Early renal failure in Fabry's disease.

Two young males were observed with renal failure from Fabry's disease. These two patients had progressive decrease of renal function and required hemodialysis at ages 16 and 24. Diagnosis was confirmed by low plasma galactosidase levels and by skin and kidney biopsy. Each has had a successful kidney transplant with good graft function, the 16-year-old patient for five years and the 24-year-old for two years. Although the renal impairment usually does not appear until the fourth or fifth decade of life. Fabry's disease should be considered in the differential diagnosis of renal failure in young males.

Two

    young
    AGE

    males
    GENDER

 were observed with

    renal failure
    SYMPTOMS

 from

    Fabry's disease
    DIAGNOSIS

. These two patients had

    progressive decrease of renal function
    SYMPTOMS

 and required

    hemodialysis
    MEDICATION

 at

    ages 16 and 24
    AGE

. Diagnosis was confirmed by

    low plasma galactosidase levels
    BIOCHEMICAL

 and by

    skin and kidney biopsy
    PARACLINICAL

. Each has had a

    successful kidney transplant
    MEDICATION

 with

    good graft function
    SYMPTOMS

, the

    16-year-old
    AGE

 patient for five years and the

    24-year-old
    AGE

 for

    two years
    AGE

. Although the

    renal impairment
    SYMPTOMS

 usually does not appear until the

    fourth or fifth decade of life
    AGE

.

    Fabry's disease
    DIAGNOSIS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 of

    renal failure
    SYMPTOMS

 in

    young
    AGE

    males
    GENDER

.

renal failure
progressive decrease of renal function
good graft function
renal impairment
renal failure

hemodialysis
successful kidney transplant


Kidney involvement in systemic lupus erythematosus and Fabry's disease.

A young female patient with both systemic lupus erythematosus (SLE) glomerulonephritis and glomerular glycolipid storage of Fabry's disease is described. The causal relationship between the two conditions is discussed and it is suggested that accumulated immunogenic galactocerebroside may have incited an autoimmune disease such as SLE.

A

    young
    AGE

    female
    GENDER

 patient with both

    systemic lupus erythematosus (SLE) glomerulonephritis
    DIAGNOSIS

 and

    glomerular glycolipid storage of Fabry's disease
    MICROSCOPIC

 is described. The causal relationship between the two conditions is discussed and it is suggested that

    accumulated immunogenic galactocerebroside
    MICROSCOPIC

 may have incited an

    autoimmune disease
    DIAGNOSIS

 such as

    SLE
    DIAGNOSIS

.


A case of Fabry's disease.

A case of Fabry's disease in a 22-year-old male patient who had mild proteinuria and dark-red eruptions is reported. He had been treated as a case of a so-called "chronic glomerulonephritis" for one year. However, histopathological findings of the renal biopsy specimens showed the presence of numerous vacuolated cells in the glomeruli. These vacuolated cells contained numerous electron dense bodies observed by electron microscopy. Skin lesions of this patient were consistent with those of angiokeratoma corporis. The levels of serum alpha-galactosidase were significantly lower than those of healthy controls. The mother of this patient also showed decreased levels of serum alpha-galactosidase. The pedigree of this patient showed a familial history of various types of renal diseases. It was postulated that Fabry's disease occurring in older patients has a worse clinical course. it is concluded that early detection of this disease through biopsy and the assay of serum alpha-galactosidase levels is important in managing the future course of patients with Fabry's disease.

A case of

    Fabry's disease
    DIAGNOSIS

 in a

    22-year-old
    AGE

    male
    GENDER

 patient who had

    mild proteinuria
    BIOCHEMICAL

 and

    dark-red eruptions
    SYMPTOMS

 is reported.

    He
    GENDER

 had been treated as a case of a so-called "

    chronic glomerulonephritis"
    DIAGNOSIS

 for one year. However,

    histopathological findings of the renal biopsy specimens
    PARACLINICAL

 showed the

    presence of numerous vacuolated cells in the glomeruli
    MICROSCOPIC

. These

    vacuolated cells contained numerous electron dense bodies
    MICROSCOPIC

 observed by

    electron microscopy
    PARACLINICAL

.

    Skin lesions
    SYMPTOMS

 of this patient

    were consistent with those of angiokeratoma corporis
    SYMPTOMS

. The

    levels of serum alpha-galactosidase were significantly lower than those of healthy controls
    BIOCHEMICAL

. The

    mother of this patient also showed decreased levels of serum alpha-galactosidase
    FAMILY

.

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

. It was postulated that

    Fabry's disease
    DIAGNOSIS

 occurring in

    older
    AGE

 patients has a worse clinical course. it is concluded that early detection of this disease through

    biopsy
    PARACLINICAL

 and the

    assay of serum alpha-galactosidase levels
    PARACLINICAL

 is important in managing the future course of patients with

    Fabry's disease
    DIAGNOSIS

.

Fabry's disease
chronic glomerulonephritis"
Fabry's disease
Fabry's disease


[Fabry's disease. Light and electron microscopic cardiac findings 12 years after successful kidney transplantation].

Fabry's disease (angiokeratoma corporis diffusum universale) is a disorder of sphingolipid metabolism affecting predominantly male patients. Renal damage is usually the cause of death in the fourth or fifth decade. Renal transplantation represents a new approach to correction of uremia and perhaps even of the basic congenital metabolic anomaly. In this case the patient, a 57-year-old man, developed renal failure at the age of 45 and received a renal allograft at that age. The transplantation was followed by complete remission of uremia and concomitant symptoms, but later complicated by progressive cardiac failure, anginal chest pain and arrythmia. Necropsy findings showed persistent deposition of ceramide in the myocardium and especially in the conduction system. This was documented, for the first time to the author's knowledge, by electron microscopic investigations. Cardiac manifestations of Fabry's disease are discussed in relation to patients with renal transplants.

    Fabry's disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum universale
    SYMPTOMS

    )
    DIAGNOSIS

 is a

    disorder of sphingolipid metabolism
    DIAGNOSIS

 affecting predominantly

    male
    GENDER

 patients.

    Renal damage
    SYMPTOMS

 is usually the cause of

    death
    SYMPTOMS

 in the

    fourth or fifth decade
    AGE

.

    Renal transplantation
    MEDICATION

 represents a new approach to correction of

    uremia
    BIOCHEMICAL

 and perhaps even of the basic congenital metabolic anomaly. In this case the patient, a

    57-year-old
    AGE

    man
    GENDER

, developed

    renal failure
    SYMPTOMS

 at the

    age of 45
    AGE

 and

    received a renal allograft
    MEDICATION

    at that age
    AGE

. The

    transplantation
    MEDICATION

 was followed by

    complete remission of uremia and concomitant symptoms
    SYMPTOMS

, but later complicated by

    progressive cardiac failure
    SYMPTOMS

,

    anginal chest pain
    SYMPTOMS

 and

    arrythmia
    SYMPTOMS

.

    Necropsy findings
    PARACLINICAL

 showed

    persistent deposition of ceramide in the myocardium and especially in the conduction system
    MICROSCOPIC

. This was documented, for the first time to the author's knowledge, by

    electron microscopic investigations
    PARACLINICAL

.

    Cardiac manifestations
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

 are discussed in relation to patients with

    renal transplants
    MEDICATION

.

Fabry's disease
)
disorder of sphingolipid metabolism
Fabry's disease

Renal transplantation
received a renal allograft
transplantation
renal transplants


Pathophysiologic and ultrastructural basis for intestinal symptoms in Fabry's disease.

Fabry's disease is a rare, sex-linked disorder of glycolipid metabolism. We describe a patient with watery diarrhea, early satiety, and asymptomatic cholelithiasis. The jejunal aspirate demonstrated bacterial overgrowth; sigmoidoscopy showed rectal angiokeratoma corpora diffusum. The gastric emptying rate measured with 99mTc-sulfur colloid was markedly prolonged and the fasting gastrin was elevated at 276 pg/ml. The (14C)glycocholate breath test demonstrated a markedly elevated peak at 4 h, associated with an increased fecal bile acid loss of 0.82 g/day. Oral cholecystogram showed a solitary radiolucent stone in a functioning gallbladder. The bile acid pool size and lithogenic index were normal. Light microscopy of small bowel and rectal biopsy specimens revealed normal surface epithelium, but enlarged and vacuolated ganglion cells in Meissner's plexus. Electron microscopy showed laminated and amorphous osmiophilic deposits within ganglion cells of the submucosal plexus, within smooth muscle cells of the muscularis mucosae, and within endothelial cells lining arterioles, venules, and capillaries, but not in autonomic nerve fibers or enterocytes. The diarrhea and early satiety responded promptly to metoclopramide and to tetracycline. The early satiety was likely on the basis of delayed gastric emptying due to deposition of sphingolipid within ganglion cells of the autonomic nervous system; the diarrhea was likely on the basis of intestinal stasis with bacterial overgrowth and bile salt wastage.

    Fabry's disease
    DIAGNOSIS

 is a

    rare, sex-linked
    GENETICS

    disorder of glycolipid metabolism
    DIAGNOSIS

. We describe a patient with

    watery diarrhea
    SYMPTOMS

,

    early satiety
    SYMPTOMS

, and

    asymptomatic cholelithiasis
    SYMPTOMS

. The

    jejunal aspirate
    PARACLINICAL

 demonstrated

    bacterial overgrowth
    MICROSCOPIC

;

    sigmoidoscopy
    PARACLINICAL

 showed

    rectal angiokeratoma corpora diffusum
    SYMPTOMS

. The

    gastric emptying rate measured with 99mTc-sulfur colloid
    SYMPTOMS

    was markedly prolonged
    BIOCHEMICAL

 and the

    fasting gastrin was elevated at 276 pg/ml
    BIOCHEMICAL

. The

    (14C)glycocholate breath test
    PARACLINICAL

 demonstrated a

    markedly elevated peak at 4 h
    BIOCHEMICAL

, associated with an

    increased fecal bile acid loss of 0.82 g/day
    BIOCHEMICAL

.

    Oral cholecystogram
    PARACLINICAL

 showed a

    solitary radiolucent stone in a functioning gallbladder
    SYMPTOMS

.

    The bile acid pool size and lithogenic index were normal
    NEG_FINDINGS

.

    Light microscopy of small bowel and rectal biopsy specimens
    PARACLINICAL

 revealed

    normal surface epithelium
    NEG_FINDINGS

, but

    enlarged and vacuolated ganglion cells in Meissner's plexus
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 showed

    laminated and amorphous osmiophilic deposits within ganglion cells of the submucosal plexus, within smooth muscle cells of the muscularis mucosae, and within endothelial cells lining arterioles, venules, and capillaries
    MICROSCOPIC

,

    but not in autonomic nerve fibers or enterocytes
    NEG_FINDINGS

. The

    diarrhea
    SYMPTOMS

 and

    early satiety
    SYMPTOMS

 responded promptly to

    metoclopramide and to tetracycline
    MEDICATION

. The

    early satiety
    SYMPTOMS

 was likely on the basis of

    delayed gastric emptying
    SYMPTOMS

 due to

    deposition of sphingolipid within ganglion cells of the autonomic nervous system
    MICROSCOPIC

; the

    diarrhea
    SYMPTOMS

 was likely on the basis of

    intestinal stasis
    SYMPTOMS

 with

    bacterial overgrowth
    SYMPTOMS

 and

    bile salt wastage
    SYMPTOMS

.

Fabry's disease
disorder of glycolipid metabolism


Ocular pathology of Fabry's disease in a hemizygous male following renal transplantation.

The ocular pathology of a hemizygous male with Fabry's disease after renal transplantation is reported. The ocular pathology in this patient was essentially identical to that which has previously been reported for both hemizygotes and heterozygotes afflicted with Fabry's disease. Glycolipid deposits and/or osmophilic inclusion bodies were found universally throughout the ocular vasculature. Endothelial, perithelial and smooth muscle cells of the vessel walls were preferentially involved. Iris pigment epithelium was affected as were the corneal epithelium cells. Reduplication of the basement membrane was seen on electron microscopy. Retinal ganglion cells were unaffected. Involvement of the retinal pigment epithelium and the corneal endothelium was documented for the first time.

The

    ocular pathology
    SYMPTOMS

 of a

    hemizygous male
    GENETICS

 with

    Fabry's disease
    DIAGNOSIS

 after

    renal transplantation
    MEDICATION

 is reported. The

    ocular pathology
    SYMPTOMS

 in this patient was essentially identical to that which has previously been reported for both

    hemizygotes
    GENETICS

 and

    heterozygotes
    GENETICS

 afflicted with

    Fabry's disease
    DIAGNOSIS

.

    Glycolipid deposits and/or osmophilic inclusion bodies were found universally throughout the ocular vasculature
    MICROSCOPIC

.

    Endothelial, perithelial and smooth muscle cells of the vessel walls were preferentially involved
    MICROSCOPIC

.

    Iris pigment epithelium was affected
    MICROSCOPIC

 as

    were the corneal epithelium cells
    MICROSCOPIC

.

    Reduplication of the basement membrane
    MICROSCOPIC

 was seen on

    electron microscopy
    PARACLINICAL

.

    Retinal ganglion cells were unaffected
    NEG_FINDINGS

.

    Involvement of the retinal pigment epithelium and the corneal endothelium
    SYMPTOMS

 was documented for the first time.

hemizygous male
hemizygotes
heterozygotes


Ultrastructural and biochemical liver analyses in Fabry's disease.

Ultrastructural and biochemical analyses were made of liver biopsy material from a patient with longstanding Fabry's disease. Both hepatocytes as well as periportal macrophages showed lipid accumulations consisting of amorphous material as well as stacks of lamellar leaflets. Lipid inclusions in periportal macrophages were much larger than in hepatocytes. Furthermore, small round spheres were found exclusively in periportal macrophages. The biochemical analysis showed an increased content of ceramide -3, with only minor elevated concentrations of other glycosphingolipids. The almost normal hepatic architecture and the presence of well-preserved hepatocytic organelles are in agreement with the observation that liver involvement in Fabry's disease has only minor clinical significance.

    Ultrastructural and biochemical analyses
    PARACLINICAL

 were made of

    liver biopsy material
    PARACLINICAL

 from a patient with

    longstanding Fabry's disease
    DIAGNOSIS

.

    Both hepatocytes as well as periportal macrophages showed lipid accumulations consisting of amorphous material as well as stacks of lamellar leaflets
    MICROSCOPIC

.

    Lipid inclusions in periportal macrophages were much larger than in hepatocytes
    MICROSCOPIC

. Furthermore,

    small round spheres were found exclusively in periportal macrophages
    MICROSCOPIC

. The

    biochemical analysis
    PARACLINICAL

 showed an

    increased content of ceramide -3
    MICROSCOPIC

, with

    only minor elevated concentrations of other glycosphingolipids
    NEG_FINDINGS

. The

    almost normal hepatic architecture
    NEG_FINDINGS

 and the

    presence of well-preserved hepatocytic organelles
    MICROSCOPIC

 are in agreement with the observation that

    liver involvement
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 has only minor clinical significance.

longstanding Fabry's disease
Fabry's disease


[Case of Fabry's disease].

A patient is described, admitted to the clinic on the occasion of proteinuria, edemas and arterial hypertension. The clinical and paraclinical data formed the picture of a renal involvement of mainly glomerular type with proteinuria to 5 gr%0, nonselective type, edemas, hypertension and data of chronic renal insufficiency I degree (serum creatinine to 3.8%, blood urea to 112 mg%). What impresses are the extrarenal manifestations as paresthesia of the lower limbs, with a sense of numbness to acute burning pain, a rich psychonervous symptomatics. The skin efflorescence, followed up and observed at the clinic of dermatology and the puncture biopsy material from the kidney revealed specific signs of Fabry syndrome.

A patient is described, admitted to the clinic on the occasion of

    proteinuria
    BIOCHEMICAL

,

    edemas
    SYMPTOMS

 and

    arterial hypertension
    SYMPTOMS

. The clinical and

    paraclinical
    PARACLINICAL

 data formed the picture of a

    renal involvement of mainly glomerular type
    DIAGNOSIS

 with

    proteinuria to 5 gr%0, nonselective type
    BIOCHEMICAL

,

    edemas
    SYMPTOMS

,

    hypertension
    SYMPTOMS

 and data of

    chronic renal insufficiency I degree
    DIAGNOSIS

 (

    serum creatinine to 3.8%, blood urea to 112 mg%)
    BIOCHEMICAL

. What impresses are the

    extrarenal manifestations
    SYMPTOMS

 as

    paresthesia of the lower limbs
    SYMPTOMS

, with a

    sense of numbness to acute burning pain
    SYMPTOMS

, a

    rich psychonervous symptomatics
    SYMPTOMS

. The

    skin efflorescence
    SYMPTOMS

, followed up and observed at the

    clinic of dermatology
    PARACLINICAL

 and the

    puncture biopsy material from the kidney
    PARACLINICAL

 revealed specific signs of

    Fabry syndrome
    DIAGNOSIS

.

edemas
arterial hypertension
edemas
hypertension
extrarenal manifestations
paresthesia of the lower limbs
sense of numbness to acute burning pain
rich psychonervous symptomatics
skin efflorescence


Clinical and diagnostic considerations in Fabry's disease.

Three patients with Fabry's disease with a similar clinical picture, including recurrent burning sensations in the extremities, hypohidrosis and slowly progressive renal insufficiency, have been investigated metabolically at different stages of renal impairment. One patient died after three unsuccessful renal transplantations in a 4-year period of intermittent haemodialysis with disabling pains. One successfully transplanted patient is still alive and well, 12 years after the start of therapy. Thermolabile alpha-galactosidase has been demonstrated in his urine. The third patient has slowly progressive renal impairment. No therapeutic enzyme replacement available today is ideal. Early diagnosis is therefore necessary to increase the possibilities of prenatal diagnosis and genetic counseling.

Three patients with

    Fabry's disease
    DIAGNOSIS

 with a similar clinical picture, including

    recurrent burning sensations in the extremities
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

 and

    slowly progressive renal insufficiency
    SYMPTOMS

, have been investigated metabolically at different stages of

    renal impairment
    SYMPTOMS

. One patient

    died
    SYMPTOMS

 after

    three unsuccessful renal transplantations in a 4-year period of intermittent haemodialysis
    MEDICATION

 with

    disabling pains
    SYMPTOMS

. One

    successfully transplanted
    MEDICATION

 patient is still alive and well, 12 years after the start of therapy.

    Thermolabile alpha-galactosidase has been demonstrated in his urine
    BIOCHEMICAL

. The third patient has

    slowly progressive renal impairment
    SYMPTOMS

.

    No therapeutic enzyme replacement
    NEG_FINDINGS

 available today is ideal. Early diagnosis is therefore necessary to increase the possibilities of

    prenatal diagnosis
    PARACLINICAL

 and

    genetic counseling
    MEDICATION

.


Pseudodeficiency of alpha-galactosidase A.

Apparent deficiency of alpha-galactosidase A was observed in a 51-year-old, clinically healthy male, with no clinical symptoms of Fabry disease, and without excess urinary excretion of ceramide trihexoside. The deficiency, which was similar to that found in Fabry disease patients, could be demonstrated using both synthetic and natural substrates. This pseudodeficiency was transmitted in his family by classical X-linked inheritance. His wife showed enzyme activity in the normal range, two daughters were heterozygotes for this mutation as demonstrated by hair root assay, and three sons showed normal alpha-galactosidase activity. Kinetic studies in cultured skin fibroblasts indicated a five-fold increase in the apparent Km and a greater heat stability of the residual alpha-galactosidase activity when compared to controls. These data indicate that the residual enzyme activity in this mutation behaves similarly to that observed in Fabry disease patients but does not cause any clinical abnormalities.

    Apparent deficiency of alpha-galactosidase A
    BIOCHEMICAL

 was observed in a

    51-year-old
    AGE

, clinically healthy

    male
    GENDER

, with

    no clinical symptoms of Fabry disease
    NEG_FINDINGS

, and

    without excess urinary excretion of ceramide trihexoside
    NEG_FINDINGS

. The

    deficiency
    BIOCHEMICAL

, which was similar to that found in

    Fabry disease
    DIAGNOSIS

 patients, could be demonstrated using both synthetic and natural substrates. This

    pseudodeficiency
    BIOCHEMICAL

    was transmitted in his family by classical X-linked inheritance
    FAMILY

.

    His
    GENDER

    wife showed enzyme activity in the normal range
    FAMILY

,

    two daughters were heterozygotes for this mutation as demonstrated by hair root assay
    FAMILY

, and

    three sons showed normal alpha-galactosidase activity
    FAMILY

.

    Kinetic studies in cultured skin fibroblasts
    PARACLINICAL

 indicated a

    five-fold increase in the apparent Km and a greater heat stability of the residual alpha-galactosidase activity
    BIOCHEMICAL

 when compared to controls. These data indicate that the

    residual enzyme activity
    BIOCHEMICAL

 in this mutation behaves similarly to that observed in

    Fabry disease
    DIAGNOSIS

 patients but does

    not cause any clinical abnormalities
    NEG_FINDINGS

.


Anderson-Fabry's disease: neuropathological and neurochemical investigation.

A clinical, neuropathological and neurochemical study of a case of Anderson-Fabry's disease is described. The clinical course mainly consisted of repeated ictus with major involvement of the CNS. The neuropathological examination is dominated by severe alterations in the cerebral vessels due to glycolipid deposits on the walls, with reduction or occlusion of the lumen. This is correlated with secondary ischaemic foci scattered throughout the cortex as well as through the white matter. In addition, the cells of the cerebral cortex, thalamus, basal ganglia, amygdala, cerebellar and olivary nuclei show a marked accumulation of lipofuscin. Biochemical examination reveals a threefold increase in galactolipids due to the specific alpha-galactosidase deficiency. Cholesterol is reduced secondarily to ischaemic myelin damage. Glycosaminoglycans uronic acid is increased in cytosol and membrane-bound fractions which could be related to reactive gliosis. Glycoprotein sugars show a decrease in N-acetyl-neuraminic acid and fucose as well as an increase in hexosamines and hexoses in membrane-bound fraction, while in cytosol fraction all sugars are increased. This suggests that the alpha-galactosidase deficiency can alter not only the glycolipid but also the glycoprotein metabolism, resulting in a higher presence of hexosamines and hexoses-rich glycoproteins.

A clinical,

    neuropathological and neurochemical study
    PARACLINICAL

 of a case of

    Anderson-Fabry's disease
    DIAGNOSIS

 is described. The clinical course mainly consisted of

    repeated ictus
    SYMPTOMS

 with

    major involvement of the CNS
    SYMPTOMS

. The

    neuropathological examination
    PARACLINICAL

 is dominated by

    severe alterations in the cerebral vessels
    SYMPTOMS

 due to

    glycolipid deposits on the walls, with reduction or occlusion of the lumen
    MICROSCOPIC

. This is correlated with

    secondary ischaemic foci scattered throughout the cortex as well as through the white matter
    SYMPTOMS

. In addition,

    the cells of the cerebral cortex, thalamus, basal ganglia, amygdala, cerebellar and olivary nuclei
    MICROSCOPIC

 show a

    marked accumulation of lipofuscin
    MICROSCOPIC

.

    Biochemical examination
    PARACLINICAL

 reveals a

    threefold increase in galactolipids
    MICROSCOPIC

 due to the

    specific alpha-galactosidase deficiency
    BIOCHEMICAL

.

    Cholesterol is reduced
    MICROSCOPIC

 secondarily to

    ischaemic myelin damage
    SYMPTOMS

.

    Glycosaminoglycans uronic acid is increased in cytosol and membrane-bound fractions
    MICROSCOPIC

 which could be related to

    reactive gliosis
    MICROSCOPIC

.

    Glycoprotein sugars
    MICROSCOPIC

 show a

    decrease in N-acetyl-neuraminic acid and fucose
    BIOCHEMICAL

 as well as an

    increase in hexosamines and hexoses in membrane-bound fraction
    MICROSCOPIC

, while

    in cytosol fraction all sugars are increased
    MICROSCOPIC

. This suggests that the

    alpha-galactosidase deficiency
    BIOCHEMICAL

 can alter not only the

    glycolipid
    BIOCHEMICAL

 but also the

    glycoprotein metabolism
    BIOCHEMICAL

, resulting in a

    higher presence of hexosamines and hexoses-rich glycoproteins
    MICROSCOPIC

.


A prospective double-blind study of plasma exchange therapy for the acroparesthesia of Fabry's disease.

During a study of the effect of plasma exchange on glycosphingolipid metabolism, a patient with Fabry's disease noted a dramatic improvement in his painful acroparesthesia. A controlled study was therefore undertaken. Observations were made of nerve conduction times, graded exercise testing, and psychometric evaluations during and after two planned series of three plasma exchanges: one a true plasma exchange and the other a "sham' control in which the patient received his own plasma. All observers and the patient were blinded and unanimously attributed beneficial results to the sham procedure. This study demonstrates the need for controlled studies in diseases prone to unpredictable exacerbation or spontaneous remission and outlines one possible technique of controlling studies involving plasma exchange.

During a study of the effect of

    plasma exchange
    MEDICATION

 on

    glycosphingolipid metabolism
    BIOCHEMICAL

, a patient with

    Fabry's disease
    DIAGNOSIS

 noted a

    dramatic improvement in his painful acroparesthesia
    SYMPTOMS

. A controlled study was therefore undertaken. Observations were made of

    nerve conduction times
    PARACLINICAL

,

    graded exercise testing
    PARACLINICAL

, and

    psychometric evaluations
    PARACLINICAL

 during and after two

    planned series of three plasma exchanges: one a true plasma exchange
    MEDICATION

 and the other a "sham' control in which the patient received his own plasma. All observers and the patient were blinded and unanimously attributed beneficial results to the sham procedure. This study demonstrates the need for controlled studies in diseases prone to

    unpredictable exacerbation
    SYMPTOMS

 or

    spontaneous remission
    SYMPTOMS

 and outlines one possible technique of controlling studies involving

    plasma exchange
    MEDICATION

.


Fabry's disease and cornea verticillata. A report of 3 cases.

Fabry's disease is a rare familial disorder of glycolipid metabolism which is caused by a deficiency of a lysosomal enzyme alpha-galactosidase. A Finnish family is described in which cornea verticillata was found in the father and 2 daughters. In all cases, there were symptoms suggesting Fabry's disease: febrile episodes the origin of which was not clear, limb pains and, in the case of the father, 20 years of proteinuria with elevated ESR, and hemiplegia and aphasia following a cerebral thrombosis at the age of 43. The diagnosis was confirmed by demonstration of an alpha-galactosidase deficit in the serum and urine of all patients. Deficiency of this enzyme leads to abnormally high urinary tri- and dihexosyl ceramide levels, and this was observed in the father and the elder daughter. At the age of 12, the daughter had loss of vision in her right eye as a result of occlusion of the central retinal artery. Electron microscopic (EM) examination of the father's dermal angioma suggested Fabry's disease. Computerized cranial tomography of the father revealed not only the cerebrovascular condition but also a disease affecting the white matter of the brain.

    Fabry's disease
    DIAGNOSIS

 is a

    rare familial disorder of glycolipid metabolism
    DIAGNOSIS

 which is caused by a

    deficiency of a lysosomal enzyme alpha-galactosidase
    BIOCHEMICAL

. A

    Finnish
    ETHNICITY

 family is described in which

    cornea verticillata
    SYMPTOMS

    was found in the father and 2 daughters
    FAMILY

. In all cases, there were symptoms suggesting

    Fabry's disease
    DIAGNOSIS

:

    febrile episodes
    SYMPTOMS

 the origin of which

    was not clear
    NEG_FINDINGS

,

    limb pains
    SYMPTOMS

 and, in the case of the

    father
    GENDER

,

    20 years of proteinuria with elevated ESR
    BIOCHEMICAL

, and

    hemiplegia
    SYMPTOMS

 and

    aphasia
    SYMPTOMS

 following a

    cerebral thrombosis
    SYMPTOMS

 at the

    age of 43
    AGE

. The diagnosis was confirmed by demonstration of an

    alpha-galactosidase deficit in the serum and urine
    BIOCHEMICAL

 of all patients.

    Deficiency of this enzyme
    BIOCHEMICAL

 leads to

    abnormally high urinary tri- and dihexosyl ceramide levels
    BIOCHEMICAL

, and this was observed in the

    father
    GENDER

 and the elder daughter. At the

    age of 12
    AGE

, the daughter had

    loss of vision in her right eye
    SYMPTOMS

 as a result of

    occlusion of the central retinal artery
    SYMPTOMS

.

    Electron microscopic (EM) examination of the father's dermal angioma
    PARACLINICAL

 suggested

    Fabry's disease
    DIAGNOSIS

.

    Computerized cranial tomography of the father
    PARACLINICAL

 revealed not only the

    cerebrovascular condition
    SYMPTOMS

 but also a

    disease affecting the white matter of the brain
    SYMPTOMS

.


Fabry cardiomyopathy in the female confirmed by endomyocardial biopsy.

A 58-year-old woman with cardiac enlargement and heart failure was a member of a family with Fabry disease. In this patient, endomyocardial biopsy permitted microscopic examination of the myocardium which revealed cellular abnormalities characteristic of Fabry cardiomyopathy. It is suggested that unfavorable lyonization of the mutant-bearing X chromosome accounted for the expression of this disorder in specific organs of a female patient.

A

    58-year-old
    AGE

    woman
    GENDER

 with

    cardiac enlargement
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

 was

    a member of a family with Fabry disease
    FAMILY

. In this patient,

    endomyocardial biopsy
    PARACLINICAL

 permitted

    microscopic examination of the myocardium
    PARACLINICAL

 which revealed

    cellular abnormalities characteristic of Fabry cardiomyopathy
    MICROSCOPIC

. It is suggested that

    unfavorable lyonization of the mutant-bearing X chromosome
    GENETICS

 accounted for the expression of this disorder in specific organs of a

    female
    GENDER

 patient.


Morphological and biochemical changes in muscle and peripheral nerve in Fabry's disease.

In a case of Fabry's disease, microscopic, ultrastructural, and biochemical studies of a muscle biopsy were performed, as well as microscopic, ultrastructural, and morphometric studies of a nerve biopsy. Pleomorphic lipid inclusions were observed in muscle fibers, fibroblasts, and endomysial capillaries. Moreover, the thermolabile isoenzyme A of alpha-D-galactosidase was almost completely absent. In the nerve specimen, polymorphous lysosomes were noted in perineural cells, in fibroblasts, and in endothelial and perithelial cells in association with some nonspecific degenerative changes. The morphometric data revealed a loss of large myelinated fibers, an uncommon finding in Fabry's disease, and a decrease of the average diameter of the unmyelinated fibers, which was related to axonal sprouting. The relationship between the pain attacks and the increased number of the small unmyelinated fibers is discussed.

In a case of

    Fabry's disease
    DIAGNOSIS

,

    microscopic, ultrastructural, and biochemical studies of a muscle biopsy
    PARACLINICAL

 were performed, as well as

    microscopic, ultrastructural, and morphometric studies of a nerve biopsy
    PARACLINICAL

.

    Pleomorphic lipid inclusions were observed in muscle fibers, fibroblasts, and endomysial capillaries
    MICROSCOPIC

. Moreover,

    the thermolabile isoenzyme A of alpha-D-galactosidase was almost completely absent
    BIOCHEMICAL

. In the

    nerve specimen
    PARACLINICAL

,

    polymorphous lysosomes were noted in perineural cells, in fibroblasts, and in endothelial and perithelial cells
    MICROSCOPIC

 in association with some

    nonspecific degenerative changes
    MICROSCOPIC

. The

    morphometric data
    PARACLINICAL

 revealed a

    loss of large myelinated fibers
    SYMPTOMS

, an uncommon finding in

    Fabry's disease
    DIAGNOSIS

, and a

    decrease of the average diameter of the unmyelinated fibers
    SYMPTOMS

, which was related to

    axonal sprouting
    SYMPTOMS

. The relationship between the

    pain attacks
    SYMPTOMS

 and the

    increased number of the small unmyelinated fibers
    MICROSCOPIC

 is discussed.


Internuclear ophthalmoplegia in Fabry's disease.

A 16-year-old boy with Fabry's disease had sudden onset of diplopia unassociated with any other neurologic symptoms. A right internuclear ophthalmoplegia characterized by optokinetic phenomena and ocular dysmetria was demonstrated. The diplopia resolved spontaneously in six weeks. This is the first reported case of internuclear ophthalmoplegia occurring with Fabry's disease and represents one of the youngest patients to have unilateral internuclear ophthalmoplegia presumably caused by vascular occlusive disease.

A

    16-year-old
    AGE

    boy
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 had

    sudden onset of diplopia
    SYMPTOMS

    unassociated with any other neurologic symptoms
    NEG_FINDINGS

. A

    right internuclear ophthalmoplegia
    SYMPTOMS

 characterized by

    optokinetic phenomena
    SYMPTOMS

 and

    ocular dysmetria
    SYMPTOMS

 was demonstrated. The

    diplopia
    SYMPTOMS

 resolved spontaneously in six weeks. This is the first reported case of

    internuclear ophthalmoplegia
    SYMPTOMS

 occurring with

    Fabry's disease
    DIAGNOSIS

 and represents one of the youngest patients to have

    unilateral internuclear ophthalmoplegia
    SYMPTOMS

 presumably caused by

    vascular occlusive disease
    DIAGNOSIS

.

Fabry's disease
Fabry's disease
vascular occlusive disease

sudden onset of diplopia
right internuclear ophthalmoplegia
optokinetic phenomena
ocular dysmetria
diplopia
internuclear ophthalmoplegia
unilateral internuclear ophthalmoplegia


Light- and electron-microscopic histochemistry of Fabry's disease.

A histochemical study was performed on light- and electron-microscopic level in a case of Fabry's disease. The patient underwent kidney transplantation for renal failure and died of heart failure 6 months later. Patient's tissues were studied at the light- and electron-microscopic levels with various embedding and staining techniques for lipids and carbohydrates. Two peroxidase-labeled lectins (from Ricinus communis and from Bandeiraea simplicifolia) known to have affinity for alpha- and beta-D-galactose, were strongly reactive with the storage material on frozen sections. The ultrahistochemical and extraction tests showed that the typical granules had a variable reactivity and morphologic characteristics in different cells, probably reflecting different composition. A small number of typical deposits were also observed in the transplanted kidney. This is the first reported case of recurrence of the storage disease in the allograft. Of interest was also the fact that the patient's blood inhibited normal alpha-galactosidase activity, suggesting a possible inhibitor-related mechanism in the pathogenesis of the recurrence.

A

    histochemical study
    PARACLINICAL

 was performed on

    light- and electron-microscopic level
    PARACLINICAL

 in a case of

    Fabry's disease
    DIAGNOSIS

. The patient underwent

    kidney transplantation
    MEDICATION

 for

    renal failure
    DIAGNOSIS

 and

    died
    SYMPTOMS

 of

    heart failure
    SYMPTOMS

 6 months later. Patient's

    tissues were studied at the light- and electron-microscopic levels
    PARACLINICAL

 with

    various embedding and staining techniques for lipids and carbohydrates
    PARACLINICAL

. Two

    peroxidase-labeled lectins
    BIOCHEMICAL

 (from

    Ricinus communis
    BIOCHEMICAL

 and from

    Bandeiraea simplicifolia
    BIOCHEMICAL

) known to have affinity for alpha- and

    beta-D-galactose
    BIOCHEMICAL

, were

    strongly reactive with the storage material on frozen sections
    MICROSCOPIC

. The

    ultrahistochemical and extraction tests
    PARACLINICAL

 showed that

    the typical granules had a variable reactivity and morphologic characteristics in different cells
    MICROSCOPIC

, probably reflecting different composition. A

    small number of typical deposits were also observed in the transplanted kidney
    MICROSCOPIC

. This is the first reported case of

    recurrence of the storage disease in the allograft
    DIAGNOSIS

. Of interest was also the fact that the patient's

    blood inhibited normal alpha-galactosidase activity
    BIOCHEMICAL

, suggesting a possible

    inhibitor-
    BIOCHEMICAL

related mechanism in the pathogenesis of the recurrence.


Thrombotic angiokeratoma circumscriptum simulating melanoma.

Three patients with solitary angiokeratomas, two of the circumscribed type (Fabry) and one of the Mibelli type, are described to show that when extensive thromboses develop in an angiokeratoma, this nodular bluish-black lesion may clinically simulate a nodular melanoma.

Three patients with

    solitary angiokeratomas
    SYMPTOMS

, two

    of the circumscribed type (Fabry)
    DIAGNOSIS

 and one

    of the Mibelli type
    DIAGNOSIS

, are described to show that when

    extensive thromboses develop in an angiokeratoma
    SYMPTOMS

, this

    nodular bluish-black lesion
    SYMPTOMS

 may clinically simulate a

    nodular melanoma
    DIAGNOSIS

.

of the circumscribed type (Fabry)
of the Mibelli type
nodular melanoma


[Fabry's disease without cutaneous angiokeratoma : diagnosis by electron microscope study of skin biopsy (author's transl)].

A case of Fabry's disease without typical skin lesion is reported. Electron microscope study of normally appearing skin (at clinical and even histological levels) has shown typical inclusions within cytoplasm of various dermic cells (endothelial cells and pericytes, myocytes, fibroblasts) and adipocytes. These inclusions are made up of stacks of membranes with parallel array and periodicity about 5 nanometers. Such a case emphasizes usefulness of electron microscopy of skin, even normally appearing, for the diagnosis of Fabry disease, as it has been previously shown for other dyslipidoses.

A case of

    Fabry's disease
    DIAGNOSIS

    without typical skin lesion
    NEG_FINDINGS

 is reported.

    Electron microscope study of normally appearing skin (at clinical and even histological levels
    PARACLINICAL

) has shown

    typical inclusions within cytoplasm of various dermic cells (endothelial cells and pericytes, myocytes, fibroblasts) and adipocytes
    MICROSCOPIC

. These

    inclusions are made up of stacks of membranes with parallel array and periodicity about 5 nanometers
    MICROSCOPIC

. Such a case emphasizes usefulness of

    electron microscopy of skin
    PARACLINICAL

, even normally appearing, for the diagnosis of

    Fabry disease
    DIAGNOSIS

, as it has been previously shown for other

    dyslipidoses
    DIAGNOSIS

.

Fabry's disease
Fabry disease
dyslipidoses


Clinical and biochemical delineation of aspartyl-glycosaminuria as observed in two members of an Italian family.

Two members of a consanguineous Italian family are described with the symptoms of aspartylglycosaminuria. Both patients exhibit mental retardation, some facial dysmorphism and discrete radiological abnormalities affecting the skull and vertebrae. Peripheral blood smears revealed multivacuolated lymphocytes. Enzyme studies in leucocytes and cultured fibroblasts showed an absence of aspartylglucosaminidase activity. Urinary analysis demonstrated abnormal oligosacchariduria and aspartylglycosamine excretion. Angiokeratoma corporis diffusum was observed in one patient.

Two

    members of a consanguineous Italian
    FAMILY

    family
    FAMILY

 are described with the symptoms of

    aspartylglycosaminuria
    BIOCHEMICAL

. Both patients exhibit

    mental retardation
    SYMPTOMS

,

    some facial dysmorphism
    SYMPTOMS

 and

    discrete radiological abnormalities affecting the skull and vertebrae
    SYMPTOMS

.

    Peripheral blood smears
    PARACLINICAL

 revealed

    multivacuolated lymphocytes
    MICROSCOPIC

.

    Enzyme studies in leucocytes and cultured fibroblasts
    PARACLINICAL

 showed an

    absence of aspartylglucosaminidase activity
    BIOCHEMICAL

.

    Urinary analysis
    PARACLINICAL

 demonstrated

    abnormal oligosacchariduria and aspartylglycosamine excretion
    BIOCHEMICAL

.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 was observed in one patient.


Angiokeratoma corporis diffusum (Fabry disease): ultrastructural studies of the skin.

A case of Fabry disease in a 34-year-old male who had typical exanthemas and familial occurrence is reported. Biochemical examinations revealed a decreased level of serum alpha-galactosidase (0.04 n mol/h/cc). On electronmicroscopy the granules specific for Fabry disease were observed in the skin lesions. By the excessive accumulation of specific granules in the vascular wall, the endothelial cells were replaced by thrombi and the muscle cells were disarrayed. This process might be followed by the appearance of teleangiectatic eruptions.

A case of

    Fabry disease
    DIAGNOSIS

 in a

    34-year-old
    AGE

    male
    GENDER

 who had

    typical exanthemas
    SYMPTOMS

 and

    familial occurrence
    FAMILY

 is reported.

    Biochemical examinations
    PARACLINICAL

 revealed a

    decreased level of serum alpha-galactosidase (0.04 n mol/h/cc)
    BIOCHEMICAL

. On

    electronmicroscopy
    PARACLINICAL

    the granules specific for Fabry disease were observed in the skin lesions
    MICROSCOPIC

. By the

    excessive accumulation of specific granules in the vascular wall
    MICROSCOPIC

,

    the endothelial cells were replaced by thrombi
    MICROSCOPIC

 and

    the muscle cells were disarrayed
    MICROSCOPIC

. This process might be followed by the appearance of

    teleangiectatic eruptions
    SYMPTOMS

.

typical exanthemas
teleangiectatic eruptions


Fucosidosis: severe phenotype with survival to adult age.

A male patient with fucosidosis exhibited the following characteristics: 1. Early onset and rapid progression of neurological symptoms. 2.Skin changes compatible with angiokeratoma corporis diffusum. 3. Complete or nearly complete deficiency of alpha-fucosidase. 4. Survival to adult age (20 years). The deficiency of alpha-fucosidase was demonstrated in liver, tears, urine, sediment, and cultured fibroblasts. We conclude that severe deficiency or complete absence of alpha-fucosidase does not by itself preclude survival to adult age.

A

    male
    GENDER

 patient with

    fucosidosis
    DIAGNOSIS

 exhibited the following characteristics: 1.

    Early onset and rapid progression of neurological symptoms
    SYMPTOMS

. 2.Skin changes compatible with angiokeratoma corporis diffusum. 3.

    Complete or nearly complete deficiency of alpha-fucosidase
    BIOCHEMICAL

. 4.

    Survival to adult age (20 years)
    AGE

. The

    deficiency of alpha-fucosidase was demonstrated in liver, tears, urine, sediment, and cultured fibroblasts
    BIOCHEMICAL

. We conclude that

    severe deficiency or complete absence of alpha-fucosidase
    BIOCHEMICAL

    does not by itself preclude survival
    NEG_FINDINGS

 to

    adult age
    AGE

.


[Myocardial involvement in Fabry's disease (author's transl)].

Definitely impaired coronary reserve, as recorded in cases with coronary microangiopathy, was demonstrated in a 48-year-old female non-smoker with angina, positive ECG exercise tolerance test and negative coronary angiography with normal coronary circulation at rest. Myocardial biopsy from the right ventricle demonstrated electron-microscopically the lamellar, intracytoplasmic inclusion bodies described in Fabry's disease. This diagnosis of an X-chromosomal recessive metabolic disorder with prominent myocardial involvement was confirmed by the results of further investigations.

    Definitely impaired coronary reserve
    SYMPTOMS

, as recorded in cases with

    coronary microangiopathy
    SYMPTOMS

, was demonstrated in a

    48-year-old
    AGE

    female
    GENDER

    non-smoker
    NEG_FINDINGS

 with

    angina
    SYMPTOMS

,

    positive ECG exercise tolerance test
    SYMPTOMS

 and

    negative coronary angiography
    NEG_FINDINGS

 with

    normal coronary circulation at rest
    NEG_FINDINGS

.

    Myocardial biopsy from the right ventricle
    PARACLINICAL

 demonstrated

    electron-microscopically the lamellar, intracytoplasmic inclusion bodies described in Fabry's disease
    PARACLINICAL

. This diagnosis of an

    X-chromosomal recessive metabolic disorder
    GENETICS

 with

    prominent myocardial involvement
    SYMPTOMS

 was confirmed by the results of further investigations.

Definitely impaired coronary reserve
coronary microangiopathy
angina
positive ECG exercise tolerance test
prominent myocardial involvement

non-smoker
negative coronary angiography
normal coronary circulation at rest


[Fabry's disease].

Case reports on three patients with Fabry's disease. Two of them involved necroptic examination, in one case the authors examined bioptic specimens of a 9-years old boy's skin. The material was processed by light microscopy, by electron microscopy, and by chromatography [in one case]. The two fatal cases showed accumulation of glycolipid mainly in cardiac muscle cells, the cause of heart failure. The authors describe the morphology of granules and give a list of their tinction and histochemical properties.

Case reports on three patients with

    Fabry's disease
    DIAGNOSIS

. Two of them involved

    necroptic examination
    PARACLINICAL

, in one case the authors examined

    bioptic specimens
    PARACLINICAL

 of a

    9-years old
    AGE

    boy
    GENDER

    's skin
    PARACLINICAL

. The material was processed by

    light microscopy
    PARACLINICAL

, by

    electron microscopy
    PARACLINICAL

, and by

    chromatography
    PARACLINICAL

 [in one case]. The two fatal cases showed

    accumulation of glycolipid mainly in cardiac muscle cells
    MICROSCOPIC

, the cause of

    heart failure
    SYMPTOMS

. The authors describe the

    morphology of granules
    MICROSCOPIC

 and give a list of their tinction and histochemical properties.


[Fabry's disease and familial lymphedema. Description of 2 cases].

Two cases of Fabry's disease (FD) with lymphedema of the lower limbs are reported. On the basis of lymphographic investigations showing lymphatic aplasia, the hypothesis of an inborn error in the development of the lymphatic system of the lower limbs--Familial Lymphedema--controlled by a gene associated with FD gene on the same chromosome, is suggested.

Two cases of

    Fabry's disease (FD)
    DIAGNOSIS

 with

    lymphedema of the lower limbs
    SYMPTOMS

 are reported. On the basis of

    lymphographic investigations
    PARACLINICAL

 showing

    lymphatic aplasia
    SYMPTOMS

, the hypothesis of an

    inborn error in the development of the lymphatic system of the lower limbs
    GENETICS

--

    Familial Lymphedema
    DIAGNOSIS

    --controlled by a gene associated with FD gene on the same chromosome
    GENETICS

, is suggested.

Fabry's disease (FD)
Familial Lymphedema

lymphedema of the lower limbs
lymphatic aplasia


Chediak-Higashi syndrome: abnormal lysosomal enzyme levels in granulocytes of patients and family members.

Nine lysosomal enzyme activities were examined in granulocytes and lymphocytes from two unrelated patients with Chediak-Higashi syndrome (CHS) in "accelerated phase" and from their family members. In CHS granulocytes, there was a marked reduction of alpha-mannosidase (E.C. 3.2.1.24), alpha-galactosidase (E.C. 3.2.1.22), and alpha-fucosidase (E.C. 3.2.1.51) activities, which were below 21, 24, and 43% of mean control values, respectively. In CHS lymphocytes, beta-glucuronidase (E.C. 3.2.1.31) and alpha-mannosidase activities were also decreased. In granulocytes of family members, the activities of acid phosphatase (E.C. 3.1.3.2), N-acetyl-beta-glucosaminidase (E.C. 3.2.1.30), aryl sulphatase (E.C. 3.1.6.1), and beta-glucuronidase were significantly higher than the control values (P < 0.001), which were 262, 218, 414, and 180% of mean control values. Neither the inhibitor in CHS granulocytes nor the activator in the heterozygous granulocytes to those enzymes could be found by mixing experiments with normal ones.

    Nine lysosomal enzyme activities
    BIOCHEMICAL

 were

    examined in granulocytes and lymphocytes
    BIOCHEMICAL

 from two unrelated patients with

    Chediak-Higashi syndrome (CHS) in "accelerated phase"
    DIAGNOSIS

 and from their family members. In CHS

    granulocytes
    BIOCHEMICAL

, there was a

    marked reduction of alpha-mannosidase (E.C. 3.2.1.24), alpha-galactosidase (E.C. 3.2.1.22), and alpha-fucosidase (E.C. 3.2.1.51) activities, which were below 21, 24, and 43% of mean control values
    BIOCHEMICAL

, respectively. In CHS lymphocytes,

    beta-glucuronidase (E.C. 3.2.1.31) and alpha-mannosidase activities were also decreased
    BIOCHEMICAL

.

    In granulocytes
    BIOCHEMICAL

 of family members,

    the activities of acid phosphatase (E.C. 3.1.3.2), N-acetyl-beta-glucosaminidase (E.C. 3.2.1.30), aryl sulphatase (E.C. 3.1.6.1), and beta-glucuronidase were significantly higher than the control values
    BIOCHEMICAL

 (P < 0.001), which were

    262, 218, 414, and 180% of mean control values
    BIOCHEMICAL

.

    Neither the inhibitor in CHS granulocytes nor the activator in the heterozygous granulocytes to those enzymes could be found by mixing experiments with normal ones
    NEG_FINDINGS

.


Anderson-Fabry disease. Characteristic ultrastructural features in cutaneous blood vessels in a 1-year-old boy.

Electron microscopy of clinically uninvolved skin taken from a 12-month-old male child with biochemically proven angiokeratoma corporis diffusum showed characteristic lamellar lipid deposits within endothelial and perithelial cells of dermal blood vessels. Ultrastructural examination of skin may aid the early identification of males affected with Anderson-Fabry disease long before the development of specific skin lesions.

    Electron microscopy of clinically uninvolved skin taken
    PARACLINICAL

 from a

    12-month-old
    AGE

    male
    GENDER

    child
    AGE

 with biochemically proven

    angiokeratoma corporis diffusum
    DIAGNOSIS

 showed

    characteristic lamellar lipid deposits within endothelial and perithelial cells of dermal blood vessels
    MICROSCOPIC

.

    Ultrastructural examination of skin
    PARACLINICAL

 may aid the early identification of

    males
    GENDER

 affected with

    Anderson-Fabry disease
    DIAGNOSIS

 long before the development of specific

    skin lesions
    SYMPTOMS

.

angiokeratoma corporis diffusum
Anderson-Fabry disease


[Angiokeratoma corporis diffusum in 2 brothers].

Two brothers suffering from Fabry disease, with classical dermatological and with ophthalmological symptoms, early signs of renal lesions and diminished fertility are presented. The diagnosis is verified by electronmicroscopical investigations. Good symptomic-therapeutic effect of hydantoin-derivatives was observed.

Two

    brothers
    GENDER

 suffering from

    Fabry disease
    DIAGNOSIS

, with

    classical dermatological and with ophthalmological symptoms
    SYMPTOMS

,

    early signs of renal lesions
    SYMPTOMS

 and

    diminished fertility
    SYMPTOMS

 are presented. The diagnosis is verified by

    electronmicroscopical investigations
    PARACLINICAL

.

    Good symptomic-therapeutic effect of hydantoin-derivatives
    SYMPTOMS

 was observed.


[Heterozygous Fabry's disease. Case report with electron microscopic studies].

Fabry's disease is an inborn error of sphingolipid metabolism. The lysosomal hydrolase, alpha-galactosidase, is deficient. The full spectrum of symptoms (diffuse angiokeratoma, alpha-galactosidase deficiency) is only seen in males, who are always hemizygous. The heterozygous females may be asymptomatic and the enzyme activity can be normal. Such a case is reported. The diagnosis of this case was made by electron microscopic findings of the characteristic cellular lipid-inclusions within endothelial, perithelial, smooth muscle, and nerve sheath cells. The electron microscopic findings are a valuable clue to the diagnosis in these problem cases. The early diagnosis of female conductors is important for genetic counseling.

    Fabry's disease
    DIAGNOSIS

 is an

    inborn error of sphingolipid metabolism
    GENETICS

. The

    lysosomal hydrolase, alpha-galactosidase, is deficient
    BIOCHEMICAL

. The full spectrum of symptoms (

    diffuse angiokeratoma
    SYMPTOMS

,

    alpha-galactosidase deficiency
    BIOCHEMICAL

) is only seen in

    males
    GENDER

, who are always

    hemizygous
    GENETICS

. The

    heterozygous
    GENETICS

    females
    GENDER

 may be

    asymptomatic
    NEG_FINDINGS

 and the

    enzyme activity can be normal
    NEG_FINDINGS

. Such a case is reported. The diagnosis of this case was made by

    electron microscopic
    PARACLINICAL

 findings of the

    characteristic cellular lipid-inclusions within endothelial, perithelial, smooth muscle, and nerve sheath cells
    MICROSCOPIC

. The

    electron microscopic findings
    PARACLINICAL

 are a valuable clue to the diagnosis in these problem cases. The early diagnosis of

    female
    GENDER

 conductors is important for

    genetic counseling
    MEDICATION

.

inborn error of sphingolipid metabolism
hemizygous
heterozygous

asymptomatic
enzyme activity can be normal


Cultured skin fibroblasts in lipidoses. Enzymatic, histochemical, and ultrastructural relationship in Fabry's Tay-Sachs, and Sandhoff's diseases.

Enzymatic, histochemical, and ultrastructural studies were performed on cultured skin fibroblasts from patients with Fabry's disease, Tay-Sach's disease, and Sandhoff's disease and from their families (carriers). alpha-Galactosidase activity was deficient in the proband with Fabry's disease (lower in the homozygotes than in the heterozygote). Levels of hexosaminidase A in the patient with Tay-Sachs disease and hexosaminidase A and B in the patient with Sandhoff's disease were deficient and were lower in her mother than in the control subject. Lysosome-like structures were observed in cultured fibroblasts from the patients with each disease, as well as in the heterozygote with Fabry's disease and the carrier with Tay-Sach's disease. The amount of the accumulating arrays in the lysosome-like structures was related to low level of enzymatic activity.

    Enzymatic, histochemical, and ultrastructural studies
    PARACLINICAL

 were performed on

    cultured skin fibroblasts
    MICROSCOPIC

 from patients with

    Fabry's disease
    DIAGNOSIS

,

    Tay-Sach's disease
    DIAGNOSIS

, and

    Sandhoff's disease
    DIAGNOSIS

 and from their families (carriers).

    alpha-Galactosidase activity was deficient
    BIOCHEMICAL

 in the proband with

    Fabry's disease
    DIAGNOSIS

 (

    lower in the homozygotes than in the heterozygote)
    GENETICS

.

    Levels of hexosaminidase A
    BIOCHEMICAL

 in the patient with

    Tay-Sachs disease
    DIAGNOSIS

    and hexosaminidase A and B in
    BIOCHEMICAL

 the patient with

    Sandhoff's disease
    DIAGNOSIS

    were deficient and were lower in her mother
    BIOCHEMICAL

 than in the control subject.

    Lysosome-like structures were observed in cultured fibroblasts
    MICROSCOPIC

 from the patients with each disease, as well as in the heterozygote with

    Fabry's disease
    DIAGNOSIS

 and the

    carrier with Tay-Sach's disease
    FAMILY

. The

    amount of the accumulating arrays in the lysosome-like structures
    MICROSCOPIC

 was related to

    low level of enzymatic activity
    BIOCHEMICAL

.

Fabry's disease
Tay-Sach's disease
Sandhoff's disease
Fabry's disease
Tay-Sachs disease
Sandhoff's disease
Fabry's disease


[Fabry's disease with malocclusion and acromegalic-appearance: clinical and electromicroscopic studies (author's transl)].

The present case is a 24-years-old man who complained painful attack with numbness in both bilateral shoulder regions and distal extremities. This pain was increased by the stimulations of sunlight and heat. On physical examinations, he had an acromegalic-like-appearance, thick mustache and beard. Malocclusion of the teeth which showed the broad space was found. And skin lesion was not found out. Hypesthesia in bilateral distal extremities was revealed and no other abnormal neurological findings were observed. He was made diagnosis of Fabry's disease by laboratory examinations which were alpha-galactosidase deficiency analysed in leukocytes, increased ceramide trihexosides demonstrated in urinary sediment and electron microscopic findings in the biopsy of the skin and sural nerve. His mother had and decreased alpha-galactosidase activity which levels showed between normal and patient and was speculated to be a carrier. On an electron microscopy, "Zebra body" was observed in fibroblasts, capillary endothelial cells, their pericytes, prineural and Schwann cells. Many of them had a distinct limiting membrane and laminal structure with irregular alterations of light and dark zone. In the cytoplasma of Schwann cells, there were many rough endoplasmic reticulums which were located parallel with alignment and seemed to show the loosed laminal structure with the unclear limited membrane. Occasionally, fusions between irregular laminal structure and rough endoplasmic reticulum were also observed. These findings could be indicated that the formation of Zebra body is related to rough endoplasmic reticulum, because laminal structure which described above is corresponded to pre-Zebra body. In the cytoplasma of the prineural cells, recket-like structure which was seen in histiocytosis X were occasionally observed.

The present case is a

    24-years-old
    AGE

    man
    GENDER

 who complained

    painful attack with numbness in both bilateral shoulder regions and distal extremities
    SYMPTOMS

. This

    pain
    SYMPTOMS

 was increased by the stimulations of sunlight and heat. On physical examinations,

    he
    GENDER

 had an

    acromegalic-like-appearance
    SYMPTOMS

,

    thick mustache and beard
    SYMPTOMS

.

    Malocclusion of the teeth which showed the broad space
    SYMPTOMS

 was found. And

    skin lesion was not found out
    NEG_FINDINGS

.

    Hypesthesia in bilateral distal extremities
    SYMPTOMS

 was revealed and

    no other abnormal neurological findings were observed
    NEG_FINDINGS

.

    He
    GENDER

 was made diagnosis of

    Fabry's disease
    DIAGNOSIS

 by

    laboratory examinations
    PARACLINICAL

 which were

    alpha-galactosidase deficiency analysed in leukocytes
    BIOCHEMICAL

,

    increased ceramide trihexosides demonstrated in urinary sediment
    MICROSCOPIC

 and

    electron microscopic findings in the biopsy of the skin and sural nerve
    PARACLINICAL

.

    His
    GENDER

    mother had and decreased alpha-galactosidase activity which levels showed between normal and patient
    FAMILY

    and was speculated to be a carrier
    FAMILY

. On an

    electron microscopy
    PARACLINICAL

,

    "Zebra body" was observed in fibroblasts, capillary endothelial cells, their pericytes, prineural and Schwann cells
    MICROSCOPIC

.

    Many of them had a distinct limiting membrane and laminal structure with irregular alterations of light and dark zone
    MICROSCOPIC

.

    In the cytoplasma of Schwann cells, there were many rough endoplasmic reticulums which were located parallel with alignment and seemed to show the loosed laminal structure with the unclear limited membrane
    MICROSCOPIC

. Occasionally,

    fusions between irregular laminal structure and rough endoplasmic reticulum were also observed
    MICROSCOPIC

. These findings could be indicated that the

    formation of Zebra body
    MICROSCOPIC

 is related to

    rough endoplasmic reticulum
    MICROSCOPIC

, because

    laminal structure which described above is corresponded to pre-Zebra body
    MICROSCOPIC

.

    In the cytoplasma of the prineural cells, recket-like structure which was seen in histiocytosis X
    MICROSCOPIC

    were occasionally observed
    MICROSCOPIC

.


Angiokeratoma corporis diffusum with features of a mucopolysaccharidosis.

Two cases of angiokeratoma corporis diffusum with mental retardation and some features of a mucopolysaccharidosis have been investigated biochemically, histopathologically, and by electron microscopy. It is submitted, on this evidence, that they are examples of a hitherto undescribed form of lysosomal enzyme deficiency disease.

Two cases of

    angiokeratoma corporis diffusum
    SYMPTOMS

 with

    mental retardation
    SYMPTOMS

 and

    some features of a mucopolysaccharidosis
    SYMPTOMS

 have been investigated biochemically,

    histopathologically
    PARACLINICAL

, and by

    electron microscopy
    PARACLINICAL

. It is submitted, on this evidence, that they are examples of a hitherto undescribed form of

    lysosomal enzyme deficiency disease
    DIAGNOSIS

.


Granulomatous gingivitis in Anderson-Fabry disease.

The patient is suffering from Anderson-Fabry disease. This was documented by family history, clinical findings, histochemical and electronmicroscopic demonstration of ceramide in the blood vessels, and enzyme studies. The patient, at age 17, developed a unique gingival enlargement, gingivitis granulomatosa, a cobbled tongue, glossitis granulomatosa, and a lip enlargement, cheilitis granulomatosa. This was not found in other members of the family. The clinical, histological, and electronmicroscopic findings were analogous to Melkersson-Rosenthal syndrome. The patient did not have sarcoidosis or other specific granulomatous diseases. These were ruled out by skin examination, chest films, histology, and skin sensitivity testing, nor did he have Dilantin associated gingival enlargement. The patient had only taken the drug for a brief period at age 11 when he had a generalized granulomatous lymphadenopathy which was not categorized with certainty. This could have been secondary to Anderson-Fabry disease aggravated by a minor infection, an idiosyncratic reaction to Dilantin, or the lymph node equivalent of the granulomatous response that later affected the gingiva. Although the gingival enlargement appeared to be a manifestation of an unusual syndrome, local therapy in the form of oral hygiene instruction, dental prophylaxis, gingivectomy, and regular maintenance therapy was successful in treatment and prevention of recurrence.

The patient is suffering from

    Anderson-Fabry disease
    DIAGNOSIS

. This was documented by

    family history
    PARACLINICAL

, clinical findings,

    histochemical and electronmicroscopic demonstration of ceramide in the blood vessels
    PARACLINICAL

, and

    enzyme studies
    PARACLINICAL

. The patient, at

    age 17
    AGE

, developed a

    unique gingival enlargement
    SYMPTOMS

,

    gingivitis granulomatosa
    SYMPTOMS

, a

    cobbled tongue
    SYMPTOMS

,

    glossitis granulomatosa
    DIAGNOSIS

, and a

    lip enlargement
    SYMPTOMS

,

    cheilitis granulomatosa
    DIAGNOSIS

. This was

    not found in other members of the family
    FAMILY

. The clinical, histological, and

    electronmicroscopic
    PARACLINICAL

 findings were analogous to

    Melkersson-Rosenthal syndrome
    DIAGNOSIS

. The patient

    did not have sarcoidosis or other specific granulomatous diseases
    NEG_FINDINGS

.

    These were ruled out
    NEG_FINDINGS

 by

    skin examination, chest films, histology, and skin sensitivity testing
    NEG_FINDINGS

, nor did

    he
    GENDER

 have

    Dilantin associated gingival enlargement
    NEG_FINDINGS

. The patient had

    only taken the drug for a brief period
    MEDICATION

 at

    age 11
    AGE

 when

    he
    GENDER

 had a

    generalized granulomatous lymphadenopathy
    SYMPTOMS

 which was not categorized with certainty. This could have been secondary to

    Anderson-Fabry disease
    DIAGNOSIS

 aggravated by a

    minor infection
    SYMPTOMS

, an

    idiosyncratic reaction to Dilantin
    SYMPTOMS

, or the lymph node equivalent

    of the granulomatous response
    SYMPTOMS

 that later

    affected the gingiva
    SYMPTOMS

. Although the

    gingival enlargement
    SYMPTOMS

 appeared to be a manifestation of an unusual syndrome,

    local therapy in the form of oral hygiene instruction
    MEDICATION

,

    dental prophylaxis
    MEDICATION

,

    gingivectomy
    MEDICATION

, and

    regular maintenance therapy
    MEDICATION

 was successful in treatment and prevention of recurrence.

Anderson-Fabry disease
glossitis granulomatosa
cheilitis granulomatosa
Melkersson-Rosenthal syndrome
Anderson-Fabry disease


Basilar artery aneurysm and Anderson-Fabry disease.

A case of basilar artery aneurysm is described. The patient had a family history of similar aneurysms and also of a rare spingolipidosis, Anderson-Fabry disease.

A case of

    basilar artery aneurysm
    SYMPTOMS

 is described. The patient

    had a family history of similar aneurysms and also of a rare spingolipidosis, Anderson-Fabry disease
    FAMILY

.


Clinicopathologic, enzymatic, and genetic features in a case of Fabry's disease.

We report renal lesions and functional alterations in a 32-year-old man with Fabry's disease (ceramidetrihexosidase deficiency). By light microscopy of a renal biopsy specimen, distinctive "foamy" cytoplasmic alterations were observed in renal glomerular, tubular, vascular, and interstitial cells. Histochemical analysis of vacuolated epithelial cells showed glycolipid- and phospholipid-like material. Ultrastructurally, dense osmiophilic as well as stacked and concentric laminated profiles were observed within these epithelial cells. In addition, glomerular endocapillary, parietal, and vascular epithelial cells contained opaque osmiophilic granular deposits with paracrystalline arrays. Renal function studies indicated a glomerular filtration rate of 86.1 mL/min/1.73 sq m, effective renal plasma flow of 415 mL/min/1.73 sq m, tubular reabsorption of glucose of 356 mg/min/100 glomerular filtration rate, and maximal urinary concentrating and diluting ability of 568 and 46 mOsm/kg, respectively. Serum ceramide hexosidase activity was 0.18 nmole/hr/mL (normal, 8 to 15). We conclude that renal dysfunction associated with Fabry's disease is associated mainly with accumulation of glycolipid and phospholipid compounds in the walls of blood vessels and distal nephrons.

We report

    renal lesions
    SYMPTOMS

 and

    functional alterations
    SYMPTOMS

 in a

    32-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 (

    ceramidetrihexosidase deficiency
    BIOCHEMICAL

    )
    DIAGNOSIS

. By

    light microscopy of a renal biopsy specimen
    PARACLINICAL

,

    distinctive "foamy" cytoplasmic alterations were observed in renal glomerular, tubular, vascular, and interstitial cells
    MICROSCOPIC

.

    Histochemical analysis
    PARACLINICAL

    of vacuolated epithelial cells showed glycolipid- and phospholipid-like material
    MICROSCOPIC

.

    Ultrastructurally
    MICROSCOPIC

,

    dense osmiophilic as well as stacked and concentric laminated profiles were observed within these epithelial cells
    MICROSCOPIC

. In addition,

    glomerular endocapillary, parietal, and vascular epithelial cells contained opaque osmiophilic granular deposits with paracrystalline arrays
    MICROSCOPIC

.

    Renal function studies
    PARACLINICAL

 indicated a

    glomerular filtration rate of 86.1 mL/min/1.73 sq m
    BIOCHEMICAL

,

    effective renal plasma flow of 415 mL/min/1.73 sq m
    BIOCHEMICAL

,

    tubular reabsorption of glucose of 356 mg/min/100 glomerular filtration rate
    BIOCHEMICAL

, and

    maximal urinary concentrating and diluting ability of 568 and 46 mOsm/kg, respectively
    BIOCHEMICAL

.

    Serum ceramide hexosidase activity was 0.18 nmole/hr/mL (normal, 8 to 15)
    BIOCHEMICAL

. We conclude that

    renal dysfunction
    SYMPTOMS

 associated with

    Fabry's disease
    DIAGNOSIS

 is associated mainly with

    accumulation of glycolipid and phospholipid compounds in the walls of blood vessels and distal nephrons
    MICROSCOPIC

.

renal lesions
functional alterations
renal dysfunction


Genetic counseling for adoptees at risk for specific inherited disorders.

We present 5 cases in which family history showed that a child given up for adoption some years earlier was at 50% risk for inheritance of Huntington disease, myotonic dystrophy, myotonic dystrophy, Fabry disease, von Willebrand disease, and Waardenburg syndrome, respectively. In all cases, the biological mothers (the probands) requested that the genetic counseling provided for them and their children be shared with the adoptive family. The decision whether or not to seek out the adoptee was based upon explicit assessment of the potential benefits and potential difficulties involved in contacting the adoptive family and attempting to provide genetic counseling. We have formulated some recommendations for dealing with other families with similar separation of relatives by adoption on the basis of these experiences.

We present 5 cases in which

    family history showed that a child given up for adoption some years earlier was at 50% risk for inheritance of Huntington disease
    FAMILY

,

    myotonic dystrophy
    DIAGNOSIS

,

    myotonic dystrophy
    DIAGNOSIS

,

    Fabry disease
    DIAGNOSIS

,

    von Willebrand disease
    DIAGNOSIS

, and

    Waardenburg syndrome
    DIAGNOSIS

, respectively. In all cases, the biological mothers (the probands) requested that

    the genetic counseling provided for them and their children be shared with the adoptive family
    MEDICATION

. The decision whether or not to

    seek out the adoptee
    MEDICATION

 was based upon explicit assessment of the potential benefits and potential difficulties involved in contacting the

    adoptive family
    MEDICATION

 and attempting to provide

    genetic counseling
    MEDICATION

. We have formulated some recommendations for dealing with other families with

    similar separation of relatives
    FAMILY

    by adoption
    MEDICATION

 on the basis of these experiences.

myotonic dystrophy
myotonic dystrophy
Fabry disease
von Willebrand disease
Waardenburg syndrome


[Fabry's disease in ophthalmology (author's transl)].

The authors report a new case of Fabry's disease and emphasize the easiness of diagnosis on simple slit lamp examination of the affected males and conductor females. This disease is transmitted as X linked so that both heterozygotes and hemizygotes show a corneal storage known as cornea verticillata. The clinical features are completed by a conjunctival biopsy and the electron microscopy study shows lamellar bodies in the lysozomes.

The authors report a new case of

    Fabry's disease
    DIAGNOSIS

 and emphasize the easiness of diagnosis on

    simple slit lamp examination
    PARACLINICAL

 of the affected

    males
    GENDER

 and conductor

    females
    GENDER

. This disease is

    transmitted as X linked
    GENETICS

 so that both

    heterozygotes
    GENETICS

 and

    hemizygotes
    GENETICS

 show a

    corneal storage
    SYMPTOMS

 known as

    cornea verticillata
    SYMPTOMS

. The clinical features are completed by a

    conjunctival biopsy
    PARACLINICAL

 and the

    electron microscopy study
    PARACLINICAL

 shows

    lamellar bodies in the lysozomes
    MICROSCOPIC

.

transmitted as X linked
heterozygotes
hemizygotes


Enzyme therapy XVII: metabolic and immunologic evaluation of alpha- galactosidase A replacement in Fabry disease.

A pilot trial of enzyme replacement using splenic and plasma forms of alpha-galactosidase A was undertaken in 2 brothers with Fabry disease, an X-linked glycosphingolipid storage disease. Partially purified preparations of alpha-galactosidase A from human spleen and plasma Cohn fraction IV-1 were prepared aseptically for in vivo administration. The disappearance of enzymatic activity from plasma, levels of circulating substrate, and potential immune response were evaluated following IV administration of 6 unentrapped doses (2,000 U/kg) of each enzyme form to the respective recipient during a 117-day period. Repeated injections were well tolerated. The circulating half-life of the splenic form was about 10 min whereas that for the plasma form was approximately 70 min. No immune response was detected by skin and immunodiffusion tests or by alterations in the maximal activity or clearance kinetics for either enzyme following successive administrations. After each dose of the splenic form, the concentration of the accumulated circulating substrate globotriaosylceramide, decreased maximally (approximately 50% of initial values) in 15 min and returned to preinfusion levels by 2-3 hr. In marked contrast, injection of the plasma form decreased the circulating substrate levels 50-70% by 2-6 hr; the concentrations of globotriaosylceramide gradually returned to preinfusion values by 36-72 hr. Two consecutive doses of the plasma form, administered on days 1 and 3, reduced the circulating substrate concentration to normal levels. Prior to the 6th enzyme administration, circulating substrate was stable-isotope labeled by the infusion of dideutero-glucose, and the effects of each enzyme form on circulating substrate degradation and reaccumulation were determined. The results of this study indicated that labeled (newly synthesized) substrate reaccumulated following injection of the splenic enzyme whereas both unlabeled (previously stored?) and labeled substrate reaccumulated in the circulation after administration of the plasma form. These studies demonstrated the differential disappearance kinetics of the splenic and plasma forms of alpha-galactosidase A, their differential effects on circulating substrate degradation and reaccumulation, as well as the lack of an immune response to repeated administrations of these homologous, unentrapped enzymes.

A pilot trial of

    enzyme replacement using splenic and plasma forms of alpha-galactosidase A
    MEDICATION

 was undertaken in 2

    brothers
    GENDER

 with

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    glycosphingolipid storage disease
    DIAGNOSIS

.

    Partially purified preparations of alpha-galactosidase A from human spleen and plasma Cohn fraction IV-1
    MICROSCOPIC

 were prepared aseptically for in vivo administration. The

    disappearance of enzymatic activity from plasma
    BIOCHEMICAL

,

    levels of circulating substrate
    BIOCHEMICAL

, and potential immune response were evaluated following

    IV administration of 6 unentrapped doses (2,000 U/kg) of each enzyme form
    MEDICATION

 to the respective recipient during a

    117-day period
    MEDICATION

.

    Repeated injections
    MEDICATION

 were well tolerated. The

    circulating half-life of the splenic form
    BIOCHEMICAL

 was about 10 min whereas that for

    the plasma form
    MEDICATION

 was approximately 70 min.

    No immune response was detected by skin and immunodiffusion tests or by alterations in the maximal activity or clearance kinetics for either enzyme
    NEG_FINDINGS

 following successive administrations. After each

    dose of the splenic form
    MEDICATION

, the

    concentration of the accumulated circulating substrate globotriaosylceramide, decreased maximally (approximately 50% of initial values) in 15 min and returned to preinfusion levels by 2-3 hr
    BIOCHEMICAL

. In marked contrast,

    injection of the plasma form decreased the circulating substrate levels 50-70% by 2-6 hr
    MEDICATION

;

    the concentrations of globotriaosylceramide gradually returned to preinfusion values by 36-72 hr
    BIOCHEMICAL

.

    Two consecutive doses of the plasma form
    MEDICATION

, administered on days 1 and 3,

    reduced the circulating substrate concentration to normal levels
    BIOCHEMICAL

. Prior to the

    6th enzyme administration
    MEDICATION

,

    circulating substrate was stable-isotope labeled by the infusion of dideutero-glucose
    PARACLINICAL

, and the effects of each enzyme form on

    circulating substrate degradation and reaccumulation
    MICROSCOPIC

 were determined. The results of this study indicated that

    labeled (newly synthesized) substrate reaccumulated
    MICROSCOPIC

 following

    injection of the splenic enzyme
    MEDICATION

 whereas

    both unlabeled (previously stored?) and labeled substrate reaccumulated in the circulation
    MICROSCOPIC

 after

    administration of the plasma form
    MEDICATION

. These studies demonstrated the differential disappearance kinetics of the splenic and

    plasma forms of alpha-galactosidase A
    BIOCHEMICAL

, their differential effects on

    circulating substrate degradation and reaccumulation
    BIOCHEMICAL

, as well as the

    lack of an immune response to repeated administrations of these homologous, unentrapped enzymes
    NEG_FINDINGS

.

Fabry disease
glycosphingolipid storage disease


Myeloid bodies in patients without clinical Fabry's disease.

Electron microscopy of renal biopsy specimens obtained from three patients revealed typical laminated electron-dense bodies (myeloid bodies) previously believed to be diagnostic of Fabry's disease. None of the patients manifested clinical features characteristic of this disorder, and in one patient leukocyte alpha-galactosidase levels were normal. In comparison with patients with either the heterozygous or homozygous expression of Fabry's disease, in our patients the myeloid bodies were much fewer in number. These observations suggest that the findings of occasional myeloid bodies in renal biopsy specimens should be interpreted with caution.

    Electron microscopy of renal biopsy specimens
    PARACLINICAL

 obtained from three patients revealed

    typical laminated electron-dense bodies (myeloid bodies)
    MICROSCOPIC

 previously believed to be diagnostic of

    Fabry's disease
    MICROSCOPIC

.

    None
    NEG_FINDINGS

 of the patients

    manifested clinical features characteristic of this disorder
    NEG_FINDINGS

, and in one patient

    leukocyte alpha-galactosidase levels were normal
    NEG_FINDINGS

. In comparison with patients with either the

    heterozygous or homozygous expression of Fabry's disease
    GENETICS

, in our patients

    the myeloid bodies were much fewer in number
    MICROSCOPIC

. These observations suggest that the findings of

    occasional myeloid bodies in renal biopsy specimens
    MICROSCOPIC

 should be interpreted with caution.


Fabry's disease in a black kindred.

In a 16-member black kindred with Fabry's disease, four hemizygous males had plasma alpha-galactosidase levels less than 6% and seven heterozygous females had plasma alpha-galactosidase levels between 10% and 50% of normal. A 16-year-old index male had hypertension with left ventricular hypertrophy, abnormal renal function, tortuous retinal veins, "myelin" inclusions in bone marrow macrophages, and intraepithelial inclusion bodies in the kidney. Scrotal angiectasia developed a year after diagnosis. The three other affected males had left ventricular hypertrophy and retinal vein tortuosity. Of the seven carrier females, five had frequent headaches, four had retinal vessel changes, three had proteinuria with normal renal function, and two had bundle-branch blocks on ECGs. There was no deuteranomalopia in this family, although the inheritance pattern of the Fabry gene is X-linked recessive.

In a

    16-member black kindred with Fabry's disease
    FAMILY

, four

    hemizygous males
    GENETICS

 had

    plasma alpha-galactosidase levels less than 6%
    BIOCHEMICAL

 and seven

    heterozygous
    GENETICS

    females
    GENDER

 had

    plasma alpha-galactosidase levels between 10% and 50% of normal
    BIOCHEMICAL

. A

    16-year-old
    AGE

 index

    male
    GENDER

 had

    hypertension
    SYMPTOMS

 with

    left ventricular hypertrophy
    SYMPTOMS

,

    abnormal renal function
    SYMPTOMS

,

    tortuous retinal veins
    SYMPTOMS

,

    "myelin" inclusions in bone marrow macrophages
    MICROSCOPIC

, and

    intraepithelial inclusion bodies in the kidney
    MICROSCOPIC

.

    Scrotal angiectasia
    SYMPTOMS

 developed a year after diagnosis. The three other affected

    males
    GENDER

 had

    left ventricular hypertrophy
    SYMPTOMS

 and

    retinal vein tortuosity
    SYMPTOMS

. Of the seven carrier

    females
    GENDER

, five had

    frequent headaches
    SYMPTOMS

, four had

    retinal vessel changes
    SYMPTOMS

, three had

    proteinuria
    BIOCHEMICAL

 with

    normal renal function
    NEG_FINDINGS

, and two had

    bundle-branch blocks on ECGs
    SYMPTOMS

. There was

    no deuteranomalopia
    NEG_FINDINGS

 in this family, although the

    inheritance pattern of the Fabry gene is X-linked recessive
    GENETICS

.

hypertension
left ventricular hypertrophy
abnormal renal function
tortuous retinal veins
Scrotal angiectasia
left ventricular hypertrophy
retinal vein tortuosity
frequent headaches
retinal vessel changes
bundle-branch blocks on ECGs

normal renal function
no deuteranomalopia


Enzyme therapy in Fabry disease: differential in vivo plasma clearance and metabolic effectiveness of plasma and splenic alpha-galactosidase A isozymes.

A pilot trial of enzyme replacement with splenic and plasma alpha-galactosidase A (alpha-D-galactosidase; alpha-D-galactoside galactohydrolase, EC 3.2.1.22) isozymes was undertaken in two brothers with Fabry disease, an X-linked glycosphingolipid storage disease. Six unentrapped doses (2000 units/kg) of each isozyme were administered intravenously to the respective recipients during a 117-day period. The circulating half-life of the splenic isozyme was about 10 min, whereas that for the plasma isozyme was approximately 70 min. No immune response was detected by skin and immunodiffusion tests or by alterations in the maximal activity or clearance kinetics for either isozyme after successive administrations. After each dose of the splenic isozyme, the concentration of the accumulated circulating substrate, trihexosylceramide (globotriaosylceramide), decreased maximally (approximately 50% of initial values) in 15 min and returned to preinfusion levels by 2-3 hr. In marked contrast, injection of the plasma isozyme decreased the circulating substrate levels 50-70% by 2-6 hr; the concentrations gradually returned to preinfusion values by 36-72 hr.

A pilot trial of

    enzyme replacement with splenic and plasma alpha-galactosidase A (alpha-D-galactosidase; alpha-D-galactoside galactohydrolase, EC 3.2.1.22) isozymes
    MEDICATION

 was undertaken in two

    brothers
    GENDER

 with

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    glycosphingolipid storage disease
    DIAGNOSIS

.

    Six unentrapped doses (2000 units/kg) of each isozyme were administered intravenously
    MEDICATION

 to the respective recipients during a

    117-day period
    MEDICATION

. The

    circulating half-life of the splenic isozyme
    BIOCHEMICAL

 was about 10 min, whereas that

    for the plasma isozyme
    BIOCHEMICAL

 was approximately 70 min.

    No immune response was detected by skin and immunodiffusion tests or by alterations in the maximal activity or clearance kinetics for either isozyme after successive administrations
    NEG_FINDINGS

. After each

    dose of the splenic isozyme
    MEDICATION

, the

    concentration of the accumulated circulating substrate, trihexosylceramide (globotriaosylceramide), decreased maximally (approximately 50% of initial values) in 15 min and returned to preinfusion levels by 2-3 hr
    BIOCHEMICAL

. In marked contrast,

    injection of the plasma isozyme decreased the circulating substrate levels 50-70% by 2-6 hr
    MEDICATION

;

    the concentrations gradually returned to preinfusion values by 36-72 hr.
    BIOCHEMICAL


Fabry disease: cellular expression of enzyme deficiency in nerve xenografts.

Human sural nerve fascicles from a patient with Fabry disease were transplanted into nude-mouse sciatic nerves to determine whether transplanted perineurial cells and smooth-muscle cells of an epineurial artery would express the genetic abnormality of the disease. Four months after grafting, both perineurial cells and smooth-muscle cells contained the cytoplasmic lamellated inclusion bodies characteristic of Fabry disease. This provided evidence of human perineurial cells and smooth-muscle cells in the regenerated xenografts.

    Human sural nerve fascicles
    MICROSCOPIC

 from a patient with

    Fabry disease
    DIAGNOSIS

 were

    transplanted into nude-mouse sciatic nerves
    MEDICATION

 to determine whether

    transplanted perineurial cells and smooth-muscle cells of an epineurial artery
    MICROSCOPIC

 would express the

    genetic abnormality
    GENETICS

 of the disease. Four months after grafting,

    both perineurial cells and smooth-muscle cells contained the cytoplasmic lamellated inclusion bodies characteristic of Fabry disease
    MICROSCOPIC

. This provided

    evidence of human perineurial cells and smooth-muscle cells in the regenerated xenografts
    MICROSCOPIC

.


Fabry's disease. Primary diagnosis by electron microscopy.

Fabry's disease is a lipid storage disease found in children and adults. The lipid is stored as a myelin-figure-like whorl of membranes in endothelial and smooth muscle cells, myocardium, fibroblasts, and epithelial cells of the glomerulus. The lipid deposits are identifiable by light microscopy, but are much easier to demonstrate by electron microscopy. The disease leads to vascular insufficiency because of narrowing and thrombosis of arteries and arterioles. The resultant vascular insufficiency leads to peripheral neuritis, myocardial infarction, peripheral infarction and cerebral infarction. Corneal clouding due to lipid deposits is also seen. Renal involvement is widespread, but renal failure occurs late.

    Fabry's disease
    DIAGNOSIS

 is a

    lipid storage disease
    DIAGNOSIS

 found in

    children
    AGE

 and

    adults
    AGE

.

    The lipid is stored as a myelin-figure-like whorl of membranes in endothelial and smooth muscle cells, myocardium, fibroblasts, and epithelial cells of the glomerulus
    MICROSCOPIC

. The

    lipid deposits
    MICROSCOPIC

 are identifiable by

    light microscopy
    PARACLINICAL

, but are much easier to demonstrate by

    electron microscopy
    PARACLINICAL

. The disease leads to

    vascular insufficiency
    SYMPTOMS

 because of

    narrowing and thrombosis of arteries and arterioles
    SYMPTOMS

. The resultant

    vascular insufficiency
    SYMPTOMS

 leads to

    peripheral neuritis
    SYMPTOMS

,

    myocardial infarction
    SYMPTOMS

,

    peripheral infarction
    SYMPTOMS

 and

    cerebral infarction
    SYMPTOMS

.

    Corneal clouding due to lipid deposits
    SYMPTOMS

 is also seen.

    Renal involvement
    SYMPTOMS

 is widespread, but

    renal failure
    SYMPTOMS

 occurs late.


[Fabry's disease: two patients improved by fetal liver cells (author's transl)].

The first patient reported was a 33 years old male with clinical manifestations of Fabry's disease. The diagnosis was confirmed by ophthalmologic, histological and enzymatic studies. Because of inefficacity of treatment with plasma transfusions and of symptomatic therapies, a transplant of cells with normal enzymatic activities was envisioned. In this patient without renal failure, a renal transplant was not justified and a transplant of fetal liver cells was decided. The improvement of extra-renal manifestations of the disease with this new treatment was comparable to that obtained with kidney transplantation. In particular, objective and subjective clinical symptoms were significantly improved: sweating appeared became normal, cutaneous lesions appeared slightly decreased and pains disappeared. This improvement was still persistent 3 years after the fetal liver transplant, the viability of which was initially followed using dosages of circulating alphafoetoprotein. The second case-report is comparable. Fabry's disease was diagnosed in a 26 years old male on the clinical manifestations, the histological lesions and the enzyme deficiency. After failure of one plasma transfusion, the patient received a fetal liver transplant. It is still too early to evaluate the efficacy of the transplant in this second case, especially as the patient had normal sweating and relatively few pains except at the cold season. The mechanism which may be held responsible for possible improvement in our patients, as in recipients of a kidney transplant, is not completely elucidated. The cells, rather than steroids or azathioprine, seemed to support the efficacy. Was the enzyme activity exerted in situ? Was there a "colonization" by lysosomial enzymes? From the results observed after several years will derive the significance of this therapeutic approach in Fabry's disease, more generally, in many diseases associated with a genetic enzyme deficiency.

The first patient reported was a

    33 years old
    AGE

    male
    GENDER

 with

    clinical manifestations
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

. The diagnosis was confirmed by

    ophthalmologic
    PARACLINICAL

,

    histological and enzymatic studies
    PARACLINICAL

. Because of

    inefficacity of treatment with plasma transfusions and of symptomatic therapies
    NEG_FINDINGS

, a

    transplant of cells with normal enzymatic activities
    MEDICATION

 was envisioned. In this patient

    without renal failure
    NEG_FINDINGS

,

    a renal transplant was not justified
    NEG_FINDINGS

 and a

    transplant of fetal liver cells
    MEDICATION

 was decided. The

    improvement of extra-renal manifestations of the disease
    SYMPTOMS

 with this new treatment was comparable to that obtained with

    kidney transplantation
    MEDICATION

. In particular,

    objective and subjective clinical symptoms were significantly improved
    SYMPTOMS

:

    sweating appeared became normal
    NEG_FINDINGS

,

    cutaneous lesions appeared slightly decreased
    SYMPTOMS

 and

    pains disappeared
    SYMPTOMS

. This improvement was still persistent 3 years after the

    fetal liver transplant
    MEDICATION

, the viability of which was initially followed using

    dosages of circulating alphafoetoprotein
    BIOCHEMICAL

. The second case-report is comparable.

    Fabry's disease
    DIAGNOSIS

 was diagnosed in a

    26 years old
    AGE

    male
    GENDER

 on the clinical manifestations, the

    histological lesions
    SYMPTOMS

 and the

    enzyme deficiency
    BIOCHEMICAL

. After

    failure of one plasma transfusion
    NEG_FINDINGS

, the patient

    received a fetal liver transplant
    MEDICATION

. It is still too early to evaluate the efficacy of the

    transplant
    MEDICATION

 in this second case, especially as the patient had

    normal sweating
    NEG_FINDINGS

 and

    relatively few pains
    NEG_FINDINGS

    except at the cold season
    SYMPTOMS

. The mechanism which may be held responsible for possible improvement in our patients, as in recipients of a

    kidney transplant
    MEDICATION

, is not completely elucidated. The

    cells, rather than steroids or azathioprine
    MEDICATION

, seemed to support the efficacy. Was the

    enzyme activity exerted in situ
    BIOCHEMICAL

? Was there a "

    colonization" by lysosomial enzymes
    MICROSCOPIC

? From the results observed after several years will derive the significance of this therapeutic approach in

    Fabry's disease
    DIAGNOSIS

, more generally, in many diseases associated with a

    genetic enzyme deficiency
    BIOCHEMICAL

.

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


[Lipid thesaurismosis rheumatism. Arthropathies in alpha galactosidase A deficiency (Fabry's disease). Ultrastructural study of the synovial membrane demonstrating microcrystals in the mitochondria of synoviocytes].

Articular manifestations may be the onset of genetic alpha galactosidase deficiency (Fabry's disease). Ultrastructural study shows typical osmiophilic lamellar inclusions of trihexosylceramides in synoviocytes, capillaries and adipocytes. Furthermore microcrystals identical to those seen in Gaucher's disease and type II hyperlipoproteinemia were observed in mitochondria and free in cytoplasm. These data suggest a microcrystalline pathogenesis of these arthropathies, as in gout and chondrocalcinosis, and what we have generally called crystallopathic arthropathies.

    Articular manifestations
    SYMPTOMS

 may be the onset of

    genetic alpha galactosidase deficiency
    DIAGNOSIS

 (

    Fabry's disease)
    DIAGNOSIS

.

    Ultrastructural study
    PARACLINICAL

 shows

    typical osmiophilic lamellar inclusions of trihexosylceramides in synoviocytes, capillaries and adipocytes
    MICROSCOPIC

. Furthermore

    microcrystals identical to those seen in Gaucher's disease
    MICROSCOPIC

 and

    type II hyperlipoproteinemia were observed in mitochondria and free in cytoplasm
    MICROSCOPIC

. These data suggest a

    microcrystalline pathogenesis
    MICROSCOPIC

 of these

    arthropathies
    DIAGNOSIS

, as in

    gout
    DIAGNOSIS

 and

    chondrocalcinosis
    DIAGNOSIS

, and what we have generally called

    crystallopathic arthropathies
    DIAGNOSIS

.

genetic alpha galactosidase deficiency
Fabry's disease)
arthropathies
gout
chondrocalcinosis
crystallopathic arthropathies


Foetal liver transplant in Fabry's disease.

Two patients, 33 and 26 years old, presented with Fabry's disease and minimal renal involvement. They were treated with a transplant of foetal liver cells exhibiting normal enzymatic activities, after plasma transfusions and symptomatic therapies had proved ineffective. In the first patient, objective and subjective clinical symptoms were significantly improved: sweating appeared, cutaneous lesions seemed slightly decreased and pains disappeared. In the second patient, pains were also seemingly decreased. The mechanism which may be held responsible for improvement of our patients, as of recipients of a kidney transplant, is not completely elucidated. The cells, rather than steroids or azathioprine, seemed to be responsible for the improvement.

Two patients,

    33
    AGE

 and

    26 years old
    AGE

, presented with

    Fabry's disease
    DIAGNOSIS

 and

    minimal renal involvement
    SYMPTOMS

. They were treated with a

    transplant of foetal liver cells
    MEDICATION

 exhibiting

    normal enzymatic activities
    NEG_FINDINGS

,

    after plasma transfusions and symptomatic therapies had proved ineffective
    NEG_FINDINGS

. In the first patient,

    objective and subjective clinical symptoms were significantly improved
    SYMPTOMS

:

    sweating appeared
    SYMPTOMS

,

    cutaneous lesions seemed slightly decreased
    SYMPTOMS

 and

    pains disappeared
    SYMPTOMS

. In the second patient,

    pains were also seemingly decreased
    SYMPTOMS

. The mechanism which may be held responsible for improvement of our patients, as of recipients of a

    kidney transplant
    MEDICATION

, is not completely elucidated. The cells, rather than

    steroids or azathioprine
    MEDICATION

, seemed to be responsible for the improvement.

transplant of foetal liver cells
kidney transplant
steroids or azathioprine