[Renal involvement in Fabry disease].

Fabry disease is an X-linked recessive lysosomial storage disorder that is caused by deficient activity of alpha galactosidase A. Renal involvement occurs generally in hemizygous forms.

We report one case of renal involvement in Fabry disease.

A 47 year-old-man had focal and segmental glomerulosclerosis with moderate renal failure. As the patient presented history of acroparesthesias, hearing loss, left ventricular hypertrophy with arrhythmia and corneal deposits, hemizygous Fabry disease was suspected. This diagnosis was confirmed with low alpha galactosidase activity. After a follow up of 5 years, the renal function remains stable but the patient died by cardiac arrhythmia.

Occurrence of a glomerulonephritis associated with an hypertrophic cardiopathy without hypertension should advocate Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomial storage disorder
    DIAGNOSIS

 that is caused by deficient activity of alpha galactosidase A.

    Renal involvement
    SYMPTOMS

 occurs generally in

    hemizygous forms
    GENETICS

.

We report one case of

    renal involvement
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

.

A

    47 year-old
    AGE

-

    man
    GENDER

 had

    focal and segmental glomerulosclerosis
    DIAGNOSIS

 with

    moderate renal failure
    SYMPTOMS

. As the patient presented history of

    acroparesthesias
    SYMPTOMS

,

    hearing loss
    SYMPTOMS

,

    left ventricular hypertrophy
    SYMPTOMS

 with

    arrhythmia
    SYMPTOMS

 and

    corneal deposits
    SYMPTOMS

,

    hemizygous Fabry disease
    GENETICS

 was suspected. This diagnosis was confirmed with

    low alpha galactosidase activity
    BIOCHEMICAL

. After a follow up of 5 years, the

    renal function remains stable
    SYMPTOMS

 but the patient

    died
    SYMPTOMS

 by

    cardiac arrhythmia
    SYMPTOMS

.

Occurrence of a

    glomerulonephritis
    DIAGNOSIS

    associated with an hypertrophic cardiopathy
    SYMPTOMS

    without hypertension
    NEG_FINDINGS

 should advocate

    Fabry disease
    DIAGNOSIS

.

Fabry disease
lysosomial storage disorder
Fabry disease
focal and segmental glomerulosclerosis
glomerulonephritis
Fabry disease

X-linked recessive
hemizygous forms
hemizygous Fabry disease


Postmortem diagnosis of Fabry disease with acromegaly and a unique vasculopathy.

A 44-year-old Japanese man with elevated growth hormone levels and gradual deterioration of mental and renal function was admitted to the hospital. With his deteriorated general condition and renal failure, the patient developed pulmonary thromboembolism and died of respiratory failure. Autopsy examination was conducted, which revealed abnormal accumulation or intracytoplasmic storage of lipid-rich material in the small blood vessels, kidney, heart, and nervous system. After postmortem pathologic studies, including light-microscopic histochemistry, electron microscopy, and biochemical analysis of the stored lipid contents, a final diagnosis of Fabry disease was made. Histopathologic examination revealed a unique vasculopathy characterized by the presence of abnormal intracytoplasmic lipid inclusions and vascular remodeling. With regard to the clinical presentation of acromegaly, hyperplasia but not adenomatous transformation of the acidophils of the anterior pituitary gland with immunohistochemical detection of growth hormone within the cells was noted. In this case, the complication of acromegaly with hyperplasia of the acidophilic cells of the anterior pituitary gland and the unique vasculopathy causing significant organ failure, mainly of the kidney, heart, and central nervous systems, possibly as a result of microcirculatory failure, are considered to be not incidental findings but to be intimately involved in the pathogenesis of Farby disease.

A

    44-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 with

    elevated growth hormone levels
    BIOCHEMICAL

 and

    gradual deterioration of mental and renal function
    SYMPTOMS

 was admitted to the hospital. With his

    deteriorated general condition
    SYMPTOMS

 and

    renal failure
    SYMPTOMS

, the patient developed

    pulmonary thromboembolism
    SYMPTOMS

 and

    died
    SYMPTOMS

 of

    respiratory failure
    SYMPTOMS

.

    Autopsy examination
    PARACLINICAL

 was conducted, which revealed

    abnormal accumulation or intracytoplasmic storage of lipid-rich material in the small blood vessels, kidney, heart, and nervous system
    MICROSCOPIC

. After

    postmortem pathologic studies
    PARACLINICAL

, including

    light-microscopic histochemistry
    PARACLINICAL

,

    electron microscopy
    PARACLINICAL

, and

    biochemical analysis of the stored lipid contents
    PARACLINICAL

, a final diagnosis of

    Fabry disease
    DIAGNOSIS

 was made.

    Histopathologic examination
    PARACLINICAL

 revealed a

    unique vasculopathy
    SYMPTOMS

 characterized by the

    presence of abnormal intracytoplasmic lipid inclusions
    MICROSCOPIC

 and

    vascular remodeling
    MICROSCOPIC

. With regard to the clinical presentation of

    acromegaly
    DIAGNOSIS

,

    hyperplasia but not adenomatous transformation of the acidophils of the anterior pituitary gland
    MICROSCOPIC

 with

    immunohistochemical detection of growth hormone within the cells
    MICROSCOPIC

 was noted. In this case, the complication of

    acromegaly
    DIAGNOSIS

 with

    hyperplasia of the acidophilic cells of the anterior pituitary gland
    MICROSCOPIC

 and the

    unique vasculopathy causing significant organ failure, mainly of the kidney, heart, and central nervous systems
    SYMPTOMS

, possibly as a result of

    microcirculatory failure
    SYMPTOMS

, are considered to be not incidental findings but to be intimately involved in the pathogenesis of

    Farby disease
    DIAGNOSIS

.

Fabry disease
acromegaly
acromegaly
Farby disease


Fabry disease: case report with emphasis on enzyme replacement therapy and possible future therapeutic options.

A 38-year-old male Caucasian with Fabry disease presented with angiokeratomas and tortuous conjunctival and retinal vessels. Additionally, the patient showed characteristic skin lesions of psoriasis and seborrheic dermatitis. His past medical history revealed anhidrosis, acral paresthesias, myocardial infarction, phlebothrombosis, hypertension, antithrombin III deficiency, factor V Leiden disease, chronic obstructive lung disease, tinnitus, diarrhea, recurrent abdominal pain, headache, and depressive mood. He was treated with intravenous substitution of the deficient enzyme alpha-galactosidase A. Possible future options in treatment of Fabry disease are discussed.

A

    38-year-old
    AGE

    male
    GENDER

    Caucasian
    ETHNICITY

 with

    Fabry disease
    DIAGNOSIS

 presented with

    angiokeratomas
    SYMPTOMS

 and

    tortuous conjunctival and retinal vessels
    SYMPTOMS

. Additionally, the patient showed

    characteristic skin lesions of psoriasis and seborrheic dermatitis
    SYMPTOMS

.

    His
    GENDER

 past medical history revealed

    anhidrosis
    SYMPTOMS

,

    acral paresthesias
    SYMPTOMS

,

    myocardial infarction
    SYMPTOMS

,

    phlebothrombosis
    DIAGNOSIS

,

    hypertension
    SYMPTOMS

,

    antithrombin III deficiency
    BIOCHEMICAL

,

    factor V Leiden disease
    BIOCHEMICAL

,

    chronic obstructive lung disease
    DIAGNOSIS

,

    tinnitus
    SYMPTOMS

,

    diarrhea
    SYMPTOMS

,

    recurrent abdominal pain
    SYMPTOMS

,

    headache
    SYMPTOMS

, and

    depressive mood
    SYMPTOMS

.

    He
    GENDER

 was treated with intravenous substitution of the deficient enzyme alpha-galactosidase A. Possible future options in treatment of

    Fabry disease
    DIAGNOSIS

 are discussed.

Fabry disease
phlebothrombosis
chronic obstructive lung disease
Fabry disease

antithrombin III deficiency
factor V Leiden disease


Angiokeratoma corporis diffusum in human beta-mannosidosis: Report of a new case and a novel mutation.

Human beta-mannosidosis, a rare disorder of oligosaccharide catabolism, results from a deficiency of beta-mannosidase activity. So far, mutational analysis has been performed in only seven families and revealed 11 mutations in the MANBA gene which encodes the enzyme beta-mannosidase.

We report here a 36-year-old Arab female with beta-mannosidosis who presented with mental retardation and multiple angiokeratomas. We describe in this patient a novel null mutation and review the previously reported MANBA gene mutations and their clinical correlations.

Histopathology, ultrastructural analysis, and enzyme assays were performed. Sequencing of cDNA and genomic DNA analysis was conducted in a search for a mutation in the MANBA gene.

Histopathology of a skin biopsy specimen from the patient showed the characteristic findings of angiokeratoma. Electron microscopy showed cytoplasmic vacuolation. Enzymatic activity of beta-mannosidase in the patient's serum, leukocytes, and fibroblasts was less than 1% of control values. Sequencing of the MANBA cDNA revealed a G-->A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X).

Only one family was studied.

A new case of human beta-mannosidosis is presented and the first MANBA gene mutation from Arab ancestry is reported. Reviewing the reported MANBA gene mutations does not reveal a clear genotype-phenotype correlation. The importance of angiokeratoma corporis diffusum as the clue to the diagnosis of beta-mannosidosis and other lysosomal storage diseases is emphasized.

    Human beta-mannosidosis
    DIAGNOSIS

, a

    rare disorder of oligosaccharide catabolism
    DIAGNOSIS

, results from a

    deficiency of beta-mannosidase activity
    BIOCHEMICAL

. So far,

    mutational analysis
    PARACLINICAL

 has been performed in only seven families and revealed

    11 mutations in the MANBA gene which encodes the enzyme beta-mannosidase
    GENETICS

.

We report here a

    36-year-old
    AGE

    Arab
    ETHNICITY

    female
    GENDER

 with

    beta-mannosidosis
    DIAGNOSIS

 who presented with

    mental retardation
    SYMPTOMS

 and

    multiple angiokeratomas
    SYMPTOMS

. We describe in this patient a

    novel null mutation
    GENETICS

 and review the previously reported

    MANBA gene mutations
    GENETICS

 and their clinical correlations.

    Histopathology, ultrastructural analysis
    PARACLINICAL

, and

    enzyme assays
    PARACLINICAL

 were performed.

    Sequencing of cDNA and genomic DNA analysis
    PARACLINICAL

 was conducted in a search for a

    mutation in the MANBA gene
    GENETICS

.

    Histopathology of a skin biopsy specimen
    PARACLINICAL

 from the patient showed the

    characteristic findings of angiokeratoma
    SYMPTOMS

.

    Electron microscopy
    PARACLINICAL

 showed

    cytoplasmic vacuolation
    MICROSCOPIC

.

    Enzymatic activity of beta-mannosidase in the patient's serum, leukocytes, and fibroblasts was less than 1% of control values
    BIOCHEMICAL

.

    Sequencing of the MANBA cDNA
    PARACLINICAL

 revealed

    a G-->A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X).
    GENETICS

    Only one family was studied
    FAMILY

.

A new case of

    human beta-mannosidosis
    DIAGNOSIS

 is presented and the first

    MANBA gene mutation
    GENETICS

 from

    Arab ancestry
    ETHNICITY

 is reported. Reviewing the reported

    MANBA gene mutations
    GENETICS

 does not reveal a clear genotype-phenotype correlation. The importance of

    angiokeratoma corporis diffusum
    SYMPTOMS

 as the clue to the diagnosis of

    beta-mannosidosis
    DIAGNOSIS

 and other

    lysosomal storage diseases
    DIAGNOSIS

 is emphasized.


Gastrointestinal symptoms in Fabry disease: everything is possible, including treatment.

Gastrointestinal symptoms in Fabry disease were first described independently by William Anderson and Johannes Fabry. Case reports and case series suggest that the whole gastrointestinal tract may be affected in patients with Fabry disease. The Fabry Outcome Survey (FOS) database supports these observations. The overall prevalence of gastrointestinal involvement reported in a study of 342 patients (271 adults; 71 children) enrolled in FOS was 52% (49.8% in adults, 60.8% in children). Abdominal pain was the most prevalent symptom. The median age at onset of gastrointestinal symptoms was 14 years, similar to the age at onset of acroparaesthesia. The prevalence of gastrointestinal symptoms was reduced in patients after receiving enzyme replacement therapy with agalsidase alfa for 12 and 24 months. There was no correlation between gastrointestinal symptoms and body mass index.

Gastrointestinal symptoms in Fabry disease may have been underestimated. The FOS database supports previous reports of beneficial effects of enzyme replacement therapy on gastrointestinal symptoms in Fabry disease.

    Gastrointestinal symptoms
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 were first described independently by William Anderson and Johannes Fabry. Case reports and case series suggest that the

    whole gastrointestinal tract
    SYMPTOMS

 may be affected in patients with

    Fabry disease
    DIAGNOSIS

. The Fabry Outcome Survey (FOS) database supports these observations. The overall prevalence of

    gastrointestinal involvement
    SYMPTOMS

 reported in a study of 342 patients (271

    adults
    AGE

; 71

    children
    AGE

) enrolled in FOS was 52% (49.8% in

    adults
    AGE

, 60.8% in

    children
    AGE

).

    Abdominal pain
    SYMPTOMS

 was the most prevalent symptom. The

    median age at onset
    AGE

 of

    gastrointestinal symptoms
    SYMPTOMS

    was 14 years
    AGE

, similar to the

    age at
    AGE

 onset of

    acroparaesthesia
    SYMPTOMS

. The prevalence of

    gastrointestinal symptoms
    SYMPTOMS

 was reduced in patients after receiving

    enzyme replacement therapy with agalsidase alfa for 12 and 24 months
    MEDICATION

. There was

    no correlation between gastrointestinal symptoms
    NEG_FINDINGS

 and

    body mass index
    NEG_FINDINGS

.

    Gastrointestinal symptoms
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 may have been underestimated. The FOS database supports previous reports of beneficial effects of

    enzyme replacement therapy
    MEDICATION

 on

    gastrointestinal symptoms
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

.

Gastrointestinal symptoms
whole gastrointestinal tract
gastrointestinal involvement
Abdominal pain
gastrointestinal symptoms
acroparaesthesia
gastrointestinal symptoms
Gastrointestinal symptoms
gastrointestinal symptoms

Fabry disease
Fabry disease
Fabry disease
Fabry disease


Optimization of concomitant medication in Fabry cardiomyopathy.

We describe a male patient with Fabry disease and use this case study to illustrate the importance of a detailed cardiovascular evaluation and the role of supportive therapy in routine management of the disease. The major areas of discussion include the management of exertional chest pain, progressive heart failure and the diagnosis and treatment of atrial and ventricular arrhythmia.

In the era of enzyme replacement therapy, conventional pharmacological and device-based therapies remain central to the management of cardiovascular symptoms and the prevention of complications, such as arrhythmia and stroke.

We describe a

    male
    GENDER

 patient with

    Fabry disease
    DIAGNOSIS

 and use this case study to illustrate the importance of a

    detailed cardiovascular evaluation
    PARACLINICAL

 and the role of

    supportive therapy
    MEDICATION

 in routine management of the disease. The major areas of discussion include the management of

    exertional chest pain
    SYMPTOMS

,

    progressive heart failure
    SYMPTOMS

 and the diagnosis and treatment of

    atrial and ventricular arrhythmia
    DIAGNOSIS

.

In the era of

    enzyme replacement therapy
    MEDICATION

,

    conventional pharmacological and device-based therapies
    MEDICATION

 remain central to the management of

    cardiovascular symptoms
    SYMPTOMS

 and the prevention of complications, such as

    arrhythmia
    SYMPTOMS

 and

    stroke
    SYMPTOMS

.

Fabry disease
atrial and ventricular arrhythmia

exertional chest pain
progressive heart failure
cardiovascular symptoms
arrhythmia
stroke


Narrative review: Fabry disease.

Fabry disease is an X-linked, hereditary, lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A, which results in the accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3) in the walls of small blood vessels, nerves, dorsal root ganglia, renal glomerular and tubular epithelial cells, and cardiomyocytes. It is a complex, multisystem disorder that is characterized clinically by chronic pain and acroparesthesia, gastrointestinal disturbances, characteristic skin lesions (angiokeratomata), progressive renal impairment, cardiomyopathy, and stroke. Enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A consistently decreases Gb3 levels in plasma and clears lysosomal inclusions from vascular endothelial cells. The effects of ERT on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease are not responsive to enzymes delivered intravenously.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

,

    hereditary
    GENETICS

,

    lysosomal storage disease
    DIAGNOSIS

 caused by

    deficiency of the enzyme alpha-galactosidase A
    BIOCHEMICAL

, which results in the

    accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3) in the walls of small blood vessels, nerves, dorsal root ganglia, renal glomerular and tubular epithelial cells, and cardiomyocytes
    MICROSCOPIC

. It is a complex,

    multisystem disorder
    DIAGNOSIS

 that is characterized clinically by

    chronic pain and acroparesthesia
    SYMPTOMS

,

    gastrointestinal disturbances
    SYMPTOMS

,

    characteristic skin lesions (angiokeratomata)
    SYMPTOMS

,

    progressive renal impairment
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

, and

    stroke
    SYMPTOMS

.

    Enzyme replacement therapy (ERT) with intravenous infusions of recombinant human alpha-galactosidase A
    MEDICATION

    consistently decreases Gb3 levels in plasma
    BIOCHEMICAL

 and

    clears lysosomal inclusions from vascular endothelial cells
    MICROSCOPIC

. The effects of

    ERT
    MEDICATION

 on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease

    are not responsive to enzymes delivered intravenously
    NEG_FINDINGS

.

Fabry disease
lysosomal storage disease
multisystem disorder


A diagnosis of Fabry gastrointestinal disease by chance: a case report.

Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A. This determines an accumulation of globotriaosylceramide within lysosomes. The clinical picture is highly variable and depends on cellular storage deposition. Renal, cardiac and nervous system are the most frequent organs involved. Gastrointestinal involvement is also present, associated with other clinical signs of Fabry disease and sometimes can be a prominent clinical manifestation. We describe a Fabry disease case in which gastrointestinal involvement was the first and the only clinical sign of Fabry disease and a diagnosis of Fabry disease was made by chance during a family screening. Enzyme replacement therapy was started and after 3 months, there was a complete disappearance of signs.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a deficiency of alpha-galactosidase A. This determines an

    accumulation of globotriaosylceramide within lysosomes
    MICROSCOPIC

. The clinical picture is highly variable and depends on

    cellular storage deposition
    MICROSCOPIC

.

    Renal, cardiac and nervous system
    SYMPTOMS

 are the most frequent organs involved.

    Gastrointestinal involvement
    SYMPTOMS

 is also present, associated with other

    clinical signs of Fabry disease
    SYMPTOMS

 and sometimes can be a prominent clinical manifestation. We describe a

    Fabry disease
    DIAGNOSIS

 case in which

    gastrointestinal involvement
    SYMPTOMS

 was the first and the only clinical sign of

    Fabry disease
    SYMPTOMS

 and a diagnosis of

    Fabry disease
    DIAGNOSIS

 was made by chance during a

    family screening
    PARACLINICAL

.

    Enzyme replacement therapy
    MEDICATION

 was started and after

    3 months
    MEDICATION

, there was a

    complete disappearance of signs
    SYMPTOMS

.

Fabry disease
lysosomal storage disease
Fabry disease
Fabry disease

Renal, cardiac and nervous system
Gastrointestinal involvement
clinical signs of Fabry disease
gastrointestinal involvement
Fabry disease
complete disappearance of signs


Azoospermia as a new feature of Fabry disease.

To describe two cases of azoospermia in men with Fabry disease.

Case report.

Centre hospitalier universitaire, maternité Pellegrin, Bordeaux, France.

Two infertile men with azoospermia and with Fabry disease.

Testicular biopsies.

Histological and electron microscopy analysis of testicular biopsies.

Testicular biopsies revealed characteristic aspects of trihexosid ceramid deposits in Leydig cells by optical and electronic microscopic analysis. Using testicular sperm extraction and intracytoplasmic sperm injection, sperm retrieval led to pregnancies and deliveries of healthy children.

Azoospermia should be considered as a possible complication of Fabry disease. We recommend a routine sperm analysis in the follow-up of young patients with Fabry disease. Azoospermia was still present after 4 years of agalsidase-beta therapy. Because we do not know the efficacy of agalsidase therapy on the genital involvement in Fabry disease, sperm cryopreservation is recommended.

To describe two cases of

    azoospermia
    DIAGNOSIS

 in

    men
    GENDER

 with

    Fabry disease
    DIAGNOSIS

.

    Centre hospitalier universitaire
    DIAGNOSIS

,

    maternité Pellegrin
    DIAGNOSIS

,

    Bordeaux
    ETHNICITY

,

    France
    ETHNICITY

.

Two

    infertile
    GENDER

    men
    GENDER

 with

    azoospermia
    DIAGNOSIS

 and with

    Fabry disease
    DIAGNOSIS

.

    Testicular biopsies
    PARACLINICAL

.

    Histological and electron microscopy analysis of testicular biopsies
    PARACLINICAL

.

    Testicular biopsies
    PARACLINICAL

 revealed

    characteristic aspects of trihexosid ceramid deposits in Leydig cells
    MICROSCOPIC

 by

    optical and electronic microscopic analysis
    PARACLINICAL

. Using

    testicular sperm extraction
    MEDICATION

 and

    intracytoplasmic sperm injection
    MEDICATION

,

    sperm retrieval
    MEDICATION

 led to

    pregnancies
    SYMPTOMS

 and

    deliveries of healthy children
    MEDICATION

.

    Azoospermia
    BIOCHEMICAL

 should be considered as a possible complication of

    Fabry disease
    DIAGNOSIS

. We recommend a

    routine sperm analysis
    PARACLINICAL

 in the follow-up of

    young
    AGE

 patients with

    Fabry disease
    DIAGNOSIS

.

    Azoospermia
    BIOCHEMICAL

 was still present after

    4 years of agalsidase-beta therapy
    MEDICATION

. Because we do not know the efficacy of

    agalsidase therapy
    MEDICATION

 on the

    genital involvement
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

,

    sperm cryopreservation
    MEDICATION

 is recommended.

azoospermia
Fabry disease
Centre hospitalier universitaire
maternité Pellegrin
azoospermia
Fabry disease
Fabry disease
Fabry disease
Fabry disease

testicular sperm extraction
intracytoplasmic sperm injection
sperm retrieval
deliveries of healthy children
4 years of agalsidase-beta therapy
agalsidase therapy
sperm cryopreservation


Pulmonary manifestations of Fabry disease and positive response to enzyme replacement therapy.

Fabry disease affects multiple organs, including the lungs. To date, there have been no reports of the effect of enzyme replacement therapy on patients with pulmonary manifestations of the disease. We report on a case of marked improvement of pulmonary signs and symptoms in a patient with Fabry disease following enzyme replacement therapy. A 38-year-old female with Fabry disease presented with dyspnea requiring constant supplemental oxygen. Following bi-weekly treatment with agalsidase beta, she demonstrated marked improvement in her pulmonary symptoms, eventually no longer needing supplemental oxygen and returning to an active lifestyle. Improvement was seen on pulmonary function tests and chest CT examinations. Enzyme replacement therapy may alleviate pulmonary dysfunction in patients with Fabry disease.

    Fabry disease
    DIAGNOSIS

 affects

    multiple organs, including the lungs
    SYMPTOMS

. To date, there have been no reports of the effect of

    enzyme replacement therapy
    MEDICATION

 on patients with

    pulmonary manifestations
    SYMPTOMS

 of the disease. We report on a case of

    marked improvement of pulmonary signs and symptoms
    SYMPTOMS

 in a patient with

    Fabry disease
    DIAGNOSIS

 following

    enzyme replacement therapy
    MEDICATION

. A

    38-year-old
    AGE

    female
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 presented with

    dyspnea
    SYMPTOMS

 requiring

    constant supplemental oxygen
    MEDICATION

. Following

    bi-weekly treatment with agalsidase beta
    MEDICATION

,

    she
    GENDER

 demonstrated

    marked improvement in her pulmonary symptoms
    SYMPTOMS

, eventually

    no longer needing supplemental oxygen
    NEG_FINDINGS

 and

    returning to an active lifestyle
    MEDICATION

. Improvement was seen on

    pulmonary function tests
    PARACLINICAL

 and

    chest CT examinations
    PARACLINICAL

.

    Enzyme replacement therapy
    MEDICATION

 may alleviate

    pulmonary dysfunction
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

.


Clinical spectrum of Anderson Fabry disease in a Romanian family.

Anderson Fabry disease (alpha galactosidase A deficiency) is an X-linked recessive lysosomal storage disorder; alpha galactosidase A deficiency results in accumulation of neutral glycosphingolipids, especially globotriaosylceramide (Gb3), in various cell types promoting development of disease with renal, cardiovascular, and cerebrovascular involvement. Clinical aspects which usually begin in childhood or adolescence include intermittent pain in the extremities (acroparesthesias), episodic "Fabry crisis" of acute pain lasting hours to days, characteristic skin lesions (angiokeratomas), hypohidrosis, heat and cold intolerance. Classic phenotype conception of the disease has changed within the past decade, recognizing that disease is not limited to the classical full-blown manifestation in affected males, but may also occur in carrier females. The expanding clinical spectrum of Anderson Fabry disease (AFD) is a real challenge to diagnosis, especially in some patients whose exclusive single organ manifestation belongs to the heart or kidney. This paper reviews natural history of three unrecognized cases recently diagnosed by markedly deficient alpha galactosidase A (alpha Gal A) activity in peripheral leucocytes. Case A: A male patient, aged 24 years, experienced recurrent acroparesthesia when he was 9 years-old. His 26 years-old sister has angiokeratomas as the only sign of disease (case B). Case C: the uncle of these two cases (A, B) has a long history of disease including chronic renal failure, bilateral deafness, stroke, aseptic osteonecrosis. The purpose of the presentation is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease.

    Anderson Fabry disease
    DIAGNOSIS

 (

    alpha galactosidase A deficiency
    BIOCHEMICAL

    )
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

;

    alpha galactosidase A deficiency
    BIOCHEMICAL

 results in

    accumulation of neutral glycosphingolipids, especially globotriaosylceramide (Gb3), in various cell types
    MICROSCOPIC

 promoting development of disease with

    renal, cardiovascular, and cerebrovascular involvement
    SYMPTOMS

. Clinical aspects which usually begin in

    childhood
    AGE

 or

    adolescence
    AGE

 include

    intermittent pain in the extremities (acroparesthesias)
    SYMPTOMS

,

    episodic "Fabry crisis" of acute pain lasting hours to days
    SYMPTOMS

,

    characteristic skin lesions (angiokeratomas)
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    heat and cold intolerance
    SYMPTOMS

. Classic phenotype conception of the disease has changed within the past decade, recognizing that disease is not limited to the classical

    full-blown manifestation
    SYMPTOMS

 in affected

    males
    GENDER

, but may also occur in carrier

    females
    GENDER

. The expanding clinical spectrum of

    Anderson Fabry disease (AFD)
    DIAGNOSIS

 is a real challenge to diagnosis, especially in some patients whose

    exclusive single organ manifestation belongs to the heart or kidney
    SYMPTOMS

. This paper reviews natural history of three unrecognized cases recently diagnosed by

    markedly deficient alpha galactosidase A (alpha Gal A) activity in peripheral leucocytes
    BIOCHEMICAL

. Case A: A

    male
    GENDER

 patient,

    aged 24 years
    AGE

, experienced

    recurrent acroparesthesia
    SYMPTOMS

 when

    he
    GENDER

    was 9 years-old
    AGE

.

    His 26 years-old sister has angiokeratomas as the only sign of disease
    FAMILY

 (case B). Case C: the

    uncle of these two cases (A, B) has a long history of disease including chronic renal failure
    FAMILY

,

    bilateral deafness
    SYMPTOMS

,

    stroke
    SYMPTOMS

,

    aseptic osteonecrosis
    DIAGNOSIS

. The purpose of the presentation is to sharpen physicians' perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the

    novel enzyme replacement therapy
    MEDICATION

, a treatable disease.

Anderson Fabry disease
)
lysosomal storage disorder
Anderson Fabry disease (AFD)
aseptic osteonecrosis


Fabry disease mimicking multiple sclerosis.

Fabry disease is an X-linked recessive lysosomal storage disorder resulting from the deficiency of alpha-galactosidase. This disease causes endothelial vasculopathy and affects multiple organ systems. Hemizygous male patients represent the classical renal, cardiac and neurological symptoms of disease. Heterozygous female carriers are frequently asymptomatic, but cerebrovascular events in females are as frequent as in males. Even if rarely seen, neurological damage is an important cause of morbidity. Severe neurological signs that are due to multifocal small vessel occlusions may be present without major thrombosis. In this report, we present a 33-year-old female patient with recurrent neurological deficits secondary to multifocal small vessel involvements. The case had previously been misdiagnosed as multiple sclerosis. Cerebral MRI revealed hyperintense lesions located in bilateral thalamus, supratentorial areas, and left cerebellum. Laboratory and radiological investigations were performed for differential diagnosis, but the etiology could not be identified. During follow-up period, skin lesions and proteinuria were detected. The dermatological, neurological, laboratory, and radiological findings were all suggestive of Fabry disease and the diagnosis was confirmed by subsequent enzyme assays. Fabry disease should be considered in young patients with unexplained stroke-like episodes, especially in those who have infarction in the vertebrobasilar arterial system, angiokeratomas, and proteinuria.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from the

    deficiency of alpha-galactosidase
    BIOCHEMICAL

. This disease causes

    endothelial vasculopathy
    SYMPTOMS

 and

    affects multiple organ systems
    SYMPTOMS

.

    Hemizygous male
    GENETICS

 patients represent the

    classical renal, cardiac and neurological symptoms
    SYMPTOMS

 of disease.

    Heterozygous
    GENETICS

    female
    GENDER

 carriers are frequently

    asymptomatic
    NEG_FINDINGS

, but

    cerebrovascular events
    SYMPTOMS

 in

    females
    GENDER

 are as frequent as in

    males
    GENDER

. Even if rarely seen,

    neurological damage
    SYMPTOMS

 is an important cause of morbidity.

    Severe neurological signs
    SYMPTOMS

 that are due to

    multifocal small vessel occlusions
    SYMPTOMS

 may be present

    without major thrombosis
    NEG_FINDINGS

. In this report, we present a

    33-year-old
    AGE

    female
    GENDER

 patient with

    recurrent neurological deficits
    SYMPTOMS

 secondary to

    multifocal small vessel involvements
    SYMPTOMS

. The case had

    previously been misdiagnosed as multiple sclerosis
    NEG_FINDINGS

.

    Cerebral MRI
    PARACLINICAL

 revealed

    hyperintense lesions located in bilateral thalamus, supratentorial areas, and left cerebellum
    SYMPTOMS

.

    Laboratory and radiological investigations
    PARACLINICAL

 were performed for

    differential diagnosis
    PARACLINICAL

, but the

    etiology could not be identified
    NEG_FINDINGS

. During

    follow-up period
    PARACLINICAL

,

    skin lesions
    SYMPTOMS

 and

    proteinuria
    BIOCHEMICAL

 were detected. The

    dermatological
    SYMPTOMS

, neurological, laboratory, and radiological findings were all suggestive of

    Fabry disease
    DIAGNOSIS

 and the diagnosis was confirmed by subsequent

    enzyme assays
    PARACLINICAL

.

    Fabry disease
    DIAGNOSIS

 should be considered in

    young
    AGE

 patients with

    unexplained stroke-like episodes
    SYMPTOMS

, especially in those who have

    infarction in the vertebrobasilar arterial system
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

, and

    proteinuria
    BIOCHEMICAL

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease

X-linked recessive
Hemizygous male
Heterozygous

deficiency of alpha-galactosidase
proteinuria
proteinuria


[Intergluteal angiokeratoma circumscriptum. Report of one case].

The term angiokeratoma is applied to several diseases with cutaneous vascular lesions.

A 26-year-old male presented with an intergluteal tumor from childhood until the present time, which was treated on several occasions without results. The patient presented to the hospital complaining of a painful and bleeding intergluteal tumor.

Five types of angiokeratomas have been described (angiokeratoma corporis diffusum, angiokeratoma of Mibelli, angiokeratoma of Fordyce, solitary angiokeratoma and angiokeratoma corporal circumscriptum). This patient was identified with an angiokeratoma circumscriptum by pathological and physical characteristics of the tumor. Differential diagnosis is with verrucous hemangioma and the Fabry disease type II (angiokeratoma corporis diffusum).

Pathogenesis is unknown and surgery is the recommended treatment.

The term

    angiokeratoma
    DIAGNOSIS

 is applied to several diseases with

    cutaneous vascular lesions
    SYMPTOMS

.

A

    26-year-old
    AGE

    male
    GENDER

 presented with an

    intergluteal tumor
    SYMPTOMS

 from

    childhood
    AGE

 until the present time, which was treated on several occasions

    without results
    NEG_FINDINGS

. The patient presented to the hospital complaining of a

    painful and bleeding intergluteal tumor
    SYMPTOMS

.

Five types of

    angiokeratomas
    SYMPTOMS

 have been described (

    angiokeratoma corporis diffusum
    SYMPTOMS

,

    angiokeratoma of Mibelli
    DIAGNOSIS

,

    angiokeratoma of Fordyce
    DIAGNOSIS

,

    solitary angiokeratoma
    SYMPTOMS

 and

    angiokeratoma corporal circumscriptum
    SYMPTOMS

). This patient was identified with an

    angiokeratoma circumscriptum
    DIAGNOSIS

 by pathological and physical characteristics of the tumor.

    Differential diagnosis
    PARACLINICAL

 is with

    verrucous hemangioma
    DIAGNOSIS

 and the

    Fabry disease type II
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum)
    DIAGNOSIS

.

Pathogenesis is unknown and

    surgery
    MEDICATION

 is the recommended treatment.

angiokeratoma
angiokeratoma of Mibelli
angiokeratoma of Fordyce
angiokeratoma circumscriptum
verrucous hemangioma
Fabry disease type II
angiokeratoma corporis diffusum)

cutaneous vascular lesions
intergluteal tumor
painful and bleeding intergluteal tumor
angiokeratomas
angiokeratoma corporis diffusum
solitary angiokeratoma
angiokeratoma corporal circumscriptum


Fabry disease in a heterozygote presenting as hand ischaemia and painful acroparaesthesia.

A 48-year-old woman presented with acute unilateral ischaemia of the left hand. She had a background of chronic peripheral neuropathic pain, palpitations, anaemia and an episode of superficial thrombophlebitis. Physical examination revealed non-blanching purple discoloration of her left fingers and her left thumb, index finger and thenar eminance appeared ischaemic. Digital subtraction angiography of the left hand demonstrated reduced flow. Skin punch biopsy histology was unremarkable. The diagnosis of Fabry disease was made on urine lipid profile analysis and confirmed by reduced peripheral blood leukocyte alpha-galactosidase A activity.

A

    48-year-old
    AGE

    woman
    GENDER

 presented with

    acute unilateral ischaemia of the left hand
    SYMPTOMS

.

    She
    GENDER

 had a background of

    chronic peripheral neuropathic pain
    SYMPTOMS

,

    palpitations
    SYMPTOMS

,

    anaemia
    BIOCHEMICAL

 and an

    episode of superficial thrombophlebitis
    SYMPTOMS

.

    Physical examination
    PARACLINICAL

 revealed

    non-blanching purple discoloration of her left fingers
    SYMPTOMS

 and

    her left thumb, index finger and thenar eminance appeared ischaemic
    SYMPTOMS

.

    Digital subtraction angiography of the left hand
    PARACLINICAL

 demonstrated

    reduced flow
    SYMPTOMS

.

    Skin punch biopsy histology was unremarkable
    NEG_FINDINGS

. The diagnosis of

    Fabry disease
    DIAGNOSIS

 was made on

    urine lipid profile analysis
    PARACLINICAL

 and confirmed by

    reduced peripheral blood leukocyte alpha-galactosidase A activity
    BIOCHEMICAL

.


Clinical and molecular characterization of an extended family with Fabry disease.

To characterize clinical manifestations, biochemical changes, mutation of alpha-Galactosidase (alpha-Gal A) gene A (GLA), and functional capability of mutant protein.

Seventeen subjects from a family with a newly diagnosed patient with Fabry disease were enrolled in the present study. In each individual, clinical history, physical examination, leukocyte enzyme activity of alpha-Gal A, and mutation analysis were performed. Those with a mutation were further investigated by ophthalmological and audiological evaluations, electrocardiography, echocardiogram, urinalysis, and blood tests to determine renal insufficiency. Expression study of the mutant protein was performed using a Pichia pastoris expression system.

Four affected males and five symptomatic female carriers were identified. Clinical manifestations included severe neuropathic pain, acroparesthesia, hypo-/hyper-hidrosis, frequent syncope, ischemic stroke, cardiac hypertrophy, corneal dystrophy and cart-wheel cataract, high frequency sensorineural hearing loss, periorbital edema and subcutaneous edema over hands and interphalangeal joints. None had angiokeratoma or renal symptoms. The authors identified a novel mutation, p.L106R, in the GLA gene. Recombinant expression of the mutant protein gave little or no enzyme activity compared to the normal protein.

There were intrafamilial clinical variabilities, but consistent findings of the absence of angiokeratoma and renal symptoms, which could represent a unique feature of this particular mutation.

To characterize clinical manifestations,

    biochemical changes
    SYMPTOMS

,

    mutation of alpha-Galactosidase (alpha-Gal A) gene A (GLA)
    GENETICS

, and functional capability of mutant protein.

Seventeen subjects from a

    family with a newly diagnosed patient with Fabry disease
    FAMILY

 were enrolled in the present study. In each individual,

    clinical history
    PARACLINICAL

,

    physical examination
    PARACLINICAL

,

    leukocyte enzyme activity of alpha-Gal A
    BIOCHEMICAL

, and

    mutation analysis
    PARACLINICAL

 were performed. Those with a mutation were further investigated by

    ophthalmological and audiological evaluations
    PARACLINICAL

,

    electrocardiography
    PARACLINICAL

,

    echocardiogram
    PARACLINICAL

,

    urinalysis
    PARACLINICAL

, and

    blood tests
    PARACLINICAL

 to determine

    renal insufficiency
    DIAGNOSIS

.

    Expression study of the mutant protein
    PARACLINICAL

 was performed using a Pichia pastoris expression system.

Four affected

    males
    GENDER

 and five symptomatic

    female
    GENDER

 carriers were identified. Clinical manifestations included

    severe neuropathic pain
    SYMPTOMS

,

    acroparesthesia
    SYMPTOMS

,

    hypo-/hyper-hidrosis
    SYMPTOMS

,

    frequent syncope
    SYMPTOMS

,

    ischemic stroke
    SYMPTOMS

,

    cardiac hypertrophy
    SYMPTOMS

,

    corneal dystrophy
    SYMPTOMS

 and

    cart-wheel cataract
    SYMPTOMS

,

    high frequency sensorineural hearing loss
    SYMPTOMS

,

    periorbital edema
    SYMPTOMS

 and

    subcutaneous edema over hands and interphalangeal joints
    SYMPTOMS

.

    None
    NEG_FINDINGS

 had

    angiokeratoma or renal symptoms
    NEG_FINDINGS

. The authors identified a

    novel mutation, p.L106R, in the GLA gene
    GENETICS

.

    Recombinant
    PARACLINICAL

 expression of the mutant protein gave

    little or no enzyme activity compared to the normal protein
    BIOCHEMICAL

.

There were

    intrafamilial clinical variabilities
    SYMPTOMS

, but consistent findings of the

    absence of angiokeratoma and renal symptoms
    NEG_FINDINGS

, which could represent a unique feature of this particular mutation.


Electrophysiological study in a patient with Fabry disease and a short PQ interval.

A short PQ interval is a common finding in patients with Fabry disease. However, there have been few electrophysiological studies in Fabry disease, and it is not clear whether the short PQ interval that is present in this disease results from preexcitation or enhanced atrioventricular nodal conduction. We present a case of a 43-year-old man with syncope, sick sinus syndrome, a PQ interval of 80 ms, and palpitations. Electrophysiological study showed PA, AH, and HV intervals of 24, 32, and 34 ms, respectively, and features of enhanced atrioventricular nodal conduction. The presence of an atrioventricular accessory pathway was excluded. We conclude that the short PQ interval in Fabry disease can result from accelerated conduction in the atrioventricular node.

A

    short PQ interval
    SYMPTOMS

 is a common finding in patients with

    Fabry disease
    DIAGNOSIS

. However, there have been few electrophysiological studies in

    Fabry disease
    DIAGNOSIS

, and it is not clear whether the

    short PQ interval
    SYMPTOMS

 that is present in this disease results from

    preexcitation
    SYMPTOMS

 or

    enhanced atrioventricular nodal conduction
    SYMPTOMS

. We present a case of a

    43-year-old
    AGE

    man
    GENDER

 with

    syncope
    SYMPTOMS

,

    sick sinus syndrome
    SYMPTOMS

, a

    PQ interval of 80 ms
    SYMPTOMS

, and

    palpitations
    SYMPTOMS

.

    Electrophysiological study
    PARACLINICAL

 showed

    PA, AH, and HV intervals of 24, 32, and 34 ms
    SYMPTOMS

, respectively, and

    features of enhanced atrioventricular nodal conduction
    SYMPTOMS

.

    The presence of an atrioventricular accessory pathway was excluded
    NEG_FINDINGS

. We conclude that the

    short PQ interval
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 can result from

    accelerated conduction in the atrioventricular node
    SYMPTOMS

.

Fabry disease
Fabry disease
Fabry disease


Diagnosis of Anderson-Fabry's disease in over seventy-year-old women: description of two cases.

Anderson-Fabry's disease (AFD) is a rare inborn X-linked sphingolipid storage disorder. Deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-GAL-A) leads to progressive accumulation of glycosphingolipids within most visceral tissues and body fluids of affected patients, provoking a clinical syndrome that includes nervous system, renal, cardiac, ophthalmologic and cutaneous manifestations. Also heterozygous women, who had been considered as healthy carriers until recently, often demonstrate clinical signs of multi-organ involvement. In older women these manifestations are frequently attributed to other more common conditions of older age, and a genetic disorder is rarely hypothesized. We report the cases of two elderly women, who had been diagnosed with AFD at the ages of 70 and 74. Although it is a rare disease, AFD should be considered as a diagnostic hypothesis in women with a clinical history of cardiomyopathy and vascular encephalopathy, appearing at ages 40-50 without identification of major vascular risk factors.

    Anderson-Fabry's disease (AFD)
    DIAGNOSIS

 is a

    rare inborn X-linked
    GENETICS

    sphingolipid storage disorder
    DIAGNOSIS

.

    Deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-GAL-A)
    BIOCHEMICAL

 leads to

    progressive accumulation of glycosphingolipids within most visceral tissues and body fluids of
    MICROSCOPIC

 affected patients, provoking a clinical syndrome that includes

    nervous system, renal, cardiac, ophthalmologic and cutaneous manifestations
    SYMPTOMS

. Also

    heterozygous
    GENETICS

    women
    GENDER

, who had been considered as healthy carriers until recently, often demonstrate

    clinical signs of multi-organ involvement
    SYMPTOMS

. In

    older
    AGE

    women
    GENDER

 these manifestations are frequently attributed to other more common conditions of

    older age
    AGE

, and a

    genetic disorder
    GENETICS

 is rarely hypothesized. We report the cases of two

    elderly
    AGE

    women
    GENDER

, who had been diagnosed with

    AFD
    DIAGNOSIS

 at the

    ages of 70 and 74
    AGE

. Although it is a rare disease,

    AFD
    DIAGNOSIS

 should be considered as a diagnostic hypothesis in

    women
    GENDER

 with a clinical history of

    cardiomyopathy
    SYMPTOMS

 and

    vascular encephalopathy
    SYMPTOMS

, appearing at

    ages 40-50
    AGE

    without identification of major vascular risk factors
    NEG_FINDINGS

.

Anderson-Fabry's disease (AFD)
sphingolipid storage disorder
AFD
AFD

rare inborn X-linked
heterozygous
genetic disorder


Detection of preclinical left ventricular dysfunction in Fabry disease: the contribution of tissue Doppler.

Fabry disease is a rare X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase, which results in progressive intracellular accumulation of glycosphingolipids in various tissues. Cardiac involvement is frequent, with left ventricular (LV) hypertrophy (concentric, apical or asymmetric septal) as the most common finding. Evaluating LV systolic dysfunction with conventional echocardiography is not sufficiently sensitive to detect impaired myocardial function early in the course of the disease. Doppler myocardial imaging can quantify changes in global and regional longitudinal myocardial function with great precision.

To identify parameters of cardiac dysfunction in patients with Fabry disease with no cardiac symptoms using conventional or Doppler echocardiography and tissue Doppler (including tissue tracking, strain and strain rate).

Four patients with Fabry disease (3 female; mean age 47 +/- 17 years) and 29 healthy controls (19 female and 10 male; mean age 38 +/- 14 years) were studied with conventional echocardiography and tissue Doppler imaging using a Vivid 7 scanner. The following parameters were measured: LV dimensions, ejection fraction (using Simpson's rule), systolic and diastolic velocities and tissue tracking of the mitral annulus at six sites (apical views). LV peak systolic strain and strain rate were obtained in 12 segments from apical views.

Two patients had LV hypertrophy (one concentric and one apical). Diastolic impairment was detected in three patients by reduced flow propagation velocity of early transmitral flow (Vp) and E/Vp ratio. Mitral annulus systolic velocities were lower in Fabry disease than in the controls. Peak systolic strain and strain rate were diminished in all segments in three patients, showing impaired myocardial systolic function. The results are presented for each of the four patients.

In patients with Fabry disease, with no cardiac symptoms and normal LV systolic function on conventional echocardiography, diastolic dysfunction was detected by Vp and E/Vp ratio regardless of LV hypertrophy. However, tissue Doppler imaging was able to detect impaired myocardial systolic function, particularly in patients with LV hypertrophy.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of alpha-galactosidase
    BIOCHEMICAL

, which results in

    progressive intracellular accumulation of glycosphingolipids in various tissues
    MICROSCOPIC

.

    Cardiac involvement
    SYMPTOMS

 is frequent, with

    left ventricular (LV) hypertrophy (concentric, apical or asymmetric septal)
    SYMPTOMS

 as the most common finding. Evaluating

    LV systolic dysfunction
    SYMPTOMS

 with

    conventional echocardiography
    PARACLINICAL

 is not sufficiently sensitive to detect

    impaired myocardial function
    SYMPTOMS

 early in the course of the disease.

    Doppler myocardial imaging
    PARACLINICAL

 can quantify

    changes in global and regional longitudinal myocardial function
    SYMPTOMS

 with great precision.

To identify parameters of

    cardiac dysfunction
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

 with

    no cardiac symptoms
    NEG_FINDINGS

 using

    conventional or Doppler echocardiography
    PARACLINICAL

 and

    tissue Doppler (including tissue tracking, strain and strain rate)
    PARACLINICAL

.

Four patients with

    Fabry disease
    DIAGNOSIS

 (3

    female
    GENDER

;

    mean age 47 +/- 17 years
    AGE

) and 29 healthy controls (19

    female
    GENDER

 and 10

    male
    GENDER

;

    mean age 38 +/- 14 years
    AGE

) were studied with

    conventional echocardiography and tissue Doppler imaging using a Vivid 7 scanner
    PARACLINICAL

. The following parameters were measured:

    LV dimensions
    SYMPTOMS

,

    ejection fraction (using Simpson's rule)
    SYMPTOMS

, systolic and diastolic velocities and

    tissue tracking of the mitral annulus at six sites (apical views)
    PARACLINICAL

.

    LV peak systolic strain and strain rate were obtained in 12 segments from apical views
    PARACLINICAL

.

Two patients had

    LV hypertrophy
    SYMPTOMS

 (one concentric and one

    apical)
    SYMPTOMS

.

    Diastolic impairment
    SYMPTOMS

 was detected in three patients by

    reduced flow propagation velocity of early transmitral flow (Vp)
    SYMPTOMS

 and E/Vp ratio.

    Mitral annulus systolic velocities were lower
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 than in the controls.

    Peak systolic strain and strain rate were diminished in all segments
    SYMPTOMS

 in three patients, showing

    impaired myocardial systolic function
    SYMPTOMS

. The results are presented for each of the four patients.

In patients with

    Fabry disease
    DIAGNOSIS

, with

    no cardiac symptoms
    NEG_FINDINGS

 and

    normal LV systolic function on conventional echocardiography
    NEG_FINDINGS

,

    diastolic dysfunction
    SYMPTOMS

 was detected by Vp and E/Vp ratio

    regardless of LV hypertrophy
    NEG_FINDINGS

. However,

    tissue Doppler imaging
    PARACLINICAL

 was able to detect

    impaired myocardial systolic function
    SYMPTOMS

, particularly in patients with

    LV hypertrophy
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease
Fabry disease
Fabry disease


Hyperhidrosis: a new and often early symptom in Fabry disease. International experience and data from the Fabry Outcome Survey.

Hypohidrosis is a classic feature of Fabry disease; in contrast, hyperhidrosis has only been rarely described. The aim of the study is to characterise the baseline descriptive data on hyperhidrosis (frequency, age at onset, sex ratio and outcome with and without enzyme replacement therapy) in hemizygous male and heterozygous female patients with Fabry disease. We describe case histories of five patients with Fabry disease and hyperhidrosis seen at three different centres. We have also analysed a cohort of 21 paediatric patients in the UK and a large European cohort of patients enrolled in the Fabry Outcome Survey (FOS). Five patients (three female, two male) with hyperhidrosis were originally identified, although each had additional symptoms related to Fabry disease. The age at onset of hyperhidrosis was less than 18 years in four cases. In the cohort of 21 paediatric patients (12 female, nine male), one female had hyperhidrosis; the age at onset of this symptom was 11 years. In the FOS cohort, 66 of 714 patients with Fabry disease had hyperhidrosis (44 of 369 females, 11.9%; 22 of 345 males, 6.4%). The female predominance was observed in seven of nine countries from which data were analysed. Hyperhidrosis is an increasingly recognised feature of the Fabry disease phenotype. It is more prevalent in females than in males and often appears in childhood or adolescence. The efficacy of enzyme replacement therapy on this recently recognised symptom should be assessed.

    Hypohidrosis
    SYMPTOMS

 is a classic feature of

    Fabry disease
    DIAGNOSIS

; in contrast,

    hyperhidrosis
    SYMPTOMS

 has only been rarely described. The aim of the study is to characterise the baseline descriptive data on

    hyperhidrosis
    SYMPTOMS

 (frequency, age at onset, sex ratio and outcome with and without

    enzyme replacement therapy
    MEDICATION

) in

    hemizygous male
    GENETICS

 and

    heterozygous
    GENETICS

    female
    GENDER

 patients with

    Fabry disease
    DIAGNOSIS

. We describe case histories of five patients with

    Fabry disease
    DIAGNOSIS

 and

    hyperhidrosis
    SYMPTOMS

 seen at three different centres. We have also analysed a cohort of 21

    paediatric
    AGE

 patients in the

    UK
    ETHNICITY

 and a large European cohort of patients enrolled in the Fabry Outcome Survey (FOS). Five patients (three

    female
    GENDER

, two

    male
    GENDER

) with

    hyperhidrosis
    SYMPTOMS

 were originally identified, although each had

    additional symptoms related to Fabry disease
    SYMPTOMS

. The

    age at onset of hyperhidrosis
    AGE

    was less than 18 years
    AGE

 in four cases. In the cohort of 21

    paediatric
    AGE

 patients (12

    female
    GENDER

, nine

    male
    GENDER

), one

    female
    GENDER

 had

    hyperhidrosis
    DIAGNOSIS

; the

    age at onset of
    AGE

 this symptom

    was 11 years
    AGE

. In the FOS cohort, 66 of 714 patients with

    Fabry disease
    DIAGNOSIS

 had

    hyperhidrosis
    SYMPTOMS

 (44 of 369

    females
    GENDER

, 11.9%; 22 of 345

    males
    GENDER

, 6.4%). The

    female
    GENDER

 predominance was observed in seven of nine countries from which data were analysed.

    Hyperhidrosis
    SYMPTOMS

 is an increasingly recognised feature of the

    Fabry disease
    DIAGNOSIS

 phenotype. It is more prevalent in

    females
    GENDER

 than in

    males
    GENDER

 and often appears in

    childhood
    AGE

 or

    adolescence
    AGE

. The efficacy of

    enzyme replacement therapy
    MEDICATION

 on this recently recognised symptom should be assessed.

Fabry disease
Fabry disease
Fabry disease
hyperhidrosis
Fabry disease
Fabry disease

enzyme replacement therapy
enzyme replacement therapy


[Two cases of heterozygous Fabry disease].

We report two cases of heterozygous Fabry disease with severe organ damage. Case 1 was a 47-year-old woman. In April 1977, at the age of 27 years, she had proteinuria and edema around the 26th week of her second pregnancy and was diagnosed as toxicosis of pregnancy. She had proteinuria after the delivery. In 1990, a renal biopsy showed zebra bodies under electron microscopic findings, and the patient was diagnosed as Fabry disease. In 1998, a myocardial biopsy showed identical findings. The patient developed severe hypertension and decreased renal function, and alpha-galactosidase enzyme replacement therapy was initiated. However, despite treatment, she was started on dialysis in 2004. Case 2 was a 40-year-old woman. In March 2003, the patient presented with severe hypertension. The patient had cerebral infarction, cardiac hypertrophy, old myocardial infarction and renal failure without diabetes mellitus, hyperlipidemia and collagen disease. The patient was diagnosed as Fabry disease from persistent numbness and pain in the four extremities, a family history of mortality due to heart disease, and skin biopsy findings. She is currently undergoing enzyme replacement therapy. It is generally known that female Fabry disease patients are asymptomatic or mildly symptomatic, as were the present two patients, but some can have marked organ disorders. Hence, even in female patients, it is necessary to consider Fabry disease as a causative disease of chronic renal failure.

We report two cases of

    heterozygous Fabry disease
    DIAGNOSIS

 with

    severe organ damage
    SYMPTOMS

. Case 1 was a

    47-year-old
    AGE

    woman
    GENDER

. In April 1977, at the

    age of 27 years
    AGE

,

    she
    GENDER

 had

    proteinuria
    BIOCHEMICAL

 and

    edema around the 26th week of her second pregnancy
    SYMPTOMS

 and was diagnosed as

    toxicosis of pregnancy
    DIAGNOSIS

.

    She
    GENDER

 had

    proteinuria
    BIOCHEMICAL

 after the delivery. In 1990, a

    renal biopsy
    PARACLINICAL

 showed

    zebra bodies
    MICROSCOPIC

 under

    electron microscopic findings
    PARACLINICAL

, and the patient was diagnosed as

    Fabry disease
    DIAGNOSIS

. In 1998, a

    myocardial biopsy
    PARACLINICAL

 showed identical findings. The patient developed

    severe hypertension
    SYMPTOMS

 and

    decreased renal function
    SYMPTOMS

, and

    alpha-galactosidase enzyme replacement therapy
    MEDICATION

 was initiated. However,

    despite treatment, she
    NEG_FINDINGS

    was started on dialysis
    NEG_FINDINGS

 in 2004. Case 2 was a

    40-year-old
    AGE

    woman
    GENDER

. In March 2003, the patient presented with

    severe hypertension
    SYMPTOMS

. The patient had

    cerebral infarction
    SYMPTOMS

,

    cardiac hypertrophy
    SYMPTOMS

,

    old myocardial infarction
    SYMPTOMS

 and

    renal failure
    SYMPTOMS

    without diabetes mellitus
    NEG_FINDINGS

,

    hyperlipidemia and collagen disease
    NEG_FINDINGS

. The patient was diagnosed as

    Fabry disease
    DIAGNOSIS

 from

    persistent numbness and pain in the four extremities
    SYMPTOMS

, a

    family history of mortality due to heart disease
    FAMILY

, and

    skin biopsy
    PARACLINICAL

 findings.

    She
    GENDER

 is currently undergoing

    enzyme replacement therapy
    MEDICATION

. It is generally known that

    female
    GENDER

    Fabry disease
    DIAGNOSIS

 patients are

    asymptomatic or mildly symptomatic
    NEG_FINDINGS

, as were the present two patients, but some can have

    marked organ disorders
    SYMPTOMS

. Hence, even in

    female
    GENDER

 patients, it is necessary to consider

    Fabry disease
    DIAGNOSIS

 as a causative disease of

    chronic renal failure
    DIAGNOSIS

.

heterozygous Fabry disease
toxicosis of pregnancy
Fabry disease
Fabry disease
Fabry disease
Fabry disease
chronic renal failure

despite treatment, she
was started on dialysis
without diabetes mellitus
hyperlipidemia and collagen disease
asymptomatic or mildly symptomatic


Fabry disease in a female patient due to a de novo point mutation at position 691 of exon 5.

Fabry disease is an X-linked lysosomal disorder caused by deficiency of the lysosomal enzyme alpha-galactosidase A. We report on a 32-year-old female patient with an 8-year history of vascular lesions on the hips and periumbilical region and a presumed Fabry disease without positive family history. Ophthalmologic evaluation revealed whorl-like corneal opacities. Echocardiography revealed myxomatous degeneration and prolapse of the mitral valve. DNA analysis of the alpha-galactosidase A gene confirmed the diagnosis of Fabry disease, showing a de novo point mutation at position 691 of exon 5. The patient is now obtaining intravenous enzyme replacement therapy with agalsidase alfa and remains without drug-related reactions.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal disorder
    DIAGNOSIS

 caused by deficiency of the lysosomal enzyme alpha-galactosidase A. We report on a

    32-year-old
    AGE

    female
    GENDER

 patient with an 8-year history of

    vascular lesions on the hips and periumbilical region
    SYMPTOMS

 and a presumed

    Fabry disease
    DIAGNOSIS

    without positive family history
    NEG_FINDINGS

.

    Ophthalmologic evaluation
    PARACLINICAL

 revealed

    whorl-like corneal opacities
    SYMPTOMS

.

    Echocardiography
    PARACLINICAL

 revealed

    myxomatous degeneration and prolapse of the mitral valve
    SYMPTOMS

.

    DNA analysis of the alpha-galactosidase A gene
    PARACLINICAL

 confirmed the diagnosis of

    Fabry disease
    DIAGNOSIS

, showing a

    de novo point mutation at position 691 of exon 5
    GENETICS

. The patient is now obtaining

    intravenous enzyme replacement therapy with agalsidase alfa
    MEDICATION

 and remains

    without drug-related reactions
    NEG_FINDINGS

.

Fabry disease
lysosomal disorder
Fabry disease
Fabry disease

without positive family history
without drug-related reactions


[Ocular findings in Fabry's disease].

Fabry's disease is a recessive X-linked disorder that results from a deficiency of the lysosomal hydrolase a-galactosidase A (alpha-Gal A). The absence of alpha-Gal A enzyme activity leads to accumulation of glycosphingolipid globotryaosyl ceramide (GL-3) in the lysosomes of a variety of cell types. Subsequently, angiokeratoma and ocular signs develop until, in most cases after the third decade of life, severe renal dysfunction or cardiomyopathy becomes obvious. Corneal opacities (cornea verticillata) occur in 90% conjunctival vascular changes in 60%, retinal vessel tortuosity in 55%, and cataracts in 50% of cases. Recently, enzyme replacement therapy has been shown to be an effective treatment modality that can eliminate glycolipid stores and reverse the disease pathology.

A male patient born in 1971 was admitted for clinical examination due to proteinuria and erythrocyturia. During further evaluation nephrologist suspected Fabry's disease, because patient had skin changes early referred as petechiae, and acroparesthesias. He had also low heat tolerance and virtually no sweat. Physical status: angiokeratoma on gluteat regions and upper arms. Urine analysis in several occasions 10-15 E in sediment, alb. positive. On ECG, 2-mm depression of ST in precordial region. Heart ultrasound: low mitral regurgitation angio stage 1, left ventricle hypertrophy. Abdomen ultrasound: both kidneys around 12 cm large, parapyelic cysts in both kidneys of 2.5 cm in diameter. Biomicroscopy of both eyes: cornea verticillata. Fundus of both eyes: papillae n. optici with poorly defined edges, but without prominence, very tortuotic retinal blood vessels. In March 2002, very low alpha GAL enzyme activity in blood (alpha-Gal A = 0.5 +/- 0.2 nmol of substrate hydrolyzed hourly per serum mL--normal serum enzyme level 8.5-18.9 nmol/mL/h). In May 2002, enzyme replacement therapy was started with recombinant alpha-Gal A enzyme (Fabrazyme) 1 mg/kg every 14 days. Control evaluation and examination showed good cardiac and renal function. The patient felt better and stronger with improved heat tolerance.

Fabry's disease occurs in all ethnic groups. It is estimated that one in 200 people is a carrier, and one in 40,000-100,000 has the disease. Today in Croatia, Fabry's disease has been diagnosed in only one patient, and according to the usual prevalence there are still 45-100 unrecognized patients. The ophthalmologists are in excellent position to diagnose Fabry's disease in early stages. Therefore it is very important that the ophthalmologists in Croatia become aware of the importance of ocular findings in Fabry's disease, so they can participate in the identification of unrecognized patients.

    Fabry's disease
    DIAGNOSIS

 is a

    recessive X-linked disorder
    GENETICS

 that results from a

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

. The

    absence of alpha-Gal A enzyme activity
    BIOCHEMICAL

 leads to

    accumulation of glycosphingolipid globotryaosyl ceramide (GL-3) in the lysosomes of a variety of cell types
    MICROSCOPIC

. Subsequently,

    angiokeratoma
    SYMPTOMS

 and

    ocular signs
    SYMPTOMS

 develop until, in most cases

    after the third decade of life
    AGE

,

    severe renal dysfunction
    SYMPTOMS

 or

    cardiomyopathy
    SYMPTOMS

 becomes obvious.

    Corneal opacities
    SYMPTOMS

 (

    cornea verticillata)
    SYMPTOMS

 occur in 90% conjunctival

    vascular changes
    SYMPTOMS

 in 60%,

    retinal vessel tortuosity
    SYMPTOMS

 in 55%, and

    cataracts
    SYMPTOMS

 in 50% of cases. Recently,

    enzyme replacement therapy
    MEDICATION

 has been shown to be an effective treatment modality that can

    eliminate glycolipid stores
    MICROSCOPIC

 and reverse the disease pathology.

A

    male
    GENDER

 patient born in 1971 was admitted for

    clinical examination
    PARACLINICAL

 due to

    proteinuria
    BIOCHEMICAL

 and

    erythrocyturia
    BIOCHEMICAL

. During further evaluation

    nephrologist
    PARACLINICAL

 suspected

    Fabry's disease
    DIAGNOSIS

, because patient had

    skin changes early referred as petechiae
    SYMPTOMS

, and

    acroparesthesias
    SYMPTOMS

.

    He
    GENDER

 had also

    low heat tolerance
    SYMPTOMS

 and

    virtually no sweat
    NEG_FINDINGS

. Physical status:

    angiokeratoma on gluteat regions and upper arms
    SYMPTOMS

.

    Urine analysis in several occasions 10-15 E in sediment
    BIOCHEMICAL

,

    alb. positive
    BIOCHEMICAL

. On

    ECG
    PARACLINICAL

,

    2-mm depression of ST in precordial region
    SYMPTOMS

.

    Heart ultrasound
    PARACLINICAL

:

    low mitral regurgitation angio stage 1
    SYMPTOMS

,

    left ventricle hypertrophy
    SYMPTOMS

.

    Abdomen ultrasound
    PARACLINICAL

:

    both kidneys around 12 cm large
    SYMPTOMS

,

    parapyelic cysts in both kidneys of 2.5 cm in diameter
    SYMPTOMS

.

    Biomicroscopy of both eyes
    PARACLINICAL

:

    cornea verticillata
    SYMPTOMS

.

    Fundus of both eyes
    PARACLINICAL

:

    papillae n. optici with poorly defined edges, but without prominence
    SYMPTOMS

,

    very tortuotic retinal blood vessels
    SYMPTOMS

. In March 2002,

    very low alpha GAL enzyme activity in blood (alpha-Gal A = 0.5 +/- 0.2 nmol of substrate hydrolyzed hourly per serum mL--normal serum enzyme level 8.5-18.9 nmol/mL/h)
    BIOCHEMICAL

. In May 2002,

    enzyme replacement therapy was started with recombinant alpha-Gal A enzyme (Fabrazyme) 1 mg/kg every 14 days
    MEDICATION

.

    Control evaluation and examination
    PARACLINICAL

 showed

    good cardiac and renal function
    SYMPTOMS

. The patient felt better and stronger with

    improved heat tolerance
    SYMPTOMS

.

    Fabry's disease
    DIAGNOSIS

 occurs in all ethnic groups. It is estimated that one in 200 people is a carrier, and one in 40,000-100,000 has the disease. Today in

    Croatia
    ETHNICITY

,

    Fabry's disease
    DIAGNOSIS

 has been diagnosed in only one patient, and according to the usual prevalence there are still 45-100 unrecognized patients. The

    ophthalmologists
    PARACLINICAL

 are in excellent position to diagnose

    Fabry's disease
    DIAGNOSIS

 in early stages. Therefore it is very important that the

    ophthalmologists
    PARACLINICAL

 in

    Croatia
    ETHNICITY

 become aware of the importance of

    ocular findings
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

, so they can participate in the identification of unrecognized patients.

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


IgA nephropathy in two adolescent sisters heterozygous for Fabry disease.

We report a 16-year-old girl and her one-year-younger sister, both heterozygous for the c.34del24 mutation of the GLA (alpha-galactosidase A) gene, which they inherited from their father who is affected by Fabry disease (FD). Both girls presented with macrohematuria and rapidly progressing proteinuria. Urine analysis revealed glomerular hematuria and a nephrotic range of proteinuria suggesting a concomitant glomerulonephritis. Light microscopy of kidney biopsy was characteristic of IgA nephropathy (IgA deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity), whereas electron microscopy showed changes typical of Fabry disease (multiple osmiophilic inclusions in the subendothelial and mesangial areas). These two cases and similar reports in the literature suggest that IgA nephropathy in FD is not merely coincidental.

We report a

    16-year-old
    AGE

    girl
    GENDER

 and

    her
    GENDER

    one-year-younger sister
    AGE

, both

    heterozygous for the c.34del24 mutation of the GLA (alpha-galactosidase A) gene
    GENETICS

    , which they inherited from their father who is affected by Fabry disease (FD)
    FAMILY

. Both

    girls
    GENDER

 presented with

    macrohematuria
    BIOCHEMICAL

 and

    rapidly progressing proteinuria
    BIOCHEMICAL

.

    Urine analysis
    PARACLINICAL

 revealed

    glomerular hematuria
    BIOCHEMICAL

 and a

    nephrotic range of proteinuria
    BIOCHEMICAL

 suggesting a concomitant

    glomerulonephritis
    DIAGNOSIS

.

    Light microscopy of kidney biopsy
    PARACLINICAL

 was characteristic of

    IgA nephropathy
    DIAGNOSIS

 (

    IgA deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity)
    MICROSCOPIC

, whereas

    electron microscopy
    PARACLINICAL

 showed

    changes typical of Fabry disease
    MICROSCOPIC

 (

    multiple osmiophilic inclusions in the subendothelial and mesangial areas)
    MICROSCOPIC

. These two cases and similar reports in the literature suggest that

    IgA nephropathy
    DIAGNOSIS

 in

    FD
    DIAGNOSIS

 is not merely coincidental.

macrohematuria
rapidly progressing proteinuria
glomerular hematuria
nephrotic range of proteinuria

glomerulonephritis
IgA nephropathy
IgA nephropathy
FD


Angiokeratoma of tongue: a series of 14 cases.

Angiokeratomas (AC) are vascular lesions which are defined histologically as one or more dilated blood vessels lying directly subepidermal and showing an epidermal proliferative reaction with ectatic capillaries in the papillary dermis. Only three other cases of isolated mucosal angiokeratoma have been reported in the indexed literature. We reviewed all cases of angiokeratoma located on the tongue, diagnosed in our department during a study period of 10 years (1995-2005). Histologically all 14 cases showed dilated and congested blood vessels in the upper papillary dermis. They lack deep dermal involvement. Hyperkeratosis and acanthosis were also seen in most of the cases. No clinical data was available to assess systemic disease. A higher incidence of of AC in tongue is seen in our study.

    Angiokeratomas (AC)
    DIAGNOSIS

 are

    vascular lesions
    SYMPTOMS

 which are defined histologically as

    one or more dilated blood vessels lying directly subepidermal
    SYMPTOMS

 and showing an

    epidermal proliferative reaction with ectatic capillaries in the papillary dermis
    MICROSCOPIC

. Only three other cases of

    isolated mucosal angiokeratoma
    SYMPTOMS

 have been reported in the indexed literature. We reviewed all cases of

    angiokeratoma located on the tongue
    SYMPTOMS

, diagnosed in our department during a study period of 10 years (1995-2005). Histologically all 14 cases showed

    dilated and congested blood vessels in the upper papillary dermis
    MICROSCOPIC

. They

    lack deep dermal involvement
    NEG_FINDINGS

.

    Hyperkeratosis
    SYMPTOMS

 and

    acanthosis
    SYMPTOMS

 were also seen in most of the cases.

    No clinical data was available to assess systemic disease
    NEG_FINDINGS

. A higher incidence of of

    AC in tongue
    DIAGNOSIS

 is seen in our study.


[Manifestation of Fabry disease in a heterozygous female patient. New perspectives using enzyme replacement therapy].

A 32-year-old woman with bilateral corneal opacities was at 9 years of age diagnosed to have reduced activity of the enzyme alpha-galactosidase A. She was admitted to our hospital because of skin lesions that had developed over the last 8 years.

The clinical features included angiokeratomas on the buttocks, hips, and periumbilical region, whorl-like corneal opacity (cornea verticillata), and mitral valve prolapse. Activity of alpha-galactosidase A was reduced to about a quarter of the normal value. Histological examination revealed lipid deposits within the endothelial cells of the skin. Molecular analysis of the alpha-galactosidase A gene revealed a point mutation at nucleotide-position 691 in exon 5 (p.Asp231Asn).

Enzyme replacement therapy with agalsidase alfa 0.2 mg/kg body-weight, infused over 40 min every other week, was initiated. So far no side effects due to the infusion therapy have been noted. The therapeutic success (reduction of lipid storage) cannot be assessed as yet.

Fabry disease results from deficient activity of the enzyme alpha-galactosidase A. Affected (hemizygous) males often show the complete spectrum of symptoms and signs and have a deficient alpha-galactosidase A activity. Occasionally milder oligosymptomatic courses are observed, when residual enzyme activity is present. In contrast to previous belief, heterozygous females may be affected in the same manner as hemizygotes and may also have a significantly reduced enzyme activity.

A

    32-year-old
    AGE

    woman
    GENDER

 with

    bilateral corneal opacities
    SYMPTOMS

 was

    at 9 years of age
    AGE

 diagnosed to have reduced activity of the enzyme alpha-galactosidase A.

    She
    GENDER

 was admitted to our hospital because of

    skin lesions that had developed over the last 8 years
    SYMPTOMS

.

The clinical features included

    angiokeratomas on the buttocks, hips, and periumbilical region
    SYMPTOMS

,

    whorl-like corneal opacity (cornea verticillata)
    SYMPTOMS

, and

    mitral valve prolapse
    SYMPTOMS

.

    Activity of alpha-galactosidase A was reduced to about a quarter of the normal value
    BIOCHEMICAL

.

    Histological examination
    PARACLINICAL

 revealed

    lipid deposits within the endothelial cells of the skin
    MICROSCOPIC

.

    Molecular analysis of the alpha-galactosidase A gene
    PARACLINICAL

 revealed a point mutation at nucleotide-position 691 in exon 5 (p.Asp231Asn).

    Enzyme replacement therapy with agalsidase alfa 0.2 mg/kg body-weight, infused over 40 min every other week
    MEDICATION

, was initiated. So far

    no side effects due to the infusion therapy
    NEG_FINDINGS

 have been noted. The therapeutic success (

    reduction of lipid storage
    MICROSCOPIC

) cannot be assessed as yet.

    Fabry disease
    DIAGNOSIS

 results from deficient activity of the enzyme alpha-galactosidase A. Affected (

    hemizygous
    GENETICS

)

    males
    GENDER

 often show the

    complete spectrum of symptoms and signs
    SYMPTOMS

 and have a

    deficient alpha-galactosidase A activity
    BIOCHEMICAL

. Occasionally

    milder oligosymptomatic courses
    SYMPTOMS

 are observed, when

    residual enzyme activity is present
    BIOCHEMICAL

. In contrast to previous belief,

    heterozygous
    GENETICS

    females
    GENDER

 may be

    affected in the same manner as hemizygotes
    FAMILY

 and may also have a

    significantly reduced enzyme activity
    BIOCHEMICAL

.


Corneal clouding: An infrequent ophthalmic manifestation of mitochondrial disease.

Corneal clouding is uncommon in infants and children but when present in this age group, it is often associated with mucopolysaccharidoses or Fabry disease. This report describes the case of an 11-year-old male who demonstrated poor weight gain, short stature, segmental myoclonus, and learning problems from 5 years of age followed by general weakness and extremely poor balance. Corneal clouding was evident as a result of a blurred vision complaint at 9 years of age. Both urine metabolic screening for mucopolysaccharidoses and analysis of lysosomal enzymes displayed negative findings. Clinical conditions worsened, including ptosis, progressive weakness, and positive Gowers' sign. Oral glucose lactate stimulation test was positive, therefore a muscle biopsy was performed at 11 years of age. Light microscopy of muscle biopsy disclosed abundant ragged red fibers; electron microscopy revealed abnormal mitochondria in terms of tubular cristae, concentrated cristae, stacking cristae, and round granular patterns of inclusion bodies in the matrix. Thus mitochondrial disease was diagnosed. We conclude that mitochondrial disease should be added to the list of differential diagnosis of corneal clouding in children, especially in cases with normal urine metabolic screening for mucopolysaccharidoses or when assays of lysosomal enzymes appear normal.

    Corneal clouding
    SYMPTOMS

 is uncommon in

    infants
    AGE

 and

    children
    AGE

 but when present in this

    age group
    AGE

, it is often associated with

    mucopolysaccharidoses
    DIAGNOSIS

 or

    Fabry disease
    DIAGNOSIS

. This report describes the case of an

    11-year-old
    AGE

    male
    GENDER

 who demonstrated

    poor weight gain
    SYMPTOMS

,

    short stature
    SYMPTOMS

,

    segmental myoclonus
    SYMPTOMS

, and

    learning problems
    SYMPTOMS

    from 5 years of age
    AGE

 followed by

    general weakness
    SYMPTOMS

 and

    extremely poor balance
    SYMPTOMS

.

    Corneal clouding
    SYMPTOMS

 was evident as a result of a

    blurred vision complaint
    SYMPTOMS

 at

    9 years of age
    AGE

. Both

    urine metabolic screening for mucopolysaccharidoses
    PARACLINICAL

 and

    analysis of lysosomal enzymes displayed negative findings
    NEG_FINDINGS

. Clinical conditions worsened, including

    ptosis
    SYMPTOMS

,

    progressive weakness
    SYMPTOMS

, and

    positive Gowers' sign
    SYMPTOMS

.

    Oral glucose lactate stimulation test was positive
    PARACLINICAL

, therefore a

    muscle biopsy
    PARACLINICAL

 was performed at

    11 years of age
    AGE

.

    Light microscopy of muscle biopsy
    PARACLINICAL

 disclosed

    abundant ragged red fibers
    MICROSCOPIC

;

    electron microscopy
    PARACLINICAL

 revealed

    abnormal mitochondria in terms of tubular cristae, concentrated cristae, stacking cristae, and round granular patterns of inclusion bodies in the matrix
    MICROSCOPIC

. Thus

    mitochondrial disease
    DIAGNOSIS

 was diagnosed. We conclude that

    mitochondrial disease
    DIAGNOSIS

 should be added to the list of

    differential diagnosis
    PARACLINICAL

 of

    corneal clouding
    SYMPTOMS

 in

    children
    AGE

, especially in cases with

    normal urine metabolic screening for mucopolysaccharidoses
    NEG_FINDINGS

 or when

    assays of lysosomal enzymes appear normal
    NEG_FINDINGS

.

Corneal clouding
poor weight gain
short stature
segmental myoclonus
learning problems
general weakness
extremely poor balance
Corneal clouding
blurred vision complaint
ptosis
progressive weakness
positive Gowers' sign
corneal clouding

mucopolysaccharidoses
Fabry disease
mitochondrial disease
mitochondrial disease


The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease.

Anderson-Fabry Disease (AFD) is a storage disease that mimics hypertrophic cardiomyopathy. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance occurs in approximately 50% of patients in the basal inferolateral LV wall, but how an intracellular storage disease causes focal LGE is unknown. We present a whole-heart histological validation that LGE is caused by focal myocardial collagen scarring. This scarring may be the substrate for electrical re-entry and sudden arrhythmic death. The reasons for this distribution of fibrosis are unclear, but may reflect inhomogeneous left ventricular wall stress.

    Anderson-Fabry Disease (AFD)
    DIAGNOSIS

 is a

    storage disease
    DIAGNOSIS

 that mimics

    hypertrophic cardiomyopathy
    DIAGNOSIS

.

    Late gadolinium enhancement (LGE)
    SYMPTOMS

 by

    cardiovascular magnetic resonance
    PARACLINICAL

 occurs in approximately 50% of patients

    in the basal inferolateral LV wall
    SYMPTOMS

, but how an

    intracellular storage disease
    DIAGNOSIS

 causes

    focal LGE
    SYMPTOMS

 is unknown. We present a

    whole-heart histological validation
    PARACLINICAL

 that

    LGE
    SYMPTOMS

 is caused by

    focal myocardial collagen scarring
    SYMPTOMS

. This scarring may be the substrate for

    electrical re-entry
    SYMPTOMS

 and

    sudden arrhythmic death
    SYMPTOMS

. The reasons for this

    distribution of fibrosis
    SYMPTOMS

 are unclear, but may reflect

    inhomogeneous left ventricular wall stress
    SYMPTOMS

.

Anderson-Fabry Disease (AFD)
storage disease
hypertrophic cardiomyopathy
intracellular storage disease


Histologic and electron microscopy findings in myocardium of treated Fabry disease.

The well-described histologic and electron microscopic findings in Fabry disease cardiomyopathy are hypertrophic vacuolated cells with electron dense concentric lamellar bodies. We present altered findings in an endomyocardial biopsy from a patient with treated Fabry disease. A 51-year-old male with Fabry disease, treated with recombinant alpha-galactosidase enzyme replacement therapy for over 18 months, underwent an endomyocardial biopsy for heart failure. The histologic changes showed widespread hypertrophy and vacuolization with rare eosinophilic bodies. Electron microscopy failed to reveal the characteristic globotriaosylceramide concentric lamellar bodies (myelin figures) in the sarcoplasm. Instead, extensive aggregates and single tubular crystalline structures, giant secondary lysosomes as well as abnormal branched chain glycogen were present. This is the first histologic description of long-standing treated Fabry disease in cardiac myocytes.

The well-described histologic and

    electron microscopic
    PARACLINICAL

 findings in

    Fabry disease cardiomyopathy
    DIAGNOSIS

 are

    hypertrophic vacuolated cells with electron dense concentric lamellar bodies
    MICROSCOPIC

. We present altered findings in an

    endomyocardial biopsy
    PARACLINICAL

 from a patient with

    treated Fabry disease
    DIAGNOSIS

. A

    51-year-old
    AGE

    male
    GENDER

 with

    Fabry disease
    DIAGNOSIS

,

    treated with recombinant alpha-galactosidase enzyme replacement therapy for over 18 months
    MEDICATION

, underwent an

    endomyocardial biopsy
    PARACLINICAL

 for

    heart failure
    SYMPTOMS

. The histologic changes showed

    widespread hypertrophy
    SYMPTOMS

 and

    vacuolization with rare eosinophilic bodies
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

    failed to reveal the characteristic globotriaosylceramide concentric lamellar bodies (myelin figures) in the sarcoplasm
    NEG_FINDINGS

. Instead,

    extensive aggregates and single tubular crystalline structures, giant secondary lysosomes as well as abnormal branched chain glycogen were present
    MICROSCOPIC

. This is the first histologic description of

    long-standing treated Fabry disease
    DIAGNOSIS

 in

    cardiac myocytes
    MICROSCOPIC

.

Fabry disease cardiomyopathy
treated Fabry disease
Fabry disease
long-standing treated Fabry disease


Fabry disease and nephrogenic diabetes insipidus.

Fabry disease is a lysosomal storage disorder with kidney involvement. The initial manifestation of kidney disease is often impaired urinary concentrating ability in adolescence or young adulthood. We describe a boy diagnosed prenatally with Fabry disease who presented with polyuria, polydipsia, hypertension, hypokalaemia and proteinuria at 7 years of age. A formal water-deprivation test followed by vasopressin challenge confirmed nephrogenic diabetes insipidus. A renal biopsy revealed findings typical of Fabry disease. Angiotensin converting-enzyme therapy resulted in rapid improvement of symptoms, normalization of blood pressure and resolution of hypokalaemia and proteinuria. This child is the youngest reported Fabry disease patient with documented renal pathology and clinical manifestations of hypertension, proteinuria and nephrogenic diabetes insipidus.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 with

    kidney involvement
    SYMPTOMS

. The initial manifestation of

    kidney disease
    DIAGNOSIS

 is often

    impaired urinary concentrating ability
    SYMPTOMS

 in

    adolescence
    AGE

 or

    young adulthood
    AGE

. We describe a

    boy
    GENDER

 diagnosed

    prenatally
    AGE

 with

    Fabry disease
    DIAGNOSIS

 who presented with

    polyuria
    SYMPTOMS

,

    polydipsia
    BIOCHEMICAL

,

    hypertension
    SYMPTOMS

,

    hypokalaemia
    BIOCHEMICAL

 and

    proteinuria
    BIOCHEMICAL

 at

    7 years of age
    AGE

. A

    formal water-deprivation test
    PARACLINICAL

 followed by

    vasopressin challenge
    PARACLINICAL

 confirmed

    nephrogenic diabetes insipidus
    DIAGNOSIS

. A

    renal biopsy
    PARACLINICAL

 revealed

    findings typical of Fabry disease
    MICROSCOPIC

.

    Angiotensin converting-enzyme therapy
    MEDICATION

 resulted in

    rapid improvement of symptoms
    SYMPTOMS

,

    normalization of blood pressure
    BIOCHEMICAL

 and

    resolution of hypokalaemia and proteinuria
    BIOCHEMICAL

. This

    child
    AGE

 is the youngest reported

    Fabry disease
    DIAGNOSIS

 patient with documented

    renal pathology
    SYMPTOMS

 and clinical manifestations of

    hypertension
    SYMPTOMS

,

    proteinuria
    BIOCHEMICAL

 and

    nephrogenic diabetes insipidus
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
kidney disease
Fabry disease
nephrogenic diabetes insipidus
Fabry disease

kidney involvement
impaired urinary concentrating ability
polyuria
hypertension
rapid improvement of symptoms
renal pathology
hypertension
nephrogenic diabetes insipidus


Angiokeratoma corporis diffusum in a patient with no recognizable enzyme abnormalities.

Angiokeratoma corporis diffusum is a clinical variant of angiokeratoma that is typically associated with an enzyme deficiency in the metabolism of glycoprotein, most notably Fabry disease, resulting in many other systemic manifestations.

We report a case of angiokeratoma corporis diffusum that did not have an identifiable enzyme deficiency. A review of the literature revealed few similar cases.

Angiokeratoma corporis diffusum without recognizable enzyme deficiencies appears to be a distinct clinical entity with a benign course.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 is a clinical variant of

    angiokeratoma
    SYMPTOMS

 that is typically associated with an

    enzyme deficiency in the metabolism of glycoprotein
    BIOCHEMICAL

, most notably

    Fabry disease
    DIAGNOSIS

, resulting in many other

    systemic manifestations
    SYMPTOMS

.

We report a case of

    angiokeratoma corporis diffusum
    SYMPTOMS

 that

    did not have an identifiable enzyme deficiency
    NEG_FINDINGS

. A review of the literature revealed few similar cases.

    Angiokeratoma corporis diffusum
    DIAGNOSIS

    without recognizable enzyme deficiencies
    NEG_FINDINGS

 appears to be a distinct clinical entity with a

    benign
    NEG_FINDINGS

 course.

Angiokeratoma corporis diffusum
angiokeratoma
systemic manifestations
angiokeratoma corporis diffusum

Fabry disease
Angiokeratoma corporis diffusum


Rheumatologic aspects of lysosomal storage diseases.

Lysosomal storage diseases are rare metabolic disorders, some of which can now be treated using enzyme replacement therapies. Because the time point of treatment initiation significantly influences the outcome in Gaucher disease, Fabry disease, and mucopolysaccharidosis type I, early diagnosis is of utmost importance. All three disorders can present with musculoskeletal symptoms in early stages, therefore, the rheumatologist may be the first to be contacted by these patients. Here, we present three characteristic lysosomal storage disease cases to increase awareness in the rheumatological community of the typical symptom constellations associated with these rare but treatable disorders.

    Lysosomal storage diseases
    DIAGNOSIS

 are

    rare metabolic disorders
    DIAGNOSIS

, some of which can now be treated using

    enzyme replacement therapies
    MEDICATION

. Because the time point of treatment initiation significantly influences the outcome in

    Gaucher disease
    DIAGNOSIS

,

    Fabry disease
    DIAGNOSIS

, and

    mucopolysaccharidosis type I
    DIAGNOSIS

, early diagnosis is of utmost importance. All three disorders can present with

    musculoskeletal symptoms
    SYMPTOMS

 in early stages, therefore, the

    rheumatologist
    PARACLINICAL

 may be the first to be contacted by these patients. Here, we present three characteristic

    lysosomal storage disease
    DIAGNOSIS

 cases to increase awareness in the rheumatological community of the typical

    symptom constellations
    SYMPTOMS

 associated with these rare but treatable disorders.

Lysosomal storage diseases
rare metabolic disorders
Gaucher disease
Fabry disease
mucopolysaccharidosis type I
lysosomal storage disease

musculoskeletal symptoms
symptom constellations


Detection of Anderson-Fabry cardiomyopathy with CMR in a patient with chest pain and elevated cardiac biomarkers.

This case illustrates the utility of CMR in evaluating a patient with undiagnosed Anderson-Fabry disease who presented with chest pain, elevated cardiac biomarkers, normal coronary arteries, and an abnormal echocardiogram.

This case illustrates the utility of

    CMR
    PARACLINICAL

 in evaluating a patient with

    undiagnosed Anderson-Fabry disease
    DIAGNOSIS

 who presented with

    chest pain
    SYMPTOMS

,

    elevated cardiac biomarkers
    BIOCHEMICAL

,

    normal coronary arteries
    NEG_FINDINGS

, and an

    abnormal echocardiogram
    SYMPTOMS

.


Manifestations of Fabry disease in placental tissue.

Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-galactosidase A. Manifestations of the disease in placental tissue have been reported only twice. We report for the first time on the biochemical, histological and genetic features of two cases: placenta A derived from a mother heterozygous for Fabry disease who gave birth to a hemizygous son, and placenta B obtained from a healthy mother who carried a heterozygous daughter. Biopsies of placentae A, B and of four healthy controls were taken directly after birth. Assessment of alpha-galactosidase A (alpha-Gal) activity was performed both in fetal leukocytes (derived from umbilical cord blood) and in the biopsy specimens. The tissue was further examined by electron microscopy, immunohistochemistry and biochemical analysis for the presence of storage material (ceramide trihexoside (CTH)). In placenta A, characteristic zebra bodies reflecting accumulated storage material were seen in all biopsies evaluated. CTH values were markedly elevated as compared to the controls and alpha-Gal activity in both fetal leukocytes and placental tissue was very low. Placenta B showed no storage material at all. CTH values were within the control range. alpha-Gal activity ranged from intermediate to near normal; enzyme activity in fetal leukocytes was significantly decreased. As placental tissue is mainly derived from fetal cells, we may conclude that, in a boy suffering from Fabry disease, extensive storage of CTH is already present at birth. As complications develop only around the age of 10 years, it may be not the CTH itself but secondary processes that cause cellular and organ damage.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by deficiency of the lysosomal enzyme alpha-galactosidase A. Manifestations of the disease in

    placental tissue
    MICROSCOPIC

 have been reported only twice. We report for the first time on the biochemical, histological and genetic features of two cases:

    placenta A
    MICROSCOPIC

 derived from a

    mother heterozygous for Fabry disease who gave birth to a hemizygous son
    FAMILY

, and

    placenta B
    MICROSCOPIC

 obtained from a

    healthy mother who carried a heterozygous daughter
    FAMILY

.

    Biopsies of placentae A, B
    PARACLINICAL

 and of four healthy controls were taken directly after birth.

    Assessment of alpha-galactosidase A (alpha-Gal) activity was performed both in fetal leukocytes (derived from umbilical cord blood) and in the biopsy specimens
    PARACLINICAL

. The tissue was further examined by

    electron microscopy
    PARACLINICAL

,

    immunohistochemistry
    PARACLINICAL

 and

    biochemical analysis
    PARACLINICAL

 for the

    presence of storage material (ceramide trihexoside (CTH))
    MICROSCOPIC

. In

    placenta A
    MICROSCOPIC

,

    characteristic zebra bodies reflecting accumulated storage material were seen in all biopsies evaluated
    MICROSCOPIC

.

    CTH values were markedly elevated as compared to the controls
    BIOCHEMICAL

 and

    alpha-Gal activity in both fetal leukocytes and placental tissue was very low
    BIOCHEMICAL

.

    Placenta B showed no storage material at all
    NEG_FINDINGS

.

    CTH values were within the control range
    BIOCHEMICAL

.

    alpha-Gal activity ranged from intermediate to near normal
    BIOCHEMICAL

;

    enzyme activity in fetal leukocytes was significantly decreased
    BIOCHEMICAL

. As

    placental tissue is mainly derived from fetal cells
    MICROSCOPIC

, we may conclude that, in a

    boy
    GENDER

 suffering from

    Fabry disease
    DIAGNOSIS

,

    extensive storage of CTH
    MICROSCOPIC

 is already present at

    birth
    AGE

. As complications develop only

    around the age of 10 years
    AGE

, it may be not the

    CTH
    DIAGNOSIS

 itself but secondary processes that cause

    cellular and organ damage
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
Fabry disease
CTH