Renal transplantation between siblings with unrecognized Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of the lysosomal hydrolase, α-galactosidase A (α-Gal A). We report a case of a renal transplant recipient with unrecognized Fabry disease who received the allograft from a sibling donor with unrecognized Fabry disease. The recipient began to show a gradual increase of the serum creatinine with mild proteinuria at 3 years after transplantation. Histopathologic examination revealed finely vacuolated podocytes, demonstrated by ultrastructural examination to contain osmophilic myelin bodies. Furthermore, the recipient showed reduced circulating levels of α-Gal A and elevated urinary levels of globotriaosylceramide. These findings indicated that both the recipient and the donor suffered from Fabry disease of the renal variant phenotype. Enzyme replacement therapy (ERT) was initiated in the recipient, which resulted in a slight decrease of serum creatinine. Although mild proteinuria persisted, initiation of ERT in the recipient led to improvement of the renal function.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by

    deficiency of the lysosomal hydrolase, α-galactosidase A (α-Gal A)
    BIOCHEMICAL

. We report a case of a

    renal transplant recipient
    MEDICATION

 with

    unrecognized Fabry disease
    DIAGNOSIS

 who

    received the allograft
    MEDICATION

 from a

    sibling donor with unrecognized Fabry disease
    FAMILY

. The recipient began to show a

    gradual increase of the serum creatinine
    BIOCHEMICAL

 with

    mild proteinuria
    BIOCHEMICAL

 at 3 years after

    transplantation
    MEDICATION

.

    Histopathologic examination
    PARACLINICAL

 revealed

    finely vacuolated podocytes,
    MICROSCOPIC

 demonstrated by

    ultrastructural examination
    PARACLINICAL

    to contain osmophilic myelin bodies
    MICROSCOPIC

. Furthermore, the recipient showed

    reduced circulating levels of α-Gal A
    BIOCHEMICAL

 and

    elevated urinary levels of globotriaosylceramide
    BIOCHEMICAL

. These findings indicated that both the recipient and the donor suffered from

    Fabry disease of the renal variant phenotype
    DIAGNOSIS

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 was initiated in the

    recipient
    MEDICATION

, which resulted in a

    slight decrease of serum creatinine
    BIOCHEMICAL

. Although

    mild proteinuria persisted
    BIOCHEMICAL

,

    initiation of ERT
    MEDICATION

 in the recipient led to

    improvement of the renal function
    SYMPTOMS

.

renal transplant recipient
received the allograft
transplantation
Enzyme replacement therapy (ERT)
recipient
initiation of ERT


Screening of male dialysis patients for fabry disease by plasma globotriaosylsphingosine.

Previous reports of Fabry disease screening in dialysis patients indicate that α-galactosidase A activity alone cannot specifically and reliably identify appropriate candidates for genetic testing; a marker for secondary screening is required. Elevated plasma globotriaosylsphingosine is reported to be a hallmark of classic Fabry disease. The purpose of this study was to examine the usefulness of globotriaosylsphingosine as a secondary screening target for Fabry disease.

This study screened 1453 patients, comprising 50% of the male dialysis patients in Niigata Prefecture between July 1, 2010 and July 31, 2011. Screening for Fabry disease was performed by measuring the plasma α-galactosidase A enzyme activity and the globotriaosylsphingosine concentration, by high-performance liquid chromatography. Genetic testing and genetic counseling were provided.

A low level of plasma α-galactosidase A activity (≤4.0 nmol/h per milliliter) was observed in 47 patients (3.2%). Of these, 3 (0.2%) had detectable globotriaosylsphingosine levels. These patients all had α-galactosidase A gene mutations: one was p.Y173X and two were the nonpathogenic p.E66Q. The patient with p.Y173X started enzyme replacement therapy. Subsequent screening of his family identified the same mutation in his elder sister and her children. Genetic testing for 33 of the other 44 patients detected 7 patients with p.E66Q. Thus, the plasma lyso-Gb3 screen identified Fabry disease with high sensitivity (100%) and specificity (94.3%).

Plasma globotriaosylsphingosine is a promising secondary screening target that was effective for selecting candidates for genetic counseling and testing and for uncovering unrecognized Fabry disease cases.

Previous reports of

    Fabry disease screening
    PARACLINICAL

 in

    dialysis
    MEDICATION

 patients indicate that

    α-galactosidase A activity
    BIOCHEMICAL

 alone cannot specifically and reliably identify appropriate candidates for

    genetic testing
    MEDICATION

; a marker for secondary screening is required.

    Elevated plasma globotriaosylsphingosine
    BIOCHEMICAL

 is reported to be a hallmark of classic

    Fabry disease
    DIAGNOSIS

. The purpose of this study was to examine the usefulness of

    globotriaosylsphingosine
    BIOCHEMICAL

 as a secondary screening target for

    Fabry disease
    DIAGNOSIS

.

This study screened 1453 patients, comprising 50% of the

    male
    GENDER

 dialysis patients in

    Niigata Prefecture
    ETHNICITY

 between July 1, 2010 and July 31, 2011. Screening for

    Fabry disease
    DIAGNOSIS

 was performed by

    measuring the plasma α-galactosidase A enzyme activity and the globotriaosylsphingosine concentration
    PARACLINICAL

, by

    high-performance liquid chromatography
    PARACLINICAL

.

    Genetic testing
    MEDICATION

 and

    genetic counseling
    MEDICATION

 were provided.

A

    low level of plasma α-galactosidase A activity (≤4.0 nmol/h per milliliter)
    BIOCHEMICAL

 was observed in 47 patients (3.2%). Of these, 3 (0.2%) had

    detectable globotriaosylsphingosine levels
    BIOCHEMICAL

. These patients all had α-galactosidase A gene mutations: one was p.Y173X and two were the nonpathogenic p.E66Q. The patient with

    p.Y173X
    GENETICS

 started

    enzyme replacement therapy
    MEDICATION

. Subsequent

    screening of his family identified the same mutation in his elder sister and her children
    FAMILY

.

    Genetic testing
    PARACLINICAL

 for 33 of the other 44 patients detected 7 patients with p.E66Q. Thus, the

    plasma lyso-Gb3 screen
    PARACLINICAL

 identified

    Fabry disease
    DIAGNOSIS

 with high sensitivity (100%) and specificity (94.3%).

    Plasma globotriaosylsphingosine
    BIOCHEMICAL

 is a promising secondary screening target that was effective for selecting candidates for

    genetic counseling and testing
    MEDICATION

 and for uncovering unrecognized

    Fabry disease
    DIAGNOSIS

 cases.

dialysis
genetic testing
Genetic testing
genetic counseling
enzyme replacement therapy
genetic counseling and testing

Fabry disease
Fabry disease
Fabry disease
Fabry disease
Fabry disease


The coincidence of IgA nephropathy and Fabry disease.

IgA nephropathy (IgAN) is the most common glomerulonephritis, which may also coexist with other diseases. We present two patients with an unusual coincidence of IgAN and Fabry disease (FD).

A 26 year-old man underwent a renal biopsy in February 2001. Histopathology showed very advanced IgAN and vascular changes as a result of hypertension. Because of his progressive renal insufficiency the patient began hemodialysis in August 2001. By means of the blood spot test screening method the diagnosis of FD was suspected. Low activity of alpha-galactosidase A in the patient's plasma and leukocytes and DNA analysis confirmed the diagnosis of FD. Enzyme replacement therapy started in July 2004. Then the patient underwent kidney transplantation in November 2005. Currently, his actual serum creatinine level is 250 μmol/l. Other organ damages included hypertrophic cardiomyopathy, neuropathic pain and febrile crisis. After enzyme replacement therapy, myocardial hypertrophy has stabilized and other symptoms have disappeared. No further progression of the disease has been noted.The other patient, a 30 year-old woman, suffered from long-term hematuria with a good renal function. Recently, proteinuria (2.6 g/day) appeared and a renal biopsy was performed. Histopathology showed IgAN with remarkably enlarged podocytes. A combination of IgAN and a high suspicion of FD was diagnosed. Electron microscopy revealed dense deposits in paramesangial areas typical for IgAN and podocytes with inclusive zebra bodies and myelin figures characteristic of FD. FD was confirmed by the decreased alpha-galactosidase A activity in plasma and leukocytes and by DNA and RNA analysis. Enzyme replacement therapy and family screening were initiated.

Our results emphasize the role of complexity in the process of diagnostic evaluation of kidney biopsy samples. Electron microscopy represents an integral part of histopathology, and genetic analysis plays a more and more important role in the final diagnosis, which is followed by causal treatment.

    IgA nephropathy (IgAN)
    DIAGNOSIS

 is the most common

    glomerulonephritis
    DIAGNOSIS

, which may also coexist with other diseases. We present two patients with an

    unusual coincidence of IgAN and Fabry disease (FD)
    DIAGNOSIS

.

A

    26 year-old
    AGE

    man
    GENDER

 underwent a

    renal biopsy
    PARACLINICAL

 in February 2001.

    Histopathology
    PARACLINICAL

 showed

    very advanced IgAN
    MICROSCOPIC

 and

    vascular changes
    SYMPTOMS

 as a result of

    hypertension
    SYMPTOMS

. Because of his

    progressive renal insufficiency
    SYMPTOMS

 the patient began

    hemodialysis
    MEDICATION

 in August 2001. By means of the

    blood spot test screening method
    PARACLINICAL

 the diagnosis of

    FD
    DIAGNOSIS

 was suspected.

    Low activity of alpha-galactosidase A in the patient's plasma and leukocytes
    BIOCHEMICAL

 and

    DNA analysis
    PARACLINICAL

 confirmed the diagnosis of

    FD
    DIAGNOSIS

.

    Enzyme replacement therapy
    MEDICATION

 started in July 2004. Then the patient underwent

    kidney transplantation
    MEDICATION

 in November 2005. Currently, his actual serum creatinine level is 250 μmol/l. Other

    organ damages
    SYMPTOMS

 included

    hypertrophic cardiomyopathy
    SYMPTOMS

,

    neuropathic pain
    SYMPTOMS

 and

    febrile crisis
    SYMPTOMS

. After

    enzyme replacement therapy
    MEDICATION

,

    myocardial hypertrophy has stabilized
    SYMPTOMS

 and

    other symptoms have disappeared
    SYMPTOMS

.

    No further progression of the disease has been noted
    NEG_FINDINGS

.The other patient, a

    30 year-old
    AGE

    woman
    GENDER

, suffered from

    long-term hematuria
    SYMPTOMS

 with a

    good renal function
    SYMPTOMS

. Recently,

    proteinuria (2.6 g/day) appeared
    BIOCHEMICAL

 and a

    renal biopsy
    PARACLINICAL

 was performed.

    Histopathology
    PARACLINICAL

 showed

    IgAN
    DIAGNOSIS

 with

    remarkably enlarged podocytes
    MICROSCOPIC

. A

    combination of IgAN
    DIAGNOSIS

 and a high suspicion of

    FD
    DIAGNOSIS

 was diagnosed.

    Electron microscopy
    PARACLINICAL

 revealed

    dense deposits in paramesangial areas typical for IgAN
    MICROSCOPIC

 and

    podocytes with inclusive zebra bodies and myelin figures characteristic of FD
    MICROSCOPIC

.

    FD
    DIAGNOSIS

 was confirmed by the

    decreased alpha-galactosidase A activity in plasma and leukocytes
    BIOCHEMICAL

 and by

    DNA and RNA analysis
    PARACLINICAL

.

    Enzyme replacement therapy
    MEDICATION

 and

    family screening
    PARACLINICAL

 were initiated.

Our results emphasize the role of complexity in the process of

    diagnostic evaluation
    PARACLINICAL

 of

    kidney biopsy samples
    PARACLINICAL

.

    Electron microscopy
    PARACLINICAL

 represents an integral part of

    histopathology
    PARACLINICAL

, and

    genetic analysis
    PARACLINICAL

 plays a more and more important role in the final diagnosis, which is followed by

    causal treatment
    MEDICATION

.

vascular changes
hypertension
progressive renal insufficiency
organ damages
hypertrophic cardiomyopathy
neuropathic pain
febrile crisis
myocardial hypertrophy has stabilized
other symptoms have disappeared
long-term hematuria
good renal function

hemodialysis
Enzyme replacement therapy
kidney transplantation
enzyme replacement therapy
Enzyme replacement therapy
causal treatment


Development of hemangioma in a tongue harboring long-standing angiokeratoma circumscriptum.

Angiokeratoma is a very rare vascular lesion of the papillary dermis. It is characterized by vascular ectasia with overlying epidermal hyperkeratosis. The systemic form of angiokeratoma is associated with Fabry disease and fucosidosis. There are several localized forms. Tongue involvement is uncommon. Hemangiomas are tumors made up of capillaries; they grow by active endothelial proliferation as opposed to expansion of vascular spaces in vascular malformations. Lingual hemangiomas are usually indolent, but they can cause cosmetic deformities, recurrent hemorrhage, and functional problems with speaking, mastication, and deglutition. We report a case of angiokeratoma of the tongue with an underlying hemangioma in a 30-year-old woman. Angiokeratomas have been reported to develop over arteriovenous malformations and in the area of lymphangioma circumscriptum following repeated local trauma. To the best of our knowledge, the development of a lingual hemangioma in a patient with long-standing angiokeratomatous lesions has not been previously reported in the literature.

    Angiokeratoma
    DIAGNOSIS

 is a very rare

    vascular lesion of the papillary dermis
    SYMPTOMS

. It is characterized by

    vascular ectasia
    SYMPTOMS

 with

    overlying epidermal hyperkeratosis
    SYMPTOMS

. The

    systemic
    DIAGNOSIS

 form of

    angiokeratoma
    DIAGNOSIS

 is associated with

    Fabry disease
    DIAGNOSIS

 and

    fucosidosis
    DIAGNOSIS

. There are several localized forms.

    Tongue involvement
    SYMPTOMS

 is uncommon.

    Hemangiomas
    MICROSCOPIC

 are

    tumors made up of capillaries
    MICROSCOPIC

; they grow by

    active endothelial proliferation
    MICROSCOPIC

 as opposed to

    expansion of vascular spaces in vascular malformations
    SYMPTOMS

.

    Lingual hemangiomas
    SYMPTOMS

 are usually

    indolent
    NEG_FINDINGS

, but they can cause

    cosmetic deformities
    SYMPTOMS

,

    recurrent hemorrhage
    SYMPTOMS

, and

    functional problems with speaking, mastication, and deglutition
    SYMPTOMS

. We report a case of

    angiokeratoma of the tongue
    SYMPTOMS

 with an

    underlying hemangioma
    SYMPTOMS

 in a

    30-year-old
    AGE

    woman
    GENDER

.

    Angiokeratomas
    SYMPTOMS

 have been reported to develop over

    arteriovenous malformations
    SYMPTOMS

 and in the area of

    lymphangioma circumscriptum
    DIAGNOSIS

 following

    repeated local trauma
    SYMPTOMS

. To the best of our knowledge, the development of a

    lingual hemangioma
    DIAGNOSIS

 in a patient with

    long-standing angiokeratomatous lesions
    SYMPTOMS

 has not been previously reported in the literature.

Angiokeratoma
systemic
angiokeratoma
Fabry disease
fucosidosis
lymphangioma circumscriptum
lingual hemangioma


Outcome of septal myectomy in patients with Fabry's disease.

Fabry's disease has cardiac manifestations that may mimic hypertrophic cardiomyopathy, including left ventricular outflow tract (LVOT) obstruction. It is important to distinguish hypertrophic cardiomyopathy from Fabry's disease, which can be treated with enzyme replacement therapy (ERT). However, after adequate ERT, some patients have no resolution of cardiac symptoms; thus, septal myectomy might be considered. We present 2 cases of extended septal myectomy in patients with LVOT obstruction secondary to Fabry's disease.

    Fabry's disease
    DIAGNOSIS

 has

    cardiac manifestations
    SYMPTOMS

 that may mimic

    hypertrophic cardiomyopathy
    SYMPTOMS

, including

    left ventricular outflow tract (LVOT) obstruction
    SYMPTOMS

. It is important to distinguish

    hypertrophic cardiomyopathy
    DIAGNOSIS

 from

    Fabry's disease
    DIAGNOSIS

, which can be treated with

    enzyme replacement therapy (ERT)
    MEDICATION

. However, after

    adequate ERT
    MEDICATION

, some patients have

    no resolution of cardiac symptoms
    NEG_FINDINGS

; thus,

    septal myectomy
    MEDICATION

 might be considered. We present 2 cases of

    extended septal myectomy
    MEDICATION

 in patients with

    LVOT obstruction
    SYMPTOMS

 secondary to

    Fabry's disease
    DIAGNOSIS

.

Fabry's disease
hypertrophic cardiomyopathy
Fabry's disease
Fabry's disease

enzyme replacement therapy (ERT)
adequate ERT
septal myectomy
extended septal myectomy


Mutation identification of Fabry disease in families with other lysosomal storage disorders.

Fabry disease (FD) is an X-linked lysosomal storage disorder (LSD) caused by the deficiency of the enzyme α-galactosidase. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated Italian families in whom FD was incidentally diagnosed in two females. In both families, the risk for other lysosomal disorders was known from other members affected by fucosidosis or mucopolysaccharidosis I Hurler/Scheie. Some subjects were simultaneously heterozygous for Fabry and the other lysosomal deficiency. Our study shows that the risk for more than one LSDs can occur in a family pedigree. The diagnosis of Fabry in female probands represents a diagnostic challenge, as symptoms and signs can be variably present because of the random X-chromosome inactivation.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder (LSD)
    DIAGNOSIS

 caused by the

    deficiency of the enzyme α-galactosidase
    BIOCHEMICAL

. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated

    Italian
    ETHNICITY

 families in whom

    FD
    DIAGNOSIS

 was incidentally diagnosed in two

    females
    GENDER

.

    In both families, the risk for other lysosomal disorders was known from other members affected by fucosidosis or mucopolysaccharidosis I Hurler/Scheie
    FAMILY

. Some subjects

    were simultaneously heterozygous for Fabry and the other lysosomal deficiency
    FAMILY

. Our study shows that the risk for more than one

    LSDs
    DIAGNOSIS

 can occur in a family pedigree. The diagnosis of

    Fabry
    DIAGNOSIS

 in

    female
    GENDER

 probands represents a diagnostic challenge, as symptoms and signs can be variably present because of the

    random X-chromosome inactivation
    GENETICS

.

Fabry disease (FD)
lysosomal storage disorder (LSD)
FD
LSDs
Fabry

X-linked
random X-chromosome inactivation


Possible pathogenetic relationship between Fabry disease and renal cell carcinoma.

The occurrence of renal cell carcinoma (RCC) in Fabry disease (FD) is a rare event. We report a deep ultrastructural study of RCC in a patient with a previous histological diagnosis of FD. In order to highlight analogies and differences between the two histological samples, we used the nephrectomy specimen as a 'repeat biopsy', making a dynamic analysis of the evolution of the disease-related kidney damage. Secondly, a comparative ultrastructural analysis between non-neoplastic tissue and cancer demonstrated for the first time the presence of zebra bodies in the tumor cells. Finally, a hypothetical speculation about the relationship between the lysosomal accumulation, the oxidative damage and the genesis of the tumor was performed. The link connected the accumulation of glycosphingolipid globotriaosylceramide, characteristic of FD, with the expression of CD74 and macrophage migration inhibitory factor that may play an important role in tumorigenesis regulated by the Von Hippel-Lindau/hypoxia-inducible factor 1α pathway.

The occurrence of

    renal cell carcinoma (RCC)
    DIAGNOSIS

 in

    Fabry disease (FD)
    DIAGNOSIS

 is a rare event. We report a

    deep ultrastructural study
    PARACLINICAL

 of

    RCC
    DIAGNOSIS

 in a patient with a previous histological diagnosis of

    FD
    DIAGNOSIS

. In order to highlight analogies and differences between the two histological samples, we used the

    nephrectomy specimen
    PARACLINICAL

 as a '

    repeat biopsy'
    PARACLINICAL

, making a dynamic analysis of the evolution of the disease-related kidney

    damage
    SYMPTOMS

. Secondly, a

    comparative ultrastructural analysis between non-neoplastic tissue and cancer
    PARACLINICAL

 demonstrated for the first time the

    presence of zebra bodies in the tumor cells
    MICROSCOPIC

. Finally, a hypothetical speculation about the relationship between the

    lysosomal accumulation
    MICROSCOPIC

, the

    oxidative damage
    MICROSCOPIC

 and the genesis of the tumor was performed. The link connected the

    accumulation of glycosphingolipid globotriaosylceramide
    MICROSCOPIC

, characteristic of

    FD
    DIAGNOSIS

, with the

    expression of CD74
    GENETICS

 and

    macrophage migration inhibitory factor
    BIOCHEMICAL

 that may play an important role in

    tumorigenesis
    SYMPTOMS

 regulated by the

    Von Hippel-Lindau/hypoxia-inducible factor 1α pathway
    GENETICS

.

renal cell carcinoma (RCC)
Fabry disease (FD)
RCC
FD
FD


Alpha-galactosidase A activity levels in Turkish male hemodialysis patients.

Fabry disease is an X-linked lysosomal storage disorder due to deficient activity of alpha-galactosidase A (α-Gal A) leading to renal insufficiency in males. The aim of present study was to investigate the level of α-Gal A activity and to determine the prevalence of Fabry disease in a Turkish male hemodialysis population. The activity of plasma α-Gal A was measured in a group of 808 male hemodialysis patients using fluorimetric methods. Patients with low α-Gal A activity were evaluated clinically and genetic testing was carried out. A correlation with creatinine, uric acid, urea, white blood cell (WBC), and high sensitivity (hs)CRP and α-Gal A activity was also investigated. Plasma α-Gal A activity among this male population undergoing hemodialysis was 7.88 ± 5.18 µM/hour/L (0.40-55.72), significantly lower when compared to controls. No influence of creatinine, uric acid, WBC, or hsCRP on measured α-Gal A activity was reported. Two new Fabry disease patients were identified. Both were previously diagnosed with diabetes mellitus type 2. These findings provide, for the first time, data regarding the prevalence of α-Gal A deficiency (0.24%) in Turkish males receiving hemodialysis.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 due to

    deficient activity of alpha-galactosidase A (α-Gal A)
    BIOCHEMICAL

 leading to

    renal insufficiency
    SYMPTOMS

 in

    males
    GENDER

. The aim of present study was to investigate the

    level of α-Gal A activity
    BIOCHEMICAL

 and to determine the prevalence of

    Fabry disease
    DIAGNOSIS

 in a

    Turkish
    ETHNICITY

    male
    GENDER

    hemodialysis
    MEDICATION

 population. The

    activity of plasma α-Gal A was measured
    BIOCHEMICAL

 in a group of 808

    male
    GENDER

    hemodialysis
    MEDICATION

 patients using

    fluorimetric methods
    PARACLINICAL

. Patients with

    low α-Gal A activity
    BIOCHEMICAL

 were evaluated clinically and

    genetic testing
    PARACLINICAL

 was carried out. A correlation with

    creatinine, uric acid, urea, white blood cell (WBC), and high sensitivity (hs)CRP
    BIOCHEMICAL

 and

    α-Gal A activity
    BIOCHEMICAL

 was also investigated.

    Plasma α-Gal A activity
    BIOCHEMICAL

 among this

    male
    GENDER

 population undergoing

    hemodialysis
    MEDICATION

    was 7.88 ± 5.18 µM/hour/L (0.40-55.72), significantly lower
    BIOCHEMICAL

 when compared to controls.

    No influence of creatinine, uric acid, WBC, or hsCRP
    NEG_FINDINGS

 on

    measured α-Gal A activity
    BIOCHEMICAL

 was reported. Two new

    Fabry disease
    DIAGNOSIS

 patients were identified. Both were previously diagnosed with

    diabetes mellitus type 2
    DIAGNOSIS

. These findings provide, for the first time, data regarding the prevalence of

    α-Gal A deficiency
    BIOCHEMICAL

 (0.24%) in

    Turkish
    ETHNICITY

    males
    GENDER

 receiving

    hemodialysis
    MEDICATION

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease
diabetes mellitus type 2

hemodialysis hemodialysis hemodialysis hemodialysis


Delayed diagnosis of Fabry disease presenting as myocardial ischaemia.

ERRATUM: Hellenic J Cardiol. 2012; 53: 77-79. At the request of the authors, the name of the third author of this Case Report has been changed from Bruno Tuttolomondo to Antonino Tuttolomondo.


No accumulation of globotriaosylceramide in the heart of a patient with the E66Q mutation in the α-galactosidase A gene.

Fabry disease is an X-linked lysosomal disorder resulting from mutations in the α-galactosidase A (GLA) gene. Recent reports described that the E66Q mutation of GLA is not a disease-causing mutation. However, no pathological study was reported. We carried out pathological studies using a cardiac biopsy specimen from a patient with the E66Q mutation.

The case was a 34 year old male patient with end-stage renal failure and cardiomegaly. He was diagnosed with gout at 15 years of age and hemodialysis was started for gouty nephropathy from 31 years of age. He was suspected of having Fabry disease as the result of a screening study for Fabry disease in patients with end-stage renal failure and was referred to our hospital for mutation analysis of the GLA gene. We carried out enzymatic and genetic analysis for GLA and pathological studies of a cardiac biopsy specimen.

The patient had the E66Q mutation in the GLA gene. GLA activity in leukocytes was 36.2% of the average of normal controls. The pathological study of the cardiac biopsy sample showed no characteristic findings of Fabry disease. The immunohistochemistry for GL3 of the cardiac biopsy sample showed no positive cells.

Although the E66Q mutation reduced enzyme activity, the characteristic pathological findings of Fabry disease and the abnormal accumulation of GL3 were not detected in cardiac tissues. The E66Q mutation of the GLA gene is thought to be a functional polymorphism based on enzymatic and pathological studies.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal disorder
    DIAGNOSIS

 resulting from

    mutations in the α-galactosidase A (GLA) gene
    GENETICS

. Recent reports described that the

    E66Q mutation of GLA
    GENETICS

 is not a disease

    -causing mutation
    GENETICS

. However, no

    pathological study
    PARACLINICAL

 was reported. We carried out

    pathological studies
    PARACLINICAL

 using a

    cardiac biopsy specimen
    PARACLINICAL

 from a patient with the

    E66Q mutation
    GENETICS

.

The case was a

    34 year old
    AGE

    male
    GENDER

 patient with

    end-stage renal failure
    SYMPTOMS

 and

    cardiomegaly
    SYMPTOMS

.

    He
    GENDER

 was diagnosed with

    gout
    DIAGNOSIS

 at

    15 years of age
    AGE

 and

    hemodialysis
    MEDICATION

 was started for

    gouty nephropathy
    DIAGNOSIS

    from 31 years of age
    AGE

.

    He
    GENDER

 was suspected of having

    Fabry disease
    DIAGNOSIS

 as the result of a screening study for

    Fabry disease
    DIAGNOSIS

 in patients with

    end-stage renal failure
    DIAGNOSIS

 and was referred to our hospital for

    mutation analysis of the GLA gene
    PARACLINICAL

. We carried out

    enzymatic and genetic analysis for GLA
    PARACLINICAL

 and

    pathological studies of a cardiac biopsy specimen
    PARACLINICAL

.

The patient had

    the E66Q mutation in the GLA gene
    GENETICS

.

    GLA activity in leukocytes was 36.2% of the average of normal controls
    BIOCHEMICAL

. The

    pathological study of the cardiac biopsy sample
    PARACLINICAL

 showed

    no characteristic findings of Fabry disease
    NEG_FINDINGS

. The

    immunohistochemistry for GL3 of the cardiac biopsy sample
    PARACLINICAL

 showed

    no positive cells
    NEG_FINDINGS

.

Although the

    E66Q mutation reduced enzyme activity
    GENETICS

, the

    characteristic pathological findings of Fabry disease
    SYMPTOMS

 and the

    abnormal accumulation of GL3 were not detected in cardiac tissues
    MICROSCOPIC

. The

    E66Q mutation of the GLA gene
    GENETICS

 is thought to be a

    functional polymorphism
    GENETICS

 based on enzymatic and pathological studies.

Fabry disease
lysosomal disorder
gout
gouty nephropathy
Fabry disease
Fabry disease
end-stage renal failure


Fabry disease with atypical neurological presentation: report of a case.

Fabry disease (FD) is a rare, X-linked lysosomal storage disorder with multiorgan involvement. FD is caused by a partial or total deficit of α-galactosidase A enzyme, which is responsible for the accumulation of glycosphingolipids in a variety of cell types. Neurological complications include central nervous system involvement with cerebrovascular disease, peripheral neuropathy, and autonomic dysfunction.

We report the case of a 47-year-old man with an atypical neurological presentation of FD, characterized by 48-hour consciousness alteration with amnesia, resembling a long-lasting episode of transient global amnesia.

Our case expands the neurological presentations associated with FD.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare, X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 with

    multiorgan involvement
    SYMPTOMS

.

    FD
    DIAGNOSIS

 is caused by a

    partial or total deficit of α-galactosidase A enzyme
    BIOCHEMICAL

, which is responsible for the

    accumulation of glycosphingolipids in a variety of cell types
    MICROSCOPIC

.

    Neurological complications
    SYMPTOMS

 include

    central nervous system involvement with cerebrovascular disease
    SYMPTOMS

,

    peripheral neuropathy
    SYMPTOMS

, and

    autonomic dysfunction
    SYMPTOMS

.

We report the case of a

    47-year-old
    AGE

    man
    GENDER

 with an

    atypical neurological presentation of FD
    SYMPTOMS

, characterized by

    48-hour consciousness alteration with amnesia
    SYMPTOMS

, resembling a

    long-lasting episode of transient global amnesia
    SYMPTOMS

.

Our case expands the neurological presentations associated with

    FD
    DIAGNOSIS

.

Fabry disease (FD)
lysosomal storage disorder
FD
FD


A renal variant of Fabry disease: A case with a novel Gal A hemizygote mutation.

Fabry disease is caused by an X-linked recessive inborn error of glycosphingolipid metabolism with deficient activity of a lysosomal enzyme, alpha-galactosidase A (α-GalA).

A 46 year-old man with progressive kidney disease showed on kidney biopsy electron microscopic evidence of Fabry disease. The patient had no systemic manifestations of Fabry disease, despite residual α-GalA activity, therefore genetic testing was done by direct DNA sequencing, demonstrating a new GAL A gene mutation (C174G-exon 3). After three years of enzyme replacement therapy (agalsidase beta) treatment, a second biopsy was done. Although there was demonstrable clearance of intracellular inclusions, remarkable podocyte activation was evident.

This report represents an unusual renal variant of Fabry disease and provides histologic data on long-term follow up after enzyme replacement therapy.

    Fabry disease
    DIAGNOSIS

 is caused by an

    X-linked recessive inborn error of glycosphingolipid metabolism
    GENETICS

 with

    deficient activity of a lysosomal enzyme, alpha-galactosidase A (α-GalA)
    BIOCHEMICAL

.

A

    46 year-old
    AGE

    man
    GENDER

 with

    progressive kidney disease
    DIAGNOSIS

 showed on

    kidney biopsy
    PARACLINICAL

    electron microscopic evidence of Fabry disease
    MICROSCOPIC

. The patient had

    no systemic manifestations of Fabry disease
    NEG_FINDINGS

, despite

    residual α-GalA activity
    BIOCHEMICAL

, therefore

    genetic testing
    PARACLINICAL

 was done by

    direct DNA sequencing
    PARACLINICAL

, demonstrating a

    new GAL A gene mutation (C174G-exon 3)
    GENETICS

. After

    three years of enzyme replacement therapy (agalsidase beta) treatment
    MEDICATION

, a

    second biopsy
    PARACLINICAL

 was done. Although there was

    demonstrable clearance of intracellular inclusions
    NEG_FINDINGS

,

    remarkable podocyte activation
    MICROSCOPIC

 was evident.

This report represents an

    unusual renal variant of Fabry disease
    DIAGNOSIS

 and provides histologic data on long-term follow up after

    enzyme replacement therapy
    MEDICATION

.

Fabry disease
progressive kidney disease
unusual renal variant of Fabry disease


Electrophysiological findings in Fabry cardiomyopathy: mapping the maze of risk stratification.

We report a case of Anderson-Fabry disease in a young man presenting with cardiac hypertrophy and asymptomatic non-sustained ventricular tachycardia. The patient was referred for evaluation of implantable cardioverter/defibrillator therapy. Assessment of left ventricular ejection fraction is considered the gold standard for identifying patients at risk of sudden cardiac death. However, this patient's left ventricular function was preserved. Electrophysiological study did not reveal inducible arrhythmia or cardiac conduction abnormalities. Review of the literature indicates limited knowledge on the electrophysiology of Fabry cardiomyopathy and highlights the need for optimized risk stratification strategies.

We report a case of

    Anderson-Fabry disease
    DIAGNOSIS

 in a

    young
    AGE

    man
    GENDER

 presenting with

    cardiac hypertrophy
    SYMPTOMS

 and

    asymptomatic non-sustained ventricular tachycardia
    NEG_FINDINGS

. The patient was referred for evaluation of

    implantable cardioverter/defibrillator therapy
    MEDICATION

.

    Assessment of left ventricular ejection fraction
    PARACLINICAL

 is considered the gold standard for identifying patients at risk of

    sudden cardiac death
    SYMPTOMS

. However, this patient's

    left ventricular function was preserved
    NEG_FINDINGS

.

    Electrophysiological study
    PARACLINICAL

    did not reveal inducible arrhythmia or cardiac conduction abnormalities
    NEG_FINDINGS

. Review of the literature indicates limited knowledge on the electrophysiology of

    Fabry cardiomyopathy
    DIAGNOSIS

 and highlights the need for optimized risk stratification strategies.

Anderson-Fabry disease
Fabry cardiomyopathy

cardiac hypertrophy
sudden cardiac death


Diagnostic contribution of left ventricular endomyocardial biopsy in patients with clinical phenotype of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy phenotype is shared by heterogeneous entities. The purpose of the study was to evaluate the diagnostic role of left ventricular endomyocardial biopsy. One hundred fifty-one consecutive patients with unexplained left ventricular hypertrophy and normal/elevated QRS voltages or left bundle-branch block underwent left ventricular endomyocardial biopsy because of associated left ventricular dysfunction (37%), presence of sporadic form of left ventricular hypertrophy (32%), or patient desire for a definite diagnosis (31%). Biopsy samples were processed for histology and electron microscopy. Blood samples were collected for histologically oriented gene analysis of major sarcomeric (MYH7, MYBPC3, TNNT2, TPM1) and lysosomal (LAMP2, PRKAG2, α-galactosidase A) proteins. Histology showed changes consistent/compatible with hypertrophic cardiomyopathy in 124 patients: myocardial storage disease in 18 due to Fabry disease in 12 and glycogen-storage disease in 6 and myocardial infiltrative disease in 9 because of amyloidosis in 7 and sarcoidosis in 2. Gene analysis was positive in 67% of patients with hypertrophic cardiomyopathy (MYH7 mutation in 36, MYBP in 29, TNNT2 in 14, and TPM1 in 5) and in 83% of patients with lysosomal storage disease (α-galactosidase A mutation in 12, PRKAG2 in 2, and LAMP2 in 1). In patients with hypertrophic cardiomyopathy phenotype, left ventricular endomyocardial biopsy is safe and may recognize infiltrative/storage diseases in up to 18% of evolving and sporadic cases.

    Hypertrophic cardiomyopathy
    DIAGNOSIS

 phenotype is shared by heterogeneous entities. The purpose of the study was to evaluate the diagnostic role of

    left ventricular endomyocardial biopsy
    PARACLINICAL

. One hundred fifty-one consecutive patients with

    unexplained left ventricular hypertrophy
    SYMPTOMS

 and

    normal/elevated QRS voltages or left bundle-branch block
    NEG_FINDINGS

 underwent

    left ventricular endomyocardial biopsy
    PARACLINICAL

 because of

    associated left ventricular dysfunction
    SYMPTOMS

 (37%), presence of

    sporadic form of left ventricular hypertrophy
    SYMPTOMS

 (32%), or patient desire for a definite diagnosis (31%).

    Biopsy samples were processed for histology and electron microscopy
    PARACLINICAL

.

    Blood samples were collected for histologically oriented gene analysis of major sarcomeric (MYH7, MYBPC3, TNNT2, TPM1) and lysosomal (LAMP2, PRKAG2, α-galactosidase A) proteins
    PARACLINICAL

.

    Histology
    PARACLINICAL

 showed

    changes consistent/compatible with hypertrophic cardiomyopathy
    SYMPTOMS

 in 124 patients:

    myocardial storage disease
    DIAGNOSIS

 in 18 due to

    Fabry disease
    DIAGNOSIS

 in 12 and

    glycogen-storage disease
    DIAGNOSIS

 in 6 and

    myocardial infiltrative disease
    DIAGNOSIS

 in 9 because of

    amyloidosis
    DIAGNOSIS

 in 7 and

    sarcoidosis
    DIAGNOSIS

 in 2.

    Gene analysis
    PARACLINICAL

 was positive in 67% of patients with

    hypertrophic cardiomyopathy
    DIAGNOSIS

 (

    MYH7 mutation
    GENETICS

 in 36,

    MYBP
    GENETICS

 in 29,

    TNNT2
    GENETICS

 in 14, and

    TPM1
    GENETICS

 in 5) and in 83% of patients with

    lysosomal storage disease
    DIAGNOSIS

 (

    α-galactosidase A mutation
    GENETICS

 in 12,

    PRKAG2
    GENETICS

 in 2, and

    LAMP2
    GENETICS

 in 1). In patients with

    hypertrophic cardiomyopathy
    DIAGNOSIS

 phenotype,

    left ventricular endomyocardial biopsy
    PARACLINICAL

 is safe and may recognize

    infiltrative/storage diseases
    DIAGNOSIS

 in up to 18% of evolving and sporadic cases.

Hypertrophic cardiomyopathy
myocardial storage disease
Fabry disease
glycogen-storage disease
myocardial infiltrative disease
amyloidosis
sarcoidosis
hypertrophic cardiomyopathy
lysosomal storage disease
hypertrophic cardiomyopathy
infiltrative/storage diseases


The frequency of Fabry disease with the E66Q variant in the α-galactosidase A gene in Japanese dialysis patients: a case report and a literature review.

Fabry disease (FD) is an Xlinked disorder resulting in a deficiency in α-galactosidase A (α-Gal) activity. FD is one of the causes of progressive renal dysfunction, but its diagnosis is often delayed or missed completely. We herein report the case of a 70-year-old male who had been receiving hemodialysis (HD) for 23 y who was diagnosed with FD after his participation in a screening program for plasma α-Gal activity for 892 HD patients. He had a low plasma α-Gal activity level and was demonstrated to have an E66Q mutation in exon 2 of the α-Gal gene. One of his daughters had the same mutation. The proband died due to aspiration pneumonia before receiving enzyme replacement therapy. We reviewed previous studies and found E66Q mutation in 36% of Japanese FD patients on HD including the present case. The clinical characteristics of E66Q variant are also discussed.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    Xlinked disorder
    GENETICS

 resulting in a

    deficiency in α-galactosidase A (α-Gal) activity
    BIOCHEMICAL

.

    FD
    DIAGNOSIS

 is one of the causes of

    progressive renal dysfunction
    SYMPTOMS

, but its diagnosis is often delayed or missed completely. We herein report the case of a

    70-year-old
    AGE

    male
    GENDER

 who had been

    receiving hemodialysis (HD) for 23 y
    MEDICATION

 who was diagnosed with

    FD
    DIAGNOSIS

 after

    his
    GENDER

 participation in a screening program for

    plasma α-Gal activity
    BIOCHEMICAL

 for 892

    HD
    MEDICATION

 patients.

    He
    GENDER

 had a

    low plasma α-Gal activity level
    BIOCHEMICAL

 and was demonstrated to have an

    E66Q mutation in exon 2 of the α-Gal gene
    GENETICS

.

    One of his daughters had the same mutation
    FAMILY

. The

    proband
    GENDER

    died
    SYMPTOMS

 due to

    aspiration pneumonia
    DIAGNOSIS

 before

    receiving enzyme replacement therapy
    MEDICATION

. We reviewed previous studies and found

    E66Q mutation
    GENETICS

 in 36% of

    Japanese
    ETHNICITY

    FD
    DIAGNOSIS

 patients on

    HD
    MEDICATION

 including the present case. The clinical characteristics of

    E66Q variant
    GENETICS

 are also discussed.

Fabry disease (FD)
FD
FD
aspiration pneumonia
FD

receiving hemodialysis (HD) for 23 y
HD
receiving enzyme replacement therapy
HD


Sometimes when you hear hoof beats, it could be a zebra: consider the diagnosis of Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme α-galactosidase A. Fabry disease is present in 4-5% of men with unexplained left ventricular hypertrophy or cryptogenic stroke. As enzyme replacement therapy is now more widely available, it is important to recognise the signs and symptoms of the disease and establish the diagnosis so that early treatment can be started before irreversible organ damage occurs.

A previously fit and well 32-year-old Caucasian male presented with multisystem dysfunction including renal impairment. Although he had no suggestive symptoms, a diagnosis of Fabry disease was first established on a native renal biopsy. This was confirmed by enzymatic testing and subsequent genetic analysis that revealed a potentially new pathogenic variant.

This case highlights the importance both of Fabry disease as a differential diagnosis in patients with renal impairment in the context of multi-system disease and also of adequate tissue sampling for electron microscopy when performing native renal biopsies.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 that results from a deficiency of the enzyme α-galactosidase A.

    Fabry disease
    DIAGNOSIS

 is present in 4-5% of

    men
    GENDER

 with

    unexplained left ventricular hypertrophy
    SYMPTOMS

 or

    cryptogenic stroke
    SYMPTOMS

. As

    enzyme replacement therapy
    MEDICATION

 is now more widely available, it is important to recognise the signs and symptoms of the disease and establish the diagnosis so that

    early treatment
    MEDICATION

 can be started before

    irreversible organ damage
    SYMPTOMS

 occurs.

A previously fit and well

    32-year-old
    AGE

    Caucasian
    ETHNICITY

    male
    GENDER

 presented with

    multisystem dysfunction
    SYMPTOMS

 including

    renal impairment
    SYMPTOMS

. Although

    he
    GENDER

 had

    no suggestive symptoms
    NEG_FINDINGS

, a diagnosis of

    Fabry disease
    DIAGNOSIS

 was first established on a

    native renal biopsy
    PARACLINICAL

. This was confirmed by

    enzymatic testing
    PARACLINICAL

 and subsequent

    genetic analysis
    PARACLINICAL

 that revealed a

    potentially new pathogenic variant
    GENETICS

.

This case highlights the importance both of

    Fabry disease
    DIAGNOSIS

 as a

    differential diagnosis
    PARACLINICAL

 in patients with

    renal impairment
    SYMPTOMS

 in the context of

    multi-system disease
    DIAGNOSIS

 and also of

    adequate tissue sampling
    PARACLINICAL

 for

    electron microscopy
    PARACLINICAL

 when performing

    native renal biopsies
    PARACLINICAL

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease
Fabry disease
multi-system disease

X-linked
potentially new pathogenic variant

enzyme replacement therapy
early treatment


Fabry disease, do we think enough about this multisystemic disorder? A presentation of three cases in a Serbian family.

Fabry Disease is a rare, X-chromosomal inherited lysosomal storage disease with a consequent intracellular accumulation of neutral glycosphingolipids in various tissues. This can cause skin and ocular lessions, progressive renal, cardiac or cerebrovascular disorders. If a person in a family has Fabry disease, other family members including even extended relatives, may also be at risk.

We presented three cases pointed out various manifestation of Fabry disease, that illustrate a possible cause for otherwise unexplained cardiac hypertrophy and various rhythm and conduction abnormalities.

Although most symptoms begin in childhood, various manifestations often lead to misdiagnosis and clinical diagnosis is frequently delayed for many years, even decades. Enzyme replacement therapy has become available, pointing out the importance of early diagnosis so that treatment can be initiated before irreversible organ damage.

    Fabry Disease
    DIAGNOSIS

 is a

    rare, X-chromosomal inherited
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 with a consequent

    intracellular accumulation of neutral glycosphingolipids in various tissues
    MICROSCOPIC

. This can cause

    skin and ocular lessions
    SYMPTOMS

,

    progressive renal, cardiac or cerebrovascular disorders
    SYMPTOMS

. If a person in a

    family has Fabry disease
    FAMILY

, other family members including even extended relatives, may also be at risk.

We presented three cases pointed out various manifestation of

    Fabry disease
    DIAGNOSIS

, that illustrate a possible cause for

    otherwise unexplained cardiac hypertrophy
    NEG_FINDINGS

 and

    various rhythm and conduction abnormalities
    SYMPTOMS

.

Although most symptoms begin in

    childhood
    AGE

, various manifestations often lead to misdiagnosis and clinical diagnosis is frequently delayed for many years, even decades.

    Enzyme replacement therapy
    MEDICATION

 has become available, pointing out the importance of early diagnosis so that treatment can be initiated before

    irreversible organ damage
    SYMPTOMS

.

Fabry Disease
lysosomal storage disease
Fabry disease


Novel alpha-galactosidase A mutation in a female with recurrent strokes.

Anderson-Fabry disease (AFD) is an X-linked inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The complete genomic and cDNA sequences of the human alpha-galactosidase A gene have been determined and to date, several disease-causing alpha-galactosidase A mutations have been identified, including missense mutations, small deletions/insertions, splice mutations, and large gene rearrangements We report a case of a 56-year-old woman with recurrent cryptogenic strokes. Ophthalmological examination revealed whorled opacities of the cornea (cornea verticillata) and dilated tortuous conjunctival vessels. She did not show other typical signs of Fabry disease such as acroparesthesias and angiokeratoma. The patient's alpha-galactosidase A activity was 4.13 nmol/mL/h in whole blood. Alpha-galactosidase A gene sequence analysis revealed a heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4 in this woman, leading to the p.Tyr184Asn amino acid substitution.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    inborn error of glycosphingolipid catabolism
    DIAGNOSIS

 resulting from the deficient activity of the lysosomal exoglycohydrolase, a-galactosidase A. The

    complete genomic and cDNA sequences of the human alpha-galactosidase A gene
    PARACLINICAL

 have been determined and to date, several

    disease-causing alpha-galactosidase A mutations
    GENETICS

 have been identified, including

    missense mutations, small deletions/insertions, splice mutations
    GENETICS

, and

    large gene rearrangements
    GENETICS

 We report a case of a

    56-year-old
    AGE

    woman
    GENDER

 with

    recurrent cryptogenic strokes
    SYMPTOMS

.

    Ophthalmological examination
    PARACLINICAL

 revealed

    whorled opacities of the cornea (cornea verticillata)
    SYMPTOMS

 and

    dilated tortuous conjunctival vessels
    SYMPTOMS

.

    She
    GENDER

    did not show other typical signs of Fabry disease
    NEG_FINDINGS

 such as

    acroparesthesias
    NEG_FINDINGS

 and

    angiokeratoma
    NEG_FINDINGS

. The patient's

    alpha-galactosidase A activity was 4.13 nmol/mL/h in whole blood
    BIOCHEMICAL

.

    Alpha-galactosidase A gene sequence analysis
    PARACLINICAL

 revealed a

    heterozygous single nucleotide point mutation at nucleotide c.550T>A in exon 4
    GENETICS

 in this

    woman
    GENDER

    , leading to the p.Tyr184Asn amino acid substitution
    GENETICS

.


Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy.

Patients with Fabry disease (FD) develop progressive left ventricular hypertrophy (LVH). In screening studies in patients with LVH, the prevalence of FD ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods. In this study, we aimed to determine the prevalence of FD in an unselected population of everyday clinical practice presenting LVH, defined as a maximal end-diastolic septal or posterior wall thickness ≥ 13 mm, without exclusion of patients with arterial hypertension or valvular pathology, and using optimal screening methods.

In adult males, a two-tier approach was used; α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS) and diagnosis was confirmed by mutation analysis of the GLA gene. In females, mutation analysis was the primary screening tool.

362 men and 178 women were screened. Six patients were diagnosed with a genetic sequence alteration of the GLA gene. One man had a novel mutation, GLA p.Ala5Glu (c.44C>A), presenting as classical FD. Another man and three women had the previously described GLA p.Ala143Thr (c.427G>A) mutation, which generally presents as an attenuated phenotype. One woman had a novel sequence alteration c.639+6A>C, which appeared to be a polymorphism. All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM).

In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. AHT or type of hypertrophy should not be an exclusion criterion for screening for FD.

Patients with

    Fabry disease (FD)
    DIAGNOSIS

 develop

    progressive left ventricular hypertrophy (LVH)
    SYMPTOMS

. In screening studies in patients with

    LVH
    DIAGNOSIS

, the prevalence of

    FD
    DIAGNOSIS

 ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods. In this study, we aimed to determine the prevalence of

    FD
    DIAGNOSIS

 in an unselected population of everyday clinical practice presenting

    LVH
    SYMPTOMS

, defined as a

    maximal end-diastolic septal or posterior wall thickness ≥ 13 mm
    SYMPTOMS

, without exclusion of patients with

    arterial hypertension or valvular pathology
    NEG_FINDINGS

, and using optimal screening methods.

In

    adult
    AGE

    males
    GENDER

, a two-tier approach was used;

    α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS)
    BIOCHEMICAL

 and diagnosis was confirmed by

    mutation analysis of the GLA gene
    PARACLINICAL

. In

    females
    GENDER

,

    mutation analysis
    PARACLINICAL

 was the primary screening tool.

362

    men
    GENDER

 and 178

    women
    GENDER

 were screened. Six patients were diagnosed with a

    genetic sequence alteration of the GLA gene
    GENETICS

. One

    man
    GENDER

 had a

    novel mutation, GLA p.Ala5Glu (c.44C>A)
    GENETICS

, presenting as

    classical FD
    DIAGNOSIS

. Another

    man
    GENDER

 and three

    women
    GENDER

 had the previously described

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

, which generally presents as an attenuated phenotype. One

    woman
    GENDER

 had a

    novel sequence alteration c.639+6A>C, which appeared to be a polymorphism
    GENETICS

. All true

    Fabry
    DIAGNOSIS

 patients had

    arterial hypertension (AHT)
    SYMPTOMS

, and one had

    hypertrophic obstructive cardiomyopathy (HOCM)
    DIAGNOSIS

.

In a group of unselected patients with

    LVH
    DIAGNOSIS

, we found a prevalence of

    Fabry disease
    DIAGNOSIS

 of 0.9%.

    AHT
    SYMPTOMS

 or

    type of hypertrophy
    SYMPTOMS

 should not be an exclusion criterion for screening for

    FD
    DIAGNOSIS

.


Unusual case of subarachnoid haemorrhage in patient with Fabry's disease: case report and literature review.

Fabry's disease is a rare, X linked recessive disease affecting 1 in 40 000 persons. The symptoms result from a lack of or a non-functioning enzyme α galactosidase, which leads to globotriaosylceramide accumulation in the walls of blood vessels. Mortality is generally from cardiac or renal complications and death from subarachnoid haemorrhage is distinctly rare. The authors report a man with Fabry's disease who died after subarachnoid haemorrhage from a progressively enlarging fusiform basilar aneurysm.

    Fabry's disease
    DIAGNOSIS

 is a

    rare, X linked recessive disease
    GENETICS

 affecting 1 in 40 000 persons. The symptoms result from a

    lack of or a non-functioning enzyme α galactosidase
    BIOCHEMICAL

, which leads to

    globotriaosylceramide accumulation in the walls of blood vessels
    MICROSCOPIC

.

    Mortality
    SYMPTOMS

 is generally from

    cardiac or renal complications
    SYMPTOMS

 and

    death
    SYMPTOMS

 from

    subarachnoid haemorrhage
    SYMPTOMS

 is distinctly rare. The authors report a

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 who

    died
    SYMPTOMS

 after

    subarachnoid haemorrhage
    SYMPTOMS

 from a

    progressively enlarging fusiform basilar aneurysm
    SYMPTOMS

.


Pseudoacromegalic facial features in Fabry disease.

Although Fabry disease (FD) is an X-linked lysosomal storage disorder, there is a high prevalence of affected heterozygous females who show symptoms and have an increased mortality associated with the disease. FD usually progresses slowly, and death can result from stroke, heart disease or renal failure. Diagnosis can be delayed in female patients who often present with more subtle features. The classic cutaneous phenotype of 'angiokeratoma corporis diffusum' is less common in female patients. We report the case of a woman with a family history of FD, who showed some of the less well-recognized features of FD, including the typical 'pseudo-acromegalic' facial appearance. She had a deletion at exon 1 of the α-galactosidase (GLA) gene, confirming the diagnosis of FD. As is the case in 30% of women with FD, her plasma and leucocyte α-galactosidase levels were at the lower end of the normal range. At presentation, she already had symptoms and signs of end-organ damage.

Although

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, there is a high prevalence of affected

    heterozygous
    GENETICS

    females
    GENDER

 who show symptoms and have an increased mortality associated with the disease.

    FD
    DIAGNOSIS

 usually progresses slowly, and

    death
    SYMPTOMS

 can result from

    stroke
    SYMPTOMS

,

    heart disease
    SYMPTOMS

 or

    renal failure
    SYMPTOMS

. Diagnosis can be delayed in

    female
    GENDER

 patients who often present with more subtle features. The classic cutaneous phenotype of '

    angiokeratoma corporis diffusum'
    SYMPTOMS

 is less common in

    female
    GENDER

 patients. We report the case of a

    woman
    GENDER

    with a family history of FD
    FAMILY

, who showed

    some of the less well-recognized features of FD
    SYMPTOMS

, including the

    typical 'pseudo-acromegalic' facial appearance
    SYMPTOMS

.

    She
    GENDER

 had a

    deletion at exon 1 of the α-galactosidase (GLA) gene
    GENETICS

, confirming the diagnosis of

    FD
    DIAGNOSIS

. As is the case in 30% of

    women
    GENDER

 with

    FD
    DIAGNOSIS

,

    her
    GENDER

    plasma and leucocyte α-galactosidase levels were at the lower end of the normal range
    BIOCHEMICAL

. At presentation,

    she
    GENDER

 already had

    symptoms and signs of end-organ damage
    SYMPTOMS

.

Fabry disease (FD)
lysosomal storage disorder
FD
FD
FD


A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report.

Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA). This inactivation is responsible for the storage of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. The incidence of disease is estimated at 1:40,000 in the general population, although neonatal screening initiatives have found an unexpectedly high prevalence of genetic alterations, up to 1:3,100, in newborns in Italy, and have identified a surprisingly high frequency of newborn males with genetic alterations (about 1:1,500) in Taiwan.

We describe the case of a 40-year-old female patient who presented with transient ischemic attack (TIA), discomfort in her hands, intolerance to cold and heat, severe angina and palpitations, chronic kidney disease. Clinical, biochemical and molecular studies were performed.

Reported symptoms, peculiar findings in a renal biopsy - the evidence of occasional lamellar inclusions in podocytes and mesangial cells - and left ventricular (LV) hypertrophy, which are considered to be specific features of FD, as well as molecular evaluations, suggested the diagnosis of a classical form of FD.We detected four mutations in the GLA gene of the patient: -10C>T (g.1170C>T), c.370-77_-81del (g.7188-7192del5), c.640-16A>G (g.10115A>G), c.1000-22C>T (g.10956C>T). These mutations, located in promoter and intronic regulatory regions, have been observed in several patients with manifestations of FD. In our patient clinical picture showed a multisystemic involvement with early onset of symptoms, thus suggesting that these intronic mutations can be found even in patients with classical form of FD.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    hereditary metabolic disorder
    GENETICS

 caused by the

    partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA)
    BIOCHEMICAL

. This inactivation is responsible for the

    storage of undegraded glycosphingolipids in the lysosomes
    MICROSCOPIC

 with subsequent

    cellular and microvascular dysfunction
    SYMPTOMS

. The incidence of disease is estimated at 1:40,000 in the general population, although

    neonatal
    AGE

 screening initiatives have found an unexpectedly high prevalence of

    genetic alterations
    GENETICS

, up to 1:3,100, in

    newborns
    AGE

 in

    Italy
    ETHNICITY

, and have identified a surprisingly high frequency of

    newborn
    AGE

    males
    GENDER

 with

    genetic alterations
    GENETICS

 (about 1:1,500) in

    Taiwan
    ETHNICITY

.

We describe the case of a

    40-year-old
    AGE

    female
    GENDER

 patient who presented with

    transient ischemic attack (TIA)
    SYMPTOMS

,

    discomfort in her hands
    SYMPTOMS

,

    intolerance to cold and heat
    SYMPTOMS

,

    severe angina
    SYMPTOMS

 and

    palpitations
    SYMPTOMS

,

    chronic kidney disease
    DIAGNOSIS

.

    Clinical, biochemical and molecular studies
    PARACLINICAL

 were performed.

Reported symptoms,

    peculiar findings in a renal biopsy
    SYMPTOMS

 - the

    evidence of occasional lamellar inclusions in podocytes and mesangial cells -
    MICROSCOPIC

 and

    left ventricular (LV) hypertrophy
    SYMPTOMS

, which are considered to be specific features of

    FD
    DIAGNOSIS

, as well as

    molecular evaluations
    PARACLINICAL

, suggested the diagnosis of a classical form of FD.We detected

    four mutations in the GLA gene
    GENETICS

 of the patient

    : -10C>T (g.1170C>T), c.370-77_-81del (g.7188-7192del5), c.640-16A>G (g.10115A>G), c.1000-22C>T (g.10956C>T)
    GENETICS

. These

    mutations, located in promoter and intronic regulatory regions
    GENETICS

, have been observed in several patients with manifestations of

    FD
    DIAGNOSIS

. In our patient clinical picture showed a

    multisystemic involvement
    SYMPTOMS

 with

    early onset of symptoms
    SYMPTOMS

, thus suggesting that these

    intronic mutations
    GENETICS

 can be found even in patients with classical form of

    FD
    DIAGNOSIS

.

Fabry disease (FD)
chronic kidney disease
FD
FD
FD

cellular and microvascular dysfunction
transient ischemic attack (TIA)
discomfort in her hands
intolerance to cold and heat
severe angina
palpitations
peculiar findings in a renal biopsy
left ventricular (LV) hypertrophy
multisystemic involvement
early onset of symptoms


Cardiac surgery in patients with Fabry's disease: review of literature.

Fabry's disease is a rare but important cause of structural cardiac disease that may influence cardiac surgical decision making. Herein we present a case of mitral valve repair in a patient with Fabry's disease and review the cardiac-related literature on this lysosomal storage disease.

    Fabry's disease
    DIAGNOSIS

 is a rare but important cause of

    structural cardiac disease
    DIAGNOSIS

 that may influence cardiac surgical decision making. Herein we present a case of

    mitral valve repair
    MEDICATION

 in a patient with

    Fabry's disease
    DIAGNOSIS

 and review the cardiac-related literature on this

    lysosomal storage disease
    DIAGNOSIS

.

Fabry's disease
structural cardiac disease
Fabry's disease
lysosomal storage disease


Fabry disease presenting with sudden hearing loss and otosclerosis: a case report.

Fabry disease is an X-linked lysosomal storage disorder resulting in a multiple-system disorder with a wide spectrum of physical signs and symptoms, predominantly affecting the central and peripheral nervous systems, skin, heart, kidneys, and eyes.

We describe the case of a 26-year-old European Caucasian man who had Fabry disease and who presented with episodic sudden unilateral hearing loss and was treated with glucocorticoids, pentoxifylline, hyperbaric oxygen, and fluoride because of concomitant audiometric evidence of otosclerosis. This case demonstrates the partial and transient beneficial effect of standard treatment for sudden hearing loss not related to Fabry disease and analyzes the possible connection between typical Fabry disease inner-ear lesions and otosclerosis. Whereas hearing loss has been described in connection with Fabry disease, otosclerosis-associated hearing loss in Fabry disease has not yet been described.

Although progressive hearing loss in patients with Fabry disease seems to be influenced by replacement therapy, few data concerning treatment of sudden hearing loss are available. The lack of literature concerning the pathogenesis of the otological involvement in Fabry disease makes it impossible to identify a connection between the latter and otosclerosis. Therefore, this report may help to reinforce the importance of a thorough evaluation of hearing in patients with Fabry disease and may be of help with therapeutic decision-making.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting in a

    multiple-system disorder
    DIAGNOSIS

 with a

    wide spectrum of physical signs and symptoms
    SYMPTOMS

,

    predominantly affecting the central and peripheral nervous systems, skin, heart, kidneys, and eyes
    SYMPTOMS

.

We describe the case of a

    26-year-old
    AGE

    European
    ETHNICITY

    Caucasian
    ETHNICITY

    man
    GENDER

 who had

    Fabry disease
    DIAGNOSIS

 and who presented with

    episodic sudden unilateral hearing loss
    SYMPTOMS

 and was treated with

    glucocorticoids, pentoxifylline, hyperbaric oxygen
    MEDICATION

, and

    fluoride
    MEDICATION

 because of concomitant audiometric evidence of

    otosclerosis
    SYMPTOMS

. This case demonstrates the

    partial and transient beneficial effect
    SYMPTOMS

 of standard treatment for

    sudden hearing loss
    SYMPTOMS

    not related to Fabry disease
    NEG_FINDINGS

 and analyzes the possible connection between

    typical Fabry disease inner-ear lesions and otosclerosis
    SYMPTOMS

. Whereas

    hearing loss
    SYMPTOMS

 has been described in connection with

    Fabry disease
    DIAGNOSIS

,

    otosclerosis-associated hearing loss
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 has not yet been described.

Although

    progressive hearing loss
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

 seems to be influenced by

    replacement therapy
    MEDICATION

, few data concerning treatment of

    sudden hearing loss
    SYMPTOMS

 are available. The lack of literature concerning the pathogenesis of the

    otological involvement
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 makes it impossible to identify a connection between the latter and

    otosclerosis
    DIAGNOSIS

. Therefore, this report may help to reinforce the importance of a

    thorough evaluation of hearing
    PARACLINICAL

 in patients with

    Fabry disease
    DIAGNOSIS

 and may be of help with therapeutic decision-making.

Fabry disease
lysosomal storage disorder
multiple-system disorder
Fabry disease
Fabry disease
Fabry disease
Fabry disease
Fabry disease
otosclerosis
Fabry disease


[A case of acroparesthesias, asthenia and fever. A new mutation in Fabry's disease].

Fabry disease is an X-linked hereditary metabolic storage disorder, due to the deficiency in lysosomal alpha-galactosidase A, with the consequent glycosphingolipids accumulation, primarily globotriaosylceramide, at cellular level. Multiorganic involvement occurs progressively, leading to severe manifestations and even premature mortality. We describe a case of a 20 year-old man who was sent to Rheumatology because of inespecific symptoms that lasted for years, namely acroparesthesias and diffuse hand pain and autolimited flares of high fever and general muscular weakness. Despite denying cutaneous findings, a remarkable purplish-red rash of slightly raised angiectases in the lower trunk was present. This rash was diagnosed as angiokeratomas, and blood measurement of alpha-galactosidase A confirmed the suspicion of Fabry disease. He was referred to a rare disease consultation, where the evaluation revealed the presence of other characteristic findings, such as cornea verticilata and cerebral lacunar infarction sequelae. The authors want to remark the importance of physical examination in these cases of inespecific long-lasting symptoms, with no diagnosis and with functional impairment, and the importance of multidisciplinary evaluation and collaboration. We also highlight that this mutation was not as yet described.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked hereditary
    GENETICS

    metabolic storage disorder
    DIAGNOSIS

, due to the

    deficiency in lysosomal alpha-galactosidase A
    BIOCHEMICAL

, with the consequent

    glycosphingolipids accumulation, primarily globotriaosylceramide, at cellular level
    MICROSCOPIC

.

    Multiorganic involvement
    SYMPTOMS

 occurs progressively, leading to

    severe manifestations
    SYMPTOMS

 and even

    premature mortality
    SYMPTOMS

. We describe a case of a

    20 year-old
    AGE

    man
    GENDER

 who was sent to Rheumatology because of

    inespecific symptoms that lasted for years
    SYMPTOMS

, namely

    acroparesthesias
    SYMPTOMS

 and

    diffuse hand pain
    SYMPTOMS

 and

    autolimited flares of high fever
    SYMPTOMS

 and

    general muscular weakness
    SYMPTOMS

.

    Despite denying cutaneous findings
    NEG_FINDINGS

, a

    remarkable purplish-red rash of slightly raised angiectases in the lower trunk
    SYMPTOMS

 was present. This

    rash
    SYMPTOMS

 was diagnosed as

    angiokeratomas
    SYMPTOMS

, and

    blood measurement of alpha-galactosidase A
    PARACLINICAL

 confirmed the suspicion of

    Fabry disease
    DIAGNOSIS

.

    He
    GENDER

 was referred to a

    rare disease consultation
    PARACLINICAL

, where the evaluation revealed the presence of other characteristic findings, such as

    cornea verticilata
    SYMPTOMS

 and

    cerebral lacunar infarction sequelae
    SYMPTOMS

. The authors want to remark the importance of

    physical examination
    PARACLINICAL

 in these cases of

    inespecific long-lasting symptoms
    SYMPTOMS

, with

    no diagnosis
    NEG_FINDINGS

 and with

    functional impairment
    SYMPTOMS

, and the importance of multidisciplinary evaluation and collaboration. We also highlight that this mutation was not as yet described.

Fabry disease
metabolic storage disorder
Fabry disease

Despite denying cutaneous findings
no diagnosis


Successful salvage therapy with Daptomycin for osteomyelitis caused by methicillin-resistant Staphylococcus aureus in a renal transplant recipient with Fabry-Anderson disease.

Daptomycin is licensed in adults for the management of Staphylococcus aureus methicillin-resistant infections, including bone and skin complicated infections. We describe for the first time its use in a renal transplant recipient for Fabry-Anderson Disease with right heel osteomyelitis. The patient was unresponsive to first-line Teicoplanin and second-line Tigecycline, whereas he was successfully treated with third-line Daptomycin monotherapy at 4 mg/Kg/qd for 4 weeks. Local debridement was performed in advance of each line of treatment.

    Daptomycin
    MEDICATION

 is licensed in

    adults
    AGE

 for the management of

    Staphylococcus aureus methicillin-resistant infections
    DIAGNOSIS

, including

    bone and skin complicated infections
    DIAGNOSIS

. We describe for the first time its use in a

    renal transplant recipient
    MEDICATION

 for

    Fabry-Anderson Disease
    DIAGNOSIS

 with

    right heel osteomyelitis
    DIAGNOSIS

. The patient was

    unresponsive to first-line Teicoplanin and second-line Tigecycline
    NEG_FINDINGS

, whereas

    he
    GENDER

 was successfully treated with

    third-line Daptomycin monotherapy at 4 mg/Kg/qd for 4 weeks
    MEDICATION

.

    Local debridement
    MEDICATION

 was performed in

    advance of each line of treatment
    MEDICATION

.


Avascular necrosis of bilateral femoral heads in a patient with Fabry's disease.

The underlying cause of avascular necrosis (AVN) of the femoral head is often not apparent. We report the case of a 26 year old builder with a four month history of bilateral hip pain, and a diagnosis of bilateral femoral head avascular necrosis. Fabry's disease was identified as the probable cause. Since 2001, enzyme replacement therapy for Fabry's disease has become available, with a potential to influence the disease process, and this is of potential importance to clinicians treating AVN.

The underlying cause of

    avascular necrosis (AVN) of the femoral head
    DIAGNOSIS

 is often not apparent. We report the case of a

    26 year old
    AGE

    builder
    GENDER

 with a

    four month history of bilateral hip pain
    SYMPTOMS

, and a diagnosis of

    bilateral femoral head avascular necrosis
    DIAGNOSIS

.

    Fabry's disease
    DIAGNOSIS

 was identified as the probable cause. Since 2001,

    enzyme replacement therapy for Fabry's disease
    MEDICATION

 has become available, with a potential to influence the disease process, and this is of potential importance to clinicians treating

    AVN
    DIAGNOSIS

.


Phenotype and genotype characterization and twin association in patients with Anderson-Fabry cardiomyopathy.

Anderson-Fabry disease (FD), an X-linked recessive lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-Gal A) activity, is associated with cardiac manifestations including arrhythmias, valvular abnormalities, and cardiomyopathy. Early initiation of enzyme replacement therapy (ERT) may have the potential to delay the underlying clinical outcomes in patients with FD. Clinical electrocardiogram (ECG) and echocardiography were used to characterize the cardiomyopathy. Diagnosis of FD was performed by measuring the α-Gal A activity in plasma and mutation analysis by direct sequencing using capillary electrophoresis. We identified four adult hemizygous male patients with cardiomyopathy and other symptoms related to FD; two of them were monozygotic twins. In all cases, ECG and echocardiography showed severe left ventricular (LV) hypertrophy. Some years later, all patients showed typical symptoms of FD, including angiokeratomas and neurological, renal, gastrointestinal, and ocular involvement. A deficiency of α-Gal A activity and point mutations in exon 5 of the GLA gene were detected in all patients. ERT (agalsidase-alfa) was administered every other week as a 0.2 mg/kg intravenous infusion over 40 min. In conclusion, these findings highlight the importance of screening middle-aged patients with LV hypertrophy for the early detection of FD, particularly in direct-line relatives such as twins.

    Anderson-Fabry disease (FD)
    DIAGNOSIS

, an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of α-galactosidase A (α-Gal A) activity
    BIOCHEMICAL

, is associated with

    cardiac manifestations
    SYMPTOMS

 including

    arrhythmias
    SYMPTOMS

,

    valvular abnormalities
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

.

    Early initiation of enzyme replacement therapy (ERT)
    MEDICATION

 may have the potential to delay the underlying clinical outcomes in patients with

    FD
    DIAGNOSIS

.

    Clinical electrocardiogram (ECG)
    PARACLINICAL

 and

    echocardiography
    PARACLINICAL

 were used to characterize the

    cardiomyopathy
    DIAGNOSIS

. Diagnosis of

    FD
    DIAGNOSIS

 was performed by

    measuring the α-Gal A activity in plasma
    BIOCHEMICAL

 and

    mutation analysis by direct sequencing using capillary electrophoresis
    PARACLINICAL

. We identified four

    adult
    AGE

    hemizygous male
    FAMILY

 patients with

    cardiomyopathy
    SYMPTOMS

 and

    other symptoms related to FD
    SYMPTOMS

;

    two of them were monozygotic twins
    FAMILY

. In all cases,

    ECG
    PARACLINICAL

 and

    echocardiography
    PARACLINICAL

 showed

    severe left ventricular (LV) hypertrophy
    SYMPTOMS

. Some years later, all patients showed

    typical symptoms of FD
    SYMPTOMS

, including

    angiokeratomas
    SYMPTOMS

 and

    neurological, renal, gastrointestinal, and ocular involvement
    SYMPTOMS

. A

    deficiency of α-Gal A activity
    BIOCHEMICAL

 and

    point mutations in exon 5 of the GLA gene
    GENETICS

 were detected in all patients.

    ERT (agalsidase-alfa) was administered every other week as a 0.2 mg/kg intravenous infusion over 40 min
    MEDICATION

. In conclusion, these findings highlight the importance of screening

    middle-aged
    AGE

 patients with

    LV hypertrophy
    SYMPTOMS

 for the early detection of

    FD
    DIAGNOSIS

, particularly in

    direct-line relatives such as twins
    FAMILY

.

Anderson-Fabry disease (FD)
lysosomal storage disorder
FD
cardiomyopathy
FD
FD


[Anderson-Fabry disease and renal transplantation].

Anderson-Fabry disease is a rare disease associated with progressive accumulation of globotriaosylceramide in visceral organs and vascular endothelium. The disease primarily affects male patients. It has long been considered that females are asymptomatic carriers of Anderson-Fabry disease. However, recent results demonstrated a significant proportion of symptomatic affected females. We present our experience in the treatment of patients with Anderson-Fabry disease having received allograft from deceased donor, as well as follow-up of patients having received allograft from donor with unrecognized Anderson-Fabry disease.

    Anderson-Fabry disease
    DIAGNOSIS

 is a rare disease associated with

    progressive accumulation of globotriaosylceramide in visceral organs and vascular endothelium
    MICROSCOPIC

. The disease primarily affects

    male
    GENDER

 patients. It has long been considered that

    females
    GENDER

 are

    asymptomatic
    NEG_FINDINGS

 carriers of

    Anderson-Fabry disease
    DIAGNOSIS

. However, recent results demonstrated a significant proportion of symptomatic affected

    females
    GENDER

. We present our experience in the treatment of patients with

    Anderson-Fabry disease
    DIAGNOSIS

 having

    received allograft from deceased donor
    MEDICATION

, as well as follow-up of patients having received

    allograft
    MEDICATION

 from donor with

    unrecognized Anderson-Fabry disease
    DIAGNOSIS

.

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

received allograft from deceased donor
allograft


Fabry disease presenting with multiple hemorrhagic cerebral infarction. A case report.

We describe a 57-year-old woman, a heterozygote for Fabry disease who had multiple hemorrhagic cerebral infarctions. Her clinical course and radiological findings suggested cardiogenic cerebral embolus, but distinction from multiple cerebral infarction associated with Fabry disease seemed necessary. Our present case is reported with reference to the literature to introduce various types of stroke, which can develop in patients with Fabry disease.

We describe a

    57-year-old
    AGE

    woman
    GENDER

, a

    heterozygote for Fabry disease
    GENETICS

 who had

    multiple hemorrhagic cerebral infarctions
    SYMPTOMS

.

    Her
    GENDER

 clinical course and radiological findings suggested

    cardiogenic cerebral embolus
    SYMPTOMS

, but distinction from

    multiple cerebral infarction
    SYMPTOMS

    associated with Fabry disease
    DIAGNOSIS

 seemed necessary. Our present case is reported with reference to the literature to introduce various types of

    stroke
    SYMPTOMS

, which can develop in patients with

    Fabry disease
    DIAGNOSIS

.

associated with Fabry disease
Fabry disease


Mutation analysis of alpha-galactosidase a gene in Hungarian Fabry patients.

AIM was to detect the mutations of alpha-galactosidase A gene in two Hungarian Fabry patients.

Mutation analysis was performed by polymerase chain reaction (PCR) sequencing of the seven exons and adjacent introns of the alpha-galactosidase A gene.

Case 1. (19 y. male patient) Mutation analysis was done for alpha-galactosidase gene, a missence mutation has been identified in the 5th exon, the aspartic acid at codon 266 has been substituted by a tyrosine (notation D266Y) due to a G-T transversion at position 10287 of the alpha GAL-A gene. Case 2. (28 y. male Fabry patient) The GAL-A mutation has been proven to be R220X mutation in exon 5 of the alpha-galactosidase A gene.

AIM was to detect the

    mutations of alpha-galactosidase A gene
    GENETICS

 in two

    Hungarian
    ETHNICITY

    Fabry
    DIAGNOSIS

 patients.

    Mutation analysis
    PARACLINICAL

 was performed by

    polymerase chain reaction (PCR) sequencing of the seven exons and adjacent introns of the alpha-galactosidase A gene
    PARACLINICAL

.

Case 1. (19 y.

    male
    GENDER

 patient)

    Mutation analysis was done for alpha-galactosidase gene
    PARACLINICAL

, a

    missence mutation has been identified in the 5th exon
    GENETICS

,

    the aspartic acid at codon 266 has been substituted by a tyrosine (notation D266Y) due to a G-T transversion at position 10287 of the alpha GAL-A gene
    GENETICS

. Case 2. (28 y.

    male
    GENDER

    Fabry
    DIAGNOSIS

 patient) The

    GAL-A mutation has been proven to be R220X mutation in exon 5 of the alpha-galactosidase A gene
    GENETICS

.


A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, and largely caused by mutations in genes encoding sarcomere proteins. However, GLA mutations causing Fabry disease, an X-linked lysosomal storage disorder, may also present with isolated HCM. As HCM genetic testing panels are increasingly being used clinically, variants of unknown significance (VUS) are encountered, leading to challenges in interpretation. We present an illustrative case: a 10-year-old girl with isolated HCM who, on testing with a HCM multi-gene panel, was found to carry a maternally inherited p.W24R variant in GLA. Attempts to evaluate the significance of this variant, by direct biochemical testing of patient specimens, gave inconclusive results. Subsequent in vitro protein expression studies suggested that the variant is unlikely to be pathogenic. This case highlights diagnostic dilemmas that can be provoked by VUS in general, and specifically raises a question whether GLA sequencing should be included in first-line diagnostic testing for female children with isolated hypertrophic cardiomyopathy.

    Hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 is genetically heterogeneous, and largely caused by

    mutations in genes encoding sarcomere proteins
    GENETICS

. However,

    GLA mutations
    GENETICS

 causing

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, may also present with

    isolated HCM
    DIAGNOSIS

. As

    HCM genetic testing panels
    PARACLINICAL

 are increasingly being used clinically, variants of unknown significance (VUS) are encountered, leading to challenges in interpretation. We present an illustrative case: a

    10-year-old
    AGE

    girl
    GENDER

 with

    isolated HCM
    SYMPTOMS

 who, on testing with a

    HCM multi-gene panel
    PARACLINICAL

, was found to carry a

    maternally inherited p.W24R variant in GLA
    GENETICS

.

    Attempts to
    NEG_FINDINGS

 evaluate the significance of this variant, by

    direct biochemical testing of patient specimens
    PARACLINICAL

    , gave inconclusive results
    NEG_FINDINGS

. Subsequent

    in vitro protein expression studies
    PARACLINICAL

 suggested that the variant

    is unlikely to be pathogenic
    NEG_FINDINGS

. This case highlights diagnostic dilemmas that can be provoked by VUS in general, and specifically raises a question whether

    GLA sequencing
    PARACLINICAL

 should be included in first-line diagnostic testing for

    female
    GENDER

    children
    AGE

 with

    isolated hypertrophic cardiomyopathy
    DIAGNOSIS

.

Hypertrophic cardiomyopathy (HCM)
Fabry disease
lysosomal storage disorder
isolated HCM
isolated hypertrophic cardiomyopathy

Attempts to
, gave inconclusive results
is unlikely to be pathogenic


Fabry disease - importance of screening in cornea verticillata: case report.

Fabry disease is an X-linked disease of glycosphingolipid (GL) metabolism. The accumulation of GL in tissues can affect multiple organ systems. Initial symptoms includes episodes of severe pain in the extremities, cornea verticillata and skin lesions. In late stages, kidney, heart and brain can be involved. This report attempts for importance of cornea verticillata in the diagnosis of Fabry disease in a young patient with pain in the lower limb extremities.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disease of glycosphingolipid (GL) metabolism
    DIAGNOSIS

. The

    accumulation of GL in tissues
    MICROSCOPIC

 can

    affect multiple organ systems
    SYMPTOMS

. Initial symptoms includes

    episodes of severe pain in the extremities
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

 and

    skin lesions
    SYMPTOMS

. In late stages,

    kidney, heart and brain
    SYMPTOMS

 can be involved. This report attempts for importance of

    cornea verticillata
    SYMPTOMS

 in the diagnosis of

    Fabry disease
    DIAGNOSIS

 in a

    young
    AGE

 patient with

    pain in the lower limb extremities
    SYMPTOMS

.


A novel GLA mutation in a Fabry family with glucose-6-phosphate dehydrogenase deficiency.

Fabry disease is an X-linked lysosomal disease caused by mutations of the alpha-galactosidase A (GLA) gene at chromosome subband Xq22.1. To date, more than 600 genetic mutations have been identified to determine the nature and frequency of the molecular lesions causing the classical and milder variant phenotypes and for precise carrier detection. We report here a Fabry family (mother, son and daughter) where the alpha-galactosidase A defect was associated with a glucose-6-phosphate dehydrogenase (G6PD) deficiency. Mutation analysis revealed for the GLA gene the presence of a new mutation, i.e., a small deletion (c.452delA) on exon 3 and for the G6PD gene the presence of 2 mutations, p.V68M (G6PD Asahi, G6PD A+) and p.N126D (G6PD A+) on exon 3 and exon 4, respectively.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal disease
    DIAGNOSIS

 caused by

    mutations of the alpha-galactosidase A (GLA) gene at chromosome subband Xq22.1
    GENETICS

. To date, more than 600 genetic mutations have been identified to determine the nature and frequency of the molecular lesions causing the classical and milder variant phenotypes and for precise carrier detection. We report here a

    Fabry
    DIAGNOSIS

    family (mother, son and daughter)
    FAMILY

 where the

    alpha-galactosidase A defect
    BIOCHEMICAL

 was associated with a

    glucose-6-phosphate dehydrogenase (G6PD) deficiency
    BIOCHEMICAL

.

    Mutation analysis
    PARACLINICAL

 revealed for the

    GLA gene
    GENETICS

 the

    presence of a new mutation, i.e., a small deletion (c.452delA) on exon 3
    GENETICS

 and for the

    G6PD gene
    GENETICS

 the

    presence of 2 mutations, p.V68M (G6PD Asahi, G6PD A+) and p.N126D (G6PD A+) on exon 3 and exon 4, respectively.
    GENETICS


Delayed diagnosis of Fabry disease presenting as myocardial ischaemia.

Cardiovascular complications due to the accumulation of globotriaosylceramide in cardiac cells occur in almost all patients affected by Anderson-Fabry disease. Cardiac manifestations include left ventricular hypertrophy, mitral regurgitation, conduction disturbances and myocardial ischaemia. We report a case of Fabry's disease diagnosed several years after the onset of early cardiac symptoms.

    Cardiovascular complications
    SYMPTOMS

 due to the

    accumulation of globotriaosylceramide in cardiac cells
    MICROSCOPIC

 occur in almost all patients affected by

    Anderson-Fabry disease
    DIAGNOSIS

.

    Cardiac manifestations
    SYMPTOMS

 include

    left ventricular hypertrophy
    SYMPTOMS

,

    mitral regurgitation
    SYMPTOMS

,

    conduction disturbances
    SYMPTOMS

 and

    myocardial ischaemia
    SYMPTOMS

. We report a case of

    Fabry's disease
    DIAGNOSIS

 diagnosed several years after the onset of

    early cardiac symptoms
    SYMPTOMS

.

Cardiovascular complications
Cardiac manifestations
left ventricular hypertrophy
mitral regurgitation
conduction disturbances
myocardial ischaemia
early cardiac symptoms


A novel small insertion mutation, C.1030_1031ins (T) in α-galactosidase A leads to renal variant fabry disease.

Fabry disease is a rare X-linked recessive glycosphingolipid storage disease that is caused by a deficiency of the lysosomal α-galactosidase A (GLA) enzyme, encoded by the GLA gene. This deficiency leads to the accumulation of glycosphingolipids throughout the body, which, in turn, causes multisystem diseases associated with renal, cardiovascular, and cerebrovascular complications. Recent molecular studies of GLA have demonstrated the existence of atypical variants in Fabry disease, suggesting significant genotype-phenotype correlations. In this study, we describe a renal variant of Fabry disease caused by a novel small insertion mutation in the GLA gene.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked recessive
    GENETICS

    glycosphingolipid storage disease
    DIAGNOSIS

 that is caused by a

    deficiency of the lysosomal α-galactosidase A (GLA) enzyme
    BIOCHEMICAL

, encoded by the

    GLA gene
    BIOCHEMICAL

. This

    deficiency
    BIOCHEMICAL

 leads to the

    accumulation of glycosphingolipids throughout the body
    MICROSCOPIC

, which, in turn, causes

    multisystem diseases
    DIAGNOSIS

 associated with

    renal, cardiovascular, and cerebrovascular complications
    SYMPTOMS

. Recent molecular studies of GLA have demonstrated the existence of atypical variants in

    Fabry disease
    DIAGNOSIS

, suggesting significant genotype-phenotype correlations. In this study, we describe a

    renal variant of Fabry disease
    DIAGNOSIS

 caused by a

    novel small insertion mutation in the GLA gene
    GENETICS

.

Fabry disease
glycosphingolipid storage disease
multisystem diseases
Fabry disease
renal variant of Fabry disease


Improved hearing with cochlear implantation in Fabry's disease.

To describe our center's experience with cochlear implantation in patients suffering from Fabry's disease, an inherited mutation resulting in an alpha-galactosidase A enzyme deficiency.

Case report of two patients aged 49 and 59 at implant, with genetically confirmed Fabry's disease and progressive hearing loss.

Surgical implantation of Clarion (Advanced Bionics) and Nucleus Freedom (Cochlear) cochlear implants.

Cochlear implantation improves hearing discrimination by 60 points on the HINT scale. This suggests that cochlear implantation is a safe and effective intervention that improves hearing discrimination in patients suffering from Fabry's disease.

To describe our center's experience with

    cochlear implantation
    MEDICATION

 in patients suffering from

    Fabry's disease
    DIAGNOSIS

, an

    inherited mutation resulting in
    GENETICS

 an

    alpha-galactosidase A enzyme deficiency
    BIOCHEMICAL

.

Case report of two patients

    aged 49 and 59
    AGE

 at

    implant
    MEDICATION

, with genetically confirmed

    Fabry's disease
    DIAGNOSIS

 and

    progressive hearing loss
    SYMPTOMS

.

    Surgical implantation of Clarion (Advanced Bionics) and Nucleus Freedom (Cochlear) cochlear implants
    MEDICATION

.

    Cochlear implantation
    MEDICATION

 improves

    hearing discrimination by 60 points on the HINT scale
    SYMPTOMS

. This suggests that

    cochlear implantation
    MEDICATION

 is a safe and effective intervention that improves

    hearing discrimination
    SYMPTOMS

 in patients suffering from

    Fabry's disease
    DIAGNOSIS

.

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


[Description of a new mutation in a female patient with Fabry disease].

Fabry disease is caused by intracellular accumulation of glycosphingolipids in various tissues, secondary to mutations in the GLA gene (Xq22). Classically described as affecting hemizygous males with no residual alpha-galactosidase A activity, it is now known to affect both sexes, with later and less severe manifestations in females. The manifestations of this disease are systemic: neurological, cutaneous (angiokeratomas), renal, cardiovascular (left ventricular hypertrophy, valve thickening or rhythm disturbances), cochlear-vestibular, and cerebrovascular. In the absence of treatment there is progressive damage to vital organs with renal failure, stroke, heart failure or rhythm perturbations, leading to severe impairment of quality of life as well as reduced life expectancy. We describe the case of a female patient with a history of cryptogenic ischemic stroke at the age of 38 years and chronic renal failure with proteinuria, who presented to the emergency room with atrial fibrillation. The echocardiogram revealed concentric left ventricular hypertrophy, diastolic dysfunction and decreased longitudinal strain in the basal septum. In the context of a screening protocol, she was diagnosed with Fabry disease and a previously undescribed mutation was identified.

    Fabry disease
    DIAGNOSIS

 is caused by

    intracellular accumulation of glycosphingolipids in various tissues
    MICROSCOPIC

, secondary to

    mutations in the GLA gene (Xq22)
    GENETICS

. Classically described as affecting

    hemizygous males
    GENETICS

 with

    no residual alpha-galactosidase A activity
    NEG_FINDINGS

, it is now known to affect both

    sexes
    GENDER

, with later and less severe manifestations in

    females
    GENDER

. The manifestations of this disease are

    systemic: neurological, cutaneous (angiokeratomas), renal, cardiovascular (left ventricular hypertrophy, valve thickening or rhythm disturbances), cochlear-vestibular
    SYMPTOMS

, and

    cerebrovascular
    SYMPTOMS

. In the

    absence of treatment
    NEG_FINDINGS

 there is

    progressive damage to vital organs
    SYMPTOMS

 with

    renal failure
    SYMPTOMS

,

    stroke
    SYMPTOMS

,

    heart failure
    SYMPTOMS

 or

    rhythm perturbations
    SYMPTOMS

, leading to

    severe impairment of quality of life
    SYMPTOMS

 as well as

    reduced life expectancy
    SYMPTOMS

. We describe the case of a

    female
    GENDER

 patient with a history of

    cryptogenic ischemic stroke
    SYMPTOMS

 at the

    age of 38 years
    AGE

 and

    chronic renal failure
    SYMPTOMS

 with

    proteinuria
    BIOCHEMICAL

, who presented to the emergency room with

    atrial fibrillation
    SYMPTOMS

. The

    echocardiogram
    PARACLINICAL

 revealed

    concentric left ventricular hypertrophy
    SYMPTOMS

,

    diastolic dysfunction
    SYMPTOMS

 and

    decreased longitudinal strain in the basal septum
    SYMPTOMS

. In the context of a screening protocol,

    she
    GENDER

 was diagnosed with

    Fabry disease
    DIAGNOSIS

 and a

    previously undescribed mutation
    GENETICS

 was identified.

mutations in the GLA gene (Xq22)
hemizygous males
previously undescribed mutation


Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A, resulting in the accumulation of globotriaosylceramide. Many women experience symptoms, but the understanding of placental and fetal aspects of the disease is limited. We report the pregnancy outcome in and placental pathology of a 37-year-old woman with Fabry disease. She became pregnant 2 years after starting enzyme replacement therapy and continued therapy throughout her pregnancy. At 38 weeks' gestation, she gave birth to a healthy boy with the same maternal Fabry mutation. The present case describes more extensive placental involvement by Fabry disease than has been previously reported. Globotriaosylceramide deposits were found within multiple cell types of the placenta, cord, and membranes. Because of the small numbers of cases described in the literature for comparison, it remains unclear if placental tissues are also targeted by enzyme replacement therapy.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by

    deficiency of α-galactosidase A
    BIOCHEMICAL

, resulting in the

    accumulation of globotriaosylceramide
    MICROSCOPIC

. Many

    women
    GENDER

 experience symptoms, but the understanding of placental and fetal aspects of the disease is limited. We report the pregnancy outcome in and

    placental pathology
    DIAGNOSIS

 of a

    37-year-old
    AGE

    woman
    GENDER

 with

    Fabry disease
    DIAGNOSIS

.

    She
    GENDER

 became

    pregnant
    MEDICATION

 2 years after starting

    enzyme replacement therapy
    MEDICATION

 and

    continued therapy throughout her pregnancy
    MEDICATION

.

    At 38 weeks' gestation
    MEDICATION

,

    she
    GENDER

    gave birth to a healthy boy with the same maternal Fabry mutation
    FAMILY

. The present case describes

    more extensive placental involvement
    SYMPTOMS

 by

    Fabry disease
    DIAGNOSIS

 than has been previously reported.

    Globotriaosylceramide deposits were found within multiple cell types of the placenta, cord, and membranes
    MICROSCOPIC

. Because of the small numbers of cases described in the literature for comparison, it remains unclear if placental tissues are also targeted by

    enzyme replacement therapy
    MEDICATION

.

Fabry disease
lysosomal storage disease
placental pathology
Fabry disease
Fabry disease