The mutation p.D313Y is associated with organ manifestation in Fabry disease.

Fabry disease (FD) is a multisystem lysosomal storage disorder caused by mutations in the GLA gene. The clinical significance of the mutation p.D313Y is still under debate. Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3; enzyme activity) data was performed in all our patients carrying the p.D313Y mutation. Fourteen patients from 5 families (10 female, 4 male; age range 10-51) were included. Symptoms and organ manifestations compatible with FD could be identified in 10 patients. Cerebrovascular events occurred in 4 females. Seven patients reported pain or acroparaesthesia. Cornea verticillata was found in 1 patient, mild retinal vascular tortuosity in 5 patients. Lyso-Gb3 was elevated in 2 females with cerebrovascular involvement. Classical cardiac, renal or skin manifestations could not be identified. The mutation p.D313Y in the GLA gene may lead to organ manifestations and elevation of the Fabry-specific biomarker lyso-Gb3. Neurological symptoms (stroke and pain) and ocular manifestations seem to be the leading findings. Annual routine visits are recommended for patients carrying the p.D313Y mutation. Enzyme replacement therapy might be considered in symptomatic patients.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    multisystem lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations in the GLA gene
    GENETICS

. The clinical significance of the

    mutation p.D313Y
    GENETICS

 is still under debate.

    Retrospective chart analysis of clinical (neurological, cardiac, renal, and ophthalmological), genetic, and biochemical (lyso-globotriaosylsphingosine, lyso-Gb3
    PARACLINICAL

;

    enzyme activity) data
    PARACLINICAL

 was performed in all our patients carrying the

    p.D313Y mutation
    GENETICS

. Fourteen patients from 5 families (10

    female
    GENDER

, 4

    male
    GENDER

;

    age range 10-51
    AGE

) were included.

    Symptoms and organ manifestations compatible with FD
    SYMPTOMS

 could be identified in 10 patients.

    Cerebrovascular events
    SYMPTOMS

 occurred in 4

    females
    GENDER

. Seven patients reported

    pain
    SYMPTOMS

 or

    acroparaesthesia
    SYMPTOMS

.

    Cornea verticillata
    SYMPTOMS

 was found in 1 patient,

    mild retinal vascular tortuosity
    SYMPTOMS

 in 5 patients.

    Lyso-Gb3 was elevated
    BIOCHEMICAL

 in 2

    females
    GENDER

 with

    cerebrovascular involvement
    SYMPTOMS

.

    Classical cardiac, renal or skin manifestations could not be identified
    NEG_FINDINGS

. The

    mutation p.D313Y in the GLA gene
    GENETICS

 may lead to

    organ manifestations
    SYMPTOMS

 and

    elevation of the Fabry-specific biomarker lyso-Gb3
    BIOCHEMICAL

.

    Neurological symptoms (stroke and pain)
    SYMPTOMS

 and

    ocular manifestations
    SYMPTOMS

 seem to be the leading findings. Annual routine visits are recommended for patients carrying the

    p.D313Y mutation
    GENETICS

.

    Enzyme replacement therapy
    MEDICATION

 might be considered in symptomatic patients.

Fabry disease (FD)
multisystem lysosomal storage disorder

mutations in the GLA gene
mutation p.D313Y
p.D313Y mutation
mutation p.D313Y in the GLA gene
p.D313Y mutation


Life-threatening bleeding from gastric mucosal angiokeratomas during anticoagulation: A case report of Fabry disease.

Angiokeratomas are the earliest manifestation of Fabry disease (FD), and the extent of their appearance is related to disease severity. Angiokeratomas are mostly found on cutaneous regions.

Here we report an FD patient with widespread gastrointestinal angiokeratomas who developed life-threatening bleeding following anticoagulation for atrial fibrillation.

Careful observation for gastrointestinal bleeding is warranted for patients on anticoagulation with extensive cutaneous angiokeratomas. Furthermore, our experience suggests that surveillance is needed to assess the prevalence and extent of gastrointestinal angiokeratomas in patients with FD.

    Angiokeratomas
    SYMPTOMS

 are the earliest manifestation of

    Fabry disease (FD)
    DIAGNOSIS

, and the extent of their appearance is related to disease severity.

    Angiokeratomas
    SYMPTOMS

 are mostly found

    on cutaneous regions
    SYMPTOMS

.

Here we report an

    FD
    DIAGNOSIS

 patient with

    widespread gastrointestinal angiokeratomas
    SYMPTOMS

 who developed

    life-threatening bleeding
    SYMPTOMS

 following

    anticoagulation for atrial fibrillation
    MEDICATION

.

    Careful observation
    PARACLINICAL

 for

    gastrointestinal bleeding
    SYMPTOMS

 is warranted for patients on

    anticoagulation
    MEDICATION

 with

    extensive cutaneous angiokeratomas
    SYMPTOMS

. Furthermore, our experience suggests that surveillance is needed to assess the prevalence and extent of

    gastrointestinal angiokeratomas
    SYMPTOMS

 in patients with

    FD
    DIAGNOSIS

.

anticoagulation for atrial fibrillation
anticoagulation


Inherited and Uncommon Causes of Stroke.

This article is a practical guide to identifying uncommon causes of stroke and offers guidance for evaluation and management, even when large controlled trials are lacking in these rarer forms of stroke.

Fabry disease causes early-onset stroke, particularly of the vertebrobasilar system; enzyme replacement therapy should be considered in affected patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), often misdiagnosed as multiple sclerosis, causes migraines, early-onset lacunar strokes, and dementia. Moyamoya disease can cause either ischemic or hemorrhagic stroke; revascularization is recommended in some patients. Cerebral amyloid angiopathy causes both microhemorrhages and macrohemorrhages, resulting in typical stroke symptoms and progressive dementia. Pregnancy raises the risk of both ischemic and hemorrhagic stroke, particularly in women with preeclampsia/eclampsia. Pregnant women are also at risk for posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome, and cerebral venous sinus thrombosis. Experts recommend that pregnant women with acute ischemic stroke not be systematically denied the potential benefits of IV recombinant tissue plasminogen activator.

Neurologists should become familiar with these uncommon causes of stroke to provide future risk assessment and family counseling and to implement appropriate treatment plans to prevent recurrence.

This article is a practical guide to identifying uncommon causes of

    stroke
    SYMPTOMS

 and offers guidance for evaluation and management, even when large controlled trials are lacking in these rarer forms of

    stroke
    SYMPTOMS

.

    Fabry disease
    DIAGNOSIS

 causes

    early-onset stroke, particularly of the vertebrobasilar system
    SYMPTOMS

;

    enzyme replacement therapy
    MEDICATION

 should be considered in affected patients.

    Cerebral autosomal dominant arteriopathy
    DIAGNOSIS

 with

    subcortical infarcts
    SYMPTOMS

 and

    leukoencephalopathy
    DIAGNOSIS

 (

    CADASIL)
    DIAGNOSIS

, often misdiagnosed as

    multiple sclerosis
    DIAGNOSIS

, causes

    migraines
    SYMPTOMS

,

    early-onset lacunar strokes
    SYMPTOMS

, and

    dementia
    SYMPTOMS

.

    Moyamoya disease
    DIAGNOSIS

 can cause either

    ischemic or hemorrhagic stroke
    SYMPTOMS

;

    revascularization
    MEDICATION

 is recommended in some patients.

    Cerebral amyloid angiopathy
    DIAGNOSIS

 causes both

    microhemorrhages and macrohemorrhages
    SYMPTOMS

, resulting in

    typical stroke symptoms
    SYMPTOMS

 and

    progressive dementia
    SYMPTOMS

.

    Pregnancy
    AGE

 raises the risk of both

    ischemic and hemorrhagic stroke
    SYMPTOMS

, particularly in

    women
    GENDER

 with

    preeclampsia
    DIAGNOSIS

/

    eclampsia
    DIAGNOSIS

.

    Pregnant
    AGE

    women
    GENDER

 are also at risk for

    posterior reversible encephalopathy syndrome (PRES)
    SYMPTOMS

,

    reversible cerebral vasoconstriction syndrome
    SYMPTOMS

, and

    cerebral venous sinus thrombosis
    SYMPTOMS

. Experts recommend that

    pregnant
    AGE

    women
    GENDER

 with

    acute ischemic stroke
    SYMPTOMS

 not be systematically denied the potential benefits of

    IV recombinant tissue plasminogen activator
    MEDICATION

.

    Neurologists
    PARACLINICAL

 should become familiar with these uncommon causes of

    stroke
    SYMPTOMS

 to provide future risk assessment and

    family counseling
    MEDICATION

 and to implement appropriate treatment plans to prevent recurrence.


Mild Left Ventricular Hypertrophy Unravels a Novel Nonsense Mutation of the GLA Gene Associated with the Classical Phenotype of Fabry Disease.

We report on the clinical, biochemical, and genetic findings of a large family with the classical phenotype of Fabry disease due to the novel nonsense mutation c.607G>T (p.E203X) of the GLA gene, which occurs in the active site of the α-galactosidase A enzyme. This report highlights that (i) Fabry disease diagnosis should be considered in all cases of unexplained left ventricular hypertrophy (LVH), even in its milder forms; (ii) a complete evaluation of patients with unexplained LVH is important to find diagnostic red flags of treatable causes of LVH, such as Fabry disease; (iii) cascade family screening is paramount to the earlier diagnosis and treatment of other affected family members; and (iv) the Fabry disease phenotype is highly variable in heterozygote females, even within the same family.

We report on the clinical, biochemical, and genetic findings of a large family with the classical phenotype of

    Fabry disease
    DIAGNOSIS

 due to the

    novel nonsense mutation c.607G>T (p.E203X) of the GLA gene, which occurs in the active site of the α-galactosidase A enzyme
    GENETICS

. This report highlights that (i)

    Fabry disease
    DIAGNOSIS

 diagnosis should be considered in all cases of

    unexplained left ventricular hypertrophy (LVH)
    SYMPTOMS

, even in its milder forms; (ii) a complete evaluation of patients with

    unexplained LVH
    SYMPTOMS

 is important to find diagnostic red flags of treatable causes of

    LVH
    SYMPTOMS

, such as

    Fabry disease
    DIAGNOSIS

; (iii)

    cascade family screening
    PARACLINICAL

 is paramount to the earlier diagnosis and treatment of other affected family members; and (iv) the

    Fabry disease
    DIAGNOSIS

 phenotype is highly variable in

    heterozygote females
    GENETICS

, even within the same family.

Fabry disease
Fabry disease
Fabry disease
Fabry disease


Ventricular Tachycardia in Fabry Disease Detected in a 50-Year-Old Woman during 14-Day Continuous Cardiac Monitoring.

Fabry disease is an X-linked lysosomal storage disorder. Female carriers were long thought to be asymptomatic; however, research has revealed the opposite. Cardiac conditions are the chief causes of death in women with Fabry disease. Although ventricular tachycardia has been reported in male patients with Fabry disease, it is not thought to be a frequent finding in females. We describe the case of a 50-year-old woman in whom we used 14-day continuous electrocardiographic monitoring to identify nonsustained ventricular tachycardia, after electrocardiograms and 24-hour Holter monitoring failed to detect the arrhythmia. A permanent implantable cardioverter-defibrillator relieved the patient's symptoms. We discuss why this case supports the need for more extensive electrophysiologic evaluation in women who have Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

.

    Female
    GENDER

 carriers were long thought to be

    asymptomatic
    NEG_FINDINGS

; however, research has revealed the opposite.

    Cardiac conditions
    SYMPTOMS

 are the chief causes of

    death
    SYMPTOMS

 in

    women
    GENDER

 with

    Fabry disease
    DIAGNOSIS

. Although

    ventricular tachycardia
    SYMPTOMS

 has been reported in

    male
    GENDER

 patients with

    Fabry disease
    DIAGNOSIS

, it is not thought to be a frequent finding in

    females
    GENDER

. We describe the case of a

    50-year-old
    AGE

    woman
    GENDER

 in whom we used

    14-day continuous electrocardiographic monitoring
    PARACLINICAL

 to identify

    nonsustained ventricular tachycardia
    SYMPTOMS

, after

    electrocardiograms and 24-hour Holter monitoring
    PARACLINICAL

    failed to detect the arrhythmia
    NEG_FINDINGS

. A

    permanent implantable cardioverter-defibrillator
    MEDICATION

    relieved the patient's symptoms
    SYMPTOMS

. We discuss why this case supports the need for more extensive

    electrophysiologic evaluation
    PARACLINICAL

 in

    women
    GENDER

 who have

    Fabry disease
    DIAGNOSIS

.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease
Fabry disease

asymptomatic
failed to detect the arrhythmia

Cardiac conditions
death
ventricular tachycardia
nonsustained ventricular tachycardia
relieved the patient's symptoms


Fabry Disease Presenting with Hypertrophic Cardiomyopathy and Tricuspid Regurgitation.

A 71-year-old female who was diagnosed with nonobstructive hypertrophic cardiomyopathy since 1999 presented with dyspnea and severe edema on both legs. For the management of her symptom, cardiac surgery including tricuspid annuloplasty, Maze operation and right atrial reduction plasty was performed. During follow-up after cardiac surgery, a plasma α-galactosidase activity was checked for the screening of Fabry disease and the result was around lower normal limit. DNA analysis was implemented for confirmation and it revealed a heterozygote α-galactosidase mutation at exon 6 [c.901C>T (p.Arg301Ter)]. This case suggests that Fabry disease might be easily undetected, and clinical suspicion is critical.

A

    71-year-old
    AGE

    female
    GENDER

 who was diagnosed with

    nonobstructive hypertrophic cardiomyopathy
    SYMPTOMS

 since 1999 presented with

    dyspnea
    SYMPTOMS

 and

    severe edema on both legs
    SYMPTOMS

. For the management of

    her
    GENDER

 symptom,

    cardiac surgery
    MEDICATION

 including

    tricuspid annuloplasty
    MEDICATION

,

    Maze operation
    MEDICATION

 and

    right atrial reduction plasty
    MEDICATION

 was performed. During

    follow-up
    PARACLINICAL

 after

    cardiac surgery
    MEDICATION

, a

    plasma α-galactosidase activity
    BIOCHEMICAL

 was checked for the screening of

    Fabry disease
    DIAGNOSIS

 and the result was

    around lower normal limit
    BIOCHEMICAL

.

    DNA analysis
    PARACLINICAL

 was implemented for confirmation and it revealed a

    heterozygote α-galactosidase mutation at exon 6 [c.901C>T (p.Arg301Ter)]
    GENETICS

. This case suggests that

    Fabry disease
    DIAGNOSIS

 might be easily undetected, and clinical suspicion is critical.

cardiac surgery
tricuspid annuloplasty
Maze operation
right atrial reduction plasty
cardiac surgery

plasma α-galactosidase activity
around lower normal limit


The severe clinical phenotype for a heterozygous Fabry female patient correlates to the methylation of non-mutated allele associated with chromosome 10q26 deletion syndrome.

Heterozygous Fabry females usually have an attenuated form of Fabry disease, causing them to be symptomatic; however, in rare cases, they can present with a severe phenotype. In this study, we report on a 37-year-old woman with acroparesthesia, a dysmorphic face, left ventricular hypertrophy, and intellectual disability. Her father had Fabry disease and died due to chronic renal and congestive cardiac failure. Her paternal uncle had chronic renal failure and intellectual disability, and her paternal aunt was affected with congestive cardiac failure. The patient has two sisters with no significant medical illness. However, her nephew has acroparesthesia, anhidrosis, and school phobia, and her niece shows mild phenotypes. The patient's enzyme analysis showed very low α-galactosidase A (α-gal A) activity in dried blood spot (DBS), lymphocytes, and skin fibroblasts with massive excretion of Gb3 and Gb2 in urine and lyso-Gb3 in DBS and plasma. Electron microscopic examination showed a large accumulation of sphingolipids in vascular endothelial cells and keratinocytes. Chromosomal analysis and comparative genomic hybridization microarray showed 10q26 terminal deletion. Molecular data showed a novel heterozygous stop codon mutation in exon 1 of the GLA gene in her sisters and niece, and a hemizygous state in her nephew. When we checked the methylation status, we found her non-mutated allele in the GLA gene was methylated. However, the non-mutated alleles of her sisters were non-methylated, and those of her niece were partially methylated. The chromosomal and methylation study may speculate the severity of her clinical phenotypes.

    Heterozygous
    GENETICS

    Fabry
    DIAGNOSIS

    females
    GENDER

 usually have an

    attenuated form of Fabry disease
    DIAGNOSIS

, causing them to be symptomatic; however, in rare cases, they can present with a severe phenotype. In this study, we report on a

    37-year-old
    AGE

    woman
    GENDER

 with

    acroparesthesia
    SYMPTOMS

, a

    dysmorphic face
    SYMPTOMS

,

    left ventricular hypertrophy
    SYMPTOMS

, and

    intellectual disability
    SYMPTOMS

.

    Her
    GENDER

    father had Fabry disease and died due to chronic renal and congestive cardiac failure
    FAMILY

.

    Her
    GENDER

    paternal uncle had chronic renal failure and intellectual disability
    FAMILY

, and

    her
    GENDER

    paternal aunt was affected with congestive cardiac failure
    FAMILY

. The

    patient has two sisters with no significant medical illness
    FAMILY

. However,

    her
    GENDER

    nephew has acroparesthesia, anhidrosis, and school phobia
    FAMILY

, and

    her
    GENDER

    niece shows mild phenotypes
    FAMILY

. The patient's

    enzyme analysis
    PARACLINICAL

 showed

    very low α-galactosidase A (α-gal A) activity in dried blood spot (DBS), lymphocytes, and skin fibroblasts
    BIOCHEMICAL

 with

    massive excretion of Gb3 and Gb2 in urine and lyso-Gb3 in DBS and plasma
    BIOCHEMICAL

.

    Electron microscopic examination
    PARACLINICAL

 showed a

    large accumulation of sphingolipids in vascular endothelial cells and keratinocytes
    MICROSCOPIC

.

    Chromosomal analysis
    PARACLINICAL

 and

    comparative genomic hybridization microarray
    PARACLINICAL

 showed

    10q26 terminal deletion
    GENETICS

.

    Molecular data
    PARACLINICAL

 showed

    a novel heterozygous stop codon mutation in exon 1 of the GLA gene in her sisters and niece, and a hemizygous state in her nephew
    FAMILY

. When we

    checked the methylation status
    PARACLINICAL

, we found

    her
    GENDER

    non-mutated allele in the GLA gene was methylated
    GENETICS

.

    However, the non-mutated alleles of her sisters were non-methylated, and those of her niece were partially methylated
    FAMILY

. The

    chromosomal and methylation study
    PARACLINICAL

 may speculate the severity of her clinical phenotypes.

acroparesthesia
dysmorphic face
left ventricular hypertrophy
intellectual disability


General Anesthesia and Fabry Disease: A Case Report.

Fabry disease is an inherited X-linked disorder characterized by the absence (in men) or deficiency (in women) in α-galactosidase A activity that causes a progressive accumulation of glycosphingolipids within lysosomes of cells of all the major organ systems. The subsequent organ damage that manifests in childhood and early adulthood presents a widely variable clinical picture of pain, hypertension, and cardiac, renal, nervous system, and lung dysfunction. We present 2 female patients with Fabry disease who required general anesthesia twice for gynecological and trauma surgery, respectively, and discuss their perioperative management based on new information in the medical literature.

    Fabry disease
    DIAGNOSIS

 is an

    inherited X-linked disorder
    GENETICS

 characterized by the

    absence
    BIOCHEMICAL

 (in

    men
    GENDER

) or

    deficiency
    BIOCHEMICAL

 (in

    women
    GENDER

)

    in α-galactosidase A activity
    BIOCHEMICAL

 that causes a

    progressive accumulation of glycosphingolipids within lysosomes of cells of all the major organ systems
    MICROSCOPIC

. The subsequent

    organ damage
    SYMPTOMS

 that manifests in

    childhood
    AGE

    and early adulthood
    AGE

 presents a widely variable clinical picture of

    pain
    SYMPTOMS

,

    hypertension
    SYMPTOMS

, and

    cardiac
    SYMPTOMS

,

    renal, nervous system
    SYMPTOMS

, and

    lung dysfunction
    SYMPTOMS

. We present 2

    female
    GENDER

 patients with

    Fabry disease
    DIAGNOSIS

 who required

    general anesthesia
    MEDICATION

 twice for

    gynecological
    MEDICATION

 and

    trauma surgery
    MEDICATION

, respectively, and discuss their perioperative management based on new information in the medical literature.

absence
deficiency
in α-galactosidase A activity

organ damage
pain
hypertension
cardiac
renal, nervous system
lung dysfunction

general anesthesia
gynecological
trauma surgery


Clinicopathological Features of Cardiac Glycolipid Storage Disease in an Adult Pug.

A 12-year-old neutered male pug suffered cardiac arrest and died under general anaesthesia during diagnostic imaging for evaluation of exercise intolerance and respiratory crisis. Histopathological evaluation revealed two types of storage material, glycolipid and lipopigment, having differential distributions in multiple organs. The heart was most strikingly affected and other less affected tissues included the liver, brain, kidneys and skin. Cardiomyocytes were swollen with extensive sarcoplasmic vacuolation together with coalescing areas of myocardial fibrosis. Transmission electron microscopy revealed irregular myelin-like structures and complex concentric lamellar bodies dominating the sarcoplasm and displacing myofibrils. These findings were consistent with a lysosomal storage disease (LSD) as the cause of cardiac disease and death. The unique clinical presentation, histomorphology and ultrastructural features of the material suggested a glycolipid storage disease most closely resembling Anderson-Fabry (Fabry) disease in man. Fabry disease is a LSD that can present in later life and is characterized by loss of α-galactosidase A function and, often, accumulation of glycosphingolipids in tissues including the heart, kidneys, vascular endothelium and smooth muscle.

A

    12-year-old
    AGE

 neutered

    male
    GENDER

    pug
    ETHNICITY

 suffered

    cardiac arrest
    SYMPTOMS

 and

    died
    SYMPTOMS

    under general anaesthesia
    MEDICATION

 during

    diagnostic imaging
    PARACLINICAL

 for evaluation of

    exercise intolerance
    SYMPTOMS

 and

    respiratory crisis
    SYMPTOMS

.

    Histopathological evaluation
    PARACLINICAL

 revealed

    two types of storage material, glycolipid and lipopigment, having differential distributions in multiple organs
    MICROSCOPIC

.

    The heart was most strikingly affected
    SYMPTOMS

 and

    other less affected tissues included the liver, brain, kidneys and skin
    SYMPTOMS

.

    Cardiomyocytes were swollen
    SYMPTOMS

 with

    extensive sarcoplasmic vacuolation
    SYMPTOMS

 together with

    coalescing areas of myocardial fibrosis
    SYMPTOMS

.

    Transmission electron microscopy
    PARACLINICAL

 revealed

    irregular myelin-like structures and complex concentric lamellar bodies dominating the sarcoplasm and displacing myofibrils
    MICROSCOPIC

. These findings were consistent with a

    lysosomal storage disease (LSD)
    DIAGNOSIS

 as the cause of

    cardiac disease
    SYMPTOMS

 and

    death
    SYMPTOMS

. The unique clinical presentation, histomorphology and ultrastructural features of the material suggested a

    glycolipid storage disease
    DIAGNOSIS

 most closely resembling

    Anderson-Fabry (Fabry) disease
    DIAGNOSIS

 in

    man
    GENDER

.

    Fabry disease
    DIAGNOSIS

 is a

    LSD
    DIAGNOSIS

 that can present in

    later life
    AGE

 and is characterized by

    loss of α-galactosidase A function
    BIOCHEMICAL

 and, often,

    accumulation of glycosphingolipids in tissues including the heart, kidneys, vascular endothelium and smooth muscle
    MICROSCOPIC

.

lysosomal storage disease (LSD)
glycolipid storage disease
Anderson-Fabry (Fabry) disease
Fabry disease
LSD


A Renal Variant of Fabry Disease Diagnosed by the Presence of Urinary Mulberry Cells.

Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A. This disease is classified into two types, namely a classical and variant type. We herein present the case of a 36-year-old man who showed a renal variant of Fabry disease and was diagnosed at an early stage by the presence of mulberry cells. He had no history of general symptoms except for proteinuria. The presence of mulberry cells caused us to suspect Fabry disease and he was thereafter diagnosed to have a renal variant of Fabry disease based on the findings of a renal biopsy, a mutation analysis and a low level of α-galactosidase A activity.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 caused by a deficiency of α-galactosidase A. This disease is classified into two types, namely a classical and variant type. We herein present the case of a

    36-year-old
    AGE

    man
    GENDER

 who showed a

    renal variant of Fabry disease
    DIAGNOSIS

 and was diagnosed at an early stage by the

    presence of mulberry cells
    MICROSCOPIC

.

    He
    GENDER

 had

    no history of general symptoms
    NEG_FINDINGS

 except for

    proteinuria
    BIOCHEMICAL

. The

    presence of mulberry cells
    MICROSCOPIC

 caused us to suspect

    Fabry disease
    DIAGNOSIS

 and

    he
    GENDER

 was thereafter diagnosed to have a

    renal variant of Fabry disease
    DIAGNOSIS

 based on the findings of a

    renal biopsy
    PARACLINICAL

, a

    mutation analysis
    PARACLINICAL

 and a

    low level of α-galactosidase A activity
    BIOCHEMICAL

.

Fabry disease
lysosomal storage disorder
renal variant of Fabry disease
Fabry disease
renal variant of Fabry disease

proteinuria
low level of α-galactosidase A activity


Presymptomatic diagnosis of Fabry's disease: a case report.

Fabry's disease is a rare X-linked genetic disorder characterized by reduced levels of the α-galactosidase A enzyme. It may present with a cardiac phenotype resembling hypertrophic cardiomyopathy. However, as a specific enzyme replacement therapy is available, it remains an important differential diagnoses in patients presenting with cardiac hypertrophy. In boys, onset has been reported in early childhood with complaints initially comprising neuropathic pain, reduced sweat production, and gastrointestinal symptoms. Later the cardiac, renal, and central nervous systems may become affected. Female mutation carriers may remain asymptomatic or present at a later age with varying symptoms and clinical manifestations due to random inactivation of the X chromosome in different organs.

Here we present a case of Fabry's disease diagnosed in the daughter of an elderly, Caucasian woman (81 years old) with late-onset cardiac conduction disease and heart failure. We discuss the implications of cascade screening relatives of elderly probands.

Irrespective of the patient's age, physicians must be on the lookout for phenocopies when identifying patients with possibly inheritable cardiomyopathies. The specific - precise - diagnosis may be crucial for the patient as well as the relatives.

    Fabry's disease
    DIAGNOSIS

 is a

    rare X-linked genetic disorder
    GENETICS

 characterized by

    reduced levels of the α-galactosidase A enzyme
    BIOCHEMICAL

. It may present with a

    cardiac phenotype resembling hypertrophic cardiomyopathy
    SYMPTOMS

. However, as a specific

    enzyme replacement therapy
    MEDICATION

 is available, it remains an important differential diagnoses in patients presenting with

    cardiac hypertrophy
    SYMPTOMS

. In

    boys
    GENDER

, onset has been reported

    in early childhood
    AGE

 with complaints initially comprising

    neuropathic pain
    SYMPTOMS

,

    reduced sweat production
    SYMPTOMS

, and

    gastrointestinal symptoms
    SYMPTOMS

. Later the

    cardiac, renal, and central nervous systems
    SYMPTOMS

 may become affected.

    Female
    GENDER

 mutation carriers may remain

    asymptomatic
    NEG_FINDINGS

 or present at a later

    age
    AGE

 with varying symptoms and clinical manifestations due to

    random inactivation of the X chromosome in different organs
    GENETICS

.

Here we present a case of

    Fabry's disease
    DIAGNOSIS

 diagnosed in the daughter of an

    elderly
    AGE

,

    Caucasian
    ETHNICITY

    woman
    GENDER

 (

    81 years old
    AGE

) with

    late-onset cardiac conduction disease
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

. We discuss the implications of

    cascade screening
    PARACLINICAL

 relatives of

    elderly
    AGE

 probands.

Irrespective of the patient's age, physicians must be on the lookout for

    phenocopies
    FAMILY

 when identifying patients with possibly

    inheritable cardiomyopathies
    DIAGNOSIS

. The specific - precise - diagnosis may be crucial for the patient as well as the relatives.

Fabry's disease
Fabry's disease
inheritable cardiomyopathies


Identification of a novel GLA mutation (Y88C) in a Korean family with Fabry nephropathy: a case report.

Fabry disease is a rare X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. With the advancement of molecular diagnostic tools, more disease-causing mutations in α-galactosidase A (GLA) have been identified in Fabry disease. We found a novel mutation in a Korean family with predominant renal manifestations of the disease.

A 24-year-old man who wanted to donate a kidney to his 28-year-old brother with end-stage renal disease of unknown cause was evaluated. The 24-year-old man underwent percutaneous renal biopsy because of an accidentally found proteinuria. Electron microscopy of his renal biopsy showed numerous electron-dense multi-lamellar inclusions in the epithelial cytoplasm, typical for Fabry disease. Clinical and laboratory evaluation including the assessment of GLA enzyme activity and direct DNA sequencing in four members of the family were performed. Renal biopsy findings in the two affected male patients were described. Re-evaluation of a renal biopsy specimen of his 28-year-old brother obtained when he was diagnosed with renal failure revealed a very focal area of suspicious multilamellated structures in the Bowman's space. DNA sequencing on the young man, his brother, and his mother revealed a novel GLA gene mutation, c.263A > G (p.Tyr88Cys). The three all showed decreased α-galactosidase A activity.

A novel GLA mutation, c.263A > G (p.Tyr88Cys), was found in a Korean family with predominant renal manifestations of Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    α-galactosidase A deficiency
    BIOCHEMICAL

. With the advancement of molecular diagnostic tools, more

    disease-causing mutations in α-galactosidase A (GLA)
    GENETICS

 have been identified in

    Fabry disease
    DIAGNOSIS

. We found a

    novel mutation
    GENETICS

 in a

    Korean
    ETHNICITY

 family with

    predominant renal manifestations of the disease
    SYMPTOMS

.

A

    24-year-old
    AGE

    man
    GENDER

 who wanted to

    donate a kidney to
    MEDICATION

 his

    28-year-old
    AGE

    brother
    GENDER

 with

    end-stage renal disease of unknown cause
    DIAGNOSIS

 was evaluated. The

    24-year-old
    AGE

    man
    GENDER

 underwent

    percutaneous renal biopsy
    PARACLINICAL

 because of an accidentally found

    proteinuria
    BIOCHEMICAL

.

    Electron microscopy of his renal biopsy
    PARACLINICAL

 showed

    numerous electron-dense multi-lamellar inclusions in the epithelial cytoplasm, typical for Fabry disease
    MICROSCOPIC

.

    Clinical and laboratory evaluation
    PARACLINICAL

 including the

    assessment of GLA enzyme activity
    PARACLINICAL

 and

    direct DNA sequencing
    PARACLINICAL

 in four members of the family were performed.

    Renal biopsy
    PARACLINICAL

 findings in the two affected

    male
    GENDER

 patients were described.

    Re-evaluation of a renal biopsy specimen
    PARACLINICAL

 of his

    28-year-old
    AGE

    brother
    GENDER

 obtained when

    he
    GENDER

 was diagnosed with

    renal failure
    SYMPTOMS

 revealed a

    very focal area of suspicious multilamellated structures in the Bowman's space
    MICROSCOPIC

.

    DNA sequencing
    PARACLINICAL

 on the

    young
    AGE

    man
    GENDER

, his

    brother
    GENDER

, and his

    mother
    GENDER

 revealed a

    novel GLA gene mutation, c.263A > G (p.Tyr88Cys)
    GENETICS

. The three all showed

    decreased α-galactosidase A activity
    BIOCHEMICAL

.

A

    novel GLA mutation, c.263A > G (p.Tyr88Cys)
    GENETICS

, was found in a

    Korean
    ETHNICITY

    family with predominant renal manifestations of Fabry disease
    FAMILY

.

α-galactosidase A deficiency
proteinuria
decreased α-galactosidase A activity


Differential diagnosis of left ventricular hypertrophy: usefulness of multimodality imaging and tissue characterization with cardiac magnetic resonance.

Differential diagnosis of asymmetrical left ventricular hypertrophy may be challenging, particularly in patients with history of hypertension. A middle-aged man underwent an echocardiographic examination during workup for hypertension, which unexpectedly showed significant asymmetrical septal hypertrophy and raised suspicion for hypertrophic cardiomyopathy. Cardiovascular magnetic resonance confirmed the asymmetrical hypertrophy. No myocardial late gadolinium contrast enhancement was seen. However, precontrast T1 mapping revealed a low native myocardial T1 value. This was highly suggestive of Anderson-Fabry disease, which was subsequently proved with very low alpha galactosidase enzyme levels and mutation analysis. The case illustrates clinical usefulness of multimodality imaging and the novel tissue characterization techniques for assessment of left ventricular hypertrophy.

    Differential diagnosis
    PARACLINICAL

 of

    asymmetrical left ventricular hypertrophy
    SYMPTOMS

 may be challenging, particularly in patients with history of

    hypertension
    SYMPTOMS

. A

    middle-aged
    AGE

    man
    GENDER

 underwent an

    echocardiographic examination
    PARACLINICAL

 during workup for

    hypertension
    DIAGNOSIS

, which unexpectedly showed

    significant asymmetrical septal hypertrophy
    SYMPTOMS

 and raised suspicion for

    hypertrophic cardiomyopathy
    DIAGNOSIS

.

    Cardiovascular magnetic resonance
    PARACLINICAL

 confirmed the

    asymmetrical hypertrophy
    SYMPTOMS

.

    No myocardial late gadolinium contrast enhancement was seen
    NEG_FINDINGS

. However,

    precontrast T1 mapping
    PARACLINICAL

 revealed a

    low native myocardial T1 value
    SYMPTOMS

. This was highly suggestive of

    Anderson-Fabry disease
    DIAGNOSIS

, which was subsequently proved with

    very low alpha galactosidase enzyme levels
    BIOCHEMICAL

 and

    mutation analysis
    PARACLINICAL

. The case illustrates clinical usefulness of

    multimodality imaging
    PARACLINICAL

 and the novel tissue characterization techniques for assessment of

    left ventricular hypertrophy
    SYMPTOMS

.

hypertension
hypertrophic cardiomyopathy
Anderson-Fabry disease


Novel α-Galactosidase A Mutation (K391E) in a Young Woman With Severe Cardiac and Renal Manifestations of Fabry Disease.

Fabry disease, an X-linked lysosomal storage disorder due to α-galactosidase A deficiency, is associated with dysfunction of various cell types and results in a systemic vasculopathy. We describe a 29-year-old woman with Fabry disease presenting with severe cardiac and renal manifestations. Gene analysis demonstrated a novel mutation (K391E) in the GLA gene. Enzyme replacement therapy (ERT) was started with agalsidase-β after confirming the diagnosis of Fabry disease, resulting in normalization of LV systolic function and improvement of renal function. As early therapy is crucial for preventing life-threatening sequelae, clinicians should consider Fabry disease in young patients presenting with cardiac and renal disease without any likely causes.

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 due to

    α-galactosidase A deficiency
    BIOCHEMICAL

, is associated with

    dysfunction of various cell types
    MICROSCOPIC

 and results in a

    systemic vasculopathy
    SYMPTOMS

. We describe a

    29-year-old
    AGE

    woman
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 presenting with

    severe cardiac and renal manifestations
    SYMPTOMS

.

    Gene analysis
    PARACLINICAL

 demonstrated a

    novel mutation (K391E) in the GLA gene
    GENETICS

.

    Enzyme replacement therapy (ERT) was started with agalsidase-β
    MEDICATION

 after confirming the diagnosis of

    Fabry disease
    DIAGNOSIS

, resulting in

    normalization of LV systolic function
    SYMPTOMS

 and

    improvement of renal function
    SYMPTOMS

. As

    early therapy
    MEDICATION

 is crucial for preventing

    life-threatening sequelae
    SYMPTOMS

, clinicians should consider

    Fabry disease
    DIAGNOSIS

 in

    young
    AGE

 patients presenting with

    cardiac and renal disease
    SYMPTOMS

    without any likely causes
    NEG_FINDINGS

.

X-linked
novel mutation (K391E) in the GLA gene

systemic vasculopathy
severe cardiac and renal manifestations
normalization of LV systolic function
improvement of renal function
life-threatening sequelae
cardiac and renal disease


Case report of a 45-year old female Fabry disease patient carrying two alpha-galactosidase A gene mutation alleles.

X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown.

This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations.

This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation.

    X-chromosomal inheritance patterns
    GENETICS

 and generally rare occurrence of

    Fabry disease (FD)
    DIAGNOSIS

 account for

    mono-mutational hemizygous male
    GENETICS

 and

    heterozygous
    GENETICS

    female
    GENDER

 patients.

    Female
    GENDER

    mutation carriers
    GENETICS

 are usually

    clinically much less severely affected
    SYMPTOMS

, which has been explained by a suggested

    mosaicism in cell phenotype
    GENETICS

 due to

    random allele shutdown
    GENETICS

. However, clinical evidence is scarce and potential additional effects in

    female
    GENDER

    gene carriers
    GENETICS

, which might account for specific clinical characteristics such as

    less severe chronic kidney disease
    SYMPTOMS

, are yet unknown.

This article reports on a

    45 year old
    AGE

    female
    GENDER

 patient carrying

    the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5
    GENETICS

, but still showing

    only mild organ manifestations
    SYMPTOMS

.

This current case highlights the importance of careful clinical characterization in patients with

    Fabry disease
    DIAGNOSIS

, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the

    presence of a non-pathogenic GLA allele
    GENETICS

 in

    female
    GENDER

    gene carriers
    GENETICS

 requires further investigation.

clinically much less severely affected
less severe chronic kidney disease
only mild organ manifestations


Fabry's Disease: Case Series and Review of Literature.

Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A enzyme with the progressive accumulation of globotriaosylceramide in vascular endothelial cells leading to cardiovascular, renal, gastrointestinal, neuropathic, lenticular, and dermatological manifestations. It is a rare cause of end-stage renal disease. It classically affects males whereas 10-15% of female heterozygote carriers are affected depending on localization. Both the FD and its association with ESRD is rare. With this background, this case series of five patient's along with the review of literature is presented here.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of alpha-galactosidase A enzyme
    BIOCHEMICAL

 with the

    progressive accumulation of globotriaosylceramide in vascular endothelial cells
    MICROSCOPIC

 leading to

    cardiovascular, renal, gastrointestinal, neuropathic, lenticular, and dermatological manifestations
    SYMPTOMS

. It is a rare cause of

    end-stage renal disease
    DIAGNOSIS

. It classically affects

    males
    GENDER

 whereas 10-15% of

    female
    GENDER

    heterozygote
    GENETICS

 carriers are affected depending on localization. Both the

    FD
    DIAGNOSIS

 and its association with

    ESRD
    DIAGNOSIS

 is rare. With this background, this case series of five patient's along with the review of literature is presented here.

Fabry's disease
lysosomal storage disorder
end-stage renal disease
FD
ESRD


59-year-old female with breathlessness.

A 59-year-old female underwent an electrocardiogram (ECG) and echocardiographic screening. Her brother died at quite a young age of kidney failure. Resting ECG showed borderline voltage criteria for left ventricular hypertrophy (LVH), with marked widespread T-wave inversion. Echocardiogram was normal, but in consideration of exertional breathlessness and abnormal baseline ECG, she underwent a coronary angiogram, which showed unobstructed coronaries. She was then referred to have a cardiac MR (CMR) for further characterisation. CMR images were acquired with a 1.5 T scanner and the imaging protocol included Steady-State Free Precession (SSFP) cine images (Figure 1A) as well as late gadolinium enhancement (LGE) images in the long-axis and short-axis planes covering the whole left ventricle (Figure 1B). In addition, native and postcontrast T1 mapping (Modified Look-Locker (MOLLI)) images were acquired for further tissue characterisation (Figure 1C and D, respectively).

What is the most likely diagnosis based on CMR findings? Anderson-Fabry's disease (AFD)Cardiac amyloidosisGenotype (+), phenotype (-) hypertrophic cardiomyopathy (HCM)Myocardial iron overloadNormal heart.

A

    59-year-old
    AGE

    female
    GENDER

 underwent an

    electrocardiogram (ECG)
    PARACLINICAL

 and

    echocardiographic screening
    PARACLINICAL

.

    Her
    GENDER

    brother died at quite a young age of kidney failure
    FAMILY

.

    Resting ECG
    PARACLINICAL

 showed

    borderline voltage criteria for left ventricular hypertrophy (LVH)
    SYMPTOMS

, with

    marked widespread T-wave inversion
    SYMPTOMS

.

    Echocardiogram was normal
    NEG_FINDINGS

, but in consideration of

    exertional breathlessness
    SYMPTOMS

 and

    abnormal baseline ECG
    SYMPTOMS

,

    she
    GENDER

 underwent a

    coronary angiogram
    PARACLINICAL

, which showed

    unobstructed coronaries
    NEG_FINDINGS

.

    She
    GENDER

 was then referred to have a

    cardiac MR (CMR)
    PARACLINICAL

 for further characterisation.

    CMR images were acquired with a 1.5 T scanner
    PARACLINICAL

 and the imaging protocol included

    Steady-State Free Precession (SSFP) cine images
    PARACLINICAL

 (Figure 1A) as well as

    late gadolinium enhancement (LGE) images in the long-axis and short-axis planes covering the whole left ventricle
    PARACLINICAL

 (Figure 1B). In addition,

    native and postcontrast T1 mapping (Modified Look-Locker (MOLLI)) images
    PARACLINICAL

 were acquired for further tissue characterisation (Figure 1C and D, respectively).

What is the most likely diagnosis based on

    CMR
    PARACLINICAL

 findings?

    Anderson-Fabry's disease (AFD)Cardiac amyloidosisGenotype (+)
    DIAGNOSIS

,

    phenotype (-) hypertrophic cardiomyopathy (HCM)Myocardial iron overloadNormal heart
    DIAGNOSIS

.

Echocardiogram was normal
unobstructed coronaries


[Combined heart and kidney transplantation in Fabry's disease: Long-term outcomes in two patients].

Fabry disease is a lysosomal storage disorder linked to an alpha-galactosidase A deficiency that can lead to heart and kidney failure. There is little data about the prognosis of patients who undergo a combined heart and kidney transplantation.

Two brothers who were diagnosed with Fabry disease after the age of 30 years underwent a combined heart and kidney transplantation at respectively 49 and 42 years of age because of a severe hypertrophic cardiomyopathy with end stage renal failure. They are alive respectively 4 and 9 years after the transplantation. No recurrence of the disease in the transplanted organs has been found.

Combined heart and kidney transplantation in Fabry disease is an efficient therapy for the cardiomyopathy and kidney failure. Its prognosis can be good when the patients are carefully selected. However, an early diagnosis is critical in order to avoid a procedure associated with a high perioperative mortality.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 linked to an

    alpha-galactosidase A deficiency
    BIOCHEMICAL

 that can lead to

    heart and kidney failure
    SYMPTOMS

. There is little data about the prognosis of patients who undergo a

    combined heart and kidney transplantation
    MEDICATION

.

Two

    brothers
    GENDER

 who were diagnosed with

    Fabry disease
    DIAGNOSIS

    after the age of 30 years
    AGE

    underwent a combined heart and kidney transplantation
    MEDICATION

 at respectively

    49 and 42 years of age
    AGE

 because of a

    severe hypertrophic cardiomyopathy
    DIAGNOSIS

 with

    end stage renal failure
    SYMPTOMS

. They are alive respectively 4 and 9 years after the

    transplantation
    MEDICATION

.

    No recurrence of the disease in the transplanted organs
    NEG_FINDINGS

 has been found.

    Combined heart and kidney transplantation
    MEDICATION

 in

    Fabry disease
    DIAGNOSIS

 is an efficient therapy for the

    cardiomyopathy
    DIAGNOSIS

 and

    kidney failure
    SYMPTOMS

. Its prognosis can be good when the patients are carefully selected. However, an early diagnosis is critical in order to avoid a procedure associated with a high perioperative mortality.

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

heart and kidney failure
end stage renal failure
kidney failure


Sudden death following AV node ablation in a man with Fabry disease mimicking hypertrophic cardiomyopathy.

We present a case of Fabry disease with an uncommon pattern of asymmetrical hypertrophy with septal prominence resulting in an erroneous diagnosis of hypertrophic cardilmyopathy clinically. The deceased presented for a medicolegal autopsy following his sudden death after an AV node ablation. Fabry disease continues to be an important misdiagnosis of hypertrophic cardiomyopathy in a clinical setting. Early diagnosis of Fabry disease is essential so that early treatment can be instituted.

We present a case of

    Fabry disease
    DIAGNOSIS

 with an

    uncommon pattern of asymmetrical hypertrophy with septal prominence
    SYMPTOMS

 resulting in an

    erroneous diagnosis of hypertrophic cardilmyopathy clinically
    NEG_FINDINGS

. The

    deceased
    GENDER

 presented for a

    medicolegal autopsy
    PARACLINICAL

 following

    his
    GENDER

    sudden death
    SYMPTOMS

 after an

    AV node ablation
    MEDICATION

.

    Fabry disease
    DIAGNOSIS

 continues to be an important misdiagnosis of

    hypertrophic cardiomyopathy
    DIAGNOSIS

 in a clinical setting. Early diagnosis of

    Fabry disease
    DIAGNOSIS

 is essential so that

    early treatment
    MEDICATION

 can be instituted.

Fabry disease
Fabry disease
hypertrophic cardiomyopathy
Fabry disease


Reaccumulation of globotriaosylceramide in podocytes after agalsidase dose reduction in young Fabry patients.

Agalsidase-α 0.2 mg/kg every other week (eow) and agalsidase-β 1.0 mg/kg/eow are licensed in Europe as equipotent treatment of the α-galactosidase deficiency in Fabry disease. This case series describes the effects of agalsidase dose adjustments in serial kidney biopsies in switch patients.

All treatment-naïve patients with classical Fabry disease in our centre started on agalsidase-β 1.0 mg/kg/eow and subsequently switched to agalsidase-α 0.2 mg/kg/eow were included (n = 3). The median age at enzyme replacement therapy start was 11 (range 7-18) years. Kidney biopsies were performed at baseline, after 5 years of agalsidase-β 1.0 mg/kg/eow and after 3 subsequent years of agalsidase-α 0.2 mg/kg/eow. One patient was re-biopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. The scoring system of the International Scoring Group of Fabry Nephropathy was used.

The patients completely cleared globotriaosylceramide (GL3) from mesangial and endothelial cells and partly cleared podocytes on agalsidase-β 1.0 mg/kg/eow. Reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium, occurred after 3 years of agalsidase-α 0.2 mg/kg/eow. Subsequent reduction of podocyte GL3 was observed in the single patient rebiopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow.

Partial clearance, reaccumulation and renewed partial clearance of podocyte GL3 deposits in serial kidney biopsies over 8-10 years were seen in parallel with agalsidase dose adjustments. Repeated kidney biopsies may impact therapeutic choices in Fabry disease.

    Agalsidase-α 0.2 mg/kg every other week (eow) and agalsidase-β 1.0 mg/kg/eow
    MEDICATION

 are licensed in Europe as equipotent treatment of the

    α-galactosidase deficiency
    BIOCHEMICAL

 in

    Fabry disease
    DIAGNOSIS

. This case series describes the effects of

    agalsidase dose adjustments
    MEDICATION

 in

    serial kidney biopsies
    PARACLINICAL

 in switch patients.

All

    treatment-naïve
    MEDICATION

 patients with

    classical Fabry disease
    DIAGNOSIS

 in our centre

    started on agalsidase-β 1.0 mg/kg/eow
    MEDICATION

 and subsequently

    switched to agalsidase-α 0.2 mg/kg/eow
    MEDICATION

 were included (n = 3). The

    median age at enzyme replacement therapy start
    AGE

    was 11 (range 7-18) years
    AGE

.

    Kidney biopsies
    PARACLINICAL

 were performed at baseline,

    after 5 years of agalsidase-β 1.0 mg/kg/eow
    MEDICATION

 and

    after 3 subsequent years of agalsidase-α 0.2 mg/kg/eow
    MEDICATION

. One patient was

    re-biopsied
    PARACLINICAL

 2 years after

    reswitch to agalsidase-β 1.0 mg/kg/eow
    MEDICATION

. The scoring system of the International Scoring Group of

    Fabry Nephropathy
    DIAGNOSIS

 was used.

The patients

    completely cleared globotriaosylceramide (GL3) from mesangial and endothelial cells
    MICROSCOPIC

 and

    partly cleared podocytes
    MICROSCOPIC

    on agalsidase-β 1.0 mg/kg/eow
    MEDICATION

.

    Reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium
    MICROSCOPIC

, occurred after

    3 years of agalsidase-α 0.2 mg/kg/eow
    MEDICATION

.

    Subsequent reduction of podocyte GL3
    BIOCHEMICAL

 was observed in the single patient rebiopsied 2 years after

    reswitch to agalsidase-β 1.0 mg/kg/eow
    MEDICATION

.

    Partial clearance
    BIOCHEMICAL

,

    reaccumulation
    MICROSCOPIC

 and

    renewed partial clearance of podocyte GL3 deposits in serial kidney biopsies over 8-10 years
    MICROSCOPIC

 were seen in parallel with

    agalsidase dose adjustments
    MEDICATION

.

    Repeated kidney biopsies
    PARACLINICAL

 may impact therapeutic choices in

    Fabry disease
    DIAGNOSIS

.

α-galactosidase deficiency
Subsequent reduction of podocyte GL3
Partial clearance

Fabry disease
classical Fabry disease
Fabry Nephropathy
Fabry disease


X-Chromosome Inactivation Analysis in Different Cell Types and Induced Pluripotent Stem Cells Elucidates the Disease Mechanism in a Rare Case of Mucopolysaccharidosis Type II in a Female.

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder resulting from deficiency of iduronate-2-sulphatase activity. The disease manifests almost exclusively in males; only 16 symptomatic heterozygote girls have been reported so far. We describe the results of X-chromosome inactivation analysis in a 5-year-old girl with clinically severe disease and heterozygous mutation p.Arg468Gln in the IDS gene. X inactivation analysed at three X-chromosome loci showed extreme skewing (96/4 to 99/1) in two patient's cell types. This finding correlated with exclusive expression of the mutated allele. Induced pluripotent stem cells (iPSC) generated from the patient's peripheral blood demonstrated characteristic pluripotency markers, deficiency of enzyme activity, and mutation in the IDS gene. These cells were capable of differentiation into other cell types (cardiomyocytes, neurons). In MPS II iPSC clones, the X inactivation ratio remained highly skewed in culture conditions that led to partial X inactivation reset in Fabry disease iPSC clones. Our data, in accordance with the literature, suggest that extremely skewed X inactivation favouring the mutated allele is a crucial condition for manifestation of MPS II in females. This suggests that the X inactivation status and enzyme activity have a prognostic value and should be used to evaluate MPS II in females. For the first time, we show generation of iPSC from a symptomatic MPS II female patient that can serve as a cellular model for further research of the pathogenesis and treatment of this disease.

    Mucopolysaccharidosis type II (MPS II)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from

    deficiency of iduronate-2-sulphatase activity
    BIOCHEMICAL

. The disease manifests almost exclusively in

    males
    GENDER

; only 16 symptomatic heterozygote

    girls
    GENDER

 have been reported so far. We describe the results of

    X-chromosome inactivation analysis
    PARACLINICAL

 in a

    5-year-old
    AGE

    girl
    GENDER

 with

    clinically severe disease
    SYMPTOMS

 and

    heterozygous mutation p.Arg468Gln in the IDS gene
    GENETICS

.

    X inactivation analysed at three X-chromosome loci showed extreme skewing (96/4 to 99/1) in two patient's cell types
    GENETICS

. This finding correlated with

    exclusive expression of the mutated allele
    GENETICS

.

    Induced pluripotent stem cells (iPSC)
    MICROSCOPIC

 generated from the patient's

    peripheral blood
    MICROSCOPIC

 demonstrated

    characteristic pluripotency markers
    MICROSCOPIC

,

    deficiency of enzyme activity
    BIOCHEMICAL

, and

    mutation in the IDS gene
    GENETICS

. These cells were

    capable of differentiation into other cell types (cardiomyocytes, neurons)
    MICROSCOPIC

. In

    MPS II iPSC clones
    MICROSCOPIC

,

    the X inactivation ratio remained highly skewed
    GENETICS

 in culture conditions that led to

    partial X inactivation reset
    GENETICS

    in Fabry disease iPSC clones
    MICROSCOPIC

. Our data, in accordance with the literature, suggest that

    extremely skewed X inactivation favouring the mutated allele
    GENETICS

 is a crucial condition for manifestation of

    MPS II
    DIAGNOSIS

 in

    females
    GENDER

. This suggests that the

    X inactivation status
    PARACLINICAL

 and

    enzyme activity
    BIOCHEMICAL

 have a prognostic value and should be used to evaluate

    MPS II
    DIAGNOSIS

 in

    females
    GENDER

. For the first time, we show generation of

    iPSC
    MEDICATION

 from a symptomatic

    MPS II
    DIAGNOSIS

    female
    GENDER

 patient that can serve as a cellular model for further research of the pathogenesis and treatment of this disease.

Mucopolysaccharidosis type II (MPS II)
lysosomal storage disorder
MPS II
MPS II
MPS II


Familial hypertrophic obstructive cardiomyopathy with the GLA E66Q mutation and zebra body.

Fabry disease is caused by mutations in the α-galactosidase A (GLA) gene, which is located in X-chromosome coding for the lysosomal enzyme of GLA. Among many gene mutations, E66Q mutation is under discussion for its pathogenicity because there is no clinical report showing pathological evidence of Fabry disease with E66Q mutation.

A 65-year-old Japanese female was referred to our hospital for chest discomfort on effort. Transthoracic echocardiography showed severe left ventricular (LV) hypertrophy with LV outflow obstruction. Maximum LV outflow pressure gradient was 87 mmHg, and Valsalva maneuver increased the pressure gradient up to 98 mmHg. According to medical interview, one of her younger sister and a nephew died suddenly at age 42 and 36, respectively. Another younger sister also presented LV hypertrophy with outflow obstruction. Maximum LV outflow pressure gradient was 100 mmHg, and the E66Q mutation was detected similar to the case. Endomyocardial biopsy specimens presented vacuolation of cardiomyocytes, in which zebra bodies were detected by electron microscopic examination. Although the enzymatic activity of GLA was within normal range, the c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene, was detected. We initially diagnosed her as cardiac Fabry disease based on the findings of zebra body. However, immunostaining showed few deposition of globotriaosylceramide in left ventricular myocardium, and gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6, were detected. Although the pathogenicity of the E66Q mutation cannot be ruled out, hypertrophic obstructive cardiomyopathy (HOCM) was more reasonable to explain the pathophysiology in the case.

This is the confusable case of HOCM with Fabry disease with the GLA E66Q mutation. We have to take into consideration the possibility that some patients with the E66Q mutation may have similar histological findings of Fabry disease, and should be examed the possibility for harboring gene mutations associated with HCM.

    Fabry disease
    DIAGNOSIS

 is caused by

    mutations in the α-galactosidase A (GLA) gene, which is located in X-chromosome coding for the lysosomal enzyme of GLA
    GENETICS

. Among many

    gene mutations
    GENETICS

,

    E66Q mutation
    GENETICS

 is under discussion for its pathogenicity because there is no clinical report showing pathological evidence of

    Fabry disease
    DIAGNOSIS

 with

    E66Q mutation
    GENETICS

.

A

    65-year-old
    AGE

    Japanese
    ETHNICITY

    female
    GENDER

 was referred to our hospital for

    chest discomfort on effort
    SYMPTOMS

.

    Transthoracic echocardiography
    PARACLINICAL

 showed

    severe left ventricular (LV) hypertrophy
    SYMPTOMS

 with

    LV outflow obstruction
    SYMPTOMS

.

    Maximum LV outflow pressure gradient was 87 mmHg
    SYMPTOMS

, and Valsalva maneuver

    increased the pressure gradient up to 98 mmHg
    SYMPTOMS

. According to medical interview,

    one of her younger sister and a nephew died suddenly at age 42 and 36, respectively
    FAMILY

.

    Another younger sister also presented LV hypertrophy with outflow obstruction
    FAMILY

.

    Maximum LV outflow pressure gradient was 100 mmHg
    SYMPTOMS

, and the

    E66Q mutation
    GENETICS

 was detected similar to the case.

    Endomyocardial biopsy specimens
    PARACLINICAL

 presented

    vacuolation of cardiomyocytes, in which zebra bodies
    MICROSCOPIC

 were detected by

    electron microscopic examination
    PARACLINICAL

.

    Although the enzymatic activity of GLA was within normal range
    NEG_FINDINGS

, the

    c. 196G>C nucleotide change, which lead to the E66Q mutation of GLA gene
    GENETICS

, was detected. We initially diagnosed

    her
    GENDER

 as

    cardiac Fabry disease
    DIAGNOSIS

 based on the findings of

    zebra body
    MICROSCOPIC

. However,

    immunostaining
    PARACLINICAL

 showed

    few deposition of globotriaosylceramide in left ventricular myocardium
    MICROSCOPIC

, and

    gene mutations in the disease genes for hypertrophic cardiomyopathy (HCM), MYBPC3 and MYH6
    GENETICS

, were detected. Although the pathogenicity of the

    E66Q mutation
    GENETICS

 cannot be ruled out,

    hypertrophic obstructive cardiomyopathy (HOCM)
    DIAGNOSIS

 was more reasonable to explain the pathophysiology in the case.

This is the confusable case of

    HOCM
    DIAGNOSIS

 with

    Fabry disease
    DIAGNOSIS

 with the

    GLA E66Q mutation
    GENETICS

. We have to take into consideration the possibility that some patients with the

    E66Q mutation
    GENETICS

 may have

    similar histological findings of Fabry disease
    SYMPTOMS

, and should be examed the possibility for harboring

    gene mutations associated with HCM
    GENETICS

.


p.R301X Mutation and Variable Phenotypic Appearance of Fabry Disease.

Fabry disease is an X-linked disorder. Due to deficiency of the enzyme a-galactosidase A, neutral glycosphingolipids (primarily globotriaosylceramide) progressively accumulate within lysosomes of cells in various organ systems, resulting in a multi-system disorder, affecting both men and women. Misdiagnosis and delayed diagnosis are common because of the nature of Fabry disease.

We report a case of Fabry disease with a p.R301X (c.901 C>T) mutation in a 39-year-old man who was being treated for chronic sclerosing glomerulonephritis for 2 years. Family screening tests showed that the proband's mother, sister, and daughter had the same mutation with different phenotypes. Levels of α-galactosidase A were low in the proband and his mother and sister. Cornea verticillata and heart involvement were present in multiple family members. Agalsidase alfa treatment was started in patients where indicated.

Pedigree analysis is still a powerful, readily available tool to identify individuals at risk for genetic diseases and allows earlier detection and management of disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

. Due to

    deficiency of the enzyme a-galactosidase A
    BIOCHEMICAL

,

    neutral glycosphingolipids (primarily globotriaosylceramide) progressively accumulate within lysosomes of cells in various organ systems
    MICROSCOPIC

, resulting in a

    multi-system disorder
    DIAGNOSIS

, affecting both

    men
    GENDER

 and

    women
    GENDER

. Misdiagnosis and delayed diagnosis are common because of the nature of

    Fabry disease
    DIAGNOSIS

.

We report a case of

    Fabry disease
    DIAGNOSIS

 with a

    p.R301X (c.901 C>T) mutation
    GENETICS

 in a

    39-year-old
    AGE

    man
    GENDER

 who was being treated for

    chronic sclerosing glomerulonephritis for 2 years
    DIAGNOSIS

.

    Family screening tests
    PARACLINICAL

 showed that

    the proband's mother, sister, and daughter had the same mutation with different phenotypes
    FAMILY

.

    Levels of α-galactosidase A were low in the proband and his mother and sister
    BIOCHEMICAL

.

    Cornea verticillata
    SYMPTOMS

 and

    heart involvement
    SYMPTOMS

    were present in multiple family members
    FAMILY

.

    Agalsidase alfa treatment
    MEDICATION

 was started in patients where indicated.

    Pedigree analysis
    PARACLINICAL

 is still a powerful, readily available tool to identify individuals at risk for

    genetic diseases
    GENETICS

 and allows earlier detection and management of disease.

X-linked disorder
p.R301X (c.901 C>T) mutation
genetic diseases


Severe Cardiomyopathy as the Isolated Presenting Feature in an Adult with Late-Onset Pompe Disease: A Case Report.

Many inborn errors of metabolism can cause cardiomyopathy. Cardiomyopathy associated with glycogen storage includes PRKAG2-associated glycogen storage disease (GSD), Danon disease, infantile-onset Pompe disease (GSD II), GSD III, GSD IV, and phosphofructokinase deficiency (Tarui disease or GSD VII).We present a 35-year-old female who presented with cardiomyopathy after a pregnancy complicated by primary hyperparathyroidism. She had enjoyed excellent health until her first pregnancy at age 33. One week postpartum, she developed dyspnea and an echocardiogram revealed left ventricular ejection fraction (LVEF) of 35%. A cardiac MRI was consistent with nonischemic cardiomyopathy with an infiltrative process. Endomyocardial biopsy showed striking sarcoplasmic vacuolization, excess glycogen by PAS staining, and frequent membrane-bound glycogen by electron microscopy, consistent with lysosomal GSD. Acid alpha-glucosidase (GAA) activity in skin fibroblasts was in the affected range for Pompe disease. Sequencing of the GAA gene revealed a paternally inherited pathogenic c.525delT (p.Glu176Argfs*45) and a de novo c.309C>G (p.Cys103Trp) with unknown pathogenicity. Testing of the familial mutations in her daughter indicated that the variants in the proband were in trans. 26-gene cardiomyopathy sequencing panel had normal results thereby excluding GSD III, Danon disease, Fabry disease, and PRKAG2-associated cardiomyopathy. Therefore, results strongly suggest a diagnosis of Pompe disease.Pompe disease has a broad disease spectrum, including infantile-onset (IOPD) and late-onset (LOPD) forms. LOPD typically presents with proximal muscle weakness and respiratory insufficiency in childhood or late adulthood. Our case may represent a very unusual presentation of adult LOPD with isolated cardiomyopathy without skeletal muscle involvement or respiratory failure.

Many

    inborn errors of metabolism
    GENETICS

 can cause

    cardiomyopathy
    DIAGNOSIS

.

    Cardiomyopathy associated with glycogen storage
    DIAGNOSIS

 includes

    PRKAG2-associated glycogen storage disease (GSD)
    DIAGNOSIS

,

    Danon disease
    DIAGNOSIS

,

    infantile-onset Pompe disease (GSD II)
    DIAGNOSIS

,

    GSD III
    DIAGNOSIS

,

    GSD IV
    DIAGNOSIS

, and phosphofructokinase deficiency (Tarui disease or GSD VII).We present a

    35-year-old
    AGE

    female
    GENDER

 who presented with

    cardiomyopathy
    SYMPTOMS

 after a

    pregnancy
    DIAGNOSIS

 complicated by

    primary hyperparathyroidism
    SYMPTOMS

.

    She
    GENDER

 had

    enjoyed excellent health until her first pregnancy at age 33
    MEDICATION

. One week

    postpartum
    AGE

,

    she
    GENDER

 developed

    dyspnea
    SYMPTOMS

 and an

    echocardiogram
    PARACLINICAL

 revealed

    left ventricular ejection fraction (LVEF) of 35%
    SYMPTOMS

. A

    cardiac MRI
    PARACLINICAL

 was consistent with

    nonischemic cardiomyopathy with an infiltrative process
    SYMPTOMS

.

    Endomyocardial biopsy
    PARACLINICAL

 showed

    striking sarcoplasmic vacuolization
    MICROSCOPIC

,

    excess glycogen by PAS staining
    MICROSCOPIC

, and

    frequent membrane-bound glycogen
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

, consistent with

    lysosomal GSD
    DIAGNOSIS

.

    Acid alpha-glucosidase (GAA) activity in skin fibroblasts was in the affected range for Pompe disease
    BIOCHEMICAL

.

    Sequencing of the GAA gene
    PARACLINICAL

 revealed a

    paternally inherited pathogenic c.525delT (p.Glu176Argfs*45) and a de novo c.309C>G (p.Cys103Trp) with unknown pathogenicity
    GENETICS

.

    Testing of the familial mutations in her daughter indicated that the variants in the proband were in trans
    FAMILY

.

    26-gene cardiomyopathy sequencing panel had normal results
    NEG_FINDINGS

 thereby

    excluding GSD III
    NEG_FINDINGS

,

    Danon disease
    DIAGNOSIS

,

    Fabry disease
    DIAGNOSIS

, and

    PRKAG2-associated cardiomyopathy
    DIAGNOSIS

. Therefore, results strongly suggest a diagnosis of

    Pompe disease
    DIAGNOSIS

.

    Pompe disease
    DIAGNOSIS

 has a broad disease spectrum, including

    infantile-onset (IOPD)
    DIAGNOSIS

 and

    late-onset (LOPD) forms
    DIAGNOSIS

.

    LOPD
    DIAGNOSIS

 typically presents with

    proximal muscle weakness
    SYMPTOMS

 and

    respiratory insufficiency
    SYMPTOMS

    in childhood or late adulthood
    AGE

. Our case may represent a very unusual presentation of

    adult LOPD
    DIAGNOSIS

 with

    isolated cardiomyopathy
    SYMPTOMS

    without skeletal muscle involvement
    NEG_FINDINGS

 or

    respiratory failure
    SYMPTOMS

.


Wolff-Parkinson-White and left ventricular noncompaction in a Fabry patient: A case report.

Fabry disease is the second most common inherited (X-linked recessive) lysosomal storage disease associated with multiple organ involvement. Cardiac involvement of Fabry disease varies. Successful radiofrequency ablation of a Fabry disease patient with Wolff-Parkinson-White syndrome and left ventricular noncompaction is described in the present report.

    Fabry disease
    DIAGNOSIS

 is the second most common

    inherited (X-linked recessive)
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 associated with

    multiple organ involvement
    SYMPTOMS

.

    Cardiac involvement
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

 varies. Successful

    radiofrequency ablation
    MEDICATION

 of a

    Fabry disease
    DIAGNOSIS

 patient with

    Wolff-Parkinson-White syndrome
    DIAGNOSIS

 and

    left ventricular noncompaction
    SYMPTOMS

 is described in the present report.

Fabry disease
lysosomal storage disease
Fabry disease
Fabry disease
Wolff-Parkinson-White syndrome

multiple organ involvement
Cardiac involvement
left ventricular noncompaction


Coronary artery bypass graft in a patient with Fabry's disease.

Fabry's disease is a lysosomal storage disease characterized by intracellular accumulation of ceramide trihexoside resulting from alpha-galactosidase A deficiency. While the heart is often involved, coronary artery disease and its management in Fabry's disease patients are extremely rare clinical entities. We report a case of a 72-year-old man with left main disease in Fabry's disease with special consideration of the arterial wall pathology.

    Fabry's disease
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 characterized by

    intracellular accumulation of ceramide trihexoside
    MICROSCOPIC

 resulting from

    alpha-galactosidase A deficiency
    BIOCHEMICAL

. While the

    heart
    SYMPTOMS

 is often involved,

    coronary artery disease
    DIAGNOSIS

 and its management in

    Fabry's disease
    DIAGNOSIS

 patients are extremely rare clinical entities. We report a case of a

    72-year-old
    AGE

    man
    GENDER

 with

    left main disease
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

 with special consideration of the

    arterial wall pathology
    SYMPTOMS

.

Fabry's disease
lysosomal storage disease
coronary artery disease
Fabry's disease
Fabry's disease

heart
left main disease
arterial wall pathology


Significant improvement in Fabry disease podocytopathy after 3 years of treatment with agalsidase beta.

Fabry disease is an X-linked lysosomal disorder caused by decreased activity of α-galactosidase A (GLA). Consequent accumulation of globotriaosylceramide (GL-3) in lysosomes results in damage to a variety of organs, including the kidneys. Enzyme replacement therapy (ERT) is an effective treatment, but whether it should be started before organ damage is evident is a matter of debate.

A 10-year-old boy who complained of severe sole pain for 3 years had been misdiagnosed with juvenile idiopathic arthritis. Further investigations revealed decreased GLA activity and a M1T mutation in the GLA gene causing protein truncation, suggestive of Fabry disease. Despite normal renal function and urinalysis, renal biopsy showed abnormal structure, with marked accumulation of GL-3 in podocytes, partial effacement of foot processes and irregularly reduced expression of nephrin in the slit diaphragm. After 1 year of ERT with 1 mg/kg agalsidase beta once every 2 weeks, his pain had resolved with ERT combined with carbamazepine and pregabalin. After 3 years of the ERT, repeat biopsy showed little renal GL-3 deposition, resolution of foot process effacement, and a dramatic improvement in nephrin expression.

There may be a window of opportunity in which pain and renal injury can be addressed in the early stages of Fabry disease. Early initiation of ERT should therefore be considered for children with Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal disorder
    DIAGNOSIS

 caused by

    decreased activity of α-galactosidase A (GLA)
    BIOCHEMICAL

. Consequent

    accumulation of globotriaosylceramide (GL-3) in lysosomes
    MICROSCOPIC

 results in

    damage to a variety of organs, including the kidneys
    MICROSCOPIC

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 is an effective treatment, but whether it should be started before

    organ damage
    SYMPTOMS

 is evident is a matter of debate.

A

    10-year-old
    AGE

    boy
    GENDER

 who complained of

    severe sole pain for 3 years
    SYMPTOMS

 had been

    misdiagnosed with juvenile idiopathic arthritis
    NEG_FINDINGS

. Further investigations revealed

    decreased GLA activity
    BIOCHEMICAL

 and a

    M1T mutation in the GLA gene causing protein truncation
    GENETICS

, suggestive of

    Fabry disease
    DIAGNOSIS

. Despite

    normal renal function and urinalysis
    NEG_FINDINGS

,

    renal biopsy
    PARACLINICAL

 showed

    abnormal structure, with marked accumulation of GL-3 in podocytes
    MICROSCOPIC

,

    partial effacement of foot processes
    MICROSCOPIC

 and

    irregularly reduced expression of nephrin in the slit diaphragm
    MICROSCOPIC

. After

    1 year of ERT with 1 mg/kg agalsidase beta once every 2 weeks
    MEDICATION

, his

    pain had resolved
    SYMPTOMS

 with

    ERT combined with carbamazepine and pregabalin
    MEDICATION

. After

    3 years of the ERT
    MEDICATION

,

    repeat biopsy
    PARACLINICAL

 showed

    little renal GL-3 deposition
    MICROSCOPIC

,

    resolution of foot process effacement
    SYMPTOMS

, and a

    dramatic improvement in nephrin expression
    BIOCHEMICAL

.

There may be a window of opportunity in which

    pain
    SYMPTOMS

 and

    renal injury
    SYMPTOMS

 can be addressed in the early stages of

    Fabry disease
    DIAGNOSIS

.

    Early initiation of ERT
    MEDICATION

 should therefore be considered for

    children
    AGE

 with

    Fabry disease
    DIAGNOSIS

.

Fabry disease
lysosomal disorder
Fabry disease
Fabry disease
Fabry disease

organ damage
severe sole pain for 3 years
pain had resolved
resolution of foot process effacement
pain
renal injury


Multiple parapelvic cysts in Fabry disease.

Fabry disease is an inherited, X-linked lysosomal storage disorder caused by deficiency of the enzyme alpha galactosidase A (alpha-GLA A), which leads to glycosphingolipid accumulation, mainly globotriaosylceramide, in tissues. Disease prevalence and the index of suspicion are both low, which tends to result in delayed diagnosis and treatment. We present the case of a male Fabry disease patient who manifested no angiokeratoma lesions but presented multiple parapelvic cysts and renal failure. The genetic study revealed an alpha-GLA A gene mutation that had not been recorded in the mutations registry. The de novo mutation was not found in his relatives and it was not transmitted to his offspring. The large number and peculiar appearance of the parapelvic cysts led to the diagnosis.

    Fabry disease
    DIAGNOSIS

 is an

    inherited, X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    deficiency of the enzyme alpha galactosidase A (alpha-GLA A)
    BIOCHEMICAL

, which leads to

    glycosphingolipid accumulation, mainly globotriaosylceramide, in tissues
    MICROSCOPIC

. Disease prevalence and the index of suspicion are both low, which tends to result in delayed diagnosis and treatment. We present the case of a

    male
    GENDER

    Fabry disease
    DIAGNOSIS

 patient who manifested

    no angiokeratoma lesions
    NEG_FINDINGS

 but presented

    multiple parapelvic cysts
    SYMPTOMS

 and

    renal failure
    SYMPTOMS

. The

    genetic study
    PARACLINICAL

 revealed an

    alpha-GLA A gene mutation
    GENETICS

 that had not been recorded in the mutations registry.

    The de novo mutation was not found in his relatives and it was not transmitted to his offspring
    FAMILY

. The

    large number and peculiar appearance of the parapelvic cysts
    SYMPTOMS

 led to the diagnosis.

Fabry disease
lysosomal storage disorder
Fabry disease

inherited, X-linked
alpha-GLA A gene mutation


D313Y mutation in the differential diagnosis of white matter lesions: Experiences from a multiple sclerosis outpatient clinic.

White matter lesions (WML) in younger patients might be due to a variety of neurological disorders. Fabry disease (FD), an x-linked inherited lysosomal storage disorder, happens to be misdiagnosed as multiple sclerosis (MS). In two middle-aged female patients, presenting bilateral WML, diagnosis of MS turned out to be doubtful. Human genetic analysis presented the Fabry mutation D313Y, in which clinical impact is still unclear. Disease manifestations outside the central nervous system were not detected. Our findings support the suspicion that Fabry mutation D313Y may be involved in neural damage resulting in WML.

    White matter lesions (WML)
    SYMPTOMS

 in

    younger
    AGE

 patients might be due to a variety of

    neurological disorders
    DIAGNOSIS

.

    Fabry disease (FD)
    DIAGNOSIS

, an

    x-linked inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, happens to be misdiagnosed as

    multiple sclerosis (MS)
    DIAGNOSIS

. In two

    middle-aged
    AGE

    female
    GENDER

 patients, presenting

    bilateral WML
    SYMPTOMS

,

    diagnosis of MS turned out to be doubtful
    NEG_FINDINGS

.

    Human genetic analysis
    PARACLINICAL

 presented the

    Fabry mutation D313Y
    GENETICS

, in which clinical impact is still unclear.

    Disease manifestations outside the central nervous system were not detected
    NEG_FINDINGS

. Our findings support the suspicion that

    Fabry mutation D313Y
    GENETICS

 may be involved in

    neural damage
    SYMPTOMS

 resulting in

    WML
    SYMPTOMS

.

White matter lesions (WML)
bilateral WML
neural damage
WML

neurological disorders
Fabry disease (FD)
lysosomal storage disorder
multiple sclerosis (MS)

x-linked inherited
Fabry mutation D313Y
Fabry mutation D313Y


Atypical patterns of cardiac involvement in Fabry disease.

A 58-year-old woman was referred to our cardiology service with chest pain, exertional dyspnoea and palpitations on a background of known Fabry disease diagnosed with genetic testing in 1994. ECG showed sinus rhythm, shortened PR interval, widespread t wave inversion, q waves in the lateral leads and left ventricular hypertrophy (LVH). Coronary angiogram showed only mild atheroma. Transthoracic echocardiogram showed anterolateral LVH and reduced left ventricular cavity size in keeping with Fabry cardiomyopathy. Cardiac MRI demonstrated asymmetric hypertrophy with evidence of diffuse myocardial fibrosis in the maximally hypertrophied segments from base to apex with late gadolinium enhancement in the anterior and anteroseptal walls. This was quite an atypical appearance for Fabry cardiomyopathy. This case highlights the heterogeneity of patterns of cardiac involvement that may be associated with this rare X-linked lysosomal disorder.

A

    58-year-old
    AGE

    woman
    GENDER

 was referred to our cardiology service with

    chest pain
    SYMPTOMS

,

    exertional dyspnoea
    SYMPTOMS

 and

    palpitations
    SYMPTOMS

 on a background of known

    Fabry disease
    DIAGNOSIS

 diagnosed with genetic testing in 1994.

    ECG
    PARACLINICAL

 showed

    sinus rhythm
    SYMPTOMS

,

    shortened PR interval
    SYMPTOMS

,

    widespread t wave inversion, q waves in the lateral leads
    SYMPTOMS

 and

    left ventricular hypertrophy (LVH)
    SYMPTOMS

.

    Coronary angiogram
    PARACLINICAL

 showed

    only mild atheroma
    SYMPTOMS

.

    Transthoracic echocardiogram
    PARACLINICAL

 showed

    anterolateral LVH
    SYMPTOMS

 and

    reduced left ventricular cavity size
    SYMPTOMS

 in keeping with

    Fabry cardiomyopathy
    DIAGNOSIS

.

    Cardiac MRI
    PARACLINICAL

 demonstrated

    asymmetric hypertrophy
    SYMPTOMS

 with

    evidence of diffuse myocardial fibrosis in the maximally hypertrophied segments from base to apex with late gadolinium enhancement in the anterior and anteroseptal walls
    SYMPTOMS

. This was quite an atypical appearance for

    Fabry cardiomyopathy
    DIAGNOSIS

. This case highlights the heterogeneity of patterns of

    cardiac involvement
    SYMPTOMS

 that may be associated with this

    rare X-linked
    GENETICS

    lysosomal disorder
    DIAGNOSIS

.

Fabry disease
Fabry cardiomyopathy
Fabry cardiomyopathy
lysosomal disorder


Kidney transplantation from a mother with unrecognized Fabry disease to her son with low α-galactosidase A activity: A 14-year follow-up without enzyme replacement therapy.

We report a case of kidney transplantation from mother to son, both of whom were likely to have had an unrecognized renal variant phenotype of Fabry disease. The patient was a 54-year-old man, with an unknown primary cause of end stage renal disease. He had no notable past medical history, other than end stage renal disease. He underwent living-related kidney transplantation from his mother at age 40 years. Foam cells in the glomeruli were identified on histology assessment of a 0-hour allograft biopsy, with zebra bodies identified in the glomerular visceral epithelial cells by electron microscopy. These findings were indicative of Fabry disease in the donated kidney. As a definitive diagnosis of Fabry's disease could not be confirmed, enzyme replacement therapy was not initiated. Thirteen years after kidney transplantation, the patient underwent left nephrectomy for a left renal tumour, with pathological findings of clear cell carcinoma, foam cells and zebra bodies in the native kidney. Detailed examinations identified low α-galactosidase A activity and mutation of the α-Gal A gene, confirming a diagnosis of a renal variant phenotype of Fabry disease. Histology of several allograft biopsies performed over the 14 years from the time of kidney transplantation revealed only moderate interstitial fibrosis and tubular atrophy, with no evidence of disease progression on electron microscopy, despite the presence of zebra bodies in the glomerular visceral epithelial cells.

We report a case of

    kidney transplantation from mother to son
    MEDICATION

,

    both of whom were likely to have had an unrecognized renal variant phenotype of Fabry disease
    FAMILY

. The patient was a

    54-year-old
    AGE

    man
    GENDER

, with an unknown primary cause of

    end stage renal disease
    DIAGNOSIS

.

    He
    GENDER

 had

    no notable past medical history
    NEG_FINDINGS

, other than

    end stage renal disease
    DIAGNOSIS

.

    He
    GENDER

 underwent

    living-related kidney transplantation from his mother
    MEDICATION

 at

    age 40 years
    AGE

.

    Foam cells in the glomeruli
    MICROSCOPIC

 were identified on

    histology assessment of a 0-hour allograft biopsy
    PARACLINICAL

, with

    zebra bodies identified in the glomerular visceral epithelial cells
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. These findings were indicative of

    Fabry disease in the donated kidney
    MICROSCOPIC

. As a

    definitive diagnosis of Fabry's disease could not be confirmed
    NEG_FINDINGS

,

    enzyme replacement therapy was not initiated
    NEG_FINDINGS

. Thirteen years after

    kidney transplantation
    MEDICATION

, the patient underwent

    left nephrectomy
    MEDICATION

 for a

    left renal tumour
    DIAGNOSIS

, with pathological findings of

    clear cell carcinoma
    MICROSCOPIC

,

    foam cells and zebra bodies in the native kidney
    MICROSCOPIC

.

    Detailed examinations
    PARACLINICAL

 identified

    low α-galactosidase A activity
    BIOCHEMICAL

 and

    mutation of the α-Gal A gene
    GENETICS

, confirming a diagnosis of a

    renal variant phenotype of Fabry disease
    DIAGNOSIS

.

    Histology of several allograft biopsies
    PARACLINICAL

 performed over the 14 years from the time of

    kidney transplantation
    MEDICATION

 revealed

    only moderate interstitial fibrosis
    SYMPTOMS

 and

    tubular atrophy
    SYMPTOMS

, with

    no evidence of disease progression on electron microscopy
    NEG_FINDINGS

, despite the presence of

    zebra bodies in the glomerular visceral epithelial cells
    MICROSCOPIC

.

only moderate interstitial fibrosis
tubular atrophy


Pain management strategies for neuropathic pain in Fabry disease--a systematic review.

Neuropathic pain is one of the key features of (classical) Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies.

PubMed and Embase were searched up to September 2014 for relevant articles on treatment of neuropathic pain in FD.

Seven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8. Carbamazepine appeared most beneficial: complete pain relief in 5/25, partial relief in 17/25, and no benefit in 3/25 patients. Phenytoin resulted in complete relief in 1/27, partial relief in 12/27 and no benefit in 6/27 patients. In 8 patients a significant reduction in the frequency of pain attacks was described. Gabapentin caused partial relief in 6/7 and no relief in 1/7 patients. Little evidence was reported for SSNRI's or treatment combinations. Adverse-effects were reported in all treatment strategies.

Only for carbamazepine, phenytoin and gabapentin there is evidence of effectiveness in neuropathic pain due to FD, but comparison of effectiveness between these drugs is lacking. In routine clinical practice adverse-effects may discourage use of carbamazepine and phenytoin in favor of second-generation antiepileptic drugs, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies.

    Neuropathic pain
    DIAGNOSIS

 is one of the key features of (classical)

    Fabry disease (FD)
    DIAGNOSIS

. No randomized clinical trials comparing effectiveness of different

    pain management strategies
    MEDICATION

 have been performed. This review aims to give an overview of existing

    pain management
    MEDICATION

 strategies.

PubMed and Embase were searched up to September 2014 for relevant articles on

    treatment of neuropathic pain
    MEDICATION

 in

    FD
    DIAGNOSIS

.

Seven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8.

    Carbamazepine
    MEDICATION

 appeared most beneficial:

    complete pain relief
    SYMPTOMS

 in 5/25,

    partial relief
    SYMPTOMS

 in 17/25, and

    no benefit
    NEG_FINDINGS

 in 3/25 patients.

    Phenytoin
    MEDICATION

 resulted in

    complete relief
    SYMPTOMS

 in 1/27,

    partial relief
    SYMPTOMS

 in 12/27 and

    no benefit
    NEG_FINDINGS

 in 6/27 patients. In 8 patients a

    significant reduction in the frequency of pain attacks
    SYMPTOMS

 was described.

    Gabapentin
    MEDICATION

 caused

    partial relief
    SYMPTOMS

 in 6/7 and

    no relief
    NEG_FINDINGS

 in 1/7 patients. Little evidence was reported for

    SSNRI's
    MEDICATION

 or

    treatment combinations
    MEDICATION

.

    Adverse-effects
    SYMPTOMS

 were reported in all treatment strategies.

Only for

    carbamazepine
    MEDICATION

,

    phenytoin
    MEDICATION

 and

    gabapentin
    MEDICATION

 there is evidence of effectiveness in

    neuropathic pain due to FD
    DIAGNOSIS

, but comparison of effectiveness between these drugs is lacking. In routine clinical practice

    adverse-effects
    SYMPTOMS

 may discourage use of

    carbamazepine and phenytoin
    MEDICATION

 in favor of

    second-generation antiepileptic drugs
    MEDICATION

, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies.

Neuropathic pain
Fabry disease (FD)
FD
neuropathic pain due to FD

pain management strategies
pain management
treatment of neuropathic pain
Carbamazepine
Phenytoin
Gabapentin
SSNRI's
treatment combinations
carbamazepine
phenytoin
gabapentin
carbamazepine and phenytoin
second-generation antiepileptic drugs


Coexistence of Fabry Disease and Membranous Nephropathy.

A 21-year-old man with no family history or characteristic symptoms of Fabry disease presented with proteinuria. Histological and immunofluorescent analysis of kidney tissue collected revealed stage 1 membranous nephropathy. Electron microscopy of the same tissue revealed a large number of myeloid bodies (zebra bodies) in the glomerular epithelial cytoplasm and a mild irregular thickening of basement membrane. A diagnosis of Fabry disease was supported by the low α-galactosidase A activity detected in the patient's plasma, and confirmed by the detection of a pathogenic homozygous mutation in the α-galactosidase A gene. Therefore, the final diagnosis was of coexistent Fabry disease and stage 1 membranous nephropathy. This is the first case study reporting the coexistence of Fabry disease and membranous nephropathy. Our results emphasize the importance of electron microscopy in Fabry disease diagnosis.

A

    21-year-old
    AGE

    man
    GENDER

 with

    no family history or characteristic symptoms of Fabry disease
    NEG_FINDINGS

 presented with

    proteinuria
    BIOCHEMICAL

.

    Histological and immunofluorescent analysis of kidney tissue collected
    PARACLINICAL

 revealed

    stage 1 membranous nephropathy
    DIAGNOSIS

.

    Electron microscopy of the same tissue
    PARACLINICAL

 revealed a

    large number of myeloid bodies (zebra bodies) in the glomerular epithelial cytoplasm
    MICROSCOPIC

 and a

    mild irregular thickening of basement membrane
    MICROSCOPIC

. A diagnosis of

    Fabry disease
    DIAGNOSIS

 was supported by the

    low α-galactosidase A activity detected in the patient's plasma
    BIOCHEMICAL

, and confirmed by the detection of a

    pathogenic homozygous mutation in the α-galactosidase A gene
    GENETICS

. Therefore, the final diagnosis was of

    coexistent Fabry disease and stage 1 membranous nephropathy
    DIAGNOSIS

. This is the first case study reporting the

    coexistence of Fabry disease and membranous nephropathy
    DIAGNOSIS

. Our results emphasize the importance of

    electron microscopy
    PARACLINICAL

 in

    Fabry disease
    DIAGNOSIS

 diagnosis.


Extensive angiokeratoma circumscriptum - successful treatment with 595-nm variable-pulse pulsed dye laser and 755-nm long-pulse pulsed alexandrite laser.

Angiokeratomas are rare vascular mucocutaneous lesions characterized by small-vessel ectasias in the upper dermis with reactive epidermal changes. Angiokeratoma circumscriptum (AC) is the rarest among the five types in the current classification of angiokeratoma. We present a case of an extensive AC in 19-year-old women with Fitzpatrick skin type I of the left lower extremity, characterized by a significant morphological heterogeneity of the lesions, intermittent bleeding, and negative psychological impact. Histopathological examination after deep biopsy was consistent with that of angiokeratoma. The association with metabolic diseases (Fabry disease) was excluded by ophthalmological, biochemical, and genetic examinations. Nuclear magnetic resonance imaging has not detected deep vascular hyperplasia pathognomic for verrucous hemangioma. The combined treatment with 595-nm variable-pulse pulsed dye laser (VPPDL) and 755-nm long-pulse pulsed alexandrite laser (LPPAL) with dynamic cooling device led to significant removal of the pathological vascular tissue of AC. Only a slight degree of secondary reactions (dyspigmentations and texture changes) occurred. No recurrence was observed after postoperative interval of 9 months. We recommend VPPDL and LPPAL for the treatment of extensive AC.

    Angiokeratomas
    DIAGNOSIS

 are

    rare vascular mucocutaneous lesions
    SYMPTOMS

 characterized by

    small-vessel ectasias in the upper dermis with reactive epidermal changes
    SYMPTOMS

.

    Angiokeratoma circumscriptum
    DIAGNOSIS

    (AC)
    DIAGNOSIS

 is the rarest among the five types in the current classification of

    angiokeratoma
    DIAGNOSIS

. We present a case of an

    extensive AC
    DIAGNOSIS

 in

    19-year-old
    AGE

    women
    GENDER

 with

    Fitzpatrick skin type I of the left lower extremity
    SYMPTOMS

, characterized by a

    significant morphological heterogeneity of the lesions
    SYMPTOMS

,

    intermittent bleeding
    SYMPTOMS

, and

    negative psychological impact
    SYMPTOMS

.

    Histopathological examination
    PARACLINICAL

 after

    deep biopsy
    PARACLINICAL

 was consistent with that of

    angiokeratoma
    DIAGNOSIS

. The

    association with metabolic diseases (Fabry disease) was excluded
    NEG_FINDINGS

 by

    ophthalmological, biochemical, and genetic examinations
    NEG_FINDINGS

.

    Nuclear magnetic resonance imaging has not detected deep vascular hyperplasia pathognomic for verrucous hemangioma
    NEG_FINDINGS

. The

    combined treatment with 595-nm variable-pulse pulsed dye laser (VPPDL) and 755-nm long-pulse pulsed alexandrite laser (LPPAL) with dynamic cooling device
    MEDICATION

 led to

    significant removal of the pathological vascular tissue of AC
    SYMPTOMS

.

    Only a slight degree of secondary reactions (dyspigmentations and texture changes)
    SYMPTOMS

 occurred.

    No recurrence
    NEG_FINDINGS

 was observed after postoperative interval of 9 months. We recommend

    VPPDL and LPPAL
    MEDICATION

 for the treatment of

    extensive AC
    DIAGNOSIS

.

Angiokeratomas
Angiokeratoma circumscriptum
(AC)
angiokeratoma
extensive AC
angiokeratoma
extensive AC