A Sporadic Case of Fabry Disease Involving Repeated Fever, Psychiatric Symptoms, Headache, and Ischemic Stroke in an Adult Japanese Woman.

Fabry disease can cause various neurological manifestations. We describe the case of a Japanese woman with Fabry disease who presented with ischemic stroke, aseptic meningitis, and psychiatric symptoms. The patient had a mutation in intron 4 of her α-galactosidase A gene, which was not detected in her family. This case suggests that Fabry disease should be considered in young patients who exhibit central nervous system symptoms such as ischemic stroke, even if there is no family history of the condition. The episodes of aseptic meningitis and stroke experienced by our patient suggest that persistent inflammation might be the mechanism underlying Fabry disease.

    Fabry disease
    DIAGNOSIS

 can cause various

    neurological manifestations
    SYMPTOMS

. We describe the case of a

    Japanese
    ETHNICITY

    woman
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 who presented with

    ischemic stroke
    SYMPTOMS

,

    aseptic meningitis
    SYMPTOMS

, and

    psychiatric symptoms
    SYMPTOMS

. The patient had a

    mutation in intron 4 of her α-galactosidase A gene
    GENETICS

    , which was not detected in her family
    FAMILY

. This case suggests that

    Fabry disease
    DIAGNOSIS

 should be considered in

    young
    AGE

 patients who exhibit

    central nervous system symptoms
    SYMPTOMS

 such as

    ischemic stroke
    SYMPTOMS

, even if there is

    no family history of the condition
    NEG_FINDINGS

. The

    episodes of aseptic meningitis
    SYMPTOMS

 and

    stroke
    SYMPTOMS

 experienced by our patient suggest that

    persistent inflammation
    SYMPTOMS

 might be the mechanism underlying

    Fabry disease
    DIAGNOSIS

.

Fabry disease
Fabry disease
Fabry disease
Fabry disease

neurological manifestations
ischemic stroke
aseptic meningitis
psychiatric symptoms
central nervous system symptoms
ischemic stroke
episodes of aseptic meningitis
stroke
persistent inflammation


Late diagnosis of Fabry disease caused by a de novo mutation in a patient with end stage renal disease.

We present the case of a white 35-year-old male with a diagnosis of Fabry disease and negative family history.

At the age of 31, he underwent a renal biopsy with a diagnosis of hypertension-induced nephroangiosclerosis. At the age of 35, he was referred to our hospital and started dialysis: the unusual finding of left ventricular hypertrophy with a normal ejection fraction and of myocardial fibrosis at the cardiac magnetic resonance suggested a diagnosis of Fabry disease, although there was no apparent family history-so extensive tests were subsequently undertaken. The patient had low plasma levels of α-galactosidase A and the genetic analysis showed a single nucleotide point mutation in hemizygosis at nucleotide c.901 C>T in exon 6 of the GLA gene, confirming the diagnosis of Fabry disease. We extended the genetic analysis to all family members of the patient (mother, sister and brothers) and none of them had any alteration in the GLA gene, suggesting a de novo mutation in the patient.

In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counseling and studying the genealogical tree of suspicious patients, even in absence of a typical family history.

We present the case of a

    white
    ETHNICITY

    35-year-old
    AGE

    male
    GENDER

 with a diagnosis of

    Fabry disease
    DIAGNOSIS

 and

    negative family history
    NEG_FINDINGS

.

At the

    age of 31
    AGE

,

    he
    GENDER

 underwent a

    renal biopsy
    PARACLINICAL

 with a diagnosis of

    hypertension-induced nephroangiosclerosis
    DIAGNOSIS

. At the

    age of 35
    AGE

,

    he
    GENDER

 was referred to our hospital and started

    dialysis
    MEDICATION

: the unusual finding of

    left ventricular hypertrophy with a normal ejection fraction
    SYMPTOMS

 and of

    myocardial fibrosis
    SYMPTOMS

 at the

    cardiac magnetic resonance
    PARACLINICAL

 suggested a diagnosis of

    Fabry disease
    DIAGNOSIS

, although there was

    no apparent family history
    NEG_FINDINGS

-so extensive tests were subsequently undertaken. The patient had

    low plasma levels of α-galactosidase A
    BIOCHEMICAL

 and the

    genetic analysis
    PARACLINICAL

 showed a

    single nucleotide point mutation in hemizygosis at nucleotide c.901 C>T in exon 6 of the GLA gene
    GENETICS

, confirming the diagnosis of

    Fabry disease
    DIAGNOSIS

. We extended the

    genetic analysis
    PARACLINICAL

 to

    all family members of the patient (mother, sister and brothers)
    FAMILY

 and

    none of them had any alteration in the GLA gene
    NEG_FINDINGS

, suggesting a

    de novo mutation
    GENETICS

 in the patient.

In a family, it is rare to find only one

    Fabry disease affected subject with a de novo mutation
    DIAGNOSIS

. These findings emphasize the importance of early diagnosis,

    genetic counseling
    MEDICATION

 and

    studying the genealogical tree
    PARACLINICAL

 of suspicious patients, even in

    absence of a typical family history
    NEG_FINDINGS

.


Surges in proteinuria are associated with plasma GL-3 elevations in a young patient with classic Fabry disease.

Fabry disease is an X-linked glycosphingolipidosis caused by deficient synthesis of the enzyme α-galactosidase A, which results in accumulations of globotriaosylceramide (GL-3) in systemic tissues. Nephropathy is a dominant feature of Fabry disease. It still remains unclear how the nephropathy progresses. Recombinant agalsidase replacement therapy is currently the only approved, specific therapy for Fabry disease. The optimal dose of replacement enzyme also still remains unclear. The worldwide shortage of agalsidase-β in 2009 forced dose reduction of administration. It showed that the proteinuria emerged like surges, followed by temporary plasma GL-3 elevations in the early stages of classic Fabry disease. Additionally, it also showed that 1 mg/kg of agalsidase-β every other week could clear the GL-3 accumulations from podocytes and was required to maintain negative proteinuria and normal plasma GL-3 levels.

This observation of a young patient with classic Fabry disease about 5 years reveals that the long-term, low-dose agalsidase-β caused proteinuria surges, but not persistent proteinuria, followed by temporary plasma GL-3 elevations, and agalsidase-β at 1 mg/kg every other week could clear accumulated GL-3 from podocytes and was required to maintain normal urinalysis and plasma GL-3 levels.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    glycosphingolipidosis
    DIAGNOSIS

 caused by

    deficient synthesis of the enzyme α-galactosidase A
    BIOCHEMICAL

, which results in

    accumulations of globotriaosylceramide (GL-3) in systemic tissues
    MICROSCOPIC

.

    Nephropathy
    DIAGNOSIS

 is a dominant feature of

    Fabry disease
    DIAGNOSIS

. It still remains unclear how the

    nephropathy
    DIAGNOSIS

 progresses.

    Recombinant agalsidase replacement therapy
    MEDICATION

 is currently the only approved, specific therapy for

    Fabry disease
    DIAGNOSIS

. The optimal dose of

    replacement enzyme
    MEDICATION

 also still remains unclear. The worldwide

    shortage of agalsidase-β
    MEDICATION

 in 2009 forced

    dose reduction of administration
    MEDICATION

. It showed that the

    proteinuria emerged like surges
    BIOCHEMICAL

, followed by

    temporary plasma GL-3 elevations
    BIOCHEMICAL

 in the early stages of

    classic Fabry disease
    MICROSCOPIC

. Additionally, it also showed that

    1 mg/kg of agalsidase-β every other week
    MEDICATION

 could

    clear the GL-3 accumulations from podocytes
    MICROSCOPIC

 and was required to maintain

    negative proteinuria
    BIOCHEMICAL

 and

    normal plasma GL-3 levels
    BIOCHEMICAL

.

This observation of a

    young
    AGE

 patient with

    classic Fabry disease
    DIAGNOSIS

    about 5 years
    AGE

 reveals that the

    long-term, low-dose agalsidase-β
    MEDICATION

 caused

    proteinuria surges, but not persistent proteinuria
    BIOCHEMICAL

, followed by

    temporary plasma GL-3 elevations
    BIOCHEMICAL

, and

    agalsidase-β at 1 mg/kg every other week
    MEDICATION

 could

    clear accumulated GL-3 from podocytes
    MICROSCOPIC

 and was required to maintain

    normal urinalysis and plasma GL-3 levels
    NEG_FINDINGS

.

Fabry disease
glycosphingolipidosis
Nephropathy
Fabry disease
nephropathy
Fabry disease
classic Fabry disease


A Patient with the GLA p.E66Q Mutation Exhibiting Vascular Parkinsonism and Bilateral Pulvinar Lesions.

A 76-year-old man was admitted to our hospital due to gait difficulty. Brain imaging indicated bilateral pulvinar lesions and moderate white matter lesions. The serum α-galactosidase A levels were measured for the differential diagnosis of bilateral pulvinar lesions and were found to be abnormally low. Therefore, the patient was suspected to have variant Fabry disease. A GLA mutation analysis showed the p.E66Q mutation, which is speculated to be a functional polymorphism rather than a disease-causing mutation of Fabry disease. Enzyme replacement therapy did not result in a marked improvement, however, the disease progression stopped.

A

    76-year-old
    AGE

    man
    GENDER

 was admitted to our hospital due to

    gait difficulty
    SYMPTOMS

.

    Brain imaging
    PARACLINICAL

 indicated

    bilateral pulvinar lesions
    SYMPTOMS

 and

    moderate white matter lesions
    SYMPTOMS

. The

    serum α-galactosidase A levels
    BIOCHEMICAL

 were measured for the

    differential diagnosis
    PARACLINICAL

 of

    bilateral pulvinar lesions
    SYMPTOMS

 and were found

    to be abnormally low
    BIOCHEMICAL

. Therefore, the patient was suspected to have

    variant Fabry disease
    DIAGNOSIS

. A

    GLA mutation analysis
    PARACLINICAL

 showed the

    p.E66Q mutation, which is speculated to be a functional polymorphism rather than a disease-causing mutation of Fabry disease
    GENETICS

.

    Enzyme replacement therapy did not result in a marked improvement
    NEG_FINDINGS

, however, the

    disease progression stopped
    SYMPTOMS

.

gait difficulty
bilateral pulvinar lesions
moderate white matter lesions
bilateral pulvinar lesions
disease progression stopped

serum α-galactosidase A levels
to be abnormally low


Control of proteinuria with increased doses of agalsidase alfa in a patient with Fabry disease with atypical genotype-phenotype expression.

Fabry disease is a rare X-linked lysosomal storage disorder of glycosphingolipids, caused by the partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A). The missense mutation pN215S usually causes a milder form of the disease with isolated cardiac involvement. We report a case of a male Fabry patient with the pN215S mutation and a generalized disease. He suffered a relapse in proteinuria which responded to increased doses of the administered recombinant enzyme. Individualization of enzyme replacement therapy must be considered in selected cases characterized by clinical deterioration.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder of glycosphingolipids
    DIAGNOSIS

, caused by the

    partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (a-Gal A)
    BIOCHEMICAL

. The

    missense mutation pN215S
    GENETICS

 usually causes a milder form of the disease with

    isolated cardiac involvement
    SYMPTOMS

. We report a case of a

    male
    GENDER

    Fabry
    DIAGNOSIS

 patient with the

    pN215S mutation
    GENETICS

 and a

    generalized disease
    DIAGNOSIS

.

    He
    GENDER

 suffered a

    relapse in proteinuria
    BIOCHEMICAL

 which responded to

    increased doses of the administered recombinant enzyme
    MEDICATION

.

    Individualization of enzyme replacement therapy
    MEDICATION

 must be considered in selected cases characterized by

    clinical deterioration
    SYMPTOMS

.

rare X-linked
missense mutation pN215S
pN215S mutation

isolated cardiac involvement
clinical deterioration


Safe and Successful Treatment With Agalsidase Beta During Pregnancy in Fabry Disease.

Fabry disease, an X-linked lysosomal storage disorder, is caused by α-galactosidase A deficiency and leads to accumulation of glycospinhgolipids in most tissues, with life-theratening consequences in the kidney, heart, and cerebrovascular system. Enzyme replacement therapy is available as 2 different preparations: agalsidase alfa and agalsidase beta. Enzyme replacement therapy is started as soon as the diagnosis is confirmed, but there is no data available in the literature about its safety during preganacy. Herein, we described 2 patients with Fabry disease who received agalsidase beta during their pregnancy. This report is important as the data about enzyme replacement therapy during pregnancy is restricted with case reports.

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, is caused by

    α-galactosidase A deficiency
    BIOCHEMICAL

 and leads to

    accumulation of glycospinhgolipids in most tissues
    MICROSCOPIC

, with

    life-theratening consequences in the kidney, heart, and cerebrovascular system
    SYMPTOMS

.

    Enzyme replacement therapy
    MEDICATION

 is available as

    2 different preparations: agalsidase alfa and agalsidase beta
    MEDICATION

.

    Enzyme replacement therapy
    MEDICATION

 is started as soon as the diagnosis is confirmed, but there is no data available in the literature about its safety during

    preganacy
    MEDICATION

. Herein, we described 2 patients with

    Fabry disease
    DIAGNOSIS

 who

    received agalsidase beta
    MEDICATION

 during their

    pregnancy
    MEDICATION

. This report is important as the data about

    enzyme replacement therapy
    MEDICATION

 during

    pregnancy
    MEDICATION

 is restricted with case reports.

Fabry disease
lysosomal storage disorder
Fabry disease


Fabry cardiomyopathy presenting with a high defibrillation threshold: A short case report.

Fabry disease is an X-linked recessive glycosphingolipid storage disorder caused by a deficiency of lysosomal enzyme α-galactosidase A. It is recognized that Fabry disease patients often have ventricular arrhythmias. Although the effectiveness of implantable cardioverter-defibrillator (ICD) therapy in patients with ventricular fibrillation is established, there is little evidence regarding ICD therapy for Fabry disease. Here, we report the case of patient with Fabry disease who was treated with an ICD and presented with high defibrillation thresholds.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    glycosphingolipid storage disorder
    DIAGNOSIS

 caused by a deficiency of lysosomal enzyme α-galactosidase A. It is recognized that

    Fabry disease
    DIAGNOSIS

 patients often have

    ventricular arrhythmias
    SYMPTOMS

. Although the effectiveness of

    implantable cardioverter-defibrillator (ICD) therapy
    MEDICATION

 in patients with

    ventricular fibrillation
    SYMPTOMS

 is established, there is little evidence regarding

    ICD therapy
    MEDICATION

 for

    Fabry disease
    DIAGNOSIS

. Here, we report the case of patient with

    Fabry disease
    DIAGNOSIS

 who was treated with an

    ICD
    MEDICATION

 and presented with

    high defibrillation thresholds
    SYMPTOMS

.

Fabry disease
glycosphingolipid storage disorder
Fabry disease
Fabry disease
Fabry disease

ventricular arrhythmias
ventricular fibrillation
high defibrillation thresholds


Gastrointestinal involvement in Fabry disease. So important, yet often neglected.

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    metabolic storage disorder
    DIAGNOSIS

 due to the

    deficiency of lysosomal alpha-galactosidase A
    BIOCHEMICAL

 which causes

    accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body
    MICROSCOPIC

.

    Gastrointestinal signs and symptoms
    SYMPTOMS

-

    abdominal pain
    SYMPTOMS

,

    nausea
    SYMPTOMS

,

    diarrhea
    SYMPTOMS

 and

    diverticular disease
    SYMPTOMS

--are some of the most frequently reported complaints in patients with

    Fabry disease
    DIAGNOSIS

 but are often neglected.

    Gastrointestinal symptoms
    SYMPTOMS

 are due to

    intestinal dysmotility
    SYMPTOMS

 as well as

    impaired autonomic function
    SYMPTOMS

,

    vasculopathy
    SYMPTOMS

 and

    myopathy
    SYMPTOMS

. Since 2001,

    enzyme replacement therapy
    MEDICATION

 has been a mainstay in treatment of

    gastrointestinal symptoms
    SYMPTOMS

 of

    Fabry disease (FD)
    DIAGNOSIS

, resulting in

    reduced gastrointestinal symptoms
    SYMPTOMS

. Here, we report on four patients with

    Fabry disease (FD)
    DIAGNOSIS

 who manifested

    early gastrointestinal involvement
    SYMPTOMS

.

Fabry disease
metabolic storage disorder
Fabry disease
Fabry disease (FD)
Fabry disease (FD)

Gastrointestinal signs and symptoms
abdominal pain
nausea
diarrhea
diverticular disease
Gastrointestinal symptoms
intestinal dysmotility
impaired autonomic function
vasculopathy
myopathy
gastrointestinal symptoms
reduced gastrointestinal symptoms
early gastrointestinal involvement


Clinical and biochemical investigation of male patients exhibiting membranous cytoplasmic bodies in biopsied kidney tissues; a pitfall in diagnosis of Fabry disease.

The existence of membranous cytoplasmic bodies in biopsied kidney tissues is one of the important findings when considering Fabry disease as the first choice diagnosis. However, there are possible acquired lysosomal diseases associated with pharmacological toxicity, although less attention has been paid to them.

We experienced 3 male patients presenting with proteinuria and specific pathological changes strongly suggesting Fabry disease. We sought detailed clinical and biochemical information to avoid a wrong diagnosis. The patients were examined clinically and pathologically, and plasma α-galactosidase A (GLA) activity and the globotriaosylsphingosine (lyso-Gb3) concentrations were measured. Electron microscopic examination revealed numerous membranous inclusion bodies in podocytes, and biochemical analysis revealed normal GLA activity and a normal lyso-Gb3 level in plasma, showing that they did not have Fabry disease. They suffered from hyperlipidemia, myeloma, or lupus nephritis. They had received pitavastatin calcium, clarithromycin, loxoprofen and/or prednisolone, and there was no medication history of cationic amphiphilic drugs.

In this case series, the etiology of the inclusions was not clarified. However, these cases indicate that careful attention should be paid on diagnosis of patients exhibiting inclusion bodies in kidney cells, and it is important to confirm their past and present illnesses, and medication history as well as to measure the GLA activity and lyso-Gb3 level.

The

    existence of membranous cytoplasmic bodies in biopsied kidney tissues
    MICROSCOPIC

 is one of the important findings when considering

    Fabry disease
    DIAGNOSIS

 as the first choice diagnosis. However, there are possible

    acquired lysosomal diseases
    DIAGNOSIS

 associated with

    pharmacological toxicity
    SYMPTOMS

, although less attention has been paid to them.

We experienced 3

    male
    GENDER

 patients presenting with

    proteinuria
    BIOCHEMICAL

 and

    specific pathological changes
    SYMPTOMS

 strongly suggesting

    Fabry disease
    DIAGNOSIS

. We sought detailed clinical and biochemical information to avoid a wrong diagnosis. The patients were examined clinically

    and pathologically
    PARACLINICAL

, and

    plasma α-galactosidase A (GLA) activity and the globotriaosylsphingosine (lyso-Gb3) concentrations
    BIOCHEMICAL

 were measured.

    Electron microscopic examination
    PARACLINICAL

 revealed

    numerous membranous inclusion bodies in podocytes
    MICROSCOPIC

, and

    biochemical analysis
    PARACLINICAL

 revealed

    normal GLA activity
    NEG_FINDINGS

 and a

    normal lyso-Gb3 level in plasma
    NEG_FINDINGS

, showing that they

    did not have Fabry disease
    NEG_FINDINGS

. They suffered from

    hyperlipidemia
    DIAGNOSIS

,

    myeloma
    DIAGNOSIS

, or

    lupus nephritis
    DIAGNOSIS

. They had

    received pitavastatin calcium, clarithromycin, loxoprofen and/or prednisolone
    MEDICATION

, and there was

    no medication history of cationic amphiphilic drugs
    NEG_FINDINGS

.

In this case series, the

    etiology of the inclusions was not clarified
    NEG_FINDINGS

. However, these cases indicate that careful attention should be paid on diagnosis of patients exhibiting

    inclusion bodies in kidney cells
    MICROSCOPIC

, and it is important to confirm their past and present illnesses, and medication history as well as to measure the

    GLA activity
    BIOCHEMICAL

 and

    lyso-Gb3 level
    BIOCHEMICAL

.

Fabry disease
acquired lysosomal diseases
Fabry disease
hyperlipidemia
myeloma
lupus nephritis

pharmacological toxicity
specific pathological changes


Pathological Renal Findings of Chronic Renal Failure in a Patient with the E66Q Mutation in the α-galactosidase A Gene.

A 66-year-old Japanese man was diagnosed with interstitial nephritis on a renal biopsy at 45 years of age and began to receive hemodialysis at 65 years of age. He was suspected of having Fabry disease as a result of a screening study for Fabry disease performed in hemodialysis patients. He had an E66Q mutation in the α-galactosidase A gene. We conducted an electron microscopic examination of a renal biopsy specimen obtained when the patient was diagnosed with chronic renal failure at 45 years of age in order to elucidate the pathogenicity of the E66Q mutation. Interestingly, an electron microscopic examination of the renal biopsy specimen indicated no characteristic findings of Fabry disease.

A

    66-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 was diagnosed with

    interstitial nephritis
    DIAGNOSIS

 on a

    renal biopsy
    PARACLINICAL

 at

    45 years of age
    AGE

 and began to receive

    hemodialysis
    MEDICATION

 at

    65 years of age
    AGE

.

    He
    GENDER

 was suspected of having

    Fabry disease
    DIAGNOSIS

 as a result of a screening study for

    Fabry disease
    DIAGNOSIS

 performed in

    hemodialysis
    MEDICATION

 patients.

    He
    GENDER

 had an

    E66Q mutation in the α-galactosidase A gene
    GENETICS

. We conducted an

    electron microscopic examination of a renal biopsy specimen
    PARACLINICAL

 obtained when the patient was diagnosed with

    chronic renal failure
    SYMPTOMS

 at

    45 years of age
    AGE

 in order to elucidate the pathogenicity of the

    E66Q mutation
    GENETICS

. Interestingly, an

    electron microscopic examination of the renal biopsy specimen
    PARACLINICAL

 indicated

    no characteristic findings of Fabry disease
    NEG_FINDINGS

.

interstitial nephritis
Fabry disease
Fabry disease


Advanced Anderson-Fabry disease presenting with left ventricular apical aneurysm and ventricular tachycardia.

A 54-year-old female with Anderson-Fabry disease (AFD)-R342Q missense mutation on exon 7 in alpha-galactosidase A (GLA) gene - presented with sustained ventricular tachycardia. Imaging confirmed the presence of a new left ventricular apical aneurysm (LVAA) and a significantly reduced intra-cavitary gradient compared to two years prior. AFDcv is an X-linked lysosomal storage disorder caused by GLA enzyme deficiency. The phenotypic expression of AFD in the heart is not well described. Cardiac involvement can include left ventricular hypertrophy (LVH), which is typically symmetric, but can also mimic hypertrophic cardiomyopathy (HCM). Left ventricular apical aneurysm is a rare finding in HCM. We suggest a shared mechanism of LVAA formation in AFD and HCM, independent of the underlying cardiomyopathy. Mechanisms of LVAA formation in HCM include genetic predisposition and long-standing left ventricular wall stress from elevated intra-cavitary systolic pressures due to mid-cavitary obstruction. Both mechanisms are supported in this patient (a brother with AFD also developed a small LVAA). Screening for AFD should be considered in cases of unexplained LVH, particularly in patients with the aneurysmal variant of HCM.

A

    54-year-old
    AGE

    female
    GENDER

 with Anderson-Fabry disease (AFD)-R342Q missense mutation on exon 7 in alpha-galactosidase A (GLA) gene - presented with

    sustained ventricular tachycardia
    SYMPTOMS

.

    Imaging
    PARACLINICAL

 confirmed the presence of a

    new left ventricular apical aneurysm (LVAA)
    SYMPTOMS

 and a

    significantly reduced intra-cavitary gradient
    SYMPTOMS

 compared to two years prior.

    AFDcv
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    GLA enzyme deficiency
    BIOCHEMICAL

. The phenotypic expression of

    AFD
    DIAGNOSIS

 in the heart is not well described.

    Cardiac involvement
    SYMPTOMS

 can include

    left ventricular hypertrophy (LVH)
    SYMPTOMS

, which is typically symmetric, but can also mimic

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

.

    Left ventricular apical aneurysm
    SYMPTOMS

 is a rare finding in

    HCM
    DIAGNOSIS

. We suggest a shared mechanism of

    LVAA formation
    SYMPTOMS

 in

    AFD
    DIAGNOSIS

 and

    HCM
    DIAGNOSIS

, independent of the underlying

    cardiomyopathy
    DIAGNOSIS

. Mechanisms of

    LVAA formation
    SYMPTOMS

 in

    HCM
    DIAGNOSIS

 include

    genetic predisposition
    GENETICS

 and

    long-standing left ventricular wall stress from elevated intra-cavitary systolic pressures due to mid-cavitary obstruction
    SYMPTOMS

. Both mechanisms are supported in this patient (

    a brother with AFD also developed a small LVAA)
    FAMILY

. Screening for

    AFD
    DIAGNOSIS

 should be considered in cases of

    unexplained LVH
    SYMPTOMS

, particularly in patients with the

    aneurysmal variant of HCM
    SYMPTOMS

.

AFDcv
lysosomal storage disorder
AFD
hypertrophic cardiomyopathy (HCM)
HCM
AFD
HCM
cardiomyopathy
HCM
AFD


High variability of Fabry disease manifestations in an extended Italian family.

Fabry disease (FD) is an inherited metabolic disorder caused by partial or full inactivation of the lysosomal hydrolase α-galactosidase A (α-GAL). The impairment of α-GAL results in the accumulation of undegraded glycosphingolipids in lysosomes and subsequent cell and microvascular dysfunctions. This study reports the clinical, biochemical, and molecular characterization of 15 members of the same family. Eight members showed the exonic mutation M51I in the GLA gene, a disease-causing mutation associated with the atypical phenotype. The clinical history of this family highlights a wide phenotypic variability, in terms of involved organs and severity. The phenotypic variability of two male patients is not related to differences in α-GAL enzymatic activity: though both have no enzymatic activity, the youngest shows severe symptoms, while the eldest is asymptomatic. It is noticeable that for two female patients with the M51I mutation the initial clinical diagnosis was different from FD. One of them was diagnosed with Familial Mediterranean Fever, the other with Multiple Sclerosis. Overall, this study confirms that the extreme variability of the clinical manifestations of FD is not entirely attributable to different mutations in the GLA gene and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of Fabry Disease.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    inherited
    GENETICS

    metabolic disorder
    DIAGNOSIS

 caused by

    partial or full inactivation of the lysosomal hydrolase α-galactosidase A (α-GAL)
    BIOCHEMICAL

. The

    impairment of α-GAL
    BIOCHEMICAL

 results in the

    accumulation of undegraded glycosphingolipids in lysosomes
    MICROSCOPIC

 and subsequent

    cell and microvascular dysfunctions
    MICROSCOPIC

. This study reports the clinical, biochemical, and molecular characterization of 15 members of the same family. Eight members showed the

    exonic mutation M51I in the GLA gene, a disease-causing mutation
    GENETICS

 associated with the atypical phenotype. The clinical history of this family highlights a wide phenotypic variability, in terms of involved organs and severity. The phenotypic variability of two

    male
    GENDER

 patients is

    not related to differences in α-GAL enzymatic activity
    NEG_FINDINGS

: though both have

    no enzymatic activity
    NEG_FINDINGS

, the youngest shows

    severe symptoms
    SYMPTOMS

, while the eldest is

    asymptomatic
    NEG_FINDINGS

. It is noticeable that for two

    female
    GENDER

 patients with the

    M51I mutation
    GENETICS

 the initial clinical diagnosis was different from

    FD
    DIAGNOSIS

. One of them was diagnosed with

    Familial Mediterranean Fever
    DIAGNOSIS

, the other with

    Multiple Sclerosis
    DIAGNOSIS

. Overall, this study confirms that the extreme variability of the clinical manifestations of

    FD
    DIAGNOSIS

 is not entirely attributable to different

    mutations in the GLA gene
    GENETICS

 and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of

    Fabry Disease
    DIAGNOSIS

.

Fabry disease (FD)
metabolic disorder
FD
Familial Mediterranean Fever
Multiple Sclerosis
FD
Fabry Disease


Lessons from two cases: is Fabry disease the correct diagnosis?

Fabry disease (FD) is an X linked inherited lysosomal storage disorder with complex multisystem involvement; it is caused by deficiency of the lysosomal enzyme α-galactosidase. Deficient enzyme activity leads to a wide spectrum of clinical manifestations consisting of dermatological, ophthalmological, cardiovascular, and urinary and central nervous system findings. As a result, FD should be considered in the differential diagnosis of many systemic diseases. Diagnosis of FD can arise from careful clinical and instrumental investigations, together with family history data and accurate interpretation of genetic and enzymatic analyses. Lack of knowledge on clinical findings of the disease and inept investigation methods unfortunately result in erroneous diagnosis. We present two patients who were referred to our clinic with a suspicion of ED and finally diagnosed as glycogen storage disorder type III and ornithine transcarbamylase deficiency, respectively.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X linked inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 with

    complex multisystem involvement
    SYMPTOMS

; it is caused by

    deficiency of the lysosomal enzyme α-galactosidase
    BIOCHEMICAL

.

    Deficient enzyme activity
    BIOCHEMICAL

 leads to a

    wide spectrum of clinical manifestations
    SYMPTOMS

 consisting of

    dermatological, ophthalmological, cardiovascular, and urinary and central nervous system findings
    SYMPTOMS

. As a result,

    FD
    DIAGNOSIS

 should be considered in the

    differential diagnosis
    PARACLINICAL

 of many

    systemic diseases
    DIAGNOSIS

. Diagnosis of

    FD
    DIAGNOSIS

 can arise from

    careful clinical and instrumental investigations
    PARACLINICAL

, together with

    family history data
    PARACLINICAL

 and

    accurate interpretation of genetic and enzymatic analyses
    PARACLINICAL

. Lack of knowledge on clinical findings of the disease and inept investigation methods unfortunately result in erroneous diagnosis. We present two patients who were referred to our clinic with a suspicion of

    ED
    DIAGNOSIS

 and finally diagnosed as

    glycogen storage disorder type III
    DIAGNOSIS

 and

    ornithine transcarbamylase deficiency
    BIOCHEMICAL

, respectively.

Fabry disease (FD)
lysosomal storage disorder
FD
systemic diseases
FD
ED
glycogen storage disorder type III


Fabry disease mimicking multiple sclerosis: Lessons from two case reports.

Fabry disease is an X-linked lysosomal storage disorder that can mimic multiple sclerosis. We present two cases of heterozygous adult women where clinical and radiological features initially suggested a diagnosis of multiple sclerosis. This led us to review the early clinical course and neurological features of Fabry disease and highlight the importance of assessing non-neurologic (systemic) symptoms when considering a diagnosis of multiple sclerosis and the need for specialist interpretation of neuroradiological findings.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 that can mimic

    multiple sclerosis
    DIAGNOSIS

. We present two cases of

    heterozygous
    GENETICS

    adult
    AGE

    women
    GENDER

 where

    clinical and radiological features
    SYMPTOMS

 initially suggested a diagnosis of

    multiple sclerosis
    DIAGNOSIS

. This led us to review the early clinical course and neurological features of

    Fabry disease
    DIAGNOSIS

 and highlight the importance of assessing

    non-neurologic (systemic) symptoms
    SYMPTOMS

 when considering a diagnosis of

    multiple sclerosis
    DIAGNOSIS

 and the need for

    specialist interpretation of neuroradiological findings
    PARACLINICAL

.

Fabry disease
lysosomal storage disorder
multiple sclerosis
multiple sclerosis
Fabry disease
multiple sclerosis

clinical and radiological features
non-neurologic (systemic) symptoms


Apical left ventricular hypertrophy and mid-ventricular obstruction in fabry disease.

We report the case of a rare cardiac presentation of Fabry disease. Although concentric left ventricular hypertrophy is a major cardiac finding in Fabry disease, there is no case report of dynamic obstruction at mid-left ventricular level. We describe a 59-year-old-woman suffering from a severe form of Fabry disease, mimicking an apical hypertrophic cardiomyopathy with mid-ventricular obstruction. Differentiation of Fabry disease from hypertrophic cardiomyopathy is crucial given the therapeutic and prognostic differences. Fabry disease should always be suspected in an adult, independently of the pattern of left ventricular hypertrophy.

We report the case of a rare cardiac presentation of

    Fabry disease
    DIAGNOSIS

. Although

    concentric left ventricular hypertrophy
    SYMPTOMS

 is a major cardiac finding in

    Fabry disease
    DIAGNOSIS

, there is no case report of

    dynamic obstruction at mid-left ventricular level
    SYMPTOMS

. We describe a

    59-year-old
    AGE

-

    woman
    GENDER

 suffering from a

    severe form of Fabry disease
    DIAGNOSIS

, mimicking an

    apical hypertrophic cardiomyopathy with mid-ventricular obstruction
    SYMPTOMS

. Differentiation of

    Fabry disease
    DIAGNOSIS

 from

    hypertrophic cardiomyopathy
    DIAGNOSIS

 is crucial given the therapeutic and prognostic differences.

    Fabry disease
    DIAGNOSIS

 should always be suspected in an

    adult
    AGE

, independently of the pattern of

    left ventricular hypertrophy
    SYMPTOMS

.

Fabry disease
Fabry disease
severe form of Fabry disease
Fabry disease
hypertrophic cardiomyopathy
Fabry disease


Familial angiokeratoma corporis diffusum without identified enzyme defect.

Angiokeratoma corporis diffusum is the cutaneous hallmark of several rare inherited lysosomal diseases associated with specific enzyme deficiencies in the metabolism of glycoproteins, most notably Fabry disease. These defects result in many systemic manifestations. Here, we report a rare familial case of angiokeratoma corporis diffusum that developed at puberty with no major systemic manifestations and no underlying enzyme defect or gene mutation. Familial angiokeratoma corporis diffusum without identified enzyme defect appears to be a distinct clinical entity with a benign course.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 is the cutaneous hallmark of several

    rare inherited
    GENETICS

    lysosomal diseases
    DIAGNOSIS

 associated with specific

    enzyme deficiencies in the metabolism of glycoproteins
    BIOCHEMICAL

, most notably

    Fabry disease
    DIAGNOSIS

. These defects result in many

    systemic manifestations
    SYMPTOMS

. Here, we report a rare familial case of

    angiokeratoma corporis diffusum
    SYMPTOMS

 that developed at

    puberty
    AGE

 with

    no major systemic manifestations
    NEG_FINDINGS

 and

    no underlying enzyme defect or gene mutation
    NEG_FINDINGS

.

    Familial angiokeratoma corporis diffusum
    SYMPTOMS

    without identified enzyme defect
    NEG_FINDINGS

 appears to be a distinct clinical entity with a benign course.


Angiokeratoma of the nasal vestibule: a case report.

Angiokeratomas are benign mucocutaneous lesions which are composed of enlarged veins in the dermis of the skin. Although angiokeratomas may be part of a systemic disease, it is important to distinguish them from other vascular lesions. In this report, we present a rare case of angiokeratoma of the nasal vestibule. To our knowledge, this is the first nasal angiokeratoma case in the literature. The diagnostic and treatment features of this case and the association of angiokeratoma with systemic diseases like Fabry disease were discussed.

    Angiokeratomas
    SYMPTOMS

 are

    benign mucocutaneous lesions
    SYMPTOMS

 which are composed of

    enlarged veins in the dermis of the skin
    SYMPTOMS

. Although

    angiokeratomas
    SYMPTOMS

 may be part of a

    systemic disease
    DIAGNOSIS

, it is important to distinguish them from other

    vascular lesions
    SYMPTOMS

. In this report, we present a rare case of

    angiokeratoma of the nasal vestibule
    SYMPTOMS

. To our knowledge, this is the first

    nasal angiokeratoma
    DIAGNOSIS

 case in the literature. The diagnostic and treatment features of this case and the association of

    angiokeratoma
    SYMPTOMS

 with

    systemic diseases
    DIAGNOSIS

 like

    Fabry disease
    DIAGNOSIS

 were discussed.

systemic disease
nasal angiokeratoma
systemic diseases
Fabry disease


Ophthalmic experience over 10 years in an observational nationwide Danish cohort of Fabry patients with access to enzyme replacement.

Enzyme replacement therapy (ERT) was offered from year 2001 to patients with Fabry disease. The ophthalmic experience was analysed, as part of a general 10-year status.

A retrospective observational series comprising 39 patients (25 females, 14 males) closely followed by the endocrinologists, and with regular ophthalmic control. Time of inclusion was when the option of ERT was started, at age 11-60 years. Eye data (standard eye examination, including retinal imaging) were incomplete in five, due to death or non-attendance, and five patients had refused treatment.

Vision was normal throughout, except in two young males with total unilateral central retinal artery occlusion, prior to and during enzyme replacement, respectively. Cornea verticillata and conjunctival vessel ectasies were common. Tortuosity of retinal arterioles and venules was recorded in eight and 18 patients, respectively, and phlebopathy in 22, although generally without evidence of loss of vessel wall integrity. Systemic vascular lesions with or without loss of function were recorded for kidney (n = 23), heart (n = 17) and brain (n = 7), and an association was suggested between nephropathy and abnormal morphology of retinal vessels.

Thirteen of 32 patients on ERT showed a reduction of corneal deposits over the study period. Abnormal ocular vessel morphology was a frequent finding. In contrast to the function loss related to systemic ischaemic lesions, we found no indication of impairment of visual parameters in 37. Compared to other Fabry series, two of 39 patients with serious unilateral occlusive retinal disease may appear a high number. The presence of retinal tortuosity is discussed, possibly reflecting haemodynamic events related to vessel wall deposits, but could also be 'constitutional', as part of the Fabry inheritance.

    Enzyme replacement therapy (ERT)
    MEDICATION

 was offered from year 2001 to patients with

    Fabry disease
    DIAGNOSIS

. The ophthalmic experience was analysed, as part of a general 10-year status.

A retrospective observational series comprising 39 patients (25

    females
    GENDER

, 14

    males
    GENDER

) closely followed by the

    endocrinologists
    PARACLINICAL

, and with

    regular ophthalmic control
    PARACLINICAL

. Time of inclusion was when the option of

    ERT
    MEDICATION

 was started, at

    age 11-60 years
    AGE

.

    Eye data (standard eye examination, including retinal imaging)
    PARACLINICAL

 were incomplete in five, due to

    death
    SYMPTOMS

 or

    non-attendance
    NEG_FINDINGS

, and five patients had

    refused treatment
    NEG_FINDINGS

.

    Vision was normal throughout
    NEG_FINDINGS

, except in two

    young
    AGE

    males
    GENDER

 with

    total unilateral central retinal artery occlusion
    SYMPTOMS

, prior to and during

    enzyme replacement
    MEDICATION

, respectively.

    Cornea verticillata
    SYMPTOMS

 and

    conjunctival vessel ectasies
    SYMPTOMS

 were common.

    Tortuosity of retinal arterioles and venules
    SYMPTOMS

 was recorded in eight and 18 patients, respectively, and

    phlebopathy
    SYMPTOMS

 in 22, although generally

    without evidence of loss of vessel wall integrity
    NEG_FINDINGS

.

    Systemic vascular lesions with or without loss of function
    SYMPTOMS

 were recorded

    for kidney
    SYMPTOMS

 (n = 23)

    , heart
    SYMPTOMS

 (n = 17)

    and brain
    SYMPTOMS

 (n = 7), and an association was suggested between

    nephropathy
    DIAGNOSIS

 and

    abnormal morphology of retinal vessels
    SYMPTOMS

.

Thirteen of 32 patients on

    ERT
    MEDICATION

 showed a

    reduction of corneal deposits
    SYMPTOMS

 over the study period.

    Abnormal ocular vessel morphology
    SYMPTOMS

 was a frequent finding. In contrast to the

    function loss related to systemic ischaemic lesions
    SYMPTOMS

, we found

    no indication of impairment of visual parameters
    NEG_FINDINGS

 in 37. Compared to other

    Fabry
    DIAGNOSIS

 series, two of 39 patients with

    serious unilateral occlusive retinal disease
    DIAGNOSIS

 may appear a high number. The presence of

    retinal tortuosity
    SYMPTOMS

 is discussed, possibly reflecting

    haemodynamic events related to vessel wall deposits
    SYMPTOMS

, but could also be 'constitutional', as part of the

    Fabry inheritance
    GENETICS

.

Enzyme replacement therapy (ERT)
ERT
enzyme replacement
ERT


A male Fabry disease patient treated with intravenous thrombolysis for acute ischemic stroke.

The use of intravenous thrombolytic therapy for acute ischemic stroke is associated with improved outcomes. Fabry disease is an X-linked glycosphingolipid storage disease with vascular endothelial deposits. Affected males with the classic phenotype develop renal, cardiac, and cerebrovascular disease and die prematurely. However, Fabry disease is rare in young men with first ischemic stroke of undetermined cause. We report a 38-year-old man with acute aphasia and a left M2 segment of the middle cerebral artery thrombus with no recanalization who was finally diagnosed with Fabry disease after left ventricular hypertrophy of undetermined cause had been identified. A gene test revealed a R227X mutation typical of Fabry disease with the classical phenotype. To our knowledge our patient is the first reported male Fabry patient who was given intravenous thrombolytic therapy and the first reported Fabry patient who received intravenous thrombolytic therapy between 3 and 4.5 hours of the symptom onset. Despite favorable prognostic indicators on admission imaging, our patient suffered a significant stroke and had an unfavorable clinical outcome. Fortunately, the episode was not complicated by intracranial hemorrhage. Further studies are needed to evaluate the efficacy and safety of intravenous thrombolytic therapy in treating patients with Fabry disease and acute ischemic stroke.

The use of

    intravenous thrombolytic therapy
    MEDICATION

 for

    acute ischemic stroke
    SYMPTOMS

 is associated with improved outcomes.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    glycosphingolipid storage disease
    DIAGNOSIS

 with

    vascular endothelial deposits
    MICROSCOPIC

. Affected

    males
    GENDER

 with the classic phenotype develop

    renal, cardiac, and cerebrovascular disease
    SYMPTOMS

 and

    die
    SYMPTOMS

 prematurely. However,

    Fabry disease
    DIAGNOSIS

 is rare in

    young
    AGE

    men
    GENDER

 with

    first ischemic stroke of undetermined cause
    SYMPTOMS

. We report a

    38-year-old
    AGE

    man
    GENDER

 with

    acute aphasia
    SYMPTOMS

 and a

    left M2 segment of the middle cerebral artery thrombus with no recanalization
    SYMPTOMS

 who was finally diagnosed with

    Fabry disease
    DIAGNOSIS

 after

    left ventricular hypertrophy of undetermined cause
    SYMPTOMS

 had been identified. A

    gene test
    PARACLINICAL

 revealed a

    R227X mutation typical of Fabry disease with the classical phenotype
    GENETICS

. To our knowledge our patient is the first reported

    male
    GENDER

    Fabry
    DIAGNOSIS

 patient who was given

    intravenous thrombolytic therapy
    MEDICATION

 and the first reported

    Fabry
    DIAGNOSIS

 patient who received

    intravenous thrombolytic therapy
    MEDICATION

 between 3 and 4.5 hours of the symptom onset.

    Despite favorable prognostic indicators on admission imaging
    NEG_FINDINGS

, our patient suffered a

    significant stroke
    SYMPTOMS

 and had an

    unfavorable clinical outcome
    SYMPTOMS

. Fortunately, the episode was

    not complicated by intracranial hemorrhage
    NEG_FINDINGS

. Further studies are needed to evaluate the efficacy and safety of

    intravenous thrombolytic therapy
    MEDICATION

 in treating patients with

    Fabry disease
    DIAGNOSIS

 and

    acute ischemic stroke
    SYMPTOMS

.

intravenous thrombolytic therapy
intravenous thrombolytic therapy
intravenous thrombolytic therapy
intravenous thrombolytic therapy

Fabry disease
glycosphingolipid storage disease
Fabry disease
Fabry disease
Fabry
Fabry
Fabry disease


Teenager male with burning pain in extremities--suspect Fabry disease, 2 case reports.

We present 2 cases of teenager males presented with burning pain in extremities and turned out to be cases of Fabry disease.The purpose of presenting this case is to highlight the fact that suspicion of Fabry disease in patients presenting with these symptoms will lead to early diagnosis and treatment of this condition before occurrences of complications.

A 14-year-old male presented with severe burning pain in both hands and feet since last 4 yrs which persisted despite consumption of painkillers and becoming more disabling and without having any family history for such condition. On general examination patient had small reddish coloured lesions around the umbilicus, appearing like angiokeratomas. Skin biopsy confirmed the lesion. On enzyme assay his alpha galactosidase activity found to be '0' nmol/hr/mg of protein, confirming his diagnosis. Patient's creatinine and 2 D ECHO were normal and urine had 1+ proteinuria. Patient started on carbamazepine tablets for pain and referred to higher centre for genetic diagnosis and enzyme replacement therapy. CASE REPORT 2: An 18-year-old male referred to our hospital by general practitioner for fatigue and pedal oedema with deranged renal function tests. On history taking patient gave history of severe burning pain in both hands and feet since age of 9 yrs. Patient's general examination revealed hypertension with pallor, pedal oedema along with angiokeratomas in bathing suit distribution. Patient's ultrasonography of kidney revealed bilaterally normal sized kidneys with altered echotexture and urine examination showed fine granular foamy cells with sub nephrotic range proteinuria. 2 D ECHO revealed concentric left ventricular hypertrophy. Skin biopsy report supported the diagnosis of Fabry disease. Patient advised to undergo renal biopsy to confirm Fabry nephropathy but patient denied any further diagnostic workup for nephropathy or Fabry disease. Patient started on conservative treatment and carbamazepine in renal dose given for acroparaesthesias. On discharge patient has been advised to visit higher centre for further diagnostic work up and enzyme replacement therapy.

Suspicion of Fabry disease in teenager males presenting with symptoms of burning pain in extremities may lead to early diagnosis and treatment of this condition before occurrences of complications.

We present 2 cases of

    teenager
    AGE

    males
    GENDER

 presented with

    burning pain in extremities
    SYMPTOMS

 and turned out to be cases of

    Fabry disease
    DIAGNOSIS

.The purpose of presenting this case is to highlight the fact that suspicion of

    Fabry disease
    DIAGNOSIS

 in patients presenting with these symptoms will lead to early diagnosis and treatment of this condition before occurrences of complications.

A

    14-year-old
    AGE

    male
    GENDER

 presented with

    severe burning pain in both hands and feet
    SYMPTOMS

 since last

    4 yrs
    SYMPTOMS

 which persisted

    despite consumption of painkillers
    NEG_FINDINGS

 and becoming more disabling and

    without having any family history for such condition
    NEG_FINDINGS

. On general examination patient had

    small reddish coloured lesions around the umbilicus, appearing like angiokeratomas
    SYMPTOMS

.

    Skin biopsy
    PARACLINICAL

 confirmed the lesion. On

    enzyme assay
    PARACLINICAL

 his

    alpha galactosidase activity found to be '0' nmol/hr/mg of protein
    BIOCHEMICAL

, confirming his diagnosis. Patient's

    creatinine and 2 D ECHO were normal
    NEG_FINDINGS

 and

    urine had 1+ proteinuria
    BIOCHEMICAL

. Patient started on

    carbamazepine tablets
    MEDICATION

 for

    pain
    MEDICATION

 and referred to higher centre for

    genetic diagnosis
    MEDICATION

 and

    enzyme replacement therapy
    MEDICATION

. CASE REPORT 2: An

    18-year-old
    AGE

    male
    GENDER

 referred to our hospital by

    general practitioner
    PARACLINICAL

 for

    fatigue
    SYMPTOMS

 and

    pedal oedema
    SYMPTOMS

 with

    deranged renal function tests
    BIOCHEMICAL

. On

    history taking
    PARACLINICAL

 patient gave history of

    severe burning pain in both hands and feet
    SYMPTOMS

 since

    age of 9 yrs
    AGE

. Patient's

    general examination
    PARACLINICAL

 revealed

    hypertension
    SYMPTOMS

 with

    pallor
    SYMPTOMS

,

    pedal oedema
    SYMPTOMS

 along with

    angiokeratomas in bathing suit distribution
    SYMPTOMS

. Patient's

    ultrasonography of kidney
    PARACLINICAL

 revealed

    bilaterally normal sized kidneys with altered echotexture
    SYMPTOMS

 and

    urine examination
    PARACLINICAL

 showed

    fine granular foamy cells
    MICROSCOPIC

 with

    sub nephrotic range proteinuria
    BIOCHEMICAL

.

    2 D ECHO
    PARACLINICAL

 revealed

    concentric left ventricular hypertrophy
    SYMPTOMS

.

    Skin biopsy report
    PARACLINICAL

 supported the diagnosis of

    Fabry disease
    DIAGNOSIS

. Patient advised to undergo

    renal biopsy
    PARACLINICAL

 to confirm

    Fabry nephropathy
    DIAGNOSIS

 but patient

    denied any further diagnostic workup for nephropathy or Fabry disease
    NEG_FINDINGS

. Patient started on

    conservative treatment
    MEDICATION

 and

    carbamazepine in renal dose
    MEDICATION

 given for

    acroparaesthesias
    SYMPTOMS

. On discharge patient has been advised to visit higher centre for further diagnostic work up and

    enzyme replacement therapy
    MEDICATION

.

Suspicion of

    Fabry disease
    DIAGNOSIS

 in

    teenager
    AGE

    males
    GENDER

 presenting with

    symptoms of burning pain in extremities
    SYMPTOMS

 may lead to early diagnosis and treatment of this condition before occurrences of complications.

Fabry disease
Fabry disease
Fabry disease
Fabry nephropathy
Fabry disease

carbamazepine tablets
pain
genetic diagnosis
enzyme replacement therapy
conservative treatment
carbamazepine in renal dose
enzyme replacement therapy


A heterozygous female with Fabry disease due to a novel α-galactosidase A mutation exhibits a unique synaptopodin distribution in vacuolated podocytes.

We report the case of a 42-yearold woman diagnosed with heterozygous Fabry disease (FD) due to a novel α-galactosidase A Pro210Ser mutation and exhibiting a unique distribution of synaptopodin within podocytes. The patient was referred to our hospital with moderate proteinuria, and a renal biopsy was performed. Light microscopic examination of the specimen revealed diffuse global enlargement of podocytes, which also showed foamy changes. Electron microscopy revealed abundant myeloid bodies in podocytes and focal mitochondrial abnormalities within the tubules. The patient exhibited none of the characteristic symptoms of FD except hypohidrosis and had no obvious family history. Genetic analysis revealed a novel missense mutation (Pro210Ser) in the α-galactosidase A gene. She was ultimately diagnosed with FD based on immunohistochemical staining indicating large amounts of accumulated globotriaosylceramide in her podocytes, detection of urinary globotriaosylceramide secretion using high-performance thin-layer chromatography/ immunostaining, and structural modeling of the mutated α-galactosidase A (Pro210Ser). Immunostaining of the swollen and foamy podocytes using podocyte-associated antibodies (against podocalyxin, Wilms tumor-1, vimentin, and synaptopodin) revealed a unique distribution of synaptopodin surrounding globotriaosylceramide. To our knowledge, this is the first report of immunohistologically detected synaptopodin upregulation in foamy podocytes in a patient with FD.

We report the case of a

    42-yearold
    AGE

    woman
    GENDER

 diagnosed with

    heterozygous Fabry disease (FD)
    DIAGNOSIS

 due to a

    novel α-galactosidase A Pro210Ser mutation
    GENETICS

 and exhibiting a

    unique distribution of synaptopodin within podocytes
    MICROSCOPIC

. The patient was referred to our hospital with

    moderate proteinuria
    BIOCHEMICAL

, and a

    renal biopsy
    PARACLINICAL

 was performed.

    Light microscopic examination of the specimen
    PARACLINICAL

 revealed

    diffuse global enlargement of podocytes, which also showed foamy changes
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 revealed

    abundant myeloid bodies in podocytes
    MICROSCOPIC

 and

    focal mitochondrial abnormalities within the tubules
    MICROSCOPIC

. The patient exhibited

    none of the characteristic symptoms of FD
    NEG_FINDINGS

 except

    hypohidrosis
    NEG_FINDINGS

 and had

    no obvious family history
    NEG_FINDINGS

.

    Genetic analysis
    PARACLINICAL

 revealed a

    novel missense mutation (Pro210Ser) in the α-galactosidase A gene
    GENETICS

.

    She
    GENDER

 was ultimately diagnosed with

    FD
    DIAGNOSIS

 based on

    immunohistochemical staining
    PARACLINICAL

 indicating

    large amounts of accumulated globotriaosylceramide in her podocytes
    MICROSCOPIC

,

    detection of urinary globotriaosylceramide secretion
    BIOCHEMICAL

 using

    high-performance thin-layer chromatography/ immunostaining
    PARACLINICAL

, and

    structural modeling of the mutated α-galactosidase A (Pro210Ser)
    GENETICS

.

    Immunostaining of the swollen and foamy podocytes
    PARACLINICAL

 using podocyte-associated antibodies (against

    podocalyxin
    BIOCHEMICAL

, Wilms tumor-1, vimentin, and

    synaptopodin
    BIOCHEMICAL

) revealed a

    unique distribution of synaptopodin surrounding globotriaosylceramide
    MICROSCOPIC

. To our knowledge, this is the first report of

    immunohistologically detected synaptopodin upregulation in foamy podocytes
    PARACLINICAL

 in a patient with

    FD
    DIAGNOSIS

.


A family with various symptomatology suggestive of Anderson-Fabry disease and a genetic polymorphism of alpha galactosidase A gene.

Anderson/Fabry disease expresses a wide range of clinical variability in patients that it is possible to explain referring to a genetic variability with numerous mutations described in the literature (more than 600).

We report some clinical cases of some members of a Sicilian family to express phenotypical variability of this disease in subjects with the same genetic mutation

The first case was a 59-year-old female. Brain MRI revealed right frontal periventricular white matter of likely vascular-degenerative origin. The proband's alpha galactosidase A activity was 3.7nmol/mL/h. Molecular genetics revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C>T. The second case was a 30year-old male affected by acroparesthesias and hypoidrosis since he was an adolescent. Renal impairment was first detected at age 29; it began with high plasma levels of creatinine and microalbuminuria date. The third case was a 41year-old daughter that presented with acroparesthesias, hypoidrosis since she was very young. The patient's alpha galactosidase A activity was 4.1nmol/mL/h, in whole blood, which is compatible with heterozygote subject for Fabry's disease or healthy control. The fourth case was a male grandson of the proband, 9year-old child. He had a classic gastrointestinal involvement. He complained of recurrent abdominal pain, post prandial bloating and pain. This child's enzyme activity was 1.65nmol/mL/h. In cases 2, 3, and 4, molecular genetics revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C<T DISCUSSION: A recent study reported that IVS4+68 A>G, IVS6-22C>T polymorphisms occurred in 8.9% and 3.7% of the subjects respectively, and the significance of this haplotype in FD pathology remains unknown but possibly suggestive of Anderson/Fabry disease.

    Anderson/Fabry disease
    DIAGNOSIS

 expresses a wide range of clinical variability in patients that it is possible to explain referring to a

    genetic variability
    GENETICS

 with numerous mutations described in the literature (more than 600).

The first case was a

    59-year-old
    AGE

    female
    GENDER

.

    Brain MRI
    PARACLINICAL

 revealed

    right frontal periventricular white matter of likely vascular-degenerative origin
    SYMPTOMS

. The proband's alpha galactosidase A activity was 3.7nmol/mL/h.

    Molecular genetics
    PARACLINICAL

 revealed a polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C>T. The second case was a

    30year-old
    AGE

    male
    GENDER

 affected by

    acroparesthesias
    SYMPTOMS

 and

    hypoidrosis
    SYMPTOMS

 since

    he
    GENDER

 was an

    adolescent
    AGE

.

    Renal impairment
    SYMPTOMS

 was first detected at

    age 29
    AGE

; it began with

    high plasma levels of creatinine
    BIOCHEMICAL

 and

    microalbuminuria date
    BIOCHEMICAL

. The third case was a

    41year-old
    AGE

    daughter
    GENDER

 that presented with

    acroparesthesias
    SYMPTOMS

,

    hypoidrosis
    SYMPTOMS

 since

    she
    GENDER

 was

    very young
    AGE

. The patient's

    alpha galactosidase A activity was 4.1nmol/mL/h, in whole blood
    BIOCHEMICAL

, which is compatible with

    heterozygote subject for Fabry's disease
    GENETICS

 or healthy control. The fourth case was a

    male
    GENDER

    grandson of the proband
    FAMILY

,

    9year-old child
    AGE

.

    He
    GENDER

 had a

    classic gastrointestinal involvement
    SYMPTOMS

.

    He
    GENDER

 complained of

    recurrent abdominal pain
    SYMPTOMS

,

    post prandial bloating
    SYMPTOMS

 and

    pain
    SYMPTOMS

. This

    child
    AGE

's enzyme activity was 1.65nmol/mL/h. In cases 2, 3, and 4,

    molecular genetics
    PARACLINICAL

 revealed a

    polymorphism: -10 C>T; IVS 2-76_80del5; IVS4-16 A>G; IVS6-22 C<T
    GENETICS

 DISCUSSION: A recent study reported that

    IVS4+68 A>G, IVS6-22C>T polymorphisms
    GENETICS

 occurred in 8.9% and 3.7% of the subjects respectively, and the significance of this haplotype in

    FD
    DIAGNOSIS

 pathology remains unknown but possibly suggestive of

    Anderson/Fabry disease
    DIAGNOSIS

.

Anderson/Fabry disease
FD
Anderson/Fabry disease


A rare association between Fabry's disease and granulomatosis with polyangiitis: a potential pathogenic link.

Fabry's disease is a rare X-linked, hereditary lysosomal storage disease caused by a deficiency of the enzyme α-galactosidase A. Granulomatosis with polyangiitis is characterized by the involvement of the respiratory tract and kidneys. Here, we report the first case of the coexistence of these diseases.

We describe a 29-year-old man suffering from fever with maxillary sinusitis, multiple lung nodules, and proteinuria. He was diagnosed with Fabry's disease accompanying granulomatosis with polyangiitis on the basis of the low activity of peripheral leukocyte α-galactosidase A and pathological findings in the lung and kidney. Glucocorticoid and cyclophosphamide were administered, followed by enzyme replacement therapy. Progression to end-stage renal disease has not been observed for 6 years until the time of drafting this manuscript.

Because both Fabry's disease and granulomatosis with polyangiitis or crescentic glomerulonephritis are rare diseases, their concurrence in this and related cases suggests there may be a pathogenic link between these two conditions. Fabry's disease may be underdiagnosed, particularly in cases of granulomatosis with polyangiitis or crescentic glomerulonephritis.

    Fabry's disease
    DIAGNOSIS

 is a

    rare X-linked, hereditary
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a deficiency of the enzyme α-galactosidase A.

    Granulomatosis with polyangiitis
    DIAGNOSIS

 is characterized by the

    involvement of the respiratory tract and kidneys
    SYMPTOMS

. Here, we report the first case of the

    coexistence of these diseases
    DIAGNOSIS

.

We describe a

    29-year-old
    AGE

    man
    GENDER

 suffering from

    fever
    SYMPTOMS

 with

    maxillary sinusitis
    SYMPTOMS

,

    multiple lung nodules
    SYMPTOMS

, and

    proteinuria
    BIOCHEMICAL

.

    He
    GENDER

 was diagnosed with

    Fabry's disease
    DIAGNOSIS

 accompanying

    granulomatosis with polyangiitis
    DIAGNOSIS

 on the basis of the

    low activity of peripheral leukocyte α-galactosidase A
    BIOCHEMICAL

 and

    pathological findings in the lung and kidney
    MICROSCOPIC

.

    Glucocorticoid and cyclophosphamide
    MEDICATION

 were administered, followed by

    enzyme replacement therapy
    MEDICATION

.

    Progression to end-stage renal disease has not been observed for 6 years
    NEG_FINDINGS

 until the time of drafting this manuscript.

Because both

    Fabry's disease
    DIAGNOSIS

 and

    granulomatosis with polyangiitis or crescentic glomerulonephritis
    DIAGNOSIS

 are rare diseases, their concurrence in this and related cases suggests there may be a pathogenic link between these two conditions.

    Fabry's disease
    DIAGNOSIS

 may be underdiagnosed, particularly in cases of

    granulomatosis with polyangiitis
    DIAGNOSIS

 or

    crescentic glomerulonephritis
    DIAGNOSIS

.

Glucocorticoid and cyclophosphamide
enzyme replacement therapy


Histopathological evidence of Fabry disease in a female patient with left ventricular noncompaction.

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase gene. The most frequent cardiac presentation of Fabry disease is cardiomyopathy characterized by left ventricular (LV) hypertrophy, usually concentric. Heart disease in affected females tends to be clinically recognized later than in males and cardiac complications are the most frequently reported cause of death in females with Fabry disease. There are few data regarding the association between Fabry disease and LV noncompaction. We report a case of a 30-year-old asymptomatic woman, heterozygous for a nonsense alpha-galactosidase gene mutation (p.R220X), who presented LV noncompaction on cardiac magnetic resonance imaging, without LV wall hypertrophy. Histopathological examination of myocardial fragments showed marked deposition of glycosphingolipids in cardiomyocytes, confirming the diagnosis of Fabry cardiomyopathy. Based on this finding, the patient was proposed for enzyme replacement therapy. This case illustrates the role of endomyocardial biopsy in the clarification of doubtful or atypical findings related to cardiac Fabry disease, even in heterozygous women, and corroborates the contention that Fabry disease should be included in the differential diagnosis of LV hypertrabeculation/noncompaction.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations in the alpha-galactosidase gene
    GENETICS

. The most frequent cardiac presentation of

    Fabry disease
    DIAGNOSIS

 is

    cardiomyopathy
    DIAGNOSIS

 characterized by

    left ventricular (LV) hypertrophy, usually concentric
    SYMPTOMS

.

    Heart disease
    DIAGNOSIS

 in affected

    females
    GENDER

 tends to be clinically recognized later than in

    males
    GENDER

 and

    cardiac complications
    SYMPTOMS

 are the most frequently reported cause of

    death
    SYMPTOMS

 in

    females
    GENDER

 with

    Fabry disease
    DIAGNOSIS

. There are few data regarding the association between

    Fabry disease
    DIAGNOSIS

 and

    LV noncompaction
    SYMPTOMS

. We report a case of a

    30-year-old
    AGE

    asymptomatic
    NEG_FINDINGS

    woman
    GENDER

,

    heterozygous for a nonsense alpha-galactosidase gene mutation (p.R220X)
    GENETICS

, who presented

    LV noncompaction
    SYMPTOMS

 on

    cardiac magnetic resonance imaging
    PARACLINICAL

,

    without LV wall hypertrophy
    NEG_FINDINGS

.

    Histopathological examination of myocardial fragments
    PARACLINICAL

 showed

    marked deposition of glycosphingolipids in cardiomyocytes
    MICROSCOPIC

, confirming the diagnosis of

    Fabry cardiomyopathy
    DIAGNOSIS

. Based on this finding, the patient was proposed for

    enzyme replacement therapy
    MEDICATION

. This case illustrates the role of

    endomyocardial biopsy
    PARACLINICAL

 in the clarification of doubtful or atypical findings related to

    cardiac Fabry disease
    SYMPTOMS

, even in

    heterozygous
    GENETICS

    women
    GENDER

, and corroborates the contention that

    Fabry disease
    DIAGNOSIS

 should be included in the

    differential diagnosis
    PARACLINICAL

 of

    LV hypertrabeculation/noncompaction
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
Fabry disease
cardiomyopathy
Heart disease
Fabry disease
Fabry disease
Fabry cardiomyopathy
Fabry disease

asymptomatic
without LV wall hypertrophy


Fabry disease in infancy and early childhood: a systematic literature review.

Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood.

A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the pediatric Fabry population was performed to review symptoms in patients reported before 5 years of age.

The most frequently reported symptom in all age groups under 5 years was acroparesthesias/neuropathic pain, reported in 9 children, ranging in age from 2.0-4.0 years. Also notable is the frequency of gastrointestinal issues reported in 6 children aged 1.0-4.1 years of age.

This article finds clear evidence that symptoms can occur in early childhood, before age 5 years. Given early presenting symptoms and the ability to monitor these disease hallmarks, a timely referral to a medical geneticist or other specialty clinician experienced in managing children with Fabry disease is strongly indicated.

    Fabry disease
    DIAGNOSIS

 is a

    pan-ethnic
    GENETICS

,

    progressive, X-linked genetic disorder
    GENETICS

 that commonly presents in

    childhood
    AGE

 and is caused by

    deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A)
    BIOCHEMICAL

. Symptoms of

    Fabry disease
    DIAGNOSIS

 in the

    pediatric
    AGE

 population are well described for patients

    over five years of age
    AGE

; however, data are limited for

    infancy
    AGE

    and early childhood
    AGE

. The purpose of this article is to delineate the age of detection for specific

    Fabry symptoms
    SYMPTOMS

 in

    early childhood
    AGE

.

A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the

    pediatric
    AGE

    Fabry
    DIAGNOSIS

 population was performed to review symptoms in patients reported

    before 5 years of age
    AGE

.

The most frequently reported symptom in

    all age groups under 5 years
    AGE

 was

    acroparesthesias/neuropathic pain
    SYMPTOMS

, reported in 9

    children
    AGE

,

    ranging in age from 2.0-4.0 years
    AGE

. Also notable is the frequency of

    gastrointestinal issues
    SYMPTOMS

 reported in 6

    children
    AGE

    aged 1.0-4.1 years of age
    AGE

.

This article finds clear evidence that symptoms can occur in

    early childhood
    AGE

,

    before age 5 years
    AGE

. Given

    early presenting symptoms
    SYMPTOMS

 and the ability to monitor these disease hallmarks, a timely referral to a

    medical geneticist
    PARACLINICAL

 or other specialty clinician experienced in managing

    children
    AGE

 with

    Fabry disease
    DIAGNOSIS

 is strongly indicated.

Fabry disease
Fabry disease
Fabry
Fabry disease

pan-ethnic
progressive, X-linked genetic disorder

Fabry symptoms
acroparesthesias/neuropathic pain
gastrointestinal issues
early presenting symptoms


Klinefelter syndrome with fabry disease--a case of nondisjunction of the X-chromosome with sex-linked recessive mutation.

A 52 year-old male with Klinefelter syndrome presented with chest tightness and rapid atrial fibrillation with hypotension. His echocardiogram demonstrated symmetrical left ventricular hypertrophy with minimal diastolic dysfunction. Subsequent investigations confirmed the diagnosis of Fabry cardiomyopathy. This is the first reported case of Klinefelter syndrome with homozygous sex-linked recessive mutation presenting primarily with cardiac manifestation.

A

    52 year-old
    AGE

    male
    GENDER

 with

    Klinefelter syndrome
    DIAGNOSIS

 presented with

    chest tightness
    SYMPTOMS

 and

    rapid atrial fibrillation
    SYMPTOMS

 with

    hypotension
    SYMPTOMS

. His echocardiogram demonstrated

    symmetrical left ventricular hypertrophy
    SYMPTOMS

 with

    minimal diastolic dysfunction
    SYMPTOMS

. Subsequent investigations confirmed the diagnosis of

    Fabry cardiomyopathy
    DIAGNOSIS

. This is the first reported case of

    Klinefelter syndrome
    DIAGNOSIS

 with

    homozygous sex-linked recessive mutation
    GENETICS

 presenting primarily with

    cardiac manifestation
    SYMPTOMS

.

Klinefelter syndrome
Fabry cardiomyopathy
Klinefelter syndrome


Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance.

Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory.

    Fabry disease' (FD)
    DIAGNOSIS

 phenotype is heterogeneous:

    alpha-galactosidase A gene mutations (GLA)
    GENETICS

 can lead to classical or

    non-classical FD
    DIAGNOSIS

, or

    no FD
    NEG_FINDINGS

. The aim of this study is to describe pitfalls in diagnosing

    non-classical FD
    DIAGNOSIS

 and assess the diagnostic value of

    plasma globotriaosylsphingosine
    BIOCHEMICAL

. This is a case series study. Family 1 (

    p.A143T)
    GENETICS

 presented with

    hypertrophic cardiomyopathy (HCM)
    SYMPTOMS

,

    absent classical FD signs
    NEG_FINDINGS

,

    high residual alpha-galactosidase A activity (AGAL-A)
    BIOCHEMICAL

 and

    normal plasma globotriaosylsphingosine
    NEG_FINDINGS

.

    Co-segregating sarcomeric mutations
    GENETICS

 were found.

    Cardiac biopsy excluded FD
    NEG_FINDINGS

. In family 2 (

    p.P60L)
    GENETICS

,

    FD
    DIAGNOSIS

 was suspected after

    kidney biopsy
    PARACLINICAL

 in a

    female
    GENDER

 with

    chloroquine use
    MEDICATION

.

    Males
    GENDER

 had

    residual AGAL-A
    BIOCHEMICAL

,

    no classical FD signs
    NEG_FINDINGS

 and

    minimally increased plasma globotriaosylsphingosine
    BIOCHEMICAL

, indicating that

    p.P60L is
    GENETICS

 most likely

    non-pathogenic
    NEG_FINDINGS

.

    Non-specific complications
    NEG_FINDINGS

 and

    histology
    SYMPTOMS

 can be explained by chloroquine and alternative causes.

    Males
    GENDER

 of two unrelated families (

    p.R112H
    GENETICS

) show

    AGAL-A <5%
    BIOCHEMICAL

, but

    slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l)
    BIOCHEMICAL

.

    Histological evidence
    PARACLINICAL

 suggests a

    variable penetrance of this mutation
    GENETICS

. Patients with

    GLA mutations
    GENETICS

 and

    non-specific findings
    SYMPTOMS

 such as

    HCM
    SYMPTOMS

 may have

    non-classical FD
    DIAGNOSIS

 or

    no FD
    NEG_FINDINGS

.

    Other (genetic) causes of FD-like findings
    NEG_FINDINGS

 should be excluded, including medication inducing

    FD-like storage
    DIAGNOSIS

.

    Plasma globotriaosylsphingosine
    PARACLINICAL

 may serve as a diagnostic tool, but

    histology of an affected organ
    PARACLINICAL

 is often mandatory.

Fabry disease' (FD)
non-classical FD
non-classical FD
FD
non-classical FD
FD-like storage

hypertrophic cardiomyopathy (HCM)
histology
non-specific findings
HCM


Anderson-Fabry cardiomyopathy: prevalence, pathophysiology, diagnosis and treatment.

Anderson-Fabry disease (AFD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide in tissues due to a deficiency in the enzyme α-galactosidase A (α-Gal A). Anderson-Fabry cardiomyopathy is characterized by structural, valvular, vascular and conduction abnormalities, and is now the most common cause of mortality in patients with AFD. Large-scale metabolic and genetic screening studies have revealed AFD to be prevalent in populations of diverse ethnic origins, and the variant form of AFD represents an unrecognized health burden. Anderson-Fabry disease is an X-linked disorder, and genetic testing is critical for the diagnosis of AFD in women. Echocardiography with strain imaging and cardiac magnetic resonance imaging using late enhancement and T1 mapping are important imaging tools. The current therapy for AFD is enzyme replacement therapy (ERT), which can reverse or prevent AFD progression, while gene therapy and the use of molecular chaperones represent promising novel therapies for AFD. Anderson-Fabry cardiomyopathy is an important and potentially reversible cause of heart failure that involves LVH, increased susceptibility to arrhythmias and valvular regurgitation. Genetic testing and cardiac MRI are important diagnostic tools, and AFD cardiomyopathy is treatable if ERT is introduced early.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is a

    lysosomal storage disease
    DIAGNOSIS

 caused by the

    inappropriate accumulation of globotriaosylceramide in tissues
    MICROSCOPIC

 due to a

    deficiency in the enzyme α-galactosidase A (α-Gal A)
    BIOCHEMICAL

.

    Anderson-Fabry cardiomyopathy
    DIAGNOSIS

 is characterized by

    structural, valvular, vascular and conduction abnormalities
    SYMPTOMS

, and is now the most common cause of mortality in patients with

    AFD
    DIAGNOSIS

. Large-scale metabolic and genetic screening studies have revealed

    AFD
    DIAGNOSIS

 to be prevalent in populations of diverse ethnic origins, and the variant form of

    AFD
    DIAGNOSIS

 represents an unrecognized health burden.

    Anderson-Fabry disease
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

, and

    genetic testing
    PARACLINICAL

 is critical for the diagnosis of

    AFD
    DIAGNOSIS

 in

    women
    GENDER

.

    Echocardiography with strain imaging
    PARACLINICAL

 and

    cardiac magnetic resonance imaging using late enhancement and T1 mapping
    PARACLINICAL

 are important imaging tools. The current therapy for

    AFD
    DIAGNOSIS

 is

    enzyme replacement therapy (ERT)
    MEDICATION

, which can reverse or prevent

    AFD progression
    SYMPTOMS

, while

    gene therapy
    MEDICATION

 and the use of

    molecular chaperones
    MEDICATION

 represent promising novel therapies for

    AFD
    DIAGNOSIS

.

    Anderson-Fabry cardiomyopathy
    DIAGNOSIS

 is an important and potentially reversible cause of

    heart failure
    SYMPTOMS

 that involves

    LVH
    SYMPTOMS

,

    increased susceptibility to arrhythmias
    SYMPTOMS

 and

    valvular regurgitation
    SYMPTOMS

.

    Genetic testing
    PARACLINICAL

 and

    cardiac MRI
    PARACLINICAL

 are important diagnostic tools, and

    AFD cardiomyopathy
    DIAGNOSIS

 is treatable if

    ERT
    MEDICATION

 is introduced early.

Anderson-Fabry disease (AFD)
lysosomal storage disease
Anderson-Fabry cardiomyopathy
AFD
AFD
AFD
Anderson-Fabry disease
AFD
AFD
AFD
Anderson-Fabry cardiomyopathy
AFD cardiomyopathy

enzyme replacement therapy (ERT)
gene therapy
molecular chaperones
ERT


Myocardial fibrosis as the first sign of cardiac involvement in a male patient with Fabry disease: report of a clinical case and discussion on the utility of the magnetic resonance in Fabry pathology.

Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging is increasingly used to assess myocardial involvement in patients with Fabry disease, an X linked lipid storage disorder. However, it is often proposed as an optional tool. A different cardiomyopathic disease progression between male and female patients was hypothesised in previous studies, as in female myocardial fibrosis was found without left ventricular (LV) hypertrophy, while myocardial fibrosis was always detected in association to LV hypertrophy in men.

A male Caucasian patient, 19 years old, diagnosed through a family-based molecular screening, presented with LGE of the LV inferolateral wall evidenced at the CMR, without LV hypertrophy, or other clinical signs of the disease.

This is the first report of cardiac fibrosis as the first sign of organ involvement in a male patient with Fabry disease. This finding stresses the importance of performing CMR with LGE imaging for the initial staging and monitoring of Fabry patients of both genders.

    Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging
    PARACLINICAL

 is increasingly used to assess

    myocardial involvement
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

, an

    X linked
    GENETICS

    lipid storage disorder
    DIAGNOSIS

. However, it is often proposed as an optional tool. A different

    cardiomyopathic
    DIAGNOSIS

 disease progression between

    male
    GENDER

 and

    female
    GENDER

 patients was hypothesised in previous studies, as in

    female
    GENDER

    myocardial fibrosis
    SYMPTOMS

 was found

    without left ventricular (LV) hypertrophy
    NEG_FINDINGS

, while

    myocardial fibrosis
    SYMPTOMS

 was always detected in association to

    LV hypertrophy
    SYMPTOMS

 in

    men
    GENDER

.

A

    male
    GENDER

    Caucasian
    ETHNICITY

 patient,

    19 years old
    AGE

, diagnosed through a

    family-based molecular screening
    PARACLINICAL

, presented with

    LGE of the LV inferolateral wall
    SYMPTOMS

 evidenced at the

    CMR
    PARACLINICAL

,

    without LV hypertrophy
    NEG_FINDINGS

,

    or other clinical signs of the disease
    NEG_FINDINGS

.

This is the first report of

    cardiac fibrosis
    SYMPTOMS

 as the first sign

    of organ involvement
    SYMPTOMS

 in a

    male
    GENDER

 patient with

    Fabry disease
    DIAGNOSIS

. This finding stresses the importance of performing

    CMR with LGE imaging
    PARACLINICAL

 for the initial staging and monitoring of

    Fabry
    DIAGNOSIS

 patients of both

    genders
    GENDER

.

myocardial involvement
myocardial fibrosis
myocardial fibrosis
LV hypertrophy
LGE of the LV inferolateral wall
cardiac fibrosis
of organ involvement

Fabry disease
lipid storage disorder
cardiomyopathic
Fabry disease
Fabry


Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy.

Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. The aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician.

We retrospectively assessed all patients who had received a diagnosis of a rare genetic disorder after KTx.

In our center, more than 30% (278/911) of kidney transplant (KTx) recipients were diagnosed with a causal nephropathy: Prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8-dihydroxyadeninuria (2,8-DHA) disease (n = 2), HNF-1B-associated nephropathy (n = 2), UMOD-related nephropathy (n = 5), Fabry disease (n = 1), INF2 focal segmental glomerulosclerosis (n = 1), and Senior-Løken syndrome (n = 1). 2,8-DHA nephropathy relapsed in both patients causing an acute renal failure and jeopardizing the graft.

Kidney transplant recipients without a diagnosis of causal nephropathy appear to be a selected population in which rare genetic diseases might be more common than expected. As even a belated diagnosis after KTx can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in KTx recipients without a known causal nephropathy.

Patients with a

    rare genetic disease
    DIAGNOSIS

 may receive

    renal transplantation (KTx)
    MEDICATION

    without a correct diagnosis of causal nephropathy
    NEG_FINDINGS

 and therefore develop unexpected and even

    severe complications
    SYMPTOMS

. The aim of the study was to describe the cases of

    rare genetic disorders
    DIAGNOSIS

 diagnosed after

    KTx
    MEDICATION

, in order to draw clinical lessons for the transplant physician.

We retrospectively assessed all patients who had received a diagnosis of a

    rare genetic disorder
    DIAGNOSIS

 after

    KTx
    MEDICATION

.

In our center, more than 30% (278/911) of

    kidney transplant (KTx) recipients
    MEDICATION

 were diagnosed with a

    causal nephropathy
    DIAGNOSIS

: Prevalence of

    rare genetic disorders
    GENETICS

 in this group was 4.32% (12/278), including

    2,8-dihydroxyadeninuria (2,8-DHA) disease
    BIOCHEMICAL

 (n = 2),

    HNF-1B-associated nephropathy
    DIAGNOSIS

 (n = 2),

    UMOD-related nephropathy
    DIAGNOSIS

 (n = 5),

    Fabry disease
    DIAGNOSIS

 (n = 1),

    INF2 focal segmental glomerulosclerosis
    DIAGNOSIS

 (n = 1), and

    Senior-Løken syndrome
    DIAGNOSIS

 (n = 1).

    2,8-DHA nephropathy
    DIAGNOSIS

 relapsed in both patients causing an

    acute renal failure and jeopardizing the graft
    SYMPTOMS

.

    Kidney transplant recipients
    MEDICATION

    without a diagnosis of causal nephropathy
    NEG_FINDINGS

 appear to be a selected population in which

    rare genetic diseases
    GENETICS

 might be more common than expected. As even a belated diagnosis after

    KTx
    MEDICATION

 can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in

    KTx recipients
    MEDICATION

    without a known causal nephropathy
    NEG_FINDINGS

.

rare genetic disease
rare genetic disorders
rare genetic disorder
causal nephropathy
HNF-1B-associated nephropathy
UMOD-related nephropathy
Fabry disease
INF2 focal segmental glomerulosclerosis
Senior-Løken syndrome
2,8-DHA nephropathy

renal transplantation (KTx)
KTx
KTx
kidney transplant (KTx) recipients
Kidney transplant recipients
KTx
KTx recipients

rare genetic disorders
rare genetic diseases


[Ischemic stroke in a young woman of Turner syndrome with T1-weighted imaging-pulvinar sign].

A 39-year-old woman developed right hemiparesis in a few days. Magnetic resonance images revealed cerebral infarction in the territory of the left lenticulostriate artery, and MR angiography showed severe stenosis of the middle and anterior cerebral arteries and moderate one of the vertebral arteries. Bilateral and symmetric T1 hyperintensity in the pulvinar (T1-weighted imaging-pulvinar sign; "T1 pulvinar sign") was detected, which is recognized as a key imaging of Fabry disease. The α-galactosidase A gene analysis, however, showed no mutation. Although specific physical symptoms were solely short stature and oligomenorrhea, the diagnosis of Turner syndrome was confirmed by the chromosome analysis which showed mosaicism of 45XO and 46X,r(X) (60%:40%). To our knowledge, this is the first report of Turner syndrome with "T1 pulvinar sign".

A

    39-year-old
    AGE

    woman
    GENDER

 developed

    right hemiparesis in a few days
    SYMPTOMS

.

    Magnetic resonance images
    PARACLINICAL

 revealed

    cerebral infarction in the territory of the left lenticulostriate artery
    SYMPTOMS

, and

    MR angiography
    PARACLINICAL

 showed

    severe stenosis of the middle and anterior cerebral arteries and moderate one of the vertebral arteries
    SYMPTOMS

.

    Bilateral and symmetric T1 hyperintensity in the pulvinar (T1-weighted imaging-pulvinar sign; "T1 pulvinar sign")
    SYMPTOMS

 was detected, which is recognized as a key imaging of

    Fabry disease
    DIAGNOSIS

. The

    α-galactosidase A gene analysis, however, showed no mutation
    NEG_FINDINGS

. Although specific physical symptoms were

    solely short stature
    SYMPTOMS

 and

    oligomenorrhea
    SYMPTOMS

, the diagnosis of

    Turner syndrome
    DIAGNOSIS

 was confirmed by the

    chromosome analysis
    PARACLINICAL

 which showed

    mosaicism of 45XO and 46X,r(X) (60%:40%)
    GENETICS

. To our knowledge, this is the first report of

    Turner syndrome
    DIAGNOSIS

 with

    "T1 pulvinar sign"
    SYMPTOMS

.

Fabry disease
Turner syndrome
Turner syndrome


Coexistence of Fabry disease and IgA nephropathy: a report of two cases.

Coexistence of Fabry disease and IgA nephropathy is rare. Moreover, the coexisting Fabry disease may be unrecognized due to unapparent clinical manifestations.

We described two cases with coexisting Fabry disease and IgA nephropathy. The clinicopathological features of these two patients were studied.

A 54-year-old male presented with proteinuria, hematuria, and hypertension, and a 33-year-old male presented with proteinuria without clinical signs or family history of Fabry disease. Both of them were diagnosed with IgA nephropathy at admission, whereas Fabry disease was not suspected. Subsequent immunofluorescent study confirmed the diagnosis of IgA nephropathy by showing positive staining for IgA and complement C3 in the mesangium. Meanwhile, light microscopy showed remarkable vacuolation of podocytes with mild mesangial expansion, which was characteristic of Fabry nephropathy. Further examination of toluidine blue-stained semi-thin sections and electron microscopy demonstrated blue bodies and myelin figures in the cytoplasm of podocytes, respectively. The diagnosis of coexisting Fabry disease was finally established based on deficient α-galactosidase A activity in both patients.

This case study is an important reminder of the role of kidney biopsy as an indicator of Fabry disease and its rare coexistence with IgA nephropathy.

    Coexistence of Fabry disease and IgA nephropathy
    DIAGNOSIS

 is rare. Moreover, the

    coexisting Fabry disease
    DIAGNOSIS

 may be unrecognized due to unapparent clinical manifestations.

We described two cases with

    coexisting Fabry disease and IgA nephropathy
    DIAGNOSIS

. The clinicopathological features of these two patients were studied.

A

    54-year-old
    AGE

    male
    GENDER

 presented with

    proteinuria
    BIOCHEMICAL

,

    hematuria
    BIOCHEMICAL

, and

    hypertension
    SYMPTOMS

, and a

    33-year-old
    AGE

    male
    GENDER

 presented with

    proteinuria
    BIOCHEMICAL

    without clinical signs or family history of Fabry disease
    NEG_FINDINGS

. Both of them were diagnosed with

    IgA nephropathy
    DIAGNOSIS

 at admission, whereas

    Fabry disease was not suspected
    NEG_FINDINGS

. Subsequent

    immunofluorescent study
    PARACLINICAL

 confirmed the diagnosis of

    IgA nephropathy
    DIAGNOSIS

 by showing

    positive staining for IgA and complement C3 in the mesangium
    MICROSCOPIC

. Meanwhile,

    light microscopy
    PARACLINICAL

 showed

    remarkable vacuolation of podocytes with mild mesangial expansion
    MICROSCOPIC

, which was characteristic of

    Fabry nephropathy
    MICROSCOPIC

. Further

    examination of toluidine blue-stained semi-thin sections
    PARACLINICAL

 and

    electron microscopy
    PARACLINICAL

 demonstrated

    blue bodies and myelin figures in the cytoplasm of podocytes
    MICROSCOPIC

, respectively. The diagnosis of

    coexisting Fabry disease
    DIAGNOSIS

 was finally established based on

    deficient α-galactosidase A activity
    BIOCHEMICAL

 in both patients.

This case study is an important reminder of the role of

    kidney biopsy
    PARACLINICAL

 as an indicator of

    Fabry disease
    DIAGNOSIS

 and its

    rare coexistence with IgA nephropathy
    DIAGNOSIS

.

proteinuria
hematuria
proteinuria
deficient α-galactosidase A activity


Dermatologic manifestations and neuropathic symptoms in women with Fabry disease.

Fabry disease (angiokeratoma corporis diffusum universale) is a rare, progressive, X-linked lysosomal storage disease. Deficiency of the α-galactosidase A (α-gal A) enzyme leads to accumulation of neutral glycosphingolipids within vascular endothelial lysosomes of various organs, including skin, kidneys, heart, and brain (1). We herein describe the case of a 30-year-old female presenting two classic signs of Fabry disease, angiokeratomas and episodic acroparesthesias, in the absence of other clinical manifestations. An haplotype corresponding to the combination of three different nucleotide polymorphic variants (g. 7192-7198del5+ g. 10115A>G + g. 10956 C>T) at the heterozygous state, was identified (2).

    Fabry disease
    DIAGNOSIS

 (

    angiokeratoma corporis diffusum universale
    SYMPTOMS

    )
    DIAGNOSIS

 is a

    rare, progressive
    DIAGNOSIS

,

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

.

    Deficiency of the α-galactosidase A (α-gal A) enzyme
    BIOCHEMICAL

 leads to

    accumulation of neutral glycosphingolipids within vascular endothelial lysosomes of various organs, including skin, kidneys, heart, and brain
    MICROSCOPIC

 (1). We herein describe the case of a

    30-year-old
    AGE

    female
    GENDER

 presenting

    two classic signs of Fabry disease
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

 and

    episodic acroparesthesias
    SYMPTOMS

, in the

    absence of other clinical manifestations
    NEG_FINDINGS

. An

    haplotype corresponding to the combination of three different nucleotide polymorphic variants (g. 7192-7198del5+ g. 10115A>G + g. 10956 C>T) at the heterozygous state,
    GENETICS

 was identified (2).

Fabry disease
)
rare, progressive
lysosomal storage disease


Cardiac Anderson-Fabry disease: lessons from a 25-year-follow up.

Sarcomeric hypertrophic cardiomyopathy (HCM) is the most common genetic cause of unexplained left ventricular hypertrophy and has no specific treatment. Anderson-Fabry disease (AFD) is rare and usually multisystemic, but occasionally expresses clinically as a predominantly cardiac phenotype mimicking HCM. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of familial HCM and no identified sarcomeric mutations. Next-generation sequencing analysis identified a novel pathogenic mutation in the GLA gene, leading to a diagnosis of previously unknown multisystemic AFD, with consequent implications for the patient's treatment and prognosis and familial screening.

    Sarcomeric hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 is the most common genetic cause of

    unexplained left ventricular hypertrophy
    SYMPTOMS

 and has no specific treatment.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is rare and usually

    multisystemic
    DIAGNOSIS

, but occasionally expresses clinically as a

    predominantly cardiac phenotype mimicking HCM
    SYMPTOMS

. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of

    familial HCM
    DIAGNOSIS

 and

    no identified sarcomeric mutations
    NEG_FINDINGS

.

    Next-generation sequencing analysis
    PARACLINICAL

 identified a

    novel pathogenic mutation in the GLA gene
    GENETICS

, leading to a diagnosis of

    previously unknown multisystemic AFD
    DIAGNOSIS

, with consequent implications for the patient's treatment and prognosis and

    familial screening
    PARACLINICAL

.