Generation of the human induced pluripotent stem cell line (UKWNLi001-A) from skin fibroblasts of a woman with Fabry disease carrying the X-chromosomal heterozygous c.708 G > C (W236C) missense mutation in exon 5 of the alpha-galactosidase-A gene.

Human dermal fibroblasts (HDF) were isolated from the skin punch biopsy of a 25-year-old woman with Fabry disease (FD), carrying a heterozygous c.708 G > C missense mutation in the alpha-galactosidase A gene. HDF were reprogrammed to induced pluripotent stem cells (iPSC) using synthetic mRNA, preventing the alteration of the genome and retaining the original genotype. FD-W236C-iPSC (UKWNLi001-A) showed typical human embryonic stem cell (hESC)-like morphology, expressed all analyzed pluripotency-associated markers, could be differentiated into cells from all three germ layers, and demonstrated a normal female karyotype. We provide a novel patient-specific cell line, allowing further insights into the pathophysiology of FD. Resource table.

    Human dermal fibroblasts (HDF)
    MICROSCOPIC

 were isolated from the

    skin punch biopsy
    PARACLINICAL

 of a

    25-year-old
    AGE

    woman
    GENDER

 with

    Fabry disease (FD)
    DIAGNOSIS

, carrying a

    heterozygous c.708 G > C missense mutation in the alpha-galactosidase A gene
    GENETICS

.

    HDF
    MICROSCOPIC

 were reprogrammed to

    induced pluripotent stem cells (iPSC)
    MICROSCOPIC

 using

    synthetic mRNA
    MEDICATION

, preventing the alteration of the genome and retaining the original genotype. FD-W236C-iPSC (UKWNLi001-A) showed

    typical human embryonic stem cell (hESC)-like morphology
    MICROSCOPIC

,

    expressed all analyzed pluripotency-associated markers
    GENETICS

,

    could be differentiated into cells from all three germ layers
    MICROSCOPIC

, and demonstrated a

    normal female karyotype
    NEG_FINDINGS

. We provide a novel patient-specific cell line, allowing further insights into the pathophysiology of

    FD
    DIAGNOSIS

. Resource table.


An atypical p.N215S variant of Fabry disease with end-stage renal failure.

Fabry disease is an X-linked metabolic disorder resulting in widespread deposition of Globotriaosylceramide within a variety of human tissues. The classical Fabry phenotype is one of early onset disease, with extensive tissue involvement resulting in acroparaesthesia, gastrointestinal disturbances, angiokeratoma, cornea verticillata renal failure, and cardiovascular disease. We describe two brothers exhibiting the GLA p.N215S mutation, a variant most often conferring a late-onset disease confined to the myocardium. The proband was diagnosed aged 34, following investigation into proteinuria. Despite Enzyme Replacement Therapy, he progressed to end-stage renal failure, and subsequently received a renal transplant. He also developed hypertrophic cardiomyopathy. His sibling however, whose disease was detected aged 32 following screening, exhibits mild left ventricular hypertrophy, and no evidence of renal disease. He remains clinically asymptomatic. This case report details a discordant phenotype in brothers with Fabry disease and p.N215S mutation. Despite the fact that in the majority of patients this mutation is associated with a late onset presentation with hypertrophic cardiomyopathy, we have clearly demonstrated that patients with GLA p.N215S mutation can present with the classical phenotype. Further studies are required to elucidate the underlying modifying factors that influence clinical presentation with a more severe phenotype.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    metabolic disorder
    DIAGNOSIS

 resulting in

    widespread deposition of Globotriaosylceramide within a variety of human tissues
    MICROSCOPIC

. The classical

    Fabry
    DIAGNOSIS

 phenotype is one of

    early onset disease
    SYMPTOMS

, with

    extensive tissue involvement
    SYMPTOMS

 resulting in

    acroparaesthesia
    SYMPTOMS

,

    gastrointestinal disturbances
    SYMPTOMS

,

    angiokeratoma
    SYMPTOMS

, cornea verticillata

    renal failure
    SYMPTOMS

, and

    cardiovascular disease
    SYMPTOMS

. We describe two

    brothers
    GENDER

 exhibiting the

    GLA p.N215S mutation
    GENETICS

, a variant most often conferring a

    late-onset disease confined to the myocardium
    SYMPTOMS

. The

    proband
    GENDER

 was diagnosed

    aged 34
    AGE

, following investigation into

    proteinuria
    BIOCHEMICAL

.

    Despite Enzyme Replacement Therapy
    NEG_FINDINGS

,

    he
    GENDER

 progressed to

    end-stage renal failure
    SYMPTOMS

, and subsequently

    received a renal transplant
    MEDICATION

.

    He
    GENDER

 also developed

    hypertrophic cardiomyopathy
    SYMPTOMS

.

    His
    GENDER

    sibling however, whose disease was detected aged 32
    FAMILY

 following

    screening
    FAMILY

, exhibits

    mild left ventricular hypertrophy
    SYMPTOMS

, and

    no evidence of renal disease
    NEG_FINDINGS

.

    He
    GENDER

    remains clinically asymptomatic
    NEG_FINDINGS

. This case report details a

    discordant
    FAMILY

 phenotype in

    brothers with Fabry disease
    FAMILY

 and

    p.N215S mutation
    GENETICS

. Despite the fact that in the majority of patients this mutation is associated with a late onset presentation with

    hypertrophic cardiomyopathy
    SYMPTOMS

, we have clearly demonstrated that patients with

    GLA p.N215S mutation
    GENETICS

 can present with the classical phenotype. Further studies are required to elucidate the underlying modifying factors that influence clinical presentation with a more severe phenotype.

X-linked
GLA p.N215S mutation
p.N215S mutation
GLA p.N215S mutation

Despite Enzyme Replacement Therapy
no evidence of renal disease
remains clinically asymptomatic


A Cardiac Variant of Fabry Disease Diagnosed with Chance Urinary Mulberry Cells.

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A and is classified into two types: classical and variant. The classical type exhibits classic manifestations, but the variant type does not and is therefore difficult to identify sometimes. A 73-year-old woman with a first episode of heart failure was admitted to our hospital. Her left ventricular wall motion was mildly reduced without hypertrophy. Urine sediment revealed mulberry cells, leading to the diagnosis of Fabry disease. In cases without typical clinical findings, urinary mulberry cells may help diagnose Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of α-galactosidase A
    BIOCHEMICAL

 and is classified into two types: classical and variant. The classical type exhibits classic manifestations, but the variant type does not and is therefore difficult to identify sometimes. A

    73-year-old
    AGE

    woman
    GENDER

 with a first episode of

    heart failure
    SYMPTOMS

 was admitted to our hospital.

    Her
    GENDER

    left ventricular wall motion was mildly reduced without hypertrophy
    SYMPTOMS

.

    Urine sediment revealed mulberry cells
    MICROSCOPIC

, leading to the diagnosis of

    Fabry disease
    DIAGNOSIS

. In cases

    without typical clinical findings
    NEG_FINDINGS

,

    urinary mulberry cells
    MICROSCOPIC

 may help diagnose

    Fabry disease
    DIAGNOSIS

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease


Role of Handheld In Vivo Reflectance Confocal Microscopy for the Diagnosis of Fabry Disease: A Case Report.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase that leads to a systemic accumulation of globotriaosylceramide. Handheld in vivo reflectance confocal microscopy (HH-RCM) is a useful modern technique in diagnosis and follow-ups of many skin diseases. This noninvasive device provides high-resolution and high-contrast real-time images to study both the skin and the ocular surface structures that can help clinicians to confirm the diagnosis of FD. HH-RCM could be helpful even for the follow-ups of these patients, enabling us to monitor the effect of enzyme replacement therapy on corneal cells and keratinocytes.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by the

    deficient activity of the lysosomal enzyme &alpha;-galactosidase
    BIOCHEMICAL

 that leads to a

    systemic accumulation of globotriaosylceramide
    MICROSCOPIC

.

    Handheld in vivo reflectance confocal microscopy (HH-RCM)
    PARACLINICAL

 is a useful modern technique in diagnosis and follow-ups of many

    skin diseases
    DIAGNOSIS

. This noninvasive device provides high-resolution and high-contrast real-time images to

    study both the skin and the ocular surface structures
    PARACLINICAL

 that can help clinicians to confirm the diagnosis of

    FD
    DIAGNOSIS

.

    HH-RCM
    PARACLINICAL

 could be helpful even for the follow-ups of these patients, enabling us to monitor the effect of

    enzyme replacement therapy
    MEDICATION

 on corneal cells and keratinocytes.

Fabry disease (FD)
lysosomal storage disorder
skin diseases
FD


Genital angiokeratoma in a woman with Fabry disease: the dermatologist's role.

Fabry disease is a rare lysosomal storage disorder, inherited in an X-linked manner. It is characterized by the deficiency of the enzyme alpha-galactosidase, leading to a buildup of glycosphingolipids in the cells. Angiokeratoma is one of the cutaneous manifestations of this condition, and it helps making the diagnosis. The typical site involves the genital area in men and lumbosacral, buttocks and trunk region in both sexes. We report a case of genital angiokeratoma in a woman with Fabry disease. The diagnosis is through molecular analysis and, when made early, starting treatment reduces the morbidity and mortality of the disease. Thus, the dermatologist has an important role in the identification of angiokeratoma as a cutaneous marker, and the knowledge of its different presentations is essential for the early diagnosis and management of Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a

    rare lysosomal storage disorder
    DIAGNOSIS

,

    inherited in an X-linked manner
    GENETICS

. It is characterized by the

    deficiency of the enzyme alpha-galactosidase
    BIOCHEMICAL

, leading to a

    buildup of glycosphingolipids in the cells
    MICROSCOPIC

.

    Angiokeratoma
    SYMPTOMS

 is one of the cutaneous manifestations of this condition, and it helps making the diagnosis. The typical site

    involves the genital area
    SYMPTOMS

 in

    men
    GENDER

 and

    lumbosacral, buttocks and trunk region
    SYMPTOMS

 in

    both sexes
    GENDER

. We report a case of

    genital angiokeratoma
    SYMPTOMS

 in a

    woman
    GENDER

 with

    Fabry disease
    DIAGNOSIS

. The diagnosis is through

    molecular analysis
    PARACLINICAL

 and, when made early, starting treatment reduces the morbidity and mortality of the disease. Thus, the

    dermatologist
    PARACLINICAL

 has an important role in the identification of

    angiokeratoma
    SYMPTOMS

 as a cutaneous marker, and the knowledge of its different presentations is essential for the early diagnosis and management of

    Fabry disease
    DIAGNOSIS

.

Fabry disease
rare lysosomal storage disorder
Fabry disease
Fabry disease

Angiokeratoma
involves the genital area
lumbosacral, buttocks and trunk region
genital angiokeratoma
angiokeratoma


Diagnostic Clues for the Diagnosis of Nonsarcomeric Hypertrophic Cardiomyopathy (Phenocopies): Amyloidosis, Fabry Disease, and Mitochondrial Disease.

Hypertrophic cardiomyopathy (HCM) is the most common known inherited heart disorder, with a prevalence of 1:500 of the adult population. Etiology of HCM can be heterogeneous, with sarcomeric gene disease as the leading cause in up to 60% of the patients, and with a number of possible different diseases (phenocopies) in about 10%-15% of the patients. Early diagnosis of storage and infiltrative disorders, particularly those with specific treatments (i.e., Fabry disease and/or amyloidosis), means early management and treatment, with a significant impact on patients prognosis. Here, we report on four different cases of HCM, highlighting difficulties to make differential diagnosis of different forms of cardiomyopathies, and their potential impact on the management.

    Hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 is the most common known

    inherited heart disorder
    DIAGNOSIS

, with a prevalence of 1:500 of the adult population. Etiology of

    HCM
    DIAGNOSIS

 can be heterogeneous, with

    sarcomeric gene disease
    DIAGNOSIS

 as the leading cause in up to 60% of the patients, and with a number of possible different diseases (phenocopies) in about 10%-15% of the patients. Early diagnosis of

    storage and infiltrative disorders
    DIAGNOSIS

, particularly those with specific treatments (i.e.,

    Fabry disease
    DIAGNOSIS

 and/or

    amyloidosis
    DIAGNOSIS

), means

    early management and treatment
    MEDICATION

, with a significant impact on patients prognosis. Here, we report on four different cases of

    HCM
    DIAGNOSIS

, highlighting difficulties to make differential diagnosis of different forms of

    cardiomyopathies
    DIAGNOSIS

, and their potential impact on the management.

Hypertrophic cardiomyopathy (HCM)
inherited heart disorder
HCM
sarcomeric gene disease
storage and infiltrative disorders
Fabry disease
amyloidosis
HCM
cardiomyopathies


Galactosidase Alpha p.A143T Variant Fabry Disease May Result in a Phenotype With Multifocal Microvascular Cerebral Involvement at a Young Age.

A 16-year-old male presented with episodic headaches and a brain magnetic resonance imaging (MRI) that showed multifocal punctate to patchy white matter lesions. The diagnosis of Fabry disease (FD) was suggested upon the finding of significantly reduced plasma alpha-galactosidase A activity (0.62 µmol/L or 13% of normal; normal range ≥ 1.65 μmol/L) and genetic investigation confirmed the presence of a hemizygous missense variant in the galactosidase alpha (GLA) gene (p.A143T). Baseline assessment of other systemic involvement showed only a discrete proteinuria.

FD is a rare lysosomal storage disorder. Genetic screening studies have revealed over 600 variants in the GLA gene. The p.A143T variant is a genetic variant of unknown significance, with its associated phenotype ranging from classical FD to healthy unaffected patients. Some authors, however, deem this variant non-pathogenic. We describe the case of a 16-year-old male with multifocal white matter lesions on brain MRI, who was diagnosed with FD and carried this genetic variant.

The causative p.A143T mutation can be associated with a more severe subclinical phenotype than has been reported to date. Furthermore, a diagnosis of FD should be considered when finding asymptomatic cerebral white matter lesions in a young patient.

A

    16-year-old
    AGE

    male
    GENDER

 presented with

    episodic headaches
    SYMPTOMS

 and a

    brain magnetic resonance imaging (MRI)
    PARACLINICAL

 that showed

    multifocal punctate to patchy white matter lesions
    SYMPTOMS

. The diagnosis of

    Fabry disease (FD)
    DIAGNOSIS

 was suggested upon the finding of

    significantly reduced plasma alpha-galactosidase A activity (0.62 µmol/L or 13% of normal; normal range ≥ 1.65 μmol/L)
    BIOCHEMICAL

 and

    genetic investigation
    PARACLINICAL

 confirmed the

    presence of a hemizygous missense variant in the galactosidase alpha (GLA) gene (p.A143T)
    GENETICS

. Baseline assessment of other

    systemic involvement
    SYMPTOMS

 showed only a

    discrete proteinuria
    BIOCHEMICAL

.

    FD
    DIAGNOSIS

 is a

    rare lysosomal storage disorder
    DIAGNOSIS

.

    Genetic screening
    PARACLINICAL

 studies have revealed over 600

    variants in the GLA gene
    GENETICS

. The

    p.A143T variant
    GENETICS

 is a genetic variant of unknown significance, with its associated phenotype ranging from

    classical FD to healthy unaffected patients
    SYMPTOMS

. Some authors, however, deem this variant non-pathogenic. We describe the case of a

    16-year-old
    AGE

    male
    GENDER

 with

    multifocal white matter lesions on brain MRI
    SYMPTOMS

, who was diagnosed with

    FD
    DIAGNOSIS

 and carried this genetic variant.

The

    causative p.A143T mutation
    GENETICS

 can be associated with a more severe subclinical phenotype than has been reported to date. Furthermore, a diagnosis of

    FD
    DIAGNOSIS

 should be considered when finding

    asymptomatic cerebral white matter lesions
    SYMPTOMS

 in a

    young
    AGE

 patient.

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


Hemizygous Fabry disease associated with membranous nephropathy: A rare case report
.

Fabry disease may coexist with various glomerular diseases, including IgA nephropathy, focal segmental glomerulosclerosis, etc. In this study, we report a rare case of Fabry disease associated with membranous nephropathy (MN).

A 30-year-old man with nephrotic proteinuria, normal renal function, and no other extrarenal manifestations underwent a renal biopsy in February 2017. Light microscopy and immunofluorescence indicated MN (stage 1). Under an electron microscope, there were subepithelial electron-dense deposits and abundant zebra bodies in podocytes. Both the findings of low-activity α-galactosidase A (α-Gal A, GLA) and base deletion in exon 7 of the GLA gene (GLA-E07.1286_*7 del, a newly reported mutation) confirmed that this patient was simultaneously afflicted with Fabry disease.

This case report is an important reminder of the role of kidney biopsy, especially electron microscopy, as an indicator of Fabry disease and its rare coexistence with MN.
.

    Fabry disease
    DIAGNOSIS

 may coexist with various

    glomerular diseases
    DIAGNOSIS

, including

    IgA nephropathy
    DIAGNOSIS

,

    focal segmental glomerulosclerosis
    DIAGNOSIS

, etc. In this study, we report a rare case of

    Fabry disease associated with membranous nephropathy (MN)
    DIAGNOSIS

.

A

    30-year-old
    AGE

    man
    GENDER

 with

    nephrotic proteinuria
    BIOCHEMICAL

,

    normal renal function
    NEG_FINDINGS

, and

    no other extrarenal manifestations
    NEG_FINDINGS

 underwent a

    renal biopsy
    PARACLINICAL

 in February 2017.

    Light microscopy
    PARACLINICAL

 and

    immunofluorescence
    PARACLINICAL

 indicated

    MN (stage 1)
    DIAGNOSIS

. Under an

    electron microscope
    PARACLINICAL

, there were

    subepithelial electron-dense deposits and abundant zebra bodies in podocytes
    MICROSCOPIC

. Both the findings of

    low-activity α-galactosidase A (α-Gal A, GLA)
    BIOCHEMICAL

 and

    base deletion in exon 7 of the GLA gene (GLA-E07.1286_*7 del, a newly reported mutation)
    GENETICS

 confirmed that this patient was simultaneously afflicted with

    Fabry disease
    DIAGNOSIS

.

This case report is an important reminder of the role of

    kidney biopsy
    PARACLINICAL

, especially

    electron microscopy
    PARACLINICAL

, as an indicator of

    Fabry disease
    DIAGNOSIS

 and its

    rare coexistence with MN
    DIAGNOSIS

.
.

normal renal function
no other extrarenal manifestations


Time of Anderson-Fabry Disease Detection and Cardiovascular Presentation.

Anderson-Fabry disease is an X-linked inherited disease, which manifests in a different manner depending on gender and genotype. Making a working diagnosis of Anderson-Fabry disease is difficult because of several reasons: (a) that it is a multiorgan disease with wide variety of phenotypes, (b) different timelines of presentation, (c) gender differences, and (d) possible coexistence with other comorbidities. Late-onset/cardiac type of presentation with minimal involvement of other organs can additionally make diagnosis difficult.

To describe different cardiac manifestations at different time points in the course of the disease: (1) 72-year-old female (echocardiography detection), heterozygote, significant left and mild right ventricular hypertrophy; (2) 62-year-old male (echocardiography detection), hemizygote, left ventricular hypertrophy, implanted cardiac pacemaker, a performed percutaneous coronary intervention after myocardial infarction, degenerative medium degree aortic valve stenosis; (3) 45-year-old female (asymptomatic/family screening), heterozygote, thickened mitral papillary muscle, mild left ventricular hypertrophy, first degree diastolic dysfunction; and (4) 75-year-old female (symptomatic/family screening), heterozygote, cardiomyopathy with reduced left ventricular ejection fraction after heart surgery (mitral valve annuloplasty and plastic repair of the tricuspid valve).

All patients have Anderson-Fabry disease but with different clinical presentations depending on the gender, the type of mutation, and the time of detection. All these features can make the patients' profiles unique and delay the time of detection.

    Anderson-Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited disease
    GENETICS

, which manifests in a different manner depending on gender and genotype. Making a working diagnosis of

    Anderson-Fabry disease
    DIAGNOSIS

 is difficult because of several reasons: (a) that it is a

    multiorgan disease
    DIAGNOSIS

 with wide variety of phenotypes, (b) different timelines of presentation, (c) gender differences, and (d) possible coexistence with other comorbidities.

    Late-onset/cardiac type of presentation
    SYMPTOMS

 with

    minimal involvement of other organs
    SYMPTOMS

 can additionally make diagnosis difficult.

To describe different

    cardiac manifestations
    SYMPTOMS

 at different time points in the course of the disease: (1)

    72-year-old
    AGE

    female
    GENDER

 (

    echocardiography detection
    PARACLINICAL

),

    heterozygote
    GENETICS

,

    significant left and mild right ventricular hypertrophy
    SYMPTOMS

; (2)

    62-year-old
    AGE

    male
    GENDER

 (

    echocardiography detection
    PARACLINICAL

),

    hemizygote
    GENETICS

,

    left ventricular hypertrophy
    SYMPTOMS

,

    implanted cardiac pacemaker
    MEDICATION

, a

    performed percutaneous coronary intervention
    MEDICATION

 after

    myocardial infarction
    SYMPTOMS

,

    degenerative medium degree aortic valve stenosis
    SYMPTOMS

; (3)

    45-year-old
    AGE

    female
    GENDER

 (

    asymptomatic
    NEG_FINDINGS

/

    family screening
    PARACLINICAL

),

    heterozygote
    GENETICS

,

    thickened mitral papillary muscle
    SYMPTOMS

,

    mild left ventricular hypertrophy
    SYMPTOMS

,

    first degree diastolic dysfunction
    SYMPTOMS

; and (4)

    75-year-old
    AGE

    female
    GENDER

 (

    symptomatic
    SYMPTOMS

/

    family screening
    PARACLINICAL

),

    heterozygote
    GENETICS

,

    cardiomyopathy with reduced left ventricular ejection fraction
    SYMPTOMS

 after

    heart surgery (mitral valve annuloplasty and plastic repair of the tricuspid valve)
    MEDICATION

.

All patients have

    Anderson-Fabry disease
    DIAGNOSIS

 but with different clinical presentations depending on the gender, the type of mutation, and the time of detection. All these features can make the patients' profiles unique and delay the time of detection.

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

X-linked inherited disease
heterozygote
hemizygote
heterozygote
heterozygote


[Fabry disease: about an uncommon case].

We here report the case of a 60-year old patient with congestive heart failure due to Fabry disease-related cardiopathy. This study has offered the opportunity to perform a literature review on cardiopathy related to this disease as well as to highlight the features of cardiac manifestation in Fabry disease.

We here report the case of a

    60-year old
    AGE

 patient with

    congestive heart failure
    SYMPTOMS

 due to

    Fabry disease-related cardiopathy
    DIAGNOSIS

. This study has offered the opportunity to perform a literature review on

    cardiopathy
    DIAGNOSIS

 related to this disease as well as to highlight the features of

    cardiac manifestation
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

.

congestive heart failure
cardiac manifestation

Fabry disease-related cardiopathy
cardiopathy
Fabry disease


Case report: lipid inclusion in glomerular endothelial and mesangial cells in a patient after contrast medium injection.

It is well-recognized that injection of iodinated radiographic contrast media (CM) sometimes causes acute renal injury via multiple mechanisms, such as vasoconstriction, toxicity on glomerular endothelium and tubular epithelium and so forth.

A 51-year-old man developed acute renal injury with proteinuria after CM administration. To our surprise, in his renal biopsy sample the myelin figure like structure was observed in glomerular endothelium and mesangial cells by transmission electron microscopy. However the patient didn't has any clinic clues of Fabry disease and other lysosomal storage disorders. Moreover in vitro cultured glomerular endothelial and mesangial cells we found CM triggers lipid aggregation along with the increased CD36 and decreased ABCA1 abundance. Thus this patient was administrated statin to correct the aberrant lipid trafficking, 2 months later at his next visit we found his renal function partially recovered with reduced proteinuria.

Besides the well-known underlying mechanisms, CM may cause renal impairment by triggering the dysregulated transportation of lipid. Furthermore statin is suggested to be a very promising medicine to decrease side effects of CM.

It is well-recognized that

    injection of iodinated radiographic contrast media (CM)
    PARACLINICAL

 sometimes causes

    acute renal injury
    SYMPTOMS

 via

    multiple mechanisms
    SYMPTOMS

, such as

    vasoconstriction
    SYMPTOMS

,

    toxicity on glomerular endothelium and tubular epithelium
    SYMPTOMS

 and so forth.

A

    51-year-old
    AGE

    man
    GENDER

 developed

    acute renal injury
    SYMPTOMS

 with

    proteinuria
    BIOCHEMICAL

 after

    CM administration
    MEDICATION

. To our surprise, in his

    renal biopsy sample
    PARACLINICAL

    the myelin figure like structure was observed in glomerular endothelium and mesangial cells
    MICROSCOPIC

 by

    transmission electron microscopy
    PARACLINICAL

. However the patient

    didn't has any clinic clues of Fabry disease and other lysosomal storage disorders
    NEG_FINDINGS

. Moreover

    in vitro cultured glomerular endothelial and mesangial cells we found CM triggers lipid aggregation along with the increased CD36 and decreased ABCA1 abundance
    MICROSCOPIC

. Thus this patient was administrated

    statin
    MEDICATION

 to correct the

    aberrant lipid trafficking
    MICROSCOPIC

, 2 months later at his next visit we found his

    renal function partially recovered
    SYMPTOMS

 with

    reduced proteinuria
    BIOCHEMICAL

.

Besides the well-known underlying mechanisms,

    CM
    DIAGNOSIS

 may cause

    renal impairment
    SYMPTOMS

 by triggering the

    dysregulated transportation of lipid
    BIOCHEMICAL

. Furthermore

    statin
    MEDICATION

 is suggested to be a very promising medicine to

    decrease side effects of CM
    SYMPTOMS

.

proteinuria
reduced proteinuria
dysregulated transportation of lipid


Mulberries in the urine: a tell-tale sign of Fabry disease.

Fabry disease is a treatable progressive illness of inborn error causing eventual multiple organ dysfunction in advanced untreated cases. We report on a classic Fabry child patient presenting with urinary mulberry cells and bodies without renal involvement. This report emphasizes the usefulness of urinary microscopic findings in the early diagnosis of Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a

    treatable progressive illness of inborn error
    DIAGNOSIS

 causing

    eventual multiple organ dysfunction
    SYMPTOMS

 in advanced untreated cases. We report on a classic

    Fabry
    DIAGNOSIS

    child
    AGE

 patient presenting with

    urinary mulberry cells and bodies
    MICROSCOPIC

    without renal involvement
    NEG_FINDINGS

. This report emphasizes the usefulness of

    urinary microscopic findings
    PARACLINICAL

 in the early diagnosis of

    Fabry disease
    DIAGNOSIS

.


Chloroquine-induced cardiomyopathy: a reversible cause of heart failure.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are anti-rheumatic medications frequently used in the treatment of connective tissue disorders. We present the case of a 45-year-old woman with CQ-induced cardiomyopathy leading to severe heart failure. Electrocardiographic abnormalities included bifascicular block, while structural disease consisted of severe biventricular and biatrial hypertrophy. Appropriate diagnosis via endomyocardial biopsy led to cessation of CQ and subsequent dramatic improvement in symptoms and structural heart disease. Cardiac toxicity is an under-recognized adverse effect of CQ/HCQ leading to cardiomyopathy with concentric hypertrophy and conduction abnormalities, with the potential for significant morbidity and mortality. Predisposing factors for CQ/HCQ-induced cardiomyopathy have been proposed. CQ/HCQ cardiomyopathy is a phenocopy of Fabry disease, and α-galactosidase A polymorphism may account for some heterogeneity of disease presentation.

    Chloroquine (CQ)
    MEDICATION

 and

    hydroxychloroquine (HCQ)
    MEDICATION

 are

    anti-rheumatic medications
    MEDICATION

 frequently used in the treatment of

    connective tissue disorders
    DIAGNOSIS

. We present the case of a

    45-year-old
    AGE

    woman
    GENDER

 with

    CQ-induced cardiomyopathy
    DIAGNOSIS

 leading to

    severe heart failure
    SYMPTOMS

.

    Electrocardiographic abnormalities
    SYMPTOMS

 included

    bifascicular block
    SYMPTOMS

, while structural disease consisted of

    severe biventricular and biatrial hypertrophy
    SYMPTOMS

. Appropriate diagnosis via

    endomyocardial biopsy
    PARACLINICAL

 led to

    cessation of CQ
    MEDICATION

 and subsequent

    dramatic improvement in symptoms and structural heart disease
    SYMPTOMS

.

    Cardiac toxicity
    SYMPTOMS

 is an under-recognized

    adverse effect of CQ/HCQ
    SYMPTOMS

 leading to

    cardiomyopathy
    SYMPTOMS

 with

    concentric hypertrophy
    SYMPTOMS

 and

    conduction abnormalities
    SYMPTOMS

, with the potential for significant morbidity and mortality. Predisposing factors for

    CQ/HCQ-induced cardiomyopathy
    DIAGNOSIS

 have been proposed.

    CQ/HCQ cardiomyopathy
    DIAGNOSIS

 is a

    phenocopy of Fabry disease
    DIAGNOSIS

, and

    α-galactosidase A polymorphism
    GENETICS

 may account for some heterogeneity of disease presentation.

Chloroquine (CQ)
hydroxychloroquine (HCQ)
anti-rheumatic medications
cessation of CQ

connective tissue disorders
CQ-induced cardiomyopathy
CQ/HCQ-induced cardiomyopathy
CQ/HCQ cardiomyopathy
phenocopy of Fabry disease


IgG4-related disease with possible myocardial involvement.

IgG4-related disease is characterized by mass lesions, a dense lymphoplasmacytic infiltrate with immunohistochemical positivity for IgG4, storiform fibrosis and, frequently, elevated serum IgG4 levels. It can be multisystemic; however, myocardial involvement, which is objectively determined by imaging tests, has not been described in the medical literature. We report the case of a man with IgG4-related disease with possible myocardial involvement, detected by cardiac magnetic resonance. This raises the question of a differential diagnosis with other diseases such as sarcoidosis and Fabry disease, the differential diagnosis of which is of great importance due to its therapeutic impact.

    IgG4-related disease
    DIAGNOSIS

 is characterized by

    mass lesions
    SYMPTOMS

, a

    dense lymphoplasmacytic infiltrate with immunohistochemical positivity for IgG4
    MICROSCOPIC

,

    storiform fibrosis
    MICROSCOPIC

 and, frequently,

    elevated serum IgG4 levels
    BIOCHEMICAL

. It can be

    multisystemic
    DIAGNOSIS

; however,

    myocardial involvement
    SYMPTOMS

, which is objectively determined by

    imaging tests
    PARACLINICAL

, has not been described in the medical literature. We report the case of a

    man
    GENDER

 with

    IgG4-related disease
    DIAGNOSIS

 with

    possible myocardial involvement
    SYMPTOMS

, detected by

    cardiac magnetic resonance
    PARACLINICAL

. This raises the question of a

    differential diagnosis
    PARACLINICAL

 with other diseases such as

    sarcoidosis
    DIAGNOSIS

 and

    Fabry disease
    DIAGNOSIS

, the

    differential diagnosis
    PARACLINICAL

 of which is of great importance due to its therapeutic impact.

IgG4-related disease
multisystemic
IgG4-related disease
sarcoidosis
Fabry disease

mass lesions
myocardial involvement
possible myocardial involvement


Early Renal Involvement in a Girl with Classic Fabry Disease.

Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency or absence of the enzyme alpha galactosidase A; this defect leads to the systemic accumulation of globotriaosylceramide and its metabolites. Organic involvement in men is well known, but in women it is controversial, mainly due to the random X-chromosome inactivation in each of their cells (Lyon hypothesis). This would explain why women (heterozygotes) present a wide variability in the severity of their phenotype. The manifestations are multisystemic and begin in early childhood, reaching a severe compromise in adulthood. Typical acroparesthesia in hands and feet, gastrointestinal symptoms, angiokeratomas, dyshidrosis, hearing loss, arrhythmias, hypertrophic cardiomyopathy, cerebrovascular accidents, and renal failure can be observed. Nephropathy is one of the major complications of Fabry disease. Glomerular and vascular changes are present before progression to overt proteinuria and decreased glomerular filtration rate, even in pediatric patients. A case of incipient renal involvement in a girl with classic Fabry disease is reported.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from the

    deficiency or absence of the enzyme alpha galactosidase A
    BIOCHEMICAL

; this defect leads to the

    systemic accumulation of globotriaosylceramide and its metabolites
    MICROSCOPIC

.

    Organic involvement
    SYMPTOMS

 in

    men
    GENDER

 is well known, but in

    women
    GENDER

 it is controversial, mainly due to the

    random X-chromosome inactivation in each of their cells (Lyon hypothesis
    GENETICS

). This would explain why

    women
    GENDER

 (

    heterozygotes
    GENETICS

) present a wide variability in the severity of their phenotype. The manifestations are

    multisystemic
    SYMPTOMS

 and begin

    in early childhood
    AGE

, reaching a

    severe compromise
    SYMPTOMS

    in adulthood
    AGE

. Typical

    acroparesthesia in hands and feet
    SYMPTOMS

,

    gastrointestinal symptoms
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    dyshidrosis
    SYMPTOMS

,

    hearing loss
    SYMPTOMS

,

    arrhythmias
    SYMPTOMS

,

    hypertrophic cardiomyopathy
    SYMPTOMS

,

    cerebrovascular accidents
    SYMPTOMS

, and

    renal failure
    SYMPTOMS

 can be observed.

    Nephropathy
    DIAGNOSIS

 is one of the major complications of

    Fabry disease
    DIAGNOSIS

.

    Glomerular and vascular changes
    SYMPTOMS

 are present before progression to

    overt proteinuria
    BIOCHEMICAL

 and

    decreased glomerular filtration rate
    BIOCHEMICAL

, even in

    pediatric
    AGE

 patients. A case of

    incipient renal involvement
    SYMPTOMS

 in a

    girl
    GENDER

 with

    classic Fabry disease
    DIAGNOSIS

 is reported.

Fabry disease
lysosomal storage disorder
Nephropathy
Fabry disease
classic Fabry disease

Organic involvement
multisystemic
severe compromise
acroparesthesia in hands and feet
gastrointestinal symptoms
angiokeratomas
dyshidrosis
hearing loss
arrhythmias
hypertrophic cardiomyopathy
cerebrovascular accidents
renal failure
Glomerular and vascular changes
incipient renal involvement


Case report: is low α-Gal enzyme activity sufficient to establish the diagnosis of Fabry disease?

Fabry disease is an X-linked lysosomal storage disease due to alpha-galactosidase A (α-Gal A) deficient activity which leads to the accumulation of glucoesphingolipids, such as globotriaosilceramide. There are over 700 known mutations of the enzyme gene, and most of them cause Fabry Disease. This case report describes a hemodialysis patient with a rare and controversial GLA gene mutation, the D313Y. The medecial investigation confirmed that D313Y is an alpha-galactosidase A sequence variant that causes pseudo deficient enzyme activity in plasma but not Fabry disease. Thus, clinical symptoms that prompted Fabry disease investigation could not be attributable to Fabry disease and therefore enzyme replacement therapy was not indicated.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 due to

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

 which leads to the

    accumulation of glucoesphingolipids, such as globotriaosilceramide
    MICROSCOPIC

. There are over 700 known

    mutations of the enzyme gene
    GENETICS

, and most of them cause

    Fabry Disease
    DIAGNOSIS

. This case report describes a

    hemodialysis
    MEDICATION

 patient with a rare and controversial GLA gene mutation, the D313Y. The

    medecial investigation
    PARACLINICAL

 confirmed that

    D313Y is an alpha-galactosidase A sequence variant
    GENETICS

 that causes

    pseudo deficient enzyme activity in plasma
    BIOCHEMICAL

 but

    not Fabry disease
    NEG_FINDINGS

. Thus,

    clinical symptoms
    SYMPTOMS

 that prompted

    Fabry disease investigation
    PARACLINICAL

    could not be attributable to Fabry disease
    NEG_FINDINGS

 and therefore

    enzyme replacement therapy was not indicated
    NEG_FINDINGS

.

Fabry disease
lysosomal storage disease
Fabry Disease


Fabry disease; early diagnosis improves prognosis but diagnosis is often delayed.

Fabry disease (FD) is a rare X-linked deficiency of lysosomal enzyme alpha-galactosidase (AGAL) resulting in accumulation of globotriaosylceramide (Gb-3) in the cells, with protean manifestations. Major organs affected are the kidneys, heart and nervous system. The diagnosis of FD is often delayed by many years. Enzyme replacement started early might reverse the organ damage while delayed initiation may only stabilize the disease progression.

We describe a patient in whom involvement of different organs unfolded at different times and a detailed review of history by the clinician led to the diagnosis. The importance of electron microscopy (EM) of renal biopsy is highlighted.

Patients with FD are often diagnosed late because the manifestations can be variable and spread over different time periods. Detailed history including family history and examining the renal biopsy by EM are crucial for early diagnosis.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    deficiency of lysosomal enzyme alpha-galactosidase (AGAL)
    BIOCHEMICAL

 resulting in

    accumulation of globotriaosylceramide (Gb-3) in the cells
    MICROSCOPIC

, with

    protean manifestations
    SYMPTOMS

.

    Major organs affected are the kidneys, heart and nervous system
    SYMPTOMS

. The diagnosis of

    FD
    DIAGNOSIS

 is often delayed by many years.

    Enzyme replacement started early
    MEDICATION

 might

    reverse the organ damage
    SYMPTOMS

 while

    delayed initiation
    MEDICATION

 may only stabilize the disease progression.

We describe a patient in whom

    involvement of different organs
    SYMPTOMS

 unfolded at different times and a detailed review of history by the clinician led to the diagnosis. The importance of

    electron microscopy (EM) of renal biopsy
    PARACLINICAL

 is highlighted.

Patients with

    FD
    DIAGNOSIS

 are often diagnosed late because the manifestations can be variable and spread over different time periods.

    Detailed history
    PARACLINICAL

 including

    family history
    PARACLINICAL

 and

    examining the renal biopsy by EM
    PARACLINICAL

 are crucial for early diagnosis.

Enzyme replacement started early
delayed initiation


Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy.

Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease-specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy.

We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene.

In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy.

These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease-affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by the

    deficient activity of α-galactosidase A
    BIOCHEMICAL

 due to

    mutations in the GLA gene
    GENETICS

, which may be associated with

    increased left ventricular wall thickness
    SYMPTOMS

 and

    mimic the morphologic features of hypertrophic cardiomyopathy
    SYMPTOMS

. Management strategies for these 2 diseases diverge, with

    Fabry disease
    DIAGNOSIS

    -specific treatment
    MEDICATION

 utilizing

    recombinant α-galactosidase A enzyme replacement therapy
    MEDICATION

.

We studied a prospectively assembled consecutive cohort of 585 patients (71%

    male
    GENDER

) from 2

    hypertrophic cardiomyopathy
    DIAGNOSIS

 tertiary referral centers by screening for

    low α-galactosidase A activity in dried blood spots
    BIOCHEMICAL

.

    Male
    GENDER

 patients with

    low α-galactosidase A activity levels
    BIOCHEMICAL

 and all

    females
    GENDER

 were tested for

    mutations in the GLA gene
    GENETICS

.

In 585 patients previously diagnosed with

    hypertrophic cardiomyopathy
    DIAGNOSIS

, we identified 2 unrelated patients (0.34%), both with the

    GLA mutation encoding P.N215S
    GENETICS

, the most common mutation causing

    later-onset
    GENETICS

    Fabry disease
    DIAGNOSIS

 phenotype. These patients were both

    asymptomatic
    GENDER

, a

    man
    GENDER

    aged 53 years
    AGE

 and a

    woman
    GENDER

    aged 69 years
    AGE

, and demonstrated a

    mild cardiac phenotype
    SYMPTOMS

 with

    symmetric distribution of left ventricular hypertrophy
    SYMPTOMS

. After

    family screening
    PARACLINICAL

, a total of 27 new

    Fabry disease
    DIAGNOSIS

 patients

    aged 2-81 years
    AGE

 were identified in the 2 families, including 12 individuals who are now receiving

    enzyme replacement therapy
    MEDICATION

.

These observations support consideration for routine

    prospective screening
    PARACLINICAL

 for

    Fabry disease
    DIAGNOSIS

 in all patients

    without a definitive etiology for left ventriclar hypertrophy
    NEG_FINDINGS

. This strategy would likely result, through

    cascade family testing
    PARACLINICAL

, in the earlier identification of new

    Fabry disease
    DIAGNOSIS

-affected

    males
    GENDER

 and

    female
    GENDER

    heterozygotes
    GENETICS

 who may benefit from

    monitoring
    MEDICATION

 and/or

    enzyme replacement therapy
    MEDICATION

.

Fabry disease
lysosomal storage disorder
Fabry disease
hypertrophic cardiomyopathy
hypertrophic cardiomyopathy
Fabry disease
Fabry disease
Fabry disease
Fabry disease

X-linked
mutations in the GLA gene
mutations in the GLA gene
GLA mutation encoding P.N215S
later-onset
heterozygotes


Severe hypertrophic cardiomyopathy in a patient with atypical Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a hereditary disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A which causes dysfunctions in multiple organ systems. Cardiac manifestation includes left ventricular hypertrophy, thickening of the valves, conduction disturbances and in the late phase, extensive areas of myocardial fibrosis with increased risk of sudden cardiac death. Case example: A case of AFD with exclusive cardiac involvement is described. During follow-up, due to the high risk of life-threatening arrhythmic events, implantation of an implantable cardioverter defibrillator is performed.

AFD patients with advanced cardiac disease might represent a subgroup of patients who may require an implantable cardioverter defibrillator for primary prevention of sudden cardiac death.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is a

    hereditary disorder
    GENETICS

 caused by a

    deficiency in the lysosomal enzyme α-galactosidase A
    BIOCHEMICAL

 which causes

    dysfunctions in multiple organ systems
    SYMPTOMS

.

    Cardiac manifestation
    SYMPTOMS

 includes

    left ventricular hypertrophy
    SYMPTOMS

,

    thickening of the valves
    SYMPTOMS

,

    conduction disturbances
    SYMPTOMS

 and in the late phase,

    extensive areas of myocardial fibrosis
    SYMPTOMS

 with increased risk of

    sudden cardiac death
    SYMPTOMS

. Case example: A case of

    AFD
    DIAGNOSIS

 with

    exclusive cardiac involvement
    SYMPTOMS

 is described. During follow-up, due to the high risk of

    life-threatening arrhythmic events
    SYMPTOMS

,

    implantation of an implantable cardioverter defibrillator
    MEDICATION

 is performed.

    AFD
    DIAGNOSIS

 patients with

    advanced cardiac disease
    DIAGNOSIS

 might represent a subgroup of patients who may require an

    implantable cardioverter defibrillator
    MEDICATION

 for primary prevention of

    sudden cardiac death
    SYMPTOMS

.

Anderson-Fabry disease (AFD)
AFD
AFD
advanced cardiac disease

dysfunctions in multiple organ systems
Cardiac manifestation
left ventricular hypertrophy
thickening of the valves
conduction disturbances
extensive areas of myocardial fibrosis
sudden cardiac death
exclusive cardiac involvement
life-threatening arrhythmic events
sudden cardiac death


[Fabry disease: An overlooked diagnosis in adult cardiac patients].

Fabry disease is a rare, X-linked, lysosomal glycosphingolipid storage disorder. A deficiency of the enzyme alpha-galactosidase results in intracellular accumulation of globotriaosylceramide in multiple cell types, such as those of the nerves, kidneys, cardiac, and cutaneous tissues, leading to a multisystem disease. Male patients are more severely affected; however, heterozygous female patients may also be afflicted, though often the symptoms develop later. Cardiac involvement can include left ventricular hypertrophy, conduction abnormalities, arrhythmias, valvular abnormalities, and heart failure. A variant of the disease affects only cardiac tissue and mostly manifests as unexplained ventricular hypertrophy. Presently described are 2 cases of Fabry disease and the signs and symptoms of cardiac involvement, as well as the importance of early diagnosis to start enzyme replacement therapy before the development of irreversible tissue damage.

    Fabry disease
    DIAGNOSIS

 is a

    rare, X-linked
    GENETICS

,

    lysosomal glycosphingolipid storage disorder
    DIAGNOSIS

. A

    deficiency of the enzyme alpha-galactosidase
    BIOCHEMICAL

 results in

    intracellular accumulation of globotriaosylceramide in multiple cell types, such as those of the nerves, kidneys, cardiac, and cutaneous tissues
    MICROSCOPIC

, leading to a

    multisystem disease
    DIAGNOSIS

.

    Male
    GENDER

 patients are more severely affected; however,

    heterozygous
    GENETICS

    female
    GENDER

 patients may also be afflicted, though often the symptoms develop later.

    Cardiac involvement
    SYMPTOMS

 can include

    left ventricular hypertrophy
    SYMPTOMS

,

    conduction abnormalities
    SYMPTOMS

,

    arrhythmias
    SYMPTOMS

,

    valvular abnormalities
    SYMPTOMS

, and

    heart failure
    SYMPTOMS

. A variant of the disease

    affects only cardiac tissue
    SYMPTOMS

 and mostly manifests as

    unexplained ventricular hypertrophy
    SYMPTOMS

. Presently described are 2 cases of

    Fabry disease
    DIAGNOSIS

 and the signs and symptoms of

    cardiac involvement
    SYMPTOMS

, as well as the importance of early diagnosis to start

    enzyme replacement therapy
    MEDICATION

 before the development of

    irreversible tissue damage
    SYMPTOMS

.

Cardiac involvement
left ventricular hypertrophy
conduction abnormalities
arrhythmias
valvular abnormalities
heart failure
affects only cardiac tissue
unexplained ventricular hypertrophy
cardiac involvement
irreversible tissue damage


Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits.

A previous case report found stereomicroscopic changes typical for Fabry disease in a kidney biopsy. This case series evaluates an expanded diagnostic capacity of the method.

Bedside stereomicroscopy was performed in a cross-sectional prospective study of 31 consecutive enzyme-treated or treatment-naïve male (n = 14) and female Fabry disease patients. The burden of glomerular storage material was scored semiquantitatively on a visual analog scale (range 0-3) and a blinded comparison was done with a reference histologic method.

Significant correlations (p < 0.001) were found between the stereomicroscopic scoring of glomerular characteristic white storage material and the amount of podocyte globotriaosylceramide (Gb3) deposits scored by standardized light microscopy. The bedside method correctly identified the variability of podocyte Gb3 accumulation after 10 years of identical agalsidase therapy in 2 brothers aged 24 and 27 years, and also identified tubular cell deposits. Stereomicroscopy correctly verified the absence of sphingolipid deposits in the biopsy of a female index patient with a genetic variant of unknown significance, and the diagnosis of Fabry disease was finally discarded.

Bedside stereomicroscopy of kidney biopsies is an easily available, low-cost microscopy method handled by the clinician. The method carries a high diagnostic sensitivity for Fabry disease, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the grading of the podocyte Gb3 burden and assessment of effectiveness of enzyme replacement therapy. We recommend the method as complementary to current standard histologic evaluation of Fabry kidney biopsies.

A previous case report found

    stereomicroscopic changes typical for Fabry disease
    SYMPTOMS

 in a

    kidney biopsy
    PARACLINICAL

. This case series evaluates an expanded diagnostic capacity of the method.

    Bedside stereomicroscopy
    PARACLINICAL

 was performed in a cross-sectional prospective study of 31 consecutive

    enzyme-treated or treatment-naïve
    MEDICATION

    male
    GENDER

 (n = 14) and

    female
    GENDER

    Fabry disease
    DIAGNOSIS

 patients.

    The burden of glomerular storage material
    PARACLINICAL

    was scored semiquantitatively on a visual analog scale (range 0-3)
    PARACLINICAL

 and a blinded comparison was done with a

    reference histologic method
    PARACLINICAL

.

Significant correlations (p < 0.001) were found between the

    stereomicroscopic scoring of glomerular characteristic white storage material
    PARACLINICAL

 and the

    amount of podocyte globotriaosylceramide (Gb3) deposits
    BIOCHEMICAL

 scored by

    standardized light microscopy
    PARACLINICAL

. The bedside method correctly identified the

    variability of podocyte Gb3 accumulation
    BIOCHEMICAL

 after 10 years of

    identical agalsidase therapy
    MEDICATION

 in 2

    brothers
    GENDER

    aged 24 and 27 years
    AGE

, and also identified

    tubular cell deposits
    BIOCHEMICAL

.

    Stereomicroscopy
    PARACLINICAL

 correctly verified the

    absence of sphingolipid deposits in the biopsy
    SYMPTOMS

 of a

    female
    GENDER

 index patient with a

    genetic variant of unknown significance
    NEG_FINDINGS

, and

    the diagnosis of Fabry disease was finally discarded
    NEG_FINDINGS

.

    Bedside stereomicroscopy of kidney biopsies
    PARACLINICAL

 is an easily available,

    low-cost microscopy method
    PARACLINICAL

 handled by the clinician. The method carries a high diagnostic sensitivity for

    Fabry disease
    DIAGNOSIS

, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the

    grading of the podocyte Gb3 burden
    PARACLINICAL

 and assessment of effectiveness of

    enzyme replacement therapy
    MEDICATION

. We recommend the method as complementary to current standard

    histologic evaluation of Fabry kidney biopsies
    PARACLINICAL

.

enzyme-treated or treatment-naïve
identical agalsidase therapy
enzyme replacement therapy


The Psychosocial Impact of Carrying a Debated Variant in the GLA Gene.

The clinical significance of the c.427G>A (p.A143T) variant in GLA is a topic of debate within the lysosomal storage disease community. A review of the literature and published case reports found the clinical impact of the variant to range from classic Fabry symptoms to healthy unaffected males with normal alpha- galactosidase enzyme levels, leaving clinicians unsure of how to manage these individuals. As the number of states testing for Fabry disease on their newborn screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the p.A143T variant affects those with this change. A self-response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals' beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the p.A143T variant. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.

The clinical significance of the

    c.427G>A (p.A143T) variant in GLA
    GENETICS

 is a topic of debate within the

    lysosomal storage disease
    DIAGNOSIS

 community. A review of the literature and published case reports found the clinical impact of the variant to range from

    classic Fabry symptoms
    SYMPTOMS

 to healthy unaffected

    males
    GENDER

 with

    normal alpha- galactosidase enzyme levels
    NEG_FINDINGS

, leaving clinicians unsure of how to manage these individuals. As the number of states testing for

    Fabry disease
    DIAGNOSIS

 on their

    newborn
    AGE

 screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the

    p.A143T variant
    GENETICS

 affects those with this change. A self-response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals' beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the

    p.A143T variant
    GENETICS

. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.

c.427G>A (p.A143T) variant in GLA
p.A143T variant
p.A143T variant


Fabry disease: Four case reports of meningioma and a review of the literature on other malignancies.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by loss of function mutations in the GLA gene at Xq22 with subsequent functional deficiency of alpha-galactosidase A, resulting in the accumulation of globotriaosylceramide (GL-3 or Gb3) in multiple cells types throughout the body. As with other rare metabolic disorders, little is known about the incidence of malignancies in these populations and the relationship to the underlying disease, if any. We report the occurrence of meningioma in four female patients with Fabry disease. Two of the cases are from the same family and shared the same GLA mutation. All four patients underwent surgical excision of their tumor. High resolution light microscopy and electron microscopy examination of one case revealed extensive involvement of tumor cells and associated blood vessels by GL-3 accumulation. Because of the small number of Fabry-associated cancer cases reported in the literature, questions about a possible link between lysosomal storage disorders and the development of malignancy remain open.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    loss of function mutations in the GLA gene at Xq22
    GENETICS

 with subsequent

    functional deficiency of alpha-galactosidase A
    BIOCHEMICAL

, resulting in the

    accumulation of globotriaosylceramide (GL-3 or Gb3) in multiple cells types throughout the body
    MICROSCOPIC

. As with other

    rare metabolic disorders
    DIAGNOSIS

, little is known about the incidence of

    malignancies
    DIAGNOSIS

 in these populations and the relationship to the underlying disease, if any. We report the occurrence of

    meningioma
    DIAGNOSIS

 in four

    female
    GENDER

 patients with

    Fabry disease
    DIAGNOSIS

.

    Two of the cases are from the same family and shared the same GLA mutation
    FAMILY

. All four patients underwent

    surgical excision of their tumor
    MEDICATION

.

    High resolution light microscopy
    PARACLINICAL

 and

    electron microscopy examination
    PARACLINICAL

 of one case revealed

    extensive involvement of tumor cells and associated blood vessels by GL-3 accumulation
    MICROSCOPIC

. Because of the small number of

    Fabry-associated cancer
    DIAGNOSIS

 cases reported in the literature, questions about a possible link between

    lysosomal storage disorders
    DIAGNOSIS

 and the development of

    malignancy
    DIAGNOSIS

 remain open.

Fabry disease (FD)
lysosomal storage disorder
rare metabolic disorders
malignancies
meningioma
Fabry disease
Fabry-associated cancer
lysosomal storage disorders
malignancy


Paricalcitol as an Antiproteinuric Agent Can Result in the Deterioration of Renal and Heart Function in a Patient with Fabry Disease.

BACKGROUND Fabry disease is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism that is due to deficient or absent lysosomal a-galactosidase A activity. Among its other associated signs and symptoms, patients present with renal failure and proteinuria, which are markers of disease progression. Renin-angiotensin-aldosterone system (RAAS) blockers can slow the progression of chronic renal failure and proteinuria. In fact, some studies have shown the beneficial effects of paricalcitol on proteinuria. CASE REPORT We present a case of a female patient with the classic variant of Fabry disease. She was treated with a high dose of paricalcitol as an antiproteinuric agent due to unsatisfactory double-RAAS blockage, which resulted in transient worsening of cardiac and renal function. CONCLUSIONS Despite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case highlights the possible serious adverse effects associated with the use of high doses of this drug.

BACKGROUND

    Fabry disease
    DIAGNOSIS

 is a

    rare and progressive X-linked inherited
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 that is due to

    deficient or absent lysosomal a-galactosidase A activity
    BIOCHEMICAL

. Among its other associated signs and symptoms, patients present with

    renal failure
    SYMPTOMS

 and

    proteinuria
    BIOCHEMICAL

, which are markers of disease progression.

    Renin-angiotensin-aldosterone system (RAAS) blockers
    MEDICATION

 can slow the progression of

    chronic renal failure
    SYMPTOMS

 and

    proteinuria
    BIOCHEMICAL

. In fact, some studies have shown the beneficial effects of

    paricalcitol
    MEDICATION

 on

    proteinuria
    BIOCHEMICAL

. CASE REPORT We present a case of a

    female
    GENDER

 patient with the classic variant of

    Fabry disease
    DIAGNOSIS

.

    She
    GENDER

 was treated with a

    high dose of paricalcitol as an antiproteinuric agent
    MEDICATION

 due to

    unsatisfactory double-RAAS blockage
    NEG_FINDINGS

, which resulted in

    transient worsening of cardiac and renal function
    SYMPTOMS

. CONCLUSIONS Despite the positive effects of

    paricalcitol as an antiproteinuric agent
    MEDICATION

, as previously shown by some authors, our case highlights the

    possible serious adverse effects associated with the use of high doses of this drug
    SYMPTOMS

.


Fabry heterozygote mimicking multiple sclerosis.

Fabry's disease (FD) is a recognised mimic of multiple sclerosis (MS). It is an X-linked storage lysosomal disorder with deficiency of α-galactosidase A and enzyme replacement therapy is available. Patients with FD may satisfy modified McDonald criteria if the diagnosis of FD has not been pursued. We present a case of FD in a 65-year-old woman masquerading as benign MS for 40 years. She has recurrent posterior circulation stroke-like symptoms, hearing loss and acroparaesthesia, but typical radiological features of MS on MRI brain. Later she developed an ischaemic stroke, infiltrative cardiomyopathy and chronic renal failure. There was a missense mutation at p.R342Q in the galactodisdase alpha (GLA) gene. Neurologists need to consider FD and look for red flags in atypical MS cases and should not be over-reliant on MRI findings. Missed diagnosis of FD could lead to unnecessary immunosuppression, inappropriate disease counselling and missed treatment opportunity.

    Fabry's disease (FD)
    DIAGNOSIS

 is a recognised mimic of

    multiple sclerosis (MS)
    DIAGNOSIS

. It is an

    X-linked
    GENETICS

    storage lysosomal disorder
    DIAGNOSIS

 with

    deficiency of α-galactosidase A
    BIOCHEMICAL

 and

    enzyme replacement therapy
    MEDICATION

 is available. Patients with

    FD
    DIAGNOSIS

 may satisfy modified McDonald criteria if the diagnosis of

    FD
    DIAGNOSIS

 has not been pursued. We present a case of

    FD
    DIAGNOSIS

 in a

    65-year-old
    AGE

    woman
    GENDER

    masquerading as benign MS for 40 years
    NEG_FINDINGS

.

    She
    GENDER

 has

    recurrent posterior circulation stroke-like symptoms
    SYMPTOMS

,

    hearing loss
    SYMPTOMS

 and

    acroparaesthesia
    SYMPTOMS

, but

    typical radiological features of MS on MRI brain
    SYMPTOMS

. Later

    she
    GENDER

 developed an

    ischaemic stroke
    SYMPTOMS

,

    infiltrative cardiomyopathy
    SYMPTOMS

 and

    chronic renal failure
    SYMPTOMS

. There was a

    missense mutation at p.R342Q in the galactodisdase alpha (GLA) gene
    GENETICS

.

    Neurologists
    PARACLINICAL

 need to consider

    FD
    DIAGNOSIS

 and look for red flags in

    atypical MS
    DIAGNOSIS

 cases and should not be over-reliant on

    MRI
    PARACLINICAL

 findings. Missed diagnosis of

    FD
    DIAGNOSIS

 could lead to

    unnecessary immunosuppression
    NEG_FINDINGS

,

    inappropriate disease counselling
    NEG_FINDINGS

 and

    missed treatment opportunity
    NEG_FINDINGS

.

Fabry's disease (FD)
multiple sclerosis (MS)
storage lysosomal disorder
FD
FD
FD
FD
atypical MS
FD

masquerading as benign MS for 40 years
unnecessary immunosuppression
inappropriate disease counselling
missed treatment opportunity


Ultrastructural deposits appearing as "zebra bodies" in renal biopsy: Fabry disease?- comparative case reports.

Fabry Disease (FD) is a genetic disorder caused by alpha-galactosidase A deficiency. Certain drugs, such as hydroxychloroquine, can produce renal deposits that mimic morphological findings seen in FD, characterizing a type of drug-induced renal phospholipidosis.

Case 1: A 28-year-old female patient with systemic lupus erythematosus who had been using hydroxychloroquine for 14 months presented subnephrotic proteinuria. Renal biopsy showed deposits compatible with FD. Neither activity analysis of alpha-galactosidase A nor genetic analysis were available and were not performed. These deposits were not detected in a subsequent renal biopsy three years after withdrawal of the medication, characterizing a possible hydroxychloroquine-induced renal phospholipidosis. Case 2: A 29-year-old male patient presented with acroparesthesia, angiokeratomas, cornea verticillata and subnephrotic proteinuria. Deposits compatible with FD were detected upon renal biopsy. The evaluation of alpha-galactosidase A showed no activity in both blood and leukocytes. Genetic analysis identified an M284 T mutation in exon 6, and such mutation was also found in other family members.

Clinical investigation is necessary in suspected cases of Fabry Disease upon renal biopsy in order to confirm diagnosis. Drug-induced renal phospholipidosis should be considered in differential diagnosis in cases with intracellular osmiophilic, lamellar inclusions in electron microscopy.

    Fabry Disease (FD)
    DIAGNOSIS

 is a

    genetic disorder
    GENETICS

 caused by

    alpha-galactosidase A deficiency
    BIOCHEMICAL

. Certain drugs, such as

    hydroxychloroquine
    MEDICATION

, can produce

    renal deposits that mimic morphological findings seen in FD
    MICROSCOPIC

, characterizing a type of

    drug-induced renal phospholipidosis
    DIAGNOSIS

.

Case 1: A

    28-year-old
    AGE

    female
    GENDER

 patient with

    systemic lupus erythematosus
    DIAGNOSIS

 who had been

    using hydroxychloroquine for 14 months
    MEDICATION

 presented

    subnephrotic proteinuria
    BIOCHEMICAL

.

    Renal biopsy
    PARACLINICAL

 showed

    deposits compatible with FD
    MICROSCOPIC

.

    Neither activity analysis of alpha-galactosidase A nor genetic analysis were available and were not performed
    NEG_FINDINGS

. These

    deposits were not detected in a subsequent renal biopsy three years after withdrawal of the medication
    NEG_FINDINGS

, characterizing a possible

    hydroxychloroquine-induced renal phospholipidosis
    DIAGNOSIS

. Case 2: A

    29-year-old
    AGE

    male
    GENDER

 patient presented with

    acroparesthesia
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

 and

    subnephrotic proteinuria
    BIOCHEMICAL

.

    Deposits compatible with FD
    MICROSCOPIC

 were detected upon

    renal biopsy
    PARACLINICAL

. The

    evaluation of alpha-galactosidase A showed no activity in both blood and leukocytes
    BIOCHEMICAL

.

    Genetic analysis
    PARACLINICAL

 identified an

    M284 T mutation in exon 6
    GENETICS

, and such

    mutation was also found in other family members
    FAMILY

.

    Clinical investigation
    PARACLINICAL

 is necessary in suspected cases of

    Fabry Disease
    DIAGNOSIS

 upon

    renal biopsy
    PARACLINICAL

 in order to confirm diagnosis.

    Drug-induced renal phospholipidosis
    DIAGNOSIS

 should be considered in

    differential diagnosis
    PARACLINICAL

 in cases with

    intracellular osmiophilic, lamellar inclusions
    MICROSCOPIC

 in

    electron microscopy
    PARACLINICAL

.

genetic disorder
M284 T mutation in exon 6

hydroxychloroquine
using hydroxychloroquine for 14 months

acroparesthesia
angiokeratomas
cornea verticillata


[Cryptogenic stroke in a young patient with heart disease and kidney failure].

Fabry's disease is an infrequent metabolic pathology linked to the X chromosome which causes a wide variety of signs and symptoms.

A 39-year-old male who was admitted to our stroke unit with right-side hemiparesis (1 + 0) and dysarthria (1). The score on the National Institute of Health Stroke Scale was 2. The patient presented angiokeratomas in both thighs. A computerised axial tomography scan of the head showed left thalamic acute infarction. The duplex scan of the supra-aortic trunks was normal, and the transcranial Doppler reflected a generalised increase in the pulsatility indices. Transthoracic echocardiography showed left ventricular hypertrophy and left atrial dilatation. He was discharged five days later, with antiaggregating medication but asymptomatic. The prolonged Holter-electrocardiogram recording showed paroxysmal atrial fibrillation. One notable value in the urine analysis was microalbuminuria of 281 mg/L. In view of the multi-organic involvement and the family history, a study for Fabry's disease was performed. Activity of the enzyme alpha-galactosidase A was diminished, and the presence of a mutation in the GLA gene was found. The patient's brother, who suffered from kidney failure and atrial fibrillation, was positive for this mutation. The patient is on treatment with agalsidase beta.

Fabry's disease must be suspected in young males with heart disease, stroke or peripheral neuropathy, skin lesions, kidney failure and a history of cases in the family. Hormone replacement therapy must be established at an early stage, as it can improve the prognosis.

    Fabry's disease
    DIAGNOSIS

 is an

    infrequent metabolic pathology linked to the X chromosome
    GENETICS

 which causes a wide variety of signs and symptoms.

A

    39-year-old
    AGE

    male
    GENDER

 who was admitted to our

    stroke unit
    MEDICATION

 with

    right-side hemiparesis (1 + 0)
    SYMPTOMS

 and

    dysarthria (1)
    SYMPTOMS

. The

    score on the National Institute of Health Stroke Scale was 2
    SYMPTOMS

. The patient presented

    angiokeratomas in both thighs
    SYMPTOMS

. A

    computerised axial tomography scan of the head
    PARACLINICAL

 showed

    left thalamic acute infarction
    SYMPTOMS

. The

    duplex scan of the supra-aortic trunks was normal
    NEG_FINDINGS

, and the

    transcranial Doppler
    PARACLINICAL

 reflected a

    generalised increase in the pulsatility indices
    SYMPTOMS

.

    Transthoracic echocardiography
    PARACLINICAL

 showed

    left ventricular hypertrophy
    SYMPTOMS

 and

    left atrial dilatation
    SYMPTOMS

.

    He
    GENDER

 was discharged five days later,

    with antiaggregating medication
    MEDICATION

 but

    asymptomatic
    NEG_FINDINGS

. The

    prolonged Holter-electrocardiogram recording
    PARACLINICAL

 showed

    paroxysmal atrial fibrillation
    SYMPTOMS

. One notable value in the

    urine analysis
    BIOCHEMICAL

 was microalbuminuria of 281 mg/L. In view of the

    multi-organic involvement
    SYMPTOMS

 and the family history, a study for

    Fabry's disease
    DIAGNOSIS

 was performed.

    Activity of the enzyme alpha-galactosidase A was diminished
    BIOCHEMICAL

, and the

    presence of a mutation in the GLA gene
    GENETICS

 was found.

    The patient's brother, who suffered from kidney failure and atrial fibrillation, was positive for this mutation
    FAMILY

. The patient is on

    treatment with agalsidase beta.
    MEDICATION

    Fabry's disease
    DIAGNOSIS

 must be suspected in

    young
    AGE

    males
    GENDER

 with

    heart disease
    DIAGNOSIS

,

    stroke
    SYMPTOMS

 or

    peripheral neuropathy
    SYMPTOMS

,

    skin lesions
    SYMPTOMS

,

    kidney failure
    SYMPTOMS

 and a

    history of cases in the family
    FAMILY

.

    Hormone replacement therapy
    MEDICATION

 must be established at an early stage, as it can improve the prognosis.

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

stroke unit
with antiaggregating medication
treatment with agalsidase beta.
Hormone replacement therapy


Identification of a Novel GLA Gene Mutation, p.Ile239Met, in Fabry Disease With a Predominant Cardiac Phenotype.

Fabry disease (FD) is an X-linked inherited lysosomal storage disorder caused by mutations in the GLA gene, encoding for the enzyme α-galactosidase A. Although hundreds of mutations in the GLA gene have been described, many of them are variants of unknown significance. Here we report a novel GLA mutation, p.Ile239Met, identified in a large Hungarian three-generation family with FD. A 69 year-old female index patient with a clinical history of renal failure, hypertrophic cardiomyopathy, and 2nd degree AV block was screened for mutation in the GLA gene. Genetic screening identified a previously unreported heterozygous mutation in exon 5 of the GLA gene (c.717A>G; p.Ile239Met). Family screening indicated that altogether 6 family members carried the mutation (5 females, 1 male, average age: 55 ± 16 years). Three family members, including the index patient, manifested the cardiac phenotype of hypertrophic cardiomyopathy, while two other family members were diagnosed with left ventricular hypertrophy. Taking affection status as the presence of hypertrophic cardiomyopathy, left ventricular hypertrophy or elevated lyso-Gb3 levels, all affected family members carried the mutation. Linkage analysis of the family gave a two-point LOD score of 2.01 between the affection status and the p.Ile239Met GLA mutation. Lyso-Gb3 levels were elevated in all carrier family members (range: 2.4-13.8 ng/mL; upper limit of normal +2STD: ≤ 1.8 ng/mL). The GLA enzyme level was markedly reduced in the affected male family member (< 0.2 µmol/L/hour; upper limit of normal ± 2STD: ≥ 2.6 µmol/L/hour). We conclude that the p. Ile239Met GLA mutation is a pathogenic mutation for FD associated with predominant cardiac phenotype.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations in the GLA gene
    GENETICS

, encoding for the enzyme α-galactosidase A. Although hundreds of mutations in the

    GLA gene
    GENETICS

 have been described, many of them are variants of unknown significance. Here we report a

    novel GLA mutation, p.Ile239Met
    GENETICS

, identified in a large

    Hungarian
    ETHNICITY

    three-generation family with FD
    FAMILY

. A

    69 year-old
    AGE

    female
    GENDER

 index patient with a clinical history of

    renal failure
    SYMPTOMS

,

    hypertrophic cardiomyopathy
    SYMPTOMS

, and

    2nd degree AV block
    SYMPTOMS

 was screened for

    mutation in the GLA gene
    GENETICS

.

    Genetic screening
    PARACLINICAL

 identified a

    previously unreported heterozygous mutation in exon 5 of the GLA gene (c.717A>G; p.Ile239Met)
    GENETICS

.

    Family screening
    PARACLINICAL

 indicated that altogether

    6 family members carried the mutation
    FAMILY

 (5

    females
    GENDER

, 1

    male
    GENDER

,

    average age: 55 ± 16 years
    AGE

). Three family members, including the index patient, manifested the

    cardiac phenotype of hypertrophic cardiomyopathy
    SYMPTOMS

, while two other family members were diagnosed with

    left ventricular hypertrophy
    SYMPTOMS

. Taking affection status as the presence of

    hypertrophic cardiomyopathy
    SYMPTOMS

,

    left ventricular hypertrophy
    SYMPTOMS

 or

    elevated lyso-Gb3 levels
    BIOCHEMICAL

,

    all affected family members carried the mutation
    FAMILY

.

    Linkage analysis of the family
    PARACLINICAL

 gave a two-point LOD score of 2.01 between the affection status and the

    p.Ile239Met GLA mutation
    GENETICS

.

    Lyso-Gb3 levels were elevated in all carrier family members (range: 2.4-13.8 ng/mL; upper limit of normal +2STD: ≤ 1.8 ng/mL)
    BIOCHEMICAL

.

    The GLA enzyme level was markedly reduced in the affected male family member (< 0.2 µmol/L/hour; upper limit of normal ± 2STD: ≥ 2.6 µmol/L/hour)
    BIOCHEMICAL

. We conclude that the

    p. Ile239Met GLA mutation
    GENETICS

 is a pathogenic mutation for

    FD
    DIAGNOSIS

 associated with

    predominant cardiac phenotype
    SYMPTOMS

.

Fabry disease (FD)
lysosomal storage disorder
FD


The Coexistence of Multiple Myeloma-associated Amyloid Light-chain Amyloidosis and Fabry Disease in a Hemodialysis Patient.

Fabry disease (FD) is an inherited lysosomal disorder caused by an X-linked α-galactosidase A deficiency. We report the case of a 50-year-old male FD patient on hemodialysis who presented with macroglossia-related speaking difficulty and gastrointestinal symptoms. An endoscopic analysis revealed multiple gastric ulcers, and a histological examination led to a diagnosis of amyloid light-chain amyloidosis. Serum free light-chain and bone marrow analyses detected multiple myeloma (MM). Treatment with bortezomib and dexamethasone significantly improved the patient's symptoms. This is the first case to demonstrate a potential pathogenic relationship between FD and MM. The similar gastrointestinal manifestations might have contributed to the diagnostic difficulty.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    inherited lysosomal disorder
    GENETICS

 caused by an

    X-linked
    GENETICS

    α-galactosidase A deficiency
    BIOCHEMICAL

. We report the case of a

    50-year-old
    AGE

    male
    GENDER

    FD
    DIAGNOSIS

 patient on

    hemodialysis
    MEDICATION

 who presented with

    macroglossia-related speaking difficulty
    SYMPTOMS

 and

    gastrointestinal symptoms
    SYMPTOMS

. An

    endoscopic analysis
    PARACLINICAL

 revealed

    multiple gastric ulcers
    SYMPTOMS

, and a

    histological examination
    PARACLINICAL

 led to a diagnosis of

    amyloid light-chain amyloidosis
    DIAGNOSIS

.

    Serum free light-chain and bone marrow analyses
    PARACLINICAL

 detected

    multiple myeloma (MM)
    DIAGNOSIS

. Treatment with

    bortezomib and dexamethasone
    MEDICATION

 significantly improved the patient's symptoms. This is the first case to demonstrate a

    potential pathogenic relationship between FD and MM
    SYMPTOMS

. The

    similar gastrointestinal manifestations
    SYMPTOMS

 might have contributed to the diagnostic difficulty.

Fabry disease (FD)
FD
amyloid light-chain amyloidosis
multiple myeloma (MM)

hemodialysis
bortezomib and dexamethasone


Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these two disorders. In Fabry disease, gastrointestinal symptoms occur in approximately 70% of male patients, but the frequency ranges from 19% to 69% in different series. In some patients, colonic dysmotility due glycolipid deposition in autonomic plexus and ganglia can lead to the pseudo-obstruction syndrome, simulating intestinal necrosis. That is why up to this date colostomy has been performed in some cases, even for children with FD without cardiac, renal or cerebrovascular compromise. Early treatment with enzyme replacement therapy in asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression. Several studies have demonstrated that enzyme replacement therapy alleviates GI manifestations. Because of the non-specific nature of the gastrointestinal symptoms, diagnosis of Fabry disease is often delayed for several years. Gastrointestinal involvement is often misdiagnosed or under-reported. It is therefore very important to consider Fabry disease in the differential diagnosis of chronic intestinal pseudo-obstruction.

    Chronic intestinal pseudo-obstruction
    SYMPTOMS

 results in clinical manifestations that resemble

    intestinal obstruction
    SYMPTOMS

 but in the

    absence of any physical obstructive process
    NEG_FINDINGS

.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 characterized by the

    dysfunction of multiple systems
    SYMPTOMS

, including

    significant gastrointestinal involvement
    SYMPTOMS

. We report the occurrence of

    chronic intestinal pseudo-obstruction
    SYMPTOMS

 in two unrelated patients with

    Fabry disease
    DIAGNOSIS

 and the possible explanation of a direct relation of these two disorders. In

    Fabry disease
    DIAGNOSIS

,

    gastrointestinal symptoms
    SYMPTOMS

 occur in approximately 70% of

    male
    GENDER

 patients, but the frequency ranges from 19% to 69% in different series. In some patients,

    colonic dysmotility
    SYMPTOMS

 due

    glycolipid deposition in autonomic plexus and ganglia
    MICROSCOPIC

 can lead to the

    pseudo-obstruction syndrome, simulating intestinal necrosis
    SYMPTOMS

. That is why up to this date

    colostomy
    MEDICATION

 has been performed in some cases, even for

    children
    AGE

 with

    FD
    DIAGNOSIS

    without cardiac, renal or cerebrovascular compromise
    NEG_FINDINGS

.

    Early treatment with enzyme replacement therapy
    MEDICATION

 in

    asymptomatic
    NEG_FINDINGS

 or

    mildly symptomatic
    SYMPTOMS

 patients may be justified in order to prevent disease progression. Several studies have demonstrated that

    enzyme replacement therapy
    MEDICATION

    alleviates GI manifestations
    SYMPTOMS

. Because of the

    non-specific nature of the gastrointestinal symptoms
    NEG_FINDINGS

, diagnosis of

    Fabry disease
    DIAGNOSIS

 is often delayed for several years.

    Gastrointestinal involvement
    SYMPTOMS

 is often misdiagnosed or under-reported. It is therefore very important to consider

    Fabry disease
    DIAGNOSIS

 in the

    differential diagnosis
    PARACLINICAL

 of

    chronic intestinal pseudo-obstruction
    SYMPTOMS

.

Fabry disease
lysosomal storage disease
Fabry disease
Fabry disease
FD
Fabry disease
Fabry disease


Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reduction in vitro.

It is still not entirely clear how α-galactosidase A (GAA) deficiency translates into clinical symptoms of Fabry disease (FD). The present communication investigates the effects of the mutation N215S in FD on the trafficking and processing of lysosomal GAA and their potential association with alterations in the membrane lipid composition. Abnormalities in lipid rafts (LRs) were observed in fibroblasts isolated from a male patient with FD bearing the mutation N215S. Interestingly, LR analysis revealed that the distribution of cholesterol and flotillin-2 are distinctly altered in the Fabry fibroblasts when compared with that of the wild-type cells. Furthermore, increased levels of glycolipid globotriaosylceramide 3 (Gb3) and sphingomyelin (SM) were observed in non-raft membrane fractions of Fabry cells. Substrate reduction with N-butyldeoxynojirimycin (NB-DNJ) in vitro was capable of reversing these abnormalities in this patient. These data led to the hypothesis that alterations of LRs may contribute to the pathophysiology of Morbus Fabry. Furthermore, it may be suggested that substrate reduction therapy with NB-DNJ might be a promising approach for the treatment of GAA deficiency at least for the selected patients.

It is still not entirely clear how

    α-galactosidase A (GAA) deficiency
    BIOCHEMICAL

 translates into clinical symptoms of

    Fabry disease (FD)
    DIAGNOSIS

. The present communication investigates the effects of the

    mutation N215S
    GENETICS

 in

    FD
    DIAGNOSIS

 on the trafficking and

    processing of lysosomal GAA
    BIOCHEMICAL

 and their potential association with

    alterations in the membrane lipid composition
    MICROSCOPIC

.

    Abnormalities in lipid rafts (LRs) were observed in fibroblasts
    MICROSCOPIC

 isolated from a

    male
    GENDER

 patient with

    FD
    DIAGNOSIS

 bearing the mutation N215S. Interestingly,

    LR analysis
    PARACLINICAL

 revealed that

    the distribution of cholesterol and flotillin-2 are distinctly altered in the Fabry fibroblasts
    MICROSCOPIC

 when compared with that of the wild-type cells. Furthermore,

    increased levels of glycolipid globotriaosylceramide 3 (Gb3) and sphingomyelin (SM) were observed in non-raft membrane fractions of Fabry cells
    MICROSCOPIC

.

    Substrate reduction with N-butyldeoxynojirimycin (NB-DNJ) in vitro
    MEDICATION

 was capable of

    reversing these abnormalities
    SYMPTOMS

 in this patient. These data led to the hypothesis that

    alterations of LRs
    MICROSCOPIC

 may contribute to the pathophysiology of

    Morbus Fabry
    DIAGNOSIS

. Furthermore, it may be suggested that

    substrate reduction therapy with NB-DNJ
    MEDICATION

 might be a promising approach for the treatment of

    GAA deficiency
    BIOCHEMICAL

 at least for the selected patients.

α-galactosidase A (GAA) deficiency
processing of lysosomal GAA
GAA deficiency


[The Fabry's Disease Cardiomyopathy as Differential Diagnosis of Acute Coronary Syndrome].

The progressive cardiomyopathy in patients with Fabry disease is often accompanied by angina pectoris and elevated levels of high-sensitive troponin T (hs-TnT), potentially mimicking acute coronary syndrome. Here, we present to representative cases with focus on clinical, diagnostic and therapeutic settings. An overview on the cardiomyopathy associated with Fabry disease and its role as differential diagnosis of acute coronary syndrome is provided. Fabry cardiomyopathy might exhibit similar clinical and biochemical constellations as seen in acute coronary syndrome. Thus, Fabry cardiomyopathy should be considered a differential diagnosis in acute coronary syndrome, particularly in patients demonstrating left ventricular hypertrophy of unknown origin.

The

    progressive cardiomyopathy
    DIAGNOSIS

 in patients with

    Fabry disease
    DIAGNOSIS

 is often accompanied by

    angina pectoris
    SYMPTOMS

 and

    elevated levels of high-sensitive troponin T (hs-TnT)
    BIOCHEMICAL

, potentially mimicking

    acute coronary syndrome
    SYMPTOMS

. Here, we present to representative cases with focus on clinical, diagnostic and therapeutic settings. An overview on the

    cardiomyopathy associated with Fabry disease
    DIAGNOSIS

 and its role as

    differential diagnosis
    PARACLINICAL

 of

    acute coronary syndrome
    DIAGNOSIS

 is provided.

    Fabry cardiomyopathy
    DIAGNOSIS

 might exhibit

    similar clinical and biochemical constellations as seen in acute coronary syndrome
    SYMPTOMS

. Thus,

    Fabry cardiomyopathy
    DIAGNOSIS

 should be considered a

    differential diagnosis
    PARACLINICAL

 in

    acute coronary syndrome
    DIAGNOSIS

, particularly in patients demonstrating

    left ventricular hypertrophy of unknown origin
    SYMPTOMS

.


The Impact of Fabry Disease on Reproductive Fitness.

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    pan-ethnic
    GENETICS

,

    X-linked
    GENETICS

,

    progressive lysosomal storage disorder
    DIAGNOSIS

 caused by

    pathogenic mutations in the GLA gene
    GENETICS

. Published case reports and abstracts suggest that

    decreased reproductive fitness
    SYMPTOMS

 may occur in

    males
    GENDER

 with

    FD
    DIAGNOSIS

. In order to understand the impact of

    FD
    DIAGNOSIS

 on

    reproductive fitness
    SYMPTOMS

 and increase the accuracy of

    reproductive genetic counseling
    MEDICATION

, this study examines a large, multi-centered population of individuals with

    FD
    DIAGNOSIS

 to determine if

    males
    GENDER

 have

    reduced reproductive fitness
    SYMPTOMS

. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and

    Canada
    ETHNICITY

. The number of

    biological live-born children
    MEDICATION

 among individuals with

    FD
    DIAGNOSIS

 was compared to statistics from the general population. Information was also collected on

    reduced sperm count
    BIOCHEMICAL

,

    depression
    SYMPTOMS

,

    pain
    SYMPTOMS

, use of

    assisted reproductive technology
    MEDICATION

, and

    reproductive choice
    MEDICATION

. On average,

    females
    GENDER

 affected by

    FD
    DIAGNOSIS

 had

    more biological live-born children
    MEDICATION

 (1.8) than

    males
    GENDER

 affected by

    FD
    DIAGNOSIS

 (1.1). However,

    males
    GENDER

 affected by

    FD
    DIAGNOSIS

 had an increased mean number of biological children (1.1) compared to the mean number of

    biological children fathered
    MEDICATION

 by

    men
    GENDER

 in the United States (0.9). Sixteen of the 134

    males
    GENDER

 with

    FD
    DIAGNOSIS

 reported

    oligospermia
    BIOCHEMICAL

, which suggests that an

    infertility work up
    PARACLINICAL

 may be indicated for

    males
    GENDER

 having

    difficulty impregnating their partners
    NEG_FINDINGS

. In our large multicenter sample,

    males
    GENDER

 and

    females
    GENDER

 with

    FD
    DIAGNOSIS

 do not exhibit

    reduced reproductive fitness
    NEG_FINDINGS

; on average they have

    more biological children
    MEDICATION

 than the general population in the United States. This information should assist clinicians in providing accurate

    reproductive genetic counseling and treatment
    MEDICATION

 for individuals with

    FD
    DIAGNOSIS

.

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

pan-ethnic
X-linked
pathogenic mutations in the GLA gene

decreased reproductive fitness
reproductive fitness
reduced reproductive fitness
depression
pain

difficulty impregnating their partners
reduced reproductive fitness


Cilioretinal artery occlusion and anterior ischemic optic neuropathy as the initial presentation in a child female carrier of Fabry disease.

To report the youngest female carrier of Fabry disease, complicated by cilioretinal artery occlusion and anterior ischemic optic neuropathy (AION).

Case report.

An 11-year-old girl was referred to our clinic with painless, acute loss of vision in her right eye. Posterior segment examination and fluorescein angiography revealed cilioretinal artery occlusion and AION. Systemic evaluations were unremarkable, except for a low blood α-galactosidase A enzyme level of 242.27 pmol/spot*20 h (reference range: 450-2000 pmol/spot*20 h). The patient was diagnosed with female carrier of Fabry disease.

Retinal vascular occlusions are rare in childhood, and Fabry disease may present with retinal vascular occlusion. Ophthalmological examinations may be contributing for early detection of the disease. To the best of our knowledge, this is the first report of a child female carrier of Fabry disease, complicated by cilioretinal artery occlusion and AION.

To report the youngest

    female
    GENDER

 carrier of

    Fabry disease
    DIAGNOSIS

, complicated by

    cilioretinal artery occlusion
    SYMPTOMS

 and

    anterior ischemic optic neuropathy (AION)
    SYMPTOMS

.

An

    11-year-old
    AGE

    girl
    GENDER

 was referred to our clinic with

    painless, acute loss of vision in her right eye
    SYMPTOMS

.

    Posterior segment examination
    PARACLINICAL

 and

    fluorescein angiography
    PARACLINICAL

 revealed

    cilioretinal artery occlusion
    SYMPTOMS

 and

    AION
    SYMPTOMS

.

    Systemic evaluations were unremarkable
    NEG_FINDINGS

, except for a

    low blood α-galactosidase A enzyme level of 242.27 pmol/spot*20 h (reference range: 450-2000 pmol/spot*20 h)
    BIOCHEMICAL

. The patient was diagnosed with

    female
    GENDER

 carrier of

    Fabry disease
    DIAGNOSIS

.

    Retinal vascular occlusions
    SYMPTOMS

 are rare in

    childhood
    AGE

, and

    Fabry disease
    DIAGNOSIS

 may present with

    retinal vascular occlusion
    SYMPTOMS

.

    Ophthalmological examinations
    PARACLINICAL

 may be contributing for early detection of the disease. To the best of our knowledge, this is the first report of a

    child
    AGE

    female
    GENDER

 carrier of

    Fabry disease
    DIAGNOSIS

, complicated by

    cilioretinal artery occlusion
    SYMPTOMS

 and

    AION
    SYMPTOMS

.

Fabry disease
Fabry disease
Fabry disease
Fabry disease