Fabry disease and chemosis.

To report the case of a patient with Fabry disease (FD) whose ocular presentation with chronic chemosis we feel is related to FD and to describe the conjunctival fluorescein angiographic findings.

A 51-year-old male patient with FD on enzyme replacement therapy presented with 1-month chemosis and mild irritation in the left eye. Ocular examination revealed pronounced noninflammatory chemosis inferotemporally in the left eye with conjunctival tortuosity and microaneurysms bilaterally. There was mild corneal verticillata, spoke-like lens opacities, and retinal vascular tortuosity bilaterally, with no evidence of disc or macular edema. Evaluation revealed no systemic cause for his chemosis, including an orbital computerized tomography scan, which showed clear sinuses and no evidence of an intraorbital mass.

Conjunctival fluorescein angiography revealed rapid subconjunctival accumulation of dye in the involved eye but failed to demonstrate leakage from tortuous conjunctival vessels or microaneurysms.

Although the pathology of chronic chemosis in patients with FD is as yet unknown, we believe that FD should be considered in the differential diagnosis of patients presenting with chronic chemosis of unknown etiology.

To report the case of a patient with

    Fabry disease (FD)
    DIAGNOSIS

 whose

    ocular presentation with chronic chemosis
    SYMPTOMS

 we feel is related to

    FD
    DIAGNOSIS

 and to describe the

    conjunctival fluorescein angiographic findings
    PARACLINICAL

.

A

    51-year-old
    AGE

    male
    GENDER

 patient with

    FD
    DIAGNOSIS

 on

    enzyme replacement therapy
    MEDICATION

 presented with

    1-month chemosis
    SYMPTOMS

 and

    mild irritation in the left eye
    SYMPTOMS

.

    Ocular examination
    PARACLINICAL

 revealed

    pronounced noninflammatory chemosis inferotemporally in the left eye
    SYMPTOMS

 with

    conjunctival tortuosity
    SYMPTOMS

 and

    microaneurysms bilaterally
    SYMPTOMS

. There was

    mild corneal verticillata
    SYMPTOMS

,

    spoke-like lens opacities
    SYMPTOMS

, and

    retinal vascular tortuosity bilaterally
    SYMPTOMS

, with

    no evidence of disc or macular edema
    NEG_FINDINGS

. Evaluation revealed

    no systemic cause for his chemosis
    NEG_FINDINGS

, including an

    orbital computerized tomography scan
    PARACLINICAL

, which showed

    clear sinuses
    SYMPTOMS

 and

    no evidence of an intraorbital mass
    NEG_FINDINGS

.

    Conjunctival fluorescein angiography
    PARACLINICAL

 revealed

    rapid subconjunctival accumulation of dye in the involved eye
    SYMPTOMS

 but

    failed to demonstrate leakage from tortuous conjunctival vessels or microaneurysms
    NEG_FINDINGS

.

Although the pathology of

    chronic chemosis
    SYMPTOMS

 in patients with

    FD
    DIAGNOSIS

 is as yet unknown, we believe that

    FD
    DIAGNOSIS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 of patients presenting with

    chronic chemosis of unknown etiology
    SYMPTOMS

.


Excessive Daytime Sleepiness Is a Common Symptom in Fabry Disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O(2) desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%), and the prevalence of chronic fatigue (48%). EDS was independently associated with the physical component summary of the SF-36 data (corrected R(2) = -0.323, p < 0.001). EDS and age explained a quarter of variance in mental component summary (corrected R(2) = -0.253, p < 0.001). We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 characterized by a

    deficient activity of the enzyme α-galactosidase A
    BIOCHEMICAL

, resulting in a

    vasculopathic involvement of various organ systems, e.g. cerebral structures
    SYMPTOMS

.

    Marked cerebral vasculopathy
    SYMPTOMS

 with subsequent

    white matter lesions (WML)
    SYMPTOMS

 are a frequent finding in

    FD
    DIAGNOSIS

 patients. Recent studies discussed an association between

    cerebral white matter changes
    SYMPTOMS

 and

    sleep-related disturbances of breathing
    SYMPTOMS

, which may lead to

    excessive daytime sleepiness (EDS)
    SYMPTOMS

. A

    56-year-old
    AGE

    Caucasian
    ETHNICITY

    female
    GENDER

    FD
    DIAGNOSIS

 patient with

    EDS
    DIAGNOSIS

 was admitted to our

    sleep laboratory
    PARACLINICAL

.

    Overnight polysomnography
    PARACLINICAL

 showed a

    Cheyne-Stokes respiration pattern
    SYMPTOMS

 with

    significant O(2) desaturation
    SYMPTOMS

.

    MR imaging
    PARACLINICAL

 revealed

    confluent WML including the brain stem
    SYMPTOMS

, but

    no renal or cardiac involvement
    NEG_FINDINGS

. We then evaluated the clinical data of 49 genetically proven

    FD
    DIAGNOSIS

 patients (27

    males
    GENDER

;

    mean age 43 years
    AGE

) from our

    FD
    DIAGNOSIS

 centre. With a frequency of 68%,

    EDS
    DIAGNOSIS

 exceeds the prevalence of other common symptoms of

    FD
    DIAGNOSIS

 (

    angiokeratomas
    SYMPTOMS

 61%;

    acroparaesthesia
    SYMPTOMS

 51%;

    renal involvement
    SYMPTOMS

 29%;

    cardiac involvement
    SYMPTOMS

 27%), and the prevalence of

    chronic fatigue
    SYMPTOMS

 (48%).

    EDS
    DIAGNOSIS

 was independently associated with the

    physical component summary of the SF-36 data
    SYMPTOMS

 (corrected R(2) = -0.323, p < 0.001).

    EDS
    DIAGNOSIS

 and age explained a quarter of variance in mental component summary (corrected R(2) = -0.253, p < 0.001). We conclude that

    EDS
    DIAGNOSIS

 is a common and underdiagnosed symptom in

    FD
    DIAGNOSIS

 patients, accompanied by a significant

    impact on quality of life
    SYMPTOMS

.

    EDS
    DIAGNOSIS

 might be caused by

    central breathing disorders
    SYMPTOMS

 due to an

    affection of brain regions associated with respiratory control
    SYMPTOMS

 in

    FD
    DIAGNOSIS

.

Fabry disease (FD)
lysosomal storage disorder
FD
FD
EDS
FD
FD
EDS
FD
EDS
EDS
EDS
FD
EDS
FD


[Ophthalmological manifestations in Fabry's disease. Four clinical cases showing deficient alpha-galactosidase-A activity].

Fabry's disease is an illness produced by an alteration in the catabolism of the glycosphingolipids. We report ophthalmologic findings in 4 people, detected after 113 patient evaluations from an analytical, cardiological and genetic point of view.

Fabry's disease is uncommon and shows variable ophthalmologic affectation. Some patients with Fabry's disease do not present ocular affectation, while, on the other hand, healthy carriers with important ocular alterations have been described. The deposit of glycosphingolipids produces affectation at the corneal, crystalline, vascular and retinal levels. The vascular alterations affect not only the veins but also the arteries, as we report in our patients.

    Fabry's disease
    DIAGNOSIS

 is an illness produced by an

    alteration in the catabolism of the glycosphingolipids
    BIOCHEMICAL

. We report

    ophthalmologic findings
    SYMPTOMS

 in 4 people, detected after 113 patient evaluations from an

    analytical, cardiological and genetic
    PARACLINICAL

 point of view.

    Fabry's disease
    DIAGNOSIS

 is uncommon and shows

    variable ophthalmologic affectation
    SYMPTOMS

. Some patients with

    Fabry's disease
    DIAGNOSIS

 do

    not present ocular affectation
    NEG_FINDINGS

, while, on the other hand, healthy carriers with

    important ocular alterations
    SYMPTOMS

 have been described. The

    deposit of glycosphingolipids
    MICROSCOPIC

 produces

    affectation at the corneal, crystalline, vascular and retinal levels
    SYMPTOMS

. The

    vascular alterations affect not only the veins but also the arteries
    SYMPTOMS

, as we report in our patients.

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


The g.1170C>T polymorphism of the 5' untranslated region of the human alpha-galactosidase gene is associated with decreased enzyme expression--evidence from a family study.

Subnormal leukocyte α-galactosidase (α-Gal) activity was found during evaluation of an adolescent male with cryptogenic cerebrovascular small-vessel disease. The only molecular abnormality found was the g.1170C>T single-nucleotide polymorphism (SNP) in the 5' untranslated region of exon 1 in the α-Gal gene (GLA). Historically, this polymorphism has been considered to be biologically neutral. To test the hypothesis that the g.1170T allele might be associated with lower α-Gal expression, we genotyped GLA exon 1 and measured leukocyte and plasma α-Gal in the parents, brother and sister of the index case. The g.1170T allele co-segregated with a subnormal leukocyte α-Gal activity in the three siblings. Although plasma enzyme activities were within the normal range in all five relatives, the ranking of their values suggested a dosage effect of the g.1170T allele. Western blotting assays of leukocyte protein extracts showed that the relative expression of α-Gal in both the patient and his sister was significantly lower than in sex-matched hemizygous or homozygous controls for the g.1170C allele, either normalized to the β-actin immunoblot expression or standardized to a known amount of recombinant human α-Gal. These family data, in combination with results from a recent GLA SNP screening study among healthy Portuguese individuals, suggest that the g.1170C>T SNP may be co-dominantly associated with a relatively decreased GLA expression at the transcription and/or translation level. Larger population studies are needed to confirm these findings and to test the hypothesis that the GLA g.1170C>T may contribute to the multifactorial risk of ischaemic small-vessel cerebrovascular disease.

    Subnormal leukocyte α-galactosidase (α-Gal) activity
    BIOCHEMICAL

 was found during evaluation of an

    adolescent
    AGE

    male
    GENDER

 with

    cryptogenic cerebrovascular small-vessel disease
    SYMPTOMS

. The only

    molecular abnormality
    GENETICS

 found was the

    g.1170C>T single-nucleotide polymorphism (SNP) in the 5' untranslated region of exon 1 in the α-Gal gene (GLA)
    GENETICS

. Historically, this polymorphism has been considered to be biologically neutral. To test the hypothesis that the

    g.1170T allele
    GENETICS

 might be associated with

    lower α-Gal expression
    BIOCHEMICAL

, we

    genotyped GLA exon 1 and measured leukocyte and plasma α-Gal in the parents, brother
    PARACLINICAL

 and sister of the index case. The

    g.1170T allele
    GENETICS

    co-segregated with a subnormal leukocyte α-Gal activity in the three siblings
    FAMILY

. Although

    plasma enzyme activities were within the normal range in all five relatives
    NEG_FINDINGS

, the ranking of their values suggested a

    dosage effect of the g.1170T allele
    GENETICS

.

    Western blotting assays of leukocyte protein extracts
    PARACLINICAL

 showed that the

    relative expression of α-Gal in both the patient and his sister was significantly lower than
    BIOCHEMICAL

 in sex-matched

    hemizygous or homozygous controls for the g.1170C allele
    GENETICS

, either normalized to the

    β-actin immunoblot expression
    BIOCHEMICAL

 or standardized to a known amount of

    recombinant human α-Gal
    BIOCHEMICAL

. These family data, in combination with results from a recent

    GLA SNP screening
    PARACLINICAL

 study among healthy

    Portuguese
    ETHNICITY

 individuals, suggest that the

    g.1170C>T SNP may be co-dominantly associated with a relatively decreased GLA expression at the transcription and/or translation level
    GENETICS

. Larger population studies are needed to confirm these findings and to test the hypothesis that the

    GLA g.1170C>T
    GENETICS

 may contribute to the multifactorial risk of

    ischaemic small-vessel cerebrovascular disease
    DIAGNOSIS

.


Anderson-Fabry disease: a case-finding study among male kidney transplant recipients in Austria.

The diagnosis of Anderson-Fabry disease is often delayed or even missed. As severe renal manifestations are a hallmark of alfa-galactosidase A (AGAL) deficiency, we tested the hypothesis that Anderson-Fabry disease is under-recognized among male kidney transplant recipients. This nation-wide study in Austria enrolled 1306 patients (ca 65% of all kidney transplanted males) from 30 kidney centers. AGAL activity was determined from filter paper dried blood spots by a fluorescence assay. A positive screening test was defined by an AGAL activity below 1.5 nmol/h/ml. In patients with a positive blood spot-screening test, AGAL activity was re-examined in peripheral blood leukocytes. Genetic testing for mutations in the GLA gene was performed by sequencing to confirm the diagnosis of Anderson-Fabry disease. Two previously not recognized cases with Anderson-Fabry disease were identified. Our study is the first showing that a diagnosis of Anderson-Fabry disease can be missed even in patients who undergo kidney transplantation. Case-finding strategies may be considered a useful tool for diagnosis of this rare disease that may be somewhat more prevalent among kidney transplant recipients compared with dialysis populations.

The diagnosis of

    Anderson-Fabry disease
    DIAGNOSIS

 is often delayed or even missed. As

    severe renal manifestations
    SYMPTOMS

 are a hallmark of

    alfa-galactosidase A (AGAL) deficiency
    BIOCHEMICAL

, we tested the hypothesis that

    Anderson-Fabry disease
    DIAGNOSIS

 is under-recognized among

    male
    GENDER

    kidney transplant recipients
    MEDICATION

. This nation-wide study in

    Austria
    ETHNICITY

 enrolled 1306 patients (ca 65% of all

    kidney transplanted
    MEDICATION

    males
    GENDER

) from 30 kidney centers.

    AGAL activity was determined from filter paper dried blood spots by a fluorescence assay
    BIOCHEMICAL

. A positive screening test was defined by an

    AGAL activity below 1.5 nmol/h/ml
    BIOCHEMICAL

. In patients with a

    positive blood spot-screening test
    PARACLINICAL

,

    AGAL activity was re-examined in peripheral blood leukocytes
    BIOCHEMICAL

.

    Genetic testing for mutations in the GLA gene
    PARACLINICAL

 was performed by sequencing to confirm the diagnosis of

    Anderson-Fabry disease
    DIAGNOSIS

. Two previously not recognized cases with

    Anderson-Fabry disease
    DIAGNOSIS

 were identified. Our study is the first showing that a diagnosis of

    Anderson-Fabry disease
    DIAGNOSIS

 can be missed even in patients who undergo

    kidney transplantation
    MEDICATION

. Case-finding strategies may be considered a useful tool for diagnosis of this rare disease that may be somewhat more prevalent among

    kidney transplant
    MEDICATION

 recipients compared with dialysis populations.

Anderson-Fabry disease
Anderson-Fabry disease
Anderson-Fabry disease
Anderson-Fabry disease
Anderson-Fabry disease

kidney transplant recipients
kidney transplanted
kidney transplantation
kidney transplant


Enzyme replacement therapy stabilizes obstructive pulmonary Fabry disease associated with respiratory globotriaosylceramide storage.

Fabry disease is an X-linked glycosphingolipidosis caused by a deficiency of α-galactosidase A, a lysosomal enzyme. Symptoms in hemizygous males and heterozygous females are due to lysosomal storage of globotriaosylceramide in the central and peripheral nervous system, vascular endothelium, cardiac valves and myocytes, gastrointestinal tract, and renal epithelium. Pulmonary involvement is also a recognized manifestation of Fabry disease, but histopathological evidence of pulmonary lysosomal storage is scant. We report a 51-year-old woman with a G43R α-galactosidase A mutation and normal spirometry testing 2.5 years prior to presentation, who experienced a dry, nonproductive cough that persisted despite treatment with antibiotics and bronchodilators. Spirometry demonstrated a mixed restrictive/obstructive pattern as well as impaired gas exchange. Patchy ground-glass pulmonary interstitial infiltrates were found on plain radiography and computerized tomography. She underwent an open lung biopsy that demonstrated peribronchiolar fibrosis and smooth-muscle hyperplasia. Prominent inclusion bodies of the bronchiolar/arteriolar smooth muscle and endothelium were present. Electron microscopy indicated the inclusion bodies were lamellated zebra bodies consistent with globotriaosylceramide storage. Enzyme replacement therapy (ERT) with agalsidase-beta was instituted. Since initiation of therapy, she occasionally has a dry cough but markers of obstructive lung disease have remained stable in the past 4 years. This report demonstrates that pulmonary involvement in Fabry disease is due to lysosomal storage, and suggests that ERT is capable of stabilizing pulmonary Fabry disease. However, progressive worsening of her total lung capacity indicates that ERT cannot reverse the ongoing process of fibrosis also seen in Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    glycosphingolipidosis
    DIAGNOSIS

 caused by a

    deficiency of α-galactosidase A, a lysosomal enzyme
    BIOCHEMICAL

. Symptoms in

    hemizygous males
    GENETICS

 and

    heterozygous
    GENETICS

    females
    GENDER

 are due to

    lysosomal storage of globotriaosylceramide in the central and peripheral nervous system, vascular endothelium, cardiac valves and myocytes, gastrointestinal tract, and renal epithelium
    MICROSCOPIC

.

    Pulmonary involvement
    SYMPTOMS

 is also a recognized manifestation of

    Fabry disease
    DIAGNOSIS

, but histopathological evidence of

    pulmonary lysosomal storage
    MICROSCOPIC

 is scant. We report a

    51-year-old
    AGE

    woman
    GENDER

 with a

    G43R α-galactosidase A mutation
    GENETICS

 and

    normal spirometry testing 2.5 years
    NEG_FINDINGS

 prior to presentation, who experienced a

    dry, nonproductive cough
    SYMPTOMS

 that persisted

    despite treatment with antibiotics and bronchodilators
    NEG_FINDINGS

.

    Spirometry
    PARACLINICAL

 demonstrated a

    mixed restrictive/obstructive pattern
    SYMPTOMS

 as well as

    impaired gas exchange
    SYMPTOMS

.

    Patchy ground-glass pulmonary interstitial infiltrates
    SYMPTOMS

 were found on

    plain radiography and computerized tomography
    PARACLINICAL

.

    She
    GENDER

 underwent an

    open lung biopsy
    PARACLINICAL

 that demonstrated

    peribronchiolar fibrosis and smooth-muscle hyperplasia
    MICROSCOPIC

.

    Prominent inclusion bodies of the bronchiolar/arteriolar smooth muscle and endothelium were present
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 indicated

    the inclusion bodies were lamellated zebra bodies consistent with globotriaosylceramide storage
    MICROSCOPIC

.

    Enzyme replacement therapy (ERT) with agalsidase-beta
    MEDICATION

 was instituted. Since initiation of therapy,

    she
    GENDER

 occasionally has a

    dry cough
    SYMPTOMS

 but

    markers of obstructive lung disease have remained stable in the past 4 years
    NEG_FINDINGS

. This report demonstrates that

    pulmonary involvement
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 is due to

    lysosomal storage
    MICROSCOPIC

, and suggests that

    ERT
    MEDICATION

 is capable of

    stabilizing pulmonary Fabry disease
    DIAGNOSIS

. However,

    progressive worsening of her total lung capacity
    SYMPTOMS

 indicates that

    ERT
    MEDICATION

    cannot reverse the ongoing process of fibrosis
    NEG_FINDINGS

 also seen in

    Fabry disease
    DIAGNOSIS

.

Fabry disease
glycosphingolipidosis
Fabry disease
Fabry disease
stabilizing pulmonary Fabry disease
Fabry disease

X-linked
hemizygous males
heterozygous
G43R α-galactosidase A mutation


Fabry disease in hemodialysis patients in southern Brazil: prevalence study and clinical report.

Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of alpha-Galactosidase A (alpha-Gal A). Fabry nephropathy typically progresses throughout the fifth decade to end-stage renal disease (ESRD), requiring hemodialysis and/or kidney transplantation.

To estimate the prevalence of FD among ESRD males on hemodialysis treatment in Rio Grande do Sul, the southernmost state of Brazil.

Screening for alpha-Gal A activity was performed by a dried blood spot (normal reference value: >1.5 nmoles/hour/mL). Positive screening results were confirmed by plasma alpha-Gal A activity assay (reference value: >3.3 nmoles/hour/mL).

Five hundred fifty-eight male patients on hemodialysis were evaluated. Of these, only two had low alpha-Gal A activity and were diagnosed with Fabry disease (0.36%). One of these, age 42, had left ventricular hypertrophy and renal manifestations of Fabry disease without the classic symptoms. The other, age 46, had the classical manifestations of angiokeratomas, acroparesthesias, hypohidrosis, and ocular opacities.

Although the prevalence of Fabry disease was very low in our study (0.36%), routine screening of male hemodialysis patients would enable earlier identification of many other affected relatives in their families who might benefit from specific clinical treatment.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of alpha-Galactosidase A (alpha-Gal A)
    BIOCHEMICAL

.

    Fabry nephropathy
    DIAGNOSIS

 typically progresses

    throughout the fifth decade
    AGE

 to

    end-stage renal disease (ESRD)
    DIAGNOSIS

, requiring

    hemodialysis
    MEDICATION

    and/or kidney transplantation
    MEDICATION

.

To estimate the prevalence of

    FD
    DIAGNOSIS

 among

    ESRD
    DIAGNOSIS

    males
    GENDER

 on

    hemodialysis treatment
    MEDICATION

 in

    Rio Grande do Sul
    ETHNICITY

, the southernmost state of

    Brazil
    ETHNICITY

.

    Screening for alpha-Gal A activity
    PARACLINICAL

 was performed by a

    dried blood spot
    PARACLINICAL

 (

    normal reference value: >1.5 nmoles/hour/mL)
    BIOCHEMICAL

. Positive screening results were confirmed by

    plasma alpha-Gal A activity assay (reference value: >3.3 nmoles/hour/mL)
    BIOCHEMICAL

.

Five hundred fifty-eight

    male
    GENDER

 patients on

    hemodialysis
    MEDICATION

 were evaluated. Of these, only two had

    low alpha-Gal A activity
    BIOCHEMICAL

 and were diagnosed with

    Fabry disease
    DIAGNOSIS

 (0.36%). One of these,

    age 42
    AGE

, had

    left ventricular hypertrophy
    SYMPTOMS

 and

    renal manifestations of Fabry disease
    SYMPTOMS

    without the classic symptoms
    NEG_FINDINGS

. The other,

    age 46
    AGE

, had the classical manifestations of

    angiokeratomas
    SYMPTOMS

,

    acroparesthesias
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

, and

    ocular opacities
    SYMPTOMS

.

Although the prevalence of

    Fabry disease
    DIAGNOSIS

 was very low in our study (0.36%), routine screening of

    male
    GENDER

    hemodialysis
    MEDICATION

 patients would enable earlier identification of many other affected relatives in their families who might benefit from specific clinical treatment.

Fabry disease (FD)
lysosomal storage disorder
Fabry nephropathy
end-stage renal disease (ESRD)
FD
ESRD
Fabry disease
Fabry disease

hemodialysis
and/or kidney transplantation
hemodialysis treatment
hemodialysis
hemodialysis

left ventricular hypertrophy
renal manifestations of Fabry disease
angiokeratomas
acroparesthesias
hypohidrosis
ocular opacities


Angiokeratomas of Fabry successfully treated with intense pulsed light.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder resulting from the deficient activity of the enzyme alpha-galactosidase A. Angiokeratomas (AKs) are a frequent manifestation of this disease. They usually become apparent during childhood and can cause important cosmetic disability. Current treatment of this feature in the setting of FD has been mainly based on the application of laser systems, namely the argon laser, the variable pulse width 532-nm Nd:YAG laser, the 578-nm copper vapor laser and the flashlamp-pumped pulsed dye laser. We report the case of a 31-year-old Caucasian woman with a clinical and molecular (GLA p.R118C) diagnosis of FD, presenting multiple AKs scattered over the buttocks and thighs. She was treated with 10 sessions of intense pulsed light (IPL), with a 4-8-week interval between them. An almost complete clearance of the lesions was obtained, with no scars or significant complaints. No recurrence occurred during a 12-month follow-up period. The IPL source can be considered a suitable, effective and safe treatment modality for these cutaneous lesions that typically affect patients with FD, with no need for local anesthesia and with very satisfactory cosmetic results. To our best knowledge, there are no reports in the literature of Fabry's AKs treated with IPL.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from the deficient activity of the enzyme alpha-galactosidase A.

    Angiokeratomas (AKs)
    SYMPTOMS

 are a frequent manifestation of this disease. They usually become apparent during

    childhood
    AGE

 and can cause important

    cosmetic disability
    SYMPTOMS

. Current treatment of this feature in the setting of

    FD
    DIAGNOSIS

 has been mainly based on the application of

    laser systems
    MEDICATION

, namely the

    argon laser, the variable pulse width 532-nm Nd:YAG laser
    MEDICATION

, the

    578-nm copper vapor laser
    MEDICATION

 and the

    flashlamp-pumped pulsed dye laser
    MEDICATION

. We report the case of a

    31-year-old
    AGE

    Caucasian
    ETHNICITY

    woman
    GENDER

 with a clinical and molecular (

    GLA p.R118C)
    GENETICS

 diagnosis of

    FD
    DIAGNOSIS

, presenting

    multiple AKs scattered over the buttocks and thighs
    SYMPTOMS

.

    She
    GENDER

 was treated with

    10 sessions of intense pulsed light (IPL), with a 4-8-week interval between them
    MEDICATION

. An

    almost complete clearance of the lesions
    SYMPTOMS

 was obtained, with

    no scars or significant complaints
    NEG_FINDINGS

.

    No recurrence
    NEG_FINDINGS

 occurred during a

    12-month follow-up period
    PARACLINICAL

. The

    IPL source
    MEDICATION

 can be considered a suitable, effective and safe treatment modality for these

    cutaneous lesions
    SYMPTOMS

 that typically affect patients with

    FD
    DIAGNOSIS

, with

    no need for local anesthesia
    NEG_FINDINGS

 and with very satisfactory cosmetic results. To our best knowledge, there are no reports in the literature of

    Fabry's AKs
    DIAGNOSIS

 treated with

    IPL
    MEDICATION

.

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

no scars or significant complaints
No recurrence
no need for local anesthesia


Subfoveal choroidal neovascularization in a patient with Fabry's disease.

Fabry disease (FD) is an X-linked, inherited disorder caused by a deficiency of the enzyme alpha-galactosidase A, with progressive accumulation of glycosphingolipids within several tissues and organs, including the eye. Ophthalmological manifestations include conjunctival vessel tortuosity, cornea verticillata, lens opacity, and retinochoroidal vessel abnormalities.

In FD, the presence of macular choroidal neovascularization (CNV) has never been previously described.

We report the case of a FD patient who developed an early-onset CNV, when he was still in his 40s.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked, inherited disorder
    GENETICS

 caused by a

    deficiency of the enzyme alpha-galactosidase A
    BIOCHEMICAL

, with

    progressive accumulation of glycosphingolipids within several tissues and organs, including the eye
    MICROSCOPIC

.

    Ophthalmological manifestations
    SYMPTOMS

 include

    conjunctival vessel tortuosity
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

,

    lens opacity
    SYMPTOMS

, and

    retinochoroidal vessel abnormalities
    SYMPTOMS

.

In

    FD
    DIAGNOSIS

, the presence of

    macular choroidal neovascularization (CNV)
    SYMPTOMS

 has never been previously described.

We report the case of a

    FD
    DIAGNOSIS

 patient who developed an

    early-onset CNV
    SYMPTOMS

, when

    he
    GENDER

 was

    still in his 40s
    AGE

.


Splenomegaly, hypersplenism and peripheral blood cytopaenias in patients with classical Anderson-Fabry disease.

A 39-year-old male with classical Anderson-Fabry disease (AFD) and long-standing idiopathic splenomegaly, who had been on haemodialysis since the age of 24, was splenectomised for symptomatic pancytopaenia. Spleen enlargement was first noted at clinical presentation, at age 16, but despite thorough investigation its cause remained unclear. Anaemia, leukopaenia and thrombocytopaenia were first observed a few years thereafter, but well before the start of dialytic treatment. On gross pathological examination the spleen weighed 700 g and had a fibrocongestive appearance. Histologically, it showed expansion of the red pulp and decreased white pulp. Some histiocytes and many of the endothelial cells lining the sinusoids had vacuolated cytoplasm with argyrophilic material within, suggesting their involvement in the storage pathology of AFD. In a retrospective review of our cohort of patients with classical AFD (n = 10), complete blood counts showing anaemia, leukopaenia or thrombocytopaenia were found in five, two and four patients, respectively, including a 6-year-old boy, whose spleen was also enlarged. Data from AFD international registries show that peripheral blood cytopaenias, particularly anaemia, are prevalent among these patients. Sinusoidal endothelial involvement resulting in compromise of splenic blood flow may be the cause of congestive splenomegaly and hypersplenism in classical AFD.

A

    39-year-old
    AGE

    male
    GENDER

 with

    classical Anderson-Fabry disease (AFD)
    DIAGNOSIS

 and

    long-standing idiopathic splenomegaly
    SYMPTOMS

, who had been

    on haemodialysis since the age of 24
    MEDICATION

, was

    splenectomised
    MEDICATION

 for symptomatic

    pancytopaenia
    BIOCHEMICAL

.

    Spleen enlargement
    SYMPTOMS

 was first noted at clinical presentation, at

    age 16
    AGE

, but despite thorough investigation its cause remained unclear.

    Anaemia
    BIOCHEMICAL

,

    leukopaenia
    BIOCHEMICAL

 and

    thrombocytopaenia
    BIOCHEMICAL

 were first observed a few years thereafter, but well before the start of

    dialytic treatment
    MEDICATION

. On

    gross pathological examination
    PARACLINICAL

 the

    spleen weighed 700 g and had a fibrocongestive appearance
    SYMPTOMS

. Histologically, it showed

    expansion of the red pulp and decreased white pulp
    MICROSCOPIC

.

    Some histiocytes and many of the endothelial cells lining the sinusoids had vacuolated cytoplasm with argyrophilic material within
    MICROSCOPIC

, suggesting their

    involvement in the storage pathology of AFD
    MICROSCOPIC

. In a retrospective review of our cohort of patients with

    classical AFD
    DIAGNOSIS

 (n = 10),

    complete blood counts
    PARACLINICAL

 showing

    anaemia
    BIOCHEMICAL

,

    leukopaenia
    BIOCHEMICAL

 or

    thrombocytopaenia
    BIOCHEMICAL

 were found in five, two and four patients, respectively, including a

    6-year-old
    AGE

    boy
    GENDER

, whose

    spleen was also enlarged
    SYMPTOMS

. Data from

    AFD
    DIAGNOSIS

 international registries show that

    peripheral blood cytopaenias
    BIOCHEMICAL

, particularly

    anaemia
    BIOCHEMICAL

, are prevalent among these patients.

    Sinusoidal endothelial involvement
    MICROSCOPIC

 resulting in

    compromise of splenic blood flow
    SYMPTOMS

 may be the cause of

    congestive splenomegaly
    SYMPTOMS

 and

    hypersplenism
    BIOCHEMICAL

 in

    classical AFD
    DIAGNOSIS

.

classical Anderson-Fabry disease (AFD)
classical AFD
AFD
classical AFD

on haemodialysis since the age of 24
splenectomised
dialytic treatment

pancytopaenia
Anaemia
leukopaenia
thrombocytopaenia
anaemia
leukopaenia
thrombocytopaenia
peripheral blood cytopaenias
anaemia
hypersplenism


Absence of cornea verticillata in hemizygotes of a novel mutation in fabry disease.

To report a new pedigree of Fabry disease that does not display corneal involvement in hemizygotes.

A 44-year-old man presented with proteinuria, chronic obstructive airway disease, hypoacusia, teleangiectasis, and hypohidrosis. A kidney biopsy, genetic study, and ophthalmological examination were conducted. The patient's 66-year-old mother and 45-year-old sister were also investigated.

Glomerular changes associated with Fabry disease were found. The diagnosis was confirmed by genetic study of the alpha-galactosidase A gene. In exon 2, an adenine was changed to a guanine at codon 92. This mutation is called D92G or Asp92Gly. This mutation has not been reported previously. Systemic examination showed cardiac involvement and chronic obstructive airway disease in the mother of the patient. The same mutation was present in the mother and in the sister of the patient. Cornea verticillata was not present in the hemizygous male. The mother and the sister of the patient showed the features of cornea verticillata. The patient and his mother were treated with enzyme replacement therapy using recombinant alpha-galactosidase A.

We report here a new mutation in Fabry disease. The hemizygote did not show corneal manifestations as opposed to heterozygotes in the described family. The severity of systemic disease was not correlated with the presence of corneal deposits.

To report a new pedigree of

    Fabry disease
    DIAGNOSIS

 that

    does not display corneal involvement in hemizygotes
    NEG_FINDINGS

.

A

    44-year-old
    AGE

    man
    GENDER

 presented with

    proteinuria
    BIOCHEMICAL

,

    chronic obstructive airway disease
    DIAGNOSIS

,

    hypoacusia
    SYMPTOMS

,

    teleangiectasis
    SYMPTOMS

, and

    hypohidrosis
    SYMPTOMS

. A

    kidney biopsy
    PARACLINICAL

,

    genetic study
    PARACLINICAL

, and

    ophthalmological examination
    PARACLINICAL

 were conducted. The patient's

    66-year-old
    AGE

    mother and 45-year-old
    FAMILY

    sister
    FAMILY

 were also investigated.

    Glomerular changes associated with Fabry disease
    MICROSCOPIC

 were found. The diagnosis was confirmed by

    genetic study of the alpha-galactosidase A gene
    PARACLINICAL

.

    In exon 2, an adenine was changed to a guanine at codon 92
    GENETICS

. This

    mutation is called D92G or Asp92Gly
    GENETICS

. This mutation has not been reported previously.

    Systemic examination
    PARACLINICAL

 showed

    cardiac involvement
    SYMPTOMS

 and

    chronic obstructive airway disease in the mother of the patient
    FAMILY

.

    The same mutation was present in the mother and in the sister of the patient
    FAMILY

.

    Cornea verticillata
    NEG_FINDINGS

    was not present in the hemizygous male
    FAMILY

.

    The mother and the sister of the patient showed the features of cornea verticillata
    FAMILY

. The patient and

    his
    GENDER

    mother
    GENDER

 were treated with

    enzyme replacement therapy using recombinant alpha-galactosidase A.
    MEDICATION

We report here a

    new mutation in
    GENETICS

    Fabry disease
    DIAGNOSIS

. The

    hemizygote
    GENETICS

    did not show corneal manifestations
    NEG_FINDINGS

 as opposed to

    heterozygotes
    GENETICS

    in the described family
    FAMILY

. The severity of

    systemic disease
    SYMPTOMS

 was not correlated with the presence of

    corneal deposits
    SYMPTOMS

.

Fabry disease
chronic obstructive airway disease
Fabry disease

hypoacusia
teleangiectasis
hypohidrosis
cardiac involvement
systemic disease
corneal deposits


Creating genetics-based infusion centers: a case study of two models.

In 1993, the first effective enzyme replacement therapy for a genetic disease, Ceredase (Genzyme Corporation, Cambridge, MA), was approved for use in patients with Gaucher disease. Over the next 13 years, enzyme replacement therapy became clinically available for the treatment of Fabry disease, mucopolysaccharidosis Type I, mucopolysaccharidosis Type II, mucopolysaccharidosis Type VI, and glycogen storage disease Type II. The development of enzyme replacement therapy to treat lysosomal storage diseases has resulted in an increasing number of genetic patients undergoing weekly or biweekly intravenous enzyme replacement therapy and an expanded role of the genetics team to include comprehensive care involving therapeutic intervention for lysosomal storage diseases. This article describes the development of two outpatient genetics-based infusion centers: the Northshore Genetics Infusion Clinic as part of the Children's Hospital of Wisconsin Lysosomal Diseases Treatment Center in conjunction with the Medical College of Wisconsin and the Emory Lysosomal Storage Disease Center for Genetic Infusions in the Emory University Department of Human Genetics.

In 1993, the first

    effective enzyme replacement therapy for a genetic disease
    MEDICATION

,

    Ceredase (
    MEDICATION

Genzyme Corporation, Cambridge, MA), was approved for use in patients with

    Gaucher disease
    DIAGNOSIS

. Over the next 13 years,

    enzyme replacement therapy
    MEDICATION

 became clinically available for the treatment of

    Fabry disease
    DIAGNOSIS

,

    mucopolysaccharidosis Type I
    DIAGNOSIS

,

    mucopolysaccharidosis Type II
    DIAGNOSIS

,

    mucopolysaccharidosis Type VI
    DIAGNOSIS

, and

    glycogen storage disease Type II
    DIAGNOSIS

. The development of

    enzyme replacement therapy
    MEDICATION

 to treat

    lysosomal storage diseases
    DIAGNOSIS

 has resulted in an increasing number of genetic patients undergoing

    weekly or biweekly intravenous enzyme replacement therapy
    MEDICATION

 and an expanded role of the genetics team to include

    comprehensive care involving therapeutic intervention
    MEDICATION

 for

    lysosomal storage diseases
    DIAGNOSIS

. This article describes the development of two

    outpatient genetics-based infusion centers
    MEDICATION

: the

    Northshore Genetics Infusion Clinic as part of the Children's Hospital of Wisconsin Lysosomal Diseases Treatment Center
    MEDICATION

 in conjunction with the Medical College of Wisconsin and the Emory

    Lysosomal Storage Disease Center for Genetic Infusions
    DIAGNOSIS

 in the Emory University Department of Human Genetics.


A case of Fabry disease with central nervous system (CNS) demyelinating lesions: a double trouble?

We present the case of a 36-year-old woman affected with Fabry disease (FD), with neuroradiologic and laboratory tests suggestive of a coexistent inflammatory demyelinating disease. Since the age of 23, she presented recurrent neurologic deficits, such as right limb paresthesias, diplopia, and right leg weakness. Magnetic resonance imaging revealed multiple demyelinating lesions in periventricular areas, corpus callosum, and spinal cord. Cerebrospinal fluid analysis showed the presence of oligoclonal bands, while visual-evoked potentials were delayed with preserved morphology. FD is usually considered as a differential diagnosis of multiple sclerosis, but we think that the best explanation of all pathological features in this case is the coexistence of the two diseases.

We present the case of a

    36-year-old
    AGE

    woman
    GENDER

 affected with

    Fabry disease (FD)
    DIAGNOSIS

, with

    neuroradiologic and laboratory tests
    PARACLINICAL

 suggestive of a

    coexistent inflammatory demyelinating disease
    DIAGNOSIS

. Since the

    age of 23
    AGE

,

    she
    GENDER

 presented

    recurrent neurologic deficits
    SYMPTOMS

, such as

    right limb paresthesias
    SYMPTOMS

,

    diplopia
    SYMPTOMS

, and

    right leg weakness
    SYMPTOMS

.

    Magnetic resonance imaging
    PARACLINICAL

 revealed

    multiple demyelinating lesions in periventricular areas, corpus callosum, and spinal cord
    SYMPTOMS

.

    Cerebrospinal fluid analysis
    PARACLINICAL

 showed the

    presence of oligoclonal bands
    BIOCHEMICAL

, while

    visual-evoked potentials were delayed with preserved morphology
    SYMPTOMS

.

    FD
    DIAGNOSIS

 is usually considered as a

    differential diagnosis
    PARACLINICAL

 of

    multiple sclerosis
    DIAGNOSIS

, but we think that the best explanation of all pathological features in this case is the

    coexistence of the two diseases
    DIAGNOSIS

.


Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients.

Anderson-Fabry disease (AFD) is an X-linked condition originating from a deficiency in alpha-galactosidase, a lysosomal enzyme. Multi-organ involvement ensues in early adulthood and vital organs are affected: the kidneys, brain, heart. Several reports however suggest that AFD is underdiagnosed.

We screened a kidney transplant population using a two-tier approach. The first tier was the determination of alpha-galactosidase A (AGALA) activity using a dried blood spot on filter paper (DBFP); in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene.

From the database of 2328 patients, 1233 subjects met the inclusion criteria. Finally, after informed consent, 673 patients were screened (54.5%-395 women and 278 men). DBFP analysis resulted in a mean AGALA of 2.63 +/- 2.48 micromol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 micromol/L/h, respectively). Eleven patients were subjected to further genetic analysis. In a male patient a pathogenic missense mutation p.Ala143Thr (c.427A>G) was identified.

Our results show that the proposed approach can detect AFD patients in a until now seldomly screened high-risk group: kidney transplant patients. We conclude that screening for AFD in high-risk populations is a cost-effective, technically feasible and clinically valuable objective.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

 condition originating from a

    deficiency in alpha-galactosidase, a lysosomal enzyme
    BIOCHEMICAL

.

    Multi-organ involvement
    SYMPTOMS

 ensues in

    early adulthood
    AGE

 and

    vital organs are affected: the kidneys, brain, heart
    SYMPTOMS

. Several reports however suggest that

    AFD
    DIAGNOSIS

 is underdiagnosed.

We screened a

    kidney transplant
    MEDICATION

 population using a two-tier approach. The first tier was the

    determination of alpha-galactosidase A (AGALA) activity using a dried blood spot on filter paper (DBFP)
    PARACLINICAL

; in the second tier, patients with the

    lowest alpha-galactosidase levels
    BIOCHEMICAL

 were further subjected to

    mutation analysis of the GLA gene
    PARACLINICAL

.

From the database of 2328 patients, 1233 subjects met the inclusion criteria. Finally, after informed consent, 673 patients were screened (54.5%-395

    women
    GENDER

 and 278

    men
    GENDER

).

    DBFP analysis
    PARACLINICAL

 resulted in a

    mean AGALA of 2.63 +/- 2.48 micromol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 micromol/L/h, respectively)
    BIOCHEMICAL

. Eleven patients were subjected to further

    genetic analysis
    PARACLINICAL

. In a

    male
    GENDER

 patient a

    pathogenic missense mutation p.Ala143Thr (c.427A>G)
    GENETICS

 was identified.

Our results show that the proposed approach can detect

    AFD
    DIAGNOSIS

 patients in a until now seldomly screened high-risk group:

    kidney transplant
    MEDICATION

 patients. We conclude that screening for

    AFD
    DIAGNOSIS

 in high-risk populations is a cost-effective, technically feasible and clinically valuable objective.

Anderson-Fabry disease (AFD)
AFD
AFD
AFD


Fabry's disease: An ultrastructural study of nerve biopsy.

Fabry's disease, an X linked recessive disorder caused by the deficiency of alpha-galactosidase A (alpha-gal A), leads to progressive accumulation of glycosphingolipids. We report this rare disease in a 19-year-old boy who presented with angiokeratomas, paresthesia and corneal opacities, and nerve biopsy revealed by electron microscopy lamellated inclusions in the smooth muscle, perineurial and endothelial cells characteristic of Fabry's disease.

    Fabry's disease
    DIAGNOSIS

, an

    X linked recessive disorder
    GENETICS

 caused by the

    deficiency of alpha-galactosidase A (alpha-gal A)
    BIOCHEMICAL

, leads to

    progressive accumulation of glycosphingolipids
    MICROSCOPIC

. We report this rare disease in a

    19-year-old
    AGE

    boy
    GENDER

 who presented with

    angiokeratomas
    SYMPTOMS

,

    paresthesia
    SYMPTOMS

 and

    corneal opacities
    SYMPTOMS

, and

    nerve biopsy
    PARACLINICAL

 revealed by

    electron microscopy
    PARACLINICAL

    lamellated inclusions in the smooth muscle, perineurial and endothelial cells characteristic of Fabry's disease
    MICROSCOPIC

.

angiokeratomas
paresthesia
corneal opacities


[Corneal findings in Fabry disease-related keratopathy using in vivo confocal microscopy].

Description of corneal findings in Fabry disease-related keratopathy using in vivo confocal microscopy.

A 65-year-old man presenting with a cerebral ischemic lesion was referred to our clinic for ophthalmologic evaluation with a suspicion of inaugural Fabry disease. Slit lamp biomicroscopy showed whorl-like lines in the inferior cornea of both eyes. In vivo confocal microscopy revealed the presence of numerous hyperreflective intracellular inclusions in the corneal epithelium and stroma.

The whorl-like lines are related to deposition and accumulation of glycosphingolipids in the epithelial and stromal layers of the cornea. This case is also interesting for the late manifestation of Fabry disease, showing the variability in the expression of this condition.

In vivo confocal microscopy may be an important tool in the follow-up of Fabry disease-related keratopathy, enabling us to monitor the effect of enzyme replacement therapy.

Description of corneal findings in

    Fabry disease-related keratopathy
    DIAGNOSIS

 using

    in vivo confocal microscopy
    PARACLINICAL

.

A

    65-year-old
    AGE

    man
    GENDER

 presenting with a

    cerebral ischemic lesion
    SYMPTOMS

 was referred to our clinic for

    ophthalmologic evaluation
    PARACLINICAL

 with a suspicion of

    inaugural Fabry disease
    DIAGNOSIS

.

    Slit lamp biomicroscopy
    PARACLINICAL

 showed

    whorl-like lines in the inferior cornea of both eyes
    SYMPTOMS

.

    In vivo confocal microscopy
    PARACLINICAL

 revealed the

    presence of numerous hyperreflective intracellular inclusions in the corneal epithelium and stroma
    MICROSCOPIC

.

The

    whorl-like lines
    MICROSCOPIC

 are related to

    deposition and accumulation of glycosphingolipids in the epithelial and stromal layers of the cornea
    MICROSCOPIC

. This case is also interesting for the late manifestation of

    Fabry disease
    DIAGNOSIS

, showing the variability in the expression of this condition.

    In vivo confocal microscopy
    PARACLINICAL

 may be an important tool in the follow-up of

    Fabry disease-related keratopathy
    DIAGNOSIS

, enabling us to monitor the effect of

    enzyme replacement therapy
    MEDICATION

.

Fabry disease-related keratopathy
inaugural Fabry disease
Fabry disease
Fabry disease-related keratopathy


Preservation of renal function in a patient with Fabry nephropathy on enzyme replacement therapy.

Fabry disease is an X-linked recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A. Enzyme replacement therapy (ERT) for this disorder has been available in Europe since 2001. However, its effect on advanced renal failure remains controversial. We report the case of a patient whose decline in renal function was reduced by the administration of ERT (agalsidase-alpha). This reduction was more pronounced after doubling the dose of the enzyme. The rate of deterioration of eGFR went from 6.3 ml/min/year prior to the start of ERT (0.2 mg/kg) to 2 ml/min/year (0.4 mg/kg). To our knowledge, this is the first reported case of a patient with moderately impaired renal function treated with high doses of ERT and follow-up of 6 years. The data shown here suggest that ERT may have a very positive impact on renal function even in advanced stages. The role of proteinuria and its control seem to have a clear responsibility for this favorable outcome.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    inborn error of glycosphingolipid metabolism
    DIAGNOSIS

 caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A.

    Enzyme replacement therapy (ERT)
    MEDICATION

 for this disorder has been available in Europe since 2001. However, its effect on

    advanced renal failure
    SYMPTOMS

 remains controversial. We report the case of a patient whose

    decline in renal function
    BIOCHEMICAL

 was reduced by the

    administration of ERT (agalsidase-alpha)
    MEDICATION

. This reduction was more pronounced after

    doubling the dose of the enzyme
    MEDICATION

. The rate of

    deterioration of eGFR went from 6.3 ml/min/
    BIOCHEMICAL

year prior to the start

    of ERT (0.2 mg/kg) to 2 ml/min/year (0.4 mg/kg)
    MEDICATION

. To our knowledge, this is the first reported case of a patient with

    moderately impaired renal function
    SYMPTOMS

 treated with

    high doses of ERT
    MEDICATION

 and

    follow-up of 6 years
    PARACLINICAL

. The data shown here suggest that

    ERT
    MEDICATION

 may have a very positive impact on

    renal function
    SYMPTOMS

 even in advanced stages. The role of

    proteinuria
    BIOCHEMICAL

 and its control seem to have a clear responsibility for this favorable outcome.

advanced renal failure
moderately impaired renal function
renal function


Combined heart and kidney transplantation in a patient with Fabry disease in the enzyme replacement therapy era.

Fabry disease (FD) is an X-linked genetic disease, resulting from the deficiency of alpha-galactosidase A, a lysosomal enzyme responsible for the cleavage of glycosphingolipids. In absence of enzyme replacement therapy (ERT), globotriaosylceramide (Gb3) accumulates in tissue, leading to progressive organ damage with severe renal, cardiac and central nervous system complications. We herein describe the first case of successful combined and simultaneous heart and kidney transplantation in a young male patient with FD complicated by end-stage renal disease and severe heart failure not responding to late-onset ERT. Combined heart and kidney transplantation can be recommended for Fabry patients with end-stage renal disease and overt hypertrophic cardiomyopathy, severe ischemic or valvular heart disease.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked genetic disease
    GENETICS

, resulting from the

    deficiency of alpha-galactosidase A, a lysosomal enzyme
    BIOCHEMICAL

 responsible for the

    cleavage of glycosphingolipids
    BIOCHEMICAL

. In

    absence of enzyme replacement therapy (ERT)
    NEG_FINDINGS

,

    globotriaosylceramide (Gb3) accumulates in tissue
    MICROSCOPIC

, leading to

    progressive organ damage
    SYMPTOMS

 with

    severe renal, cardiac and central nervous system complications
    SYMPTOMS

. We herein describe the first case of

    successful combined and simultaneous heart and kidney transplantation
    MEDICATION

 in a

    young
    AGE

    male
    GENDER

 patient with

    FD
    DIAGNOSIS

 complicated by

    end-stage renal disease
    DIAGNOSIS

 and

    severe heart failure
    SYMPTOMS

    not responding to late-onset ERT
    NEG_FINDINGS

.

    Combined heart and kidney transplantation
    MEDICATION

 can be recommended for

    Fabry
    DIAGNOSIS

 patients with

    end-stage renal disease
    DIAGNOSIS

 and

    overt hypertrophic cardiomyopathy
    SYMPTOMS

,

    severe ischemic or valvular heart disease
    SYMPTOMS

.

Fabry disease (FD)
FD
end-stage renal disease
Fabry
end-stage renal disease


Short PR interval in the absence of preexcitation: a characteristic finding in a patient with Fabry disease.

Fabry disease (FD) is a rare lysosomal storage disease characterized by intracellular deposition of glycosphingolipids that can involve various organs including the heart. Here, we report the finding of a short PR interval in a patient with FD and recurrent syncope associated with short atrial-His (A-H) and His-ventricular (H-V) intervals in the absence of preexcitation. While electrocardiographic abnormalities are not uncommon among FD patients, there have been few reports on electrophysiological studies performed on these patients. The exact mechanism for the short A-H and H-V intervals remains unclear, but they may result from accelerated conduction in the AV node-His-Purkinje system.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare lysosomal storage disease
    DIAGNOSIS

 characterized by

    intracellular deposition of glycosphingolipids
    MICROSCOPIC

 that can involve

    various organs including the heart
    SYMPTOMS

. Here, we report the finding of a

    short PR interval
    SYMPTOMS

 in a patient with

    FD
    DIAGNOSIS

 and

    recurrent syncope
    SYMPTOMS

 associated with

    short atrial-His (A-H) and His-ventricular (H-V) intervals
    SYMPTOMS

 in the

    absence of preexcitation
    NEG_FINDINGS

. While

    electrocardiographic abnormalities
    SYMPTOMS

 are not uncommon among

    FD
    DIAGNOSIS

 patients, there have been few reports on electrophysiological studies performed on these patients. The exact mechanism for the

    short A-H and H-V intervals
    SYMPTOMS

 remains unclear, but they may result from

    accelerated conduction in the AV node-His-Purkinje system
    SYMPTOMS

.

Fabry disease (FD)
rare lysosomal storage disease
FD
FD


Nomen est omen. Fabry disease.

A 47-year-old woman was referred with increasing dyspnoea and neuropathic pain. During echocardiography, she showed the typical signs for a Fabry cardiomyopathy: global left ventricular function was normal with an ejection fraction of 65%. She had a concentric left ventricular hypertrophy with very prominent papillary muscles. In addition, the magnetic resonance tomography showed regional late enhancement in the postero-lateral wall which is the typical location of fibrosis in Fabry patients. She suffered from a genetically proven Fabry disease, and interestingly her family name is Mrs Fabry. Thus summarized, Mrs Fabry with a confirmed Fabry disease presented with a typically Fabry cardiomyopathy.

A

    47-year-old
    AGE

    woman
    GENDER

 was referred with

    increasing dyspnoea
    SYMPTOMS

 and

    neuropathic pain
    SYMPTOMS

. During

    echocardiography
    PARACLINICAL

,

    she
    GENDER

 showed the typical signs for a

    Fabry cardiomyopathy
    DIAGNOSIS

:

    global left ventricular function was normal
    NEG_FINDINGS

 with an

    ejection fraction of 65%
    NEG_FINDINGS

.

    She
    GENDER

 had a

    concentric left ventricular hypertrophy with very prominent papillary muscles
    SYMPTOMS

. In addition, the

    magnetic resonance tomography
    PARACLINICAL

 showed

    regional late enhancement in the postero-lateral wall
    SYMPTOMS

 which is the typical location

    of fibrosis
    SYMPTOMS

 in

    Fabry
    DIAGNOSIS

 patients.

    She
    GENDER

 suffered from a

    genetically proven Fabry disease
    DIAGNOSIS

, and interestingly

    her
    GENDER

    family name is Mrs Fabry
    FAMILY

. Thus summarized,

    Mrs Fabry
    DIAGNOSIS

 with a confirmed

    Fabry disease
    DIAGNOSIS

 presented with a typically

    Fabry cardiomyopathy
    DIAGNOSIS

.

Fabry cardiomyopathy
Fabry
genetically proven Fabry disease
Mrs Fabry
Fabry disease
Fabry cardiomyopathy


Fabry's disease presenting as ventricular tachycardia and left ventricular 'hypertrophy'.

Fabry's disease (FD) is a genetic disorder leading to deficiency of alpha-galactosidase A. Enzymatic replacement therapy has recently become available. Patients with classical FD develop multi-system involvement; however, there is an increasingly recognized cardiac variant that presents as unexplained left ventricular hypertrophy. We describe a patient with Fabry's disease who presented with ventricular tachycardia.

    Fabry's disease (FD)
    DIAGNOSIS

 is a

    genetic disorder
    GENETICS

 leading to deficiency of alpha-galactosidase A.

    Enzymatic replacement therapy
    MEDICATION

 has recently become available. Patients with

    classical FD
    DIAGNOSIS

 develop

    multi-system involvement
    SYMPTOMS

; however, there is an increasingly recognized cardiac variant that presents as

    unexplained left ventricular hypertrophy
    SYMPTOMS

. We describe a patient with

    Fabry's disease
    DIAGNOSIS

 who presented with

    ventricular tachycardia
    SYMPTOMS

.

Fabry's disease (FD)
classical FD
Fabry's disease


An autopsy case of Fabry disease with neuropathological investigation of the pathogenesis of associated dementia.

The pathogenesis of dementia associated with Fabry disease was examined neuropathologically in an autopsy case. The patient was a 47-year-old computer programmer who developed renal failure at the age of 36, necessitating peritoneal dialysis, and thereafter suffered in succession episodic pulmonary congestion, bradyacusia, heart failure, and dementia, before dying of acute myocardial infarction. MRI of the brain demonstrated leuko-araiosis. The CNS parenchyma showed widespread segmental hydropic swelling of axons in the bilateral cerebral and cerebellar deep white matter in addition to neuronal ballooning due to glycolipid storage in a few restricted nuclei and multiple tiny lacunae. Hydropic axonal swelling was also sparsely distributed in the pyramidal tract, pedunculus cerebellaris superior and brachium colliculi inferioris, but wallerian degeneration of these tracts was absent. Additional features included angiopathy of the subarachnoidal arteries due to Fabry disease, such as medial thickening resulting from glycolipid deposition in smooth muscle cells (SMCs) and adventitial fibrosis with lymphocytic infiltration, together with widespread subtotal or total replacement of medial SMCs by fibrosis, associated with prominent intimal fibrous thickening and undulation of the internal elastic membrane of medium-sized (1000-100 microm diameter) arteries. The findings in this case suggest that axonopathic leukoencephalopathy due to multisegmental hydropic swelling of axons in the bilateral cerebral deep white matter is responsible for the dementia associated with Fabry disease, and may be caused by ischemia resulting from widespread narrowing and stiffening of medium-sized subarachnoidal arteries and progressive heart failure.

The pathogenesis of

    dementia associated with Fabry disease
    DIAGNOSIS

 was examined

    neuropathologically
    PARACLINICAL

 in an

    autopsy
    PARACLINICAL

 case. The patient was a

    47-year-old
    AGE

    computer programmer
    MEDICATION

 who developed

    renal failure
    SYMPTOMS

 at the

    age of 36
    AGE

, necessitating

    peritoneal dialysis
    MEDICATION

, and thereafter suffered in succession

    episodic pulmonary congestion
    SYMPTOMS

,

    bradyacusia
    SYMPTOMS

,

    heart failure
    SYMPTOMS

, and

    dementia
    SYMPTOMS

, before dying of

    acute myocardial infarction
    SYMPTOMS

.

    MRI of the brain
    PARACLINICAL

 demonstrated

    leuko-araiosis
    DIAGNOSIS

. The

    CNS parenchyma
    PARACLINICAL

 showed

    widespread segmental hydropic swelling of axons in the bilateral cerebral and cerebellar deep white matter
    SYMPTOMS

 in addition to

    neuronal ballooning due to glycolipid storage in a few restricted nuclei
    MICROSCOPIC

 and

    multiple tiny lacunae
    SYMPTOMS

.

    Hydropic axonal swelling was also sparsely distributed in the pyramidal tract, pedunculus cerebellaris superior and brachium colliculi inferioris
    SYMPTOMS

, but

    wallerian degeneration of these tracts was absent
    NEG_FINDINGS

. Additional features included

    angiopathy of the subarachnoidal arteries
    SYMPTOMS

 due to

    Fabry disease
    MICROSCOPIC

, such as

    medial thickening resulting from glycolipid deposition in smooth muscle cells (SMCs)
    SYMPTOMS

 and

    adventitial fibrosis with lymphocytic infiltration
    MICROSCOPIC

, together with

    widespread subtotal or total replacement of medial SMCs by fibrosis
    SYMPTOMS

, associated with

    prominent intimal fibrous thickening and undulation of the internal elastic membrane of medium-sized (1000-100 microm diameter) arteries
    SYMPTOMS

. The findings in this case suggest that

    axonopathic leukoencephalopathy
    DIAGNOSIS

 due to

    multisegmental hydropic swelling of axons in the bilateral cerebral deep white matter
    SYMPTOMS

 is responsible for the

    dementia
    DIAGNOSIS

 associated with

    Fabry disease
    DIAGNOSIS

, and may be caused by

    ischemia
    SYMPTOMS

 resulting from

    widespread narrowing and stiffening of medium-sized subarachnoidal arteries
    SYMPTOMS

 and

    progressive heart failure
    SYMPTOMS

.

dementia associated with Fabry disease
leuko-araiosis
axonopathic leukoencephalopathy
dementia
Fabry disease


Hyperbaric oxygen treatment restores sudden hearing loss in a patient with Fabry disease.

Fabry disease is an X-linked inherited disorder of glycosphingolipid metabolism due to the deficient activity of a lysosomal enzyme, alpha-galactosidase A. The resultant systemic accumulation of sphingolipids can lead to progressive and sudden hearing loss alongside renal, cardiac and cerebrovascular complications. Although replacement therapy seems to be beneficial for cochlear function, few data are available regarding treatment of sudden hearing loss. This case report describes the course of a unilateral sudden hearing loss in a young (15-year-old) male patient and its improvement following hyperbaric oxygen treatment.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 due to the deficient activity of a lysosomal enzyme, alpha-galactosidase A. The resultant

    systemic accumulation of sphingolipids
    MICROSCOPIC

 can lead to

    progressive and sudden hearing loss
    SYMPTOMS

 alongside

    renal, cardiac and cerebrovascular complications
    SYMPTOMS

. Although

    replacement therapy
    MEDICATION

 seems to be beneficial for

    cochlear function
    SYMPTOMS

, few data are available regarding treatment of

    sudden hearing loss
    SYMPTOMS

. This case report describes the course of a

    unilateral sudden hearing loss
    SYMPTOMS

 in a

    young (15-year-old
    AGE

)

    male
    GENDER

 patient and its improvement following

    hyperbaric oxygen treatment
    MEDICATION

.

replacement therapy
hyperbaric oxygen treatment


Fabry's disease.

Fabry's disease is a rare X-linked, recessive, glycolipid storage disorder. It is caused by the deficient activity of a lysosomal enzyme, alpha-galactosidase A. Deficiency of alpha-GAL causes an inability to catabolize the lipids with cellular accumulation of its most abundant substrate, globotriaosylceramide (GL-3), and other neutral glycosphingolipids in the vascular endothelium and numerous tissues throughout the body. This progressive glycosphingolipid accumulation leads to life-threatening clinical sequelae in renal, cardiac and cerebrovascular systems. Heterozygous Fabry's disease is less studied. We present a patient, 43 years old, with cardiac (hypertrophic cardiomyopathy), neurological (sensitive-motive polyneuropathy), digestive (chronic diarrheea), renal and cutaneous involvements.

    Fabry's disease
    DIAGNOSIS

 is a

    rare X-linked, recessive
    GENETICS

,

    glycolipid storage disorder
    DIAGNOSIS

. It is caused by the deficient activity of a lysosomal enzyme, alpha-galactosidase A.

    Deficiency of alpha-GAL
    BIOCHEMICAL

 causes an

    inability to catabolize the lipids
    BIOCHEMICAL

 with

    cellular accumulation of its most abundant substrate, globotriaosylceramide (GL-3), and other neutral glycosphingolipids in the vascular endothelium and numerous tissues throughout the body
    MICROSCOPIC

. This

    progressive glycosphingolipid accumulation
    MICROSCOPIC

 leads to

    life-threatening clinical sequelae in renal, cardiac and cerebrovascular systems
    SYMPTOMS

.

    Heterozygous Fabry's disease
    DIAGNOSIS

 is less studied. We present a patient,

    43 years old
    AGE

, with

    cardiac (hypertrophic cardiomyopathy)
    SYMPTOMS

,

    neurological (sensitive-motive polyneuropathy), digestive (chronic diarrheea), renal and cutaneous involvements
    SYMPTOMS

.

Fabry's disease
glycolipid storage disorder
Heterozygous Fabry's disease

Deficiency of alpha-GAL
inability to catabolize the lipids


[Classical type of Fabry disease without angiokeratomas--a case report].

A patient with classical type of Fabry disease is described. The appearance and character of neuropathic pain during hemodyalisis is described. Characteristic changes in head shape and changes of hands and fingers are the additional phenotypic characteristics of Fabry disease. Enzyme replacement therapy administered in the early phase of the disease could prevent disease complications and early patient's death.

A patient with

    classical type of Fabry disease
    DIAGNOSIS

 is described. The appearance and character of

    neuropathic pain during hemodyalisis
    SYMPTOMS

 is described.

    Characteristic changes in head shape and changes of hands and fingers
    SYMPTOMS

 are the additional phenotypic characteristics of

    Fabry disease
    DIAGNOSIS

.

    Enzyme replacement therapy
    MEDICATION

 administered in the early phase of the disease could prevent

    disease complications
    SYMPTOMS

 and early patient's

    death
    SYMPTOMS

.

classical type of Fabry disease
Fabry disease


Fabry disease and treatment with agalsidase alpha: unsuspected cardiac arrhythmia in two heterozygous women. In reference to pharmacovigilance.

Two women treated with agalsidase alpha for Fabry disease developed severe heart dysfunctions a few months after the beginning of enzyme replacement therapy (ERT). An adverse effect caused by the treatment was suspected; therefore we informed the French pharmacovigilance authorities about these two events.

Collecting data systematically about adverse effects which might be caused by drugs is essential for orphan diseases in order to detect potential adverse effects which cannot be suspected at first.

Two

    women
    GENDER

    treated with agalsidase alpha
    MEDICATION

 for

    Fabry disease
    DIAGNOSIS

 developed

    severe heart dysfunctions
    SYMPTOMS

 a few months after the beginning of

    enzyme replacement therapy (ERT)
    MEDICATION

. An

    adverse effect caused by the treatment
    SYMPTOMS

 was suspected; therefore we informed the French pharmacovigilance authorities about these two events.

Collecting data systematically about

    adverse effects
    SYMPTOMS

 which might be caused by drugs is essential for

    orphan diseases
    DIAGNOSIS

 in order to detect potential adverse effects which cannot be suspected at first.

treated with agalsidase alpha
enzyme replacement therapy (ERT)

severe heart dysfunctions
adverse effect caused by the treatment
adverse effects


Coronary artery bypass grafting for Fabry's disease: veins more suitable than arteries?

Coronary artery bypass grafting was performed in a 54-year-old man affected by untreated Fabry's disease. Left internal mammary artery (LIMA) and saphenous vein grafts were implanted. Surgical samples of LIMA revealed diffuse glycosphyngolipid infiltration of smooth muscle cells, whereas SV was normal. After surgery, the patient received antithrombotic and enzyme replacement therapy. At 1-year follow-up, LIMA graft occluded, whereas saphenous vein graft remained patent. In Fabry's disease, veins, probably because of a low pressure load, seem to be spared from glycosphingolipid accumulation and are more suitable than arteries for grafting. A preventive histology of conduits is suggested before graft selection.

    Coronary artery bypass grafting
    MEDICATION

 was performed in a

    54-year-old
    AGE

    man
    GENDER

 affected by

    untreated Fabry's disease
    DIAGNOSIS

.

    Left internal mammary artery (LIMA) and saphenous vein grafts were implanted
    MEDICATION

.

    Surgical samples of LIMA
    PARACLINICAL

 revealed

    diffuse glycosphyngolipid infiltration of smooth muscle cells
    MICROSCOPIC

, whereas

    SV was normal
    NEG_FINDINGS

. After

    surgery
    MEDICATION

, the patient

    received antithrombotic and enzyme replacement therapy
    MEDICATION

. At 1-year

    follow-up
    PARACLINICAL

,

    LIMA graft occluded
    SYMPTOMS

, whereas

    saphenous vein graft remained patent
    NEG_FINDINGS

. In

    Fabry's disease
    DIAGNOSIS

, veins, probably because of a

    low pressure load
    SYMPTOMS

, seem to be spared from

    glycosphingolipid accumulation
    MICROSCOPIC

 and are more suitable than arteries for grafting. A

    preventive histology of conduits
    MEDICATION

 is suggested before

    graft selection
    MEDICATION

.

untreated Fabry's disease
Fabry's disease

SV was normal
saphenous vein graft remained patent


[Fabry's disease: a clinical case and literature review].

Fabry's disease is a congenital disorder of glycosphingolipid metabolism with an X-linked recessive inheritance, presenting with typical symptoms of pain crises, acroparesthesias, cutaneous and mucosal angiokeratomas, hypohidrosis, heart and kidney lesions, and other symptoms, which are described below. From 2001, this disease is one of inborn errors of metabolism in which enzyme replacement therapy is applied very effectively. Two atypical forms of the disease were discovered, and the first surveys were done revealing that the incidence of Fabry's disease can be much more higher than it was considered before. Not only pediatricians can encounter with these patients in their practice, but also family doctors, nephrologists, cardiologists, neurologists, and physicians of other specialties. A clinical case of Fabry's disease is described, and actual issues of diagnostics and treatment of Fabry's disease are discussed. In spite of very typical symptoms, delayed diagnosis was made: after the first investigation of alpha-galactosidase A activity in dry blood sample, diagnosis of Fabry's disease was rejected; only after lysosomal enzyme activity assay in heparinized blood leukocytes, this diagnosis was confirmed.

    Fabry's disease
    DIAGNOSIS

 is a

    congenital disorder of glycosphingolipid metabolism
    DIAGNOSIS

    with an X-linked recessive inheritance
    GENETICS

, presenting with typical symptoms of

    pain crises
    SYMPTOMS

,

    acroparesthesias
    SYMPTOMS

,

    cutaneous and mucosal angiokeratomas
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    heart and kidney lesions
    SYMPTOMS

, and other symptoms, which are described below. From 2001, this disease is one of

    inborn errors of metabolism
    GENETICS

 in which

    enzyme replacement therapy
    MEDICATION

 is applied very effectively. Two atypical forms of the disease were discovered, and the first surveys were done revealing that the incidence of

    Fabry's disease
    DIAGNOSIS

 can be much more higher than it was considered before. Not only

    pediatricians
    PARACLINICAL

 can encounter with these patients in their practice, but also

    family doctors
    PARACLINICAL

,

    nephrologists
    PARACLINICAL

,

    cardiologists
    PARACLINICAL

,

    neurologists
    PARACLINICAL

, and physicians of other specialties. A clinical case of

    Fabry's disease
    DIAGNOSIS

 is described, and actual issues of diagnostics and treatment of

    Fabry's disease
    DIAGNOSIS

 are discussed. In spite of very typical symptoms, delayed diagnosis was made: after the first investigation of

    alpha-galactosidase A activity in dry blood sample
    BIOCHEMICAL

,

    diagnosis of Fabry's disease was rejected
    NEG_FINDINGS

; only after

    lysosomal enzyme activity assay in heparinized blood leukocytes
    PARACLINICAL

, this diagnosis was confirmed.

with an X-linked recessive inheritance
inborn errors of metabolism

pain crises
acroparesthesias
cutaneous and mucosal angiokeratomas
hypohidrosis
heart and kidney lesions


Fabry disease: renal biopsy-proven cases from China.

Fabry disease is a rare metabolic disorder resulting from deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-GalA). Renal involvement is the major cause of morbidity and mortality in male patients. Here, we describe the largest series ever reported for this condition in China.

Nine patients were enrolled in this study. Routine light microscopy (including toluidine blue staining), immunofluorescence and electron microscopic examinations were performed. We measured alpha-GalA activity in leukocyte and gene mutation analysis. Clinical and laboratory data of the patients were collected.

Eight of the 9 patients were hemizygous males. Proteinuria was obvious in all patients. Three patients presented with mild renal function impairment. Light microscopy revealed glomeruli full of enlarged podocytes with abundant foamy cytoplasm. Toluidine blue stain revealed abundant cytoplasmic granular inclusions within the podocytes, tubular epithelial cells and endothelial cells of peritubular capillaries. Electron microscopy showed abundant electron-dense myelin figures within the podocyte cytoplasm. Arteriolar hyalinization and occlusion were also observed. Extrarenal manifestations, including acroparesthesia, hypohidrosis, abnormal electrocardiography and angiokeratoma were noted. No cornea verticillata or lenticular opacities were observed. These patients had about 0.3%-1.3% residual alpha-GalA activity in leukocytes. We identified a novel missense mutation (F273L) causing nonclassical Fabry disease.

Fabry disease is relatively rare in China. Renal biopsy and specific staining is efficacious in the correct diagnosis of the disease. Discrepancies in the clinical manifestations of Fabry disease (i.e., eye disorders and hypertension) exist between cases found in China and those detailed in Western reports.

    Fabry disease
    DIAGNOSIS

 is a

    rare metabolic disorder
    DIAGNOSIS

 resulting from

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

.

    Renal involvement
    SYMPTOMS

 is the major cause of morbidity and mortality in

    male
    GENDER

 patients. Here, we describe the largest series ever reported for this condition in

    China
    ETHNICITY

.

Nine patients were enrolled in this study.

    Routine light microscopy (including toluidine blue staining)
    PARACLINICAL

,

    immunofluorescence and electron microscopic examinations
    PARACLINICAL

 were performed. We measured

    alpha-GalA activity in leukocyte
    BIOCHEMICAL

 and

    gene mutation analysis
    PARACLINICAL

. Clinical and laboratory data of the patients were collected.

Eight of the 9 patients were

    hemizygous males
    GENETICS

.

    Proteinuria
    BIOCHEMICAL

 was obvious in all patients. Three patients presented with

    mild renal function impairment
    SYMPTOMS

.

    Light microscopy
    PARACLINICAL

 revealed

    glomeruli full of enlarged podocytes with abundant foamy cytoplasm
    MICROSCOPIC

.

    Toluidine blue stain
    PARACLINICAL

 revealed

    abundant cytoplasmic granular inclusions within the podocytes, tubular epithelial cells and endothelial cells of peritubular capillaries
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 showed

    abundant electron-dense myelin figures within the podocyte cytoplasm
    MICROSCOPIC

.

    Arteriolar hyalinization and occlusion
    MICROSCOPIC

 were also observed.

    Extrarenal manifestations
    SYMPTOMS

, including

    acroparesthesia
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    abnormal electrocardiography
    SYMPTOMS

 and

    angiokeratoma
    SYMPTOMS

 were noted.

    No cornea verticillata
    NEG_FINDINGS

 or

    lenticular opacities
    NEG_FINDINGS

    were observed
    NEG_FINDINGS

. These patients had

    about 0.3%-1.3% residual alpha-GalA activity in leukocytes
    BIOCHEMICAL

. We identified a

    novel missense mutation (F273L)
    GENETICS

 causing

    nonclassical Fabry disease
    DIAGNOSIS

.

    Fabry disease
    DIAGNOSIS

 is relatively rare in

    China
    ETHNICITY

.

    Renal biopsy
    PARACLINICAL

 and

    specific staining
    PARACLINICAL

 is efficacious in the correct diagnosis of the disease. Discrepancies in the clinical manifestations of

    Fabry disease
    DIAGNOSIS

 (i.e.,

    eye disorders
    SYMPTOMS

 and

    hypertension
    SYMPTOMS

) exist between cases found in

    China
    ETHNICITY

 and those detailed in Western reports.

Fabry disease
rare metabolic disorder
nonclassical Fabry disease
Fabry disease
Fabry disease

Renal involvement
mild renal function impairment
Extrarenal manifestations
acroparesthesia
hypohidrosis
abnormal electrocardiography
angiokeratoma
eye disorders
hypertension

hemizygous males
novel missense mutation (F273L)

No cornea verticillata
lenticular opacities
were observed


[Clinical stability of Fabry disease in 54 months' enzyme replacement therapy--follow-up of the first Polish study].

We present outcomes of 54 months' agalsidase beta enzyme replacement therapy of two 48- and 46-year-old brothers with Fabry disease. The diagnosis was confirmed in 1997, and at that moment serious damage of internal organs was observed. During enzyme replacement therapy in both brothers the following changes were observed: amelioration of gastrointestinal symptoms, gain of body weight and reduction of cardiac hypertrophy in ECG. In older brother we observed: improvement in coronary blood flow, absence of angina pectoris, dyspnea, partial remission of headache and acroparaesthesia. Reduction of proteinuria, stabilization of creatinine clearance and appearance of perspiration were also noticed. In a younger brother, with a milder form of disease, we observed: improvement of hearing and vertigo, headache reduction, as well as stabilization of kidney function (although proteinuria was slightly increased). Unfortunately, acroparaesthesia and muscle pains in the legs became more severe. Enzyme replacement therapy in Fabry disease, even started in late adulthood, is effective by stabilizing organ function and markedly improving of quality of life.

We present outcomes of

    54 months' agalsidase beta enzyme replacement therapy
    MEDICATION

 of two

    48- and 46-year-old
    AGE

    brothers
    GENDER

 with

    Fabry disease
    DIAGNOSIS

. The diagnosis was confirmed in 1997, and at that moment

    serious damage of internal organs
    SYMPTOMS

 was observed. During

    enzyme replacement therapy
    MEDICATION

 in both

    brothers
    GENDER

 the following changes were observed:

    amelioration of gastrointestinal symptoms
    SYMPTOMS

,

    gain of body weight
    SYMPTOMS

 and

    reduction of cardiac hypertrophy in ECG
    SYMPTOMS

. In

    older brother
    AGE

 we observed:

    improvement in coronary blood flow
    SYMPTOMS

,

    absence of angina pectoris
    SYMPTOMS

,

    dyspnea
    SYMPTOMS

,

    partial remission of headache
    SYMPTOMS

 and

    acroparaesthesia
    SYMPTOMS

.

    Reduction of proteinuria
    BIOCHEMICAL

,

    stabilization of creatinine clearance
    BIOCHEMICAL

 and

    appearance of perspiration
    SYMPTOMS

 were also noticed. In a

    younger brother
    AGE

, with a milder form of disease, we observed:

    improvement of hearing and vertigo
    SYMPTOMS

,

    headache reduction
    SYMPTOMS

, as well as

    stabilization of kidney function
    BIOCHEMICAL

 (although

    proteinuria was slightly increased
    BIOCHEMICAL

). Unfortunately,

    acroparaesthesia
    SYMPTOMS

 and

    muscle pains in the legs became more severe
    SYMPTOMS

.

    Enzyme replacement therapy
    MEDICATION

 in

    Fabry disease
    DIAGNOSIS

, even started in

    late adulthood
    AGE

, is effective by

    stabilizing organ function
    SYMPTOMS

 and

    markedly improving of quality of life
    SYMPTOMS

.

Reduction of proteinuria
stabilization of creatinine clearance
stabilization of kidney function
proteinuria was slightly increased


Kidney transplantation and enzyme alpha-galactosidase A therapy in patient with Fabry disease: a case report.

Fabry disease, an X-linked recessive glycolipid storage disease, is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A), which cleaves a fatty substance called globotriaosylceramide (GL3). The abnormal storage of GL3 in blood vessel walls leads to ischemia and necrosis, particularly in blood vessels of the skin, kidneys, heart, brain, and nervous system. The aim of our study was to present the results of cadaveric kidney transplantation with enzyme alpha-Gal A therapy in a patient with Fabry disease. The patient was diagnosed with Fabry disease at the age of 33 years, based on enzymatic tests. Renal manifestations occurred a year later as proteinuria. At the age of 35 years, the glomerular filtration rate (GFR) was within the normal range. The patient received supplemental enzyme treatment with alpha-Gal (1 mg/kg every 2 weeks). At 3 months after starting supplementation, renal function worsened with serum creatinine levels at 1.7 to 1.8 mg/dL. The following months of supplementation (alpha-Gal 1 mg/kg) concurred with progressive renal dysfunction. After 27 months of supplementation at 37 years, with a creatinine value of 5.5 mg/dL, hemodialysis began and months later the patient received a cadaveric kidney graft. The patient no longer required dialysis. On postoperative day 5 the serum creatinine was 3.9 mg/dL; on day 7, 2.2 mg/dL; on day 14, 1.5 mg/dL. Enzyme supplementation began on posttransplant day 13. Renal graft function has been good during 5 months of observation with creatinine levels at 1.2 to 1.3 mg/dL. The treatment does not interfere with tacrolimus metabolism. Simultaneous chronic enzyme supplementation is the optimal treatment in the fifth stage of end-stage renal disease in Fabry disease.

    Fabry disease
    DIAGNOSIS

, an

    X-linked recessive
    GENETICS

    glycolipid storage disease
    DIAGNOSIS

, is caused by a

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

, which

    cleaves a fatty substance called globotriaosylceramide (GL3)
    MICROSCOPIC

. The

    abnormal storage of GL3 in blood vessel walls
    MICROSCOPIC

 leads to

    ischemia and necrosis, particularly in blood vessels of the skin, kidneys, heart, brain, and nervous system
    SYMPTOMS

. The aim of our study was to present the results of

    cadaveric kidney transplantation with enzyme alpha-Gal A therapy
    MEDICATION

 in a patient with

    Fabry disease
    DIAGNOSIS

. The patient was diagnosed with

    Fabry disease
    DIAGNOSIS

 at the

    age of 33 years
    AGE

, based on

    enzymatic tests
    PARACLINICAL

.

    Renal manifestations
    SYMPTOMS

 occurred a year later as

    proteinuria
    BIOCHEMICAL

. At the

    age of 35 years
    AGE

, the

    glomerular filtration rate (GFR) was within the normal range
    NEG_FINDINGS

. The patient received

    supplemental enzyme treatment with alpha-Gal (1 mg/kg every 2 weeks)
    MEDICATION

. At 3 months after starting

    supplementation
    MEDICATION

,

    renal function worsened
    SYMPTOMS

 with serum creatinine levels at 1.7 to 1.8 mg/dL. The following

    months of supplementation (alpha-Gal 1 mg/kg)
    MEDICATION

 concurred with

    progressive renal dysfunction
    SYMPTOMS

. After

    27 months of supplementation
    MEDICATION

 at

    37 years
    AGE

, with a

    creatinine value of 5.5 mg/dL
    BIOCHEMICAL

,

    hemodialysis
    MEDICATION

    began
    MEDICATION

 and months later the patient

    received a cadaveric kidney graft
    MEDICATION

. The patient

    no longer required dialysis
    NEG_FINDINGS

. On postoperative day 5 the

    serum creatinine was 3.9 mg/dL; on day 7, 2.2 mg/dL;
    BIOCHEMICAL

 on day 14, 1.5 mg/dL.

    Enzyme supplementation
    MEDICATION

 began on

    posttransplant
    MEDICATION

 day 13.

    Renal graft function has been good
    SYMPTOMS

 during 5 months of observation with creatinine levels at 1.2 to 1.3 mg/dL. The treatment does

    not interfere with tacrolimus metabolism
    NEG_FINDINGS

.

    Simultaneous chronic enzyme supplementation
    MEDICATION

 is the optimal treatment in the fifth stage of

    end-stage renal disease
    DIAGNOSIS

 in

    Fabry disease
    DIAGNOSIS

.

Fabry disease
glycolipid storage disease
Fabry disease
Fabry disease
end-stage renal disease
Fabry disease


Cardiac Fabry's disease: an unusual cause of left ventricular hypertrophy.

A 64-year-old male was observed as an outpatient with atypical, non-exercise-induced chest pain and palpitations. He had arterial hypertension and marked concentric left ventricular hypertrophy. After 2.5 years of antihypertensive drug therapy the patient's blood pressure had returned to normal, but his left ventricular hypertrophy was unchanged.

Electrocardiography, transthoracic echocardiography, myocardial perfusion scintigraphic imaging, measurement of alpha-galactosidase A activity, gene sequencing, brain MRI, carotid artery ultrasonography, biochemical renal evaluation and cardiac Doppler tissue imaging.

Cardiac Fabry's disease.

Losartan, hydrochlorothiazide, low-dose aspirin and bisoprolol. The patient is expected to begin enzyme replacement therapy.

A

    64-year-old
    AGE

    male
    GENDER

 was observed as an outpatient with

    atypical, non-exercise-induced chest pain
    SYMPTOMS

 and

    palpitations
    SYMPTOMS

.

    He
    GENDER

 had

    arterial hypertension
    SYMPTOMS

 and

    marked concentric left ventricular hypertrophy
    SYMPTOMS

. After

    2.5 years of antihypertensive drug therapy
    MEDICATION

 the patient's

    blood pressure had returned to normal
    BIOCHEMICAL

, but his

    left ventricular hypertrophy was unchanged
    NEG_FINDINGS

.

    Electrocardiography
    PARACLINICAL

,

    transthoracic echocardiography
    PARACLINICAL

,

    myocardial perfusion scintigraphic imaging
    PARACLINICAL

,

    measurement of alpha-galactosidase A activity
    PARACLINICAL

,

    gene sequencing
    PARACLINICAL

,

    brain MRI
    PARACLINICAL

,

    carotid artery ultrasonography
    PARACLINICAL

,

    biochemical renal evaluation
    PARACLINICAL

 and

    cardiac Doppler tissue imaging
    PARACLINICAL

.

    Cardiac Fabry's disease
    DIAGNOSIS

.

    Losartan, hydrochlorothiazide, low-dose aspirin and bisoprolol
    MEDICATION

. The patient is expected to begin

    enzyme replacement therapy
    MEDICATION

.


Anderson-Fabry disease in kidneys from deceased donor.

Anderson-Fabry disease (AFD) is a rare, X-linked lysosomal storage disease that leads to progressive intracellular accumulation of globotriaosylceramide in visceral organs and the vascular endothelium. We report two patients with end-stage renal disease who received renal allograft from deceased female donor who died from heart failure. A 62-year-old women received a renal allograft in July 2006. Except for low-range proteinuria, renal function was normal until 6 months after transplantation when serum creatinine increased from 120 to 150 micromol/L. A renal biopsy was performed. Based on the specific pathological finding, AFD in donor was suspected. In order to prove the diagnosis, the other recipient also underwent renal biopsy 3 months later. This was 45-year-old female with stable graft function and nonnephrotic proteinuria. Light microscopic findings included a 'foamy' appearance of affected cells with swelling and vacuolization of podocytes. Electron microscopic finding show mesangial cells and podocytes filled with dense lysosomal granules appearing as myelin figures and 'zebra bodies'. Changes were less intensive than in the biopsy of the first recipient. The donor was 54-year-old Italian women who died on the Adriatic coast after heart attack. This is the first case of AFD found in a kidney allograft from deceased donor.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is a rare,

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 that leads to

    progressive intracellular accumulation of globotriaosylceramide in visceral organs and the vascular endothelium
    MICROSCOPIC

. We report two patients with

    end-stage renal disease
    DIAGNOSIS

 who received

    renal allograft
    MEDICATION

 from

    deceased female
    MEDICATION

 donor who

    died
    SYMPTOMS

 from

    heart failure
    SYMPTOMS

. A

    62-year-old
    AGE

    women
    GENDER

    received a renal allograft
    MEDICATION

 in July 2006. Except for

    low-range proteinuria
    BIOCHEMICAL

,

    renal function was normal
    NEG_FINDINGS

 until 6 months after

    transplantation
    MEDICATION

 when serum creatinine increased from 120 to 150 micromol/L. A

    renal biopsy
    PARACLINICAL

 was performed. Based on the specific pathological finding,

    AFD
    DIAGNOSIS

 in donor was suspected. In order to prove the diagnosis, the other recipient also underwent

    renal biopsy
    PARACLINICAL

 3 months later. This was

    45-year-old
    AGE

    female
    GENDER

 with

    stable graft function
    SYMPTOMS

 and

    nonnephrotic proteinuria
    BIOCHEMICAL

.

    Light microscopic
    PARACLINICAL

 findings included a

    'foamy' appearance of affected cells with swelling and vacuolization of podocytes
    MICROSCOPIC

.

    Electron microscopic finding
    PARACLINICAL

 show

    mesangial cells and podocytes filled with dense lysosomal granules appearing as myelin figures and 'zebra bodies'
    MICROSCOPIC

.

    Changes were less intensive
    SYMPTOMS

 than in the biopsy of the first recipient. The donor was

    54-year-old
    AGE

    Italian
    ETHNICITY

    women
    GENDER

 who

    died
    SYMPTOMS

 on the

    Adriatic coast
    ETHNICITY

 after

    heart attack
    SYMPTOMS

. This is the first case of

    AFD
    DIAGNOSIS

 found in a

    kidney allograft
    MEDICATION

 from

    deceased donor
    MEDICATION

.

Anderson-Fabry disease (AFD)
lysosomal storage disease
end-stage renal disease
AFD
AFD

renal allograft
deceased female
received a renal allograft
transplantation
kidney allograft
deceased donor

died
heart failure
stable graft function
Changes were less intensive
died
heart attack

low-range proteinuria
nonnephrotic proteinuria


[Cornea verticillata - a clinical marker of Fabry disease: case report].

Fabry's disease is a rare X-linked lysosomal storage disorder of glycosphingolipid (GL) metabolism, caused by a deficiency of alpha-galactosidase A activity. The progressive accumulation of GL in tissues results in the clinical manifestations of the disease, that are more evident in hemizygous males, and include angiokeratomas, acroparesthesia, cornea verticillata, cardiac and kidney involvement, cerebrovascular manifestations. A family with Fabry's disease including 2 female patients and 3 male patients is reported. The patients were submitted to complete medical history, ophthalmological examination and alpha-galactosidase activity test. Cornea verticillata was a constant finding in all patients. This demonstrates the important role of the ophtalmological examination for the diagnosis of Fabry's disease since the eye findings are so characteristic of the disease.

    Fabry's disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder of glycosphingolipid (GL) metabolism
    DIAGNOSIS

, caused by a

    deficiency of alpha-galactosidase A activity
    BIOCHEMICAL

. The

    progressive accumulation of GL in tissues
    MICROSCOPIC

 results in the clinical manifestations of the disease, that are more evident in

    hemizygous males
    GENETICS

, and include

    angiokeratomas
    SYMPTOMS

,

    acroparesthesia
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

,

    cardiac and kidney involvement
    SYMPTOMS

,

    cerebrovascular manifestations
    SYMPTOMS

. A

    family with Fabry's disease
    FAMILY

 including 2

    female
    GENDER

 patients and 3

    male
    GENDER

 patients is reported. The patients were submitted to

    complete medical history
    PARACLINICAL

,

    ophthalmological examination
    PARACLINICAL

 and

    alpha-galactosidase activity test
    PARACLINICAL

.

    Cornea verticillata
    SYMPTOMS

 was a constant finding in all patients. This demonstrates the important role of the

    ophtalmological examination
    PARACLINICAL

 for the diagnosis of

    Fabry's disease
    DIAGNOSIS

 since the

    eye findings
    SYMPTOMS

 are so characteristic of the disease.

angiokeratomas
acroparesthesia
cornea verticillata
cardiac and kidney involvement
cerebrovascular manifestations
Cornea verticillata
eye findings


Enzyme replacement therapy in patients with Fabry's disease.

Fabry's disease, a disorder affecting the gene for the lysosomal enzyme alpha-galactosidase A (alpha-GAL A), can cause accumulation of globotriaosylceramide (GL-3) in the vascular endothelial cells. Symptoms include pain, angiokeratoma, corneal clouding, and damage to the heart and kidneys. Human recombinant alpha-GAL A for use as an enzyme replacement therapy was launched in Japan in April 2004. Eleven ambulatory patients with Fabry's disease were given replacement alpha-GAL A therapy. Three patients died due to factors associated with Fabry's disease. The enzyme replacement therapies in the remaining eight patients continued safely without any notable adverse events. The following were observed: a lowering of the plasma levels of GL-3 in seven cases, an improvement in the daily activities in six cases, and a reduction in corneal clouding in three cases. Although careful observation is necessary, these results suggest that replacement alpha-GAL A therapy may be a safe and effective treatment of Fabry's disease.

    Fabry's disease
    DIAGNOSIS

, a

    disorder affecting the gene for the lysosomal enzyme alpha-galactosidase A (alpha-GAL A)
    GENETICS

, can cause

    accumulation of globotriaosylceramide (GL-3) in the vascular endothelial cells
    MICROSCOPIC

. Symptoms include

    pain
    SYMPTOMS

,

    angiokeratoma
    SYMPTOMS

,

    corneal clouding
    SYMPTOMS

, and

    damage to the heart and kidneys
    SYMPTOMS

.

    Human recombinant alpha-GAL A for use as an enzyme replacement therapy
    MEDICATION

 was launched in

    Japan
    ETHNICITY

 in April 2004. Eleven ambulatory patients with

    Fabry's disease
    DIAGNOSIS

 were given

    replacement alpha-GAL A therapy
    MEDICATION

. Three patients

    died
    SYMPTOMS

 due to

    factors associated with Fabry's disease
    SYMPTOMS

. The

    enzyme replacement therapies
    MEDICATION

 in the remaining eight patients continued safely

    without any notable adverse events
    NEG_FINDINGS

. The following were observed: a

    lowering of the plasma levels of GL-3
    BIOCHEMICAL

 in seven cases, an

    improvement in the daily activities
    SYMPTOMS

 in six cases, and a

    reduction in corneal clouding
    SYMPTOMS

 in three cases. Although careful observation is necessary, these results suggest that

    replacement alpha-GAL A therapy
    MEDICATION

 may be a safe and effective treatment of

    Fabry's disease
    DIAGNOSIS

.

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

pain
angiokeratoma
corneal clouding
damage to the heart and kidneys
died
factors associated with Fabry's disease
improvement in the daily activities
reduction in corneal clouding