than normal level
    BIOCHEMICAL

.

    The pedigree of this patient showed a familial history of various types of renal disease
    FAMILY

.

    One of the patient's brothers also showed decreased level of WBC alpha-galactosidase
    FAMILY

, who has been

    treated by maintenance hemodialysis for 2 years
    MEDICATION

. It is concluded that early diagnosis of this disease through

    renal biopsy
    PARACLINICAL

 and

    WBC alpha-galactosidase level
    PARACLINICAL

 is important to manage the future course of patients with

    Fabry's disease
    DIAGNOSIS

.


[Priapism associated with Fabry's disease].

We present a rare case of priapism in a child, ten years old, in association with Fabry's disease. The child had a history of disseminated nodular enlargement, crises of fever, intermittent pain in the extremities and ten hours persistent painful erection of the penis. We don't obtain pain or erection relief with sedation, epidural block and irrigation of the corporal bodies. A saphenous-cavernous shunt, in the Grayhack fashion made, being results satisfactory. In the follow-up, the child had sporadic pain in the extremities and no erection of the penis. The cavernosography showed the shunt open. Fabry's disease was confirmed by nodular biopsy and the demonstration of deficient alpha-galactosidase.

We present a rare case of

    priapism
    SYMPTOMS

 in a

    child
    AGE

,

    ten years old
    AGE

, in association with

    Fabry's disease
    DIAGNOSIS

. The

    child
    AGE

 had a history of

    disseminated nodular enlargement
    SYMPTOMS

,

    crises of fever
    SYMPTOMS

,

    intermittent pain in the extremities
    SYMPTOMS

 and

    ten hours persistent painful erection of the penis
    SYMPTOMS

. We

    don't obtain pain or erection relief with sedation, epidural block
    NEG_FINDINGS

 and

    irrigation of the corporal bodies
    MEDICATION

. A

    saphenous-cavernous shunt, in the Grayhack
    MEDICATION

 fashion made, being results satisfactory. In the follow-up, the

    child
    AGE

 had

    sporadic pain in the extremities
    SYMPTOMS

 and

    no erection of the penis
    NEG_FINDINGS

. The

    cavernosography
    PARACLINICAL

 showed the

    shunt open
    MEDICATION

.

    Fabry's disease
    DIAGNOSIS

 was confirmed by

    nodular biopsy
    PARACLINICAL

 and the demonstration of

    deficient alpha-galactosidase
    BIOCHEMICAL

.


Effect of acid-base changes on urinary hydrolases in Fabry's disease after renal transplantation.

Fabry's disease, which is characterized by alpha-galactosidase A (AG) deficiency, causes early renal failure. Kidney transplants do not reliably supply the deficient enzyme. To assess both urinary excretion of AG by the transplant and the relationship between urine and serum hydrolase activity, acute and chronic acid-base studies were performed in normal control subjects and in the patient with Fabry's disease who had undergone renal transplantation. For the acute studies, alkalosis was induced by intravenous infusion of sodium bicarbonate and acidosis was induced by ingestion of ammonium chloride. The chronic study involved long-term ingestion of NH4Cl by only the patient with Fabry's disease. The results show that AG is secreted by the renal graft. Urinary hydrolase excretion was increased by acute alkalinization and decreased by acute acidification. Acute, but not chronic, acidification increased the patient's serum AG activity, indicating that long-term acidification is not useful for treating Fabry's disease after transplantation. The large changes in hydrolyase excretion induced by acute and chronic acid-base changes show the difficulty of using lysosomal enzymuria as a diagnostic marker for renal disorders without knowledge of acid-base conditions.

    Fabry's disease
    DIAGNOSIS

, which is characterized by

    alpha-galactosidase A (AG) deficiency
    BIOCHEMICAL

, causes

    early renal failure
    SYMPTOMS

.

    Kidney transplants do not reliably supply the deficient enzyme
    NEG_FINDINGS

. To assess both

    urinary excretion of AG by the transplant
    BIOCHEMICAL

 and the

    relationship between urine and serum hydrolase activity
    BIOCHEMICAL

,

    acute and chronic acid-base studies
    PARACLINICAL

 were performed in normal control subjects and in the patient with

    Fabry's disease
    DIAGNOSIS

 who had undergone

    renal transplantation
    MEDICATION

. For the

    acute studies
    PARACLINICAL

,

    alkalosis
    BIOCHEMICAL

 was induced by

    intravenous infusion of sodium bicarbonate
    MEDICATION

 and

    acidosis
    BIOCHEMICAL

 was induced by

    ingestion of ammonium chloride
    MEDICATION

. The chronic study involved

    long-term ingestion of NH4Cl
    MEDICATION

 by only the patient with

    Fabry's disease
    DIAGNOSIS

. The results show that

    AG is secreted by the renal graft
    MICROSCOPIC

.

    Urinary hydrolase excretion was increased
    BIOCHEMICAL

 by

    acute alkalinization
    BIOCHEMICAL

 and

    decreased by acute acidification
    BIOCHEMICAL

. Acute, but not

    chronic, acidification
    MEDICATION

    increased the patient's serum AG activity
    BIOCHEMICAL

, indicating that

    long-term acidification
    MEDICATION

 is not useful for treating

    Fabry's disease
    DIAGNOSIS

 after

    transplantation
    MEDICATION

. The

    large changes in hydrolyase excretion
    BIOCHEMICAL

 induced by acute and chronic

    acid-base changes
    BIOCHEMICAL

 show the difficulty of using

    lysosomal enzymuria
    BIOCHEMICAL

 as a diagnostic marker for

    renal disorders
    DIAGNOSIS

 without knowledge of

    acid-base conditions
    NEG_FINDINGS

.

Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease
renal disorders


A Fabry's disease heterozygote with a new mutation: biochemical, ultrastructural, and clinical investigations.

A Fabry heterozygote with early clinical manifestations of this X linked disorder is described. Her symptoms, including febrile attacks, arthralgia, abdominal pain, and neurological signs, were characteristic of Fabry's disease hemizygotes. The neurological findings were compatible with a brain stem infarction. The diagnosis was confirmed by the finding of low activities of alpha-galactosidase A (alpha-galA) in plasma, lymphocytes, and cultured fibroblasts, and by the observation of typical lamellar inclusions in the lysosomes of cultured fibroblasts. Increased levels of ceramide trihexoside were also found by TLC of urine sediment. The family history gave no indication of Fabry's disease in the patient's relatives, and biochemical and ultrastructural investigations of their cells were also normal. Our findings therefore suggest that the defective gene in the heterozygote has resulted from a new mutation.

A

    Fabry heterozygote
    DIAGNOSIS

 with

    early clinical manifestations
    SYMPTOMS

 of this

    X linked disorder
    GENETICS

 is described.

    Her
    GENDER

 symptoms, including

    febrile attacks
    SYMPTOMS

,

    arthralgia
    SYMPTOMS

,

    abdominal pain
    SYMPTOMS

, and

    neurological signs
    SYMPTOMS

, were characteristic of

    Fabry's disease hemizygotes
    DIAGNOSIS

. The

    neurological findings
    SYMPTOMS

 were compatible with a

    brain stem infarction
    SYMPTOMS

. The diagnosis was confirmed by the finding of

    low activities of alpha-galactosidase A (alpha-galA) in plasma, lymphocytes, and cultured fibroblasts
    BIOCHEMICAL

, and by the observation of

    typical lamellar inclusions in the lysosomes of cultured fibroblasts
    MICROSCOPIC

.

    Increased levels of ceramide trihexoside
    MICROSCOPIC

 were also found by

    TLC of urine sediment
    PARACLINICAL

. The

    family history gave no indication of Fabry's disease in the patient's relatives
    FAMILY

, and

    biochemical and ultrastructural investigations of their cells were also normal
    NEG_FINDINGS

. Our findings therefore suggest that

    the defective gene in the heterozygote has resulted from a new mutation
    GENETICS

.

Fabry heterozygote
Fabry's disease hemizygotes

early clinical manifestations
febrile attacks
arthralgia
abdominal pain
neurological signs
neurological findings
brain stem infarction


Relief of chronic burning pain in Fabry disease with neurotropin.

Neurotropin, an extract from the inflamed skin of vaccinia virus-inoculated rabbits, was effective in the relief of sharp or burning pain induced by pyrexia, hot weather, bathing, or exercise in 2 siblings with Fabry disease. Neither neurotropin nor carbamazepine mono-therapy relieved the episodic colicky pain in 1 patient; however, therapy with both drugs eliminated the pain completely. This result suggests that the mechanisms underlying the analgesic actions of both drugs may be complementary in ameliorating the pain of Fabry disease, even though the mechanism underlying the pain has not been clearly elucidated.

    Neurotropin, an extract from the inflamed skin of vaccinia virus-inoculated rabbits
    MEDICATION

, was effective in the

    relief of sharp or burning pain induced by pyrexia
    SYMPTOMS

,

    hot weather
    SYMPTOMS

,

    bathing
    MEDICATION

, or

    exercise
    MEDICATION

 in 2 siblings with

    Fabry disease
    DIAGNOSIS

.

    Neither neurotropin nor carbamazepine mono-therapy relieved the episodic colicky pain
    NEG_FINDINGS

 in 1 patient; however,

    therapy with both drugs
    MEDICATION

    eliminated the pain completely
    SYMPTOMS

. This result suggests that the mechanisms underlying the analgesic actions of both drugs may be complementary in ameliorating the pain of

    Fabry disease
    DIAGNOSIS

, even though the mechanism underlying the pain has not been clearly elucidated.


Priapism and Fabry disease: a case report.

A 10-year-old boy presented with priapism of 10 h duration which after unsuccessful conservative measures, was relieved by a saphenocorporeal shunt. A 4-year history of intermittent vague aching of fingers and toes accompanied by low-grade fever was reported. Fabry disease was confirmed by the lack alpha-galactosidase activity in serum and leucocytes. Other characteristic features of Fabry disease were not present. The condition was also diagnosed in his 14-year-old brother and suspected in his maternal grandfather who died at the age of 49 from renal failure of unknown aetiology.

A

    10-year-old
    AGE

    boy
    GENDER

 presented with

    priapism of 10 h duration
    SYMPTOMS

 which after

    unsuccessful conservative measures
    NEG_FINDINGS

, was relieved by a

    saphenocorporeal shunt
    MEDICATION

. A 4-year history of

    intermittent vague aching of fingers and toes
    SYMPTOMS

 accompanied by

    low-grade fever
    SYMPTOMS

 was reported.

    Fabry disease
    DIAGNOSIS

 was confirmed by the

    lack alpha-galactosidase activity in serum and leucocytes
    BIOCHEMICAL

.

    Other characteristic features of Fabry disease were not present
    NEG_FINDINGS

. The condition was also diagnosed in

    his
    GENDER

    14-year-old
    AGE

    brother
    GENDER

    and suspected in his maternal grandfather who died at the age of 49
    FAMILY

 from

    renal failure of unknown aetiology
    SYMPTOMS

.


[Fabry's disease with isolated disease of the cardiac muscle, manifesting as hypertrophic cardiomyopathy].

A case is presented of Fabry's disease manifesting in an adult (aged 64) as hypertrophic nonobstructive cardiomyopathy caused by massive ceramidtrihexoside storage confined exclusively to the cardiocytes. There was no storage detectable in capillaries or in any other structure of the organs examined (liver, pancreas, brain, aorta, pulmonary artery, coronary arteries, heart valves). The clinical picture was dominated by heart failure slowly progressing during the last fifteen years of the patient's life terminated by pulmonary thromboembolism. There were no clinical signs of ocular, renal or skin affection. Since no unfixed tissues were available for enzyme analysis diagnosis had to be done using formaldehyde fixed tissues. The isolated stored lipid was characterized by TLC and by proton magnetic resonance analysis as globotriaosyl ceramide (Gal alpha 1-4 Gal beta 1-4 Glc beta 1-1' Cer) and was proved to be cleaved by control cell homogenates but left intact by those prepared from Fabry mutant cells (leukocytes, cultured fibroblasts). alpha galactosidase activity in each of his four daughters was in heterozygous range (peripheral leukocytes were used for analysis). The existing variants of cardiological syndromes in Fabry's disease are reviewed together with problems of diagnosis of atypical cases.

A case is presented of

    Fabry's disease
    DIAGNOSIS

 manifesting in an

    adult
    AGE

 (

    aged 64
    AGE

) as

    hypertrophic nonobstructive cardiomyopathy
    SYMPTOMS

 caused by

    massive ceramidtrihexoside storage confined exclusively to the cardiocytes
    MICROSCOPIC

. There was

    no storage detectable in capillaries or in any other structure of the organs examined (liver, pancreas, brain, aorta, pulmonary artery, coronary arteries, heart valves)
    NEG_FINDINGS

. The clinical picture was dominated by

    heart failure slowly progressing during the last fifteen years of the
    SYMPTOMS

 patient's life terminated by

    pulmonary thromboembolism
    SYMPTOMS

. There were

    no clinical signs of ocular, renal or skin affection
    NEG_FINDINGS

. Since

    no unfixed tissues were available for enzyme analysis
    NEG_FINDINGS

 diagnosis had to be done using

    formaldehyde fixed tissues
    PARACLINICAL

. The

    isolated stored lipid
    MICROSCOPIC

 was characterized by

    TLC and by proton magnetic resonance analysis
    PARACLINICAL

 as

    globotriaosyl ceramide (Gal alpha 1-4 Gal beta 1-4 Glc beta 1-1' Cer) and was proved to be cleaved by control cell homogenates
    MICROSCOPIC

 but

    left intact by those prepared from Fabry mutant cells (leukocytes, cultured fibroblasts)
    MICROSCOPIC

.

    alpha galactosidase activity in each of his four daughters was in heterozygous range
    BIOCHEMICAL

 (

    peripheral leukocytes were used for analysis
    PARACLINICAL

). The existing variants of

    cardiological syndromes
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 are reviewed together with problems of diagnosis of atypical cases.


Biochemical and clinical analysis of accumulated glycolipids in symptomatic heterozygotes of angiokeratoma corporis diffusum (Fabry's disease) in comparison with hemizygotes.

Angiokeratoma corporis diffusum (Fabry's disease) is an X-linked disorder of glycosphingolipid catabolism. Heterozygous females, although usually asymptomatic, are occasionally as severely afflicted as hemizygous males; recently we identified a heterozygous patient with cardiomyopathy and severe pain in the extremities. In order to elucidate the difference of the clinical features, we analyzed the glycolipid composition of the heart, liver, and kidney obtained from the patient and from a hemizygote. Gas-liquid chromatography revealed that globotriaosylceramide (Gb3) was markedly increased in the heart (32.4 times higher than control) and increased to a lesser extent in the liver and kidney (3.74 and 6.79 times, respectively). The pattern of Gb3 accumulation in the heterozygote, where the highest increases were seen in the heart, was distinct from that in the hemizygote, where elevated levels of Gb3 and Ga2 were found in the kidney. Furthermore, the alpha-galactosidase activity in the heart, liver, and kidney of the heterozygote was 17%, 26%, and 36%, respectively, of normal controls, which correlated well with the accumulation of glycosphingolipid in the heart and with the disease's clinical manifestations. Two other hemizygotic patients, who were identified by low alpha-galactosidase activities, demonstrated the cardiac involvement.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 (

    Fabry's disease)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disorder of glycosphingolipid catabolism
    DIAGNOSIS

.

    Heterozygous
    GENETICS

    females
    GENDER

, although usually

    asymptomatic
    NEG_FINDINGS

, are occasionally as severely afflicted as

    hemizygous males
    GENETICS

; recently we identified a

    heterozygous
    GENETICS

 patient with

    cardiomyopathy
    SYMPTOMS

 and

    severe pain in the extremities
    SYMPTOMS

. In order to elucidate the difference of the clinical features, we

    analyzed the glycolipid composition of the heart, liver, and kidney
    PARACLINICAL

 obtained from the patient and from a hemizygote.

    Gas-liquid chromatography
    PARACLINICAL

 revealed that

    globotriaosylceramide (Gb3) was markedly increased in the heart (32.4 times higher than control) and increased to a lesser extent in the liver and kidney (3.74 and 6.79 times
    MICROSCOPIC

, respectively). The

    pattern of Gb3 accumulation
    MICROSCOPIC

 in the heterozygote, where the

    highest increases were seen in the heart
    MICROSCOPIC

, was distinct from that in the

    hemizygote
    GENETICS

, where

    elevated levels of Gb3 and Ga2 were found in the kidney
    MICROSCOPIC

. Furthermore,

    the alpha-galactosidase activity in the heart, liver, and kidney of the heterozygote
    BIOCHEMICAL

    was 17%, 26%, and 36%, respectively, of normal controls
    BIOCHEMICAL

, which correlated well with the

    accumulation of glycosphingolipid in the heart
    MICROSCOPIC

 and with the disease's clinical manifestations. Two other

    hemizygotic
    GENETICS

 patients, who were identified by

    low alpha-galactosidase activities
    BIOCHEMICAL

, demonstrated the

    cardiac involvement
    SYMPTOMS

.

Angiokeratoma corporis diffusum
cardiomyopathy
severe pain in the extremities
cardiac involvement

X-linked
Heterozygous
hemizygous males
heterozygous
hemizygote
hemizygotic


Demonstration of Fabry's disease deposits in placenta.

Involvement of the placenta by glycosphingolipid deposits in Fabry's disease has not been previously reported. We describe the presence of such deposits in the maternal half of a placenta obtained from a heterozygous carrier of the disease.

    Involvement of the placenta by glycosphingolipid deposits
    MICROSCOPIC

 in

    Fabry's disease
    DIAGNOSIS

 has not been previously reported. We describe the

    presence of such deposits in the maternal half of a placenta
    MICROSCOPIC

 obtained from a

    heterozygous carrier of the disease
    GENETICS

.


[Clinico-pathological features in four patients with Fabry's disease. The possible role of degenerative lesions in the interstitial vessels in renal dysfunction].

Clinical courses and histopathological changes of four patients with Fabry's disease were discussed in this report. All of them were male and revealed to have angiokeratomas of the skin and markedly decreased activity of alpha-galactosidase--A in leukocytes. They were from different families. No consanguinity was noted. Two of them, around 40 years of age, showed rapid impairment of renal function with simultaneously development of hypertension, progressing to uremia within several months. Their light and electron microscopic findings in renal biopsies were similar: severe degenerative changes in muscle cells of small arteries and arterioles with remarkable swelling of intima, and multiple sclerosing and collaptic lesions in glomeruli. The other 2 patients were about 20 years old and their renal functions were almost normal. No significant changes but fine vacuolization of epithelial cells of glomeruli were observed in renal biopsy specimens. It is concluded that marked degenerative changes in the vessels due to Fabry's disease might be the principal etiology of hypertension and rapid deterioration of renal function.

Clinical courses and histopathological changes of four patients with

    Fabry's disease
    DIAGNOSIS

 were discussed in this report. All of them were

    male
    GENDER

 and revealed to have

    angiokeratomas of the skin
    SYMPTOMS

 and

    markedly decreased activity of alpha-galactosidase--A in leukocytes
    BIOCHEMICAL

. They were

    from different families
    FAMILY

.

    No consanguinity was noted
    FAMILY

. Two of them,

    around 40 years of age
    AGE

, showed

    rapid impairment of renal function
    SYMPTOMS

 with simultaneously development of

    hypertension
    SYMPTOMS

, progressing to

    uremia
    BIOCHEMICAL

 within several

    months
    SYMPTOMS

. Their

    light and electron microscopic findings in renal biopsies
    PARACLINICAL

 were similar:

    severe degenerative changes in muscle cells of small arteries and arterioles
    MICROSCOPIC

 with

    remarkable swelling of intima
    SYMPTOMS

, and

    multiple sclerosing and collaptic lesions in glomeruli
    MICROSCOPIC

. The other 2 patients were

    about 20 years old
    AGE

 and their

    renal functions were almost normal
    NEG_FINDINGS

.

    No significant changes
    NEG_FINDINGS

 but

    fine vacuolization of epithelial cells of glomeruli
    MICROSCOPIC

 were observed in

    renal biopsy specimens
    PARACLINICAL

. It is concluded that

    marked degenerative changes in the vessels
    MICROSCOPIC

 due to

    Fabry's disease
    DIAGNOSIS

 might be the principal etiology of

    hypertension
    SYMPTOMS

 and

    rapid deterioration of renal function
    SYMPTOMS

.

angiokeratomas of the skin
rapid impairment of renal function
hypertension
months
remarkable swelling of intima
hypertension
rapid deterioration of renal function

renal functions were almost normal
No significant changes


Renal changes in heterozygous Fabry's disease--a family study.

Two sisters, one with a long history of proteinuria and the other of hematuria, came for examination. Physical examination and routine laboratory workups did not show any significant abnormalities. The renal ultrastructural changes in case 1 showed marked enlargement and foamy vacuolation of all the glomerular capillary visceral epithelial cells, which was not found in other glomerular cells. The renal changes in case 2 showed similar lesions but with fewer cells involved and also with less severity, but the involved cells showed marked lamellation within the vacuoles. The serum alpha-galactosidase activity was 4.9 and 3.0 nmol/h/mL serum, respectively (normal values, 12.1 +/- 1.6 nmol/h/mL serum, mean +/- SD, n = 11), thus confirming the heterozygous variety of Fabry's disease. Our findings in these two cases reveal that patients with heterozygous Fabry's disease may present with renal symptoms only, which may be either proteinuria or hematuria.

    Two sisters, one with a long history of proteinuria and the other of hematuria
    FAMILY

, came for examination.

    Physical examination
    PARACLINICAL

 and

    routine laboratory workups did not show any significant abnormalities
    NEG_FINDINGS

. The

    renal ultrastructural changes
    MICROSCOPIC

 in case 1 showed

    marked enlargement and foamy vacuolation of all the glomerular capillary visceral epithelial cells, which was not found in other glomerular cells
    MICROSCOPIC

. The

    renal changes
    MICROSCOPIC

 in case 2 showed

    similar lesions
    SYMPTOMS

 but with

    fewer cells involved
    MICROSCOPIC

 and also with less severity, but

    the involved cells showed marked lamellation within the vacuoles
    MICROSCOPIC

. The

    serum alpha-galactosidase activity was 4.9 and 3.0 nmol/h/mL serum, respectively (normal values, 12.1 +/- 1.6 nmol/h/mL serum
    BIOCHEMICAL

, mean +/- SD, n = 11), thus confirming the

    heterozygous variety of Fabry's disease
    GENETICS

. Our findings in these two cases reveal that patients with

    heterozygous Fabry's disease
    DIAGNOSIS

 may present with

    renal symptoms
    SYMPTOMS

 only, which may be either

    proteinuria
    BIOCHEMICAL

 or

    hematuria
    BIOCHEMICAL

.


Cardiocyte storage and hypertrophy as a sole manifestation of Fabry's disease. Report on a case simulating hypertrophic non-obstructive cardiomyopathy.

Fabry's disease was diagnosed in an adult patient as a lipid storage-induced non-obstructive hypertrophic cardiomyopathy. Stable angina pectoris started 15 years before death, was followed by slowly progressive heart failure and repeated pulmonary thromboembolism with death at 63 years. Autopsy disclosed enormous cardiomegaly (1100 g), cardiac storage of ceramide trihexoside (CTH) of the same intensity as in classical cases of generalized Fabry's disease (11 mg lipid/g wet weight) restricted to cardiocytes. Other tissues (liver, kidney, brain, pancreas, pulmonary artery, coronary arteries) were free of storage. Using proton magnetic resonance analysis on formaldehyde-fixed tissue the stored CTH was identified as globotriaosylceramide. It was enzymatically degradable by control cell cultures but left uncleaved by mutant reference Fabry cells. Alpha-galactosidase activities in peripheral leucocytes of all four of the patient's daughters were in the heterozygous range. The diagnostic difficulties in this monosymptomatic novel variant of Fabry's disease are stressed.

    Fabry's disease
    DIAGNOSIS

 was diagnosed in an

    adult
    AGE

 patient as a

    lipid storage-induced non-obstructive hypertrophic cardiomyopathy
    DIAGNOSIS

.

    Stable angina pectoris
    SYMPTOMS

 started 15 years before

    death
    SYMPTOMS

, was followed by

    slowly progressive heart failure
    SYMPTOMS

 and

    repeated pulmonary thromboembolism
    SYMPTOMS

 with

    death
    SYMPTOMS

 at

    63 years
    AGE

.

    Autopsy
    PARACLINICAL

 disclosed

    enormous cardiomegaly (1100 g)
    SYMPTOMS

,

    cardiac storage of ceramide trihexoside (CTH) of the same intensity as in classical cases of generalized Fabry's disease (11 mg lipid/g wet weight) restricted to cardiocytes
    MICROSCOPIC

.

    Other tissues (liver, kidney, brain, pancreas, pulmonary artery, coronary arteries) were free of storage
    NEG_FINDINGS

. Using

    proton magnetic resonance analysis on formaldehyde-fixed tissue
    PARACLINICAL

 the

    stored CTH was identified as globotriaosylceramide
    MICROSCOPIC

. It was

    enzymatically degradable by control cell cultures but left uncleaved by mutant reference Fabry cells
    NEG_FINDINGS

.

    Alpha-galactosidase activities in peripheral leucocytes of all four of the patient's daughters were in the heterozygous range
    BIOCHEMICAL

. The diagnostic difficulties in this

    monosymptomatic novel variant of Fabry's disease
    DIAGNOSIS

 are stressed.

Stable angina pectoris
death
slowly progressive heart failure
repeated pulmonary thromboembolism
death
enormous cardiomegaly (1100 g)


[Fabry's disease: kidney insufficiency in heterozygous patient].

We report a rare heterozygous status for Fabry's gene with severe kidney involvement and normal alpha-galactosidase A activity, together with the intrafamilial variations in the clinical expression of the disease. The random X inactivation hypothesis seems to explain such a variable expression of the alpha-galactosidase gene in our cases.

We report a

    rare heterozygous status for Fabry's gene
    GENETICS

 with

    severe kidney involvement
    SYMPTOMS

 and

    normal alpha-galactosidase A activity
    NEG_FINDINGS

, together with the intrafamilial variations in the clinical expression of the disease. The

    random X inactivation hypothesis
    GENETICS

 seems to explain such a

    variable expression of the alpha-galactosidase gene
    GENETICS

 in our cases.


Anorexia, weight loss, and diarrhea as presenting symptoms of angiokeratoma corporis diffusum (Fabry-Anderson's disease).

Fabry-Anderson's disease or angiokeratoma corporis diffusum (ACD) is an X-linked sphingolipidosis with a systemic character and occurs in 2-5 per million births (1-3). The basic defect is the absence of a lysosomal enzyme x-galactosidase A. This enzyme is necessary for the metabolization of ceramide trihexoside (globotriglycosyl ceramide), a breakdown product of cell membranes (4, 5). Clinically the disease is characterized by cutaneous angiokeratoma's and severe pain in the limbs from the second decade, followed by progressive renal insufficiency and cardiovascular and cerebrovascular damage in the third or fourth decade (6-8). In patients with established ACD, gastrointestinal symptoms have been described incidentally, mainly mild diarrhea (9, 10). We describe a kindred with ACD showing two extraordinary clinical features: (1) Anorexia, weight loss, and diarrhea were the presenting symptoms and antedated limb pain by many years, which has not been described before. (2) The disease was associated with another rare X-linked disorder: hypoplastic amelogenesis imperfecta.

    Fabry-Anderson's disease
    DIAGNOSIS

 or

    angiokeratoma corporis diffusum
    SYMPTOMS

    (ACD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    sphingolipidosis
    DIAGNOSIS

 with a systemic character and occurs in 2-5 per million births (1-3). The basic defect is the absence of a lysosomal enzyme x-galactosidase A. This enzyme is necessary for the

    metabolization of ceramide trihexoside (globotriglycosyl ceramide), a breakdown product of cell membranes
    MICROSCOPIC

 (4, 5). Clinically the disease is characterized by

    cutaneous angiokeratoma's
    SYMPTOMS

 and

    severe pain in the limbs
    SYMPTOMS

    from the second decade
    AGE

, followed by

    progressive renal insufficiency
    SYMPTOMS

 and

    cardiovascular and cerebrovascular damage
    SYMPTOMS

    in the third or fourth decade
    AGE

 (6-8). In patients with

    established ACD
    DIAGNOSIS

,

    gastrointestinal symptoms
    SYMPTOMS

 have been described incidentally, mainly

    mild diarrhea
    SYMPTOMS

 (9, 10). We describe a kindred with

    ACD
    DIAGNOSIS

 showing two extraordinary clinical features: (1)

    Anorexia
    SYMPTOMS

,

    weight loss
    SYMPTOMS

, and

    diarrhea
    SYMPTOMS

 were the presenting symptoms and antedated

    limb pain
    SYMPTOMS

 by many years, which has not been described before. (2) The disease was associated with another

    rare X-linked disorder
    GENETICS

:

    hypoplastic amelogenesis imperfecta
    DIAGNOSIS

.

Fabry-Anderson's disease
(ACD)
sphingolipidosis
established ACD
ACD
hypoplastic amelogenesis imperfecta


Angiokeratoma corporis diffusum in GM1 gangliosidosis, type 1.

A patient with severe deficiency of beta-galactosidase, who developed skin lesions of angiokeratoma corporis diffusum between the 3rd and 10th month of life, is described. The activity of other lysosomal enzymes, including alpha-neuraminidase, was normal. The first signs of the disease were noticed during the first month of life. By 3 months coarseness of the face and psychomotor retardation were present. In addition to angiokeratoma, he had large mongolian spots and several scattered slate-blue spots of pigmentation over his body. With the exception of the skin lesions, the other clinical signs and the course of the psychomotor deterioration were within the clinical picture of GM1 gangliosidosis, Type 1. Angiokeratoma, a manifestation of several lysosomal disorders, may appear in GM1 gangliosidosis during the first year of life.

A patient with

    severe deficiency of beta-galactosidase
    BIOCHEMICAL

, who developed

    skin lesions of angiokeratoma corporis diffusum
    SYMPTOMS

    between the 3rd and 10th month of life
    AGE

, is described. The

    activity of other lysosomal enzymes, including alpha-neuraminidase, was normal
    NEG_FINDINGS

. The first signs of the disease were noticed

    during the first month of life
    AGE

.

    By 3 months
    AGE

    coarseness of the face
    SYMPTOMS

 and

    psychomotor retardation
    SYMPTOMS

 were present. In addition to

    angiokeratoma
    SYMPTOMS

, he had

    large mongolian spots
    SYMPTOMS

 and

    several scattered slate-blue spots of pigmentation over his body
    SYMPTOMS

. With the exception of the

    skin lesions
    SYMPTOMS

, the other clinical signs and the course of the

    psychomotor deterioration
    SYMPTOMS

 were within the clinical picture of

    GM1 gangliosidosis, Type 1
    DIAGNOSIS

.

    Angiokeratoma
    SYMPTOMS

, a manifestation of several

    lysosomal disorders
    DIAGNOSIS

, may appear in

    GM1 gangliosidosis
    DIAGNOSIS

 during the

    first year of life
    AGE

.

GM1 gangliosidosis, Type 1
lysosomal disorders
GM1 gangliosidosis


Accumulation of glycosphingolipids in spinal and sympathetic ganglia of a symptomatic heterozygote of Fabry's disease.

Fabry's disease is an X-linked disorder of glycolipid catabolism. We have found a symptomatic heterozygous female with cardiomyopathy and severe pain in the extremities. We studied histochemically and biochemically the accumulated glycolipids in spinal and sympathetic ganglia of the patient. Histochemical examination demonstrated the marked glycolipid deposits that have been observed in heterozygous males in these ganglia. Gas-liquid chromatography (GLC) revealed that these accumulated glycolipids were characterized as globotriaosylceramide (Gb3cer) and galabiosylceramide (Ga2cer). In the heterozygous female, the accumulations of Gb3cer in spinal and sympathetic ganglia were, respectively, 34 and 48 times the amount in normal controls. This is the first report on quantitative and qualitative analyses of the accumulated glycolipids in spinal and sympathetic ganglia of a heterozygous carrier female.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disorder of glycolipid catabolism
    DIAGNOSIS

. We have found a symptomatic

    heterozygous
    GENETICS

    female
    GENDER

 with

    cardiomyopathy
    SYMPTOMS

 and

    severe pain in the extremities
    SYMPTOMS

. We studied

    histochemically and biochemically
    PARACLINICAL

 the

    accumulated glycolipids in spinal and sympathetic ganglia
    MICROSCOPIC

 of the patient.

    Histochemical examination
    PARACLINICAL

 demonstrated the

    marked glycolipid deposits
    MICROSCOPIC

 that have been observed in

    heterozygous males
    GENETICS

    in these ganglia
    MICROSCOPIC

.

    Gas-liquid chromatography (GLC)
    PARACLINICAL

 revealed that these

    accumulated glycolipids were characterized as globotriaosylceramide (Gb3cer) and galabiosylceramide (Ga2cer)
    MICROSCOPIC

. In the

    heterozygous
    GENETICS

    female
    GENDER

, the

    accumulations of Gb3cer in spinal and sympathetic ganglia
    MICROSCOPIC

 were, respectively,

    34 and 48 times the amount in
    MICROSCOPIC

 normal controls. This is the first report on

    quantitative and qualitative analyses of the accumulated glycolipids in spinal and sympathetic ganglia
    PARACLINICAL

 of a

    heterozygous
    GENETICS

 carrier

    female
    GENDER

.

Fabry's disease
disorder of glycolipid catabolism

X-linked
heterozygous
heterozygous males
heterozygous
heterozygous

cardiomyopathy
severe pain in the extremities