Otologic histopathology of Fabry's disease.

Fabry's disease is a rare progressive X-linked recessive disorder of glycosphingolipid metabolism. The accumulation of glycosphingolipids occurs in virtually all areas of the body, including the endothelial, perithelial, and smooth-muscle cells of blood vessels, the ganglion cells of the autonomic nervous system, and the glomeruli and tubules of the kidney. Although otologic symptoms have been described in these patients, to our knowledge there have been no temporal bone histopathologic reports. We describe the clinical histories, audiometric results, and temporal bone findings of two patients with this rare disorder. Both patients demonstrated a bilateral sloping sensorineural hearing loss audiometrically. Middle ear findings of seropurulent effusions and hyperplastic mucosa were seen in all four temporal bones. Strial and spiral ligament atrophy in all turns, and hair cell loss mainly in the basal turns, were also common findings. The number of spiral ganglion cells was reduced in all temporal bones; however, evidence of glycosphingolipid accumulation was not observed in the spiral ganglia.

    Fabry's disease
    DIAGNOSIS

 is a

    rare progressive X-linked recessive
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

. The

    accumulation of glycosphingolipids occurs in virtually all areas of the body, including the endothelial, perithelial, and smooth-muscle cells of blood vessels, the ganglion cells of the autonomic nervous system, and the glomeruli and tubules of the kidney
    MICROSCOPIC

. Although

    otologic symptoms
    SYMPTOMS

 have been described in these patients, to our knowledge there have been no

    temporal bone histopathologic
    PARACLINICAL

 reports. We describe the clinical histories,

    audiometric results
    PARACLINICAL

, and

    temporal bone findings
    PARACLINICAL

 of two patients with this

    rare disorder
    DIAGNOSIS

. Both patients demonstrated a

    bilateral sloping sensorineural hearing loss
    SYMPTOMS

 audiometrically.

    Middle ear findings
    SYMPTOMS

 of

    seropurulent effusions
    SYMPTOMS

 and

    hyperplastic mucosa were seen in all four temporal bones
    SYMPTOMS

.

    Strial and spiral ligament atrophy in all turns
    SYMPTOMS

, and

    hair cell loss mainly in the basal turns
    SYMPTOMS

, were also common findings.

    The number of spiral ganglion cells was reduced in all temporal bones
    MICROSCOPIC

; however,

    evidence of glycosphingolipid accumulation was not observed in the spiral ganglia
    NEG_FINDINGS

.


Novel lysosomal glycoaminoacid storage disease with angiokeratoma corporis diffusum.

A 46-year-old Japanese woman had disseminated angiokeratoma, confirmed by electron microscopy which showed numerous cytoplasmic vacuoles in cells of the kidney and skin. Enzyme activities against synthetic and natural substrates in leucocytes and fibroblasts were normal. Her urine contained a large amount of sialylglycoaminoacids, with predominant excretion of an O-glycoside-linked glycoaminoacid.

A

    46-year-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

 had

    disseminated angiokeratoma
    DIAGNOSIS

, confirmed by

    electron microscopy
    PARACLINICAL

 which showed

    numerous cytoplasmic vacuoles in cells of the kidney and skin
    MICROSCOPIC

.

    Enzyme activities against synthetic and natural substrates in leucocytes and fibroblasts were normal
    NEG_FINDINGS

.

    Her
    GENDER

    urine contained a large amount of sialylglycoaminoacids
    BIOCHEMICAL

, with

    predominant excretion of an O-glycoside-linked glycoaminoacid
    MICROSCOPIC

.


[Transvenous permanent pacemaker implantation for Fabry's disease. 3 cases report].

Three men with Fabry's disease (angiokeratoma corporis diffusum universal) are described. In the first patient, atrial fibrillation appeared, and a permanent cardiac pacemaker (VVI) was implanted. Sick sinus syndrome with complete atrioventricular block was occurred on the second patient. Transvenous pacemaker (DDD) implantation was performed for him. The last patient was younger brother of the second patient. He demonstrated complete atrio-ventricular block, so cardiac pace maker (VAT) was implanted. They showed a low value of granulocyte's alpha-galactosidase activity. During 1 to 4 year follow up period, they showed no trouble about pacemaking. Fabry's disease is an disorder of glycosphingolipid metabolism. This disorder is characterized by the accumulation of trihexosyl ceramide in many sites. Cardiac involvement and abnormal electrocardiographic manifestations are common in this disorder. Permanent cardiac pacemaker is necessary for severe bradycardia caused by this disorder.

Three

    men
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum universal
    SYMPTOMS

) are described. In the first patient,

    atrial fibrillation
    SYMPTOMS

 appeared, and a

    permanent cardiac pacemaker (VVI) was implanted
    MEDICATION

.

    Sick sinus syndrome
    DIAGNOSIS

 with

    complete atrioventricular block
    SYMPTOMS

 was occurred on the second patient.

    Transvenous pacemaker (DDD) implantation
    MEDICATION

 was performed for

    him
    GENDER

. The last patient was

    younger brother
    GENDER

 of the second patient.

    He
    GENDER

 demonstrated

    complete atrio-ventricular block
    SYMPTOMS

, so

    cardiac pace maker (VAT) was implanted
    MEDICATION

. They showed a

    low value of granulocyte's alpha-galactosidase activity
    BIOCHEMICAL

. During 1 to 4 year follow up period, they showed

    no trouble about pacemaking
    NEG_FINDINGS

.

    Fabry's disease
    DIAGNOSIS

 is an

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

. This disorder is characterized by the

    accumulation of trihexosyl ceramide in many sites
    MICROSCOPIC

.

    Cardiac involvement
    SYMPTOMS

 and

    abnormal electrocardiographic manifestations
    SYMPTOMS

 are common in this disorder.

    Permanent cardiac pacemaker
    MEDICATION

 is necessary for

    severe bradycardia
    SYMPTOMS

 caused by this disorder.


Lymphadenopathy and entero-vesical fistula in Fabry's disease.

A case of a 55-year-old man with known Fabry's disease, complicated by entero-vesical fistula and associated with enlarged mesenteric lymph nodes, is reported. Histopathologic and ultrastructural findings of the involved lymph nodes are described, and pathogenesis of the entero-vesical fistula is briefly discussed. This is the first case, to the authors' knowledge, of urologic complication in Fabry's disease.

A case of a

    55-year-old
    AGE

    man
    GENDER

 with known

    Fabry's disease
    DIAGNOSIS

, complicated by

    entero-vesical fistula
    SYMPTOMS

 and associated with

    enlarged mesenteric lymph nodes
    SYMPTOMS

, is reported.

    Histopathologic and ultrastructural findings of the involved lymph nodes
    PARACLINICAL

 are described, and pathogenesis of the

    entero-vesical fistula
    SYMPTOMS

 is briefly discussed. This is the first case, to the authors' knowledge, of

    urologic complication
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

.

entero-vesical fistula
enlarged mesenteric lymph nodes
entero-vesical fistula
urologic complication


[Four cases of Fabry's disease mimicking hypertrophic cardiomyopathy].

Four patients with Fabry's disease diagnosed by right ventricular endomyocardial biopsy had cardiac manifestations simulating hypertrophic cardiomyopathy (HCM). Case 1: A 51-year-old woman, whose elder sister had congestive heart failure, was hospitalized for exertional dyspnea and cardiomegaly. Her electrocardiogram (ECG) showed a short PQ interval (0.10 sec) and left ventricular hypertrophy. Her echocardiogram (Echo) showed moderate symmetrical hypertrophy of the left ventricle (IVST/PWT = 18 mm/17 mm). Case 2: A 32-year-old woman, whose elder sister had an abnormal ECG, was hospitalized for the ECG abnormalities consisting of a short PQ interval (0.10 sec) and ST-T changes in the left precordial leads. The Echo revealed mild symmetrical hypertrophy of the left ventricle (IVST = 13 mm, PWT = 13 mm). Case 3: A 44-year-old man was hospitalized for his ECG suggestive of left ventricular hypertrophy, and his Echo showed asymmetrical septal hypertrophy (ASH; IVST = 22 mm). Case 4: A 51-year-old man was hospitalized for his ECG showing high voltage in the left precordial leads, and his Echo showed ASH (IVST = 20 mm). The cardiac histopathological findings of these cases included cytoplasmic vacuolization by light microscopy, and electron-dense deposits consisting of parallel or concentric lamellae with periodic spacing, suggesting Fabry's disease. The urinary glycolipids of Case 1 were increased biochemically; then the diagnosis of Fabry's disease was confirmed. Cardiac hypertrophy in Fabry's disease has many aspects, because the histopathological changes and clinical manifestations are determined by genetic factors. It was concluded that Fabry's disease may be concealed in some patients with the clinical diagnosis of HCM.

Four patients with

    Fabry's disease
    DIAGNOSIS

 diagnosed by

    right ventricular endomyocardial biopsy
    PARACLINICAL

 had

    cardiac manifestations
    SYMPTOMS

 simulating

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

. Case 1: A

    51-year-old
    AGE

    woman
    GENDER

, whose

    elder sister had congestive heart failure
    FAMILY

, was hospitalized for

    exertional dyspnea
    SYMPTOMS

 and

    cardiomegaly
    SYMPTOMS

.

    Her
    GENDER

    electrocardiogram (ECG)
    PARACLINICAL

 showed a

    short PQ interval (0.10 sec)
    SYMPTOMS

 and

    left ventricular hypertrophy
    SYMPTOMS

.

    Her
    GENDER

    echocardiogram (Echo)
    PARACLINICAL

 showed

    moderate symmetrical hypertrophy of the left ventricle (IVST/PWT = 18 mm/17 mm)
    SYMPTOMS

. Case 2: A

    32-year-old
    AGE

    woman
    GENDER

,

    whose elder sister had an abnormal ECG
    FAMILY

, was hospitalized for the

    ECG abnormalities
    SYMPTOMS

 consisting of a

    short PQ interval (0.10 sec) and ST-T changes in the left precordial leads
    SYMPTOMS

. The

    Echo
    PARACLINICAL

 revealed

    mild symmetrical hypertrophy of the left ventricle (IVST = 13 mm, PWT = 13 mm)
    SYMPTOMS

. Case 3: A

    44-year-old
    AGE

    man
    GENDER

 was hospitalized for his

    ECG suggestive of left ventricular hypertrophy
    SYMPTOMS

, and

    his
    GENDER

    Echo
    PARACLINICAL

 showed

    asymmetrical septal hypertrophy (ASH; IVST = 22 mm)
    SYMPTOMS

. Case 4: A

    51-year-old
    AGE

    man
    GENDER

 was hospitalized for his

    ECG
    SYMPTOMS

 showing

    high voltage in the left precordial leads
    SYMPTOMS

, and

    his
    GENDER

    Echo
    PARACLINICAL

 showed

    ASH (IVST = 20 mm)
    SYMPTOMS

. The

    cardiac histopathological
    PARACLINICAL

 findings of these cases included

    cytoplasmic vacuolization
    MICROSCOPIC

 by

    light microscopy
    PARACLINICAL

, and

    electron-dense deposits consisting of parallel or concentric lamellae with periodic spacing
    MICROSCOPIC

, suggesting

    Fabry's disease
    DIAGNOSIS

. The

    urinary glycolipids
    MICROSCOPIC

 of Case 1

    were increased biochemically
    BIOCHEMICAL

; then the diagnosis of

    Fabry's disease
    DIAGNOSIS

 was confirmed.

    Cardiac hypertrophy
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 has many aspects, because the histopathological changes and clinical manifestations are determined by

    genetic factors
    GENETICS

. It was concluded that

    Fabry's disease
    DIAGNOSIS

 may be concealed in some patients with the clinical diagnosis of

    HCM
    DIAGNOSIS

.

Fabry's disease
hypertrophic cardiomyopathy (HCM)
Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease
HCM


Angiokeratoma corporis diffusum (Fabry's disease) with unusual features in a female patient. Light- and electron-microscopic investigation.

A case of clinically apparent angiokeratoma corporis diffusum (Fabry's disease) in an adult female carrier is presented. The patient had biochemical evidence of the disease, and showed multiple cutaneous lesions, in the absence of other major organ involvement. Ultrastructural examination of tissue fragments obtained by skin biopsies demonstrated the presence of a few typical electron-dense lamellar structures in endothelial cells, but not in smooth muscle cells. Electron microscopy proved to be the only effective way of detecting the intracytoplasmic inclusions, since light-microscopic histochemistry failed to reveal small amounts of the stored glycolipid. The exclusive involvement of endothelial cells suggests that they are more prone to store glycolipid than are all other types of cells usually involved in the disease. The abundance of intermediate filaments in the cytoplasm of endothelial cells is related exclusively to the high blood pressure in angiomatous arteriovenous shunts.

A case of clinically apparent

    angiokeratoma corporis diffusum
    SYMPTOMS

 (

    Fabry's disease)
    DIAGNOSIS

 in an

    adult
    AGE

    female
    GENDER

 carrier is presented. The patient had

    biochemical evidence
    SYMPTOMS

 of the disease, and showed

    multiple cutaneous lesions
    SYMPTOMS

, in the

    absence of other major organ involvement
    NEG_FINDINGS

.

    Ultrastructural examination of tissue fragments obtained by skin biopsies
    PARACLINICAL

 demonstrated the

    presence of a few typical electron-dense lamellar structures in endothelial cells, but not in smooth muscle cells
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 proved to be the only effective way of detecting the

    intracytoplasmic inclusions
    MICROSCOPIC

, since

    light-microscopic histochemistry
    PARACLINICAL

    failed to reveal small amounts of the stored glycolipid
    NEG_FINDINGS

. The

    exclusive involvement of endothelial cells
    MICROSCOPIC

 suggests that they are more prone to

    store glycolipid
    MICROSCOPIC

 than are all other types of cells usually involved in the disease. The

    abundance of intermediate filaments in the cytoplasm of endothelial cells
    MICROSCOPIC

 is related exclusively to the

    high blood pressure
    SYMPTOMS

 in

    angiomatous arteriovenous shunts
    SYMPTOMS

.

angiokeratoma corporis diffusum
biochemical evidence
multiple cutaneous lesions
high blood pressure
angiomatous arteriovenous shunts


Oral inflammatory changes as an initial manifestation of Crohn's disease antedating abdominal diagnosis. Report of a case.

The case of a 14-year-old boy who had oral ulcers with histologic proof of granulomatous disease nine months before the diagnosis of intestinal Crohn's disease is presented. Additional extraintestinal manifestations of this case were cheilitis, anal fissures, and "metastatic" disease to the umbilicus. The diagnosis was established after the onset of abdominal symptoms. All manifestations responded rapidly to systemic prednisone, sulfasalazine, and metronidazole.

The case of a

    14-year-old
    AGE

    boy
    GENDER

 who had

    oral ulcers
    SYMPTOMS

 with

    histologic proof of granulomatous disease
    SYMPTOMS

 nine months before the diagnosis of

    intestinal Crohn's disease
    DIAGNOSIS

 is presented. Additional

    extraintestinal manifestations
    SYMPTOMS

 of this case were

    cheilitis
    SYMPTOMS

,

    anal fissures
    SYMPTOMS

, and

    "metastatic" disease to the umbilicus
    SYMPTOMS

. The diagnosis was established after the onset of

    abdominal symptoms
    SYMPTOMS

. All manifestations responded rapidly to

    systemic prednisone, sulfasalazine, and metronidazole
    MEDICATION

.


[Echocardiographic findings in a case of Fabry's disease with aortic regurgitation and complete AV block, and in his family members].

A 46-year-old man with Fabry's disease having aortic regurgitation and complete atrioventricular (AV) block was presented. In spite of severe aortic regurgitation (Seller's grade 3/4), his two-dimensional (2-D) echocardiogram revealed increased thickness of the left ventricular wall with mild dilatation. The myocardial echo showed a fine granular sparkling texture suggesting phospholipid deposition in the myocardial tissue. The membranous portion of the interventricular septum was thickened, and the aortic valve was thickened and had imperfect coaptation. Endomyocardial biopsy of the right side of the interventricular septum revealed intramyocardial vacuolization by light microscopy. Electron microscopy confirmed the presence of myelinoid lamellar inclusion. Electrophysiologic examination revealed an intra-Hissian AV block. A DDD pacemaker was implanted and the patient's symptoms were improved. Valvular replacement was not attempted due to the danger of suture failure. The patient's brother (41-year-old) also had increased thickness of his left ventricular wall on echocardiography, and a complete AV block by ECG, but no valvular abnormalities. His sister (45-year-old) had increased thickness of the left ventricular wall on echocardiography, and negative T waves by ECG, but she had no cardiac symptoms. The possibility of cardiac involvement in this heterozygous woman with Fabry's disease should also be considered. The patient's 38-year-old sister and all the children of all family members had normal left ventricular wall thicknesses and normal ECG. These findings may correspond to the age-related disease severity. The possibility of cardiac abnormalities should be considered in heterozygous women with Fabry's disease.

A

    46-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 having

    aortic regurgitation
    SYMPTOMS

 and

    complete atrioventricular (AV) block
    SYMPTOMS

 was presented. In spite of

    severe aortic regurgitation (Seller's grade 3/4)
    SYMPTOMS

, his

    two-dimensional (2-D) echocardiogram
    PARACLINICAL

 revealed

    increased thickness of the left ventricular wall
    SYMPTOMS

 with

    mild dilatation
    SYMPTOMS

. The

    myocardial echo
    PARACLINICAL

 showed a

    fine granular sparkling texture suggesting phospholipid deposition in the myocardial tissue
    SYMPTOMS

.

    The membranous portion of the interventricular septum was thickened
    SYMPTOMS

, and

    the aortic valve was thickened and had imperfect coaptation
    SYMPTOMS

.

    Endomyocardial biopsy of the right side of the interventricular septum
    PARACLINICAL

 revealed

    intramyocardial vacuolization
    MICROSCOPIC

 by

    light microscopy
    PARACLINICAL

.

    Electron microscopy
    PARACLINICAL

 confirmed the

    presence of myelinoid lamellar inclusion
    MICROSCOPIC

.

    Electrophysiologic examination
    PARACLINICAL

 revealed an

    intra-Hissian AV block
    SYMPTOMS

. A

    DDD pacemaker was implanted
    MEDICATION

 and the patient's

    symptoms were improved
    SYMPTOMS

.

    Valvular replacement was not attempted
    NEG_FINDINGS

 due to the danger of

    suture failure
    SYMPTOMS

. The patient's

    brother (41-year-old
    FAMILY

) also had

    increased thickness of his left ventricular wall
    SYMPTOMS

 on

    echocardiography
    PARACLINICAL

, and a

    complete AV block
    SYMPTOMS

 by

    ECG
    SYMPTOMS

, but

    no valvular abnormalities
    NEG_FINDINGS

.

    His
    GENDER

    sister (45-year-old
    FAMILY

    ) had increased thickness of the left ventricular wall on echocardiography
    FAMILY

, and

    negative T waves by ECG
    SYMPTOMS

, but

    she
    GENDER

 had

    no cardiac symptoms
    NEG_FINDINGS

. The possibility of

    cardiac involvement
    SYMPTOMS

 in this

    heterozygous
    GENETICS

    woman
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 should also be considered. The patient's

    38-year-old sister and all the children of all family members
    FAMILY

 had

    normal left ventricular wall thicknesses
    NEG_FINDINGS

 and

    normal ECG
    NEG_FINDINGS

. These findings may correspond to the age-related disease severity. The possibility of

    cardiac abnormalities
    SYMPTOMS

 should be considered in

    heterozygous
    GENETICS

    women
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

.

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


Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation.

A detailed neuropathological and biochemical study was performed to evaluate the accumulation of ceramide trihexoside within the central and peripheral nervous systems of 2 patients with Fabry's disease. Luxol fast blue-staining lipid was noted in the leptomeninges and in the choroidal stroma; biochemical studies showed increased quantities of ceramide trihexoside in the cerebrospinal fluid. The permeable blood-brain barrier regions of the central and peripheral nervous systems contained increased quantities of ceramide trihexoside. Some central nervous system nuclei associated with autonomic function were also noted to store lipid. Other areas of increased ceramide trihexoside accumulation included specific cortical and brainstem structures. Possible sources for this selective accumulation of ceramide trihexoside within the central and peripheral nervous system include transport of glycolipid from the systemic vascular network and retrograde transsynaptic glycolipid transport.

A

    detailed neuropathological and biochemical study
    PARACLINICAL

 was performed to evaluate the

    accumulation of ceramide trihexoside within the central and peripheral nervous systems
    MICROSCOPIC

 of 2 patients with

    Fabry's disease
    DIAGNOSIS

.

    Luxol fast blue-staining lipid was noted in the leptomeninges and in the choroidal stroma
    MICROSCOPIC

;

    biochemical studies
    PARACLINICAL

 showed

    increased quantities of ceramide trihexoside in the cerebrospinal fluid
    MICROSCOPIC

.

    The permeable blood-brain barrier regions of the central and peripheral nervous systems contained increased quantities of ceramide trihexoside
    MICROSCOPIC

.

    Some central nervous system nuclei associated with autonomic function were also noted to store lipid
    MICROSCOPIC

. Other areas of

    increased ceramide trihexoside accumulation
    MICROSCOPIC

 included

    specific cortical and brainstem structures
    SYMPTOMS

. Possible sources for this

    selective accumulation of ceramide trihexoside within the central and peripheral nervous system
    MICROSCOPIC

 include

    transport of glycolipid from the systemic vascular network
    MICROSCOPIC

 and

    retrograde transsynaptic glycolipid transport
    MICROSCOPIC

.


An unusual cause of lymphoedema--confirmed by isotopic lymphangiography.

We describe here a rare case of lymphoedema (Anderson-Fabry's disease) and its examination using isotopic lymphography. Anderson-Fabry's disease gives rise to various multisystem problems including lymphoedema which are all secondary to the deposition of glycosphingolipids in venous tissue. The prognosis particularly in homozygote males is poor.

We describe here a rare case of

    lymphoedema (Anderson-Fabry's disease)
    DIAGNOSIS

 and its examination using

    isotopic lymphography
    PARACLINICAL

.

    Anderson-Fabry's disease
    DIAGNOSIS

 gives rise to various

    multisystem problems
    SYMPTOMS

 including

    lymphoedema
    SYMPTOMS

 which are all secondary to the

    deposition of glycosphingolipids in venous tissue
    MICROSCOPIC

. The prognosis particularly in

    homozygote males
    GENETICS

 is poor.

lymphoedema (Anderson-Fabry's disease)
Anderson-Fabry's disease


Severe orthostatic hypotension in a female carrier of Fabry's disease.

A 21-year-old woman in a family with a history of Fabry's disease showed orthostatic hypotension and whorl-like corneal opacity typical for Fabry's disease. Biochemical studies revealed that she was a heterozygote of the Fabry gene. A variety of autonomic function tests demonstrated both sympathetic and parasympathetic dysfunction. To our knowledge, the present case is the first report of a heterozygous female carrier of Fabry's disease presenting dysfunction of the autonomic nervous system.

A

    21-year-old
    AGE

    woman
    GENDER

    in a family with a history of Fabry's disease
    FAMILY

 showed

    orthostatic hypotension
    SYMPTOMS

 and

    whorl-like corneal opacity typical for Fabry's disease
    SYMPTOMS

.

    Biochemical studies
    PARACLINICAL

 revealed that

    she
    GENDER

 was a

    heterozygote of the Fabry gene
    GENETICS

. A variety of

    autonomic function tests
    PARACLINICAL

 demonstrated

    both sympathetic and parasympathetic dysfunction
    SYMPTOMS

. To our knowledge, the present case is the first report of a

    heterozygous
    GENETICS

    female
    GENDER

 carrier of

    Fabry's disease
    DIAGNOSIS

 presenting

    dysfunction of the autonomic nervous system
    SYMPTOMS

.

heterozygote of the Fabry gene
heterozygous


[Myocardial involvement in female Fabry's disease: evaluation by thallium-201 myocardial scintigraphy].

Fabry's disease is characterized by an inherited X-linked disorder of glycosphingolipid catabolism, and heterozygous women affected with this disease who show overt symptoms including cardiac manifestations have rarely been reported. To elucidate the features of myocardial involvement in female patients, noninvasive techniques including exercise stress thallium-201 myocardial scintigraphy were performed. Three female patients, Cases 1-3, 26, 29 and 50 years of age, were documented low leucocytic alpha-galactosidase activities of less than 48% of normal (67.92-16.2 nmol/mg protein/h). They were examined using ECG, two-dimensional echocardiography (2-D Echo), Holter ECG, treadmill test and stress scintigraphy. On the ECG, negative T waves were shown in leads III and aVF in Cases 1 and 2. Left ventricular high voltage, giant negative T waves and short PR intervals were seen in Case 3. The 2-D Echo revealed neither valvular change nor left ventricular hypertrophy. On the Holter ECG, monofocal ventricular premature beats were occasionally observed in Cases 1 and 3. The treadmill test showed positive ST changes only in Case 2. On the exercise stress scintigraphy, uptake of thallium-201 was enhanced in the apex of the heart in Cases 2 and 3. Low uptake areas of thallium-201 were observed in Case 3. The ventricular angiogram revealed slight hypertrophy of the wall of the apical portion. In endocardial biopsies from the right ventricle, myelinoid lamellar inclusions were demonstrated in myocardial cells electron microscopically. Increased uptake of thallium-201 in the apex was noted in two of the three patients, but no apical thickening was noticed in any of the three cases by 2-D Echo. From the result of the biopsy of Case 3, the increased apical uptake of thallium-201 seems to reflect thickening caused by the deposition of glycosphingolipid. It was concluded that myocardial involvement in female Fabry's disease may occur early in the third decade and that the lesions could be detected with high sensitivity by thallium-201 myocardial scintigraphy.

    Fabry's disease
    DIAGNOSIS

 is characterized by an

    inherited X-linked
    GENETICS

    disorder of glycosphingolipid catabolism
    DIAGNOSIS

, and

    heterozygous
    GENETICS

    women
    GENDER

 affected with this disease who show

    overt symptoms
    SYMPTOMS

 including

    cardiac manifestations
    SYMPTOMS

 have rarely been reported. To elucidate the features of

    myocardial involvement
    SYMPTOMS

 in

    female
    GENDER

 patients, noninvasive techniques including

    exercise stress thallium-201 myocardial scintigraphy
    PARACLINICAL

 were performed. Three

    female
    GENDER

 patients, Cases 1-3,

    26, 29 and 50 years of age
    AGE

, were documented

    low leucocytic alpha-galactosidase activities of less than 48% of normal (67.92-16.2 nmol/mg protein/h)
    BIOCHEMICAL

. They were examined using

    ECG
    PARACLINICAL

,

    two-dimensional echocardiography (2-D Echo)
    PARACLINICAL

,

    Holter ECG
    PARACLINICAL

,

    treadmill test
    PARACLINICAL

 and

    stress scintigraphy
    PARACLINICAL

. On the ECG,

    negative T waves were shown in leads III and aVF
    SYMPTOMS

 in Cases 1 and 2.

    Left ventricular high voltage
    SYMPTOMS

,

    giant negative T waves
    SYMPTOMS

 and

    short PR intervals
    SYMPTOMS

 were seen in Case 3. The

    2-D Echo
    PARACLINICAL

 revealed

    neither valvular change nor left ventricular hypertrophy
    NEG_FINDINGS

. On the

    Holter ECG
    PARACLINICAL

,

    monofocal ventricular premature beats
    SYMPTOMS

 were occasionally observed in Cases 1 and 3. The

    treadmill test
    PARACLINICAL

 showed

    positive ST changes
    SYMPTOMS

 only in Case 2. On the

    exercise stress scintigraphy
    PARACLINICAL

,

    uptake of thallium-201 was enhanced in the apex of the heart
    SYMPTOMS

 in Cases 2 and 3.

    Low uptake areas of thallium-201
    SYMPTOMS

 were observed in Case 3. The

    ventricular angiogram
    PARACLINICAL

 revealed

    slight hypertrophy of the wall of the apical portion
    SYMPTOMS

. In

    endocardial biopsies from the right ventricle
    PARACLINICAL

,

    myelinoid lamellar inclusions were demonstrated in myocardial cells
    MICROSCOPIC

    electron microscopically
    PARACLINICAL

.

    Increased uptake of thallium-201 in the apex
    SYMPTOMS

 was noted in two of the three patients, but

    no apical thickening was noticed in any of the three cases by 2-D Echo
    NEG_FINDINGS

. From the result of the

    biopsy
    PARACLINICAL

 of Case 3, the

    increased apical uptake of thallium-201
    SYMPTOMS

 seems to reflect thickening caused by the

    deposition of glycosphingolipid
    MICROSCOPIC

. It was concluded that

    myocardial involvement
    SYMPTOMS

 in

    female
    GENDER

    Fabry's disease
    DIAGNOSIS

 may occur

    early in the third decade
    AGE

 and that the lesions could be detected with high sensitivity by

    thallium-201 myocardial scintigraphy
    PARACLINICAL

.


Manifestation of angiokeratoma diffusum in a girl patient with heterozygous genotype for Fabry disease.

The case of a 16 years old girl patient having angiokeratoma corporis diffusum with Fabry heterozygosity is published together with the clinical and genetical screening investigations of the family members. The problem of the detection of the heterozygotes is discussed.

The case of a

    16 years old
    AGE

    girl
    GENDER

 patient having

    angiokeratoma corporis diffusum
    SYMPTOMS

 with

    Fabry heterozygosity
    DIAGNOSIS

 is published together with the

    clinical and genetical screening investigations of the family members
    PARACLINICAL

. The problem of the detection of the

    heterozygotes
    GENETICS

 is discussed.


Several functional and fluorescein fundus angiographic findings in Fabry's disease.

Fabry's disease has well-known characteristic morphological findings, i.e., the whorl-like corneal opacity and the posterior spoke-like cataract, etc. But its functional aspect has not been investigated fully. Thus, a 47-year-old male with Fabry's disease was examined with Cochet-Bonnet's esthesiometer, photokeratometry, ultrasonography, electropupillography, electroretinography, electro-oculography and fluorescein fundus angiography. Most of functional findings remained normal in spite of corneal opacity, cataract, retinal and conjunctival vascular tortuosity, choroidal vascular disturbance and delayed retinal circulation time. We discuss the reasons why significant functional disturbance has not developed.

    Fabry's disease
    DIAGNOSIS

 has well-known characteristic morphological findings, i.e., the

    whorl-like corneal opacity
    SYMPTOMS

 and the

    posterior spoke-like cataract
    SYMPTOMS

, etc. But its functional aspect has not been investigated fully. Thus, a

    47-year-old
    AGE

    male
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 was examined with

    Cochet-Bonnet's esthesiometer
    PARACLINICAL

,

    photokeratometry
    PARACLINICAL

,

    ultrasonography
    PARACLINICAL

,

    electropupillography
    PARACLINICAL

,

    electroretinography
    PARACLINICAL

,

    electro-oculography
    PARACLINICAL

 and

    fluorescein fundus angiography
    PARACLINICAL

.

    Most of functional findings remained normal
    NEG_FINDINGS

 in spite of

    corneal opacity
    SYMPTOMS

,

    cataract
    SYMPTOMS

,

    retinal and conjunctival vascular tortuosity
    SYMPTOMS

,

    choroidal vascular disturbance
    SYMPTOMS

 and

    delayed retinal circulation time
    SYMPTOMS

. We discuss the reasons why

    significant functional disturbance has not developed
    NEG_FINDINGS

.


Generalized anhidrosis associated with Fabry's disease.

A 28-year-old Korean man suffered from generalized acquired anhidrosis and heat intolerance that were confirmed by a sweat test. Other clinical features consistent with Fabry's disease were fever and severe pain of the lower extremities and leg edema. Although the patients lacked cutaneous angiokeratomas, ultrastructural studies of the normal skin demonstrated diagnostic intracytoplasmic inclusions in the endothelial cells and pericytes of dermal vessels, fibroblasts, perineural cells, and secretory cells of eccrine glands. alpha-Galactosidase assay of the patient's leukocytes showed markedly decreased activity, which confirms the diagnosis.

A

    28-year-old
    AGE

    Korean
    ETHNICITY

    man
    GENDER

 suffered from

    generalized acquired anhidrosis
    SYMPTOMS

 and

    heat intolerance
    SYMPTOMS

 that were confirmed by a

    sweat test
    PARACLINICAL

. Other clinical features consistent with

    Fabry's disease
    DIAGNOSIS

 were

    fever
    SYMPTOMS

 and

    severe pain of the lower extremities
    SYMPTOMS

 and

    leg edema
    SYMPTOMS

. Although the patients

    lacked cutaneous angiokeratomas
    NEG_FINDINGS

,

    ultrastructural studies of the normal skin
    PARACLINICAL

 demonstrated

    diagnostic intracytoplasmic inclusions in the endothelial cells and pericytes of dermal vessels, fibroblasts, perineural cells, and secretory cells of eccrine glands
    MICROSCOPIC

.

    alpha-Galactosidase assay of the patient's leukocytes
    BIOCHEMICAL

 showed

    markedly decreased activity
    BIOCHEMICAL

, which confirms the diagnosis.

generalized acquired anhidrosis
heat intolerance
fever
severe pain of the lower extremities
leg edema


Autosomal dominant hypophosphataemia with elevated serum 1,25 dihydroxyvitamin D and hypercalciuria.

A 14-year-old boy presented with the clinical and radiological features of rickets. Serum inorganic phosphate levels were constantly low, whereas serum calcium and parathyroid hormone levels were within the normal range. Laboratory investigation did not show any evidence for vitamin-D deficiency, chronic renal insufficiency, Fanconi syndrome, tubular acidosis, hepatic disease or intestinal malabsorption. A family study comprising 34 members over four generations revealed 10 other individuals to be affected and the mode of inheritance to be autosomal dominant. In addition to hypophosphataemia and normocalcaemia, the disease is characterized by elevated serum 1,25 dihydroxyvitamin D levels and hypercalciuria. This hereditary syndrome of renal hypophosphataemia differs from the common familial X-linked hypophosphataemia and the recently described autosomal recessive hypophosphataemic rickets with hypercalciuria by its dominant mode of inheritance; it differs from hypophosphataemic non-rachitic bone disease by the elevated serum 1,25 dihydroxyvitamin D levels and hypercalciuria.

A

    14-year-old
    AGE

    boy
    GENDER

 presented with the

    clinical and radiological features of rickets
    SYMPTOMS

.

    Serum inorganic phosphate levels were constantly low
    BIOCHEMICAL

, whereas

    serum calcium and parathyroid hormone levels were within the normal range
    NEG_FINDINGS

.

    Laboratory investigation
    PARACLINICAL

 did

    not show any evidence for vitamin-D deficiency
    NEG_FINDINGS

,

    chronic renal insufficiency
    NEG_FINDINGS

,

    Fanconi syndrome
    NEG_FINDINGS

,

    tubular acidosis
    BIOCHEMICAL

,

    hepatic disease
    DIAGNOSIS

 or

    intestinal malabsorption
    SYMPTOMS

. A

    family study
    PARACLINICAL

 comprising

    34 members over four generations
    FAMILY

 revealed

    10 other individuals to be affected
    FAMILY

 and the

    mode of inheritance to be autosomal dominant
    FAMILY

. In addition to

    hypophosphataemia
    BIOCHEMICAL

 and

    normocalcaemia
    BIOCHEMICAL

, the disease is characterized by

    elevated serum 1,25 dihydroxyvitamin D levels
    BIOCHEMICAL

 and

    hypercalciuria
    BIOCHEMICAL

. This

    hereditary syndrome of renal hypophosphataemia
    DIAGNOSIS

 differs from the common

    familial X-linked hypophosphataemia
    GENETICS

 and the recently described

    autosomal recessive hypophosphataemic rickets
    DIAGNOSIS

 with

    hypercalciuria
    BIOCHEMICAL

 by its

    dominant mode of inheritance
    GENETICS

; it differs from

    hypophosphataemic non-rachitic bone disease
    DIAGNOSIS

 by the

    elevated serum 1,25 dihydroxyvitamin D levels
    BIOCHEMICAL

 and

    hypercalciuria
    BIOCHEMICAL

.

familial X-linked hypophosphataemia
dominant mode of inheritance


Renal biopsy in Fabry's disease eight years after successful renal transplantation.

Late graft histology after renal transplantation for Fabry's disease has only once been previously reported. Clinical data and kidney biopsy findings in a case of Fabry's disease before and eight years after successful kidney transplantation are presented. The graft maintains normal function. Graft histology in light microscopy showed no abnormalities reminiscent of the diseased native kidney. Electron microscopy revealed occasional small myelin figures which were present only in the vascular endothelium. Their significance and a review of conflicting reports and opinions from the literature are discussed.

    Late graft histology
    SYMPTOMS

 after

    renal transplantation
    MEDICATION

 for

    Fabry's disease
    DIAGNOSIS

 has only once been previously reported. Clinical data and

    kidney biopsy
    PARACLINICAL

 findings in a case of

    Fabry's disease
    DIAGNOSIS

 before and eight years after

    successful kidney transplantation
    MEDICATION

 are presented. The

    graft maintains normal function
    NEG_FINDINGS

.

    Graft histology in light microscopy
    PARACLINICAL

 showed

    no abnormalities reminiscent of the diseased native kidney
    NEG_FINDINGS

.

    Electron microscopy
    PARACLINICAL

 revealed

    occasional small myelin figures which were present only in the vascular endothelium
    MICROSCOPIC

. Their significance and a review of conflicting reports and opinions from the literature are discussed.

renal transplantation
successful kidney transplantation


A case of heterozygous Fabry's disease with a short PR interval and giant negative T waves.

A 55 year old woman with heterozygous Fabry's disease presented with cardiac symptoms. The electrocardiogram showed a PR interval of 0.12 s and giant negative T waves, suggesting apical hypertrophic cardiomyopathy. Endomyocardial biopsy, however, revealed myelin like substances characteristic of Fabry's disease. Increasing thickness of the left ventricular wall was seen by echocardiography over a period of five years. A deficiency of alpha galactosidase activity in the leucocytes confirmed the diagnosis of Fabry's disease, although this patient had neither angiokeratoma or proteinuria. The possibility of Fabry's disease should be considered in patients with cardiomegaly of unknown cause and the following electrocardiographic abnormalities: a PR interval less than or equal to 0.12 s, high voltage QRS complexes in the left precordial leads, and giant negative T waves.

A

    55 year old
    AGE

    woman
    GENDER

 with

    heterozygous Fabry's disease
    GENETICS

 presented with

    cardiac symptoms
    SYMPTOMS

. The

    electrocardiogram
    PARACLINICAL

 showed a

    PR interval of 0.12 s
    SYMPTOMS

 and

    giant negative T waves
    SYMPTOMS

, suggesting

    apical hypertrophic cardiomyopathy
    SYMPTOMS

.

    Endomyocardial biopsy
    PARACLINICAL

, however, revealed

    myelin like substances characteristic of Fabry's disease
    MICROSCOPIC

.

    Increasing thickness of the left ventricular wall
    SYMPTOMS

 was seen by

    echocardiography
    PARACLINICAL

 over a period of five years. A

    deficiency of alpha galactosidase activity in the leucocytes
    BIOCHEMICAL

 confirmed the diagnosis of

    Fabry's disease
    DIAGNOSIS

, although this patient had

    neither angiokeratoma or proteinuria
    NEG_FINDINGS

. The possibility of

    Fabry's disease
    DIAGNOSIS

 should be considered in patients with

    cardiomegaly of unknown cause
    SYMPTOMS

 and the following

    electrocardiographic abnormalities
    SYMPTOMS

: a

    PR interval less than or equal to 0.12 s
    SYMPTOMS

,

    high voltage QRS complexes in the left precordial leads
    SYMPTOMS

, and

    giant negative T waves
    SYMPTOMS

.


Involvement of renal allograft by Fabry's disease.

A man with Fabry's disease received a renal allograft from a heterozygous sister. Renal allograft dysfunction necessitated an allograft biopsy 5.5 years after transplantation. Extensive accumulation of Fabry's disease deposits in the glomeruli, tubules, blood vessels and interstitium was noted.

A

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

    received a renal allograft from a heterozygous sister
    MEDICATION

.

    Renal allograft dysfunction
    SYMPTOMS

 necessitated an

    allograft biopsy
    PARACLINICAL

 5.5 years after

    transplantation
    MEDICATION

.

    Extensive accumulation of Fabry's disease deposits in the glomeruli, tubules, blood vessels and interstitium
    MICROSCOPIC

 was noted.


[Visceral manifestations of glycosphingolipidosis (Fabry's disease)].

Fabry's disease is glycolipid sphingolipidosis which belongs to the group of lipid storage diseases and has as its underlying cause congenital deficiency of alpha-galactosidase. The pathologic anatomy of visceral lesions is described at the macroscopic, light-optical, and electron-microscopic levels in a 50-year-old male with striking systemic manifestations of Fabry's disease. In addition to lesions typical for glycolipid sphingolipidosis, atherosclerosis involving primarily heart arteries (which is not characteristic for this disease) was found in the patient. This case demonstrates that although cutaneous lesions underlie the traditional designation of Fabry's disease as angiokeratoma corporis diffusum, skin involvement is only one of its external signs.

    Fabry's disease
    DIAGNOSIS

 is

    glycolipid sphingolipidosis
    DIAGNOSIS

 which belongs to the group of

    lipid storage diseases
    DIAGNOSIS

 and has as its underlying cause

    congenital deficiency of alpha-galactosidase
    BIOCHEMICAL

. The pathologic anatomy of

    visceral lesions
    SYMPTOMS

 is described at the macroscopic,

    light-optical, and electron-microscopic levels
    PARACLINICAL

 in a

    50-year-old
    AGE

    male
    GENDER

 with

    striking systemic manifestations
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

. In addition to

    lesions typical for glycolipid sphingolipidosis
    SYMPTOMS

,

    atherosclerosis involving primarily heart arteries
    SYMPTOMS

 (which is not characteristic for this disease) was found in the patient. This case demonstrates that although

    cutaneous lesions
    SYMPTOMS

 underlie the traditional designation of

    Fabry's disease
    DIAGNOSIS

 as

    angiokeratoma corporis diffusum
    SYMPTOMS

,

    skin involvement
    SYMPTOMS

 is only one of its external signs.

Fabry's disease
glycolipid sphingolipidosis
lipid storage diseases
Fabry's disease
Fabry's disease


[Anderson-Fabry disease. Current status. Apropos of a case].

After submitting a typical case of Anderson-Fabry disease in a 38 years old male, we discuss the eminent aspects of this metabolic disorder and, above all, the clinical, biochemical and ultrastructural problems of diagnosis in the heterozygotic relatives.

After submitting a typical case of

    Anderson-Fabry disease
    DIAGNOSIS

 in a

    38 years old
    AGE

    male
    GENDER

, we discuss the eminent aspects of this

    metabolic disorder
    DIAGNOSIS

 and, above all, the clinical, biochemical and ultrastructural problems of diagnosis in the heterozygotic relatives.

Anderson-Fabry disease
metabolic disorder


[Fabry's disease. Rare etiology of a long-term inflammatory syndrome. Apropos of a case].

A man aged 54 years presented multiple symptoms (acroparesthesia, familial deafness, cardiomyopathy, diarrhea, adenopathy with infiltration of frothy macrophages, pancytopenia with a dense marrow, chronic meningitis, renal failure) associated with intermittent fever, with feverish attacks and a temperature of 40 degrees C, and with a severe biologic febrile syndrome. Fabry's disease was diagnosed only after 3 years of fruitless explorations. The reasons for this delay are analysed and it is suggested than Fabry's disease be added to the list of conditions responsible for fever or for a persistent inflammatory syndrome.

A

    man
    GENDER

    aged 54 years
    AGE

 presented

    multiple symptoms
    SYMPTOMS

 (

    acroparesthesia
    SYMPTOMS

,

    familial deafness
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

,

    diarrhea
    SYMPTOMS

,

    adenopathy with infiltration of frothy macrophages
    MICROSCOPIC

,

    pancytopenia with a dense marrow
    BIOCHEMICAL

,

    chronic meningitis
    DIAGNOSIS

,

    renal failure
    SYMPTOMS

) associated with

    intermittent fever
    SYMPTOMS

, with

    feverish attacks
    SYMPTOMS

 and a

    temperature of 40 degrees C
    SYMPTOMS

, and with a

    severe biologic febrile syndrome
    DIAGNOSIS

.

    Fabry's disease
    DIAGNOSIS

 was diagnosed only after 3 years of fruitless explorations. The reasons for this delay are analysed and it is suggested than

    Fabry's disease
    DIAGNOSIS

 be added to the list of conditions responsible for

    fever
    DIAGNOSIS

 or for a

    persistent inflammatory syndrome
    SYMPTOMS

.

multiple symptoms
acroparesthesia
familial deafness
cardiomyopathy
diarrhea
renal failure
intermittent fever
feverish attacks
temperature of 40 degrees C
persistent inflammatory syndrome

chronic meningitis
severe biologic febrile syndrome
Fabry's disease
Fabry's disease
fever


[Biochemical diagnosis of Anderson-Fabry disease in two brothers].

Activity of several lysosomal enzymes was studied in leukocytes, blood plasma and skin fibroblasts of two adult brothers with clinical diagnosis of Fabry disease. Activity of ceramide trihexoside-galactosidase was distinctly decreased in both patients. The residual enzymatic activity constituted 5-6% in the patients leukocytes, less than 10% in blood plasma and 25% in fibroblasts as compared with controls. Differences in composition of alpha-D-galactosidase multiple forms were detected in fibroblasts and blood cells of the patients with Fabry disease as compared with normal leukocytes by means of isoelectric focusing.

    Activity of several lysosomal enzymes
    BIOCHEMICAL

 was studied

    in leukocytes, blood plasma
    BIOCHEMICAL

 and

    skin fibroblasts
    MICROSCOPIC

 of two

    adult
    AGE

    brothers
    GENDER

 with clinical diagnosis of

    Fabry disease
    DIAGNOSIS

.

    Activity of ceramide trihexoside-galactosidase was distinctly decreased
    BIOCHEMICAL

 in both patients.

    The residual enzymatic activity constituted 5-6% in the patients leukocytes, less than 10% in blood plasma and 25% in fibroblasts
    BIOCHEMICAL

 as compared with controls.

    Differences in composition of alpha-D-galactosidase multiple forms were detected in fibroblasts and blood cells
    MICROSCOPIC

 of the patients with

    Fabry disease
    DIAGNOSIS

 as compared with normal leukocytes by means of

    isoelectric focusing
    PARACLINICAL

.


Ocular manifestations of Fabry's disease.

A 52-year-old black female teacher's aide presented for an eye examination with a complaint of progressively worsening vision, stinging and burning of the eyes, and occasional foreign body sensation. Examination revealed a dry eye syndrome and corneal dystrophy consistent with Fabry's disease, a cardiovascular disease with significant systemic as well as ocular findings. The patient was treated for the acute corneal symptoms and closely followed for progression of the dystrophic corneal changes.

A

    52-year-old
    AGE

    black
    ETHNICITY

    female
    GENDER

    teacher's
    MEDICATION

 aide presented for an

    eye examination
    PARACLINICAL

 with a complaint of

    progressively worsening vision
    SYMPTOMS

,

    stinging and burning of the eyes
    SYMPTOMS

, and

    occasional foreign body sensation
    SYMPTOMS

. Examination revealed a

    dry eye syndrome
    DIAGNOSIS

 and

    corneal dystrophy
    SYMPTOMS

 consistent with

    Fabry's disease
    DIAGNOSIS

, a

    cardiovascular disease
    DIAGNOSIS

 with

    significant systemic as well as ocular findings
    SYMPTOMS

. The patient was treated for the

    acute corneal symptoms
    SYMPTOMS

 and closely followed for progression of the

    dystrophic corneal changes
    SYMPTOMS

.

dry eye syndrome
Fabry's disease
cardiovascular disease


Cardiovascular manifestations in Fabry's disease. A high incidence of mitral valve prolapse in hemizygotes and heterozygotes.

Cardiovascular manifestations of Fabry's disease were studied clinically in 10 hemizygous males and 13 heterozygous females. Mitral valve prolapse was found in 5 of 9 hemizygotes and in 5 of 13 heterozygotes examined by echocardiography. Ordinary medical examinations revealed cardiomyopathy in some asymptomatic females, and the diagnosis of the Fabry heterozygote was established by demonstration of specific inclusion bodies in the biopsied myocardium and low alpha-galactosidase activity in leukocytes. Renovascular hypertension of juvenile onset and thromboembolism were also found in 7 patients. It was concluded that Fabry's disease should always be considered in cases of mitral valve prolapse, cardiomyopathy, renovascular hypertension and thrombosis of unknown etiology, and that the Fabry patients should be followed carefully for the early detection of cardiovascular involvements in this disease.

    Cardiovascular manifestations
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

 were studied clinically in 10

    hemizygous males
    GENETICS

 and 13

    heterozygous
    GENETICS

    females
    GENDER

.

    Mitral valve prolapse
    SYMPTOMS

 was found in 5 of 9

    hemizygotes
    GENETICS

 and in 5 of 13

    heterozygotes
    GENDER

 examined by

    echocardiography
    PARACLINICAL

.

    Ordinary medical examinations
    PARACLINICAL

 revealed

    cardiomyopathy
    SYMPTOMS

 in some

    asymptomatic
    NEG_FINDINGS

    females
    GENDER

, and the diagnosis of the

    Fabry heterozygote
    DIAGNOSIS

 was established by demonstration of

    specific inclusion bodies in the biopsied myocardium
    MICROSCOPIC

 and

    low alpha-galactosidase activity in leukocytes
    BIOCHEMICAL

.

    Renovascular hypertension of juvenile onset
    SYMPTOMS

 and

    thromboembolism
    SYMPTOMS

 were also found in 7 patients. It was concluded that

    Fabry's disease
    DIAGNOSIS

 should always be considered in cases of

    mitral valve prolapse
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

,

    renovascular hypertension
    SYMPTOMS

 and

    thrombosis of unknown etiology
    SYMPTOMS

, and that the

    Fabry
    DIAGNOSIS

 patients should be followed carefully for the early detection of

    cardiovascular involvements
    SYMPTOMS

 in this disease.

Fabry's disease
Fabry heterozygote
Fabry's disease
Fabry

hemizygous males
heterozygous
hemizygotes


Short PR intervals and tachyarrhythmias in Fabry's disease.

Two brothers with Fabry's disease presenting with palpitations were found to have intermittent supraventricular tachycardias. Their electrocardiograms, when symptom-free, revealed short PR intervals consistent with ventricular pre-excitation. Treatment of one of the brothers with verapamil resulted in improvement of the palpitations and reduction in frequency of the tachycardia. Recurrent supraventricular tachycardia associated with ventricular pre-excitation has not previously been described in Fabry's disease. Evidence suggests that this complication may be due to glycolipid deposition in the conducting system around the atrioventricular node.

Two

    brothers
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 presenting with

    palpitations
    SYMPTOMS

 were found to have

    intermittent supraventricular tachycardias
    SYMPTOMS

. Their

    electrocardiograms
    PARACLINICAL

,

    when symptom-free
    NEG_FINDINGS

, revealed

    short PR intervals consistent with ventricular pre-excitation
    SYMPTOMS

. Treatment of one of the

    brothers
    GENDER

 with

    verapamil
    MEDICATION

 resulted in

    improvement of the palpitations
    SYMPTOMS

 and

    reduction in frequency of the tachycardia
    SYMPTOMS

.

    Recurrent supraventricular tachycardia associated with ventricular pre-excitation
    SYMPTOMS

 has not previously been described in

    Fabry's disease
    DIAGNOSIS

. Evidence suggests that this complication may be due to

    glycolipid deposition in the conducting system around the atrioventricular node
    MICROSCOPIC

.


[Fabry disease, a disease with rheumatic aspects: radiology of soft tissue and bone changes in the hand].

Fabry's disease is a hereditary lipid storage disease with deposition of ceramides in nearly all tissues. The lipid deposition in the skin and the synovial compartments causes an enlargement of the skin, the joint capsules and the tendon sheaths, which are recognizable by low KV radiography. The bones of the hand mainly show multiple enthesopathic ossifications of a peculiar kind at the insertions of fibrous structures and few intra- and extraarticular erosions. The clinical picture often simulates an inflammatory rheumatic disease.

    Fabry's disease
    DIAGNOSIS

 is a

    hereditary
    GENETICS

    lipid storage disease
    DIAGNOSIS

 with

    deposition of ceramides in nearly all tissues
    MICROSCOPIC

. The

    lipid deposition in the skin and the synovial compartments
    MICROSCOPIC

 causes an

    enlargement of the skin, the joint capsules and the tendon sheaths
    SYMPTOMS

, which are recognizable by

    low KV radiography
    PARACLINICAL

.

    The bones of the hand
    SYMPTOMS

 mainly show

    multiple enthesopathic ossifications of a peculiar kind at the insertions of fibrous structures
    SYMPTOMS

 and

    few intra- and extraarticular erosions
    SYMPTOMS

. The clinical picture often simulates an

    inflammatory rheumatic disease
    DIAGNOSIS

.

Fabry's disease
lipid storage disease
inflammatory rheumatic disease


Corneal changes in Fabry's disease: a clinico-pathologic case report of a heterozygote.

Fabry's disease is an X-linked recessive inborn error of metabolism, caused by a deficiency of alpha galactosidase A. This report describes a heterozygote patient with multiple system problems diagnosed eventually as Fabry's disease by the ocular findings. The clinical diagnosis was confirmed by enzymatic assay. Our report emphasizes: The variability of the non-ocular manifestations in the heterozygote of Fabry's disease. The diagnosis of Fabry's disease in our patient was made by the ophthalmologist. The ultra-structural changes in the cornea and conjunctiva of the heterozygote confirm those reported in the literature; in addition we describe changes in the goblet cells. The clinical and ultra-structural similarities of the deposits in Fabry's disease, Chloroquin keratopathy and Amiodarone keratopathy are striking and will be discussed.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked recessive inborn error of metabolism
    GENETICS

, caused by a deficiency of alpha galactosidase A. This report describes a

    heterozygote
    GENETICS

 patient with

    multiple system problems
    SYMPTOMS

 diagnosed eventually as

    Fabry's disease
    DIAGNOSIS

 by the

    ocular findings
    SYMPTOMS

. The clinical diagnosis was confirmed by

    enzymatic assay
    PARACLINICAL

. Our report emphasizes: The variability of the

    non-ocular manifestations
    SYMPTOMS

 in the

    heterozygote
    GENETICS

 of

    Fabry's disease
    DIAGNOSIS

. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 in our patient was made by the

    ophthalmologist
    PARACLINICAL

. The

    ultra-structural changes in the cornea and conjunctiva
    SYMPTOMS

 of the heterozygote confirm those reported in the literature; in addition we describe

    changes in the goblet cells
    MICROSCOPIC

. The

    clinical and ultra-structural similarities of the deposits
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

,

    Chloroquin keratopathy
    DIAGNOSIS

 and

    Amiodarone keratopathy
    DIAGNOSIS

 are striking and will be discussed.

Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease
Chloroquin keratopathy
Amiodarone keratopathy


Fabry's Disease.

A case of Fabry' disease (angiokeratoma corporis diffusum universale) is reported. Presence of uncommon physical thick lips, large ears and proportion are high - lighted.

A case of

    Fabry' disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum universale)
    DIAGNOSIS

 is reported.

    Presence of uncommon physical thick lips
    SYMPTOMS

,

    large ears
    SYMPTOMS

 and

    proportion are high - lighted
    SYMPTOMS

.


Fabry's disease with partially deficient hydrolysis of ceramide trihexoside.

A report is presented on biochemical studies of the fibroblasts from a 26-year-old man with Fabry's disease whose clinical picture was atypical. The patient had severe pain in the extremities, but no angiokeratomas, corneal clouding or hypohidrosis. The trihexosylceramidase activity in the fibroblasts in vitro was deficient. The level and Km value of the residual activity were similar to levels seen in typical Fabry's patients. However, fibroblasts from the patient cultured in medium supplemented with [3H]ceramide trihexoside hydrolyzed the labeled ceramide trihexoside much higher than did cells from typical Fabry's patients, implying that the patient has a partial defect in hydrolysis of trihexosylceramide in cultured fibroblasts.

A report is presented on

    biochemical studies
    PARACLINICAL

 of the fibroblasts from a

    26-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 whose clinical picture was atypical. The patient had

    severe pain in the extremities
    SYMPTOMS

, but

    no angiokeratomas
    NEG_FINDINGS

,

    corneal clouding
    SYMPTOMS

 or

    hypohidrosis
    NEG_FINDINGS

.

    The trihexosylceramidase activity in the fibroblasts in vitro was deficient
    BIOCHEMICAL

. The

    level and Km value of the residual activity were similar to levels seen
    BIOCHEMICAL

 in typical

    Fabry's
    DIAGNOSIS

 patients. However,

    fibroblasts
    MICROSCOPIC

 from the patient

    cultured in medium supplemented with [3H]ceramide trihexoside hydrolyzed the labeled ceramide trihexoside much higher than did cells from typical Fabry's patients
    MICROSCOPIC

, implying that the patient has a

    partial defect in hydrolysis of trihexosylceramide
    BIOCHEMICAL

    in cultured fibroblasts
    MICROSCOPIC

.

severe pain in the extremities
corneal clouding


Progressive cardiac involvement by Fabry's disease despite successful renal allotransplantation.

Enzyme replacement by renal allotransplantation has been suggested as a specific mode of therapy for Fabry's disease. We report a case of Fabry's disease who developed symptoms and signs of heart failure despite successful renal transplantation 14 years ago. Echo- and angiocardiographic features resembled findings in patients with hypertrophic non-obstructive cardiomyopathy. Endomyocardial biopsy specimens demonstrated cardiac manifestation of Fabry's disease.

    Enzyme replacement by renal allotransplantation
    MEDICATION

 has been suggested as a specific mode of therapy for

    Fabry's disease
    DIAGNOSIS

. We report a case of

    Fabry's disease
    DIAGNOSIS

 who developed

    symptoms and signs of heart failure
    SYMPTOMS

    despite successful renal transplantation
    NEG_FINDINGS

 14 years ago.

    Echo- and angiocardiographic features
    SYMPTOMS

 resembled findings in patients with

    hypertrophic non-obstructive cardiomyopathy
    SYMPTOMS

.

    Endomyocardial biopsy specimens
    PARACLINICAL

 demonstrated

    cardiac manifestation of Fabry's disease
    MICROSCOPIC

.


Diagnostic value of kidney biopsy in heterozygous Fabry's disease.

We studied a case of abnormal renal pathologic findings in a female patient that were suggestive of Fabry's disease. Except for corneal clouding, no other clinical findings were consistent with this diagnosis. The serum and urinary enzyme levels were all within normal limits; the ceramide trihexoside level was slightly increased in the urine. We examined the pathologic changes in the context of the present knowledge of renal lesions in storage diseases.

We studied a case of

    abnormal renal pathologic findings
    SYMPTOMS

 in a

    female
    GENDER

 patient that were suggestive of

    Fabry's disease
    DIAGNOSIS

. Except for

    corneal clouding
    SYMPTOMS

,

    no other clinical findings were consistent with
    NEG_FINDINGS

 this diagnosis. The

    serum and urinary enzyme levels were all within normal limits
    NEG_FINDINGS

; the

    ceramide trihexoside level was slightly increased in the urine
    BIOCHEMICAL

. We examined the pathologic changes in the context of the present knowledge of

    renal lesions
    SYMPTOMS

 in

    storage diseases
    DIAGNOSIS

.

abnormal renal pathologic findings
corneal clouding
renal lesions


Biochemical phenotyping of a single sibship with both cystinosis and Fabry disease.

Two lysosomal storage diseases, cystinosis and Fabry disease, were diagnosed clinically in different members of a single sibship. The possibility that the affected sister and brother might have related disorders with disparate manifestations was pursued. The four principal family members were tested for heterozygote status with respect to serum and leukocyte alpha-galactosidase A activity, urinary trihexosylceramide excretion, and the capacity to engage in cystine counter-transport across leukocyte lysosome membranes. Results were consistent with classical autosomal recessive inheritance in the case of cystinosis and X-linked inheritance for Fabry disease, confirming that this family represents an example of two rare disorders occurring in the same sibship.

Two

    lysosomal storage diseases
    DIAGNOSIS

,

    cystinosis
    DIAGNOSIS

 and

    Fabry disease
    DIAGNOSIS

, were diagnosed

    clinically in different members of a single sibship
    FAMILY

. The possibility that

    the affected sister and brother might have related disorders with disparate manifestations
    FAMILY

 was pursued. The four principal family members were tested for heterozygote status with respect to

    serum and leukocyte alpha-galactosidase A activity
    BIOCHEMICAL

,

    urinary trihexosylceramide excretion
    BIOCHEMICAL

, and the

    capacity to engage in cystine counter-transport across leukocyte lysosome membranes
    BIOCHEMICAL

. Results were consistent with

    classical autosomal recessive inheritance
    GENETICS

 in the case of

    cystinosis
    DIAGNOSIS

 and

    X-linked inheritance
    GENETICS

 for

    Fabry disease
    DIAGNOSIS

, confirming that this family represents an example

    of two rare disorders occurring in the same sibship
    FAMILY

.

lysosomal storage diseases
cystinosis
Fabry disease
cystinosis
Fabry disease


[Ultrastructural changes in the skin of patients with Fabry's angiokeratoma].

The skin of a patient with Fabry's diffuse angiokeratoma accompanied by a severe decrease of leucocyte alpha-galactosidase (0,7-1,2 nmol/mg protein/h) was studied by a method of semithin and ultrathin sections. Cytoplasmic inclusions having lamellar structure in the form of alternating electron-dense and light strips with a period about 6 nm were found in the endotheliocytes of dilated vessels, lymphoid cells, neutrophil leucocytes, axons and leucocytes of nerve trunks. The presence of these specific inclusions together with the decrease of leucocytic alpha-galactosidase allows the differential diagnosis with other types of angiokeratomas and some skin angiomas.

The skin of a patient with

    Fabry's diffuse angiokeratoma
    DIAGNOSIS

 accompanied by a

    severe decrease of leucocyte alpha-galactosidase (0,7-1,2 nmol/mg protein/h)
    BIOCHEMICAL

 was studied by a

    method of semithin and ultrathin sections
    PARACLINICAL

.

    Cytoplasmic inclusions having lamellar structure in the form of alternating electron-dense and light strips with a period about 6 nm were found in the endotheliocytes of dilated vessels, lymphoid cells, neutrophil leucocytes, axons and leucocytes of nerve trunks
    MICROSCOPIC

. The

    presence of these specific inclusions
    MICROSCOPIC

 together with the

    decrease of leucocytic alpha-galactosidase
    BIOCHEMICAL

 allows the

    differential diagnosis
    PARACLINICAL

 with other types of

    angiokeratomas
    DIAGNOSIS

 and some

    skin angiomas
    DIAGNOSIS

.

Fabry's diffuse angiokeratoma
angiokeratomas
skin angiomas


[Angiokeratoma corporis diffusum (Fabry's disease). Update. Apropos of 2 cases].

Fabry's disease (angiokeratoma corporis diffusum) is an X-linked recessive inherited metabolic defect due to the lack of the enzyme alpha-galactosidase A. We reviewed the Argentine literature on the subject, the main features of the disease and its differential diagnosis. Two patients aged ten and fifteen are described showing the characteristic clinical picture of the disease since ages four and nine respectively. Skin and conjunctival ultrastructural studies showed intracytoplasmatic granules with a lamellar appearance in the endothelial cells, pericytes and fibroblasts. Plasma levels of alpha-galactosidase activity were sharply decreased in the two patients studied and partially decreased in their heterozygous mothers.

    Fabry's disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum
    SYMPTOMS

    )
    DIAGNOSIS

 is an

    X-linked recessive inherited metabolic defect
    GENETICS

 due to the lack of the enzyme alpha-galactosidase A. We reviewed the

    Argentine
    ETHNICITY

 literature on the subject, the main features of the disease and its

    differential diagnosis
    PARACLINICAL

. Two patients

    aged ten and fifteen
    AGE

 are described showing the characteristic clinical picture of the disease

    since ages four and nine respectively
    AGE

.

    Skin and conjunctival ultrastructural studies
    PARACLINICAL

 showed

    intracytoplasmatic granules with a lamellar appearance in the endothelial cells, pericytes and fibroblasts
    MICROSCOPIC

.

    Plasma levels of alpha-galactosidase activity were sharply decreased
    BIOCHEMICAL

 in the two patients studied and

    partially decreased
    BIOCHEMICAL

    in their heterozygous mothers
    FAMILY

.


Fabry's disease in a heterozygous woman.

Fabry's disease is a rare, X-linked disorder of glycolipid metabolism that is usually recognized in men in the third and fourth decades of life. A heterozygous state in women has been documented, but reports about women who are affected are confined to isolated case reports and to rare small series. We report a case of a 42-year-old woman with persistent proteinuria who was found to have Fabry's disease. The characteristic lesion was readily seen using routine high-resolution light microscopy (HRLM) tissue sections without the need of multiple extra tissue sections and special stains. We discuss the correlation of clinical findings, fluorescent microscopy, HRLM, electron microscopy, and biochemical enzymatic studies in establishing the diagnosis.

    Fabry's disease
    DIAGNOSIS

 is a

    rare, X-linked
    GENETICS

    disorder of glycolipid metabolism
    DIAGNOSIS

 that is usually recognized in

    men
    GENDER

 in the

    third and fourth decades of life
    AGE

. A heterozygous state in

    women
    GENDER

 has been documented, but reports about

    women
    GENDER

 who are affected are confined to isolated case reports and to rare small series. We report a case of a

    42-year-old
    AGE

    woman
    GENDER

 with

    persistent proteinuria
    BIOCHEMICAL

 who was found to have

    Fabry's disease
    DIAGNOSIS

. The characteristic lesion was readily seen using

    routine high-resolution light microscopy (HRLM) tissue sections
    PARACLINICAL

    without the need of multiple extra tissue sections and special stains
    NEG_FINDINGS

. We discuss the correlation of clinical findings,

    fluorescent microscopy
    PARACLINICAL

,

    HRLM
    PARACLINICAL

,

    electron microscopy
    PARACLINICAL

, and

    biochemical enzymatic studies
    PARACLINICAL

 in establishing the diagnosis.

Fabry's disease
disorder of glycolipid metabolism
Fabry's disease


[Significance of early ophthalmologic detection of Fabry disease].

A case of cornea verticillata discovered by chance is reported; as a result of this finding, a mother and daughter were found to be heterozygous carriers of Fabry's disease. The ocular and internal symptoms as well as the biochemical analysis are discussed. Early ophthalmologic diagnosis is essential. The patient should be informed of the genetic risk.

A case of

    cornea verticillata
    SYMPTOMS

 discovered by chance is reported; as a result of this finding,

    a mother and daughter were found to be heterozygous carriers of Fabry's disease
    FAMILY

. The

    ocular and internal symptoms
    SYMPTOMS

 as well as the

    biochemical analysis
    PARACLINICAL

 are discussed. Early

    ophthalmologic diagnosis
    PARACLINICAL

 is essential. The patient should be informed of the genetic risk.

cornea verticillata
ocular and internal symptoms


Corneal findings in a foetus with Fabry's disease.

The cornea of a 22-week foetus with Fabry's disease was examined biochemically and histopathologically. The alpha-galactosidase activity in the cornea was very low compared with that of the normal control. Histopathologic examination revealed that intracytoplasmic lamellar bodies surrounded by a single membrane were present in the epithelial cells. The lamellar bodies were thought to result from the abnormal accumulation of ceramide trihexoside. We conclude that ceramide trihexoside already has begun to accumulate progressively in the epithelial cells in the mid-trimester of gestation.

The cornea of a

    22-week foetus
    AGE

 with

    Fabry's disease
    DIAGNOSIS

 was examined

    biochemically and histopathologically
    PARACLINICAL

.

    The alpha-galactosidase activity in the cornea was very low compared with that of
    BIOCHEMICAL

 the normal control.

    Histopathologic examination
    PARACLINICAL

 revealed that

    intracytoplasmic lamellar bodies surrounded by a single membrane were present in the epithelial cells
    MICROSCOPIC

.

    The lamellar bodies
    MICROSCOPIC

 were thought to result from the

    abnormal accumulation of ceramide trihexoside
    MICROSCOPIC

. We conclude that

    ceramide trihexoside already has begun to accumulate progressively in the epithelial cells
    MICROSCOPIC

 in the

    mid-trimester of gestation
    AGE

.


beta-Galactosidase and neuraminidase deficiency associated with angiokeratoma corporis diffusum.

A 17-year-old Japanese boy was found to have ataxia, generalized angiokeratomas, skeletal deformities, visual impairment, and macular cherry-red spots, without hepatomegaly, splenomegaly, or renal failure. Laboratory examination disclosed a deficiency of beta-galactosidase as well as of neuraminidase activity in the leukocytes and fibroblasts, while alpha-galactosidase and alpha-L-fucosidase activities were normal. On electron microscopic examination, numerous cytoplasmic vacuoles containing flocculated material were found in the vascular endothelial cells, histiocytes, perineurial cells, and Schwann's cells.

A

    17-year-old
    AGE

    Japanese
    ETHNICITY

    boy
    GENDER

 was found to have

    ataxia
    SYMPTOMS

,

    generalized angiokeratomas
    SYMPTOMS

,

    skeletal deformities
    SYMPTOMS

,

    visual impairment
    SYMPTOMS

, and

    macular cherry-red spots
    SYMPTOMS

,

    without hepatomegaly
    NEG_FINDINGS

,

    splenomegaly
    NEG_FINDINGS

    , or renal failure
    NEG_FINDINGS

.

    Laboratory examination
    PARACLINICAL

 disclosed a

    deficiency of beta-galactosidase as well as of neuraminidase activity in the leukocytes and fibroblasts
    BIOCHEMICAL

, while

    alpha-galactosidase and alpha-L-fucosidase activities were normal
    NEG_FINDINGS

. On

    electron microscopic examination
    PARACLINICAL

,

    numerous cytoplasmic vacuoles containing flocculated material were found in the vascular endothelial cells, histiocytes, perineurial cells, and Schwann's cells
    MICROSCOPIC

.

ataxia
generalized angiokeratomas
skeletal deformities
visual impairment
macular cherry-red spots


Fabry's disease: an ultrastructural study of muscle and peripheral nerve.

A 9-year-old boy, presented with disseminated angiomatous lesions on the right leg. Ultrastructural examination of muscle and peripheral nerve showed numerous lamellar inclusions characteristic of Fabry's disease in the vessel's walls and perineurial cells. In addition, there were typical lamellar inclusions in some muscle fibers. Large myelinated fibers were reduced in number and some myelinated fibers showed segmental demyelination. Some lipid deposits displaying a lamellar pattern were occasionally seen in a few myelinated and unmyelinated axons. These abnormalities of nervous fibers are uncommon in Fabry's disease.

A

    9-year-old
    AGE

    boy
    GENDER

, presented with

    disseminated angiomatous lesions on the right leg
    SYMPTOMS

.

    Ultrastructural examination of muscle and peripheral nerve
    PARACLINICAL

 showed

    numerous lamellar inclusions characteristic of Fabry's disease in the vessel's walls and perineurial cells
    MICROSCOPIC

. In addition, there were

    typical lamellar inclusions in some muscle fibers
    MICROSCOPIC

.

    Large myelinated fibers were reduced in number
    MICROSCOPIC

 and

    some myelinated fibers showed segmental demyelination
    SYMPTOMS

.

    Some lipid deposits displaying a lamellar pattern were occasionally seen in a few myelinated and unmyelinated axons
    MICROSCOPIC

. These

    abnormalities of nervous fibers
    SYMPTOMS

 are uncommon in

    Fabry's disease
    DIAGNOSIS

.


Ultrastructural changes in the cornea and conjunctiva of a heterozygous woman with Fabry's disease.

Heterozygous females with Fabry's disease show a typical whorled pattern in the corneal epithelium. The patient presented in this paper also had symptoms of polymyositis, necrotizing vasculitis and angiokeratomas. The diagnosis was made from the corneal changes. Electron microscopy revealed intracytoplasmic electron-dense deposits made up of lamellar stacks of uniform periodicity similar to myelin. These were present not only in the corneal epithelium but also in the epithelium, goblet cells, endothelium and mural cells of blood vessels in the conjunctiva. The material in the goblet cells may account for the known presence of ceramide trihexoside in the tears.

    Heterozygous
    GENETICS

    females
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 show a

    typical whorled pattern in the corneal epithelium
    SYMPTOMS

. The patient presented in this paper also had symptoms of

    polymyositis
    DIAGNOSIS

,

    necrotizing vasculitis
    SYMPTOMS

 and

    angiokeratomas
    SYMPTOMS

. The diagnosis was made from the

    corneal changes
    SYMPTOMS

.

    Electron microscopy
    PARACLINICAL

 revealed

    intracytoplasmic electron-dense deposits made up of lamellar stacks of uniform periodicity similar to myelin
    MICROSCOPIC

.

    These were present not only in the corneal epithelium but also in the epithelium, goblet cells, endothelium and mural cells of blood vessels in the conjunctiva
    MICROSCOPIC

. The

    material in the goblet cells
    MICROSCOPIC

 may account for the known

    presence of ceramide trihexoside in the tears
    MICROSCOPIC

.


Jejunal diverticulosis with perforation as a complication of Fabry's disease.

This study presents the case of a patient who had jejunal diverticulosis with perforation and abscess formation as a complication of Fabry's disease. Light microscopy disclosed glycolipid deposition in the neurons and nerve fibers of the intestinal nerve plexuses and smooth muscle. Silver stains of the myenteric plexus in the involved segment of the bowel showed enlarged, granular argyrophobic neurons and a marked decrease in the number of argyrophilic neurons, with those remaining being enlarged and distorted by the cytoplasmic glycolipid accumulation. These abnormalities of the myenteric plexus suggest that jejunal diverticulosis may be the result of a variety of disorders of the smooth muscle or myenteric plexus, or both. We propose that jejunal diverticulosis in our patient was a consequence of uncoordinated smooth muscle activity resulting from Fabry's involvement of myenteric plexus neurons, with mucosal protrusion through the smooth muscle.

This study presents the case of a patient who had

    jejunal diverticulosis
    SYMPTOMS

 with

    perforation
    SYMPTOMS

 and

    abscess formation
    SYMPTOMS

 as a complication of

    Fabry's disease
    DIAGNOSIS

.

    Light microscopy
    PARACLINICAL

 disclosed

    glycolipid deposition in the neurons and nerve fibers of the intestinal nerve plexuses and smooth muscle
    MICROSCOPIC

.

    Silver stains of the myenteric plexus
    PARACLINICAL

    in the involved segment of the bowel
    MICROSCOPIC

 showed

    enlarged, granular argyrophobic neurons
    MICROSCOPIC

 and a

    marked decrease in the number of argyrophilic neurons, with those remaining being enlarged and distorted by the cytoplasmic glycolipid accumulation
    MICROSCOPIC

. These

    abnormalities of the myenteric plexus
    MICROSCOPIC

 suggest that

    jejunal diverticulosis
    SYMPTOMS

 may be the result of a variety of

    disorders of the smooth muscle or myenteric plexus
    SYMPTOMS

, or both. We propose that

    jejunal diverticulosis
    SYMPTOMS

 in our patient was a consequence of

    uncoordinated smooth muscle activity
    SYMPTOMS

 resulting from

    Fabry's involvement of myenteric plexus neurons
    MICROSCOPIC

, with

    mucosal protrusion through the smooth muscle
    SYMPTOMS

.


Angiokeratoma corporis diffusum in a patient with normal enzyme activities.

A 34-year-old man is described with angiokeratoma corporis diffusum. This eruption was once thought to be diagnostic of Anderson-Fabry disease; however, recent studies have shown that it may also occur in the enzyme disorders fucosidosis and sialidosis. In our patient with widespread angiokeratomas, the results of enzyme studies were normal, and there were no systemic problems or significant family history. Our case demonstrates that angiokeratoma corporis diffusum can occur in a benign form without systemic features.

A

    34-year-old
    AGE

    man
    GENDER

 is described with

    angiokeratoma corporis diffusum
    SYMPTOMS

. This eruption was once thought to be diagnostic of

    Anderson-Fabry disease
    DIAGNOSIS

; however, recent studies have shown that it may also occur in the

    enzyme disorders fucosidosis
    DIAGNOSIS

 and

    sialidosis
    DIAGNOSIS

. In our patient with

    widespread angiokeratomas
    SYMPTOMS

,

    the results of enzyme studies were normal
    NEG_FINDINGS

, and there were

    no systemic problems or significant family history
    NEG_FINDINGS

. Our case demonstrates that

    angiokeratoma corporis diffusum
    SYMPTOMS

 can occur in a benign form

    without systemic features
    NEG_FINDINGS

.

angiokeratoma corporis diffusum
widespread angiokeratomas
angiokeratoma corporis diffusum

Anderson-Fabry disease
enzyme disorders fucosidosis
sialidosis


Pathological study of the sural nerve in Fabry's disease.

A man with Fabry's disease, who died at 52, suffered from lancinating limb pains between the age of 20 and 27, and from severe arthralgia between 20 and 40. The sural nerve showed a severe loss of fibers (1,614 myelinated fibers/mm2), chiefly affecting the small myelinated fibers. Inclusions of both homogeneous and lamellated appearance were present in the perineurial cells, fibroblasts and vessel walls. Teased fibers displayed moderate remyelination, regeneration and the presence of globular focal myelin thickening. The transient time course of painful manifestations in this case is stressed in view of a possible pathogenesis of pain in Fabry's disease. It appears that small-fiber neuropathy is not directly related to the occurrence of pain symptoms, since the prevalent loss of small myelinated fibers was seen in the absence of actual pain. The small sensory neurons in the dorsal root ganglia, that are especially affected by lipid accumulation, probably give rise to abnormal discharges producing pain via the prevalence of the small-fiber versus the large-fiber input to the dorsal horn of the spinal cord (gate control theory). Thus pain fits may spontaneously abate, as in our case, if degeneration and loss of the small sensory neurons overstep a critical level.

A

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

, who

    died
    SYMPTOMS

 at

    52
    AGE

, suffered from

    lancinating limb pains
    SYMPTOMS

    between the age of 20 and 27
    AGE

, and from

    severe arthralgia
    SYMPTOMS

    between 20 and 40
    AGE

.

    The sural nerve
    PARACLINICAL

 showed a

    severe loss of fibers (1,614 myelinated fibers/mm2), chiefly affecting the small myelinated fibers
    MICROSCOPIC

.

    Inclusions of both homogeneous and lamellated appearance were present in the perineurial cells, fibroblasts and vessel walls
    MICROSCOPIC

.

    Teased fibers displayed moderate remyelination, regeneration
    MICROSCOPIC

 and the

    presence of globular focal myelin thickening
    MICROSCOPIC

. The

    transient time course of painful manifestations
    SYMPTOMS

 in this case is stressed in view of a possible pathogenesis of

    pain
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

. It appears that

    small-fiber neuropathy
    DIAGNOSIS

 is not directly related to the occurrence of

    pain symptoms
    SYMPTOMS

, since the

    prevalent loss of small myelinated fibers
    SYMPTOMS

 was seen in the

    absence of actual pain
    NEG_FINDINGS

. The

    small sensory neurons in the dorsal root ganglia
    SYMPTOMS

, that are especially affected by

    lipid accumulation
    MICROSCOPIC

, probably give rise to abnormal discharges producing

    pain
    SYMPTOMS

 via the prevalence of the small-fiber versus the

    large-fiber input to the dorsal horn of the spinal cord
    SYMPTOMS

 (gate control theory). Thus

    pain fits
    SYMPTOMS

 may

    spontaneously abate
    SYMPTOMS

, as in our case, if

    degeneration and loss of the small sensory neurons
    SYMPTOMS

 overstep a critical level.

Fabry's disease
Fabry's disease
small-fiber neuropathy


Fabry's disease (angiokeratoma corporis diffusum universale): ocular and associated findings.

Fabry's disease is one of the sphingolipidoses which results from the enzyme deficiency, alpha-galactosidase-A. It is a rare, hereditary, multiorgan disorder affecting the eye, skin, kidney, gastrointestinal system, heart, reticuloendothelial system, and central nervous system. Because all affected males and 90% of affected females exhibit ocular abnormalities, optometrists may be the first health care practitioners to identify these individuals.

    Fabry's disease
    DIAGNOSIS

 is one of the

    sphingolipidoses
    DIAGNOSIS

 which results from the enzyme deficiency, alpha-galactosidase-A. It is a

    rare, hereditary
    DIAGNOSIS

,

    multiorgan disorder
    DIAGNOSIS

    affecting the eye, skin, kidney, gastrointestinal system, heart, reticuloendothelial system, and central nervous system
    SYMPTOMS

. Because all affected

    males
    GENDER

 and 90% of affected

    females
    GENDER

 exhibit

    ocular abnormalities
    SYMPTOMS

,

    optometrists
    PARACLINICAL

 may be the first health care practitioners to identify these individuals.

Fabry's disease
sphingolipidoses
rare, hereditary
multiorgan disorder


Testicular and epididymal involvement in Fabry's disease.

Autopsy specimens of the testes and epididymis of a 32-year-old male with Fabry's disease were studied by light and electron microscopy. The characteristic ceramide deposits (lamellar inclusions, myeloid-bodies, zebra-bodies) were found in the Leydig cells as well as in the epithelial lining of both the ductuli efferentes and the ductus of the epididymis. Similar myeloid-bodies were observed in the blood vessels, connective tissue cells and muscle cells of the testicular interstitium, tunica albuginea and epididymis. In contrast, myeloid-bodies were absent or scarce in both the seminiferous epithelium and the mediastinum testis. However, the seminiferous tubules were severely affected showing reduced diameter, thickening of the tunica propria, and a few degenerated spermatogonia and primary spermatocytes. The different degrees of involvement of the testicular structures might be related to their different functions, the absorptive and permeable structures being the most severely affected. The development of testicular alterations seems to have been slow, since the patient fathered three children.

    Autopsy specimens of the testes and epididymis
    PARACLINICAL

 of a

    32-year-old
    AGE

    male
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 were studied by

    light and electron microscopy
    PARACLINICAL

.

    The characteristic ceramide deposits (lamellar inclusions, myeloid-bodies, zebra-bodies) were found in the Leydig cells as well as in the epithelial lining of both the ductuli efferentes and the ductus of the epididymis
    MICROSCOPIC

.

    Similar myeloid-bodies were observed in the blood vessels, connective tissue cells and muscle cells of the testicular interstitium, tunica albuginea and epididymis
    MICROSCOPIC

. In contrast,

    myeloid-bodies were absent or scarce in both the seminiferous epithelium and the mediastinum testis
    MICROSCOPIC

. However, the

    seminiferous tubules were severely affected
    SYMPTOMS

 showing

    reduced diameter
    SYMPTOMS

,

    thickening of the tunica propria
    MICROSCOPIC

, and

    a few degenerated spermatogonia and primary spermatocytes
    MICROSCOPIC

. The different degrees of

    involvement of the testicular structures
    SYMPTOMS

 might be related to their different functions, the

    absorptive and permeable structures
    SYMPTOMS

 being the most severely affected. The development of

    testicular alterations
    SYMPTOMS

 seems to have been slow, since the patient

    fathered three children
    FAMILY

.


Two dimensional echocardiographic similarity of Fabry's disease to cardiac amyloidosis: a function of ultrastructural analogy?

A 53-year-old man with Fabry's disease was studied by echocardiography. Both M-mode and two dimensional echocardiographic examinations produced findings indistinguishable from those previously described as virtually diagnostic of cardiac amyloidosis. Possible causes for the "granular sparkling" appearance and clinical implications of the similarities were discussed.

A

    53-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 was studied by

    echocardiography
    PARACLINICAL

. Both

    M-mode and two dimensional echocardiographic examinations
    PARACLINICAL

 produced

    findings indistinguishable from those
    SYMPTOMS

 previously described as virtually diagnostic of

    cardiac amyloidosis
    SYMPTOMS

. Possible causes for the

    "granular sparkling" appearance
    SYMPTOMS

 and clinical implications of the similarities were discussed.

findings indistinguishable from those
cardiac amyloidosis
"granular sparkling" appearance


Septic arthritis of the hip in children: poor results after late and inadequate treatment.

This study reports on the late results of septic arthritis of the hip in 29 children, after an average follow-up of 12 years 7 months. The purpose of the study is to show the severe destruction caused by infection in children's hips and to reemphasize the necessity for early diagnosis and treatment. The 29 patients were divided into two groups according to age (0-4 weeks and 1 month-3 years of age) because of the different prognoses. Functional and anatomical evaluations of the hips were performed. In some cases there was no correlation between the functional results and the anatomical situation of the joint. Our results showed that the prognosis is worse in young children and also in cases with associated osteomyelitis of the proximal femur. Eleven of the 16 neonates were premature. Late reconstructive surgery is difficult and does not always give the desired functional and anatomical improvement. The most important factor influencing the end result, however, is the time between beginning of symptoms and treatment; that is the only factor, also, we can change to improve the ultimate outcome of the disease.

This study reports on the late results of

    septic arthritis of the hip
    DIAGNOSIS

 in 29

    children
    AGE

, after an average follow-up of

    12 years 7 months
    AGE

. The purpose of the study is to show the

    severe destruction caused by infection
    SYMPTOMS

 in

    children
    AGE

's

    hips
    DIAGNOSIS

 and to reemphasize the necessity for early diagnosis and treatment. The 29 patients were divided into two groups according to

    age (0-4 weeks and 1 month-3 years of age
    AGE

) because of the different prognoses.

    Functional and anatomical evaluations of the hips
    PARACLINICAL

 were performed. In some cases there was

    no correlation between the functional results and the anatomical situation of the joint
    NEG_FINDINGS

. Our results showed that the prognosis is worse in

    young children
    AGE

 and also in cases with

    associated osteomyelitis of the proximal femur
    SYMPTOMS

. Eleven of the 16

    neonates
    AGE

 were

    premature
    AGE

.

    Late reconstructive surgery
    MEDICATION

 is difficult and does not always give the desired

    functional and anatomical improvement
    SYMPTOMS

. The most important factor influencing the end result, however, is the time between beginning of symptoms and treatment; that is the only factor, also, we can change to improve the ultimate outcome of the disease.


Silicon nephropathy mimicking Fabry's disease.

Percutaneous renal biopsy was performed in a surface coal miner with radiographic and histopathologic pulmonary changes consistent with acute silicolipoproteinosis who developed proteinuria and hematuria. Electron microscopic evaluation of the renal tissue specimen revealed a diffusely thickened glomerular basement membrane, foot process effacement, and dense lamellar inclusions in swollen glomerular epithelial cells, similar to those seen in Fabry's disease. However, normal levels of plasma alpha-galactosidase A, normal urinary sediment glycosphingolipids and the absence of the clinical characteristics of Fabry's disease excluded this diagnosis. This case illustrates that electron-dense lamellar inclusions, similar to those seen in Fabry's disease, may be seen in other entities such as nephropathy associated with silicosis.

    Percutaneous renal biopsy
    PARACLINICAL

 was performed in a

    surface coal miner
    MEDICATION

 with

    radiographic and histopathologic pulmonary changes consistent with acute silicolipoproteinosis
    SYMPTOMS

 who developed

    proteinuria
    BIOCHEMICAL

 and

    hematuria
    BIOCHEMICAL

.

    Electron microscopic evaluation of the renal tissue specimen
    PARACLINICAL

 revealed a

    diffusely thickened glomerular basement membrane
    MICROSCOPIC

,

    foot process effacement
    MICROSCOPIC

, and

    dense lamellar inclusions in swollen glomerular epithelial cells, similar to those seen in Fabry's disease
    MICROSCOPIC

. However,

    normal levels of plasma alpha-galactosidase A
    NEG_FINDINGS

,

    normal urinary sediment glycosphingolipids
    NEG_FINDINGS

 and the

    absence of the clinical characteristics of Fabry's disease
    NEG_FINDINGS

 excluded this diagnosis. This case illustrates that

    electron-dense lamellar inclusions, similar to those seen in Fabry's disease
    MICROSCOPIC

, may be seen in other entities such as

    nephropathy associated with silicosis
    DIAGNOSIS

.


Myelin bodies in urine sediment in hemizygotes with Anderson-Fabry disease.

Urine sediment of a hemizygous patient with Anderson-Fabry disease contained characteristic myelin bodies on ultrastructural examination. Such examination offers an alternative, noninvasive, relatively simple means of establishing early diagnosis.

    Urine sediment
    MICROSCOPIC

 of a

    hemizygous
    GENETICS

 patient with

    Anderson-Fabry disease
    DIAGNOSIS

 contained

    characteristic myelin bodies
    MICROSCOPIC

 on

    ultrastructural examination
    PARACLINICAL

. Such examination offers an alternative, noninvasive, relatively simple means of establishing early diagnosis.


Involvement of dorsal root ganglia in Fabry's disease.

Bouts of shooting pain along the extremities are common in the early stages of Fabry's disease. No pathological explanation has been advanced to clarify the mechanism of such pain. In the present case neuronal storage of glycolipid was confined to dorsal root ganglia neurones only. It is suggested that this may explain the shooting pain in Fabry's disease. In hereditary sensory radicular neuropathy, familial dysautonomia, and tabes dorsalis, changes in dorsal root ganglia cells cause similar clinical signs and thus it may be concluded that shooting pains in Fabry's disease may be caused by damage to dorsal root ganglia neurones.

    Bouts of shooting pain along the extremities
    SYMPTOMS

 are common in the early stages of

    Fabry's disease
    DIAGNOSIS

. No pathological explanation has been advanced to clarify the mechanism of such pain. In the present case

    neuronal storage of glycolipid was confined to dorsal root ganglia neurones only
    MICROSCOPIC

. It is suggested that this may explain the

    shooting pain
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

. In

    hereditary sensory radicular neuropathy
    DIAGNOSIS

,

    familial dysautonomia
    DIAGNOSIS

, and

    tabes dorsalis
    DIAGNOSIS

,

    changes in dorsal root ganglia cells
    MICROSCOPIC

 cause

    similar clinical signs
    SYMPTOMS

 and thus it may be concluded that

    shooting pains
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 may be caused by

    damage to dorsal root ganglia neurones
    SYMPTOMS

.

Fabry's disease
Fabry's disease
hereditary sensory radicular neuropathy
familial dysautonomia
tabes dorsalis
Fabry's disease


[Anderson-Fabry disease (angiokeratoma corporis diffusum)].

A 49-year-old man with angiokeratoma corporis diffusum is reported. Dermatological, ophthalmological or renal abnormalities have so far been found in 14 of the relatives of the patient. The typical dermal signs of the patient appeared on the distal part of the trunk at the age of 5-6 years, and swelling of the left leg occurred in adulthood. Besides the bicuspidal insufficiency, examination revealed ophthalmological symptoms, signs of renal damage, and the alpha-galactosidase activity deficiency of the leucocytes.

A

    49-year-old
    AGE

    man
    GENDER

 with

    angiokeratoma corporis diffusum
    SYMPTOMS

 is reported.

    Dermatological
    SYMPTOMS

,

    ophthalmological
    SYMPTOMS

 or

    renal abnormalities
    SYMPTOMS

 have so far been found in 14 of the relatives of the patient. The

    typical dermal signs
    SYMPTOMS

 of the patient

    appeared on the distal part of the trunk
    SYMPTOMS

    at the age of 5-6 years
    AGE

, and

    swelling of the left leg
    SYMPTOMS

 occurred

    in adulthood
    AGE

. Besides the

    bicuspidal insufficiency
    SYMPTOMS

, examination revealed

    ophthalmological symptoms
    SYMPTOMS

,

    signs of renal damage
    SYMPTOMS

, and the

    alpha-galactosidase activity deficiency of the leucocytes
    BIOCHEMICAL

.