Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study.

To describe the microscopic corneal and conjunctival findings in patients with Fabry disease (FD) related keratopathy by using in vivo confocal microscopy.

Prospective observational case series.

Twelve eyes of six patients affected by Fabry disease, belonging to two different families, underwent in vivo confocal microscopic examination. Corneal and conjunctival morphology were assessed by means of a scanning slit corneal confocal white-light microscopy and confocal laser-scanning microscope.

Confocal microscopy examination evidenced two different types of corneal epithelial changes. The three hemizygous patients presented bright hyper-reflective intracellular inclusions located within the basal epithelial cells, while the three heterozygous patients showed fine diffusion of reflective substance at the level of superficial, basal epithelial cells and basal membrane, in all eyes. The complex basal-Bowman's membrane appeared irregular, distorted, and nonhomogeneous in all subjects. Stromal increased reflectivity attributable to haze and epithelial ingrowth with bright intracellular inclusions was noticed in one hemizygous patient. In all patients, conjunctival epithelial involvement represented by bright roundish intracellular inclusions was evidenced, appearing more pronounced in tarsal than in bulbar conjunctiva.

Although FD-related cornea verticillata attributable to glycosphingolipids accumulation is considered to be primarily a corneal disease, in vivo confocal microscopy demonstrated structural alterations throughout the entire ocular surface epithelia. It is still unclear whether the different type of corneal epithelial lesions observed for hemizygous and heterozygous patients is related to different physiopathological mechanisms. Confocal microscopy may assist ophthalmologists in the diagnosis of FD-related ocular surface and corneal manifestations.

To describe the

    microscopic corneal and conjunctival findings
    SYMPTOMS

 in patients with

    Fabry disease (FD) related keratopathy
    DIAGNOSIS

 by using

    in vivo confocal microscopy
    PARACLINICAL

.

    Prospective observational case series
    PARACLINICAL

.

Twelve eyes of six patients affected by

    Fabry disease
    DIAGNOSIS

, belonging to two different families, underwent

    in vivo confocal microscopic examination
    PARACLINICAL

.

    Corneal and conjunctival morphology were assessed
    PARACLINICAL

 by means of a

    scanning slit corneal confocal white-light microscopy
    PARACLINICAL

 and

    confocal laser-scanning microscope
    PARACLINICAL

.

    Confocal microscopy examination
    PARACLINICAL

 evidenced two different types of

    corneal epithelial changes
    SYMPTOMS

. The three

    hemizygous
    GENETICS

 patients presented

    bright hyper-reflective intracellular inclusions located within the basal epithelial cells
    MICROSCOPIC

, while the three

    heterozygous
    GENETICS

 patients showed

    fine diffusion of reflective substance at the level of superficial, basal epithelial cells and basal membrane
    MICROSCOPIC

, in all eyes. The

    complex basal-Bowman's membrane appeared irregular, distorted, and nonhomogeneous
    MICROSCOPIC

 in all subjects.

    Stromal increased reflectivity attributable to haze
    SYMPTOMS

 and

    epithelial ingrowth
    SYMPTOMS

 with

    bright intracellular inclusions
    MICROSCOPIC

 was noticed in one

    hemizygous
    GENETICS

 patient. In all patients,

    conjunctival epithelial involvement
    SYMPTOMS

 represented by

    bright roundish intracellular inclusions
    MICROSCOPIC

 was evidenced,

    appearing more pronounced in tarsal than in bulbar conjunctiva
    SYMPTOMS

.

Although

    FD-related cornea verticillata
    DIAGNOSIS

 attributable to

    glycosphingolipids accumulation
    MICROSCOPIC

 is considered to be primarily a corneal disease,

    in vivo confocal microscopy
    PARACLINICAL

 demonstrated

    structural alterations throughout the entire ocular surface epithelia
    SYMPTOMS

. It is still unclear whether the different type of

    corneal epithelial lesions
    SYMPTOMS

 observed for

    hemizygous
    GENETICS

 and

    heterozygous patients
    GENETICS

 is related to different physiopathological mechanisms.

    Confocal microscopy
    PARACLINICAL

 may assist

    ophthalmologists
    PARACLINICAL

 in the diagnosis of

    FD-
    DIAGNOSIS

related

    ocular surface and corneal manifestations
    SYMPTOMS

.

Fabry disease (FD) related keratopathy
Fabry disease
FD-related cornea verticillata
FD-

hemizygous
heterozygous
hemizygous
hemizygous
heterozygous patients


[Otology manifestations of the Anderson-Fabry disease].

Anderson-Fabry disease in an inherited X-linked metabolic disorder involving glycosphingolipid metabolism. Few data are available regarding cochlear involvement. Clinical manifestations of Fabry disease appeared on the first decade of life. The prognosis of males with Fabry disease is serious and life expectancy is limited; clinical evolution of heterozygous females is clearly better. We report a family with Fabry disease in several members. The mother, already dead, had two child which have been examined in our department; the male, without a risk of ototoxicity, or acoustic trauma, has progressive hearing loss, tinnitus and dizinness sometimes; the daughter, without a history of deafness, shows unilateral hearing loss on high-tone frequencies. It is important to emphasize these data to those physicians expert in children with Fabry disease because early enzyme replacement therapy intervention should offer increased possibilities of regression of the disease.

    Anderson-Fabry disease
    DIAGNOSIS

 in an

    inherited X-linked
    GENETICS

    metabolic disorder
    DIAGNOSIS

 involving

    glycosphingolipid metabolism
    DIAGNOSIS

. Few data are available regarding

    cochlear involvement
    SYMPTOMS

. Clinical manifestations of

    Fabry disease
    DIAGNOSIS

 appeared on the

    first decade of life
    AGE

. The prognosis of

    males
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 is serious and life expectancy is limited; clinical evolution of

    heterozygous
    GENETICS

    females
    GENDER

 is clearly better. We report a

    family with Fabry disease in several members
    FAMILY

. The

    mother, already dead, had two child which have been examined
    FAMILY

 in our department; the

    male
    GENDER

,

    without a risk of ototoxicity, or acoustic trauma
    NEG_FINDINGS

, has

    progressive hearing loss
    SYMPTOMS

,

    tinnitus
    SYMPTOMS

 and

    dizinness
    SYMPTOMS

 sometimes; the

    daughter, without a history of deafness
    FAMILY

, shows

    unilateral hearing loss on high-tone frequencies
    SYMPTOMS

. It is important to emphasize these data to those physicians expert in

    children
    AGE

 with

    Fabry disease
    DIAGNOSIS

 because

    early enzyme replacement therapy intervention
    MEDICATION

 should offer increased possibilities of regression of the disease.

Anderson-Fabry disease
metabolic disorder
glycosphingolipid metabolism
Fabry disease
Fabry disease
Fabry disease


Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.

Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life.

To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy.

A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed.

Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation.

The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.

    Classic Fabry disease
    DIAGNOSIS

, an

    X-linked recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 due to the

    deficient activity of alpha-galactosidase A
    BIOCHEMICAL

, typically presents in

    early childhood
    AGE

 with

    acroparesthesias
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

, and

    corneal dystrophy
    SYMPTOMS

. The

    neuropathic pain
    SYMPTOMS

 presumably results from

    glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers
    MICROSCOPIC

, and is treatable by

    enzyme replacement therapy
    MEDICATION

. Later-onset variants with

    residual alpha-galactosidase A activity
    BIOCHEMICAL

    lack vascular endothelial involvement and classic symptoms
    NEG_FINDINGS

, which lead to the development of

    cardiac and/or renal disease
    SYMPTOMS

    after the fourth decade of life
    AGE

.

To expand the later-onset

    Fabry
    DIAGNOSIS

 phenotype to include

    cramp-fasciculation syndrome
    SYMPTOMS

    without small-fiber neuropathy
    NEG_FINDINGS

.

A

    34-year-old
    AGE

    man
    GENDER

 who presented with

    chronic exercise-induced pain
    SYMPTOMS

,

    fasciculations
    SYMPTOMS

, and

    cramps of the feet and legs
    SYMPTOMS

, and

    his
    GENDER

    similarly affected mother
    FAMILY

, were evaluated.

    Clinical, biochemical, and molecular studies
    PARACLINICAL

 were performed.

    Clinical evaluation
    PARACLINICAL

 suggested the diagnosis of

    Fabry disease
    DIAGNOSIS

, which was confirmed by

    reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively)
    BIOCHEMICAL

 due to a

    missense A143T mutation
    GENETICS

.

    His
    GENDER

    mother was heterozygous for the A143T mutation
    FAMILY

.

The presentation of

    cramps
    SYMPTOMS

 and

    fasciculations
    SYMPTOMS

    without apparent small-fiber neuropathy
    NEG_FINDINGS

 expands the phenotype of

    later-onset Fabry disease
    DIAGNOSIS

.

Classic Fabry disease
lysosomal storage disease
Fabry
Fabry disease
later-onset Fabry disease

X-linked recessive
missense A143T mutation

acroparesthesias
angiokeratomas
hypohidrosis
corneal dystrophy
neuropathic pain
cardiac and/or renal disease
cramp-fasciculation syndrome
chronic exercise-induced pain
fasciculations
cramps of the feet and legs
cramps
fasciculations


Progressive hearing loss in Fabry's disease: a case report.

Fabry's disease is a chromosomal X-linked inherited disease, which causes a lack of the lysosomal alpha-galactosidase A enzyme leading to a cellular accumulation of glycosphingolipids. This accumulation leads to various clinical disorders, including inner ear lesions, with sensorineural hearing loss and dizziness. This article proposes to describe a clinical case of a patient suffering from Fabry's disease with inner ear associated problems and to review the literature focusing on this subject.

    Fabry's disease
    DIAGNOSIS

 is a

    chromosomal X-linked inherited disease
    GENETICS

, which causes a

    lack of the lysosomal alpha-galactosidase A enzyme
    BIOCHEMICAL

 leading to a

    cellular accumulation of glycosphingolipids
    MICROSCOPIC

. This accumulation leads to various clinical disorders, including

    inner ear lesions
    SYMPTOMS

, with

    sensorineural hearing loss
    SYMPTOMS

 and

    dizziness
    SYMPTOMS

. This article proposes to describe a clinical case of a patient suffering from

    Fabry's disease
    DIAGNOSIS

 with

    inner ear associated problems
    SYMPTOMS

 and to review the literature focusing on this subject.

inner ear lesions
sensorineural hearing loss
dizziness
inner ear associated problems


Relief of left ventricular outflow obstruction by cibenzoline in a patient with Fabry's disease--a case report.

A 46-year-old man was admitted for further evaluation of exertional chest discomfort. One family member had experienced sudden death, and 2 others had died of heart failure, including 1 known to have had Fabry's disease. The patient was also diagnosed with Fabry's disease, based on reduced leukocyte alpha-galactosidase A activity, 2.0 nmol/mg protein/hour, as well as endomyocardial biopsy findings of marked sarcoplasmic vacuolization of cardiac muscle cells by light microscopy and lamellated "zebra bodies'' in the cytoplasm shown by electron microscopy. Echocardiography disclosed marked left ventricular hypertrophy and systolic anterior motion of the mitral leaflets. On cardiac catheterization, a left ventricular peak systolic outflow gradient of 50 mm Hg was noted; this decreased to 10 mm Hg following intravenous administration of 100 mg of cibenzoline. It is imperative to recognize the existence of cases with Fabry's disease associated with left ventricular outflow obstruction.

A

    46-year-old
    AGE

    man
    GENDER

 was admitted for further evaluation of

    exertional chest discomfort
    SYMPTOMS

. One

    family member had experienced sudden death
    FAMILY

, and 2 others had

    died of heart failure
    FAMILY

, including 1 known to have had

    Fabry's disease
    DIAGNOSIS

. The patient was also diagnosed with

    Fabry's disease
    DIAGNOSIS

, based on

    reduced leukocyte alpha-galactosidase A activity, 2.0 nmol/mg protein/hour
    BIOCHEMICAL

, as well as

    endomyocardial biopsy
    PARACLINICAL

 findings of

    marked sarcoplasmic vacuolization of cardiac muscle cells
    MICROSCOPIC

 by

    light microscopy
    PARACLINICAL

 and

    lamellated "zebra bodies'' in the cytoplasm shown
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

.

    Echocardiography
    PARACLINICAL

 disclosed

    marked left ventricular hypertrophy
    SYMPTOMS

 and

    systolic anterior motion of the mitral leaflets
    SYMPTOMS

. On

    cardiac catheterization
    PARACLINICAL

, a

    left ventricular peak systolic outflow gradient of 50 mm Hg
    SYMPTOMS

 was noted;

    this decreased to 10 mm Hg
    SYMPTOMS

 following

    intravenous administration of 100 mg of cibenzoline
    MEDICATION

. It is imperative to recognize the existence of cases with

    Fabry's disease
    DIAGNOSIS

 associated with

    left ventricular outflow obstruction
    SYMPTOMS

.

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


Chiari type I malformation in four unrelated patients affected with Fabry disease.

Fabry disease (FD) is an X-linked inborn error of metabolism resulting from the deficient activity of alpha-galactosidase A which leads to the widespread deposition of glycosphingolipids in lysosomes, and to ischemic complications involving kidneys, heart and brain. Among neurological symptoms, strokes and transient ischemic attacks (TIA) have been reported. A 30-year-old male patient, with FD, was referred to us for evaluation of a sudden episode of dizziness, with disequilibrium, and diplopia, in agreement with the diagnosis of a TIA. Head magnetic resonance imaging (MRI) showed no cerebrovascular involvement but revealed the presence of Chiari type I malformation (CMI). We subsequently performed head MRI in a cohort of 44 consecutive hemizygous male patients and seven heterozygous females affected with FD, and identified three additional cases (two males and one female) of CMI. Whether the association is coincidental or not will need further studies but our data suggest that CMI should be ruled out in all Fabry patients.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked inborn error of metabolism
    GENETICS

 resulting from the

    deficient activity of alpha-galactosidase A
    BIOCHEMICAL

 which leads to the

    widespread deposition of glycosphingolipids in lysosomes
    MICROSCOPIC

, and to

    ischemic complications involving kidneys, heart and brain
    SYMPTOMS

. Among

    neurological symptoms
    SYMPTOMS

,

    strokes
    SYMPTOMS

 and

    transient ischemic attacks (TIA)
    SYMPTOMS

 have been reported. A

    30-year-old
    AGE

    male
    GENDER

 patient, with

    FD
    DIAGNOSIS

, was referred to us for evaluation of a

    sudden episode of dizziness
    SYMPTOMS

,

    with disequilibrium
    SYMPTOMS

, and

    diplopia
    SYMPTOMS

, in agreement with the diagnosis of a

    TIA
    DIAGNOSIS

.

    Head magnetic resonance imaging (MRI)
    PARACLINICAL

 showed

    no cerebrovascular involvement
    NEG_FINDINGS

 but revealed the presence of

    Chiari type I malformation (CMI)
    SYMPTOMS

. We subsequently performed

    head MRI
    PARACLINICAL

 in a cohort of 44 consecutive

    hemizygous male
    GENETICS

 patients and seven heterozygous

    females
    GENDER

 affected with

    FD
    DIAGNOSIS

, and identified three additional cases (two

    males
    GENDER

 and one

    female
    GENDER

) of

    CMI
    DIAGNOSIS

. Whether the association is coincidental or not will need further studies but our data suggest that

    CMI
    DIAGNOSIS

 should be ruled out in all

    Fabry
    DIAGNOSIS

 patients.

Fabry disease (FD)
FD
TIA
FD
CMI
CMI
Fabry

X-linked inborn error of metabolism
hemizygous male


Unexplained left ventricular hypertrophy: consider a diagnosis of Fabry's disease.

Lysosomal storage disorders are a group of disorders characterised by the deficiency of a specific lysosomal hydrolase. These diseases are rare, with only a few hundred patients in the Netherlands. Fabry's disease, an X-linked lysosomal storage disorder, is caused by a deficiency of the lysosomal enzyme α-galactosidase A which results in, among other things, left ventricular hypertrophy, renal failure and cerebrovascular events. Patients with Fabry's disease, especially males, have a decreased life expectancy. Recent studies have shown that Fabry's disease may be much more common among patients with left ventricular hypertrophy (LVH) than previously thought. Up to 7% of male patients with left ventricular hypertrophy and up to 12% of female patients with unexplained LVH were found to suffer from Fabry's disease. Thus, Fabry's disease should be considered in patients with unexplained LVH. This case report summarises the main features of the disease. In addition recent developments concerning prevalence, diagnosis and the current available treatments are discussed and an algorithm on who and how to screen for Fabry's disease is presented.

    Lysosomal storage disorders
    DIAGNOSIS

 are a group of disorders characterised by the

    deficiency of a specific lysosomal hydrolase
    BIOCHEMICAL

. These diseases are rare, with only a few hundred patients in the Netherlands.

    Fabry's disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, is caused by a

    deficiency of the lysosomal enzyme α-galactosidase A
    BIOCHEMICAL

 which results in, among other things,

    left ventricular hypertrophy
    SYMPTOMS

,

    renal failure
    SYMPTOMS

 and

    cerebrovascular events
    SYMPTOMS

. Patients with

    Fabry's disease
    DIAGNOSIS

, especially

    males
    GENDER

, have a decreased life expectancy. Recent studies have shown that

    Fabry's disease
    DIAGNOSIS

 may be much more common among patients with

    left ventricular hypertrophy (LVH)
    SYMPTOMS

 than previously thought. Up to 7% of

    male
    GENDER

 patients with

    left ventricular hypertrophy
    SYMPTOMS

 and up to 12% of

    female
    GENDER

 patients with

    unexplained LVH
    SYMPTOMS

 were found to suffer from

    Fabry's disease
    DIAGNOSIS

. Thus,

    Fabry's disease
    DIAGNOSIS

 should be considered in patients with

    unexplained LVH
    SYMPTOMS

. This case report summarises the main features of the disease. In addition recent developments concerning prevalence, diagnosis and the current available treatments are discussed and an algorithm on who and how to screen for

    Fabry's disease
    DIAGNOSIS

 is presented.

Lysosomal storage disorders
Fabry's disease
lysosomal storage disorder
Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease

left ventricular hypertrophy
renal failure
cerebrovascular events
left ventricular hypertrophy (LVH)
left ventricular hypertrophy
unexplained LVH
unexplained LVH


Fabry's disease as a differential diagnosis of MS.

Fabry's disease is a genetically inherited error of glycosphingolipid metabolism that results from the defective activity of the lysosomal enzyme alpha-galactosidase A (alpha-GalA). The enzymatic defect, caused by an X-linked recessive genes, leads to progressive deposition of neutral glycosphingolipids (predominantly globotriaosylceramide), with terminal alpha-galactosyl moieties, in most visceral tissues and fluids of the body. Cerebrovascular manifestations result from multifocal small-vessel involvement and may include thromboses, basilar arterial ischaemia and aneurysm, seizures, paroxystic hemiplegia or hemianaesthesia, vestibular disorders and frank cerebral haemorrhage. Severe neurological signs may be present without evidence of major thrombosis and are presumably due to multifocal small-vessel occlusive disease. Vascular ischaemia and lipid deposition in peripheral nerves may cause conduction abnormalities (slowed conduction velocities and distal latency). Sensory neurons in spinal ganglia and small myelinated and unmyelinated fibers are affected preferentially.

    Fabry's disease
    DIAGNOSIS

 is a

    genetically inherited
    GENETICS

    error of glycosphingolipid metabolism
    DIAGNOSIS

 that results from the

    defective activity of the lysosomal enzyme alpha-galactosidase A (alpha-GalA)
    BIOCHEMICAL

. The

    enzymatic defect
    GENETICS

,

    caused by an X-linked recessive genes
    GENETICS

, leads to

    progressive deposition of neutral glycosphingolipids (predominantly globotriaosylceramide), with terminal alpha-galactosyl moieties, in most visceral tissues and fluids of the body
    MICROSCOPIC

.

    Cerebrovascular manifestations
    SYMPTOMS

 result from

    multifocal small-vessel involvement
    SYMPTOMS

 and may include

    thromboses
    SYMPTOMS

,

    basilar arterial ischaemia and aneurysm
    SYMPTOMS

,

    seizures
    SYMPTOMS

,

    paroxystic hemiplegia
    SYMPTOMS

 or

    hemianaesthesia
    SYMPTOMS

,

    vestibular disorders
    SYMPTOMS

 and

    frank cerebral haemorrhage
    SYMPTOMS

.

    Severe neurological signs
    SYMPTOMS

 may be present

    without evidence of major thrombosis
    NEG_FINDINGS

 and are presumably due to

    multifocal small-vessel occlusive disease
    SYMPTOMS

.

    Vascular ischaemia
    SYMPTOMS

 and

    lipid deposition in peripheral nerves
    MICROSCOPIC

 may cause

    conduction abnormalities (slowed conduction velocities and distal latency)
    SYMPTOMS

.

    Sensory neurons in spinal ganglia and small myelinated and unmyelinated fibers
    SYMPTOMS

 are affected preferentially.

Fabry's disease
error of glycosphingolipid metabolism

genetically inherited
enzymatic defect
caused by an X-linked recessive genes


An asymptomatic heterozygous female with fabry disease: implications for enzyme replacement therapy.

We report an asymptomatic female with Fabry disease immunohistochemically diagnosed by renal biopsy. She was initially diagnosed as having nephrotic syndrome, and renal biopsy was performed for pathological diagnosis. The renal specimen revealed non-specific findings (minor glomerular abnormalities) for nephrotic syndrome. Numerous laminated bodies in glomerular epithelial cells in electron microscopic findings and accumulations of ceramidetrihexoside immunohistochemically were observed and she was diagnosed with Fabry disease. However, no other laboratory data or clinical findings supported the diagnosis of Fabry disease. Since the efficacy of recombinant human alpha-galactosidase replacement therapy in this disease has been reported, whether enzyme replacement therapy for subclinical Fabry female patients is indicated or not is an important issue.

We report an

    asymptomatic
    NEG_FINDINGS

    female
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 immunohistochemically diagnosed by

    renal biopsy
    PARACLINICAL

.

    She
    GENDER

 was

    initially diagnosed as having nephrotic syndrome
    NEG_FINDINGS

, and

    renal biopsy
    PARACLINICAL

 was performed for

    pathological diagnosis
    PARACLINICAL

. The

    renal specimen
    PARACLINICAL

 revealed

    non-specific findings (minor glomerular abnormalities) for nephrotic syndrome
    NEG_FINDINGS

.

    Numerous laminated bodies in glomerular epithelial cells
    MICROSCOPIC

 in

    electron microscopic findings
    PARACLINICAL

 and

    accumulations of ceramidetrihexoside immunohistochemically
    MICROSCOPIC

 were observed and

    she
    GENDER

 was diagnosed with

    Fabry disease
    DIAGNOSIS

. However,

    no other laboratory data or clinical findings
    NEG_FINDINGS

 supported the diagnosis of

    Fabry disease
    DIAGNOSIS

. Since the efficacy of

    recombinant human alpha-galactosidase replacement therapy
    MEDICATION

 in this disease has been reported, whether

    enzyme replacement therapy
    MEDICATION

 for

    subclinical Fabry
    DIAGNOSIS

    female
    GENDER

 patients is indicated or not is an important issue.

Fabry disease
Fabry disease
Fabry disease
subclinical Fabry


Angiokeratoma corporis diffusum (Fabry disease).

A 23-year-old man presented for cosmetic consultation for symmetrically distributed, red-to-purple, hyperkeratotic papules that had been present since early childhood. Histopathologic features included ectasia of upper dermal vessels with overlying hyperkeratosis. Serum alpha-galactosidase A level was diminished. Fabry disease is an x-linked recessive disorder in which deficiency of the lysosomal enzyme alpha-galactosidase A leads to progressive accumulation of globotriaosylceramide in vital organs. The complexity and rarity of this disease mandates a multidisciplinary approach that includes initiation of enzyme replacement therapy.

A

    23-year-old
    AGE

    man
    GENDER

 presented for

    cosmetic consultation
    PARACLINICAL

 for

    symmetrically distributed, red-to-purple, hyperkeratotic papules
    SYMPTOMS

 that had been present since

    early childhood
    AGE

. Histopathologic features included

    ectasia of upper dermal vessels
    SYMPTOMS

 with

    overlying hyperkeratosis
    SYMPTOMS

.

    Serum alpha-galactosidase A level was diminished
    BIOCHEMICAL

.

    Fabry disease
    DIAGNOSIS

 is an

    x-linked recessive disorder
    GENETICS

 in which

    deficiency of the lysosomal enzyme alpha-galactosidase A
    BIOCHEMICAL

 leads to

    progressive accumulation of globotriaosylceramide in vital organs
    MICROSCOPIC

. The complexity and rarity of this disease mandates a

    multidisciplinary approach
    MEDICATION

 that includes

    initiation of enzyme replacement therapy
    MEDICATION

.


Anderson-Fabry disease: a protean clinical behavior and a chance diagnosis.

Anderson-Fabry disease is a rare inborn X-linked glycosphingolipid storage disorder in which the deficient activity of the enzyme alfa-galactosidase A (alfa-gal A) leads to the progressive tissular accumulation of lipidic molecules which, in turn, cause a protean pattern of multi-organ disfunction. Enzyme replacement therapy has recently become available and has proved to be effective in controlling the disorder. We present and discuss the case of a family with this disease, with special attention to the variability of clinical features and the difficulty of a correct diagnosis.

    Anderson-Fabry disease
    DIAGNOSIS

 is a

    rare inborn X-linked
    GENETICS

    glycosphingolipid storage disorder
    DIAGNOSIS

 in which the

    deficient activity of the enzyme alfa-galactosidase A (alfa-gal A)
    BIOCHEMICAL

 leads to the

    progressive tissular accumulation of lipidic molecules
    MICROSCOPIC

 which, in turn, cause a

    protean pattern of multi-organ disfunction
    SYMPTOMS

.

    Enzyme replacement therapy
    MEDICATION

 has recently become available and has proved to be effective in controlling the disorder. We present and discuss the case of a

    family with
    FAMILY

 this disease, with special attention to the variability of clinical features and the difficulty of a correct diagnosis.

Anderson-Fabry disease
glycosphingolipid storage disorder


Fabry disease--a diagnostic and therapeutic problem.

The authors present a patient with Fabry syndrome that remained undiagnosed for several years. Fabry syndrome is a genetic disease related to changes on the X chromosome. Its complex clinical presentation and diverse symptomatology is caused by deficient activity of lysosomal hydrolase alpha-galactosidase enzyme. Defect in the basic alpha-galactosidase molecule implies genetic change, which can be a predisposing factor for the development of atypical and typical forms of this genetic disease. In the presented case, clinical manifestation and hemizygous symptomatology were the evidence of metabolic and genetic irregularity, typical clinical presentation of Fabry disease. Many authors report generalized vasculopathy as a basic characteristic of Fabry disease and a causative factor of multiorgan changes. Some authors indicate that persons with diagnosed asymmetric hypertrophy of the left ventricle have decreased alpha-galactosidase. Cardiac complications, coronary disease, and acute myocardial ischemia are often present in cases of Fabry disease, frequently causing death in such patients. Characteristic central nervous system symptoms with skin-burning sensation and paresthesia were also present in our case. Cerebrovascular complications were caused by changes on small blood vessels. Clinical signs of renal failure were nonspecific, and the diagnosis was based on extrarenal symptoms. Initial renal manifestations were insignificant as asymptomatic proteinuria and microhematuria, due to which our patient was referred to further examination. The level of alpha-galactosidase was significantly decreased. The severity and progression of this disease depends on the level of alpha-galactosidase enzyme in serum and its catabolic effect. More recent studies have showed that deficient enzyme can be synthetic zed and, accordingly our patient has been successfully enrolled in the replacement therapy program.

The authors present a patient with

    Fabry syndrome
    DIAGNOSIS

 that

    remained undiagnosed for several years
    NEG_FINDINGS

.

    Fabry syndrome
    DIAGNOSIS

 is a

    genetic disease
    GENETICS

 related to

    changes on the X chromosome
    GENETICS

. Its complex clinical presentation and diverse symptomatology is caused by

    deficient activity of lysosomal hydrolase alpha-galactosidase enzyme
    BIOCHEMICAL

.

    Defect in the basic alpha-galactosidase molecule
    BIOCHEMICAL

 implies

    genetic change
    GENETICS

, which can be a predisposing factor for the development of atypical and typical forms of this

    genetic disease
    GENETICS

. In the presented case, clinical manifestation and

    hemizygous symptomatology
    GENETICS

 were the evidence of

    metabolic and genetic irregularity
    SYMPTOMS

, typical clinical presentation of

    Fabry disease
    DIAGNOSIS

. Many authors report

    generalized vasculopathy
    SYMPTOMS

 as a basic characteristic of

    Fabry disease
    DIAGNOSIS

 and a causative factor of

    multiorgan changes
    SYMPTOMS

. Some authors indicate that persons with diagnosed

    asymmetric hypertrophy of the left ventricle
    SYMPTOMS

 have

    decreased alpha-galactosidase
    BIOCHEMICAL

.

    Cardiac complications
    SYMPTOMS

,

    coronary disease
    SYMPTOMS

, and

    acute myocardial ischemia
    SYMPTOMS

 are often present in cases of

    Fabry disease
    DIAGNOSIS

, frequently causing

    death
    SYMPTOMS

 in such patients.

    Characteristic central nervous system symptoms
    SYMPTOMS

 with

    skin-burning sensation
    SYMPTOMS

 and

    paresthesia
    SYMPTOMS

 were also present in our case.

    Cerebrovascular complications
    SYMPTOMS

 were caused by

    changes on small blood vessels
    SYMPTOMS

.

    Clinical signs of renal failure were nonspecific
    NEG_FINDINGS

, and the diagnosis was based on

    extrarenal symptoms
    SYMPTOMS

. Initial

    renal manifestations
    SYMPTOMS

 were insignificant as

    asymptomatic proteinuria
    BIOCHEMICAL

 and

    microhematuria
    BIOCHEMICAL

, due to which our patient was referred to further examination. The

    level of alpha-galactosidase was significantly decreased
    BIOCHEMICAL

. The severity and progression of this disease depends on the

    level of alpha-galactosidase enzyme in serum
    BIOCHEMICAL

 and its

    catabolic effect
    BIOCHEMICAL

. More recent studies have showed that

    deficient enzyme
    BIOCHEMICAL

 can be synthetic zed and, accordingly our patient has been successfully

    enrolled in the replacement therapy program
    MEDICATION

.

Fabry syndrome
Fabry syndrome
Fabry disease
Fabry disease
Fabry disease

genetic disease
changes on the X chromosome
genetic change
genetic disease
hemizygous symptomatology


Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement.

We describe the postmortem findings of a 47-year-old man with Fabry disease, an X-linked glycolipid storage disorder, who was on enzyme replacement therapy with recombinant alpha-galactosidase A for more than 2 years. The patient had widespread atherosclerotic coronary artery disease that culminated in a massive acute myocardial infarction. Atherosclerotic lesions were seen in the right and left coronary systems, aorta, and the basilar artery. Typical Fabry cardiomyopathy and glomerular nephropathy were found. With the exception of vascular endothelial cells, extensive glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems. We conclude that, at least in this patient, repeated infusions with alpha-galactosidase A over a prolonged period did not appreciably clear storage material in cells other than vascular endothelial cells. These findings also illustrate accelerated atherosclerosis in susceptible patients with Fabry disease.

We describe the

    postmortem
    PARACLINICAL

 findings of a

    47-year-old
    AGE

    man
    GENDER

 with

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    glycolipid storage disorder
    DIAGNOSIS

, who was

    on enzyme replacement therapy with recombinant alpha-galactosidase A for more than 2 years
    MEDICATION

. The patient had

    widespread atherosclerotic coronary artery disease
    SYMPTOMS

 that culminated in a

    massive acute myocardial infarction
    SYMPTOMS

.

    Atherosclerotic lesions were seen in the right and left coronary systems, aorta, and the basilar artery
    SYMPTOMS

.

    Typical Fabry cardiomyopathy
    SYMPTOMS

 and

    glomerular nephropathy
    DIAGNOSIS

 were found.

    With the exception of vascular endothelial cells
    MICROSCOPIC

,

    extensive glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems
    MICROSCOPIC

. We conclude that, at least in this patient,

    repeated infusions with alpha-galactosidase A over a prolonged period
    MEDICATION

    did not appreciably clear storage material in cells other than vascular endothelial cells
    NEG_FINDINGS

. These findings also illustrate

    accelerated atherosclerosis
    SYMPTOMS

 in susceptible patients with

    Fabry disease
    DIAGNOSIS

.

Fabry disease
glycolipid storage disorder
glomerular nephropathy
Fabry disease


[Fabry nephropathy in a female with superposed IgA glomerulonephritis].

In Anderson-Fabry disease (AFd), the kidney is affected in all hemizygous males and in some heterozygous females. Female carriers can present subtle renal abnormalities due to glycosphingolipid (GSL) accumulation within renal cells. Renal biopsy is rarely performed in female Fabry patients because clinical renal manifestations are usually lacking. However, female carriers can accumulate GSL in their renal cells despite the absence of clinically evident kidney disease.

We performed a kidney biopsy in a 52-year-old female patient, a Fabry disease carrier. The patient showed normal glomerular filtration rate, persistent microhematuria and proteinuria (about 1.7 g/24 hr), cornea "verticillata", and evident left ventricular hypertrophy. The molecular study documented a missense mutation R227Q in exon 5 of the alpha-galactosidase A gene. Optical microscopy showed electron-dense mesangial deposits due IgA glomerulonephritis, as confirmed by immunofluorescence. We decided to start therapy with angiotensin-converting enzyme inhibitors (ACE-I). After 8 months of treatment, the patient demonstrated proteinuria of 0.9 g/24 hr. To decide when to start treatment using enzyme replacement therapy (ERT) with human recombinant GAL A (Fabrazyme), we decided to perform an electron microscopy study of the renal biopsy. The renal ultrastructural findings were typical GSL inclusions in all kinds of glomerular cells, in tubular epithelial cells and in endothelial cells of interstitial capillaries, confirming the hypothesis of Fabry nephropathy. Consequently, Fabrazyme was given at a standard dose of 1 mg/kg every 2 weeks. After 24 months of combined treatment (ACE-I-Fabrazyme), proteinuria decreased to 0.2 g/24 hr.

The importance of performing the ultrastructural examination of the kidney biopsy is stressed, especially in heterozygous Fabry patients to evaluate the need to treat them with ERT and to evaluate the degree of renal involvement.

In

    Anderson-Fabry disease (AFd)
    DIAGNOSIS

, the kidney is affected in

    all hemizygous males
    GENETICS

 and in some

    heterozygous
    GENETICS

    females
    GENDER

.

    Female
    GENDER

 carriers can present

    subtle renal abnormalities
    SYMPTOMS

 due to

    glycosphingolipid (GSL) accumulation within renal cells
    MICROSCOPIC

.

    Renal biopsy
    PARACLINICAL

 is rarely performed in

    female
    GENDER

    Fabry
    DIAGNOSIS

 patients because

    clinical renal manifestations
    NEG_FINDINGS

 are usually lacking. However,

    female
    GENDER

 carriers can

    accumulate GSL in their renal cells
    MICROSCOPIC

 despite the

    absence of clinically evident kidney disease
    NEG_FINDINGS

.

We performed a

    kidney biopsy
    PARACLINICAL

 in a

    52-year-old
    AGE

    female
    GENDER

 patient, a

    Fabry disease
    DIAGNOSIS

 carrier. The patient showed

    normal glomerular filtration rate
    NEG_FINDINGS

,

    persistent microhematuria and proteinuria (about 1.7 g/24 hr)
    BIOCHEMICAL

,

    cornea "verticillata"
    SYMPTOMS

, and

    evident left ventricular hypertrophy
    SYMPTOMS

. The

    molecular study
    PARACLINICAL

 documented a

    missense mutation R227Q in exon 5 of the alpha-galactosidase A gene
    GENETICS

.

    Optical microscopy
    PARACLINICAL

 showed

    electron-dense mesangial deposits due IgA glomerulonephritis
    MICROSCOPIC

, as confirmed by

    immunofluorescence
    PARACLINICAL

. We decided to start

    therapy with angiotensin-converting enzyme inhibitors (ACE-I)
    MEDICATION

. After

    8 months of treatment
    MEDICATION

, the patient demonstrated

    proteinuria of 0.9 g/24 hr
    BIOCHEMICAL

. To decide when to start

    treatment using enzyme replacement therapy (ERT) with human recombinant GAL A (Fabrazyme)
    MEDICATION

, we decided to perform an

    electron microscopy study of the renal biopsy
    PARACLINICAL

. The

    renal ultrastructural findings
    PARACLINICAL

 were

    typical GSL inclusions in all kinds of glomerular cells, in tubular epithelial cells and in endothelial cells of interstitial capillaries
    MICROSCOPIC

, confirming the hypothesis of

    Fabry nephropathy
    DIAGNOSIS

. Consequently,

    Fabrazyme was given at a standard dose of 1 mg/kg every 2 weeks
    MEDICATION

. After

    24 months of combined treatment (ACE-I-Fabrazyme)
    MEDICATION

, proteinuria decreased to 0.2 g/24 hr.

The importance of performing the

    ultrastructural examination of the kidney biopsy
    PARACLINICAL

 is stressed, especially in

    heterozygous
    GENETICS

    Fabry
    DIAGNOSIS

 patients to evaluate the need to treat them with

    ERT
    MEDICATION

 and to evaluate the degree of renal involvement.

Anderson-Fabry disease (AFd)
Fabry
Fabry disease
Fabry nephropathy
Fabry

subtle renal abnormalities
cornea "verticillata"
evident left ventricular hypertrophy


A comprehensive assessment of renal function in patients with Gaucher disease.

Gaucher disease (GD) is caused by deficiency of acid beta-glucocerebrosidase and is the most common lysosomal storage disease. Patients may have massive hepatosplenomegaly, severe bone disease, and, occasionally, pulmonary or neurological involvement. Although other storage diseases, such as Fabry disease, frequently affect the kidneys, reports of renal abnormalities in patients with GD are limited to case reports. Our aim was to perform a comprehensive evaluation of renal function in patients with GD.

Evaluation was performed at routine clinic visits and included blood pressure recording and renal ultrasound. Serum chemistries, urinalysis, urine electrolytes, total protein, and tubular proteinuria were assessed, and estimated glomerular filtration rate (GFR) was calculated.

One hundred sixty-one patients underwent evaluation, including 26 children. GFR was significantly greater in patients with GD than in age- and sex-matched healthy controls (P = 0.01 in men, P < 0.001 in women, P = 0.003 in children). Subgroups of patients with markers of more severe disease had a greater GFR than other patients. No patient had decreased renal function. Significant proteinuria was found only in patients with such comorbidities as diabetes mellitus or multiple myeloma. No evidence of renal tubular abnormalities was found, and kidney sonographic appearance and size were normal.

Despite the multiorgan nature of the disease, a systematic evaluation did not find renal abnormalities in patients with GD. Glomerular hyperfiltration was observed in a proportion of patients, particularly those with markers of more severe disease. This phenomenon does not seem to be associated with a subsequent decline in renal function.

    Gaucher disease (GD)
    DIAGNOSIS

 is caused by

    deficiency of acid beta-glucocerebrosidase
    BIOCHEMICAL

 and is the most common

    lysosomal storage disease
    DIAGNOSIS

. Patients may have

    massive hepatosplenomegaly
    SYMPTOMS

,

    severe bone disease
    SYMPTOMS

, and, occasionally,

    pulmonary or neurological involvement
    SYMPTOMS

. Although other

    storage diseases
    DIAGNOSIS

, such as

    Fabry disease
    DIAGNOSIS

, frequently affect the

    kidneys
    SYMPTOMS

, reports of

    renal abnormalities
    SYMPTOMS

 in patients with

    GD
    DIAGNOSIS

 are limited to case reports. Our aim was to perform a comprehensive

    evaluation of renal function
    PARACLINICAL

 in patients with

    GD
    DIAGNOSIS

.

Evaluation was performed at

    routine clinic visits
    PARACLINICAL

 and included

    blood pressure recording
    PARACLINICAL

 and

    renal ultrasound
    PARACLINICAL

.

    Serum chemistries, urinalysis
    PARACLINICAL

,

    urine electrolytes, total protein, and tubular proteinuria
    BIOCHEMICAL

    were assessed
    PARACLINICAL

, and

    estimated glomerular filtration rate (GFR)
    PARACLINICAL

 was calculated.

One hundred sixty-one patients underwent evaluation, including 26

    children
    AGE

.

    GFR was
    BIOCHEMICAL

 significantly greater in patients with

    GD
    DIAGNOSIS

 than in age- and sex-matched healthy controls (P = 0.01 in

    men
    GENDER

, P < 0.001 in

    women
    GENDER

, P = 0.003 in

    children
    AGE

). Subgroups of patients with markers of more severe disease had a

    greater GFR
    BIOCHEMICAL

 than other patients. No patient had

    decreased renal function
    NEG_FINDINGS

.

    Significant proteinuria
    BIOCHEMICAL

 was found only in patients with such comorbidities as

    diabetes mellitus
    DIAGNOSIS

 or

    multiple myeloma
    DIAGNOSIS

.

    No evidence of renal tubular abnormalities
    NEG_FINDINGS

 was found, and

    kidney sonographic appearance and size were normal
    NEG_FINDINGS

.

Despite the

    multiorgan
    DIAGNOSIS

 nature of the disease, a systematic evaluation did

    not find renal abnormalities
    NEG_FINDINGS

 in patients with

    GD
    DIAGNOSIS

.

    Glomerular hyperfiltration
    BIOCHEMICAL

 was observed in a proportion of patients, particularly those with markers of more severe disease. This phenomenon does not seem to be associated with a

    subsequent decline in renal function
    NEG_FINDINGS

.

Gaucher disease (GD)
lysosomal storage disease
storage diseases
Fabry disease
GD
GD
GD
diabetes mellitus
multiple myeloma
multiorgan
GD

massive hepatosplenomegaly
severe bone disease
pulmonary or neurological involvement
kidneys
renal abnormalities


Ventricular tachycardias and dilated cardiomyopathy caused by Fabry disease.

Women with Fabry disease are considered to have a good prognosis. Here we report the clinical history of a female patient with severe Fabry disease before and after referral to our hospital. She was diagnosed to have a cardiac variant of Fabry disease since a left ventricular endomyocardial biopsy revealed specific features of this disease and that cardiac involvement was the sole manifestation. She developed sustained ventricular tachycardia and dilated cardiomyopathy requiring oral administration of amiodarone and a cardiac defibrillator implant.

    Women
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 are considered to have a good prognosis. Here we report the clinical history of a

    female
    GENDER

 patient with

    severe Fabry disease
    DIAGNOSIS

 before and after referral to our hospital.

    She
    GENDER

 was diagnosed to have a

    cardiac variant of Fabry disease
    DIAGNOSIS

 since a

    left ventricular endomyocardial biopsy
    PARACLINICAL

 revealed specific features of this disease and that

    cardiac involvement
    SYMPTOMS

 was the sole manifestation.

    She
    GENDER

 developed

    sustained ventricular tachycardia
    SYMPTOMS

 and

    dilated cardiomyopathy
    SYMPTOMS

 requiring

    oral administration of amiodarone
    MEDICATION

 and a

    cardiac defibrillator implant
    MEDICATION

.

Fabry disease
severe Fabry disease
cardiac variant of Fabry disease

cardiac involvement
sustained ventricular tachycardia
dilated cardiomyopathy

oral administration of amiodarone
cardiac defibrillator implant


Novel GLA gene mutations in two Chinese families with classic Fabry disease.

To search mutations in GLA gene in two Chinese families with classic Fabry disease.

Two families with Fabry disease confirmed by pathological and clinical studies were reported here. In pedigree 1, 12 family members had paroxysmal pain on limb extremities. In pedigree 2, there were 8 patients and most of them had multi-organ involvement at the end stage of the disease. Two probands from the two families together with several of their family members were searched for mutations in GLA gene. After extraction of genomic DNA from peripheral leukocytes, all of the 7 exons and their flanking introns were amplified by PCR and directly sequenced.

Both the proband 1 and proband 2 were identified to be hemizygotes of novel GLA missense mutations. G132T (TGG-->TGT) mutation in exon 1, resulting in the substitution of amino acid from tryptophan to cysteine (W44C), was detected in proband 1. G874C (GCT-->CCT) mutation in exon 6, resulting in the substitution of amino acid from alanine to praline (A292P), was detected in proband 2. Mothers of the 2 probands were heterozygotes carrying the same mutation as their sons.

We report here 2 novel missense mutations in two Chinese families with classic Fabry disease. Different mutations in the same gene can result in phenotypes with significant deviation. Several female patients with the same clinical manifestations as male patients in the 2 families suggest that the X-linked dominant inheritance of the disease, possibly related to be the random X chromosome inactivation.

To search

    mutations in GLA gene
    GENETICS

 in two

    Chinese
    ETHNICITY

    families with classic Fabry disease
    FAMILY

.

Two families with

    Fabry disease
    DIAGNOSIS

 confirmed by

    pathological and clinical studies
    PARACLINICAL

 were reported here. In

    pedigree 1
    FAMILY

,

    12 family members
    FAMILY

 had

    paroxysmal pain on limb extremities
    SYMPTOMS

. In

    pedigree 2
    FAMILY

, there were 8 patients and most of them had

    multi-organ involvement
    SYMPTOMS

 at the end stage of the disease. Two probands from the two families together with several of their family members were searched for

    mutations in GLA gene
    GENETICS

. After

    extraction of genomic DNA from peripheral leukocytes
    PARACLINICAL

,

    all of the 7 exons and their flanking introns were amplified by PCR and directly sequenced
    PARACLINICAL

.

Both the proband 1 and proband 2 were identified to be

    hemizygotes of novel GLA missense mutations
    GENETICS

.

    G132T (TGG-->TGT) mutation in exon 1, resulting in the substitution of amino acid from tryptophan to cysteine (W44C)
    GENETICS

, was detected in proband 1.

    G874C (GCT-->CCT) mutation in exon 6, resulting in the substitution of amino acid from alanine to praline (A292P)
    GENETICS

, was detected in proband 2.

    Mothers of the 2 probands were heterozygotes carrying the same mutation as their sons
    FAMILY

.

We report here 2

    novel missense mutations
    GENETICS

 in two

    Chinese
    ETHNICITY

 families with

    classic Fabry disease
    DIAGNOSIS

.

    Different mutations in the same gene
    GENETICS

 can result in phenotypes with significant deviation. Several

    female
    GENDER

 patients with

    the same clinical manifestations
    FAMILY

 as

    male
    GENDER

 patients in the 2 families suggest that the

    X-linked dominant inheritance of the disease
    GENETICS

, possibly related to be the

    random X chromosome inactivation
    GENETICS

.

paroxysmal pain on limb extremities
multi-organ involvement


Significance of screening for Fabry disease among male dialysis patients.

Fabry disease is an X-linked disorder resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A(alpha-Gal A). Renal insufficiency is a very important manifestation and affects the prognosis of patients. Recently, a renal variant type that is characterized by low plasma alpha-Gal A activity and a milder phenotype, but which progresses to end-stage renal failure, has been reported. In this study, we clarified the incidence of this atypical variant of Fabry disease in hemodialysis patients.

We measured plasma alpha-Gal A activity in 450 male dialysis patients who had never been diagnosed with Fabry disease.

The mean of the alpha-Gal A activity of the patients was 9.75 +/- 3.20 nmol/h/ml, while the controls with classical Fabry (n = 3) were 0.52-1.04 nmol/h/ml. Among the patients, one patient was found to exhibit low alpha-Gal A activity in plasma (3.18 nmol/h/ml) and in leukocytes (0.639 nmol/h/mg). This patient was a 43-year-old Japanese man who had been on regular dialysis since the age of 23. He did not present typical clinical signs of classical Fabry, such as acroparesthesias or hypohidrosis, but did present renal insufficiency and severe left ventricular hypertrophy which had developed only recently, suggesting a variant form of Fabry disease. Sequencing of the DNA of this patient revealed a deletion of a single amino acid of valine in 10252.

A case of an atypical variant of Fabry among 450 male dialysis patients (0.22%) was found in the survey. This indicates the potential for undiagnosed Fabry disease among dialysis patients. The results of this study indicate the significance of screening for Fabry disease among male dialysis patients.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

 resulting from a

    deficiency of the lysosomal enzyme alpha-galactosidase A(alpha-Gal A)
    BIOCHEMICAL

.

    Renal insufficiency
    SYMPTOMS

 is a very important manifestation and affects the prognosis of patients. Recently, a

    renal variant type
    DIAGNOSIS

 that is characterized by

    low plasma alpha-Gal A activity
    BIOCHEMICAL

 and a milder phenotype, but which progresses to

    end-stage renal failure
    SYMPTOMS

, has been reported. In this study, we clarified the incidence of this

    atypical variant of Fabry disease
    DIAGNOSIS

 in

    hemodialysis
    MEDICATION

 patients.

We measured

    plasma alpha-Gal A activity
    BIOCHEMICAL

 in 450

    male
    GENDER

    dialysis
    MEDICATION

 patients who had

    never been diagnosed with Fabry disease
    NEG_FINDINGS

.

The

    mean of the alpha-Gal A activity of
    BIOCHEMICAL

 the patients

    was 9.75 +/- 3.20 nmol/h/ml
    BIOCHEMICAL

, while the controls with

    classical Fabry
    DIAGNOSIS

 (n = 3)

    were 0.52-1.04 nmol/h/ml
    BIOCHEMICAL

. Among the patients, one patient was found to exhibit

    low alpha-Gal A activity in plasma (3.18 nmol/h/ml) and in leukocytes (0.639 nmol/h/mg)
    BIOCHEMICAL

. This patient was a

    43-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 who had

    been on regular dialysis
    MEDICATION

    since the age of 23
    AGE

.

    He
    GENDER

    did not present typical clinical signs of classical Fabry
    NEG_FINDINGS

    , such as acroparesthesias or hypohidrosis
    NEG_FINDINGS

, but did present

    renal insufficiency
    SYMPTOMS

 and

    severe left ventricular hypertrophy
    SYMPTOMS

 which had developed only recently, suggesting a

    variant form of Fabry disease
    DIAGNOSIS

.

    Sequencing of the DNA of
    PARACLINICAL

 this patient revealed a

    deletion of a single amino acid of valine in 10252.
    GENETICS

A case of an

    atypical variant of Fabry
    DIAGNOSIS

 among 450

    male
    GENDER

 dialysis patients (0.22%) was found in the survey. This indicates the potential for undiagnosed

    Fabry disease
    DIAGNOSIS

 among

    dialysis
    MEDICATION

 patients. The results of this study indicate the significance of screening for

    Fabry disease
    DIAGNOSIS

 among

    male
    GENDER

 dialysis patients.

Fabry disease
renal variant type
atypical variant of Fabry disease
classical Fabry
variant form of Fabry disease
atypical variant of Fabry
Fabry disease
Fabry disease

Renal insufficiency
end-stage renal failure
renal insufficiency
severe left ventricular hypertrophy

hemodialysis
dialysis
been on regular dialysis
dialysis


Successful pregnancy outcome in a patient with Fabry disease receiving enzyme replacement therapy with agalsidase alfa.

Fabry disease is an inherited lysosomal storage disease caused by deficiency of alpha-galactosidase A. Enzyme replacement therapy for this multisystem progressive disease has been available only since 2001. We here report the first known successful pregnancy of a female patient receiving such therapy.

    Fabry disease
    DIAGNOSIS

 is an

    inherited
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by deficiency of alpha-galactosidase A.

    Enzyme replacement therapy
    MEDICATION

 for this

    multisystem progressive disease
    DIAGNOSIS

 has been available only since 2001. We here report the first known successful

    pregnancy
    MEDICATION

 of a

    female
    GENDER

 patient

    receiving such therapy
    MEDICATION

.

Fabry disease
lysosomal storage disease
multisystem progressive disease

Enzyme replacement therapy
pregnancy
receiving such therapy


Parkinsonism and Anderson Fabry's disease: a case report.

We describe and present a videotape of a 57-year-old woman admitted to our Neurological Clinic at 46 years of age due to extrapyramidal manifestations suggesting Parkinson's disease (PD) and with a brain magnetic resonance imaging scan showing multi-infarctual leukoencephalopathy. Various investigations led to the diagnosis of Anderson Fabry's disease (AFD). We discuss the possibility of correlation between the patient's parkinsonism and AFD.

We describe and present a videotape of a

    57-year-old
    AGE

    woman
    GENDER

 admitted to our Neurological Clinic at

    46 years of age
    AGE

 due to

    extrapyramidal manifestations
    SYMPTOMS

 suggesting

    Parkinson's disease (PD)
    DIAGNOSIS

 and with a

    brain magnetic resonance imaging scan
    PARACLINICAL

 showing

    multi-infarctual leukoencephalopathy
    SYMPTOMS

. Various investigations led to the diagnosis of

    Anderson Fabry's disease (AFD)
    DIAGNOSIS

. We discuss the possibility of correlation between the patient's

    parkinsonism
    DIAGNOSIS

 and

    AFD
    DIAGNOSIS

.

extrapyramidal manifestations
multi-infarctual leukoencephalopathy

Parkinson's disease (PD)
Anderson Fabry's disease (AFD)
parkinsonism
AFD


Fabry disease: an atypical presentation.

Fabry disease is a rare X-linked recessive lysosomal storage disease. Patients typically have angiokeratomas distributed between the umbilicus and knees, painful crises of the hands and feet, and renal, ophthalmologic, and cardiac abnormalities. An 11-year-old boy presented with a 6-year history of widespread petechial-like lesions and painful crises of the hands and feet. On physical examination, he had numerous erythematous, nonblanching pinpoint macules and rare papules with an overlying crust. These lesions were widely distributed on his trunk, palms, and soles, while sparing the area between the umbilicus and knees. Histologic evaluation of one of these lesions found several dilated, blood-filled vessels in the upper dermis beneath a thinned epidermis. The patient also had markedly decreased alpha galactosidase A levels. Although the distribution of the angiokeratomas was atypical, the clinical and histologic findings were consistent with a diagnosis of Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

. Patients typically have

    angiokeratomas distributed between the umbilicus and knees
    SYMPTOMS

,

    painful crises of the hands and feet
    SYMPTOMS

, and

    renal, ophthalmologic
    SYMPTOMS

, and

    cardiac abnormalities
    SYMPTOMS

. An

    11-year-old
    AGE

    boy
    GENDER

 presented with a 6-year history of

    widespread petechial-like lesions
    SYMPTOMS

 and

    painful crises of the hands and feet
    SYMPTOMS

. On physical examination,

    he
    GENDER

 had

    numerous erythematous, nonblanching pinpoint macules and rare papules with an overlying crust
    SYMPTOMS

.

    These lesions were widely distributed on his trunk, palms, and soles
    SYMPTOMS

, while

    sparing the area between the umbilicus and knees
    NEG_FINDINGS

.

    Histologic evaluation
    PARACLINICAL

 of one of

    these lesions
    SYMPTOMS

 found

    several dilated, blood-filled vessels in the upper dermis beneath a thinned epidermis
    MICROSCOPIC

. The patient also had

    markedly decreased alpha galactosidase A levels
    BIOCHEMICAL

. Although the

    distribution of the angiokeratomas
    SYMPTOMS

 was atypical, the clinical and histologic findings were consistent with a diagnosis of

    Fabry disease
    DIAGNOSIS

.

Fabry disease
lysosomal storage disease
Fabry disease


[Enzyme replacement therapy in Fabry's disease].

We report a 56-year-old man with history of chronic renal failure, who was diagnosed to have Fabry's disease after performing a percutaneous kidney biopsy. The diagnosis was confirmed by the deficient level of activity of alpha-galactosidase A and by the identification of the mutation. A enzime replacement therapy with alpha-galactosidase A was administered. After 18 months of treatment, a second kidney biopsy was performed showing renal deposits of globotriaosylceramide (we did not evaluate the percentage of histologic clearance of the deposits). Six months after the end of the therapy, a reduction in the impairment of renal function is observed, and the classic manifestations of the disease are absent.

We report a

    56-year-old
    AGE

    man
    GENDER

 with

    history of chronic renal failure
    SYMPTOMS

, who was diagnosed to have

    Fabry's disease
    DIAGNOSIS

 after performing a

    percutaneous kidney biopsy
    PARACLINICAL

. The diagnosis was confirmed by the

    deficient level of activity of alpha-galactosidase A
    BIOCHEMICAL

 and by the

    identification of the mutation
    GENETICS

. A

    enzime replacement therapy with alpha-galactosidase A
    MEDICATION

 was administered. After

    18 months of treatment
    MEDICATION

, a

    second kidney biopsy
    PARACLINICAL

 was performed showing

    renal deposits of globotriaosylceramide
    MICROSCOPIC

 (we

    did not evaluate the percentage of histologic clearance of the deposits
    NEG_FINDINGS

). Six months after the end of the therapy, a

    reduction in the impairment of renal function
    SYMPTOMS

 is observed, and

    the classic manifestations of the disease are absent
    NEG_FINDINGS

.


Ultrastructural study of renal involvement in two females with Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a rare X-linked lipid storage disorder due to a deficient lysosomal a-galactosidase A (a-Gal) activity. In males with the classic form of the disease the enzymatic defect leads to progressive accumulation of glycosphingolipids (GL) in different organs, mainly in the kidney, heart, and brain, causing severe multisystem failure. AFD is usually mild in heterozygous females, but severe cerebrovascular, renal, and cardiac manifestations have been rarely described. The aim of this study is to describe renal involvement of mild symptomatic female carriers by ultrastructural analysis focusing to microvascular lesions, considered to be one of the major causes of systemic disease in AFD. Resin-embedded renal biopsies from 2 sisters with isolated mild proteinuria and belonging to a family group with AFD were observed by light and electron microscopy. In spite of the mild clinical symptoms, diffuse GL storages were demonstrated in all types of glomerular cells and in interstitial endothelial cells. Moreover, platelets were frequently observed in glomerular vassels, a feature coherent with a possible role of prothrombotic state, and platelet activation, in early glomerular lesions.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lipid storage disorder
    DIAGNOSIS

 due to a

    deficient lysosomal a-galactosidase A (a-Gal) activity
    BIOCHEMICAL

. In

    males
    GENDER

 with the classic form of the disease the enzymatic defect leads to

    progressive accumulation of glycosphingolipids (GL) in different organs, mainly in the kidney, heart, and brain
    MICROSCOPIC

, causing

    severe multisystem failure
    SYMPTOMS

.

    AFD
    DIAGNOSIS

 is usually mild in

    heterozygous
    GENETICS

    females
    GENDER

, but

    severe cerebrovascular, renal, and cardiac manifestations
    SYMPTOMS

 have been rarely described. The aim of this study is to describe

    renal involvement
    SYMPTOMS

 of mild symptomatic

    female
    GENDER

 carriers by

    ultrastructural analysis
    PARACLINICAL

 focusing to

    microvascular lesions
    SYMPTOMS

, considered to be one of the major causes of

    systemic disease
    SYMPTOMS

 in

    AFD
    DIAGNOSIS

.

    Resin-embedded renal biopsies
    PARACLINICAL

 from 2

    sisters with isolated mild proteinuria
    FAMILY

    and belonging to a family group with AFD
    FAMILY

 were observed by

    light and electron microscopy
    PARACLINICAL

. In spite of the

    mild clinical symptoms
    NEG_FINDINGS

,

    diffuse GL storages were demonstrated in all types of glomerular cells and in interstitial endothelial cells
    MICROSCOPIC

. Moreover,

    platelets were frequently observed in glomerular vassels
    MICROSCOPIC

, a feature coherent with a possible role of

    prothrombotic state
    BIOCHEMICAL

, and

    platelet activation
    BIOCHEMICAL

, in

    early glomerular lesions
    MICROSCOPIC

.

Anderson-Fabry disease (AFD)
lipid storage disorder
AFD
AFD


Radiological evidence of early cerebral microvascular disease in young children with Fabry disease.

We report on 2 children with Fabry disease who had radiologic evidence of microvascular central nervous system involvement despite the clinical absence of renal, cardiac, or cerebral manifestations. This suggests that treatment with enzyme replacement therapy may be necessary early in the disease to avoid irreversible complications.

We report on 2

    children
    AGE

 with

    Fabry disease
    DIAGNOSIS

 who had

    radiologic evidence of microvascular central nervous system involvement
    SYMPTOMS

    despite the clinical absence of renal, cardiac, or cerebral manifestations
    NEG_FINDINGS

. This suggests that

    treatment with enzyme replacement therapy
    MEDICATION

 may be necessary early in the disease to avoid

    irreversible complications
    SYMPTOMS

.


Fucosidosis with angiokeratoma. Immunohistochemical & electronmicroscopic study of a new case and literature review.

Fucosidosis is a rare lysosomal storage disease due to alpha-L-fucosidase deficiency. It presents clinically with neurological, skeletal, and cutaneous findings, including mainly angiokeratoma corporis diffusum. Electronmicroscopic examination reveals characteristic electron-lucent cytoplasmic vacuolization present in several cell types of the skin and other tissues. We present here a new patient suffering from fucosidosis with angiokeratoma, whose normal and diseased skin was studied by lightmicroscopy and electronmicroscopy. The salient clinicopathological features of this disease are briefly reviewed.

    Fucosidosis
    DIAGNOSIS

 is a

    rare lysosomal storage disease
    DIAGNOSIS

 due to

    alpha-L-fucosidase deficiency
    BIOCHEMICAL

. It presents clinically with

    neurological, skeletal, and cutaneous findings
    SYMPTOMS

, including mainly

    angiokeratoma corporis diffusum
    SYMPTOMS

.

    Electronmicroscopic examination
    PARACLINICAL

 reveals

    characteristic electron-lucent cytoplasmic vacuolization present in several cell types of the skin and other tissues
    MICROSCOPIC

. We present here a new patient suffering from

    fucosidosis
    DIAGNOSIS

 with

    angiokeratoma
    SYMPTOMS

, whose

    normal and diseased skin was studied
    PARACLINICAL

 by

    lightmicroscopy and electronmicroscopy
    PARACLINICAL

. The salient clinicopathological features of this disease are briefly reviewed.

Fucosidosis
rare lysosomal storage disease
fucosidosis


[First Polish experience with enzyme replacement therapy in patients with Fabry disease].

We report here the course and outcomes of 18-month enzyme replacement therapy in two 43 and 41-year-old brothers with Fabry disease. At 18 months of recombinant alpha-galactosidase A (Fabrazyme) infusions, we observed in the older patient: weight gain, decreased proteinuria (from 4 to 1.5 g/d), stabilization of creatinine clearance, much lower frequency and intensity of angina, and in the younger brother: weight gain, stabilization of creatinine clearance and proteinuria, prolongation of PQ interval and improvement of hearing. However, neurologic manifestations deteriorated over treatment period in both patients. No serious infusion-related side effects were observed.

We report here the course and outcomes of

    18-month enzyme replacement therapy
    MEDICATION

 in two

    43 and 41-year-old
    AGE

    brothers
    GENDER

 with

    Fabry disease
    DIAGNOSIS

. At

    18 months of recombinant alpha-galactosidase A (Fabrazyme) infusions
    MEDICATION

, we observed in the older patient:

    weight gain
    SYMPTOMS

,

    decreased proteinuria (from 4 to 1.5 g/d)
    BIOCHEMICAL

,

    stabilization of creatinine clearance
    BIOCHEMICAL

,

    much lower frequency and intensity of angina
    SYMPTOMS

, and in the

    younger brother
    AGE

:

    weight gain
    SYMPTOMS

,

    stabilization of creatinine clearance and proteinuria
    BIOCHEMICAL

,

    prolongation of PQ interval
    SYMPTOMS

 and

    improvement of hearing
    SYMPTOMS

. However,

    neurologic manifestations deteriorated
    SYMPTOMS

 over treatment period in both patients.

    No serious infusion-related side effects
    NEG_FINDINGS

 were observed.


Megadolichobasilar anomaly with thrombosis in a family with Fabry's disease and a novel mutation in the alpha-galactosidase A gene.

Fabry's disease is an X-linked lysosomal storage disorder. alpha-Galactosidase deficiency leads to accumulation of globotriaosylceramide mainly in endothelial and smooth muscle cells. Cerebrovascular symptoms with predominant affection of the vertebrobasilar circulation are one of the major sources of morbidity in Fabry's disease. We present a Hungarian family with Fabry's disease caused by a new mutation in the alpha-galactosidase A gene (GLA), and describe a variant expression of the disease. Megadolichobasilar anomaly was diagnosed in two male patients in the family who died of thrombosis. In another female patient who had suffered from disturbance of the vertebrobasilar circulation, a strongly dilated basilar artery without thrombosis was found at autopsy. Another three family members had basilar strokes and large and elongated basilar arteries on MRI. Genetic analysis disclosed a c.47T-->C missense mutation resulting in L16P in the amino acid sequence of the alpha-galactosidase protein. This report suggests that megadolichobasilar anomaly is potentially life-threatening, and that L16P is a disease-causing mutation in patients with Fabry's disease. Early enzyme replacement therapy may prevent the development of these irreversible cerebrovascular complications.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

.

    alpha-Galactosidase deficiency
    BIOCHEMICAL

 leads to

    accumulation of globotriaosylceramide mainly in endothelial and smooth muscle cells
    MICROSCOPIC

.

    Cerebrovascular symptoms
    SYMPTOMS

 with

    predominant affection of the vertebrobasilar circulation
    SYMPTOMS

 are one of the major sources of morbidity in

    Fabry's disease
    DIAGNOSIS

. We present a

    Hungarian
    ETHNICITY

 family with

    Fabry's disease
    DIAGNOSIS

 caused by a

    new mutation in the alpha-galactosidase A gene (GLA)
    GENETICS

, and describe a variant expression of the disease.

    Megadolichobasilar anomaly
    SYMPTOMS

 was diagnosed in two

    male
    GENDER

 patients in the family who

    died of thrombosis
    FAMILY

. In another

    female
    GENDER

 patient who had suffered from

    disturbance of the vertebrobasilar circulation
    SYMPTOMS

, a

    strongly dilated basilar artery
    SYMPTOMS

    without thrombosis
    NEG_FINDINGS

 was found at

    autopsy
    PARACLINICAL

. Another three family members had

    basilar strokes
    SYMPTOMS

 and

    large and elongated basilar arteries
    SYMPTOMS

 on

    MRI
    PARACLINICAL

.

    Genetic analysis
    PARACLINICAL

 disclosed a

    c.47T-->C missense mutation resulting in L16P in the amino acid sequence of the alpha-galactosidase protein
    GENETICS

. This report suggests that

    megadolichobasilar anomaly
    SYMPTOMS

 is

    potentially life-threatening
    SYMPTOMS

, and that

    L16P
    GENETICS

 is a disease

    -causing mutation
    GENETICS

 in patients with

    Fabry's disease
    DIAGNOSIS

.

    Early enzyme replacement therapy
    MEDICATION

 may prevent the development of these

    irreversible cerebrovascular complications
    SYMPTOMS

.

Fabry's disease
lysosomal storage disorder
Fabry's disease
Fabry's disease
Fabry's disease


Bilateral femoral head and distal tibial osteonecrosis in a patient with Fabry disease.

Fabry disease is a lysosomal storage disease caused by alpha-galactosidase A deficiency. The classic presentation of Fabry disease involves multiple organs, including kidneys, heart, skin, eyes, and nervous system. Osteonecrosis is rarely reported in patients with Fabry disease. In this article, we describe the case of a 37-year-old white man who had Fabry disease and no risk factors for osteonecrosis but who developed osteonecrosis in both femoral heads and in an unusual site, bilateral distal tibiae. Results of mutation analysis showed a nonsense mutation (R227X) in the alpha-galactosidase A gene. This case suggests that Fabry disease may be a risk factor for development of osteonecrosis. The enzyme replacement therapy currently available may be an effective method of preventing this complication.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 caused by

    alpha-galactosidase A deficiency
    BIOCHEMICAL

. The classic presentation of

    Fabry disease
    DIAGNOSIS

    involves multiple organs, including kidneys, heart, skin, eyes, and nervous system
    SYMPTOMS

.

    Osteonecrosis
    DIAGNOSIS

 is rarely reported in patients with

    Fabry disease
    DIAGNOSIS

. In this article, we describe the case of a

    37-year-old
    AGE

    white
    ETHNICITY

    man
    GENDER

 who had

    Fabry disease
    DIAGNOSIS

 and

    no risk factors for osteonecrosis
    NEG_FINDINGS

 but who developed

    osteonecrosis in both femoral heads and in an unusual site, bilateral distal tibiae
    SYMPTOMS

. Results of

    mutation analysis
    PARACLINICAL

 showed a

    nonsense mutation (R227X) in the alpha-galactosidase A gene
    GENETICS

. This case suggests that

    Fabry disease
    DIAGNOSIS

 may be a risk factor for development of

    osteonecrosis
    DIAGNOSIS

. The

    enzyme replacement therapy
    MEDICATION

 currently available may be an effective method of preventing this complication.

Fabry disease
lysosomal storage disease
Fabry disease
Osteonecrosis
Fabry disease
Fabry disease
Fabry disease
osteonecrosis


Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabry's disease.

We describe a man and a woman with Fabry's disease. Renal biopsies showed late and early stages respectively of focal and segmental glomerulosclerosis (FSGS) and vascular changes. Clinically the hemizygous patient had advanced renal disease with nephrotic range proteinuria and serum creatinine 122 micromol/l. The female carrier had minimal albuminuria, borderline GFR with a normal serum creatinine, acroparesthesias, moderate fatigue, tinnitus and headache accompanied by ischemic cerebral lesions. Enzyme replacement therapy (ERT) was initiated according to our Fabry protocol, partly due to the renal morphologic findings. We conclude that FSGS and vascular changes may be an early morphologic finding in Fabry's disease, even in patients with subtle albuminuria. The potential role of FSGS as a marker of progressive renal disease in some Fabry patients is discussed. As FSGS and vascular changes obviously may exist across a wide range of clinical presentations and have potential prognostic implications, we suggest that a renal biopsy should be performed prior to enzyme replacement therapy in all adult Fabry patients with proteinuria of various levels. Efforts should be made to develop a scoring system to evaluate potential histologic markers. Protocol biopsies may have therapeutic implications and may provide valuable information in the evaluation of start and dosing of ERT.

We describe a

    man
    GENDER

 and a

    woman
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

.

    Renal biopsies
    PARACLINICAL

 showed

    late and early stages respectively of focal and segmental glomerulosclerosis (FSGS)
    SYMPTOMS

 and

    vascular changes
    SYMPTOMS

. Clinically the

    hemizygous
    GENETICS

 patient had

    advanced renal disease
    DIAGNOSIS

 with

    nephrotic range proteinuria
    BIOCHEMICAL

 and serum creatinine 122 micromol/l. The

    female
    GENDER

 carrier had

    minimal albuminuria
    BIOCHEMICAL

,

    borderline GFR with a normal serum creatinine
    BIOCHEMICAL

,

    acroparesthesias
    SYMPTOMS

,

    moderate fatigue
    SYMPTOMS

,

    tinnitus
    SYMPTOMS

 and

    headache
    SYMPTOMS

 accompanied by

    ischemic cerebral lesions
    SYMPTOMS

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 was initiated according to our Fabry protocol, partly due to the renal morphologic findings. We conclude that

    FSGS
    DIAGNOSIS

 and

    vascular changes
    SYMPTOMS

 may be an early morphologic finding in

    Fabry's disease
    DIAGNOSIS

, even in patients with

    subtle albuminuria
    BIOCHEMICAL

. The potential role of

    FSGS
    DIAGNOSIS

 as a marker of

    progressive renal disease
    DIAGNOSIS

 in some

    Fabry
    DIAGNOSIS

 patients is discussed. As

    FSGS
    DIAGNOSIS

 and

    vascular changes
    SYMPTOMS

 obviously may exist across a wide range of clinical presentations and have potential prognostic implications, we suggest that a

    renal biopsy
    PARACLINICAL

 should be performed prior to

    enzyme replacement therapy
    MEDICATION

 in all

    adult
    AGE

    Fabry
    DIAGNOSIS

 patients with

    proteinuria of various levels
    BIOCHEMICAL

. Efforts should be made to develop a scoring system to evaluate potential histologic markers.

    Protocol biopsies
    PARACLINICAL

 may have therapeutic implications and may provide valuable information in the evaluation of start and dosing of

    ERT
    MEDICATION

.

Fabry's disease
advanced renal disease
FSGS
Fabry's disease
FSGS
progressive renal disease
Fabry
FSGS
Fabry

Enzyme replacement therapy (ERT)
enzyme replacement therapy
ERT


Two unusual cases of Anderson-Fabry disease in a Japanese family.

A 16-year-old Japanese girl was admitted to our hospital on February 27, 2001, for acute renal failure. She had not shown proteinuria or hematuria in any school examination through 2000. The first renal biopsy specimen showed focal segmental glomerulosclerosis and tubulointerstitial change. Electron microscopy showed numerous myeloid bodies in the glomerular epithelium suggesting the diagnosis of Anderson-Fabry disease. After electron microscopy, we measured WBC alpha-galactosidase A, which was slightly decreased to 36.1 nmol/mg P/h (normal: 49.8 - 116.4). WBC alpha-galactosidase A levels for other family members were 74.3 for the mother, 4.8 for the father, 45.6 for the elder sister, and 16.3 for the younger sister. During the follow-up, she had two episodes of nephrotic syndrome, which responded well to steroid therapy. Both second and third renal biopsy showed numerous myeloid bodies by electron microscopy. A 52-year-old man, the father of the case one patient, was admitted for renal biopsy because of proteinuria and low levels of WBC alpha-galactosidase. Biopsy specimen showed typical changes under light microscopy and typical myeloid bodies by electron microscopy. Our cases underscore the importance of electron microscopy when examining the biopsy specimen and suggest that undiagnosed Anderson-Fabry disease may be present, in particular on chronic dialysis.

A

    16-year-old
    AGE

    Japanese
    ETHNICITY

    girl
    GENDER

 was admitted to our hospital on February 27, 2001, for

    acute renal failure
    SYMPTOMS

.

    She
    GENDER

 had

    not shown proteinuria or hematuria in any school examination
    NEG_FINDINGS

 through 2000. The

    first renal biopsy specimen
    PARACLINICAL

 showed

    focal segmental glomerulosclerosis
    MICROSCOPIC

 and

    tubulointerstitial change
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 showed

    numerous myeloid bodies in the glomerular epithelium
    MICROSCOPIC

 suggesting the diagnosis of

    Anderson-Fabry disease
    DIAGNOSIS

. After

    electron microscopy
    PARACLINICAL

, we measured

    WBC alpha-galactosidase A, which was slightly decreased to 36.1 nmol/mg P/h (normal: 49.8 - 116.4)
    BIOCHEMICAL

.

    WBC alpha-galactosidase A levels for other family members were 74.3 for the mother, 4.8 for the father, 45.6 for the elder sister, and 16.3 for the younger sister
    BIOCHEMICAL

. During the follow-up,

    she
    GENDER

 had two episodes of

    nephrotic syndrome
    DIAGNOSIS

, which responded well to

    steroid therapy
    MEDICATION

.

    Both second and third renal biopsy
    PARACLINICAL

 showed

    numerous myeloid bodies
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. A

    52-year-old
    AGE

    man
    GENDER

, the

    father of the case one patient
    FAMILY

, was admitted for

    renal biopsy
    PARACLINICAL

 because of

    proteinuria
    BIOCHEMICAL

 and

    low levels of WBC alpha-galactosidase
    BIOCHEMICAL

.

    Biopsy specimen
    PARACLINICAL

 showed

    typical changes
    MICROSCOPIC

 under

    light microscopy
    PARACLINICAL

 and

    typical myeloid bodies
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. Our cases underscore the importance of

    electron microscopy
    PARACLINICAL

 when

    examining the biopsy specimen
    PARACLINICAL

 and suggest that undiagnosed

    Anderson-Fabry disease
    DIAGNOSIS

 may be present, in particular on

    chronic dialysis
    MEDICATION

.

Anderson-Fabry disease
nephrotic syndrome
Anderson-Fabry disease


[An unusual case of microhematuria].

Microhematuria is nearly always due to renal parenchymal or genito-urinary damage, with few exceptions. We report a case of microhematuria due to vascular anomaly. The diagnosis was realized making use of several imaging techniques.

    Microhematuria
    BIOCHEMICAL

 is nearly always due to

    renal parenchymal or genito-urinary damage
    SYMPTOMS

, with few exceptions. We report a case of

    microhematuria
    BIOCHEMICAL

 due to

    vascular anomaly
    DIAGNOSIS

. The diagnosis was realized making use of several imaging techniques.


Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys.

The prognosis of Fabry disease has changed since enzyme-replacement treatment was introduced. Therefore, early diagnosis is instrumental. We describe a family presenting with chronic renal failure and proteinuria in which classic skin and neurological features were absent and the diagnosis of Fabry disease was difficult and not established until a second family member developed renal abnormalities. A 35-year-old man was admitted because he was overweight and had hypertension, with a serum creatinine level of 1.3 mg/dL (115 micromol/L) and protein excretion of 870 mg/d. Because 1 brother, who died years ago at the age of 32 years of acute myeloid leukemia, also had chronic renal failure and proteinuria, the diagnosis of Fabry disease was entertained. In the index patient, acroparesthesia, hypohidrosis, pain, angiokeratomas of the skin, and cornea verticillata suggesting Fabry disease were absent. Conversely, renal biopsy showed typical globotriaosylceramide deposits, and leukocyte alpha-galactosidase (alpha-GLA) A activity was decreased. Analysis of the alpha-GLA gene showed the mutation E66K. The mutation also was found in another asymptomatic 30-year-old brother who also had chronic renal failure and proteinuria, but normal extrarenal findings. In the brother who died, Fabry disease, missed at autopsy because of cancer-related findings, could be confirmed after repeated review of histological slides. Mutation carriers also included the mother, a sister (both without abnormalities), and a nephew (with episodic pains in his feet). We conclude that familial chronic renal failure combined with proteinuria is suggestive of Fabry disease, and such specific mutations as E66K predominantly may affect the kidneys.

The prognosis of

    Fabry disease
    DIAGNOSIS

 has changed since

    enzyme-replacement treatment
    MEDICATION

 was introduced. Therefore, early diagnosis is instrumental. We describe a family presenting with

    chronic renal failure
    SYMPTOMS

 and

    proteinuria
    BIOCHEMICAL

 in which

    classic skin and neurological features were absent
    NEG_FINDINGS

 and the diagnosis of

    Fabry disease
    DIAGNOSIS

 was difficult and not established until a

    second family member developed renal abnormalities
    FAMILY

. A

    35-year-old
    AGE

    man
    GENDER

 was admitted because

    he
    GENDER

 was

    overweight
    GENDER

 and had

    hypertension
    SYMPTOMS

, with a

    serum creatinine level of 1.3 mg/dL (115 micromol/L)
    BIOCHEMICAL

 and protein excretion of 870 mg/d. Because 1

    brother, who died years ago at the age of 32 years
    FAMILY

    of acute myeloid leukemia
    FAMILY

,

    also had chronic renal failure
    FAMILY

 and

    proteinuria
    BIOCHEMICAL

, the diagnosis of

    Fabry disease
    DIAGNOSIS

 was entertained. In the index patient,

    acroparesthesia
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    pain
    SYMPTOMS

,

    angiokeratomas of the skin
    SYMPTOMS

, and

    cornea verticillata
    SYMPTOMS

 suggesting

    Fabry disease were absent
    NEG_FINDINGS

. Conversely,

    renal biopsy
    PARACLINICAL

 showed

    typical globotriaosylceramide deposits
    MICROSCOPIC

, and

    leukocyte alpha-galactosidase (alpha-GLA) A activity was decreased
    BIOCHEMICAL

.

    Analysis of the alpha-GLA gene
    PARACLINICAL

 showed the mutation E66K. The mutation also was found in another

    asymptomatic 30-year-old
    FAMILY

    brother
    GENDER

    who also had chronic renal failure
    FAMILY

 and

    proteinuria
    BIOCHEMICAL

, but

    normal extrarenal findings
    NEG_FINDINGS

. In the

    brother
    GENDER

    who died
    FAMILY

,

    Fabry disease
    DIAGNOSIS

,

    missed at autopsy
    NEG_FINDINGS

 because of

    cancer-related findings
    SYMPTOMS

, could be confirmed after

    repeated review of histological slides
    PARACLINICAL

.

    Mutation carriers also included the mother, a sister (both without abnormalities), and a nephew (with episodic pains in his feet)
    FAMILY

. We conclude that

    familial chronic renal failure
    SYMPTOMS

 combined with

    proteinuria
    BIOCHEMICAL

 is suggestive of

    Fabry disease
    DIAGNOSIS

, and such specific

    mutations as E66K
    GENETICS

 predominantly may affect

    the kidneys
    GENETICS

.

Fabry disease
Fabry disease
Fabry disease
Fabry disease
Fabry disease

chronic renal failure
hypertension
acroparesthesia
hypohidrosis
pain
angiokeratomas of the skin
cornea verticillata
cancer-related findings
familial chronic renal failure


[Clinical courses of two male siblings on hemodialysis for Fabry disease ].

Fabry disease is an X-linked recessive disease resulting from a deficiency of the lysosomal hydrolase alpha-galactosidase A. In male patients with the classic hemizygous form, acroparesthesias, hypohidrosis, corneal opacities, and dysfunction of the heart, brain, and kidney are observed. Recently, it was reported that 0.5-1.2% of male chronic hemodialysis (HD) patients were diagnosed as having Fabry disease based on the measurement of alpha-galactosidase A activity. Fabry disease is thought to be an important cause of end-stage renal disease. There are a few reports of patients with Fabry disease on long-term HD. Here we report two male siblings with classical type Fabry disease on HD. They had acroparesthesias, and hypohidrosis. Their mother had severe heart failure due to a heterozygous form of Fabry disease. Case 1 is a 44-year-old male. He had mid-cerebral apoplexy at 30 years of age. He started maintenance HD in 2000. Remarkable left ventricular hypertophy and conduction disorders of the heart were found. In 2004, he collapsed and ventricular-tachycardia and severe hypoxic brain damage were found. Now his consciousness level has been in the range of 100 to 300 on the Japan Coma Scale. Case 2 is a 40-year-old male. He started maintenance HD in 1993. Malnutrition due to chronic diarrhea and severe ischemic change in the brain were found. In 1998, he had severe joint pain of shoulders and fingers with ectopic calcifications detected by X ray. The ectopic calcifications were extended to the whole body. In 2004, his dementia by ischemic change in the brain has rapidly progressed. In conclusion, cardiovascular complications, cerebrovascular manifestations, painful ectopic carcifications, and chronic diarrheas in our patients were considered to be specific symptoms of Fabry disease. Young HD patients with these symptoms will need to be examined for Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive disease
    GENETICS

 resulting from a deficiency of the lysosomal hydrolase alpha-galactosidase A. In

    male
    GENDER

 patients with the

    classic hemizygous form
    GENETICS

,

    acroparesthesias
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    corneal opacities
    SYMPTOMS

, and

    dysfunction of the heart, brain, and kidney
    SYMPTOMS

 are observed. Recently, it was reported that 0.5-1.2% of

    male
    GENDER

    chronic hemodialysis (HD)
    MEDICATION

 patients were diagnosed as having

    Fabry disease
    DIAGNOSIS

 based on the measurement of

    alpha-galactosidase A activity
    BIOCHEMICAL

.

    Fabry disease
    DIAGNOSIS

 is thought to be an important cause of

    end-stage renal disease
    DIAGNOSIS

. There are a few reports of patients with

    Fabry disease
    DIAGNOSIS

 on

    long-term HD
    MEDICATION

. Here we report two

    male
    GENDER

    siblings with classical type Fabry disease
    FAMILY

 on

    HD
    MEDICATION

. They had

    acroparesthesias
    SYMPTOMS

, and

    hypohidrosis
    SYMPTOMS

.

    Their mother had severe heart failure due to a heterozygous form of Fabry disease
    FAMILY

. Case 1 is a

    44-year-old
    AGE

    male
    GENDER

.

    He
    GENDER

 had

    mid-cerebral apoplexy
    SYMPTOMS

    at 30 years of age
    AGE

.

    He
    GENDER

 started

    maintenance HD
    MEDICATION

 in 2000.

    Remarkable left ventricular hypertophy
    SYMPTOMS

 and

    conduction disorders of the heart
    SYMPTOMS

 were found. In 2004,

    he
    GENDER

 collapsed and

    ventricular-tachycardia
    SYMPTOMS

 and

    severe hypoxic brain damage
    SYMPTOMS

 were found. Now his

    consciousness level has been in the range of 100 to 300 on the Japan Coma Scale
    SYMPTOMS

. Case 2 is a

    40-year-old
    AGE

    male
    GENDER

.

    He
    GENDER

 started

    maintenance HD
    MEDICATION

 in 1993.

    Malnutrition
    SYMPTOMS

 due to

    chronic diarrhea
    SYMPTOMS

 and

    severe ischemic change in the brain
    SYMPTOMS

 were found. In 1998,

    he
    GENDER

 had

    severe joint pain of shoulders and fingers
    SYMPTOMS

 with

    ectopic calcifications
    SYMPTOMS

 detected by

    X ray
    PARACLINICAL

. The

    ectopic calcifications were extended to the whole body
    SYMPTOMS

. In 2004, his

    dementia by ischemic change in the brain has rapidly progressed
    SYMPTOMS

. In conclusion,

    cardiovascular complications
    SYMPTOMS

,

    cerebrovascular manifestations
    SYMPTOMS

,

    painful ectopic carcifications
    SYMPTOMS

, and

    chronic diarrheas
    SYMPTOMS

 in our patients were considered to be specific symptoms of

    Fabry disease
    DIAGNOSIS

.

    Young HD
    AGE

 patients with these symptoms will need to be examined for

    Fabry disease
    DIAGNOSIS

.

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

X-linked recessive disease
classic hemizygous form

chronic hemodialysis (HD)
long-term HD
HD
maintenance HD
maintenance HD


Reduced coronary flow reserve in Anderson-Fabry disease measured by transthoracic Doppler echocardiography.

Coronary flow reserve was assessed in a patient with Anderson-Fabry disease complicated by symmetric left ventricular hypertrophy. Coronary flow reserve was measurable in all three major coronary arteries providing an opportunity to compare regional coronary flow reserve from different vascular beds. In this patient all the three vascular beds supplied diffusely hypertrophied myocardium. Coronary flow disturbances in small intramyocardial perforating arteries were visible. The coronary flow reserve was reduced to a similar level (around to 2.0) in all three major arteries. In our patient with Anderson-Fabry disease, the coronary vasodilatation was blunted in a diffuse pattern corresponding to the myocardial hypertrophy distribution. In small intramyocardial arteries coronary flow was also disturbed. Accordingly, retrograde systolic flow and accelerated anterograde diastolic flow were documented.

    Coronary flow reserve
    PARACLINICAL

 was assessed in a patient with

    Anderson-Fabry disease
    DIAGNOSIS

 complicated by

    symmetric left ventricular hypertrophy
    SYMPTOMS

.

    Coronary flow reserve was measurable in all three major coronary arteries
    SYMPTOMS

 providing an opportunity to compare regional coronary flow reserve from different vascular beds. In this patient

    all the three vascular beds supplied diffusely hypertrophied myocardium
    SYMPTOMS

.

    Coronary flow disturbances in small intramyocardial perforating arteries
    SYMPTOMS

 were visible. The

    coronary flow reserve was reduced to a similar level (around to 2.0) in all three major arteries
    SYMPTOMS

. In our patient with

    Anderson-Fabry disease
    DIAGNOSIS

, the

    coronary vasodilatation was blunted in a diffuse pattern corresponding to the myocardial hypertrophy distribution
    SYMPTOMS

.

    In small intramyocardial arteries
    SYMPTOMS

    coronary flow was also disturbed
    SYMPTOMS

. Accordingly,

    retrograde systolic flow and accelerated anterograde diastolic flow
    SYMPTOMS

 were documented.

Anderson-Fabry disease
Anderson-Fabry disease


Fabry disease: percutaneous transluminal septal myocardial ablation markedly improved symptomatic left ventricular hypertrophy and outflow tract obstruction in a classically affected male.

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disease in which left ventricular hypertrophy (LVH) is common, and if severe, may mimic hypertrophic obstructive cardiomyopathy. Alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA) has been used as a safe and effective method to alleviate LVH obstruction in patients with hypertrophic obstructive cardiomyopathy (HCM). We describe a case of a classically affected Fabry 53-year-old male with symptomatic HCM (NYHA class III with exertional angina) who was treated with PTSMA. The procedure safely and effectively alleviated symptomatic left ventricular outflow tract obstruction at long-term follow-up, and the patient's NYHA classification was reduced to NYHA class I to II.

    Fabry disease
    DIAGNOSIS

 (

    alpha-galactosidase A deficiency)
    BIOCHEMICAL

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 in which

    left ventricular hypertrophy (LVH)
    SYMPTOMS

 is common, and if severe, may mimic

    hypertrophic obstructive cardiomyopathy
    DIAGNOSIS

.

    Alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA)
    MEDICATION

 has been used as a safe and effective method to alleviate

    LVH obstruction
    SYMPTOMS

 in patients with

    hypertrophic obstructive cardiomyopathy (HCM)
    DIAGNOSIS

. We describe a case of a classically affected

    Fabry
    DIAGNOSIS

    53-year-old
    AGE

    male
    GENDER

 with

    symptomatic HCM
    DIAGNOSIS

 (

    NYHA class III with exertional angina
    SYMPTOMS

) who was treated with

    PTSMA
    MEDICATION

. The procedure safely and effectively

    alleviated symptomatic left ventricular outflow tract obstruction
    SYMPTOMS

 at

    long-term follow-up
    PARACLINICAL

, and the patient's

    NYHA classification was reduced to NYHA class I to II
    SYMPTOMS

.