[A family with a rare disease].

Fabry disease (FD) is a rare disorder resulting from mutations of the alpha-Galactosidase A lysosomal enzyme gene. Accumulation of enzyme substrates leads to multisystemic clinical manifestations and multiorgan progressive damage with high morbidity and mortality. Recombinant enzyme replacement therapy (RERT) now available aims to delay or even avoid the complications of FD. The index case was a 50-year-old man with bone pain since childhood, coarse facies, angiokeratomas, anemia, renal failure, proteinuria, sinus node disease, valvular disease and massive left ventricular hypertrophy and brain ischemic alterations. FD diagnosis was confirmed during hospital admission for bacterial endocarditis leading to death. Family screening revealed an affected brother with acroparesthesia, chronic cough, sinus bradycardia, long QT interval and near-nephrotic proteinuria, now under RERT. Their mother was not screened due to stroke sequelae. This report illustrates the need for early diagnosis, family screening and treatment, aiming to change the natural history of FD.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare disorder
    GENETICS

 resulting from

    mutations of the alpha-Galactosidase A lysosomal enzyme gene
    GENETICS

.

    Accumulation of enzyme substrates
    MICROSCOPIC

 leads to

    multisystemic clinical manifestations
    SYMPTOMS

 and

    multiorgan progressive damage
    SYMPTOMS

 with high morbidity and mortality.

    Recombinant enzyme replacement therapy (RERT)
    MEDICATION

 now available aims to delay or even avoid the complications of

    FD
    DIAGNOSIS

. The index case was a

    50-year-old
    AGE

    man
    GENDER

 with

    bone pain
    SYMPTOMS

 since

    childhood
    AGE

,

    coarse facies
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    anemia
    BIOCHEMICAL

,

    renal failure
    SYMPTOMS

,

    proteinuria
    BIOCHEMICAL

,

    sinus node disease
    DIAGNOSIS

,

    valvular disease
    SYMPTOMS

 and

    massive left ventricular hypertrophy
    SYMPTOMS

 and

    brain ischemic alterations
    SYMPTOMS

.

    FD
    DIAGNOSIS

 diagnosis was confirmed during

    hospital admission
    MEDICATION

 for

    bacterial endocarditis
    DIAGNOSIS

 leading to

    death
    SYMPTOMS

.

    Family screening
    PARACLINICAL

 revealed

    an affected brother with acroparesthesia
    FAMILY

,

    chronic cough
    SYMPTOMS

,

    sinus bradycardia
    SYMPTOMS

,

    long QT interval
    SYMPTOMS

 and

    near-nephrotic proteinuria
    BIOCHEMICAL

, now under

    RERT
    MEDICATION

.

    Their mother was not screened
    FAMILY

 due to

    stroke sequelae
    SYMPTOMS

. This report illustrates the need for early diagnosis,

    family screening
    PARACLINICAL

 and treatment, aiming to change the natural history of

    FD
    DIAGNOSIS

.

Fabry disease (FD)
FD
sinus node disease
FD
bacterial endocarditis
FD

multisystemic clinical manifestations
multiorgan progressive damage
bone pain
coarse facies
angiokeratomas
renal failure
valvular disease
massive left ventricular hypertrophy
brain ischemic alterations
death
chronic cough
sinus bradycardia
long QT interval
stroke sequelae

anemia
proteinuria
near-nephrotic proteinuria


Enzyme replacement therapy in a patient with Fabry disease and the development of IgE antibodies against agalsidase beta but not agalsidase alpha.

Fabry disease is an X-linked inherited lysosomal storage disorder caused by an inborn deficiency of the enzyme α-galactosidase A. Enzyme replacement therapy (ERT) with agalsidase alpha or beta isozymes is an effective treatment. Cross-reactivity of immunoglobulin G (IgG) antibodies with agalsidase alpha and beta has been reported, but no such reaction has been recorded for IgE antibodies. We present the case of a patient with Fabry disease who developed antiagalsidase beta IgE antibodies without cross-reactivity to agalsidase alpha. A 17-year-old boy with Fabry disease had suffered from severe atopic dermatitis since infancy, and he complained for several years of peripheral pain during the summer months and when exercising. Fabry disease was confirmed by family history and a positive enzyme test, and ERT was commenced. Following infusion of agalsidase beta (1.0 mg/kg), the patient complained of a high temperature in his hands and feet, and purulent eczema developed. The infusion dose was reduced to 0.2 mg/kg, but the hyperthermia did not change, although its duration decreased. After three infusions, eosinophilia developed (9.4%; 573 cells/μl blood) and remained unresolved after four infusions with agalsidase beta. Treatment with this enzyme was discontinued, and agalsidase alpha (0.2 mg/kg) started. This produced immediate resolution of the eosinophilia, which has been maintained during follow-up. In conclusion, this patient developed IgE antibodies against agalsidase beta, which demonstrated no cross-reactivity to agalsidase alpha. These findings emphasize the importance of analyzing IgE antibodies against both enzymes when patients exhibit severe infusion-related events.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by an inborn deficiency of the enzyme α-galactosidase A.

    Enzyme replacement therapy (ERT) with agalsidase alpha or beta isozymes
    MEDICATION

 is an effective treatment.

    Cross-reactivity of immunoglobulin G (IgG) antibodies with agalsidase alpha and beta
    BIOCHEMICAL

 has been reported, but no such reaction has been recorded for

    IgE antibodies
    BIOCHEMICAL

. We present the case of a patient with

    Fabry disease
    DIAGNOSIS

 who developed

    antiagalsidase beta IgE antibodies
    BIOCHEMICAL

    without cross-reactivity to agalsidase alpha
    NEG_FINDINGS

. A

    17-year-old
    AGE

    boy
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 had suffered from

    severe atopic dermatitis
    SYMPTOMS

 since

    infancy
    AGE

, and

    he
    GENDER

 complained for

    several years of peripheral pain during the summer months
    SYMPTOMS

 and when

    exercising
    SYMPTOMS

.

    Fabry disease
    DIAGNOSIS

 was confirmed by

    family history
    PARACLINICAL

 and a

    positive enzyme test
    PARACLINICAL

, and

    ERT
    MEDICATION

 was commenced. Following

    infusion of agalsidase beta (1.0 mg/kg)
    MEDICATION

, the patient complained of a

    high temperature in his hands and feet
    SYMPTOMS

, and

    purulent eczema developed
    SYMPTOMS

. The

    infusion dose was reduced to 0.2 mg/kg
    MEDICATION

, but the

    hyperthermia did not change
    NEG_FINDINGS

, although

    its duration decreased
    SYMPTOMS

. After

    three infusions
    MEDICATION

,

    eosinophilia developed (9.4%; 573 cells/μl blood)
    BIOCHEMICAL

 and

    remained unresolved
    BIOCHEMICAL

 after

    four infusions with agalsidase beta
    MEDICATION

.

    Treatment with this enzyme was discontinued
    MEDICATION

, and

    agalsidase alpha (0.2 mg/kg) started
    MEDICATION

. This produced

    immediate resolution of the eosinophilia
    BIOCHEMICAL

, which has been maintained during

    follow-up
    PARACLINICAL

. In conclusion, this patient developed

    IgE antibodies against agalsidase beta
    BIOCHEMICAL

, which demonstrated

    no cross-reactivity to agalsidase alpha
    NEG_FINDINGS

. These findings emphasize the importance of analyzing

    IgE antibodies against both enzymes
    BIOCHEMICAL

 when patients exhibit

    severe infusion-related events
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease
Fabry disease


Treatment with agalsidase beta during pregnancy in Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A, which leads to excessive accumulation of glycosphingolipids in most tissues in the body, with life-threatening clinical consequences in the kidney, heart, and cerebrovascular system. Enzyme replacement therapy using exogenously produced alpha-galactosidase has been available for treatment of this multisystem progressive disease since 2001. Two different preparations of enzyme replacement therapy for Fabry disease are available outside of the USA: agalsidase alfa and agalsidase beta. Despite being X-linked, Fabry disease affects many female patients, and this report presents a successful pregnancy of a female patient receiving agalsidase beta.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a

    deficiency of alpha-galactosidase A
    BIOCHEMICAL

, which leads to

    excessive accumulation of glycosphingolipids in most tissues in the body
    MICROSCOPIC

, with

    life-threatening clinical consequences in the kidney, heart, and cerebrovascular system
    SYMPTOMS

.

    Enzyme replacement therapy using exogenously produced alpha-galactosidase
    MEDICATION

 has been available for treatment of this

    multisystem progressive disease
    DIAGNOSIS

 since 2001. Two different

    preparations of enzyme replacement therapy for Fabry disease
    MEDICATION

 are available outside of the USA:

    agalsidase alfa and agalsidase beta
    MEDICATION

. Despite being

    X-linked
    GENETICS

,

    Fabry disease
    DIAGNOSIS

 affects many

    female
    GENDER

 patients, and this report presents a successful

    pregnancy
    MEDICATION

 of a

    female
    GENDER

 patient receiving

    agalsidase beta
    MEDICATION

.

Fabry disease
lysosomal storage disease
multisystem progressive disease
Fabry disease


Co-existence of phenylketonuria and Fabry disease on a 3 year-old boy: case report.

The co-existence of two genetically distinct metabolic disorders in the same patient has rarely been reported. Phenylketonuria (PKU) is an inborn error of the metabolism resulting from a phenylalanine hydroxylase deficiency. Fabry disease (FD) is an X-linked lysosomal storage disorder due to a deficiency of the enzyme alpha-galactosidase A.

We report a case of a 3 year- old boy affected by classic PKU and FD, both confirmed by molecular data. The FD was suspected at the age of 21 months on the presence of non-specific GI symptoms (severe abdominal pain and periodically appearance of not specific episodes of gastroenteritis) apparently non related to PKU.

This is the first report of co-existence of FD and PKU, two different congenital inborn of metabolism and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of this diseases made very difficult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specific gastroenteritis episodes. Furthermore, this case report helps to define the early clinical phenotype of FD.

The

    co-existence of two genetically distinct metabolic disorders
    DIAGNOSIS

 in the same patient has rarely been reported.

    Phenylketonuria (PKU)
    DIAGNOSIS

 is an

    inborn error of the metabolism
    DIAGNOSIS

 resulting from a

    phenylalanine hydroxylase deficiency
    BIOCHEMICAL

.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 due to a deficiency of the enzyme alpha-galactosidase A.

We report a case of a

    3 year- old
    AGE

    boy
    GENDER

 affected by

    classic PKU
    DIAGNOSIS

 and

    FD
    DIAGNOSIS

, both confirmed by

    molecular data
    PARACLINICAL

. The

    FD
    DIAGNOSIS

 was suspected at the

    age of 21 months
    AGE

 on the presence of

    non-specific GI symptoms
    SYMPTOMS

 (

    severe abdominal pain
    SYMPTOMS

 and

    periodically appearance of not specific episodes of gastroenteritis)
    SYMPTOMS

 apparently

    non related to PKU
    NEG_FINDINGS

.

This is the first report of

    co-existence of FD and PKU
    DIAGNOSIS

,

    two different congenital inborn of metabolism
    GENETICS

 and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of this diseases made very difficult the correct interpretation of clinical symptoms as

    lack of appetite
    SYMPTOMS

,

    severe abdominal pain
    SYMPTOMS

 and

    non-specific gastroenteritis episodes
    SYMPTOMS

. Furthermore, this case report helps to define the early clinical phenotype of

    FD
    DIAGNOSIS

.


Unusual scarring patterns on cardiac magnetic resonance imaging: A potentially treatable etiology not to be missed.

A case of cardiomyopathy and ventricular tachycardia previously assumed to be idiopathic in origin is described. Investigation with cardiac magnetic resonance imaging prompted the diagnosis and successful treatment of an underlying disorder based on typical scarring patterns seen with late gadolinium enhancement. The present report suggests that clinicians should have a low threshold for actively excluding this condition in patients presenting with cardiomyopathy, even in the absence of other disease features, particularly if typical scarring patterns are found on cardiac magnetic resonance imaging because disease-specific therapy appears to significantly improve both symptoms and prognosis.

A case of

    cardiomyopathy
    DIAGNOSIS

 and

    ventricular tachycardia
    SYMPTOMS

    previously assumed to be idiopathic in origin
    NEG_FINDINGS

 is described. Investigation with

    cardiac magnetic resonance imaging
    PARACLINICAL

 prompted the diagnosis and successful treatment of an underlying disorder based on typical

    scarring patterns seen with late gadolinium enhancement
    SYMPTOMS

. The present report suggests that clinicians should have a low threshold for actively excluding this condition in patients presenting with

    cardiomyopathy
    DIAGNOSIS

, even in the

    absence of other disease features
    NEG_FINDINGS

, particularly if

    typical scarring patterns
    SYMPTOMS

 are found on

    cardiac magnetic resonance imaging
    PARACLINICAL

 because

    disease-specific therapy
    MEDICATION

 appears to significantly improve both symptoms and prognosis.


Cerebral hemorrhage in Fabry's disease.

Fabry's disease is an X-linked lysosomal storage disorder resulting from alpha-galactosidase A deficiency. Although ischemic stroke is recognized as an important manifestation of Fabry's disease, hemorrhagic stroke is considered to be rare. Here, we report our recent clinical experience with three hemizygous male patients with Fabry's disease who developed cerebral hemorrhage. One patient had classic type Fabry's disease with p.Ala37Val mutation and others had cerebrovascular variant with p.Glu66Gln mutation. Degeneration of the cerebral small arteries secondary to deposition of glycosphingolipids and aging, in addition to hypertension and antiplatelet/anticoagulant agents, are considered to be contributing factors for hemorrhage. Fabry's disease is frequently associated with not only ischemic but also hemorrhagic stroke, especially in elderly patients.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from

    alpha-galactosidase A deficiency
    BIOCHEMICAL

. Although

    ischemic stroke
    SYMPTOMS

 is recognized as an important manifestation of

    Fabry's disease
    DIAGNOSIS

,

    hemorrhagic stroke
    SYMPTOMS

 is considered to be rare. Here, we report our recent clinical experience with three

    hemizygous male
    GENETICS

 patients with

    Fabry's disease
    DIAGNOSIS

 who developed

    cerebral hemorrhage
    SYMPTOMS

. One patient had

    classic type Fabry's disease
    DIAGNOSIS

 with

    p.Ala37Val mutation
    GENETICS

 and others had

    cerebrovascular variant
    GENETICS

 with

    p.Glu66Gln mutation
    GENETICS

.

    Degeneration of the cerebral small arteries
    SYMPTOMS

 secondary to

    deposition of glycosphingolipids
    MICROSCOPIC

 and

    aging
    AGE

, in addition to

    hypertension
    SYMPTOMS

 and

    antiplatelet/anticoagulant agents
    MEDICATION

, are considered to be contributing factors for

    hemorrhage
    SYMPTOMS

.

    Fabry's disease
    DIAGNOSIS

 is frequently associated with not only

    ischemic
    SYMPTOMS

 but also

    hemorrhagic stroke
    SYMPTOMS

, especially in

    elderly
    AGE

 patients.

Fabry's disease
lysosomal storage disorder
Fabry's disease
Fabry's disease
classic type Fabry's disease
Fabry's disease

X-linked
hemizygous male
p.Ala37Val mutation
cerebrovascular variant
p.Glu66Gln mutation


Analysis of placental tissue in Fabry disease with and without enzyme replacement therapy.

There are only a few reports on the histology of placental tissue of pregnancies from mothers with Fabry disease. Fabry disease is a lysosomal disorder caused by alpha-galactosidase A deficiency. Extensive glycosphingolipid (GSL) accumulation in fetal and maternal placenta tissue obtained from a Fabry mother and her affected male newborn has previously been reported. Here we report the evaluation of placenta tissue of two pregnancies in Fabry mothers, one of an unaffected male newborn (placenta A) and one of an affected female newborn (placenta B). The mother of the female affected offspring was treated with recombinant alpha-galactosidase A (enzyme replacement therapy, ERT) during the pregnancy (placenta B). Storage material was only detected in smooth muscle cells of the umbilical cord of placenta B. No accumulation was seen in both placentae. Combing these results with the outcome in two earlier described placentae, a heterogeneous picture emerges. This may be due to differences in disease severity in the mothers or severity of disease in their offspring. In addition, a possible effect of ERT on placental GSL accumulation could also explain lack of GSL storage in placenta B.

There are only a few reports on the

    histology of placental tissue
    PARACLINICAL

 of

    pregnancies
    DIAGNOSIS

 from

    mothers
    GENDER

 with

    Fabry disease
    DIAGNOSIS

.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal disorder
    DIAGNOSIS

 caused by

    alpha-galactosidase A deficiency
    BIOCHEMICAL

.

    Extensive glycosphingolipid (GSL) accumulation in fetal and maternal placenta tissue
    MICROSCOPIC

 obtained from a

    Fabry
    DIAGNOSIS

 mother and her affected

    male
    GENDER

    newborn
    AGE

 has previously been reported. Here we report the

    evaluation of placenta tissue
    PARACLINICAL

 of two

    pregnancies
    DIAGNOSIS

 in

    Fabry
    DIAGNOSIS

    mothers
    GENDER

, one of an unaffected

    male
    GENDER

    newborn
    AGE

 (placenta A) and one of an affected

    female
    GENDER

    newborn
    AGE

 (placenta B). The

    mother
    GENDER

 of the

    female
    GENDER

 affected

    offspring
    GENDER

 was

    treated with recombinant alpha-galactosidase A (enzyme replacement therapy, ERT) during the pregnancy
    MEDICATION

 (

    placenta B
    DIAGNOSIS

). Storage material was only detected in smooth muscle cells of the umbilical cord of placenta B.

    No accumulation was seen in both placentae
    NEG_FINDINGS

. Combing these results with the outcome in two earlier described placentae, a heterogeneous picture emerges. This may be due to differences in disease severity in the mothers or severity

    of disease in their offspring
    FAMILY

. In addition, a possible effect of

    ERT
    MEDICATION

 on

    placental GSL accumulation
    BIOCHEMICAL

 could also explain lack of GSL storage in placenta B.

pregnancies
Fabry disease
Fabry disease
lysosomal disorder
Fabry
pregnancies
Fabry
placenta B

alpha-galactosidase A deficiency
placental GSL accumulation


New mutation in female patient with renal variant of Fabry disease and HIV.

We describe the case of a 27-year-old woman with a family history of Anderson-Fabry disease (AFD). Urinary sediment presented microhematuria and 0.9 g/24 hours proteinuria. The alpha-galactosidase A measurement in fibroblasts showed partial deficit of the enzyme, which was compatible with being a carrier of the illness. Renal biopsy gave evidence of kidney lesions from Fabry disease. Genetic study revealed mutation C52Y or Cys52Tyr, which has not been previously described and had also been detected in the father of the patient. During follow-up, the presence of hypergammaglobulinemia revealed an underlying HIV disease. She is now awaiting enzymatic substitution treatment.

We describe the case of a

    27-year-old
    AGE

    woman
    GENDER

 with a

    family history of Anderson-Fabry disease (AFD)
    FAMILY

.

    Urinary sediment
    PARACLINICAL

 presented

    microhematuria
    BIOCHEMICAL

 and

    0.9 g/24 hours proteinuria
    BIOCHEMICAL

. The

    alpha-galactosidase A measurement in fibroblasts
    BIOCHEMICAL

 showed

    partial deficit of the enzyme
    BIOCHEMICAL

, which was compatible with being a

    carrier of the illness
    FAMILY

.

    Renal biopsy
    PARACLINICAL

 gave evidence of

    kidney lesions from Fabry disease
    MICROSCOPIC

.

    Genetic study
    PARACLINICAL

 revealed

    mutation C52Y or Cys52Tyr
    GENETICS

, which has not been previously described and had also been detected

    in the father of the patient
    FAMILY

. During

    follow-up
    PARACLINICAL

, the presence of

    hypergammaglobulinemia
    BIOCHEMICAL

 revealed an underlying

    HIV disease
    DIAGNOSIS

.

    She
    GENDER

 is now awaiting

    enzymatic substitution treatment
    MEDICATION

.


A case of multiple angiomas without any angiokeratomas in a female heterozygote with Fabry disease.

Fabry disease is a rare, X-chromosome-linked lysosomal storage disease caused by a deficient alpha-galactosidase A enzyme. The disease manifests primarily in affected hemizygous males and to some extent in heterozygous females ('carrier'). A 45-year-old female Fabry disease patient without angiokeratomas but with numerous angiomas is presented. Her leukocyte alpha-galactosidase A activity was reduced (0.35 nmol/min/mg protein; normal range: 0.4-1). The analysis of her alpha-galactosidase A gene (exon 1-7) showed the transition c.427 G>A. An intrafamilial follow-up search detected a reduced leukocyte alpha-galactosidase A activity in her father, who suffered exclusively from coronary heart disease. Our case report underlines the possible wide range of clinical signs in Fabry disease patients, sometimes complicated by missing typical lesions (e.g. angiokeratomas). In oligosymptomatic Fabry disease cases, genetic analysis is recommended.

    Fabry disease
    DIAGNOSIS

 is a rare,

    X-chromosome-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a

    deficient alpha-galactosidase A enzyme
    BIOCHEMICAL

. The disease manifests primarily in affected

    hemizygous males
    GENETICS

 and to some extent in

    heterozygous
    GENETICS

    females
    GENDER

 ('carrier'). A

    45-year-old
    AGE

    female
    GENDER

    Fabry disease
    DIAGNOSIS

 patient

    without angiokeratomas
    NEG_FINDINGS

 but with

    numerous angiomas
    SYMPTOMS

 is presented.

    Her
    GENDER

    leukocyte alpha-galactosidase A activity was reduced (0.35 nmol/min/mg protein; normal range: 0.4-1)
    BIOCHEMICAL

. The

    analysis of her alpha-galactosidase A gene (exon 1-7)
    PARACLINICAL

 showed the transition c.427 G>A. An

    intrafamilial follow-up search
    PARACLINICAL

 detected a

    reduced leukocyte alpha-galactosidase A activity in her father, who suffered exclusively from coronary heart disease
    BIOCHEMICAL

. Our case report underlines the possible wide range of clinical signs in

    Fabry disease
    DIAGNOSIS

 patients, sometimes complicated by

    missing typical lesions
    SYMPTOMS

 (e.g.

    angiokeratomas
    SYMPTOMS

). In oligosymptomatic

    Fabry disease
    DIAGNOSIS

 cases,

    genetic analysis
    PARACLINICAL

 is recommended.

Fabry disease
lysosomal storage disease
Fabry disease
Fabry disease
Fabry disease

X-chromosome-linked
hemizygous males
heterozygous

numerous angiomas
missing typical lesions
angiokeratomas


Fabry disease complicating pregnancy.

Few cases of Fabry disease, an X-linked lysosomal storage disorder, complicating pregnancy are reported.

A 36-year-old primigravida with known Fabry disease manifest with acroparesthesias, tinnitus, and hearing loss delivered a healthy unaffected infant at term.

A symptomatic Fabry carrier may experience an otherwise uncomplicated pregnancy in the absence of vital organ involvement.

Few cases of

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

,

    complicating pregnancy
    DIAGNOSIS

 are reported.

A

    36-year-old
    AGE

    primigravida
    ETHNICITY

 with known

    Fabry disease
    DIAGNOSIS

 manifest with

    acroparesthesias
    SYMPTOMS

,

    tinnitus
    SYMPTOMS

, and

    hearing loss
    SYMPTOMS

    delivered a healthy unaffected infant at term
    MEDICATION

.

A symptomatic

    Fabry carrier
    DIAGNOSIS

 may experience an

    otherwise uncomplicated pregnancy
    SYMPTOMS

 in the

    absence of vital organ involvement
    NEG_FINDINGS

.

Fabry disease
lysosomal storage disorder
complicating pregnancy
Fabry disease
Fabry carrier

acroparesthesias
tinnitus
hearing loss
otherwise uncomplicated pregnancy


Neurological manifestation of Fabry disease--a case report.

Fabry disease is an X-linked recessive glycolipid storage disease. It is caused by deficiency of the lysosomal enzyme alpha-galactosidase A and leads to the accumulation of the enzyme substrate, globotriasylceramide (Gb3) in many tissues including endothelial cells, pericytes and smooth muscle cells of blood vessels, renal epithelial cells, cardiac myocytes and numerous neuronal cells. In this report, we present 20-year-old male patient with ischemic stroke in pons. The case had previously been misdiagnosed as polimyositis and vasculitis. Angiokeratomas, neuropathic pain and ischemic stroke in young age suggested a Fabry disease. The diagnosis was confirmed biochemically and genetically. All young adults with stroke, especially if they have additional symptoms like angiokeratomas, proteinuria, neuropathic pain in toes and fingers should be tested for Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    glycolipid storage disease
    DIAGNOSIS

. It is caused by

    deficiency of the lysosomal enzyme alpha-galactosidase A
    BIOCHEMICAL

 and leads to the

    accumulation of the enzyme substrate, globotriasylceramide (Gb3) in many tissues including endothelial cells, pericytes and smooth muscle cells of blood vessels, renal epithelial cells, cardiac myocytes and numerous neuronal cells
    MICROSCOPIC

. In this report, we present

    20-year-old
    AGE

    male
    GENDER

 patient with

    ischemic stroke in pons
    SYMPTOMS

. The case had

    previously been misdiagnosed as polimyositis and vasculitis
    NEG_FINDINGS

.

    Angiokeratomas
    SYMPTOMS

,

    neuropathic pain
    SYMPTOMS

 and

    ischemic stroke
    SYMPTOMS

 in

    young age
    AGE

 suggested a

    Fabry disease
    DIAGNOSIS

. The diagnosis was confirmed biochemically and genetically. All

    young adults
    AGE

 with

    stroke
    SYMPTOMS

, especially if they have additional symptoms like

    angiokeratomas
    SYMPTOMS

,

    proteinuria
    BIOCHEMICAL

,

    neuropathic pain in toes and fingers
    SYMPTOMS

 should be tested for

    Fabry disease
    DIAGNOSIS

.

Fabry disease
glycolipid storage disease
Fabry disease
Fabry disease

ischemic stroke in pons
Angiokeratomas
neuropathic pain
ischemic stroke
stroke
angiokeratomas
neuropathic pain in toes and fingers


Fabry disease and G6PD in three family members with priapism: is the nitric oxide pathway to blame?

Fabry disease is an X-linked multisystem disorder due to alpha galactosidase A deficiency leading to glycosphingolipid accumulation with a predilection for the vascular endothelium and affecting the cardiovascular, renal, and neurologic systems.

To report a familial cluster of priapism in three males from a family with Fabry disease and glucose-6-phosphate dehydrogenase (G6PD) deficiency and discuss possible mechanisms.

Patient charts, Fabry registry, and literature review.

Priapism has been reported in 6 males among the 1,558 males of the Fabry registry. Eight additional case reports of priapism in patients with Fabry disease and two reports of patients with G6PD were collected from the literature. Derangement in the nitric oxide (NO) pathway, which can occur in both Fabry disease and G6PD, is suggested as a hypothesis for the priapism in our patients.

It is suggested that priapism should be included in the list of clinical symptoms of Fabry patients and that Fabry disease should be added to the differential diagnosis of priapism. Furthermore, the association of G6PD and Fabry disease with priapism emphasizes the need for further study to explore the role of NO metabolism in the etiology of Fabry disease manifestations.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    multisystem disorder
    DIAGNOSIS

 due to

    alpha galactosidase A deficiency
    BIOCHEMICAL

 leading to

    glycosphingolipid accumulation
    MICROSCOPIC

 with a

    predilection for the vascular endothelium
    SYMPTOMS

    and affecting the cardiovascular, renal, and neurologic systems
    SYMPTOMS

.

To report a

    familial cluster of priapism
    FAMILY

 in three

    males
    GENDER

    from a family with Fabry disease and glucose-6-phosphate dehydrogenase (G6PD) deficiency
    FAMILY

 and discuss possible mechanisms.

    Patient charts
    PARACLINICAL

,

    Fabry registry
    PARACLINICAL

, and literature review.

    Priapism
    SYMPTOMS

 has been reported in 6

    males
    GENDER

 among the 1,558

    males
    GENDER

 of the Fabry registry. Eight additional case reports of

    priapism
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

 and two reports of patients with

    G6PD
    DIAGNOSIS

 were collected from the literature.

    Derangement in the nitric oxide (NO) pathway
    BIOCHEMICAL

, which can occur in both

    Fabry disease
    DIAGNOSIS

 and

    G6PD
    DIAGNOSIS

, is suggested as a hypothesis for the

    priapism
    SYMPTOMS

 in our patients.

It is suggested that

    priapism
    SYMPTOMS

 should be included in the list of clinical symptoms of

    Fabry
    DIAGNOSIS

 patients and that

    Fabry disease
    DIAGNOSIS

 should be added to the

    differential diagnosis
    PARACLINICAL

 of

    priapism
    DIAGNOSIS

. Furthermore, the association of

    G6PD
    DIAGNOSIS

 and

    Fabry disease
    DIAGNOSIS

 with

    priapism
    SYMPTOMS

 emphasizes the need for further study to explore the role of

    NO metabolism
    GENETICS

 in the etiology of

    Fabry disease manifestations
    SYMPTOMS

.

Fabry disease
multisystem disorder
Fabry disease
G6PD
Fabry disease
G6PD
Fabry
Fabry disease
priapism
G6PD
Fabry disease


Uneventful pregnancy outcome after enzyme replacement therapy with agalsidase beta in a heterozygous female with Fabry disease: A case report.

No reproductive studies have been performed with enzyme replacement therapy (ERT) for Fabry disease (FD, OMIM 301500), a lysosomal storage disorder. Therefore, use during pregnancy is theoretically contraindicated. We report the first case of agalsidase beta treatment throughout pregnancy. High-range proteinuria remained stable and the patient gave birth to a healthy boy after an uncomplicated pregnancy. The decision to administer ERT during pregnancy should be made on an individual basis, considering the FD status and possible risks.

No reproductive studies have been performed with

    enzyme replacement therapy (ERT)
    MEDICATION

 for

    Fabry disease (FD
    DIAGNOSIS

,

    OMIM 301500
    GENETICS

), a

    lysosomal storage disorder
    DIAGNOSIS

. Therefore, use during

    pregnancy
    MEDICATION

 is theoretically contraindicated. We report the first case of

    agalsidase beta treatment throughout pregnancy
    MEDICATION

.

    High-range proteinuria remained stable
    BIOCHEMICAL

 and the patient

    gave birth to a healthy boy after an uncomplicated pregnancy
    MEDICATION

. The decision to

    administer ERT during pregnancy
    MEDICATION

 should be made on an individual basis, considering the FD status and possible risks.

Fabry disease (FD
lysosomal storage disorder


Cardiac involvement in Anderson-Fabry disease.

A normotensive 50-year-old man was evaluated for cardiac symptoms associated with left ventricular hypertrophy (LFH). His symptoms were caused by cardiac involvement from Anderson-Fabry disease (AFD), an X linked lysosomal storage disease caused by mutations in the GLA gene which encodes for the lysosomal enzyme -galactosidase A. He was treated with recombinant enzyme but the clinical course was complicated by arrhythmias and the patient required an internal cardioverter defibrillator. Even though AFD is rare, this case illustrates the importance of considering the diagnosis in selected patients as effective treatment has recently become available. Recognition of AFD also allows for screening of asymptomatic relatives who may benefit from treatment before irreversible life-threatening complications develop.

A

    normotensive 50-year-old
    AGE

    man
    GENDER

 was evaluated for

    cardiac symptoms associated with left ventricular hypertrophy (LFH)
    SYMPTOMS

. His symptoms were caused by

    cardiac involvement
    SYMPTOMS

 from

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

, an

    X linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by mutations in the GLA gene which encodes for the lysosomal enzyme -galactosidase A.

    He
    GENDER

 was treated with

    recombinant enzyme
    MEDICATION

 but the clinical course was complicated by

    arrhythmias
    SYMPTOMS

 and the patient required an

    internal cardioverter defibrillator
    MEDICATION

. Even though

    AFD
    DIAGNOSIS

 is rare, this case illustrates the importance of considering the diagnosis in selected patients as effective treatment has recently become available. Recognition of

    AFD
    DIAGNOSIS

 also allows for screening of asymptomatic relatives who may benefit from treatment before

    irreversible life-threatening complications
    SYMPTOMS

 develop.

Anderson-Fabry disease (AFD)
lysosomal storage disease
AFD
AFD

recombinant enzyme
internal cardioverter defibrillator


Bone and joint involvement in Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by deficient activity of the enzyme alpha-galactosidase A. Although the disease has progressive effects on most organ systems in the body, data is limited regarding skeletal involvement in this rare disorder. We describe four family-related patients, three men and one premenopausal female, sharing a classic phenotype of FD. Dual-energy X-ray was performed in all cases and osteoporosis or osteopenia were found in all patients and osteoporotic fractures in one. One patient also showed both neuropathic joint disease and osteonecrosis. Several mechanisms that may explain osteoporosis and osteoarthropathy in the setting of FD are emphasized.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by deficient activity of the enzyme alpha-galactosidase A. Although the disease has

    progressive effects on most organ systems in the body
    SYMPTOMS

, data is limited regarding

    skeletal involvement
    SYMPTOMS

 in this rare disorder. We describe four

    family-related
    FAMILY

 patients, three

    men
    GENDER

 and one

    premenopausal
    GENDER

    female
    GENDER

, sharing a classic phenotype of

    FD
    DIAGNOSIS

.

    Dual-energy X-ray
    PARACLINICAL

 was performed in all cases and

    osteoporosis or osteopenia
    SYMPTOMS

 were found in all patients and

    osteoporotic fractures
    SYMPTOMS

 in one. One patient also showed both

    neuropathic joint disease
    DIAGNOSIS

 and

    osteonecrosis
    DIAGNOSIS

. Several mechanisms that may explain

    osteoporosis
    SYMPTOMS

 and

    osteoarthropathy
    SYMPTOMS

 in the setting of

    FD
    DIAGNOSIS

 are emphasized.

Fabry disease (FD)
lysosomal storage disease
FD
neuropathic joint disease
osteonecrosis
FD


[Cardiac manifestations of Fabry's disease].

Fabry' s disease is a rare X-linked recessive disease. Its cardiac manifestations are not well recognized.

The data of 3 patients from different Chinese kindreds with Fabry's disease and cardiac manifestations who seeked medical advice in our department in 2007 were analyzed. The age, sex, family history, main symptoms, ECG and echocardiographic findings were recorded for all the patients. The diagnostic criteria of Fabry's disease was based on alpha-galactosidase (alpha-GAL) quantity in white blood cells.

All of the patients were female. Their age was from 41 to 57. Two of them had the typical symptoms of Fabry's disease in their young age. All of them had family history of the disease and cardiac symptoms. ECG showed ST-T change and echocardiography showed hypertrophy of left ventricule of different degrees. Their alpha-galactosidase level in white blood cells was lower than normal. The alpha-galactosidase level in patient 1 was the lowest. Her cardiac symptoms were most serious in the three patients and she had involvement of other organs.

Patients with Fabry's disease may have cardiac manifestations. Family history, typical symptoms in young age and the characteristics of multisystemic disorder are helpful clues to the diagnosis.

    Fabry' s disease
    DIAGNOSIS

 is a

    rare X-linked recessive disease
    GENETICS

. Its

    cardiac manifestations
    SYMPTOMS

 are not well recognized.

The data of 3 patients from different

    Chinese
    ETHNICITY

    kindreds
    FAMILY

 with

    Fabry's disease
    DIAGNOSIS

 and

    cardiac manifestations
    SYMPTOMS

 who seeked medical advice in our department in 2007 were analyzed. The age, sex,

    family history
    FAMILY

, main symptoms, ECG and echocardiographic findings were recorded for all the patients. The diagnostic criteria of

    Fabry's disease
    DIAGNOSIS

 was based on

    alpha-galactosidase (alpha-GAL) quantity in white blood cells
    BIOCHEMICAL

.

All of the patients were

    female
    GENDER

. Their

    age was from 41 to 57
    AGE

. Two of them had the

    typical symptoms of Fabry's disease
    SYMPTOMS

 in

    their young age
    AGE

. All of them had

    family history of the disease
    FAMILY

 and

    cardiac symptoms
    SYMPTOMS

.

    ECG
    PARACLINICAL

 showed

    ST-T change
    SYMPTOMS

 and

    echocardiography
    PARACLINICAL

 showed

    hypertrophy of left ventricule of different degrees
    SYMPTOMS

. Their

    alpha-galactosidase level in white blood cells was lower than normal
    BIOCHEMICAL

. The

    alpha-galactosidase level
    BIOCHEMICAL

 in patient 1

    was the lowest
    BIOCHEMICAL

.

    Her
    GENDER

    cardiac symptoms
    SYMPTOMS

 were most serious in the three patients and

    she
    GENDER

 had

    involvement of other organs
    SYMPTOMS

.

Patients with

    Fabry's disease
    DIAGNOSIS

 may have

    cardiac manifestations
    SYMPTOMS

.

    Family history
    PARACLINICAL

,

    typical symptoms in young age
    SYMPTOMS

 and the

    characteristics of multisystemic disorder
    SYMPTOMS

 are helpful clues to the diagnosis.

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


Isolated microalbuminuria as the first clinical presentation of Fabry disease in an adult heterozygous female.

Fabry disease (FD) is a rare X-linked disorder characterized by low or absent activity of the lysosomal enzyme α-glycosidase-A that leads to progressive accumulation of glycosphingolipids in different organs and tissues. Clinical manifestations vary from classic to atypical forms characterized by one prevalent organ involvement, and a renal variant has been described in men but not in women. However, little is known about renal manifestation in females affected by FD. We herein report a case of a 22-year-old female with isolated and persistent microalbuminuria as the only sign of FD. In light of the importance of early recognition and treatment of FD organ damage, this case should call for future studies to determine how to assess organ damage, investigate the existence of a 'renal variant' in FD female patients and determine when best to start enzyme replacement therapy (ERT).

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked disorder
    GENETICS

 characterized by

    low or absent activity of the lysosomal enzyme α-glycosidase-A
    BIOCHEMICAL

 that leads to

    progressive accumulation of glycosphingolipids in different organs and tissues
    MICROSCOPIC

. Clinical manifestations vary from classic to atypical forms characterized by

    one prevalent organ involvement
    SYMPTOMS

, and a

    renal variant
    DIAGNOSIS

 has been described in

    men
    GENDER

 but not in

    women
    GENDER

. However, little is known about

    renal manifestation
    SYMPTOMS

 in

    females
    GENDER

 affected by

    FD
    DIAGNOSIS

. We herein report a case of a

    22-year-old
    AGE

    female
    GENDER

 with

    isolated and persistent microalbuminuria
    BIOCHEMICAL

 as the only sign of

    FD
    DIAGNOSIS

. In light of the importance of early recognition and treatment of

    FD organ damage
    SYMPTOMS

, this case should call for future studies to determine how to assess

    organ damage
    SYMPTOMS

, investigate the existence of a 'renal variant' in

    FD
    DIAGNOSIS

    female
    GENDER

 patients and determine when best to start

    enzyme replacement therapy (ERT)
    MEDICATION

.

Fabry disease (FD)
renal variant
FD
FD
FD

one prevalent organ involvement
renal manifestation
FD organ damage
organ damage


Enzyme therapy in Fabry disease: severe adverse events associated with anti-agalsidase cross-reactive IgG antibodies.

To report a severe adverse event related to enzyme replacement therapy with agalsidase in an hemizygous male patient treated for Fabry disease.

Retrospective analysis of clinical, radiological and biochemical data in a patient who suffered adverse events related to both agalsidase alfa and agalsidase beta treatments.

A hemizygous male patient was first treated for Fabry disease with agalsidase alfa. After more than 1 year of therapy, infusion-related symptoms necessitated systemic steroids and antihistaminic therapy. Decline in kidney function prompted a switch for agalsidase beta. Anaphylactoid shock occurred after the second infusion. No serum IgE antibodies were disclosed. Skin-test reactivity to agalsidase beta was negative. Following a published rechallenge infusion protocol, agalsidase beta was reintroduced, leading to a second anaphylactoid shock episode. Enzyme replacement therapy was stopped and the patient was treated with symptomatic therapy only. This case was referred to the pharmacovigilance department.

The negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests) does not rule out the risk of repeated anaphylactoid shock following agalsidase infusion.

To report a

    severe adverse event related to enzyme replacement therapy with agalsidase
    SYMPTOMS

 in an

    hemizygous male
    GENETICS

 patient treated for

    Fabry disease
    DIAGNOSIS

.

    Retrospective analysis of clinical, radiological and biochemical data
    PARACLINICAL

 in a patient who

    suffered adverse events related to both agalsidase alfa and agalsidase beta treatments
    SYMPTOMS

.

A

    hemizygous male
    GENETICS

 patient was first treated for

    Fabry disease
    DIAGNOSIS

    with agalsidase alfa
    MEDICATION

.

    After more than 1 year of therapy
    MEDICATION

,

    infusion-related symptoms
    SYMPTOMS

 necessitated

    systemic steroids and antihistaminic therapy
    MEDICATION

.

    Decline in kidney function
    SYMPTOMS

 prompted a

    switch for agalsidase beta
    MEDICATION

.

    Anaphylactoid shock
    SYMPTOMS

 occurred after the second infusion.

    No serum IgE antibodies were disclosed
    NEG_FINDINGS

.

    Skin-test reactivity to agalsidase beta was negative
    NEG_FINDINGS

. Following a published

    rechallenge infusion protocol
    MEDICATION

,

    agalsidase beta was reintroduced
    MEDICATION

, leading to a

    second anaphylactoid shock episode
    SYMPTOMS

.

    Enzyme replacement therapy was stopped
    MEDICATION

 and the patient was

    treated with symptomatic therapy only
    MEDICATION

. This case was referred to the

    pharmacovigilance department
    PARACLINICAL

.

The

    negativity of immunological tests (specific anti-agalsidase IgE antibodies and skin tests)
    NEG_FINDINGS

 does not rule out the risk of

    repeated anaphylactoid shock
    SYMPTOMS

 following

    agalsidase infusion
    MEDICATION

.


An autopsy case of Fabry's disease with cardiac manifestations.

We report an autopsy case of Fabry's disease with cardiac manifestations. Electron microscopic examination of rectal biopsy specimens revealed lamellar bodies and osmiophilic irregular bodies. Biochemical analysis showed low enzymatic activity of alpha-galactosidase A in plasma fluid. Microscopic examination on autopsy showed marked hypertrophy and vacuolation of cardiac muscle cells. Intracytoplasmic vacuolation was also found in glomerular epithelial or endothelial cells and smooth muscle cells of renal arteries, Meissner's plexus in the submucosa of small and large intestines, and smooth muscle cells of arterioles in the cerebrum. The diagnosis of Fabry's disease was made. The patient died suddenly of cardiomyopathy.

We report an

    autopsy
    PARACLINICAL

 case of

    Fabry's disease
    DIAGNOSIS

 with

    cardiac manifestations
    SYMPTOMS

.

    Electron microscopic examination of rectal biopsy specimens
    PARACLINICAL

 revealed

    lamellar bodies and osmiophilic irregular bodies
    MICROSCOPIC

.

    Biochemical analysis
    PARACLINICAL

 showed

    low enzymatic activity of alpha-galactosidase A in plasma fluid
    BIOCHEMICAL

.

    Microscopic examination
    PARACLINICAL

 on

    autopsy
    PARACLINICAL

 showed

    marked hypertrophy and vacuolation of cardiac muscle cells
    MICROSCOPIC

.

    Intracytoplasmic vacuolation was also found in glomerular epithelial or endothelial cells and smooth muscle cells of renal arteries, Meissner's plexus in the submucosa of small and large intestines, and smooth muscle cells of arterioles in the cerebrum
    MICROSCOPIC

. The diagnosis of

    Fabry's disease
    DIAGNOSIS

 was made. The patient

    died
    SYMPTOMS

 suddenly of

    cardiomyopathy
    SYMPTOMS

.

cardiac manifestations
died
cardiomyopathy


A case of minimal change disease in a Fabry patient.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the GLA gene and deficiency in alpha-galactosidase A activity. Glycosphingolipids accumulation causes renal injury that manifests early during childhood as tubular dysfunction and later in adulthood as proteinuria and renal insufficiency. Nephrotic syndrome as the first evidence of Fabry-related kidney damage is rare. We report the case of a teenager with known Fabry disease and normal renal function who developed acute nephrotic syndrome. He was found to have typical glycosphingolipids accumulation with no other findings suggestive of alternative causes of nephrotic syndrome on kidney biopsy. After treatment with enzyme replacement therapy and oral steroids, he went into complete remission from nephrotic syndrome, a response that is atypical for Fabry disease patients who develop heavy proteinuria as a result of longstanding disease and chronic renal injury. The nephrotic syndrome in this patient appears to have developed secondary to minimal change disease. We recommend considering immunotherapy in addition to enzyme replacement therapy in those patients with confirmed Fabry disease and acute nephrotic syndrome with clinical and microscopic findings suggestive of minimal change disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations of the GLA gene
    GENETICS

 and

    deficiency in alpha-galactosidase A activity
    BIOCHEMICAL

.

    Glycosphingolipids accumulation
    MICROSCOPIC

 causes

    renal injury
    SYMPTOMS

 that manifests

    early during childhood
    AGE

 as

    tubular dysfunction
    SYMPTOMS

 and later in adulthood as

    proteinuria
    BIOCHEMICAL

 and

    renal insufficiency
    SYMPTOMS

.

    Nephrotic syndrome
    DIAGNOSIS

 as the first evidence of

    Fabry-related kidney damage
    DIAGNOSIS

 is rare. We report the case of a

    teenager
    AGE

 with known

    Fabry disease
    DIAGNOSIS

 and

    normal renal function
    NEG_FINDINGS

 who developed

    acute nephrotic syndrome
    DIAGNOSIS

.

    He
    GENDER

 was found to have

    typical glycosphingolipids accumulation
    MICROSCOPIC

 with

    no other findings suggestive of alternative causes of nephrotic syndrome
    NEG_FINDINGS

 on

    kidney biopsy
    PARACLINICAL

. After

    treatment with enzyme replacement therapy and oral steroids
    MEDICATION

,

    he
    GENDER

 went into

    complete remission from nephrotic syndrome
    SYMPTOMS

, a response that is atypical for

    Fabry disease
    DIAGNOSIS

 patients who develop

    heavy proteinuria
    BIOCHEMICAL

 as a result of

    longstanding disease
    DIAGNOSIS

 and

    chronic renal injury
    SYMPTOMS

. The

    nephrotic syndrome
    DIAGNOSIS

 in this patient appears to have developed secondary to

    minimal change disease
    DIAGNOSIS

. We recommend considering

    immunotherapy in addition to enzyme replacement therapy
    MEDICATION

 in those patients with confirmed

    Fabry disease
    DIAGNOSIS

 and

    acute nephrotic syndrome
    DIAGNOSIS

 with

    clinical and microscopic findings suggestive of minimal change disease
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
Nephrotic syndrome
Fabry-related kidney damage
Fabry disease
acute nephrotic syndrome
Fabry disease
longstanding disease
nephrotic syndrome
minimal change disease
Fabry disease
acute nephrotic syndrome


Enzyme replacement therapy for Fabry disease: a systematic review of available evidence.

Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.

    Fabry disease
    DIAGNOSIS

 is a progressive and

    life-threatening glycolipid storage disorder
    DIAGNOSIS

 affecting both

    males
    GENDER

 and

    females
    GENDER

. The primary driver of the disease is the

    accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons
    MICROSCOPIC

, which is caused by

    deficient activity of the lysosomal enzyme, alpha-galactosidase
    BIOCHEMICAL

. The disease typically presents during

    childhood
    AGE

    or adolescence
    AGE

. First manifestations reflect

    involvement of small nerve fibres of the peripheral and autonomic nervous systems
    SYMPTOMS

. With age,

    severe complications involving the kidneys, heart and brain
    SYMPTOMS

 cause considerable morbidity and

    premature death
    SYMPTOMS

. Outside the US,

    enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW
    MEDICATION

 is available for the treatment of patients with

    Fabry disease
    DIAGNOSIS

, while

    agalsidase beta 1.0 mg/kg EOW
    MEDICATION

 is the only approved drug in the US. To analyse the evidence for

    ERT
    MEDICATION

, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of

    agalsidase alfa and agalsidase beta
    MEDICATION

. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating

    ERT
    MEDICATION

 with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of

    ERT
    MEDICATION

 at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of

    ERT
    MEDICATION

 in

    Fabry disease
    DIAGNOSIS

 has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes.

    Plasma levels of GL-3 together with accumulation in the kidney, heart and skin
    BIOCHEMICAL

 were the most commonly studied endpoints, followed by

    renal endpoints of proteinuria and glomerular filtration rate
    BIOCHEMICAL

, whereas

    cardiac and neurological endpoints
    SYMPTOMS

 were not commonly studied. To date, only one RCT with

    ERT
    MEDICATION

 defined

    hard clinical outcomes
    SYMPTOMS

 in the form of

    cardiac, renal or cerebrovascular events
    SYMPTOMS

, or

    death
    SYMPTOMS

 as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with

    Fabry disease
    DIAGNOSIS

 are more robust for

    ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW
    MEDICATION

, although the beneficial effects of

    ERT
    MEDICATION

 with either dose or preparation are variable.


Variable phenotypic expression of chylomicron retention disease in a kindred carrying a mutation of the Sara2 gene.

Chylomicron retention disease is a recessive inherited disorder characterized by fat malabsorption and steatorrhea and is associated with failure to thrive in infancy. We describe a kindred carrying a mutation of Sara2 gene causing a chylomicron retention phenotype. The proband was a 5-month-old baby, born of consanguineous, apparently healthy parents from Morocco, with failure to thrive. There was a large quantity of fats in feces and malabsorption of fat-soluble vitamins. Intestinal biopsies showed a diffused enterocyte vacuolization with large cytosolic lipid droplets. Chylomicron retention disease or Anderson disease was hypothesized, and the Sara2 gene was analyzed by direct sequencing. Analysis of the Sara2 gene in the proband identified a 2-nucleotide homozygous deletion in exon 3 leading to a premature stop codon (c.75-76 del TG-L28fsX34). The father was heterozygous for the same mutation, whereas the proband's mother was homozygous, suggesting a variable phenotypic expression of the molecular defect. More studies are needed to understand the reasons of the phenotypic variability of the same molecular defect in the same family.

    Chylomicron retention disease
    DIAGNOSIS

 is a

    recessive inherited disorder
    GENETICS

 characterized by

    fat malabsorption
    SYMPTOMS

 and

    steatorrhea
    SYMPTOMS

 and is associated with

    failure to thrive
    SYMPTOMS

 in

    infancy
    AGE

. We describe a kindred carrying a

    mutation of Sara2 gene
    GENETICS

 causing a

    chylomicron retention phenotype
    MICROSCOPIC

. The proband was a

    5-month-old
    AGE

    baby
    AGE

,

    born of consanguineous, apparently healthy parents from Morocco
    FAMILY

, with

    failure to thrive
    SYMPTOMS

. There was a

    large quantity of fats in feces
    MICROSCOPIC

 and

    malabsorption of fat-soluble vitamins
    BIOCHEMICAL

.

    Intestinal biopsies
    PARACLINICAL

 showed a

    diffused enterocyte vacuolization with large cytosolic lipid droplets
    MICROSCOPIC

.

    Chylomicron retention disease
    MICROSCOPIC

 or

    Anderson disease
    DIAGNOSIS

 was hypothesized, and the

    Sara2 gene was analyzed by direct sequencing
    PARACLINICAL

.

    Analysis of the Sara2 gene in the proband
    PARACLINICAL

 identified

    a 2-nucleotide homozygous deletion in exon 3 leading to a premature stop codon (c.75-76 del TG-L28fsX34)
    GENETICS

.

    The father was heterozygous for the same mutation, whereas the proband's mother was homozygous
    FAMILY

, suggesting a

    variable phenotypic expression of the molecular defect
    GENETICS

. More studies are needed to understand the reasons of the phenotypic variability of the same molecular defect in the same family.

Chylomicron retention disease
Anderson disease

fat malabsorption
steatorrhea
failure to thrive
failure to thrive


Aseptic meningitis and ischaemic stroke in Fabry disease.

Fabry disease (OMIM 301 500) is an X-linked lysosomal storage disease. Neurological symptoms in Fabry disease mainly include stroke, acroparesthesia, cranial nerve palsies and autonomic dysfunction. We report on aseptic meningitis in Fabry patients.

Clinical analysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, treatment and outcome data were analysed in three cases of meningitis associated with Fabry disease.

Mean age at meningitis onset was 26.6 (24-28) years. Headache was present in all cases and fever in two cases. Meningitis was always diagnosed before Fabry disease. A familial history of Fabry disease was present in two cases. Non-neurological symptoms caused by Fabry disease were present in all cases. All patients also suffered stroke and sensorineural hearing loss. Cerebrospinal fluid (CSF) analysis showed pleocytosis (mean, 36; range: 8-76 cells/mm(3)) and a high protein level (mean, 63; range, 47-70 mg/dl). C-reactive protein blood levels and erythrocyte sedimentation rate were raised. Diagnosis was assessed by low alpha-galactosidase A dosage and/or gene mutation analysis in all cases. All patients were treated with enzyme replacement therapy (ERT). In two cases, lumbar puncture was repeatedly performed and there was no normalisation of CSF under ERT alone, at 9 and 24 months of follow-up, respectively. One patient who suffered intracranial hypertension was treated efficiently with steroids, associated with azathioprine. The fact that Fabry disease could be an auto-inflammatory disorder is discussed.

Fabry disease may cause aseptic meningitis.

    Fabry disease
    DIAGNOSIS

 (

    OMIM 301 500)
    GENETICS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

.

    Neurological symptoms
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 mainly include

    stroke
    SYMPTOMS

,

    acroparesthesia
    SYMPTOMS

,

    cranial nerve palsies
    SYMPTOMS

 and

    autonomic dysfunction
    SYMPTOMS

. We report on

    aseptic meningitis
    DIAGNOSIS

 in

    Fabry
    DIAGNOSIS

 patients.

    Clinical analysis
    PARACLINICAL

,

    brain magnetic resonance imaging
    PARACLINICAL

,

    cerebrospinal fluid analysis
    PARACLINICAL

, treatment and outcome data were analysed in three cases of

    meningitis
    DIAGNOSIS

    associated with Fabry disease
    DIAGNOSIS

.

    Mean age at meningitis
    AGE

    onset was 26.6 (24-28) years
    AGE

.

    Headache
    SYMPTOMS

 was present in all cases and

    fever
    SYMPTOMS

 in two cases.

    Meningitis
    DIAGNOSIS

 was always diagnosed before

    Fabry disease
    DIAGNOSIS

. A

    familial history of Fabry disease
    FAMILY

 was present in two cases.

    Non-neurological symptoms caused by Fabry disease
    SYMPTOMS

 were present in all cases. All patients also suffered

    stroke
    SYMPTOMS

 and

    sensorineural hearing loss
    SYMPTOMS

.

    Cerebrospinal fluid (CSF) analysis
    PARACLINICAL

 showed

    pleocytosis (mean, 36; range: 8-76 cells/mm(3))
    BIOCHEMICAL

 and a

    high protein level (mean, 63; range, 47-70 mg/dl)
    BIOCHEMICAL

.

    C-reactive protein blood levels and erythrocyte sedimentation rate were raised
    BIOCHEMICAL

. Diagnosis was assessed by

    low alpha-galactosidase A dosage
    BIOCHEMICAL

 and/or

    gene mutation analysis
    PARACLINICAL

 in all cases. All patients were treated with

    enzyme replacement therapy (ERT)
    MEDICATION

. In two cases,

    lumbar puncture
    PARACLINICAL

 was repeatedly performed and there was

    no normalisation of CSF under ERT alone
    NEG_FINDINGS

, at 9 and 24 months of follow-up, respectively. One patient who suffered

    intracranial hypertension
    SYMPTOMS

 was treated

    efficiently with steroids, associated with azathioprine
    MEDICATION

. The fact that

    Fabry disease
    DIAGNOSIS

 could be an

    auto-inflammatory disorder
    DIAGNOSIS

 is discussed.

    Fabry disease
    DIAGNOSIS

 may cause

    aseptic meningitis
    DIAGNOSIS

.

Fabry disease
lysosomal storage disease
Fabry disease
aseptic meningitis
Fabry
meningitis
associated with Fabry disease
Meningitis
Fabry disease
Fabry disease
auto-inflammatory disorder
Fabry disease
aseptic meningitis


Fabry disease: recent advances in pathology, diagnosis, treatment and monitoring.

In Fabry disease (alpha-galactosidase A deficiency) accumulation of Globotriaosylceramide (Gb3) leads to progressive organ failure and premature death. The introduction of enzyme replacement therapy (ERT) was the beginning of a new era in this disorder, and has prompted a broad range of research activities. This review aims to summarize recent developments and progress with high impact for Fabry disease.

A Pubmed analysis was performed using the search terms "Fabry disease", "Anderson-Fabry disease", "alpha-galactosidase A" and "Gb3". Of the given publications by 31st January 2009 only original articles recently published in peer reviewed journals were included for this review. Case reports were included only when they comprised a new aspect. In addition we included relevant conference abstracts when the results had not already been published as original articles.

Apart from Gb3-accumulation cellular and organ specific damages may be related also to inflammatory and immunological consequences. It will be interesting whether this may lead to new therapeutic strategies in the treatment of Fabry disease. Since newborn screening is still difficult in Fabry disease, detection of patients in populations at risk is of great importance. Undiagnosed patients with Fabry disease may still be found in cohorts of subjects with renal diseases, cardiomyopathy and TIA or stroke. Efforts should be undertaken to identify these individuals and initialise ERT in order to hault disease progression. It has also been demonstrated that Gb3-accumulation leads to pre-clinical damages and it is believed that early treatment may be the only possibility so far to prevent irreversible organ damage.

In

    Fabry disease
    DIAGNOSIS

 (

    alpha-galactosidase A deficiency
    BIOCHEMICAL

)

    accumulation of Globotriaosylceramide (Gb3)
    MICROSCOPIC

 leads to

    progressive organ failure
    SYMPTOMS

 and

    premature death
    SYMPTOMS

. The introduction of

    enzyme replacement therapy (ERT)
    MEDICATION

 was the beginning of a new era in this disorder, and has prompted a broad range of research activities. This review aims to summarize recent developments and progress with high impact for

    Fabry disease
    DIAGNOSIS

.

A Pubmed analysis was performed using the search terms "

    Fabry disease
    DIAGNOSIS

", "

    Anderson-Fabry disease
    DIAGNOSIS

", "

    alpha-galactosidase A
    BIOCHEMICAL

" and "

    Gb3
    DIAGNOSIS

". Of the given publications by 31st January 2009 only original articles recently published in peer reviewed journals were included for this review. Case reports were included only when they comprised a new aspect. In addition we included relevant conference abstracts when the results had not already been published as original articles.

Apart from

    Gb3-accumulation
    MICROSCOPIC

    cellular and organ specific damages
    SYMPTOMS

 may be related also to

    inflammatory and immunological consequences
    SYMPTOMS

. It will be interesting whether this may lead to new therapeutic strategies in the treatment of

    Fabry disease
    DIAGNOSIS

. Since

    newborn
    AGE

 screening is still difficult in

    Fabry disease
    DIAGNOSIS

, detection of patients in populations at risk is of great importance. Undiagnosed patients with

    Fabry disease
    DIAGNOSIS

 may still be found in cohorts of subjects with

    renal diseases
    DIAGNOSIS

,

    cardiomyopathy
    DIAGNOSIS

 and

    TIA
    SYMPTOMS

 or

    stroke
    SYMPTOMS

. Efforts should be undertaken to identify these individuals and initialise

    ERT
    MEDICATION

 in order to hault disease progression. It has also been demonstrated that

    Gb3-accumulation
    MICROSCOPIC

 leads to

    pre-clinical damages
    SYMPTOMS

 and it is believed that

    early treatment
    MEDICATION

 may be the only possibility so far to prevent

    irreversible organ damage
    SYMPTOMS

.

Fabry disease
Fabry disease
Fabry disease
Anderson-Fabry disease
Gb3
Fabry disease
Fabry disease
Fabry disease
renal diseases
cardiomyopathy

alpha-galactosidase A deficiency
alpha-galactosidase A

enzyme replacement therapy (ERT)
ERT
early treatment


Hemizygous Fabry disease associated with IgA nephropathy: a case report.

We present a 22-year-old male patient who showed both classical Fabry disease and IgA nephropathy. He had proteinuria (1.5 g/day), hypohidrosis and neuralgia with fever. Serum creatinine and blood urea nitrogen were 0.9 mg/dL and 11.4 mg/dL, respectively. Renal biopsy showed strikingly vacuolated podocytes and tubular epithelium cells. Myelin-like bodies were detected in podocytes, mesangial cells, endothelial cells and tubular epithelium cells by electron microscopy. On immunofluorescence microscopy, IgA and C3 deposits were detected in mesangial areas. From these results and a markedly low level of alpha-galactosidase A activity, this patient was diagnosed as having classical Fabry disease and IgA nephropathy.

We present a

    22-year-old
    AGE

    male
    GENDER

 patient who showed both

    classical Fabry disease and IgA nephropathy
    DIAGNOSIS

.

    He
    GENDER

 had

    proteinuria (1.5 g/day)
    BIOCHEMICAL

,

    hypohidrosis
    SYMPTOMS

 and

    neuralgia
    SYMPTOMS

 with

    fever
    SYMPTOMS

.

    Serum creatinine and blood urea nitrogen were 0.9 mg/dL and 11.4 mg/dL, respectively
    BIOCHEMICAL

.

    Renal biopsy
    PARACLINICAL

 showed

    strikingly vacuolated podocytes and tubular epithelium cells
    MICROSCOPIC

.

    Myelin-like bodies were detected in podocytes, mesangial cells, endothelial cells and tubular epithelium cells
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. On

    immunofluorescence microscopy
    PARACLINICAL

,

    IgA and C3 deposits were detected in mesangial areas
    MICROSCOPIC

. From these results and a

    markedly low level of alpha-galactosidase A activity
    BIOCHEMICAL

, this patient was diagnosed as having

    classical Fabry disease and IgA nephropathy
    DIAGNOSIS

.


Fabry disease: a treatable lysosomal storage disorder.

Fabry disease is a lysosomal storage disease with an X-linked inheritance pattern, which presents in childhood as acroparaesthesias. Its non-specific symptoms often lead to delays in the diagnosis. We report the case of a 13-year-old boy who presented with typical acroparaesthesia of Fabry disease, his younger brother had gastrointestinal manifestations of the disease and their mother's symptoms suggested that she is a carrier. Enzyme replacement therapy helped in ameliorating the patient's symptoms and preventing complications such as renal failure, stroke and cardiovascular disorders.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

    with an X-linked inheritance pattern
    GENETICS

, which presents in

    childhood
    AGE

 as

    acroparaesthesias
    SYMPTOMS

. Its non-specific symptoms often lead to delays in the diagnosis. We report the case of a

    13-year-old
    AGE

    boy
    GENDER

 who presented with

    typical acroparaesthesia
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

,

    his younger brother had gastrointestinal manifestations of the disease
    FAMILY

 and

    their mother's symptoms suggested that she is a carrier
    FAMILY

.

    Enzyme replacement therapy
    MEDICATION

 helped in

    ameliorating the
    SYMPTOMS

 patient's symptoms and preventing complications such as

    renal failure
    SYMPTOMS

,

    stroke
    SYMPTOMS

 and

    cardiovascular disorders
    SYMPTOMS

.

Fabry disease
lysosomal storage disease
Fabry disease

acroparaesthesias
typical acroparaesthesia
ameliorating the
renal failure
stroke
cardiovascular disorders


Dilated phase of hypertrophic cardiomyopathy caused by Fabry disease with atrial flutter and ventricular tachycardia.

We describe a case of a 60-year-old male with dilated phase of hypertrophic cardiomyopathy caused by Fabry disease. He was diagnosed to have a cardiac variant of Fabry disease by an enzyme assay and a right ventricular endomyocardial biopsy which revealed specific features of this disease and cardiac involvement was the sole manifestation. He has developed dilated cardiomyopathy with sustained atrial flutter and frequent non-sustained ventricular tachycardia requiring isthmus ablation and cardiac resynchronization therapy with defibrillator.

We describe a case of a

    60-year-old
    AGE

    male
    GENDER

 with

    dilated phase of hypertrophic cardiomyopathy
    SYMPTOMS

 caused by

    Fabry disease
    DIAGNOSIS

.

    He
    GENDER

 was diagnosed to have a

    cardiac variant of Fabry disease
    DIAGNOSIS

 by an

    enzyme assay
    PARACLINICAL

 and a

    right ventricular endomyocardial biopsy
    PARACLINICAL

 which revealed specific features of this disease and

    cardiac involvement
    SYMPTOMS

 was the sole manifestation.

    He
    GENDER

 has developed

    dilated cardiomyopathy
    DIAGNOSIS

 with

    sustained atrial flutter
    SYMPTOMS

 and

    frequent non-sustained ventricular tachycardia
    SYMPTOMS

 requiring

    isthmus ablation
    MEDICATION

 and

    cardiac resynchronization therapy with defibrillator
    MEDICATION

.

Fabry disease
cardiac variant of Fabry disease
dilated cardiomyopathy


A detailed pathologic examination of heart tissue from three older patients with Anderson-Fabry disease on enzyme replacement therapy.

Cardiac disease causes considerable morbidity and mortality in men and women with Anderson-Fabry disease (AFD), an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Treatment with recombinant enzyme preparations aims to attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3). Pathologic data examining the effect of enzyme replacement therapy (ERT) in vivo are scant.

A detailed examination of three whole hearts from patients (all male, aged 55, 59, 73 years) with AFD that had received ERT prior to death (for between 18 months and 4 years) was performed.

In spite of ERT, Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue. Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm. In all three cases, there was focal myocyte apoptosis and myocyte necrosis associated with macrophage accumulation and a small T-lymphocytic infiltrate. Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray were present in all three hearts.

This study highlights the pancardiac nature of AFD; demonstrates the extent of fibrotic changes; and reports, for the first time, myocyte disarray, necrosis, and apoptosis in hearts from patients affected by AFD and receiving ERT. These findings have major implications for the timing and efficacy of ERT in AFD.

    Cardiac disease
    DIAGNOSIS

 causes considerable morbidity and mortality in

    men
    GENDER

 and

    women
    GENDER

 with

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

, an

    X-linked inborn metabolic defect
    GENETICS

 caused by deficiency of the lysosomal enzyme α-galactosidase A.

    Treatment with recombinant enzyme preparations
    MEDICATION

 aims to

    attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3)
    MICROSCOPIC

. Pathologic data examining the effect of

    enzyme replacement therapy (ERT)
    MEDICATION

 in vivo are scant.

A

    detailed examination of three whole hearts
    PARACLINICAL

 from patients (all

    male
    GENDER

,

    aged 55, 59, 73 years
    AGE

) with

    AFD
    DIAGNOSIS

 that had

    received ERT prior to death (for between 18 months and 4 years)
    MEDICATION

 was performed.

In

    spite of ERT
    NEG_FINDINGS

,

    Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue
    MICROSCOPIC

.

    Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm
    MICROSCOPIC

. In all three cases, there was

    focal myocyte apoptosis
    SYMPTOMS

 and

    myocyte necrosis
    SYMPTOMS

 associated with

    macrophage accumulation and a small T-lymphocytic infiltrate
    MICROSCOPIC

.

    Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray
    SYMPTOMS

 were present in all three hearts.

This study highlights the pancardiac nature of

    AFD
    DIAGNOSIS

; demonstrates the extent of

    fibrotic changes
    SYMPTOMS

; and reports, for the first time,

    myocyte disarray, necrosis, and apoptosis
    MICROSCOPIC

 in hearts from patients affected by

    AFD
    DIAGNOSIS

 and receiving

    ERT
    MEDICATION

. These findings have major implications for the timing and efficacy of

    ERT
    MEDICATION

 in

    AFD
    DIAGNOSIS

.

Cardiac disease
Anderson-Fabry disease (AFD)
AFD
AFD
AFD
AFD


[Ocular motility disorders in a patient with Fabry's disease].

Fabry's disease (FD) is a rare lysosomal storage disorder. Early cerebral manifestations are a major and often life-threatening burden of the disease. We present a 38-year-old male FD patient with a prior history of six different episodes of stroke and newly developing ocular disorders. He presented with nystagmus with different wave forms and directions and blepharospasm as well as cornea verticillata.

    Fabry's disease (FD)
    DIAGNOSIS

 is a

    rare lysosomal storage disorder
    DIAGNOSIS

.

    Early cerebral manifestations
    SYMPTOMS

 are a major and often life-threatening burden of the disease. We present a

    38-year-old
    AGE

    male
    GENDER

    FD
    DIAGNOSIS

 patient with a prior

    history of six different episodes of stroke
    SYMPTOMS

 and

    newly developing ocular disorders
    SYMPTOMS

.

    He
    GENDER

 presented with

    nystagmus with different wave forms and directions
    SYMPTOMS

 and

    blepharospasm
    SYMPTOMS

 as well as

    cornea verticillata
    SYMPTOMS

.

Fabry's disease (FD)
rare lysosomal storage disorder
FD


Renal histology before and after effective enzyme replacement therapy in a patient with classical Fabry's disease.

A 38-year-old man underwent renal biopsy because of proteinuria. It revealed swelling and vacuolation of glomerular epithelial cells, as well as myelin-like structures characteristic of Fabry's disease. Detection of decreased plasma activity of alpha-galactosidase A confirmed the diagnosis. Enzyme replacement therapy was provided with recombinant agalsidase-beta, resulting in improvement of his symptoms. When renal biopsy was repeated, specific staining for globotriaosylceramide showed that renal deposits were decreased by enzyme therapy.

A

    38-year-old
    AGE

    man
    GENDER

 underwent

    renal biopsy
    PARACLINICAL

 because of

    proteinuria
    BIOCHEMICAL

. It revealed

    swelling and vacuolation of glomerular epithelial cells, as well as myelin-like structures characteristic of Fabry's disease
    MICROSCOPIC

. Detection of

    decreased plasma activity of alpha-galactosidase A
    BIOCHEMICAL

 confirmed the diagnosis.

    Enzyme replacement therapy
    MEDICATION

 was

    provided with recombinant agalsidase-beta
    MEDICATION

, resulting in

    improvement of
    SYMPTOMS

 his symptoms. When

    renal biopsy
    PARACLINICAL

 was repeated,

    specific staining for globotriaosylceramide
    PARACLINICAL

 showed that

    renal deposits were decreased
    MICROSCOPIC

 by

    enzyme therapy
    MEDICATION

.


Unusual renal presentation of Fabry disease in a female patient.

A 29-year-old white woman with a family history of Fabry disease was referred to a nephrology clinic with hypertension and nephropathy. Her renal function was below normal (serum creatinine level 141 micromol/l; estimated glomerular filtration rate 41 ml/min/1.73 m2) with no proteinuria or albuminuria.

Medical history, physical examination, leukocyte alpha-galactosidase A assay, laboratory tests (for antinuclear antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant, anticardiolipin antibodies, complement and cryoglobulin), ophthalmological examination, echocardiography, brain magnetic resonance angiography, renal ultrasonography, renal color echo-Doppler scan, renal magnetic resonance angiography, renal angiography and renal biopsy.

Diffuse sclero-atrophic renal tissue changes and widespread renal arterio-arteriolosclerotic changes secondary to Fabry disease.

Angiotensin-converting-enzyme inhibitors and maintenance treatment with agalsidase-beta, 1 mg/kg body weight, every 2 weeks.

A

    29-year-old
    AGE

    white
    ETHNICITY

    woman
    GENDER

 with

    a family history of Fabry disease
    FAMILY

 was referred to a

    nephrology
    PARACLINICAL

 clinic with

    hypertension
    DIAGNOSIS

 and

    nephropathy
    DIAGNOSIS

.

    Her
    GENDER

    renal function was below normal (serum creatinine level 141 micromol/l; estimated glomerular filtration rate 41 ml/min/1.73 m2)
    BIOCHEMICAL

 with

    no proteinuria or albuminuria
    NEG_FINDINGS

.

    Medical history
    PARACLINICAL

,

    physical examination
    PARACLINICAL

,

    leukocyte alpha-galactosidase A assay
    PARACLINICAL

,

    laboratory tests (for antinuclear antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant, anticardiolipin antibodies, complement and cryoglobulin)
    PARACLINICAL

,

    ophthalmological examination
    PARACLINICAL

,

    echocardiography
    PARACLINICAL

,

    brain magnetic resonance angiography
    PARACLINICAL

,

    renal ultrasonography
    PARACLINICAL

,

    renal color echo-Doppler scan
    PARACLINICAL

,

    renal magnetic resonance angiography
    PARACLINICAL

,

    renal angiography
    PARACLINICAL

 and

    renal biopsy
    PARACLINICAL

.

    Diffuse sclero-atrophic renal tissue changes
    SYMPTOMS

 and

    widespread renal arterio-arteriolosclerotic changes
    SYMPTOMS

 secondary to

    Fabry disease
    DIAGNOSIS

.

    Angiotensin-converting-enzyme inhibitors and maintenance treatment with agalsidase-beta, 1 mg/kg body weight, every 2 weeks
    MEDICATION

.


Angiokeratoma corporis diffusum.

Angiokeratoma is a dark violaceous keratotic papule which can be solitary or multiple. Generalised systemic angiokeratoma constitute angiokeratoma corporis diffusum, a rare X-linked recessive inborn error of glycosphingolipid metabolism due to deficiency of alpha galactosidase A. Patients with this disease have premature death due to the vascular complications. A case of possible Fabry's disease is presented.

    Angiokeratoma
    SYMPTOMS

 is a

    dark violaceous keratotic papule
    SYMPTOMS

 which can be

    solitary or multiple
    SYMPTOMS

.

    Generalised systemic angiokeratoma
    SYMPTOMS

 constitute

    angiokeratoma corporis diffusum
    SYMPTOMS

, a

    rare X-linked recessive inborn error of glycosphingolipid metabolism
    GENETICS

 due to deficiency of alpha galactosidase A. Patients with this disease have

    premature death
    SYMPTOMS

 due to the

    vascular complications
    SYMPTOMS

. A case of possible

    Fabry's disease
    DIAGNOSIS

 is presented.

Angiokeratoma
dark violaceous keratotic papule
solitary or multiple
Generalised systemic angiokeratoma
angiokeratoma corporis diffusum
premature death
vascular complications


Danon disease: further clinical and molecular heterogeneity.

Two families of Greek patients with subclinical to severe cardiomyopathy are presented. The diagnosis of Danon disease was supported by a total lack of LAMP2 immunostaining in cultured skin fibroblasts and muscle biopsies. The LAMP2 mutation carried by one patient (c.928G>A) has already been reported but with different symptoms. The second patient had a novel point deletion. This has not been described previously, but it could be detected easily by restriction analysis. This mutation was also found in the patient's brother, and it was associated with severe cardiomyopathy leading to heart failure. Surprisingly, the proband also had partial reduction of alpha-galactosidase A activity, despite the absence of characteristic clinical features of Fabry disease. A substitution in the GLA gene (c.937G>T) was found, and its involvement in the cardiac disease is discussed.

Two families of

    Greek
    ETHNICITY

 patients with

    subclinical to severe cardiomyopathy
    SYMPTOMS

 are presented. The diagnosis of

    Danon disease
    DIAGNOSIS

 was supported by a

    total lack of LAMP2 immunostaining in cultured skin fibroblasts and muscle biopsies
    MICROSCOPIC

. The

    LAMP2 mutation
    GENETICS

 carried by one patient

    (c.928G>A)
    GENETICS

 has already been reported but with different symptoms. The second patient had a

    novel point deletion
    GENETICS

. This has not been described previously, but it could be detected easily by

    restriction analysis
    PARACLINICAL

. This

    mutation was also found in the patient's brother
    FAMILY

, and it was associated with

    severe cardiomyopathy
    SYMPTOMS

 leading to

    heart failure
    SYMPTOMS

. Surprisingly, the proband also had

    partial reduction of alpha-galactosidase A activity
    BIOCHEMICAL

,

    despite the absence of characteristic clinical features of Fabry disease
    NEG_FINDINGS

. A

    substitution in the GLA gene (c.937G>T)
    GENETICS

 was found, and its involvement in the

    cardiac disease
    DIAGNOSIS

 is discussed.

subclinical to severe cardiomyopathy
severe cardiomyopathy
heart failure

LAMP2 mutation
(c.928G>A)
novel point deletion
substitution in the GLA gene (c.937G>T)


Fabry disease in a patient with Turner syndrome.

We report a unique case with co-occurrence of Turner syndrome and Fabry disease (OMIM #301500). The latter is a rare X-linked lysosomal storage disease that is characterized by partial or complete deficiency of alpha-galactosidase A (GLA; EC 3.2.1.22) following mutations in the gene (GLA) localized at Xq22.1. Accumulation of metabolic intermediates can occur in many tissues and leads to severe morbidity, especially due to renal failure, cardiac involvement and stroke. It is well established that hemizygous male mutation carriers with Fabry disease are generally more severely affected than heterozygous female mutation carriers, but disabling clinical features and disease progression often occur in female Fabry patients as well. The majority of this patient's cells are of the 45,X type, making her a hemizygous GLA mutation carrier displaying a very severe Fabry disease phenotype.

We report a unique case with

    co-occurrence of Turner syndrome
    FAMILY

 and

    Fabry disease
    DIAGNOSIS

 (OMIM #

    301500)
    DIAGNOSIS

. The latter is a

    rare X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 that is characterized by

    partial or complete deficiency of alpha-galactosidase A (GLA; EC 3.2.1.22)
    BIOCHEMICAL

 following

    mutations in the gene (GLA) localized at Xq22.1
    GENETICS

.

    Accumulation of metabolic intermediates can occur in many tissues
    MICROSCOPIC

 and leads to

    severe morbidity
    SYMPTOMS

, especially due to

    renal failure
    SYMPTOMS

,

    cardiac involvement
    SYMPTOMS

 and

    stroke
    SYMPTOMS

. It is well established that

    hemizygous male
    GENETICS

    mutation carriers
    GENETICS

 with

    Fabry disease
    DIAGNOSIS

 are generally more severely affected than

    heterozygous female mutation carriers
    GENETICS

, but

    disabling clinical features
    SYMPTOMS

 and

    disease progression
    SYMPTOMS

 often occur in

    female
    GENDER

    Fabry
    DIAGNOSIS

 patients as well. The majority of this patient's

    cells are of the 45,X type
    GENETICS

, making

    her
    GENDER

 a

    hemizygous GLA mutation carrier
    GENETICS

 displaying a

    very severe Fabry disease
    DIAGNOSIS

 phenotype.

Fabry disease
301500)
lysosomal storage disease
Fabry disease
Fabry
very severe Fabry disease

severe morbidity
renal failure
cardiac involvement
stroke
disabling clinical features
disease progression


Decline of plasma brain natriuretic peptide during enzyme replacement therapy in a female patient with heterozygous Fabry's disease.

There are no data regarding changes in plasma brain natriuretic peptide (BNP) levels in patients with Fabry's diseases during enzyme replacement therapy (ERT). We describe a patient with Fabry's disease who demonstrated the improvement in plasma brain BNP levels in response to ERT. Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A, which results in progressive intracellular accumulation of globotriaosylceramide (Gb3) in various organs including the heart. Cardiac involvement is frequent in Fabry's disease, resulting in cardiac dysfunction due to hypertrophic changes of the myocardium and thickening of the valves. Although ERT has been reported to improve cardiac function, no consensus has been reached regarding the effectiveness of ERT in female patients with heterozygous Fabry's disease. We report a 44-year-old woman having heterozygous Fabry's disease, who showed mitral valve thickening and regurgitation on echocardiogram. ERT was performed by intravenous infusion of recombinant alpha-galactosidase A every 2 weeks. We assessed the influences of ERT on cardiac function by measuring echocardiograhic parameters and monitoring BNP levels, which show treatment-induced drop in patients with heart failure. Although her cardiac function and mitral regurgitation assessed by echocardiography had not improved 18 months after the beginning of ERT, the plasma BNP level, which was 91.5 pg/ml before ERT, fell to 18.9 pg/ml. In conclusion, plasma BNP levels may be useful for evaluating the effectiveness of ERT for heterozygous Fabry's disease, even in patients who demonstrate no improvement in echocardiographic parameters of cardiac structure and function.

There are no data regarding changes in

    plasma brain natriuretic peptide (BNP) levels
    BIOCHEMICAL

 in patients with

    Fabry's diseases
    DIAGNOSIS

 during

    enzyme replacement therapy (ERT)
    MEDICATION

. We describe a patient with

    Fabry's disease
    DIAGNOSIS

 who demonstrated the

    improvement in plasma brain BNP levels
    BIOCHEMICAL

 in response to

    ERT
    MEDICATION

.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of the enzyme alpha-galactosidase A
    BIOCHEMICAL

, which results in

    progressive intracellular accumulation of globotriaosylceramide (Gb3) in various organs including the heart
    MICROSCOPIC

.

    Cardiac involvement
    SYMPTOMS

 is frequent in

    Fabry's disease
    DIAGNOSIS

, resulting in

    cardiac dysfunction
    SYMPTOMS

 due to

    hypertrophic changes of the myocardium
    SYMPTOMS

 and

    thickening of the valves
    SYMPTOMS

. Although

    ERT
    MEDICATION

 has been reported to

    improve cardiac function
    SYMPTOMS

, no consensus has been reached regarding the effectiveness of

    ERT
    MEDICATION

 in

    female
    GENDER

 patients with

    heterozygous Fabry's disease
    DIAGNOSIS

. We report a

    44-year-old
    AGE

    woman
    GENDER

 having

    heterozygous Fabry's disease
    DIAGNOSIS

, who showed

    mitral valve thickening and regurgitation
    SYMPTOMS

 on

    echocardiogram
    PARACLINICAL

.

    ERT
    MEDICATION

 was performed by

    intravenous infusion of recombinant alpha-galactosidase A every 2 weeks
    MEDICATION

. We assessed the influences of

    ERT
    MEDICATION

 on

    cardiac function
    SYMPTOMS

 by

    measuring echocardiograhic parameters
    PARACLINICAL

 and

    monitoring BNP levels
    PARACLINICAL

, which show

    treatment-induced drop
    BIOCHEMICAL

 in patients with

    heart failure
    SYMPTOMS

. Although

    her
    GENDER

    cardiac function and mitral regurgitation assessed by echocardiography had not improved 18 months after the beginning of ERT
    NEG_FINDINGS

,

    the plasma BNP level, which was 91.5 pg/ml before ERT
    BIOCHEMICAL

    , fell to 18.9 pg/ml
    BIOCHEMICAL

. In conclusion,

    plasma BNP levels
    BIOCHEMICAL

 may be useful for evaluating the effectiveness of

    ERT
    MEDICATION

 for

    heterozygous Fabry's disease
    DIAGNOSIS

, even in patients who demonstrate

    no improvement in echocardiographic parameters of cardiac structure and function
    NEG_FINDINGS

.

Fabry's diseases
Fabry's disease
Fabry's disease
lysosomal storage disorder
Fabry's disease
heterozygous Fabry's disease
heterozygous Fabry's disease
heterozygous Fabry's disease


Amelioration of white-matter lesions in a patient with Fabry disease.

We report on a 27-year-old man with Fabry disease who had widespread white-matter lesions (WMLs) despite the absence of renal or cardiac manifestations. Genomic analysis revealed a novel mutation: a GAT deletion at nucleotide position 234-236 in exon 5 of the coding region. After 12 months of enzyme replacement therapy (ERT), most of the WMLs had disappeared. Cell counts and protein levels in the cerebrospinal fluid also decreased. These findings suggest that ERT may play a role in the recovery of WMLs.

We report on a

    27-year-old
    AGE

    man
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 who had

    widespread white-matter lesions (WMLs)
    SYMPTOMS

    despite the absence of renal or cardiac manifestations
    NEG_FINDINGS

.

    Genomic analysis
    PARACLINICAL

 revealed a

    novel mutation: a GAT deletion at nucleotide position 234-236 in exon 5 of the coding region
    GENETICS

. After

    12 months of enzyme replacement therapy (ERT)
    MEDICATION

,

    most of the WMLs had disappeared
    MICROSCOPIC

.

    Cell counts and protein levels in the cerebrospinal fluid also decreased
    BIOCHEMICAL

. These findings suggest that

    ERT
    MEDICATION

 may play a role in the recovery of

    WMLs
    SYMPTOMS

.

widespread white-matter lesions (WMLs)
WMLs


Fabry disease with aortic regurgitation.

Aortic regurgitation is not so rare in patients with Fabry disease. Enzyme replacement therapy has become the standard medical care for Fabry disease in recent years. A 31-year-old man with Fabry disease, treated with recombinant alpha-galactosidase enzyme replacement for 19 months was admitted for evaluation of exertional dyspnea. Cardiac workup revealed left ventricular hypertrophy, increased left ventricular size, and moderate to severe aortic regurgitation. He underwent mechanical valvular replacement and heart biopsy. Histology of his aortic valve showed myxoid degeneration of valve leaflets. His heart muscle revealed extensive hypertrophy with vacuolization and the absence of lamellar bodies. We report a case of Fabry disease with aortic regurgitation in a man who underwent valvular replacement operation during enzyme replacement therapy.

    Aortic regurgitation
    SYMPTOMS

 is not so rare in patients with

    Fabry disease
    DIAGNOSIS

.

    Enzyme replacement therapy
    MEDICATION

 has become the standard medical care for

    Fabry disease
    DIAGNOSIS

 in recent years. A

    31-year-old
    AGE

    man
    GENDER

 with

    Fabry disease
    DIAGNOSIS

,

    treated with recombinant alpha-galactosidase enzyme replacement for 19 months
    MEDICATION

 was admitted for evaluation of

    exertional dyspnea
    SYMPTOMS

.

    Cardiac workup
    PARACLINICAL

 revealed

    left ventricular hypertrophy
    SYMPTOMS

,

    increased left ventricular size
    SYMPTOMS

, and

    moderate to severe aortic regurgitation
    SYMPTOMS

.

    He
    GENDER

 underwent

    mechanical valvular replacement
    MEDICATION

 and

    heart biopsy
    PARACLINICAL

.

    Histology of his aortic valve
    PARACLINICAL

 showed

    myxoid degeneration of valve leaflets
    SYMPTOMS

. His

    heart muscle
    PARACLINICAL

 revealed

    extensive hypertrophy with vacuolization
    MICROSCOPIC

 and the

    absence of lamellar bodies
    MICROSCOPIC

. We report a case of

    Fabry disease
    DIAGNOSIS

 with

    aortic regurgitation
    SYMPTOMS

 in a

    man
    GENDER

 who underwent

    valvular replacement operation
    MEDICATION

 during

    enzyme replacement therapy
    MEDICATION

.

Aortic regurgitation
exertional dyspnea
left ventricular hypertrophy
increased left ventricular size
moderate to severe aortic regurgitation
myxoid degeneration of valve leaflets
aortic regurgitation

Fabry disease
Fabry disease
Fabry disease
Fabry disease