[Fabry's disease associated with rheumatoid arthritis. Multisystemic crossroads].

Fabry's disease is a rare congenic disorder of glycosphingolipid catabolism resulting from deficient activity of the alpha galactosidasa. Is an X-linked disorder and in hemizygous males the activity of this enzyme is very low, resulting in severe manifestations. Fabry disease is confirmed by the lack alfa-galactosidase in serum. In the literature have been reported a few cases of coexistent Fabry's disease and connective disorders, but there is not cases of rheumatoid arthritis coexistent. This report describes a case of a female with Fabry's disease who vas subsequently diagnosed with rheumatoid arthritis. The suspect diagnosis was very important because the two disorders are multisystem and new symptoms could be attributed to Fabry's disease. The accumulation of lipids may results in numerous pathogenic autoantibodies, which could make immunocomplex. This is the potential pathogenic mechanisms explaining the association between Fabry's disease and autoimmune diseases.

    Fabry's disease
    DIAGNOSIS

 is a

    rare congenic disorder of glycosphingolipid catabolism
    DIAGNOSIS

 resulting from

    deficient activity of the alpha galactosidasa
    BIOCHEMICAL

. Is an

    X-linked disorder
    GENETICS

 and in

    hemizygous males
    GENETICS

 the

    activity of this enzyme is very low
    BIOCHEMICAL

, resulting in

    severe manifestations
    SYMPTOMS

.

    Fabry disease
    DIAGNOSIS

 is confirmed by the

    lack alfa-galactosidase in serum
    BIOCHEMICAL

. In the literature have been reported a few cases of

    coexistent Fabry's disease and connective disorders
    DIAGNOSIS

, but there is not cases of

    rheumatoid arthritis coexistent
    DIAGNOSIS

. This report describes a case of a

    female
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 who vas subsequently diagnosed with

    rheumatoid arthritis
    DIAGNOSIS

. The suspect diagnosis was very important because the two disorders are

    multisystem
    DIAGNOSIS

 and

    new symptoms
    SYMPTOMS

 could be attributed to

    Fabry's disease
    SYMPTOMS

. The

    accumulation of lipids
    MICROSCOPIC

 may results in

    numerous pathogenic autoantibodies
    BIOCHEMICAL

, which could make

    immunocomplex
    BIOCHEMICAL

. This is the potential pathogenic mechanisms explaining the

    association between Fabry's disease
    DIAGNOSIS

 and

    autoimmune diseases
    DIAGNOSIS

.

severe manifestations
new symptoms
Fabry's disease


Cutaneous variant of angiokeratoma corporis diffusum.

A case of angiokeratoma corporis diffusum (ACD) involving the skin of a 22-year-old patient presenting with normal physical and mental development is reported. ACD presenting with skin lesions alone is a rare but specific clinical entity, which differs from hereditary sphingolipidoses such as Fabry's disease.

A case of

    angiokeratoma corporis diffusum (ACD) involving the skin
    SYMPTOMS

 of a

    22-year-old
    AGE

 patient presenting with

    normal physical and mental development
    NEG_FINDINGS

 is reported.

    ACD
    DIAGNOSIS

 presenting with

    skin lesions
    SYMPTOMS

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

    hereditary sphingolipidoses
    DIAGNOSIS

 such as

    Fabry's disease
    DIAGNOSIS

.

ACD
hereditary sphingolipidoses
Fabry's disease


First-degree atrioventricular block and restrictive physiology as cardiac manifestations of Fabry's disease.

Fabry's disease is an X-linked disorder of glycosphingolipid catabolism related to the defective activity of glycosphingolipid, mainly ceramide trihexoside, in the vascular smooth muscle, myocardium, cells of the sympathetic central nervous system, and epithelial cells of renal glomeruli. We describe a young man who had Fabry's disease and unusual electrocardiographic and echocardiographic patterns at admission for treatment of left leg cellulitis. Findings included a prolonged PR interval and a right bundle branch block pattern, no echocardiographic signs of septal or hypertrophic cardiomyopathy, and a restrictive physiologic pattern. This pattern of electrocardiographic and echocardiographic characteristics of Fabry's disease has not been reported previously and should be added to the other cardiac manifestations of Fabry's disease.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disorder of glycosphingolipid catabolism
    DIAGNOSIS

 related to the

    defective activity of glycosphingolipid, mainly ceramide trihexoside, in the vascular smooth muscle, myocardium, cells of the sympathetic central nervous system, and epithelial cells of renal glomeruli
    MICROSCOPIC

. We describe a

    young
    AGE

    man
    GENDER

 who had

    Fabry's disease
    DIAGNOSIS

 and

    unusual electrocardiographic and echocardiographic patterns
    SYMPTOMS

 at admission for treatment of

    left leg cellulitis
    SYMPTOMS

. Findings included a

    prolonged PR interval and a right bundle branch block pattern
    SYMPTOMS

,

    no echocardiographic signs of septal or hypertrophic cardiomyopathy
    NEG_FINDINGS

, and a

    restrictive physiologic pattern
    SYMPTOMS

. This

    pattern of electrocardiographic and echocardiographic characteristics
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

 has not been reported previously and should be added to the other

    cardiac manifestations
    SYMPTOMS

 of

    Fabry's disease
    DIAGNOSIS

.


Oligosymptomatic cornea verticillata in a heterozygote for Fabry disease: a novel mutation in the alpha-galactosidase gene.

Fabry disease is an X-linked genetic disorder involving sphingolipid catabolism, which is caused by lysosomal alpha-galactosidase A deficiency. Ophthalmological findings such as corneal and lens opacities and conjunctival and retinal vessel abnormalities can be the only and/or the first recognizable symptoms, especially in heterozygous females.

We report on a 34-year-old German woman with cornea verticillata. The alpha-galactosidase A activity was determined in leukocytes using a fluorescence substrate, and the sequence analysis of the alpha galactosidase A gene was performed with genomic DNA.

The alpha-galactosidase A activity in leukocytes was significantly low (0.24 nmol/min/mg protein; normal range, 0.4-1.2), which is compatible with a heterozygote for Fabry disease. The following sequence analysis revealed a heterozygous transition in position IVS5 + 2 T > C. Transition of thymine (T) to cytosine (C) affects the donor splice motive of exon 5 and most probably leads to an aberrant splicing procedure of the alpha-galactosidase A gene.

Our case emphasizes the importance of ophthalmological findings in Fabry disease. The subsequent biochemical and molecular analysis provides a secure diagnosis of female carriers of Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked genetic disorder
    GENETICS

 involving

    sphingolipid catabolism
    MICROSCOPIC

, which is caused by

    lysosomal alpha-galactosidase A deficiency
    BIOCHEMICAL

.

    Ophthalmological findings
    SYMPTOMS

 such as

    corneal and lens opacities
    SYMPTOMS

 and

    conjunctival and retinal vessel abnormalities
    SYMPTOMS

 can be the only and/or the first recognizable symptoms, especially in

    heterozygous
    GENETICS

    females
    GENDER

.

We report on a

    34-year-old
    AGE

    German
    ETHNICITY

    woman
    GENDER

 with

    cornea verticillata
    SYMPTOMS

. The

    alpha-galactosidase A activity was determined in leukocytes
    BIOCHEMICAL

 using a

    fluorescence substrate
    PARACLINICAL

, and the

    sequence analysis of the alpha galactosidase A gene was performed with genomic DNA
    PARACLINICAL

.

    The alpha-galactosidase A activity in leukocytes was significantly low (0.24 nmol/min/mg protein; normal range, 0.4-1.2)
    BIOCHEMICAL

, which is compatible with a

    heterozygote for Fabry disease
    GENETICS

. The

    following sequence analysis
    PARACLINICAL

 revealed a

    heterozygous transition in position IVS5 + 2 T > C. Transition of thymine (T) to cytosine (C) affects the donor splice motive of exon 5 and most probably leads to an aberrant splicing procedure of the alpha-galactosidase A gene
    GENETICS

.

Our case emphasizes the importance of

    ophthalmological findings
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

. The subsequent

    biochemical and molecular analysis
    PARACLINICAL

 provides a secure diagnosis of

    female
    GENDER

 carriers of

    Fabry disease
    DIAGNOSIS

.

Fabry disease
Fabry disease
Fabry disease


Fabry disease with few clinical signs and symptoms.

We describe a 25-year-old man with Fabry disease who remained undiagnosed until progressive renal involvement had begun, because of few clinical signs or symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria and normal renal function. Renal biopsy revealed focal and segmental glomerular sclerosis with vacuolated podocytes. Electron microscopy demonstrated characteristic lamellated bodies. Alpha-galactosidase A (alpha-galA) activity was markedly decreased. Early diagnosis of Fabry disease is becoming important because of the prospect of recombinant alpha-galA replacement therapy. Careful history taking, physical examinations, and renal histology with electron microscopy are essential for the diagnosis in the course of the disease.

We describe a

    25-year-old
    AGE

    man
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 who

    remained undiagnosed
    NEG_FINDINGS

 until

    progressive renal involvement
    SYMPTOMS

 had begun, because of

    few clinical signs or symptoms
    NEG_FINDINGS

 except

    intermittent acroparesthesia
    SYMPTOMS

.

    He
    GENDER

 had

    non-nephrotic proteinuria
    BIOCHEMICAL

 and

    normal renal function
    NEG_FINDINGS

.

    Renal biopsy
    PARACLINICAL

 revealed

    focal and segmental glomerular sclerosis
    MICROSCOPIC

 with

    vacuolated podocytes
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 demonstrated

    characteristic lamellated bodies
    MICROSCOPIC

.

    Alpha-galactosidase A (alpha-galA) activity was markedly decreased
    BIOCHEMICAL

. Early diagnosis of

    Fabry disease
    DIAGNOSIS

 is becoming important because of the prospect of

    recombinant alpha-galA replacement therapy
    MEDICATION

.

    Careful history taking
    PARACLINICAL

,

    physical examinations
    PARACLINICAL

, and

    renal histology
    PARACLINICAL

 with

    electron microscopy
    PARACLINICAL

 are essential for the diagnosis in the course of the disease.

remained undiagnosed
few clinical signs or symptoms
normal renal function

progressive renal involvement
intermittent acroparesthesia


Sisters with atypical Fabry's disease with complete atrioventricular block.

A 56 year old woman with severe right heart failure and complete atrioventricular block was referred to hospital for further examination. Symptoms and signs suggestive of Fabry's disease, such as corneal opacities, acroparaesthesias, hypohidrosis, and angiokeratoma, were not noted. Echocardiography showed a diffuse hypertrophic left ventricular wall and paradoxical movement of the interventricular septum. Cardiac catheterisation showed restrictive-type ventricular dysfunction. Left ventricular endomyocardial biopsy showed central vacuolar degeneration of myocytes with inclusion bodies, which had a concentric lamellar configuration under electron microscopy. This finding is specific for Fabry's disease. The patient's elder sister had experienced an almost identical clinical course and histological findings of myocardial cells on necropsy. In conclusion, two sisters were encountered displaying interesting cases of atypical Fabry's disease. Symptoms began with complete atrioventricular block and histological myocardial findings were specific for Fabry's disease.

A

    56 year old
    AGE

    woman
    GENDER

 with

    severe right heart failure
    SYMPTOMS

 and

    complete atrioventricular block
    SYMPTOMS

 was referred to hospital for further examination. Symptoms and signs suggestive of

    Fabry's disease
    DIAGNOSIS

, such as

    corneal opacities
    SYMPTOMS

,

    acroparaesthesias
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

, and

    angiokeratoma
    SYMPTOMS

, were

    not noted
    NEG_FINDINGS

.

    Echocardiography
    PARACLINICAL

 showed a

    diffuse hypertrophic left ventricular wall
    SYMPTOMS

 and

    paradoxical movement of the interventricular septum
    SYMPTOMS

.

    Cardiac catheterisation
    PARACLINICAL

 showed

    restrictive-type ventricular dysfunction
    SYMPTOMS

.

    Left ventricular endomyocardial biopsy
    PARACLINICAL

 showed

    central vacuolar degeneration of myocytes with inclusion bodies, which had a concentric lamellar configuration
    MICROSCOPIC

 under

    electron microscopy
    PARACLINICAL

. This finding is specific for

    Fabry's disease
    DIAGNOSIS

.

    The patient's elder sister had experienced an almost identical clinical course
    FAMILY

 and

    histological findings of myocardial cells
    MICROSCOPIC

 on

    necropsy
    PARACLINICAL

. In conclusion, two sisters were encountered displaying interesting cases of

    atypical Fabry's disease
    DIAGNOSIS

. Symptoms began with

    complete atrioventricular block
    SYMPTOMS

 and

    histological myocardial findings
    SYMPTOMS

 were specific for

    Fabry's disease
    DIAGNOSIS

.

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


Clinical features and genetic analysis of a Chinese kindred with Fabry's disease.

Fabry's disease is an X-linked recessive inborn error of glycosphingolipid catabolism resulting from deficient activity of lysosomal enzyme alpha-galactosidase A causing occlusive microvascular diseases affecting the kidney, heart, peripheral nerves and brain. It is an uncommon disease in the Oriental population.

We report a Chinese kindred of Fabry's disease and the relevant clinical features are discussed. The diagnosis of Fabry's disease was based on serum alpha-galactosidase A activity and typical histological features from renal biopsy in the index patient. Genetic analysis of two hemizygous male patients revealed a missense mutation predicting a leucine to proline substitution (L14P) in the alpha-galactosidase gene causing classical Fabry's disease in this family. This is a novel point mutation not described previously in the literature and the second report describing novel genetic mutations for Fabry's disease in Chinese patients.

Fabry's disease is rare in Chinese patients but this diagnosis should be considered in patients with positive family history of kidney disease and relevant clinical features.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked recessive inborn error of glycosphingolipid catabolism
    GENETICS

 resulting from

    deficient activity of lysosomal enzyme alpha-galactosidase A
    BIOCHEMICAL

 causing

    occlusive microvascular diseases affecting the kidney, heart, peripheral nerves and brain
    SYMPTOMS

. It is an uncommon disease in the

    Oriental
    ETHNICITY

 population.

We report a

    Chinese
    ETHNICITY

    kindred of Fabry's disease
    FAMILY

 and the relevant clinical features are discussed. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 was based on

    serum alpha-galactosidase A activity
    BIOCHEMICAL

 and

    typical histological features
    SYMPTOMS

 from

    renal biopsy
    PARACLINICAL

 in the index patient.

    Genetic analysis of two hemizygous male
    PARACLINICAL

 patients revealed a

    missense mutation predicting a leucine to proline substitution (L14P) in the alpha-galactosidase gene
    GENETICS

 causing

    classical Fabry's disease
    DIAGNOSIS

 in this family. This is a

    novel point mutation
    GENETICS

 not described previously in the literature and the second report describing

    novel genetic mutations
    GENETICS

 for

    Fabry's disease
    DIAGNOSIS

 in

    Chinese
    ETHNICITY

 patients.

    Fabry's disease
    DIAGNOSIS

 is rare in

    Chinese
    ETHNICITY

 patients but this diagnosis should be considered in patients with

    positive family history of kidney disease
    FAMILY

 and relevant clinical features.

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


Enzyme replacement therapy in Anderson-Fabry's disease: beneficial clinical effect on vital organ function.

Two recent randomized trials pointed out the beneficial effect of enzyme replacement therapy on biochemical parameters in patients with Anderson-Fabry's disease. Clinical end-points, such as amelioration or stabilization of renal function deterioration, or improvement of left ventricular hypertrophy have not been evaluated in depth. We report the case of a patient whose moderately impaired renal function was stabilized with the start of enzyme treatment. In addition, left ventricular hypertrophy tended to regress. To our knowledge this is the first observation of clinical efficacy of the enzyme replacement therapy in Anderson-Fabry's disease in patients with moderately impaired renal function.

Two recent randomized trials pointed out the beneficial effect of

    enzyme replacement therapy
    MEDICATION

 on

    biochemical parameters
    BIOCHEMICAL

 in patients with

    Anderson-Fabry's disease
    DIAGNOSIS

. Clinical end-points, such as

    amelioration or stabilization of renal function deterioration
    SYMPTOMS

, or

    improvement of left ventricular hypertrophy
    SYMPTOMS

 have not been evaluated in depth. We report the case of a patient whose

    moderately impaired renal function
    SYMPTOMS

 was stabilized with the start of

    enzyme treatment
    MEDICATION

. In addition,

    left ventricular hypertrophy tended to regress
    SYMPTOMS

. To our knowledge this is the first observation of clinical efficacy of the

    enzyme replacement therapy
    MEDICATION

 in

    Anderson-Fabry's disease
    DIAGNOSIS

 in patients with

    moderately impaired renal function
    BIOCHEMICAL

.

enzyme replacement therapy
enzyme treatment
enzyme replacement therapy

biochemical parameters
moderately impaired renal function

Anderson-Fabry's disease
Anderson-Fabry's disease


[Fabry disease: diagnostic due of substitutive enzyme-therapy].

Fabry disease is a X-linked sphingolipid storage disorder resulting from the defective activity of the lysosomal enzyme, alpha-galactosidase A. Hemizygotes develop severe multisystemic disease, dominated by renal failure and progressive neurological and cardiac involvement, causing premature death. Thirty percent of heterozygotes have severe involvement of one or several organs. With developments in molecular biology, it is now possible to produce the human recombinant enzyme alpha-galactosidase A. More than 20 patients are now treated in Switzerland.

    Fabry disease
    DIAGNOSIS

 is a

    X-linked
    GENETICS

    sphingolipid storage disorder
    DIAGNOSIS

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

    Hemizygotes
    GENETICS

 develop

    severe multisystemic disease
    DIAGNOSIS

, dominated by

    renal failure
    SYMPTOMS

 and

    progressive neurological and cardiac involvement
    SYMPTOMS

, causing

    premature death
    SYMPTOMS

. Thirty percent of

    heterozygotes
    GENETICS

 have

    severe involvement of one or several organs
    SYMPTOMS

. With developments in molecular biology, it is now possible to produce the human recombinant enzyme alpha-galactosidase A. More than 20 patients are now treated in

    Switzerland
    ETHNICITY

.

Fabry disease
sphingolipid storage disorder
severe multisystemic disease


Angiokeratoma corporis diffusum in a Spanish patient with aspartylglucosaminuria.

Angiokeratoma corporis diffusum (ACD), initially considered to be synonymous with Fabry's disease, represents a well-known cutaneous marker of some other lysosomal enzyme disorders. Aspartylglucosaminuria (AGU) is a rare hereditary disorder mostly affecting the Finnish population, with only a few sporadic patients of non-Finnish origin. To date, only three patients with AGU have been reported with cutaneous lesions of ACD. A 19-year-old Spanish woman presented with a 10-year history of progressive ACD affecting the limbs, buttocks and trunk. After the age of 6 years she had developed progressive mental deterioration, coarse facies and macroglossia with a scrotal appearance. Peripheral blood smears showed many vacuolated lymphocytes. Enzyme analysis in cultured fibroblasts revealed a decreased activity of aspartylglucosaminidase. By the age of 31 years the patient had developed a bipolar psychosis, polycystic ovarian disease and severe impairment of cognitive skills. This is the first case of AGU detected in a Spanish patient presenting with cutaneous lesions of ACD. To our knowledge, macroglossia with a scrotal appearance and polycystic ovarian disease have not been reported in previous cases of AGU.

    Angiokeratoma corporis diffusum (ACD)
    SYMPTOMS

, initially considered to be synonymous with

    Fabry's disease
    DIAGNOSIS

, represents a well-known cutaneous marker of some other

    lysosomal enzyme disorders
    DIAGNOSIS

.

    Aspartylglucosaminuria (AGU)
    DIAGNOSIS

 is a

    rare hereditary disorder
    GENETICS

 mostly affecting the

    Finnish
    ETHNICITY

 population, with only a few sporadic patients of

    non-Finnish
    ETHNICITY

 origin. To date, only three patients with

    AGU
    DIAGNOSIS

 have been reported with

    cutaneous lesions of ACD
    SYMPTOMS

. A

    19-year-old
    AGE

    Spanish
    ETHNICITY

    woman
    GENDER

 presented with a 10-year history of

    progressive ACD affecting the limbs, buttocks and trunk
    SYMPTOMS

.

    After the age of 6 years
    AGE

    she
    GENDER

 had developed

    progressive mental deterioration
    SYMPTOMS

,

    coarse facies
    SYMPTOMS

 and

    macroglossia with a scrotal appearance
    SYMPTOMS

.

    Peripheral blood smears
    PARACLINICAL

 showed

    many vacuolated lymphocytes
    MICROSCOPIC

.

    Enzyme analysis in cultured fibroblasts
    PARACLINICAL

 revealed a

    decreased activity of aspartylglucosaminidase
    BIOCHEMICAL

. By the

    age of 31 years
    AGE

 the patient had developed a

    bipolar psychosis
    DIAGNOSIS

,

    polycystic ovarian disease
    DIAGNOSIS

 and

    severe impairment of cognitive skills
    SYMPTOMS

. This is the first case of

    AGU
    DIAGNOSIS

 detected in a

    Spanish
    ETHNICITY

 patient presenting with

    cutaneous lesions of ACD
    SYMPTOMS

. To our knowledge,

    macroglossia with a scrotal appearance
    SYMPTOMS

 and

    polycystic ovarian disease
    DIAGNOSIS

 have not been reported in previous cases of

    AGU
    DIAGNOSIS

.

Fabry's disease
lysosomal enzyme disorders
Aspartylglucosaminuria (AGU)
AGU
bipolar psychosis
polycystic ovarian disease
AGU
polycystic ovarian disease
AGU


The ultrastructural study in a case of Fabry disease.

An investigation of the ultrastructural study was conducted on specimens from a typical patient with Fabry disease. Numerous characteristic cytoplasmic inclusions were observed in the vascular endothelial cell, pericyte, smooth muscle cell, nerve and eccrine sweat glands, the lamellar pattern of which were considerably variable in various types of gland cells. Large vacuolar inclusions predominated in clear cells of the secretory coil; lesser vacuoles were also seen in the coiled duct, and the basal cells of the straight duct toward the coiled duct displayed mulberry-like figures. There were some clear cells showing cell damage and necrosis in the secretory coil. Lamellated bodies were noted in the axons and schwann cells around the eccrine sweat glands. The small blood vessels around the eccrine glands were narrowed by swollen endothelial cells with heavy inclusions. These intracytoplasmic deposits may be responsible for the decreased sweating ability in Fabry disease. The factors related to hypohidrosis are also discussed.

An investigation of the

    ultrastructural study
    PARACLINICAL

 was conducted on specimens from a typical patient with

    Fabry disease
    DIAGNOSIS

.

    Numerous characteristic cytoplasmic inclusions were observed in the vascular endothelial cell, pericyte, smooth muscle cell, nerve and eccrine sweat glands, the lamellar pattern of which were considerably variable in various types of gland cells
    MICROSCOPIC

.

    Large vacuolar inclusions predominated in clear cells of the secretory coil
    MICROSCOPIC

;

    lesser vacuoles were also seen in the coiled duct
    MICROSCOPIC

, and

    the basal cells of the straight duct toward the coiled duct displayed mulberry-like figures
    MICROSCOPIC

. There were

    some clear cells showing cell damage and necrosis in the secretory coil
    MICROSCOPIC

.

    Lamellated bodies were noted in the axons and schwann cells around the eccrine sweat glands
    MICROSCOPIC

. The

    small blood vessels around the eccrine glands
    SYMPTOMS

    were narrowed by swollen endothelial cells with heavy inclusions
    MICROSCOPIC

. These

    intracytoplasmic deposits
    MICROSCOPIC

 may be responsible for the

    decreased sweating ability
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

. The factors related to

    hypohidrosis
    SYMPTOMS

 are also discussed.


Anderson-Fabry disease with cerebrovascular complications in two Italian families.

We describe four patients with cerebrovascular complications from two unrelated Italian families with Anderson-Fabry disease. Clinical examination, neuroimaging (MRI), biochemical and genetic analyses were carried out in all the patients. Alpha-galactosidase A activity was detected by fluorimetric assay and genetic analysis was performed by DNA sequencing. Family 1. A male patient presented recurrent strokes when he was 34 years old, albuminuria and subsequently progressive renal failure to renal transplantation. Family 2. A male patient, aged 32 years, had diplopia for a few days and then recurrent strokes with left spastic hemiparesis and internuclear ophthalmoplegia. A female patient, aged 48 years, presented L-dopa-responsive parkinsonism, and her sister had stroke when she was 55 years old. MRI was abnormal in all the patients and showed lacunar infarctions in the periventricular white matter, basal ganglia and pons. Lesions were detected by MRI even before stroke in a female patients. In patients with Anderson-Fabry disease, stroke is a frequent complication, and may be the first threatening clinical manifestation. In young people with undefined stroke, even without signs of renal involvement, it is important to consider the diagnosis of Anderson-Fabry disease and so to perform clinical examination and biochemical analyses. The pre-clinical stage of cerebrovascular involvement may be evaluable by MRI.

We describe four patients with

    cerebrovascular complications
    SYMPTOMS

 from two unrelated

    Italian
    ETHNICITY

 families with

    Anderson-Fabry disease
    DIAGNOSIS

.

    Clinical examination
    PARACLINICAL

,

    neuroimaging (MRI)
    PARACLINICAL

,

    biochemical and genetic analyses
    PARACLINICAL

 were carried out in all the patients.

    Alpha-galactosidase A activity
    BIOCHEMICAL

 was detected by

    fluorimetric assay
    PARACLINICAL

 and

    genetic analysis
    PARACLINICAL

 was performed by

    DNA sequencing
    PARACLINICAL

. Family 1. A

    male
    GENDER

 patient presented

    recurrent strokes
    SYMPTOMS

 when

    he
    GENDER

 was

    34 years old
    AGE

,

    albuminuria
    BIOCHEMICAL

 and subsequently

    progressive renal failure
    SYMPTOMS

 to

    renal transplantation
    MEDICATION

. Family 2. A

    male
    GENDER

 patient,

    aged 32 years
    AGE

, had

    diplopia for a few days
    SYMPTOMS

 and then

    recurrent strokes
    SYMPTOMS

 with

    left spastic hemiparesis
    SYMPTOMS

 and

    internuclear ophthalmoplegia
    SYMPTOMS

. A

    female
    GENDER

 patient,

    aged 48 years
    AGE

, presented

    L-dopa-responsive parkinsonism
    DIAGNOSIS

, and

    her
    GENDER

    sister had stroke when she was 55 years old
    FAMILY

.

    MRI
    PARACLINICAL

 was abnormal in all the patients and showed

    lacunar infarctions in the periventricular white matter, basal ganglia and pons
    SYMPTOMS

.

    Lesions
    SYMPTOMS

 were detected by

    MRI
    PARACLINICAL

 even before

    stroke
    SYMPTOMS

 in a

    female
    GENDER

 patients. In patients with

    Anderson-Fabry disease
    DIAGNOSIS

,

    stroke
    SYMPTOMS

 is a frequent complication, and may be the first threatening clinical manifestation. In

    young people
    AGE

 with

    undefined stroke
    SYMPTOMS

, even

    without signs of renal involvement
    NEG_FINDINGS

, it is important to consider the diagnosis of

    Anderson-Fabry disease
    DIAGNOSIS

 and so to perform

    clinical examination
    PARACLINICAL

 and

    biochemical analyses
    PARACLINICAL

. The pre-clinical stage of

    cerebrovascular involvement
    SYMPTOMS

 may be evaluable by

    MRI
    PARACLINICAL

.

Anderson-Fabry disease
L-dopa-responsive parkinsonism
Anderson-Fabry disease
Anderson-Fabry disease

Alpha-galactosidase A activity
albuminuria


[Fabry's disease and hypoparathyroidism].

Fabry's disease is due to alpha-galactosidase deficiency. This rare lysosomal storage disease is transmitted by recessive X-linked heredity. Sphingolipids (galactosyl-glucosyl-ceramide) accumulate in many organs.

A 19-year-old man with known hypoparathyroidism presented with telangiectasia and angiokeratomas on the buttocks, the hips, the hands and around the navel. For many years, he suffered from paroxysmal pain in the hands and feet. From childhood, he had complained of diffuse abdominal pain, associated with diarrhea. Ophthalmological slit lamp fundus examination showed corneal telangiectasia and cornea verticella. There was no kidney or heart involvement. The diagnosis of Fabry's disease was confirmed by very low levels of alpha-galactosidase.

We did not find any other association of hypoparathyroidism and Fabry's disease in the literature. Hypoparathyroidism is not a manifestation of Fabry's disease. Idiopathic hypoparathyroidism is very rare and a genetic origin is known. This disease can be recessive X-linked. A co-transmission of idiopathic hypoparathyroidism and Fabry's disease is probable in our patient.

    Fabry's disease
    DIAGNOSIS

 is due to

    alpha-galactosidase deficiency
    BIOCHEMICAL

. This

    rare lysosomal storage disease
    DIAGNOSIS

 is

    transmitted by recessive X-linked heredity
    GENETICS

.

    Sphingolipids (galactosyl-glucosyl-ceramide) accumulate in many organs
    MICROSCOPIC

.

A

    19-year-old
    AGE

    man
    GENDER

 with known

    hypoparathyroidism
    BIOCHEMICAL

 presented with

    telangiectasia and angiokeratomas on the buttocks, the hips, the hands and around the navel
    SYMPTOMS

. For many years,

    he
    GENDER

 suffered from

    paroxysmal pain in the hands and feet
    SYMPTOMS

. From

    childhood
    AGE

,

    he
    GENDER

 had complained of

    diffuse abdominal pain
    SYMPTOMS

, associated with

    diarrhea
    SYMPTOMS

.

    Ophthalmological slit lamp fundus examination
    PARACLINICAL

 showed

    corneal telangiectasia
    SYMPTOMS

 and

    cornea verticella
    SYMPTOMS

. There was

    no kidney or heart involvement
    NEG_FINDINGS

. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 was confirmed by

    very low levels of alpha-galactosidase
    BIOCHEMICAL

.

We did not find any other association of

    hypoparathyroidism
    SYMPTOMS

 and

    Fabry's disease
    DIAGNOSIS

 in the literature.

    Hypoparathyroidism
    NEG_FINDINGS

 is not a manifestation of

    Fabry's disease
    NEG_FINDINGS

.

    Idiopathic hypoparathyroidism
    DIAGNOSIS

 is very rare and a

    genetic origin
    GENETICS

 is known. This

    disease can be recessive X-linked
    GENETICS

. A

    co-transmission of idiopathic hypoparathyroidism
    FAMILY

    and Fabry's disease
    FAMILY

 is probable in our patient.

Fabry's disease
rare lysosomal storage disease
Fabry's disease
Fabry's disease
Idiopathic hypoparathyroidism

alpha-galactosidase deficiency
hypoparathyroidism
very low levels of alpha-galactosidase

no kidney or heart involvement
Hypoparathyroidism
Fabry's disease


Crescentic glomerulonephritis in a patient with heterozygous Fabry's disease.

A 58-year-old woman who suffered from a heterozygous Fabry's disease and immune complex crescentic glomerulonephritis (GN) is reviewed. The diagnosis was made on the basis of the pathologic findings and peripheral leukocyte alpha-galactosidase activity. Light microscopy revealed a vacuolization of epithelial cells and electron microscopy showed myelin figures in the cytoplasm of visceral epithelial cells typical of Fabry's disease at the first renal biopsy. During the following 4 months she developed progressive renal failure and a second renal biopsy disclosed the formation of cellular crescents in 7 of 11 glomeruli observed. A rare case of combined Fabry's disease and crescentic glomerulonephritis is discussed.

A

    58-year-old
    AGE

    woman
    GENDER

 who suffered from a

    heterozygous Fabry's disease
    DIAGNOSIS

 and

    immune complex crescentic glomerulonephritis (GN)
    DIAGNOSIS

 is reviewed. The diagnosis was made on the basis of the pathologic findings and

    peripheral leukocyte alpha-galactosidase activity
    BIOCHEMICAL

.

    Light microscopy
    PARACLINICAL

 revealed a

    vacuolization of epithelial cells
    MICROSCOPIC

 and

    electron microscopy
    PARACLINICAL

 showed

    myelin figures in the cytoplasm of visceral epithelial cells typical of Fabry's disease
    MICROSCOPIC

 at the

    first renal biopsy
    PARACLINICAL

. During the following 4 months

    she
    GENDER

 developed

    progressive renal failure
    SYMPTOMS

 and a

    second renal biopsy
    PARACLINICAL

 disclosed the

    formation of cellular crescents in 7 of 11 glomeruli observed
    MICROSCOPIC

. A rare case of

    combined Fabry's disease and crescentic glomerulonephritis
    DIAGNOSIS

 is discussed.


A novel A97P amino acid substitution in alpha-galactosidase A leads to a classical Fabry disease with cardiac manifestations.

Fabry disease results from a genetic deficiency of alpha-galactosidase A (GLA) activity. Phenotype-genotype correlations in this condition have not as yet been fully elucidated.

To report a case of a male patient with classical Fabry disease and his mother, a heterozygous female with Fabry disease, showing cardiac involvement, and to identify the underlying GLA gene mutation in this particular phenotype.

Genomic DNA was extracted from the patient, his mother and the unaffected family members. Biopsy specimens of skin, heart and kidney were examined using light and electron microscopy. The mutation was identified by polymerase chain reaction and direct sequencing and was confirmed by restriction enzyme fragment length polymorphism.

The G-->C transversion was identified in codon 97 of the GLA gene and resulted in an A97P amino acid substitution that was a novel pathogenic GLA gene mutation. The male patient who had classical Fabry disease was hemizygous and his mother was heterozygous for this mutation.

These results indicate that the A97P amino acid substitution in GLA might tend to induce classical Fabry disease.

    Fabry disease
    DIAGNOSIS

 results from a

    genetic deficiency of alpha-galactosidase A (GLA) activity
    GENETICS

. Phenotype-genotype correlations in this condition have not as yet been fully elucidated.

To report a case of a

    male
    GENDER

    patient with classical Fabry disease and his mother, a heterozygous female
    FAMILY

    with Fabry disease
    FAMILY

, showing

    cardiac involvement
    SYMPTOMS

, and to identify the underlying

    GLA gene mutation
    GENETICS

 in this particular phenotype.

    Genomic DNA was extracted from the patient, his mother
    PARACLINICAL

 and the unaffected family members.

    Biopsy specimens of skin, heart and kidney
    PARACLINICAL

 were examined using

    light and electron microscopy
    PARACLINICAL

. The mutation was identified by

    polymerase chain reaction and direct sequencing
    PARACLINICAL

 and was confirmed by

    restriction enzyme fragment length polymorphism
    PARACLINICAL

.

    The G-->C transversion was identified in codon 97 of the GLA gene and resulted in an A97P amino acid substitution that was a novel pathogenic GLA gene mutation
    GENETICS

. The

    male
    GENDER

 patient who had

    classical Fabry disease
    DIAGNOSIS

 was

    hemizygous
    GENETICS

 and

    his
    GENDER

    mother was heterozygous for this mutation
    FAMILY

.

These results indicate that the

    A97P amino acid substitution in GLA
    GENETICS

 might tend to induce

    classical Fabry disease
    DIAGNOSIS

.

Fabry disease
classical Fabry disease
classical Fabry disease


Neurological presentation of Fabry's disease in a 52 year old man.

Fabry's disease is an X linked inborn error of metabolism due to deficient activity of the lysosomal enzyme alpha galactosidase A. Previously unrecognised Fabry's disease presenting in a 52 year old man being investigated for progressive dysarthria and ataxia is discussed. Brain magnetic resonance imaging suggested the presence of small vessel disease but skin biopsy (done to exclude cerebral autosomal dominant arteriopathy with subcortical infarcts and leucencephalopathy) showed typical changes of Fabry's disease. This diagnosis was confirmed by subsequent enzyme assays. The authors contend that Fabry's disease should be excluded, at least on clinical grounds, in patients with otherwise unexplained cerebrovascular disease.

    Fabry's disease
    DIAGNOSIS

 is an

    X linked inborn error of metabolism
    GENETICS

 due to deficient activity of the lysosomal enzyme alpha galactosidase A. Previously unrecognised

    Fabry's disease
    DIAGNOSIS

 presenting in a

    52 year old
    AGE

    man
    GENDER

 being investigated for

    progressive dysarthria
    SYMPTOMS

 and

    ataxia
    SYMPTOMS

 is discussed.

    Brain magnetic resonance imaging
    PARACLINICAL

 suggested the presence of

    small vessel disease
    DIAGNOSIS

 but

    skin biopsy
    PARACLINICAL

 (done to exclude

    cerebral autosomal dominant arteriopathy with subcortical infarcts
    DIAGNOSIS

    and leucencephalopathy
    NEG_FINDINGS

) showed

    typical changes of Fabry's disease
    MICROSCOPIC

. This diagnosis was confirmed by subsequent

    enzyme assays
    PARACLINICAL

. The authors contend that

    Fabry's disease
    DIAGNOSIS

 should be excluded, at least on clinical grounds, in patients with otherwise

    unexplained cerebrovascular disease
    SYMPTOMS

.

progressive dysarthria
ataxia
unexplained cerebrovascular disease


Avascular necrosis of the femoral head in a patient with Fabry's disease: identification of ceramide trihexoside in the bone by delayed-extraction matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.

Fabry's disease is a lipid storage disease caused by an X-linked hereditary deficiency of alpha-galactosidase. The enzymatic defect causes progressive deposition of ceramide trihexoside (CTH) in various tissues, leading to renal failure, premature myocardial infarction, and stroke, with a high rate of mortality in younger patients. Among the complications associated with Fabry's disease, a few cases involving avascular necrosis (AVN) of the femoral head have been reported. However, direct evidence of deposition of CTH in bone marrow in the femoral head has not been demonstrated. This report describes a 58-year-old man who underwent total hip arthroplasty for femoral head AVN associated with Fabry's disease. The accumulation of CTH was examined by chemical analysis of the sphingolipid extracted from the femoral head, using delayed-extraction matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. This is the first report confirming the presence of CTH in the sphingolipid fraction from normal and necrotic bone of a patient with Fabry's disease.

    Fabry's disease
    DIAGNOSIS

 is a

    lipid storage disease
    DIAGNOSIS

 caused by an

    X-linked hereditary
    GENETICS

    deficiency of alpha-galactosidase
    BIOCHEMICAL

. The enzymatic defect causes

    progressive deposition of ceramide trihexoside (CTH) in various tissues
    MICROSCOPIC

, leading to

    renal failure
    SYMPTOMS

,

    premature myocardial infarction
    SYMPTOMS

, and

    stroke
    SYMPTOMS

, with a high rate of mortality in

    younger
    AGE

 patients. Among the complications associated with

    Fabry's disease
    DIAGNOSIS

, a few cases involving

    avascular necrosis (AVN) of the femoral head
    SYMPTOMS

 have been reported. However, direct evidence of

    deposition of CTH in bone marrow in the femoral head
    MICROSCOPIC

 has not been demonstrated. This report describes a

    58-year-old
    AGE

    man
    GENDER

 who underwent

    total hip arthroplasty
    MEDICATION

 for

    femoral head AVN
    DIAGNOSIS

 associated with

    Fabry's disease
    DIAGNOSIS

. The

    accumulation of CTH
    MICROSCOPIC

 was examined by

    chemical analysis of the sphingolipid extracted from the femoral head
    PARACLINICAL

, using

    delayed-extraction matrix-assisted laser desorption ionization-time-of-flight mass spectrometry
    PARACLINICAL

. This is the first report confirming the

    presence of CTH in the sphingolipid fraction from normal and necrotic bone
    MICROSCOPIC

 of a patient with

    Fabry's disease
    DIAGNOSIS

.

Fabry's disease
lipid storage disease
Fabry's disease
femoral head AVN
Fabry's disease
Fabry's disease


[Foam cell nephropathy in heterozygous female with Fabry's disease].

We describe the clinical and pathological characteristics of a 49 year-old heterozygous female carrier of Anderson-Fabry's disease. Light microscopy and ultrastructural study of a renal biopsy showed the presence of foam cell nephropathy and galactosylceramide deposits affecting podocytes, the parietal epithelium of Bowman's capsule and the distal tubular cells, endothelial cells and medullary interstitial elements. Retrospectively, the presence of storage disease was confirmed in a hysterectomy specimen obtained two years previously. Our observation shows that heterozygotes for this disorder can not only carry and transmit the disease but may also develop pathological deposits in various organs. A renal biopsy from these carriers allows precise identification of the disease, facilitates adequate genetic counseling and gives the option of enzyme replacement therapy in patients who have pathological deposits.

We describe the clinical and pathological characteristics of a

    49 year-old
    AGE

    heterozygous
    GENETICS

    female
    GENDER

 carrier of

    Anderson-Fabry's disease
    DIAGNOSIS

.

    Light microscopy
    PARACLINICAL

 and

    ultrastructural study of a renal biopsy
    PARACLINICAL

 showed the

    presence of foam cell nephropathy
    MICROSCOPIC

 and

    galactosylceramide deposits affecting podocytes, the parietal epithelium of Bowman's capsule and the distal tubular cells, endothelial cells and medullary interstitial elements
    MICROSCOPIC

. Retrospectively, the presence of

    storage disease
    DIAGNOSIS

 was confirmed in a

    hysterectomy specimen
    PARACLINICAL

 obtained two years previously. Our observation shows that

    heterozygotes
    GENETICS

 for this disorder can not only carry and transmit the disease but may also develop

    pathological deposits in various organs
    MICROSCOPIC

. A

    renal biopsy
    PARACLINICAL

 from these carriers allows precise identification of the disease, facilitates

    adequate genetic counseling
    MEDICATION

 and gives the option of

    enzyme replacement therapy
    MEDICATION

 in patients who have

    pathological deposits
    SYMPTOMS

.

Anderson-Fabry's disease
storage disease

adequate genetic counseling
enzyme replacement therapy


Intermittent claudication unmasking underlying Fabry's disease.

In a 53-year-old woman, admitted to our Department with leg pain, peripheral arterial occlusive disease (PAOD) was diagnosed. The absence of cardiovascular risk factors in this middle-aged woman, the unexplained burning pain during both effort and rest of the lower extremities mimicking severe ischemia, decreased sweating and cold induced Raynaud's phenomenon raised the suspicion of an underlying predisposing disease. The coexistence of painful acroparesthesias, angiokeratomas, left ventricular hypertrophy (LVH), corneal opacities and lenticular lesions suggested the diagnosis of Fabry's disease, which was confirmed by low serum levels of a-galactosidase-A activity. This case, presented with intermittent claudication due to generalized atherosclerosis, is quite unusual, since Fabry's disease rarely produces symptoms in female carriers.

In a

    53-year-old
    AGE

    woman
    GENDER

, admitted to our Department with

    leg pain
    SYMPTOMS

,

    peripheral arterial occlusive disease (PAOD)
    DIAGNOSIS

 was diagnosed. The

    absence of cardiovascular risk factors
    NEG_FINDINGS

 in this

    middle-aged
    AGE

    woman
    GENDER

, the

    unexplained burning pain during both effort and rest of the lower extremities
    SYMPTOMS

 mimicking

    severe ischemia
    SYMPTOMS

,

    decreased sweating
    SYMPTOMS

 and

    cold induced Raynaud's phenomenon
    SYMPTOMS

 raised the suspicion of an underlying predisposing disease. The coexistence of

    painful acroparesthesias
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    left ventricular hypertrophy (LVH)
    SYMPTOMS

,

    corneal opacities
    SYMPTOMS

 and

    lenticular lesions
    SYMPTOMS

 suggested the diagnosis of

    Fabry's disease
    DIAGNOSIS

, which was confirmed by

    low serum levels of a-galactosidase-A activity
    BIOCHEMICAL

. This case, presented with

    intermittent claudication
    SYMPTOMS

 due to

    generalized atherosclerosis
    SYMPTOMS

, is quite unusual, since

    Fabry's disease
    DIAGNOSIS

 rarely produces symptoms in

    female
    GENDER

 carriers.


[Vertebro-basilar ischemic strokes and aseptic meningitis, late complications of Fabry's disease].

Fabry's disease, also called angiokeratoma corporis diffusum universal, is a rare cause of stroke in the young. We report the case of a 39-year-old man who presented with relapsing vertebro-basilar ischemic strokes. Biological tests showed the presence of an aseptic meningitis and a biological inflammatory syndrome, suggesting a particularly progressive illness. The possible mechanisms involved in this exceptional association are discussed.

    Fabry's disease
    DIAGNOSIS

, also called

    angiokeratoma corporis diffusum universal
    DIAGNOSIS

, is a rare cause of

    stroke
    SYMPTOMS

 in the

    young
    AGE

. We report the case of a

    39-year-old
    AGE

    man
    GENDER

 who presented with

    relapsing vertebro-basilar ischemic strokes
    SYMPTOMS

.

    Biological tests
    PARACLINICAL

 showed the presence of an

    aseptic meningitis
    DIAGNOSIS

 and a

    biological inflammatory syndrome
    SYMPTOMS

, suggesting a

    particularly progressive illness
    DIAGNOSIS

. The possible mechanisms involved in this exceptional association are discussed.


Renal transplantation in patients with Fabry disease.

Anderson-Fabry disease (AFd) is a rare X-linked disorder characterized by deficiency of alpha-galactosidase A that leads to systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney. End-stage renal failure is a common manifestation in hemizygous males that often occurs by the third to fourth decade of life. Usually transplanted patients exhibit improvement in clinical symptoms of the disease, probably related to the production of alpha-galactosidase A from the grafted kidney, but mainly related to the increase in Gb3 clearance by the functioning kidney, and increased survival of red cells due to the correction of the uremic status with an evident decrease in the production of Gb3 depending from hemolysis. Several Fabry patients with successful kidney graft survived for 10-15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis. An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now. We report herein the ultrastructural study of the urinary sediment of a 35-year-old male Fabry patient with a severe clinical form of the disease with progression to ESRF at age 29, and submitted to renal transplantation at 33 years. Ultrastructural findings of the urinary sediment documented several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids. This morphological evidence arises the problem of the possible recurrence of AFd in the kidney graft in patients with severe phenotype of the metabolic disease.

    Anderson-Fabry disease (AFd)
    DIAGNOSIS

 is a

    rare X-linked disorder
    GENETICS

 characterized by

    deficiency of alpha-galactosidase A
    BIOCHEMICAL

 that leads to

    systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney
    MICROSCOPIC

.

    End-stage renal failure
    DIAGNOSIS

 is a common manifestation in

    hemizygous
    GENETICS

    males
    GENDER

 that often occurs by the

    third to fourth decade of life
    AGE

. Usually

    transplanted
    MEDICATION

 patients exhibit

    improvement in clinical symptoms of the disease
    SYMPTOMS

, probably related to the

    production of alpha-galactosidase A from the grafted kidney
    BIOCHEMICAL

, but mainly related to the

    increase in Gb3 clearance by the functioning kidney
    BIOCHEMICAL

, and

    increased survival of red cells
    MICROSCOPIC

 due to the

    correction of the uremic status
    BIOCHEMICAL

 with an evident

    decrease in the production of Gb3 depending from hemolysis
    BIOCHEMICAL

. Several

    Fabry
    DIAGNOSIS

 patients with

    successful kidney graft
    MEDICATION

 survived for 10-15 years and

    died
    SYMPTOMS

 for

    cardiovascular complications related to the metabolic disease
    SYMPTOMS

. The

    loss of grafted kidney
    SYMPTOMS

 is due to

    rejection
    SYMPTOMS

,

    thrombosis
    SYMPTOMS

 or

    sepsis
    SYMPTOMS

. An important issue considering

    renal transplantation
    MEDICATION

 in

    AFd
    DIAGNOSIS

 is the

    recurrence of the disease in the kidney graft
    SYMPTOMS

; however, no evidence regarding this possibility has occurred up to now. We report herein the

    ultrastructural study of the urinary sediment
    PARACLINICAL

 of a

    35-year-old
    AGE

    male
    GENDER

    Fabry
    DIAGNOSIS

 patient with a

    severe clinical form of the disease
    SYMPTOMS

 with

    progression to ESRF
    SYMPTOMS

 at

    age 29
    AGE

, and submitted to

    renal transplantation
    MEDICATION

    at 33 years
    AGE

.

    Ultrastructural findings of the urinary sediment
    PARACLINICAL

 documented

    several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids
    MICROSCOPIC

. This morphological evidence arises the problem of the possible

    recurrence of AFd in the kidney graft
    DIAGNOSIS

 in patients with

    severe phenotype of the metabolic disease
    DIAGNOSIS

.

transplanted
successful kidney graft
renal transplantation
renal transplantation


Co-occurrence and contribution of Fabry disease and Klippel-Trénaunay-Weber syndrome to a patient with atypical skin lesions.

Fabry disease (FD) is an X-linked recessive inborn error of glycosphingolipid metabolism. Among clinical symptoms, maculopapular skin lesions, known as angiokeratoma, most often appear on the lower abdomen, scrotum, and thighs, with a tendency toward bilateral symmetry. A 30-year-old male patient was referred to us for evaluation of a complex vascular and cutaneous malformation. Skin examination showed numerous angiokeratoma, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk. The diagnosis of FD was confirmed by demonstration of a decreased alpha-galactosidase A activity, and the patient was shown to be hemizygote for a missense mutation (R342Q) in the alpha-galactosidase A gene (GLA). This mutation was also demonstrated in DNA extracted from fibroblast cultures established from both affected and unaffected skin areas, thus excluding the hypothesis of somatic mosaicism or revertant mosaicism. Interestingly, the diagnosis of Klippel-Trénaunay-Weber syndrome (KTWS) was also made, through clinical and radiological investigations. This is the first report on the association between FD and KTWS. Karyotype analysis was normal. It is likely that the mixed vascular malformations of KTWS affecting capillary and venous systems have contributed to the unusual angiokeratoma distribution pattern observed in the patient.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked recessive inborn error of glycosphingolipid metabolism
    GENETICS

. Among clinical symptoms,

    maculopapular skin lesions, known as angiokeratoma
    SYMPTOMS

, most often

    appear on the lower abdomen, scrotum, and thighs
    SYMPTOMS

, with a

    tendency toward bilateral symmetry
    SYMPTOMS

. A

    30-year-old
    AGE

    male
    GENDER

 patient was referred to us for evaluation of a

    complex vascular and cutaneous malformation
    SYMPTOMS

.

    Skin examination
    PARACLINICAL

 showed

    numerous angiokeratoma, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk
    SYMPTOMS

. The diagnosis of

    FD
    DIAGNOSIS

 was confirmed by demonstration of a

    decreased alpha-galactosidase A activity
    BIOCHEMICAL

, and the patient was shown to be

    hemizygote for a missense mutation (R342Q) in the alpha-galactosidase A gene (GLA)
    GENETICS

. This mutation was also demonstrated in

    DNA extracted from fibroblast cultures established from both affected and unaffected skin areas
    PARACLINICAL

, thus

    excluding the hypothesis of somatic mosaicism or revertant mosaicism
    NEG_FINDINGS

. Interestingly, the diagnosis of

    Klippel-Trénaunay-Weber syndrome (KTWS)
    DIAGNOSIS

 was also made, through

    clinical and radiological investigations
    PARACLINICAL

. This is the first report on the

    association between FD and KTWS
    DIAGNOSIS

.

    Karyotype analysis was normal
    NEG_FINDINGS

. It is likely that the

    mixed vascular malformations of KTWS affecting capillary and venous systems
    SYMPTOMS

 have contributed to the

    unusual angiokeratoma distribution pattern
    SYMPTOMS

 observed in the patient.

Fabry disease (FD)
FD
Klippel-Trénaunay-Weber syndrome (KTWS)
association between FD and KTWS


[Cardiac manifestations in Fabry disease].

Fabry's disease is an X-linked inborn error of metabolism. The patients lack or have very low activity of the enzyme alpha-galactosidase A. This results in deposition of sphingolipids in endothelial cells and vascular smooth muscle cells; thus the disease can affect nearly every organ in the body. Renal failure is the most common cause of death, but cardiac involvement is frequent.

We describe two brothers with Fabry's disease and provide a review of the literature in the field.

Both patients had extensive electro- and echocardiographic findings.

Fabry's disease should be suspected in men with unexplained electro- and/or echocardiographic signs of left ventricular hypertrophy and a short PQ interval in the ECG.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked inborn error of metabolism
    GENETICS

. The patients lack or have very low activity of the enzyme alpha-galactosidase A. This results in

    deposition of sphingolipids in endothelial cells and vascular smooth muscle cells
    MICROSCOPIC

; thus the disease can affect

    nearly every organ in the body
    SYMPTOMS

.

    Renal failure
    SYMPTOMS

 is the most common cause of

    death
    SYMPTOMS

, but

    cardiac involvement
    SYMPTOMS

 is frequent.

We describe two

    brothers
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 and provide a review of the literature in the field.

Both patients had

    extensive electro- and echocardiographic findings
    SYMPTOMS

.

    Fabry's disease
    DIAGNOSIS

 should be suspected in

    men
    GENDER

 with

    unexplained electro- and/or echocardiographic signs of left ventricular hypertrophy
    SYMPTOMS

 and a

    short PQ interval in the ECG
    SYMPTOMS

.

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


Echocardiographic ultrasonic tissue characterization in a case of Fabry's disease following renal transplantation.

We report a case of Fabry's disease where stabilization of progressive cardiac involvement was recorded in a 29-yr-old Caucasian man, to our knowledge, for the first time by ultrasonic tissue characterization echocardiography after 1 yr of successful renal transplantation. Three echocardiographic evaluations have been made: the first 3 months before, the second 6 months after, and the third 1 yr after kidney transplantation. The myocardial structural damage - evaluated by integrated backscatter index - shows a persistence of the impairment of intrinsic myocardial contractility at septum level, probably due to coexistent hypertensive status, which is able to induce per se alterations of myocardial textural parameters. On the other hand, the cyclic variation index at posterior free wall, which is less dependent on strictly hemodynamic factors than the septum, appears quite normal at the third observation. These data could reflect the improvement of the ultrastuctural myocardial findings in relation to renal transplantation, which could correct not only renal failure but also the enzymatic deficiency by replacement of alpha-galactosidase A through the transplanted kidney.

We report a case of

    Fabry's disease
    DIAGNOSIS

 where

    stabilization of progressive cardiac involvement
    SYMPTOMS

 was recorded in a

    29-yr-old
    AGE

    Caucasian
    ETHNICITY

    man
    GENDER

, to our knowledge, for the first time by

    ultrasonic tissue characterization echocardiography
    PARACLINICAL

 after

    1 yr of successful renal transplantation
    MEDICATION

. Three

    echocardiographic evaluations
    PARACLINICAL

 have been made: the first 3 months before, the second 6 months after, and the third 1 yr after

    kidney transplantation
    MEDICATION

. The

    myocardial structural damage
    SYMPTOMS

 - evaluated by

    integrated backscatter index
    SYMPTOMS

 - shows a

    persistence of the impairment of intrinsic myocardial contractility at septum level
    SYMPTOMS

, probably due to

    coexistent hypertensive status
    SYMPTOMS

, which is able to induce per se

    alterations of myocardial textural parameters
    SYMPTOMS

. On the other hand, the

    cyclic variation index at posterior free wall, which is less dependent on strictly hemodynamic factors than the septum, appears quite normal
    NEG_FINDINGS

 at the third observation. These data could reflect the improvement of the

    ultrastuctural myocardial findings
    SYMPTOMS

 in relation to

    renal transplantation
    MEDICATION

, which could correct not only

    renal failure
    SYMPTOMS

 but also the

    enzymatic deficiency
    BIOCHEMICAL

 by

    replacement of alpha-galactosidase A through the transplanted kidney
    MEDICATION

.


Primary HIV-1 infection: diagnosis and prognostic impact.

Acute infection with HIV is symptomatic in approximately two thirds to three-fourths of patients. This stage is defined as primary HIV infection or acute HIV illness. The diagnosis is crucial for public health because counseling can be provided to reduce the risk of transmission and for individual because early antiretroviral treatment could improve the prognosis, slowing the rate of disease progression. Physicians should be aware of the broad clinical spectrum representative of primary HIV infection, which ranges from mild symptoms resembling classic mononucleosis infection to highly severe presentations. Progression to AIDS and to death has been associated with the severity of the acute HIV infection. Clinical trials with combined antiretroviral drugs are needed to identify the best drug combinations as well as the optimal duration of treatment.

    Acute infection with HIV
    DIAGNOSIS

 is symptomatic in approximately two thirds to three-fourths of patients. This stage is defined as

    primary HIV infection
    DIAGNOSIS

 or

    acute HIV illness
    DIAGNOSIS

. The diagnosis is crucial for public health because

    counseling
    MEDICATION

 can be provided to reduce the risk of transmission and for individual because

    early antiretroviral treatment
    MEDICATION

 could improve the prognosis, slowing the rate of disease progression. Physicians should be aware of the broad clinical spectrum representative of

    primary HIV infection
    DIAGNOSIS

, which ranges from

    mild symptoms resembling classic mononucleosis infection
    SYMPTOMS

 to

    highly severe presentations
    SYMPTOMS

. Progression to

    AIDS
    SYMPTOMS

 and to

    death
    SYMPTOMS

 has been associated with the severity of the

    acute HIV infection
    DIAGNOSIS

. Clinical trials with

    combined antiretroviral drugs
    MEDICATION

 are needed to identify the best drug combinations as well as the optimal duration of treatment.

Acute infection with HIV
primary HIV infection
acute HIV illness
primary HIV infection
acute HIV infection

counseling
early antiretroviral treatment
combined antiretroviral drugs


A missense mutation, A156T, in the alpha-galactosidase A gene causes typical Fabry disease.

Fabry disease is a rare but important cause of end-stage renal disease. Recent molecular investigations on alpha-galactosidase A (alpha-Gal A) have proven the existence of atypical variants in Fabry disease, making genotype assessment of each phenotype indispensable. We report here a missense mutation, which causes a typical form of Fabry disease.

The proband, a 45-year-old man, presented with acroparesthesias, hypohidrosis, left ventricular hypertrophy, renal involvement (proteinuria and renal insufficiency) with typical microscopic findings and extremely reduced plasma alpha-Gal A activity, indicating the typical form of the disease. Total RNA was isolated from the proband's cultured fibroblasts, reverse-transcribed and amplified for direct sequencing of alpha-Gal A. Genomic DNA of the proband's mother and 75 controls (50 males and 25 females) living in the same area as the proband was also examined.

Sequencing of the cDNA revealed a substitution of G to A in codon 156 of alpha-Gal A, resulting in a single amino acid change from alanine to threonine (A156T). The mutation can be detected with PCR-RFLP with SfaNI digestion. This technique revealed that the mother was a heterozygote of A156T with no A156T noted in the 100 haplotypes of the controls. With a vigorous search of the same mutation in the literature, no previous description was found other than one case listed in several review papers as a classic phenotype without any other information. In our study, we examined A156T in a pedigree and demonstrated that the mutation was not a polymorphic variant in our area.

Taken together, the present results strongly suggest that the missense mutation, A156T, in the alpha-Gal A gene causes typical Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a rare but important cause of

    end-stage renal disease
    DIAGNOSIS

. Recent

    molecular investigations on alpha-galactosidase A (alpha-Gal A)
    PARACLINICAL

 have proven the existence of atypical variants in

    Fabry disease
    DIAGNOSIS

, making genotype assessment of each phenotype indispensable. We report here a

    missense mutation
    GENETICS

, which causes a typical form of

    Fabry disease
    DIAGNOSIS

.

The proband, a

    45-year-old
    AGE

    man
    GENDER

, presented with

    acroparesthesias
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    left ventricular hypertrophy
    SYMPTOMS

,

    renal involvement (proteinuria and renal insufficiency)
    SYMPTOMS

 with

    typical microscopic findings
    SYMPTOMS

 and

    extremely reduced plasma alpha-Gal A activity
    BIOCHEMICAL

, indicating the typical form of the disease.

    Total RNA was isolated from the proband's cultured fibroblasts
    PARACLINICAL

, reverse-transcribed and amplified for direct sequencing of alpha-Gal A.

    Genomic DNA of the proband's mother
    PARACLINICAL

 and 75 controls (50

    males
    GENDER

 and 25

    females
    GENDER

) living in the same area as the proband was also examined.

    Sequencing of the cDNA
    PARACLINICAL

 revealed a

    substitution of G to A in codon 156 of alpha-Gal A, resulting in a single amino acid change from alanine to threonine (A156T)
    GENETICS

. The mutation can be detected with

    PCR-RFLP with SfaNI digestion
    PARACLINICAL

. This technique revealed that the

    mother was a heterozygote of A156T
    FAMILY

 with

    no A156T noted in the 100 haplotypes
    NEG_FINDINGS

 of the controls. With a vigorous search of the same mutation in the literature, no previous description was found other than one case listed in several review papers as a classic phenotype without any other information. In our study, we examined

    A156T
    GENETICS

 in a pedigree and demonstrated that the mutation was not a polymorphic variant in our area.

Taken together, the present results strongly suggest that the

    missense mutation, A156T, in the alpha-Gal A gene
    GENETICS

 causes

    typical Fabry disease
    DIAGNOSIS

.

Fabry disease
end-stage renal disease
Fabry disease
Fabry disease
typical Fabry disease


Ventricular fibrillation refractory to automatic internal cardiac defibrillator in Fabry's disease. Review of cardiovascular manifestations.

Fabry's disease is a disorder of glycosphingolipid metabolism leading to alpha-galactosidase deficiency with systemic sequelae. Clinical cardiac manifestations include dysrhythmias, structural abnormalities apparent on echocardiography, and histologic changes secondary to glycosphingolipid deposition. The introduction of automated internal cardiac defibrillators (AICD) has been shown to decrease the incidence of circulatory collapse in individuals with known terminal arrhythmias. We present a patient with Fabry's disease, who underwent coronary angiography without finding of obstructive disease. He returned after aborted sudden cardiac death necessitating the placement of an AICD. He again presented after an episode of ventricular fibrillation refractory to internal defibrillation necessitating advanced life support, and subsequently expired. We review the electrocardiographic, cardiovascular structural, and histologic manifestations of Fabry's disease.

    Fabry's disease
    DIAGNOSIS

 is a

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 leading to

    alpha-galactosidase deficiency
    BIOCHEMICAL

 with

    systemic sequelae
    SYMPTOMS

. Clinical

    cardiac manifestations
    SYMPTOMS

 include

    dysrhythmias
    SYMPTOMS

,

    structural abnormalities apparent
    SYMPTOMS

 on

    echocardiography
    SYMPTOMS

, and

    histologic changes secondary to glycosphingolipid deposition
    SYMPTOMS

. The introduction of

    automated internal cardiac defibrillators (AICD)
    MEDICATION

 has been shown to decrease the incidence of

    circulatory collapse
    SYMPTOMS

 in individuals with known

    terminal arrhythmias
    SYMPTOMS

. We present a patient with

    Fabry's disease
    DIAGNOSIS

, who underwent

    coronary angiography
    NEG_FINDINGS

    without finding of obstructive disease
    NEG_FINDINGS

.

    He
    GENDER

 returned after

    aborted sudden cardiac death
    SYMPTOMS

 necessitating the

    placement of an AICD
    MEDICATION

.

    He
    GENDER

 again presented after an

    episode of ventricular fibrillation
    SYMPTOMS

    refractory to internal defibrillation
    NEG_FINDINGS

 necessitating

    advanced life support
    MEDICATION

, and subsequently

    expired
    SYMPTOMS

. We review the electrocardiographic, cardiovascular structural, and histologic manifestations of

    Fabry's disease
    DIAGNOSIS

.

coronary angiography
without finding of obstructive disease
refractory to internal defibrillation


Co-existence of lysosomal storage diseases in a consanguineous family.

Lysosomal storage diseases are rare and coexistence of more than one in a family can present a diagnostic challenge as illustrated by this study. The index case born to consanguineous Asian parents presented with developmental delay. Investigations led to an incidental finding of Fabry disease. After numerous additional investigations over a year, a second diagnosis of aspartylglucosaminuria (AGU) was made. A family history of renal disease and developmental delay was disclosed. The sister and first cousin of the index case were diagnosed as homozygous for AGU, but do not have Fabry disease. The younger brother has since been diagnosed with both Fabry disease and AGU. Another cousin has learning difficulties and fits, but is heterozygous for AGU, and possibly has another uncharacterised autosomal recessive disorder. In a family with consanguinity when the clinical picture in an individual is not fully explained by the presence of one rare metabolic disease, it is essential to investigate further for the presence of others.

    Lysosomal storage diseases
    DIAGNOSIS

 are rare and

    coexistence of more than one in a family
    FAMILY

 can present a diagnostic challenge as illustrated by this study. The index case born to

    consanguineous Asian parents
    FAMILY

 presented with

    developmental delay
    SYMPTOMS

. Investigations led to an incidental finding of

    Fabry disease
    DIAGNOSIS

. After numerous additional investigations over a year, a second diagnosis of

    aspartylglucosaminuria (AGU)
    DIAGNOSIS

 was made. A

    family history of renal disease and developmental delay
    FAMILY

 was disclosed.

    The sister and first cousin of the index case were diagnosed as homozygous for AGU, but do not have Fabry disease
    FAMILY

. The

    younger brother has since been diagnosed with both Fabry disease and AGU
    FAMILY

.

    Another cousin has learning difficulties and fits
    FAMILY

    , but is heterozygous for AGU, and possibly has another uncharacterised autosomal recessive disorder
    FAMILY

. In a

    family with consanguinity
    FAMILY

 when the clinical picture in an individual is not fully explained by the presence of one

    rare metabolic disease
    DIAGNOSIS

, it is essential to investigate further for the presence of others.

Lysosomal storage diseases
Fabry disease
aspartylglucosaminuria (AGU)
rare metabolic disease


A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Ménière's syndrome and without mental retardation.

alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described. We report a further case in a 47-year-old Japanese woman, the product of a consanguineous marriage. The remarkable findings in this patient were her normal intelligence, Ménière's syndrome, disturbance of peripheral sensory nerves, hearing loss and cardiac hypertrophy. alpha-NAGA enzyme activity in her plasma was 0.77% of the normal value. Other enzyme activities, such as alpha-galactosidase, beta-galactosidase, alpha-L-fucosidase, beta-mannosidase and aspartylglucosaminidase, were within normal limits. A large quantity of amino acid O-glycans was detected in her urine. Gene analysis revealed a novel point mutation (G-->A transition) at nucleotide 11018 (986 in the cDNA) resulting in an Arg-329-Gln substitution. Kanzaki disease has the same enzyme defect as Schindler disease, but the manifestations are quite different.

    alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency
    BIOCHEMICAL

 is a rare

    hereditary
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

, and only three

    alpha-NAGA-deficient
    BIOCHEMICAL

 patients with

    angiokeratoma corporis diffusum
    SYMPTOMS

 (

    Kanzaki)
    DIAGNOSIS

 have been described. We report a further case in a

    47-year-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

,

    the product of a consanguineous marriage
    FAMILY

. The remarkable findings in this patient were

    her
    GENDER

    normal intelligence
    NEG_FINDINGS

,

    Ménière's syndrome
    SYMPTOMS

,

    disturbance of peripheral sensory nerves
    SYMPTOMS

,

    hearing loss
    SYMPTOMS

 and

    cardiac hypertrophy
    SYMPTOMS

.

    alpha-NAGA enzyme activity in her plasma was 0.77% of the normal value
    BIOCHEMICAL

.

    Other enzyme activities, such as alpha-galactosidase, beta-galactosidase, alpha-L-fucosidase, beta-mannosidase and aspartylglucosaminidase, were within normal limits
    NEG_FINDINGS

. A

    large quantity of amino acid O-glycans was detected in her urine
    MICROSCOPIC

.

    Gene analysis
    PARACLINICAL

 revealed a

    novel point mutation (G-->A transition) at nucleotide 11018 (986 in the cDNA) resulting in an Arg-329-Gln substitution
    GENETICS

.

    Kanzaki disease
    DIAGNOSIS

 has the same enzyme defect as

    Schindler disease
    DIAGNOSIS

, but the manifestations are quite different.

lysosomal storage disease
Kanzaki)
Kanzaki disease
Schindler disease


Histopathologic findings of cornea verticillata in a woman heterozygous for Fabry's disease.

To report the histopathologic findings of the cornea verticillata observed in a woman who was heterozygous for Fabry's disease.

A 67-year-old woman was found to have a whorl-like corneal opacity on her visit to the Department of Ophthalmology. Aichi Saiseikai Hospital. Her visit was because of a sudden loss of vision in her right eye owing to a central retinal artery occlusion in association with an ophthalmic artery occlusion. The patient died suddenly of an acute heart failure; with family consent, an autopsy was performed and the right eye was removed for histopathologic examination by light and electron microscopy.

Low levels of alpha-galactosidase in the leukocytes together with the corneal finding led to the diagnosis of heterozygous Fabry's disease. Light microscopy revealed a 0.3- to 0.5-microm thick layer between the epithelial and Bowman's layers. Oil red O positive deposits were accumulated in the subepithelial layer, and the density varied in different regions. Electron microscopy showed that subepithelial layer differed in thickness, and the basal lamina reduplicated regionally. We were not able to determine the structure that correlated with the "ridge" in the central part of the cornea.

The oil red O positive deposits and their variation in density in the subepithelial area of the cornea may have caused the characteristic whorl-like corneal opacity in this woman who was heterozygous for Fabry's disease.

To report the

    histopathologic findings of the cornea verticillata
    SYMPTOMS

 observed in a

    woman
    GENDER

 who was

    heterozygous for Fabry's disease
    GENETICS

.

A

    67-year-old
    AGE

    woman
    GENDER

 was found to have a

    whorl-like corneal opacity
    SYMPTOMS

 on her visit to the Department of Ophthalmology. Aichi Saiseikai Hospital.

    Her
    GENDER

 visit was because of a

    sudden loss of vision in her right eye
    SYMPTOMS

 owing to a

    central retinal artery occlusion in association with an ophthalmic artery occlusion
    SYMPTOMS

. The patient

    died
    SYMPTOMS

 suddenly of an

    acute heart failure
    SYMPTOMS

; with

    family consent
    PARACLINICAL

, an

    autopsy
    PARACLINICAL

 was performed and

    the right eye was removed
    PARACLINICAL

 for

    histopathologic examination by light and electron microscopy
    PARACLINICAL

.

    Low levels of alpha-galactosidase in the leukocytes
    BIOCHEMICAL

 together with the corneal finding led to the diagnosis of

    heterozygous Fabry's disease
    DIAGNOSIS

.

    Light microscopy
    PARACLINICAL

 revealed

    a 0.3- to 0.5-microm thick layer between the epithelial and Bowman's layers
    MICROSCOPIC

.

    Oil red O positive deposits were accumulated in the subepithelial layer
    MICROSCOPIC

, and the density varied in different regions.

    Electron microscopy
    PARACLINICAL

 showed that

    subepithelial layer differed in thickness
    MICROSCOPIC

, and

    the basal lamina reduplicated regionally
    MICROSCOPIC

.

    We were not able to determine
    NEG_FINDINGS

 the structure that correlated

    with the "ridge" in the central part of the cornea
    SYMPTOMS

.

The

    oil red O positive deposits and their variation in density in the subepithelial area of the cornea
    MICROSCOPIC

 may have caused the

    characteristic whorl-like corneal opacity
    SYMPTOMS

 in this

    woman
    GENDER

 who was

    heterozygous for Fabry's disease
    GENETICS

.

heterozygous for Fabry's disease
heterozygous for Fabry's disease


Coexistence of Fabry's disease and necrotizing and crescentic glomerulonephritis.

The coexistence of Fabry's disease, an X-linked hereditary disease, and other renal diseases, has rarely been described in the same patient. Combined Fabry's disease and pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) is hitherto unreported. We present the clinical and pathologic data of two patients with combined Fabry's disease and NCGN. Both patients presented with fevers of unknown origin and progressive renal insufficiency, however, lacked any other pathognomic signs of Fabry's disease such as acroparesthesias, dyshidrosis, and cutaneous angiokeratomas. The possible pathogenic mechanisms and causal relationship between the two disease processes are discussed.

The

    coexistence of Fabry's disease
    DIAGNOSIS

, an

    X-linked hereditary disease
    GENETICS

, and other

    renal diseases
    DIAGNOSIS

, has rarely been described in the same patient.

    Combined Fabry's disease and pauci-immune necrotizing and crescentic glomerulonephritis (NCGN)
    DIAGNOSIS

 is hitherto unreported. We present the clinical and pathologic data of two patients with

    combined Fabry's disease and NCGN
    DIAGNOSIS

. Both patients presented with

    fevers of unknown origin
    SYMPTOMS

 and

    progressive renal insufficiency
    SYMPTOMS

, however,

    lacked any other pathognomic signs of Fabry's disease
    NEG_FINDINGS

 such as

    acroparesthesias
    SYMPTOMS

,

    dyshidrosis
    NEG_FINDINGS

, and

    cutaneous angiokeratomas
    SYMPTOMS

. The possible pathogenic mechanisms and causal relationship between the two disease processes are discussed.

fevers of unknown origin
progressive renal insufficiency
acroparesthesias
cutaneous angiokeratomas


[Atypical phenotype of Fabry disease. Evidence of a new mutation].

Fabry disease is a lysosomal disease resulting from deficient alpha galactosidase A activity. The enzyme's gene is situated on Xq22-1. Cardiac and cerebrovascular complications are usually observed late in the disease course.

A 54-year-old patient was admitted for ischemic stroke subsequent to thrombosis of the right sylvian artery. The only significant event in the patient's history was hypertrophic cardiomyopathy that had progressed for 9 years. Search for an etiology identified alpha galacosidase A deficiency. Gene sequencing identified a new mutation.

Two clinical forms of Fabry disease are described. The classical form has an early onset and is associated with systemic manifestations. The less common atypical form is associated with late-onset cardiomyopathy with no other systemic manifestations. Several mutations of the alpha galactosidase A gene have been recognized but to date no correlation has been established between the genotype and the phenotype. Our patient had an "intermediary" form of the disease associating a late onset, predominant cardiac manifestations, and limited systemic manifestations. The mutation observed in this case has not been described previously. Its relationship with the observed clinical phenotype remains to be demonstrated.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal disease
    DIAGNOSIS

 resulting from

    deficient alpha galactosidase A activity
    BIOCHEMICAL

. The

    enzyme's gene is situated on Xq22-1
    GENETICS

.

    Cardiac and cerebrovascular complications
    SYMPTOMS

 are usually observed late in the disease course.

A

    54-year-old
    AGE

 patient was admitted for

    ischemic stroke
    SYMPTOMS

 subsequent to

    thrombosis of the right sylvian artery
    SYMPTOMS

. The only significant event in the patient's history was

    hypertrophic cardiomyopathy that had progressed for 9 years
    SYMPTOMS

. Search for an etiology identified

    alpha galacosidase A deficiency
    BIOCHEMICAL

.

    Gene sequencing
    PARACLINICAL

 identified a

    new mutation
    GENETICS

.

Two clinical forms of

    Fabry disease
    DIAGNOSIS

 are described. The classical form has an

    early onset
    SYMPTOMS

 and is associated with

    systemic manifestations
    SYMPTOMS

. The less common atypical form is associated with

    late-onset cardiomyopathy
    SYMPTOMS

 with

    no other systemic manifestations
    NEG_FINDINGS

. Several

    mutations of the alpha galactosidase A gene
    GENETICS

 have been recognized but to date no correlation has been established between the genotype and the phenotype. Our patient had an "

    intermediary" form of the disease
    DIAGNOSIS

 associating a

    late onset
    SYMPTOMS

,

    predominant cardiac manifestations
    SYMPTOMS

, and

    limited systemic manifestations
    SYMPTOMS

. The mutation observed in this case has not been described previously. Its relationship with the observed clinical phenotype remains to be demonstrated.

Fabry disease
lysosomal disease
Fabry disease
intermediary" form of the disease


[Fabry disease: data from four families].

In 1988 three families were described in this journal with Fabry's disease, an X-linked recessive lysosomal storage disorder caused by the deficiency of alpha-galactosidase A. A fourth family contained four affected men of whom one was unavailable for evaluation. The other three had the same mutation in de alpha-galactosidase gene, notably Gln386Stop, leading to the change of a glutamine codon into a stop codon. Genetic investigation in one of the other families revealed the Met72Arg mutation. The classical symptoms of the disease (angiokeratomata, acroparaesthesias, hypohidrosis and lucid areas in the cornea) are frequently only recognized after a doctor's delay that may be as long as decades. The recognition of this disease is even more important now, as therapeutic possibilities are in sight.

In 1988 three families were described in this journal with

    Fabry's disease
    DIAGNOSIS

, an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by the deficiency of alpha-galactosidase A. A fourth family contained four affected

    men
    GENDER

 of whom one was unavailable for evaluation. The other three had the same

    mutation in de alpha-galactosidase gene, notably Gln386Stop, leading to the change of a glutamine codon into a stop codon
    GENETICS

.

    Genetic investigation
    PARACLINICAL

 in one of the other families revealed the

    Met72Arg mutation
    GENETICS

. The classical symptoms of the disease (

    angiokeratomata
    SYMPTOMS

,

    acroparaesthesias
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

 and

    lucid areas in the cornea
    SYMPTOMS

) are frequently only recognized after a doctor's delay that may be as long as decades. The recognition of this disease is even more important now, as therapeutic possibilities are in sight.

Fabry's disease
lysosomal storage disorder

angiokeratomata
acroparaesthesias
hypohidrosis
lucid areas in the cornea


Clinical features of and recent advances in therapy for Fabry disease.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of alpha-galactosidase A. Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme, leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction and early death. Men are predominantly affected but many female carriers have similar clinical involvement, including increased risk of stroke. Physical stigmata, such as angiokeratomas in skin and mucous membranes and characteristic benign corneal abnormalities, facilitate identification of Fabry disease. The finding of a marked decreased activity of alpha-galactosidase A in white blood cells or cultured skin fibroblasts confirms the diagnosis. Treatment thus far has been symptomatic only. Etiology-based therapies are being developed that include enzyme replacement therapy, gene therapy, and substrate deprivation. Our recently completed double-blind, placebo-controlled trial of intravenous infusions of alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. JAMA. 2000;284:2771-2775.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a deficiency of alpha-galactosidase A.

    Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme
    MICROSCOPIC

, leads to

    severe painful neuropathy
    SYMPTOMS

 with

    progressive renal, cardiovascular, and cerebrovascular dysfunction
    SYMPTOMS

 and

    early death
    SYMPTOMS

.

    Men
    GENDER

 are predominantly affected but many

    female
    GENDER

 carriers have similar clinical involvement, including increased risk of

    stroke
    SYMPTOMS

.

    Physical stigmata
    SYMPTOMS

, such as

    angiokeratomas in skin and mucous membranes
    SYMPTOMS

 and

    characteristic benign corneal abnormalities
    SYMPTOMS

, facilitate identification of

    Fabry disease
    DIAGNOSIS

. The finding of a

    marked decreased activity of alpha-galactosidase A in white blood cells or cultured skin fibroblasts
    BIOCHEMICAL

 confirms the diagnosis. Treatment thus far has been

    symptomatic only
    NEG_FINDINGS

.

    Etiology-based therapies
    MEDICATION

 are being developed that include

    enzyme replacement therapy
    MEDICATION

,

    gene therapy
    MEDICATION

, and

    substrate deprivation
    MEDICATION

. Our recently completed double-blind, placebo-controlled trial of

    intravenous infusions of alpha-galactosidase A
    MEDICATION

 in patients with

    Fabry disease
    DIAGNOSIS

 demonstrated the safety and efficacy of this treatment. JAMA. 2000;284:2771-2775.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease


Identification of four novel mutations in five unrelated Korean families with Fabry disease.

Fabry disease is a X-linked recessively inherited metabolic disorder, which results from the deficient activity of the lysosomal hydrolase alpha-galactosidase A leading to the systemic deposition of glycosphingolipids with terminal alpha-galactosyl moieties. Single-strand conformation polymorphism (SSCP) analysis was performed, followed by DNA sequencing of PCR amplified exons of the human alpha-galactosidase A gene in 5 unrelated Korean patients with classic Fabry disease. Five different mutations were identified; two nonsense mutations (Y86X and R342X), one missense mutation (D266N), and two small deletions (296del2 and 802del4). Except for R342X mutation, four were novel mutations (Y86X, D266N, 296del2, 802del4). A T to G transversion at nucleotide position 5157 in exon 2 caused a tyrosine-to-stop substitution at codon 86. A G to A transition at position 10287 in exon 5 substituted an asparagine for an aspartate at codon 266. Mutation 296del2 in exon 2 resulted in a frame shift with a stop signal at the 22th codon downstream from the mutation, whereas mutation 802del4 resulted in a stop codon at the site of 4 bp deletion. In addition, the 802del4 was found to be a de novo mutation. This is the first report on mutation analysis of the human alpha-galactosidase A gene in Korean patients with Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a

    X-linked recessively inherited
    GENETICS

    metabolic disorder
    DIAGNOSIS

, which results from the

    deficient activity of the lysosomal hydrolase alpha-galactosidase A
    BIOCHEMICAL

 leading to the

    systemic deposition of glycosphingolipids with terminal alpha-galactosyl moieties
    MICROSCOPIC

.

    Single-strand conformation polymorphism (SSCP) analysis
    PARACLINICAL

 was performed, followed by

    DNA sequencing of PCR amplified exons of the human alpha-galactosidase A gene
    PARACLINICAL

 in 5 unrelated

    Korean
    ETHNICITY

 patients with

    classic Fabry disease
    DIAGNOSIS

. Five different mutations were identified; two

    nonsense mutations (Y86X and R342X)
    GENETICS

, one

    missense mutation (D266N)
    GENETICS

, and

    two small deletions (296del2 and 802del4)
    GENETICS

. Except for

    R342X mutation
    GENETICS

, four were

    novel mutations (Y86X, D266N, 296del2, 802del4)
    GENETICS

.

    A T to G transversion at nucleotide position 5157 in exon 2 caused a tyrosine-to-stop substitution at codon 86. A G to A transition at position 10287 in exon 5 substituted an asparagine for an aspartate at codon 266
    GENETICS

.

    Mutation 296del2 in exon 2 resulted in a frame shift with a stop signal at the 22th codon downstream from the mutation
    GENETICS

, whereas

    mutation 802del4 resulted in a stop codon at the site of 4 bp deletion
    GENETICS

. In addition, the

    802del4 was found to be a de novo mutation
    GENETICS

. This is the first report on

    mutation analysis of the human alpha-galactosidase A gene
    PARACLINICAL

 in

    Korean
    ETHNICITY

 patients with

    Fabry disease
    DIAGNOSIS

.

Fabry disease
metabolic disorder
classic Fabry disease
Fabry disease


Angiokeratoma corporis diffusum (Anderson-Fabry's disease): a case report.

We report on a 14-year-old boy who presented with a 4-year history of acral pains and febrile episodes. On physical examination, numerous small reddish papules were present on his abdomen, located predominantly on the periumbelical region. Renal function was within normal limits. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. Histopathological examination of one of the cutaneous papules showed several dilated blood vessels in the superficial dermis surrounded by collarettes of thickened rete ridges, consistent with a diagnosis of angiokeratoma. The electron-microscopic study of a skin specimen demonstrated the presence of dilated lysosomes with deposition of electron-dense bodies, some of which with laminated structure, in endothelial cells and fibroblasts. These findings were regarded as indicative of Fabry's disease. Subsequent biochemical analysis confirmed the presence of a alpha-galactosidase A deficiency in leukocytes. In conclusion, we described the clinical, histopathological and submicroscopic findings of a case of Fabry's disease, in which the combination of electron microscopic and biochemical approaches allowed the correct diagnosis.

We report on a

    14-year-old
    AGE

    boy
    GENDER

 who presented with a

    4-year history
    SYMPTOMS

 of

    acral pains
    SYMPTOMS

 and

    febrile episodes
    SYMPTOMS

. On physical examination,

    numerous small reddish papules were present on his abdomen, located predominantly on the periumbelical region
    SYMPTOMS

.

    Renal function was within normal limits
    NEG_FINDINGS

.

    Ophthalmological examination
    PARACLINICAL

 revealed

    whorled opacities of the cornea (cornea verticillata)
    SYMPTOMS

 and

    dilated tortuous conjunctival vessels
    SYMPTOMS

.

    Histopathological examination
    PARACLINICAL

 of one of the

    cutaneous papules
    SYMPTOMS

 showed

    several dilated blood vessels in the superficial dermis
    MICROSCOPIC

    surrounded by collarettes of thickened rete ridges
    SYMPTOMS

, consistent with a diagnosis of

    angiokeratoma
    DIAGNOSIS

. The

    electron-microscopic study of a skin specimen
    PARACLINICAL

 demonstrated the

    presence of dilated lysosomes with deposition of electron-dense bodies, some of which with laminated structure, in endothelial cells and fibroblasts
    MICROSCOPIC

. These findings were regarded as indicative of

    Fabry's disease
    DIAGNOSIS

. Subsequent

    biochemical analysis
    PARACLINICAL

 confirmed the

    presence of a alpha-galactosidase A deficiency in leukocytes
    BIOCHEMICAL

. In conclusion, we described the clinical, histopathological and submicroscopic findings of a case of

    Fabry's disease
    DIAGNOSIS

, in which the combination of

    electron microscopic and biochemical approaches
    PARACLINICAL

 allowed the correct diagnosis.

angiokeratoma
Fabry's disease
Fabry's disease


Atypical Fabry's disease presenting with cholesterol crystal embolization.

We describe a 65-year-old man who presented with pulmonary hemorrhage and progressive renal insufficiency three months after resection surgery for an abdominal aortic aneurysm. Intensive treatment with corticosteroids and hemodialysis were not effective, and the patient died. Postmortem examination of the kidneys revealed widespread cholesterol clefts within the renal arterioles and a number of lamellar inclusion bodies were observed by electron microscopy. The diagnosis of Fabry's disease was made by the absence of plasma alpha-galactosidase A activity. This was a very rare case of subclinical Fabry's disease coexistent with cholesterol crystal embolization, mimicking pulmonary-renal syndrome.

We describe a

    65-year-old
    AGE

    man
    GENDER

 who presented with

    pulmonary hemorrhage
    SYMPTOMS

 and

    progressive renal insufficiency
    SYMPTOMS

 three months after

    resection surgery for an abdominal aortic aneurysm
    MEDICATION

.

    Intensive treatment with corticosteroids and hemodialysis were not effective
    NEG_FINDINGS

, and the patient

    died
    SYMPTOMS

.

    Postmortem examination of the kidneys
    PARACLINICAL

 revealed

    widespread cholesterol clefts within the renal arterioles
    MICROSCOPIC

 and a

    number of lamellar inclusion bodies were observed
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 was made by the

    absence of plasma alpha-galactosidase A activity
    NEG_FINDINGS

. This was a very rare case of

    subclinical Fabry's disease
    DIAGNOSIS

 coexistent with

    cholesterol crystal embolization
    SYMPTOMS

, mimicking

    pulmonary-renal syndrome
    DIAGNOSIS

.

pulmonary hemorrhage
progressive renal insufficiency
died
cholesterol crystal embolization

Fabry's disease
subclinical Fabry's disease
pulmonary-renal syndrome


Induced sputum examination: diagnosis of pulmonary involvement in Fabry's disease.

Fabry's disease is a rare inherited metabolic disorder caused by a deficiency in the enzyme alpha-galactosidase A. It can affect almost every organ, including the lungs. Confirmation of lung involvement has depended on invasive bronchial biopsy specimens or brushings to confirm the presence of typical lamellar inclusion bodies within bronchial epithelial cells. We report a patient with known Fabry's disease in whom these inclusion bodies were identified by examination of induced sputum.

    Fabry's disease
    DIAGNOSIS

 is a

    rare inherited metabolic disorder
    GENETICS

 caused by a deficiency in the enzyme alpha-galactosidase A. It can affect almost every organ, including the lungs. Confirmation of

    lung involvement
    SYMPTOMS

 has depended on

    invasive bronchial biopsy specimens or brushings
    PARACLINICAL

 to confirm the presence of

    typical lamellar inclusion bodies within bronchial epithelial cells
    MICROSCOPIC

. We report a patient with known

    Fabry's disease
    DIAGNOSIS

 in whom

    these inclusion bodies
    MICROSCOPIC

 were identified by

    examination of induced sputum
    PARACLINICAL

.


A case of symptomatic heterozygous female Fabry's disease without detectable mutation in the alpha-galactosidase gene.

We report a case of symptomatic heterozygous female Fabry's disease with low alpha-galactosidase blood activity. We could not find any mutations in the coding regions of either the signal peptide or the enzyme subunit in our case.

We report a case of

    symptomatic heterozygous
    DIAGNOSIS

    female
    GENDER

    Fabry's disease
    DIAGNOSIS

 with

    low alpha-galactosidase blood activity
    BIOCHEMICAL

. We

    could not find any mutations in the coding regions of either the signal peptide or the enzyme subunit
    NEG_FINDINGS

 in our case.

symptomatic heterozygous
Fabry's disease