Recurrent arterial thrombosis in a patient with Fabry disease: case report.

Fabry disease is a rare disease, defined as an X-linked lysosomal deposition disease that presents with multisystemic symptoms, including vascular impairment with thrombotic events. A 57-year-old female patient diagnosed with Fabry disease 11 years previously, presented with hyperhidrosis, hypoacusis, and angiokeratoma on the hands. Her previous pathological history included an episode of ischemic stroke before the age of 40 years and chronic acute thrombosis in the right lower limb, 1 year previously, which had been treated with stent angioplasty, with temporary improvement followed by recent relapse of the condition. Thrombotic events fit the typical symptoms of Fabry disease and are caused by deposition of globotriaosylceramide in the vascular endothelium, constituting a prothrombotic state and explaining the recurrence of symptoms and arterial thrombosis in the lower limb.

    Fabry disease
    DIAGNOSIS

 is a rare disease, defined as an

    X-linked
    GENETICS

    lysosomal deposition disease
    DIAGNOSIS

 that presents with

    multisystemic symptoms
    SYMPTOMS

, including

    vascular impairment
    SYMPTOMS

 with

    thrombotic events
    SYMPTOMS

. A

    57-year-old
    AGE

    female
    GENDER

 patient diagnosed with

    Fabry disease
    DIAGNOSIS

 11 years previously, presented with

    hyperhidrosis
    SYMPTOMS

,

    hypoacusis
    SYMPTOMS

, and

    angiokeratoma on the hands
    SYMPTOMS

.

    Her
    GENDER

 previous pathological history included an

    episode of ischemic stroke
    SYMPTOMS

    before the age of 40 years
    AGE

 and

    chronic acute thrombosis in the right lower limb
    SYMPTOMS

, 1 year previously, which had been treated with

    stent angioplasty
    MEDICATION

, with

    temporary improvement
    SYMPTOMS

 followed by

    recent relapse of the condition
    SYMPTOMS

.

    Thrombotic events
    SYMPTOMS

 fit the typical symptoms of

    Fabry disease
    DIAGNOSIS

 and are caused by

    deposition of globotriaosylceramide in the vascular endothelium
    MICROSCOPIC

, constituting a

    prothrombotic state
    SYMPTOMS

 and explaining the

    recurrence of symptoms
    SYMPTOMS

 and

    arterial thrombosis in the lower limb
    SYMPTOMS

.

Fabry disease
lysosomal deposition disease
Fabry disease
Fabry disease


Angiokeratoma Corporis Diffusum: An Uncommon Case with Suspected Anderson Fabry Disease.

Angiokeratomas are variable sized hyperkeratotic vascular papules that are characterized histologically by superficial dilated capillaries in papillary dermis with epidermal proliferation. They can occur as a single lesion to a generalized form (angiokeratoma corporis diffusum). Angiokeratoma corporis diffusum though initially synonymous with Anderson Fabry disease, is now known to occur in a variety of lysosomal enzyme deficiencies. We report a case of 22 year old male with angiokeratoma corporis diffusum associated with acroparesthesias, febrile episodes, sensorineural hearing loss and renal involvement. Histopathological evaluation showed characteristic ectatic blood vessels with vacuolated endothelial cells in papillary dermis. Based on the clinical evaluation and available investigations, we suspected him to be having to Anderson fabry disease. Resource constraints limited our ability to confirm our diagnosis with enzyme assay and electron microscopy. We report this unusual case in desire of re emphasizing the importance of clinical evaluation for reaching a diagnosis in a resource poor setting.

    Angiokeratomas
    SYMPTOMS

 are

    variable sized hyperkeratotic vascular papules
    SYMPTOMS

 that are characterized histologically by

    superficial dilated capillaries in papillary dermis with epidermal proliferation
    SYMPTOMS

. They can occur as a single lesion to a

    generalized form
    SYMPTOMS

 (

    angiokeratoma corporis diffusum)
    SYMPTOMS

.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 though initially synonymous with

    Anderson Fabry disease
    DIAGNOSIS

, is now known to occur in a variety of

    lysosomal enzyme deficiencies
    BIOCHEMICAL

. We report a case of

    22 year old
    AGE

    male
    GENDER

 with

    angiokeratoma corporis diffusum
    SYMPTOMS

 associated with

    acroparesthesias
    SYMPTOMS

,

    febrile episodes
    SYMPTOMS

,

    sensorineural hearing loss
    SYMPTOMS

 and

    renal involvement
    SYMPTOMS

.

    Histopathological evaluation
    PARACLINICAL

 showed

    characteristic ectatic blood vessels with vacuolated endothelial cells in papillary dermis
    MICROSCOPIC

. Based on the clinical evaluation and available investigations, we suspected

    him
    GENDER

 to be having to

    Anderson fabry disease
    DIAGNOSIS

. Resource constraints limited our ability to confirm our diagnosis with

    enzyme assay
    PARACLINICAL

 and

    electron microscopy
    PARACLINICAL

. We report this unusual case in desire of re emphasizing the importance of

    clinical evaluation
    PARACLINICAL

 for reaching a diagnosis in a resource poor setting.

Anderson Fabry disease
Anderson fabry disease


Pulse-cancellation echocardiography in Fabry disease diagnosis.

Pulse-cancellation imaging is a novel echocardiographic imaging modality developed for detection of myocardial fibrosis. This technique cancels echocardiographic reflections from the normal myocardium but clearly displays the abnormal tissue. We describe, for the first time, pulse-cancellation echocardiography application in detecting Fabry disease myocardial involvement. We present the case where both pulse-cancellation imaging and cardiac MRI concurrently revealed myocardial deposits in a patient with genotypically confirmed Fabry disease.

    Pulse-cancellation imaging
    PARACLINICAL

 is a novel

    echocardiographic imaging
    PARACLINICAL

 modality developed for detection of

    myocardial fibrosis
    SYMPTOMS

. This technique cancels

    echocardiographic reflections from the normal myocardium
    SYMPTOMS

 but clearly displays the

    abnormal tissue
    SYMPTOMS

. We describe, for the first time,

    pulse-cancellation echocardiography
    PARACLINICAL

 application in detecting

    Fabry disease
    DIAGNOSIS

    myocardial involvement
    SYMPTOMS

. We present the case where both

    pulse-cancellation imaging
    PARACLINICAL

 and

    cardiac MRI
    PARACLINICAL

 concurrently revealed

    myocardial deposits
    MICROSCOPIC

 in a patient with genotypically confirmed

    Fabry disease
    DIAGNOSIS

.


Two related Chinese Fabry disease patients with a p.N215S pathological variant who presented with nephropathy.

Fabry disease is an X-linked lysosomal storage disease resulting from a mutation in the GLA gene that encodes α-galactosidase A. The p.N215S (c.644A > G [p.Asn215Ser]) genotype is the most common later-onset variant reported in individuals of European or North American descent. It is usually referred to as a cardiac variant, although manifestations in other organ systems have been observed. In this report, we describe a nephropathy presentation in two related Chinese Fabry disease patients with p.N215S.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 resulting from a mutation in the GLA gene that encodes α-galactosidase A. The

    p.N215S (c.644A > G [p.Asn215Ser]) genotype
    GENETICS

 is the most common

    later-onset variant
    GENETICS

 reported in individuals of

    European
    ETHNICITY

 or

    North American descent
    ETHNICITY

. It is usually referred to as a

    cardiac variant
    SYMPTOMS

, although

    manifestations in other organ systems
    SYMPTOMS

 have been observed. In this report, we describe a

    nephropathy
    DIAGNOSIS

 presentation in two related

    Chinese
    ETHNICITY

    Fabry disease
    DIAGNOSIS

 patients with p.N215S.

Fabry disease
lysosomal storage disease
nephropathy
Fabry disease

cardiac variant
manifestations in other organ systems


Late-Onset Fabry Disease Presenting With Ventricular Tachycardia Originating From Typical Inferolateral Scar.

Late-onset cardiac Fabry disease is not uncommon among patients with unexplained left ventricular hypertrophy. Despite a less severe phenotype, life-threatening complications are possible in late-onset cardiac Fabry and may be the first presentation of the disease. Classical imaging features support the diagnosis; however, the presence of less common findings, such as ischemic features, should not lead to overlooking the diagnosis. Indeed, the coexistence of Fabry and ischemic heart disease is possible, even in the absence of obstructive coronary artery disease. Therefore, a high level of suspicion should be maintained, even in the presence of atypical presentations.

    Late-onset cardiac Fabry disease
    DIAGNOSIS

 is not uncommon among patients with

    unexplained left ventricular hypertrophy
    SYMPTOMS

. Despite a less severe phenotype,

    life-threatening complications
    SYMPTOMS

 are possible in

    late-onset cardiac Fabry
    DIAGNOSIS

 and may be the first presentation of the disease. Classical imaging features support the diagnosis; however, the presence of less common findings, such as

    ischemic features
    SYMPTOMS

, should not lead to overlooking the diagnosis. Indeed, the

    coexistence of Fabry and ischemic heart disease
    DIAGNOSIS

 is possible, even in the

    absence of obstructive coronary artery disease
    NEG_FINDINGS

. Therefore, a high level of suspicion should be maintained, even in the presence of atypical presentations.


Fabry disease presenting as bilateral medial medullary infarction with a "heart appearance" sign: a case report.

The etiologic determinants of cryptogenic stroke remain a diagnostic challenge in clinical practice. Fabry disease (FD) is one of the monogenic causes of stroke that may remain unrecognized as a potential contributing causative factor, because of its rarity and difficulty in diagnosis. We report a case with rare bilateral medial medullary infarction manifesting as "heart appearance" who was diagnosed with FD.

A 51-year-old Chinese man presented with acute dysarthria and mild tetraparesis. In the 24 h following admission, the patient rapidly developed progressive flaccid quadriplegia and tongue weakness, necessitating ventilator support. Immediate magnetic resonance imaging of the brain showed heart-shaped appearance of bilateral medial medullary infarction. The patient suffered two new subcortical infarcts 40 days after the first. Detailed Family history and physical examination indicated symptoms consistent with FD, which was confirmed by very low alpha galactosidase A levels and a missense mutation of the alpha-galactosidase A gene.

We report what appears to be the first case of FD manifesting as bilateral medial medullary infarction. Our case suggests that clinicians should consider the possibility of FD in patients with cryptogenic stroke, especially when combined with infarction in the vertebrobasilar artery system, renal insufficiency, or cardiomyopathy. A detailed analysis of subtle historical clues and performing a complete physical examination on stroke patients would help promote earlier diagnosis of FD.

The etiologic determinants of

    cryptogenic stroke
    SYMPTOMS

 remain a diagnostic challenge in clinical practice.

    Fabry disease (FD)
    DIAGNOSIS

 is one of the

    monogenic
    GENETICS

 causes of

    stroke
    SYMPTOMS

 that may remain unrecognized as a potential contributing causative factor, because of its rarity and difficulty in diagnosis. We report a case with

    rare bilateral medial medullary infarction manifesting as "heart appearance"
    SYMPTOMS

 who was diagnosed with

    FD
    DIAGNOSIS

.

A

    51-year-old
    AGE

    Chinese
    ETHNICITY

    man
    GENDER

 presented with

    acute dysarthria
    SYMPTOMS

 and

    mild tetraparesis
    SYMPTOMS

. In the 24 h following admission, the patient rapidly developed

    progressive flaccid quadriplegia
    SYMPTOMS

 and

    tongue weakness
    SYMPTOMS

, necessitating

    ventilator support
    MEDICATION

.

    Immediate magnetic resonance imaging of the brain
    PARACLINICAL

 showed

    heart-shaped appearance of bilateral medial medullary infarction
    SYMPTOMS

. The patient suffered

    two new subcortical infarcts 40 days after the first
    SYMPTOMS

.

    Detailed Family history
    PARACLINICAL

 and

    physical examination
    PARACLINICAL

 indicated

    symptoms consistent with FD
    SYMPTOMS

, which was confirmed by

    very low alpha galactosidase A levels
    BIOCHEMICAL

 and a

    missense mutation of the alpha-galactosidase A gene
    GENETICS

.

We report what appears to be the first case of

    FD
    DIAGNOSIS

 manifesting as

    bilateral medial medullary infarction
    SYMPTOMS

. Our case suggests that clinicians should consider the possibility of

    FD
    DIAGNOSIS

 in patients with

    cryptogenic stroke
    SYMPTOMS

, especially when combined with

    infarction in the vertebrobasilar artery system
    SYMPTOMS

,

    renal insufficiency
    SYMPTOMS

, or

    cardiomyopathy
    SYMPTOMS

. A detailed analysis of subtle historical clues and performing a

    complete physical examination
    PARACLINICAL

 on

    stroke
    SYMPTOMS

 patients would help promote earlier diagnosis of

    FD
    DIAGNOSIS

.


[Diffuse hyperkeratotic papules of the lower abdomen and genital region in a 38-year old male patient].

A patient with diffuse angiokeratomas of the lower abdomen and genital region was diagnosed with Fabry disease on the basis of genetic testing. Fabry disease is an X-linked lysosomal storage disease that can affect several organ systems including the heart or kidneys, resulting in reduced median survival. Pathogenetically, Fabry disease leads to a deficiency of the lysosomal enzyme α‑galactosidase A (α-GAL A). Treatment options include lifelong enzyme replacement therapy or chaperone therapy.

A patient with

    diffuse angiokeratomas of the lower abdomen and genital region
    SYMPTOMS

 was diagnosed with

    Fabry disease
    DIAGNOSIS

 on the basis of

    genetic testing
    PARACLINICAL

.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 that can

    affect several organ systems including the heart or kidneys
    SYMPTOMS

, resulting in reduced median survival. Pathogenetically,

    Fabry disease
    DIAGNOSIS

 leads to a

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

. Treatment options include

    lifelong enzyme replacement therapy
    MEDICATION

 or

    chaperone therapy
    MEDICATION

.

Fabry disease
Fabry disease
lysosomal storage disease
Fabry disease

lifelong enzyme replacement therapy
chaperone therapy


Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation.

Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.

    Resistance to enzyme replacement therapy (ERT)
    NEG_FINDINGS

 is a major therapeutic challenge in

    Fabry disease (FD)
    DIAGNOSIS

. Recent reports attribute to

    immune-mediated inflammation
    MICROSCOPIC

 a main role in promoting disease progression and

    resistance to ERT
    NEG_FINDINGS

. Aim of the study is to report a

    Gb3-induced auto-reactive panmyocarditis
    DIAGNOSIS

 causing

    inefficacy of ERT
    NEG_FINDINGS

 and

    severe electrical instability
    SYMPTOMS

, which required

    cardiac transplantation
    MEDICATION

.

    Examining the explanted heart
    PARACLINICAL

 from a

    57-year-old
    AGE

    man
    GENDER

 with

    FD cardiomyopathy (CM)
    DIAGNOSIS

 on

    3-year ERT
    MEDICATION

 presenting

    incoming ventricular fibrillation
    SYMPTOMS

, we documented a

    severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia
    SYMPTOMS

.

    Serology
    PARACLINICAL

 was

    positive for anti-Gb3, anti-heart, and anti-myosin antibodies
    BIOCHEMICAL

.

    In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC)
    PARACLINICAL

 induced

    high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α
    BIOCHEMICAL

. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The

    phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%)
    BIOCHEMICAL

 in

    Fabry
    DIAGNOSIS

 patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A

    Gb3-induced auto-reactive myocarditis
    DIAGNOSIS

 is suggested as a possible cause of

    FDCM
    DIAGNOSIS

 progression and

    ERT resistance
    NEG_FINDINGS

.

    Immune-mediated inflammation of systemic Fabry cells
    MICROSCOPIC

 may coexist and be controlled by

    implemental immunosuppressive therapy
    MEDICATION

.

cardiac transplantation
3-year ERT
implemental immunosuppressive therapy


Fabry disease in two brothers with proteinuria: A case report and Fabry disease review
.

Fabry disease is an X-linked lysosomal storage disease characterized by alpha-galactosidase A (α-Gal A) enzyme deficiency. It can present with a variety of clinical manifestations ranging from complaints of extremity numbness and tingling to end-stage renal disease, cardiovascular disease, or stroke. Although it causes proteinuria and chronic kidney disease, it is often not included in the differential diagnosis of a young adult who presents with proteinuria. We describe the histories of two brothers who received a diagnosis of Fabry disease after one underwent a kidney biopsy. The diagnosis had profound implications for both individuals and their family. These cases and the accompanying review of kidney manifestations of Fabry disease demonstrate why the differential diagnosis of a young male with proteinuria and family history of kidney disease must include Fabry disease and why nephrologists should consider α-Gal A enzyme deficiency screening in the evaluation of male patients. Additionally, they highlight the importance of obtaining a kidney biopsy when the etiology of kidney disease is unknown.
.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 characterized by

    alpha-galactosidase A (α-Gal A) enzyme deficiency
    BIOCHEMICAL

. It can present with a variety of clinical manifestations ranging from complaints of

    extremity numbness
    SYMPTOMS

 and

    tingling
    SYMPTOMS

 to

    end-stage renal disease
    DIAGNOSIS

,

    cardiovascular disease
    DIAGNOSIS

, or

    stroke
    SYMPTOMS

. Although it causes

    proteinuria
    BIOCHEMICAL

 and

    chronic kidney disease
    DIAGNOSIS

, it is often not included in the

    differential diagnosis
    PARACLINICAL

 of a

    young adult
    AGE

 who presents with

    proteinuria
    BIOCHEMICAL

. We describe the histories of two

    brothers
    GENDER

 who received a diagnosis of

    Fabry disease
    DIAGNOSIS

 after one underwent a

    kidney biopsy
    PARACLINICAL

. The diagnosis had profound implications for both individuals and their family. These cases and the accompanying review of

    kidney manifestations
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

 demonstrate why the

    differential diagnosis
    PARACLINICAL

 of a

    young
    AGE

    male
    GENDER

 with

    proteinuria
    BIOCHEMICAL

 and

    family history of kidney disease
    FAMILY

 must include

    Fabry disease
    DIAGNOSIS

 and why

    nephrologists
    PARACLINICAL

 should consider

    α-Gal A enzyme deficiency screening
    PARACLINICAL

 in the evaluation of

    male
    GENDER

 patients. Additionally, they highlight the importance of obtaining a

    kidney biopsy
    PARACLINICAL

 when the

    etiology of kidney disease is unknown
    NEG_FINDINGS

.
.

Fabry disease
lysosomal storage disease
end-stage renal disease
cardiovascular disease
chronic kidney disease
Fabry disease
Fabry disease
Fabry disease

extremity numbness
tingling
stroke
kidney manifestations


An Atypical Cardiac Manifestation of Fabry Disease from a Novel Pathological Variant on the GLA Gene.

Fabry disease (FD) is one of the most common lysosomal storage disorders and is caused by an X-linked progressive inborn error of metabolism in the alpha-galactosidase A (α-Gal A) gene. This leads to intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), throughout the body. The impact of this accumulation is seen across multiple cell lines and therefore can cause multisystem organ dysfunction. The phenotype of FD results from variants on the GLA gene which codes for α-Gal A production, and variants on this gene have been shown to be strongly related to unexplained or idiopathic cardiovascular disorders. This report describes a 36-year-old Caucasian male found to have left ventricular hypertrophy (LVH) followed by genetic testing because of his family history of sudden cardiac death which revealed a variant of unknown significance for the GLA gene. Further measurement of α-Gal A leukocyte activity showed low levels, which was diagnostic for FD. The index patient had an unusual non-classic phenotype in that his sole presenting symptom was asymptomatic LVH, he presented early, and had low α-Gal A leukocyte activity. Early detection and prompt treatment with enzyme replacement therapy can improve outcomes and decrease mortality. In the absence of known risk factors, non-classical FD should be strongly considered in patients with unexplained LVH and a family history of sudden cardiac death at a young age.

    Fabry disease (FD)
    DIAGNOSIS

 is one of the most common

    lysosomal storage disorders
    DIAGNOSIS

 and is caused by an

    X-linked progressive inborn error of metabolism in the alpha-galactosidase A (α-Gal A) gene
    GENETICS

. This leads to

    intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), throughout the body
    MICROSCOPIC

. The

    impact of this accumulation is seen across multiple cell lines
    MICROSCOPIC

 and therefore can cause

    multisystem organ dysfunction
    SYMPTOMS

. The phenotype of

    FD
    DIAGNOSIS

 results from

    variants on the GLA gene which codes for α-Gal A production
    GENETICS

, and

    variants on this gene
    GENETICS

 have been shown to be strongly related to

    unexplained
    DIAGNOSIS

 or

    idiopathic cardiovascular disorders
    SYMPTOMS

. This report describes a

    36-year-old
    AGE

    Caucasian
    ETHNICITY

    male
    GENDER

 found to have

    left ventricular hypertrophy (LVH)
    SYMPTOMS

 followed by

    genetic testing
    PARACLINICAL

 because of

    his
    GENDER

    family history of sudden cardiac death
    FAMILY

 which revealed a

    variant of unknown significance for the GLA gene
    GENETICS

. Further

    measurement of α-Gal A leukocyte activity showed low levels
    BIOCHEMICAL

, which was diagnostic for

    FD
    DIAGNOSIS

. The index patient had an

    unusual non-classic
    SYMPTOMS

 phenotype in that his sole presenting symptom was

    asymptomatic LVH
    SYMPTOMS

,

    he
    GENDER

 presented

    early
    SYMPTOMS

, and had

    low α-Gal A leukocyte activity
    BIOCHEMICAL

. Early detection and

    prompt treatment with enzyme replacement therapy
    MEDICATION

 can improve outcomes and decrease mortality. In the

    absence of known risk factors
    NEG_FINDINGS

,

    non-classical FD
    DIAGNOSIS

 should be strongly considered in patients with

    unexplained LVH
    SYMPTOMS

 and a

    family history of sudden cardiac death at a young age
    FAMILY

.

Fabry disease (FD)
lysosomal storage disorders
FD
unexplained
FD
non-classical FD

multisystem organ dysfunction
idiopathic cardiovascular disorders
left ventricular hypertrophy (LVH)
unusual non-classic
asymptomatic LVH
early
unexplained LVH


Fabry Disease Screening in Patients With Kidney Transplant: A Single-Center Study in Turkey.

Fabry disease is a rare X-linked multisystemic lysosomal storage disorder of the glycosphingolipid metabolic pathway. Nephropathy is one of the most important complications of Fabry disease, and patients with classical phenotype are at risk of developing endstage kidney disease. In this study, we investigated the use of screening for Fabry disease in kidney transplant recipients at our center.

We screened 301 kidney transplant recipients with functioning grafts. Analyses for α-galactosidase A gene mutation were performed in all female and male kidney transplant recipients. We also measured leukocyte α-galactosidase A enzyme activity in patients with identified GLA mutation.

In 301 kidney transplant recipients, mean age was 42.9 ± 12.5 years, and the number of male patients was 180 (60%). Mean time after transplant was 79 ± 56 months, and estimated glomerular filtration rate was 66.8 ± 21 mL/min/1.73 m². One male patient who was diagnosed with Fabry disease before kidney transplant was also evaluated (mutation in the α-galactosidase A gene, c.1093_1101dup [p.Tyr365_lle367dup]). In 2 female patients, p.A143T (c.427G>A) mutation of unknown significance and p.D313Y (c.937G>T) heterozygous mutation were identified; however, leukocyte ?-galactosidase A enzyme activity was normal in these patients (63.7 and 67.3 nmol/h/mg protein). In the patient diagnosed with Fabry disease, family screening revealed 4 additional affected family members.

Although prevalence was shown to be low in our center (1/301 patients; 0.33%), screening studies in kidney transplant recipients may help to detect new patients before they develop life-threatening complications such as renal involvement.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    multisystemic lysosomal storage disorder of the glycosphingolipid metabolic pathway
    DIAGNOSIS

.

    Nephropathy
    DIAGNOSIS

 is one of the most important complications of

    Fabry disease
    DIAGNOSIS

, and patients with classical phenotype are at risk of developing

    endstage kidney disease
    DIAGNOSIS

. In this study, we investigated the use of screening for

    Fabry disease
    DIAGNOSIS

 in

    kidney transplant recipients
    MEDICATION

 at our center.

We screened 301

    kidney transplant recipients
    MEDICATION

 with

    functioning grafts
    MEDICATION

.

    Analyses for α-galactosidase A gene mutation
    PARACLINICAL

 were performed in all

    female
    GENDER

 and

    male
    GENDER

    kidney transplant recipients
    MEDICATION

. We also measured

    leukocyte α-galactosidase A enzyme activity
    BIOCHEMICAL

 in patients with identified

    GLA mutation
    GENETICS

.

In 301

    kidney transplant recipients
    MEDICATION

,

    mean age was 42.9 ± 12.5 years
    AGE

, and the number of

    male
    GENDER

 patients was 180 (60%). Mean time

    after transplant was 79 ± 56 months
    MEDICATION

, and

    estimated glomerular filtration rate was 66.8 ± 21 mL/min/1.73 m²
    BIOCHEMICAL

. One

    male
    GENDER

 patient who was diagnosed with

    Fabry disease
    DIAGNOSIS

 before

    kidney transplant
    MEDICATION

 was also evaluated (

    mutation in the α-galactosidase A gene, c.1093_1101dup [p.Tyr365_lle367dup])
    GENETICS

. In 2

    female
    GENDER

 patients,

    p.A143T (c.427G>A) mutation of unknown significance
    GENETICS

 and

    p.D313Y (c.937G>T) heterozygous mutation
    GENETICS

 were identified; however,

    leukocyte ?-galactosidase A enzyme activity was normal in
    NEG_FINDINGS

 these patients

    (63.7 and 67.3 nmol/h/mg protein)
    BIOCHEMICAL

. In the patient diagnosed with

    Fabry disease
    DIAGNOSIS

,

    family screening revealed 4 additional affected family members
    FAMILY

.

Although prevalence was shown to be low in our center (1/301 patients; 0.33%), screening studies in

    kidney transplant recipients
    MEDICATION

 may help to detect new patients before they develop life-threatening complications such as

    renal involvement
    SYMPTOMS

.

kidney transplant recipients
kidney transplant recipients
functioning grafts
kidney transplant recipients
kidney transplant recipients
after transplant was 79 ± 56 months
kidney transplant
kidney transplant recipients


Is the alpha-galactosidase A variant p.Asp313Tyr (p.D313Y) pathogenic for Fabry disease? A systematic review.

The identification of pathogenic GLA variants plays a central role in the establishment of a definite Fabry disease (FD) diagnosis. We aimed to review and interpret the published data on the p.Asp313Tyr (p.D313Y) variant pathogenicity and clinical relevance. We performed a systematic review of peer-reviewed publications and case-reports on individuals and populations harbouring the p.Asp313Tyr variant. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations, alpha-galactosidase A enzyme activity, levels of the biomarkers globotriaosylceramide (Gb3) and sphingosine-globotriaosylceramide (lyso-Gb3) and histological findings of p.Asp313Tyr carriers. The prevalence of p.Asp313Tyr in populations at risk for FD (kidney, heart, neurologic disorders, or symptomatic populations) was calculated. We found high residual enzyme activity, low frequency of clinical features specific for FD, non-elevated lysoGb3 /Gb3 concentrations and lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers. The prevalence of the variant in populations at risk for FD was comparable to the reported frequency in the general population. A possible higher frequency was only observed in neurologic disorders. p.Asp313Tyr can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and manifestations in the brain vessels.

The identification of

    pathogenic GLA variants
    GENETICS

 plays a central role in the establishment of a definite

    Fabry disease (FD)
    DIAGNOSIS

 diagnosis. We aimed to review and interpret the published data on the

    p.Asp313Tyr (p.D313Y)
    GENETICS

 variant pathogenicity and clinical relevance. We performed a systematic review of peer-reviewed publications and case-reports on individuals and populations harbouring the

    p.Asp313Tyr variant
    GENETICS

. Overall, 35 studies were included in this review. We collected data regarding the clinical manifestations,

    alpha-galactosidase A enzyme activity
    BIOCHEMICAL

,

    levels of the biomarkers globotriaosylceramide (Gb3) and sphingosine-globotriaosylceramide (lyso-Gb3)
    BIOCHEMICAL

 and histological findings of

    p.Asp313Tyr
    GENETICS

 carriers. The prevalence of

    p.Asp313Tyr
    GENETICS

 in populations at risk for

    FD
    DIAGNOSIS

 (

    kidney, heart, neurologic disorders
    DIAGNOSIS

, or symptomatic populations) was calculated. We found

    high residual enzyme activity
    BIOCHEMICAL

,

    low frequency of clinical features specific for FD
    NEG_FINDINGS

,

    non-elevated lysoGb3 /Gb3 concentrations
    NEG_FINDINGS

 and

    lack of intracellular Gb3 accumulation in biopsies in the p.Asp313Tyr carriers
    NEG_FINDINGS

. The prevalence of the variant in populations at risk for

    FD
    DIAGNOSIS

 was comparable to the reported frequency in the general population. A possible higher frequency was only observed in

    neurologic disorders
    DIAGNOSIS

.

    p.Asp313Tyr
    GENETICS

 can be classified as neutral or variant of unknown significance. Further investigations will be helpful to clarify a possible association between the variant and

    manifestations in the brain vessels
    SYMPTOMS

.

Fabry disease (FD)
FD
kidney, heart, neurologic disorders
FD
neurologic disorders


Urinary Mulberry Cells as a Biomarker of the Efficacy of Enzyme Replacement Therapy for Fabry Disease.

Mulberry cells are often present in the urinary sediments of patients with Fabry disease (FD). We herein report two patients with FD undergoing enzyme replacement therapy (ERT). A 41-year-old man was diagnosed based on lack of α-galactosidase A activity. ERT was subsequently administered. A 40-year-old woman was diagnosed based on urinary Mulberry cells and genetic testing, and ERT was initiated. While the renal function of the male patient deteriorated, the Mulberry cells disappeared in the female patient after ERT was administered. The detection of urinary Mulberry cells can contribute to the diagnosis as well as serve as a biomarker for the response to treatment.

    Mulberry cells are often present in the urinary sediments
    MICROSCOPIC

 of patients with

    Fabry disease (FD)
    DIAGNOSIS

. We herein report two patients with

    FD
    DIAGNOSIS

 undergoing

    enzyme replacement therapy (ERT)
    MEDICATION

. A

    41-year-old
    AGE

    man
    GENDER

 was diagnosed based on

    lack of α-galactosidase A activity
    BIOCHEMICAL

.

    ERT
    MEDICATION

 was subsequently administered. A

    40-year-old
    AGE

    woman
    GENDER

 was diagnosed based on

    urinary Mulberry cells
    MICROSCOPIC

 and

    genetic testing
    PARACLINICAL

, and

    ERT
    MEDICATION

 was initiated. While the

    renal function of
    SYMPTOMS

 the

    male
    GENDER

 patient

    deteriorated
    NEG_FINDINGS

,

    the Mulberry cells disappeared in the female
    MICROSCOPIC

 patient after

    ERT
    MEDICATION

 was administered. The

    detection of urinary Mulberry cells
    MICROSCOPIC

 can contribute to the diagnosis as well as serve as a biomarker for the response to treatment.

enzyme replacement therapy (ERT)
ERT
ERT
ERT


Ventricular fibrillation associated with vasospastic angina pectoris in Fabry disease: a case report.

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from a deficiency in alpha-galactosidase A. The major causes of death due to cardiac complications include life-threatening arrhythmias. In addition, life-threatening arrhythmias may be related to myocardial fibrosis assessed by late gadolinium enhancement (LGE).

A 43-year-old man with sinus bradycardia and left ventricular hypertrophy was referred to our cardiology department. Family history includes unexplained hypertrophy and sick sinus syndrome in mother. Additionally, his plasma alpha-galactosidase A activity was low. He was subsequently diagnosed with FD. Enzyme replacement therapy using 1.0 mg/kg agalsidase-β was initiated. During the fifth administration, he developed ventricular fibrillation (VF). Electrocardiography conducted immediately before VF revealed ST elevation in the inferior leads with reciprocated ST depression. Cardiac magnetic resonance imaging showed no LGE in the myocardium. Coronary angiography showed no organic stenosis; moreover, coronary spasms were induced by an intracoronary acetylcholine injection. Ventricular fibrillation was not observed as the patient received calcium antagonists.

This report suggests that vasospastic angina pectoris is associated with life-threatening arrhythmias in patient with FD without LGE.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from a deficiency in alpha-galactosidase A. The major causes of

    death
    SYMPTOMS

 due to

    cardiac complications
    SYMPTOMS

 include

    life-threatening arrhythmias
    SYMPTOMS

. In addition,

    life-threatening arrhythmias
    SYMPTOMS

 may be related to

    myocardial fibrosis
    SYMPTOMS

 assessed by

    late gadolinium enhancement (LGE)
    PARACLINICAL

.

A

    43-year-old
    AGE

    man
    GENDER

 with

    sinus bradycardia
    SYMPTOMS

 and

    left ventricular hypertrophy
    SYMPTOMS

 was referred to our cardiology department.

    Family history includes unexplained hypertrophy and sick sinus syndrome in mother
    FAMILY

. Additionally,

    his
    GENDER

    plasma alpha-galactosidase A activity was low
    BIOCHEMICAL

.

    He
    GENDER

 was subsequently diagnosed with

    FD
    DIAGNOSIS

.

    Enzyme replacement therapy using 1.0 mg/kg agalsidase-β
    MEDICATION

 was initiated. During the fifth administration,

    he
    GENDER

 developed

    ventricular fibrillation (VF)
    SYMPTOMS

.

    Electrocardiography
    PARACLINICAL

 conducted immediately before

    VF
    SYMPTOMS

 revealed

    ST elevation in the inferior leads with reciprocated ST depression
    SYMPTOMS

.

    Cardiac magnetic resonance imaging
    PARACLINICAL

 showed

    no LGE in the myocardium
    NEG_FINDINGS

.

    Coronary angiography
    PARACLINICAL

 showed

    no organic stenosis
    NEG_FINDINGS

; moreover,

    coronary spasms
    SYMPTOMS

 were induced by an

    intracoronary acetylcholine injection
    MEDICATION

.

    Ventricular fibrillation was not observed
    NEG_FINDINGS

 as

    the patient received calcium antagonists
    NEG_FINDINGS

.

This report suggests that

    vasospastic angina pectoris
    DIAGNOSIS

 is associated with

    life-threatening arrhythmias
    SYMPTOMS

 in patient with

    FD
    DIAGNOSIS

    without LGE
    NEG_FINDINGS

.

Fabry disease (FD)
lysosomal storage disorder
FD
vasospastic angina pectoris
FD


Demographic and Clinical Characteristics of the Full 2015-2018 Cohort of Romanian Fabry Disease Patients.

Fabry disease (FD) is a rare genetic lysosomal disease with an estimated prevalence of 1:100000. Mutations on the GLA gene lead to alpha-galactosidase deficiency and multiorgan involvement due to sphingolipid accumulation. Our aim was to present and analyze the demographic and clinical characteristics of the Fabry patients in Romania.

All known Fabry patients in Romania between 2015-2018 were prospectively included in the study. Data on personal history, family history and clinical parameters were collected and statistically analyzed.

The study included 42 patients with a mean age of 47±15 years, of which 19 (45%) were men and 23 (55%) women. Women were significantly older (52±15 years vs. 40±13 years, p=0.006) and presented similar prevalence of cardiac, renal, neurologic, ophthalmologic and otologic burden. The majority of patients presented organ damage, most prevalent being cardiac (48%), cutaneous (45%) and neurologic (52%) involvements. There were 20 families in total, comprising on average of 2.1 members each. Of the 20 families, only two had the same pathogenic GLA mutation.

FD patients in our country show a significant degree of multiorgan involvement with important psychological and social impact on the patients and their families. Women with Fabry disease show similar disease burden as men, but at a later age.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare genetic lysosomal disease
    DIAGNOSIS

 with an estimated prevalence of 1:100000.

    Mutations on the GLA gene
    GENETICS

 lead to

    alpha-galactosidase deficiency
    BIOCHEMICAL

 and

    multiorgan involvement
    SYMPTOMS

 due to

    sphingolipid accumulation
    MICROSCOPIC

. Our aim was to present and analyze the demographic and clinical characteristics of the

    Fabry
    DIAGNOSIS

 patients in

    Romania
    ETHNICITY

.

All known

    Fabry
    DIAGNOSIS

 patients in

    Romania
    ETHNICITY

 between 2015-2018 were prospectively included in the study. Data on personal history, family history and clinical parameters were collected and statistically analyzed.

The study included 42 patients with a

    mean age of 47±15 years
    AGE

, of which 19 (45%) were

    men
    GENDER

 and 23 (55%)

    women
    GENDER

.

    Women
    GENDER

 were significantly

    older (52±15 years
    AGE

 vs.

    40±13 years
    AGE

, p=0.006) and presented similar prevalence of

    cardiac, renal, neurologic, ophthalmologic and otologic burden
    SYMPTOMS

. The majority of patients presented

    organ damage
    SYMPTOMS

, most prevalent being

    cardiac
    SYMPTOMS

 (48%),

    cutaneous
    SYMPTOMS

 (45%) and

    neurologic
    SYMPTOMS

 (52%

    ) involvements
    SYMPTOMS

. There were 20 families in total, comprising on average of 2.1 members each. Of the 20 families,

    only two had the same pathogenic GLA mutation
    FAMILY

.

    FD
    DIAGNOSIS

 patients in our country show a significant degree of

    multiorgan involvement
    SYMPTOMS

 with

    important psychological and social impact on
    SYMPTOMS

 the patients and their families.

    Women
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 show similar disease burden as

    men
    GENDER

, but at a

    later age
    AGE

.

Fabry disease (FD)
rare genetic lysosomal disease
Fabry
Fabry
FD
Fabry disease


Prevalence of Anderson-Fabry disease in a cohort with unexplained late gadolinium enhancement on cardiac MRI.

Fabry disease is a rare X-linked genetic disorder in which cardiac manifestations include LVH, contractile dysfunction, and fibrosis, visible on cardiac MRI (cMRI) as late gadolinium enhancement (LGE) of the myocardium. Fabry's disease is an important diagnosis to make as treatment is available as lifelong replacement of the deficient enzyme.

To define the prevalence of Fabry disease in a cohort of patients with unexplained LGE on cMRI.

The study population was recruited from patients aged >16 years who had cMRI performed between 2010 and 2018 to investigate LVH, idiopathic LV dysfunction and/or idiopathic ventricular arrhythmia. Patients with 'unexplained' LGE i.e. without a genetic diagnosis of an alternate cardiomyopathy such as HCM or biopsy-proven infiltrative cardiomyopathy such as sarcoid or amyloid, were tested for Fabry disease by either genetic testing or the Dried Blood Spot test (Sanofi-Genzyme).

Of the 79 patients with unexplained LGE on cMRI, 2 patients tested positive for Fabry disease, both using genetic sequencing techniques. The prevalence of Fabry disease in this selected cohort was 2.5%. Specifically, 1 patient was a 65 year old male and the other patient a 75 year old female. In both cases, the pattern and distribution of LGE on cMRI was of patchy mid-wall enhancement in the inferoseptum.

Unexplained LGE on cMRI may be an isolated manifestation of late-onset Fabry disease. This finding should prompt testing for Fabry disease given this is a potentially treatable condition.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked genetic disorder
    GENETICS

 in which

    cardiac manifestations
    SYMPTOMS

 include

    LVH
    SYMPTOMS

,

    contractile dysfunction
    SYMPTOMS

, and

    fibrosis
    SYMPTOMS

, visible on

    cardiac MRI (cMRI)
    PARACLINICAL

 as

    late gadolinium enhancement (LGE) of the myocardium
    SYMPTOMS

.

    Fabry's disease
    DIAGNOSIS

 is an important diagnosis to make as treatment is available as

    lifelong replacement of the deficient enzyme
    MEDICATION

.

To define the prevalence of

    Fabry disease
    DIAGNOSIS

 in a cohort of patients with

    unexplained LGE
    SYMPTOMS

 on

    cMRI
    PARACLINICAL

.

The study population was recruited from patients

    aged >16 years
    AGE

 who had

    cMRI
    PARACLINICAL

 performed between 2010 and 2018 to investigate

    LVH
    DIAGNOSIS

,

    idiopathic LV dysfunction
    SYMPTOMS

 and/or

    idiopathic ventricular arrhythmia
    SYMPTOMS

. Patients with 'unexplained'

    LGE
    SYMPTOMS

 i.e.

    without a genetic diagnosis of an alternate cardiomyopathy such as HCM or biopsy-proven infiltrative cardiomyopathy such as sarcoid or amyloid
    NEG_FINDINGS

, were tested for

    Fabry disease
    DIAGNOSIS

 by either

    genetic testing
    PARACLINICAL

 or the

    Dried Blood Spot test
    PARACLINICAL

 (Sanofi-Genzyme).

Of the 79 patients with

    unexplained LGE
    SYMPTOMS

 on

    cMRI
    PARACLINICAL

, 2 patients tested positive for

    Fabry disease
    DIAGNOSIS

, both using

    genetic sequencing techniques
    PARACLINICAL

. The prevalence of

    Fabry disease
    DIAGNOSIS

 in this selected cohort was 2.5%. Specifically, 1 patient was a

    65 year old
    AGE

    male
    GENDER

 and the other patient a

    75 year old
    AGE

    female
    GENDER

. In both cases, the

    pattern and distribution of LGE on cMRI
    SYMPTOMS

 was of

    patchy mid-wall enhancement in the inferoseptum
    SYMPTOMS

.

    Unexplained LGE on cMRI
    SYMPTOMS

 may be an isolated manifestation of

    late-onset Fabry disease
    DIAGNOSIS

. This finding should prompt testing for

    Fabry disease
    DIAGNOSIS

 given this is a potentially treatable condition.

Fabry disease
Fabry's disease
Fabry disease
LVH
Fabry disease
Fabry disease
Fabry disease
late-onset Fabry disease
Fabry disease


RECURRENT ATYPICAL OPTIC NEURITIS AS THE LEADING SIGN OF FABRY DISEASE.

Acute optic neuritis has the age and sex adjusted incidence of 1-5/100,000 in general population. It is mostly a disorder affecting young Caucasian women (31-32 years). Patients present to a wide range of clinicians including general practitioner, emergency physician, ophthalmologist, neurologist, etc. There are two main clinical presentations of optic neuritis, typical and atypical. It is of great importance to distinguish these two types of optic neuritis in order to detect the underlying etiology and plan appropriate and timely treatment. We present a young female patient (36 years) admitted to Department of Ophthalmology due to visual loss on the left eye. Magnetic resonance imaging showed demyelinating lesions in frontal and parietal lobe, periventricularly, in mesencephalon and right cerebellar hemisphere, and left optic neuritis; magnetic resonance angiography was normal. The patient's history revealed renal dysfunction, hypothyroidism, and miscarriage in the 6th month of pregnancy due to eclampsia, and Fabry disease in family (mother and two sisters). She was transferred to the Department of Neurology for further evaluation of the demyelinating disorder of the central nervous system. The patient received corticosteroid therapy (methylprednisolone 1 g) for 5 days with regression of visual disturbances on the left eye. After this acute treatment, the question of definitive diagnosis remained, along with further treatment of the underlying cause. Considering renal dysfunction, miscarriage, arterial hypertension, positive genetic and biochemical testing for Fabry disease in close relatives (mother), we suspected that she also had Fabry disease. She was tested and the results were positive. We concluded that optic neuritis was the first sign of Fabry disease in this case, reflecting acute atypical neuroinflammatory disease.

    Acute optic neuritis
    DIAGNOSIS

 has the age and sex adjusted incidence of 1-5/100,000 in general population. It is mostly a disorder affecting

    young
    AGE

    Caucasian
    ETHNICITY

    women
    GENDER

 (

    31-32 years
    AGE

). Patients present to a wide range of clinicians including

    general practitioner
    PARACLINICAL

,

    emergency physician
    PARACLINICAL

,

    ophthalmologist
    PARACLINICAL

,

    neurologist
    PARACLINICAL

, etc. There are two main clinical presentations of

    optic neuritis
    DIAGNOSIS

, typical and atypical. It is of great importance to distinguish these two types of

    optic neuritis
    DIAGNOSIS

 in order to detect the underlying etiology and plan appropriate and timely treatment. We present a

    young
    AGE

    female
    GENDER

 patient (

    36 years
    AGE

) admitted to Department of

    Ophthalmology
    PARACLINICAL

 due to

    visual loss on the left eye
    SYMPTOMS

.

    Magnetic resonance imaging
    PARACLINICAL

 showed

    demyelinating lesions in frontal and parietal lobe, periventricularly, in mesencephalon and right cerebellar hemisphere
    SYMPTOMS

, and

    left optic neuritis
    DIAGNOSIS

;

    magnetic resonance angiography was normal
    NEG_FINDINGS

. The patient's history revealed

    renal dysfunction
    SYMPTOMS

,

    hypothyroidism
    SYMPTOMS

, and

    miscarriage in the 6th month of pregnancy
    SYMPTOMS

 due to

    eclampsia
    DIAGNOSIS

, and

    Fabry disease in family (mother and two sisters)
    FAMILY

.

    She
    GENDER

 was transferred to the Department of

    Neurology
    PARACLINICAL

 for further evaluation of the

    demyelinating disorder of the central nervous system
    DIAGNOSIS

. The patient received

    corticosteroid therapy (methylprednisolone 1 g) for 5 days
    MEDICATION

 with

    regression of visual disturbances on the left eye
    SYMPTOMS

. After this

    acute treatment
    MEDICATION

, the question of definitive diagnosis remained, along with further treatment of the underlying cause. Considering

    renal dysfunction
    SYMPTOMS

,

    miscarriage
    SYMPTOMS

,

    arterial hypertension
    SYMPTOMS

,

    positive genetic and biochemical testing for Fabry disease in close relatives (mother)
    FAMILY

, we suspected that

    she
    GENDER

 also had

    Fabry disease
    DIAGNOSIS

.

    She
    GENDER

 was tested and the results were positive. We concluded that

    optic neuritis
    DIAGNOSIS

 was the first sign of

    Fabry disease
    DIAGNOSIS

 in this case, reflecting

    acute atypical neuroinflammatory disease
    DIAGNOSIS

.


Pregnancy Outcome after Exposure to Migalastat for Fabry Disease: A Clinical Report.

Our patient was a 37-year-old woman with Fabry disease (GLA p.R112H) with a medical history of recurrent headache, nausea, vomiting, vertigo, and tobacco use (20 cigarettes/day). Fabry disease was diagnosed in 2005 when she experienced proteinuria, preeclampsia, and hypertension (201/130 mm Hg) during pregnancy (delivered 50 cm, 3.4 kg healthy boy; GLA wild type [WT]). Enzyme replacement therapy was initiated in 2009. The patient enrolled in the phase 3 ATTRACT trial (ClinicalTrials.gov; NCT01218659) and started migalastat in May 2012 while taking hormonal contraceptives. Two years after initiating migalastat, the patient had proteinuria (2166 mg/24 h) without hypertension (131/68 mm Hg), which persisted (788 mg/24 h a month later). Kidney biopsy results were consistent with existing Fabry disease. A serum pregnancy test and ultrasound confirmed pregnancy (18 weeks' gestation). Migalastat and hormonal contraceptives were stopped; the patient continued to smoke. Fetal MRI was normal at ~29 weeks' gestation. In October 2014, at 37+ weeks' gestation, the patient delivered a 45-cm, 2.29-kg healthy girl (GLA WT). Excepting low birth weight, which may be related to the patient's smoking, pregnancy outcome was normal despite exposure to migalastat for 18 weeks. Migalastat therapy during pregnancy is not advised.

Our patient was a

    37-year-old
    AGE

    woman
    GENDER

 with

    Fabry disease
    DIAGNOSIS

 (

    GLA p.R112H)
    GENETICS

 with a medical history of

    recurrent headache
    SYMPTOMS

,

    nausea
    SYMPTOMS

,

    vomiting
    SYMPTOMS

,

    vertigo
    SYMPTOMS

, and

    tobacco use (20 cigarettes/day)
    MEDICATION

.

    Fabry disease
    DIAGNOSIS

 was diagnosed in 2005 when

    she
    GENDER

 experienced

    proteinuria
    BIOCHEMICAL

,

    preeclampsia
    SYMPTOMS

, and

    hypertension (201/130 mm Hg)
    SYMPTOMS

 during

    pregnancy
    DIAGNOSIS

 (

    delivered 50 cm, 3.4 kg healthy boy
    MEDICATION

; GLA wild type [WT]).

    Enzyme replacement therapy
    MEDICATION

 was initiated in 2009. The patient

    enrolled in the phase 3 ATTRACT trial (ClinicalTrials.gov; NCT01218659)
    MEDICATION

 and started

    migalastat
    MEDICATION

 in May 2012

    while taking hormonal contraceptives
    MEDICATION

. Two years after initiating

    migalastat
    MEDICATION

, the patient had

    proteinuria (2166 mg/24 h)
    BIOCHEMICAL

    without hypertension (131/68 mm Hg)
    NEG_FINDINGS

, which persisted (788 mg/24 h a month later).

    Kidney biopsy results
    PARACLINICAL

 were consistent with

    existing Fabry disease
    DIAGNOSIS

. A

    serum pregnancy test
    PARACLINICAL

 and

    ultrasound
    PARACLINICAL

 confirmed

    pregnancy (18 weeks' gestation)
    DIAGNOSIS

.

    Migalastat and hormonal contraceptives were stopped
    MEDICATION

; the patient

    continued to smoke
    MEDICATION

.

    Fetal MRI was normal at ~29 weeks' gestation
    NEG_FINDINGS

. In October 2014,

    at 37+ weeks' gestation, the patient delivered a 45-cm, 2.29-kg healthy girl
    MEDICATION

 (GLA WT). Excepting

    low birth weight
    SYMPTOMS

, which may be related to the patient's

    smoking
    MEDICATION

,

    pregnancy outcome was normal
    NEG_FINDINGS

 despite

    exposure to migalastat for 18 weeks
    MEDICATION

.

    Migalastat therapy
    MEDICATION

 during

    pregnancy
    DIAGNOSIS

 is not advised.

Fabry disease
Fabry disease
pregnancy
existing Fabry disease
pregnancy (18 weeks' gestation)
pregnancy

recurrent headache
nausea
vomiting
vertigo
preeclampsia
hypertension (201/130 mm Hg)
low birth weight


Hydroxychloroquine-induced renal phospholipidosis resembling Fabry disease in undifferentiated connective tissue disease: A case report.

Fabry disease is a kind of lysosomal storage disease resulting from deficient activity of the lysosomal hydrolase alpha-galactosidase A (GLA). A mutation in the GLA gene leads to a loss of activity of alpha-galactosidase A. Some drugs, such as hydroxychloroquine, can cause pathological changes similar to those usually seen in Fabry disease.

We report the case of a 41-year-old female patient who was diagnosed with undifferentiated connective tissue disease in 2008. Hydroxychloroquine treatment started 2 years ago, and proteinuria and hematuria increased. Renal biopsy demonstrated renal phospholipidosis. Zebra bodies and myelin figures were found by renal electron microscopy and were initially thought to be indicators of Fabry disease. A genetic analysis of the patient and her family members did not reveal mutations in the GLA gene, supporting a diagnosis of hydroxychloroquine-induced renal phospholipidosis.

This report reveals one of the adverse effects of hydroxychloroquine. We should pay more attention to hydroxychloroquine-induced renal phospholipidosis.

    Fabry disease
    DIAGNOSIS

 is a kind of

    lysosomal storage disease
    DIAGNOSIS

 resulting from

    deficient activity of the lysosomal hydrolase alpha-galactosidase A (GLA)
    BIOCHEMICAL

. A

    mutation in the GLA gene
    GENETICS

 leads to a loss of activity of alpha-galactosidase A. Some drugs, such as

    hydroxychloroquine
    MEDICATION

, can cause

    pathological changes similar to those usually seen in Fabry disease
    SYMPTOMS

.

We report the case of a

    41-year-old
    AGE

    female
    GENDER

 patient who was diagnosed with

    undifferentiated connective tissue disease
    DIAGNOSIS

 in 2008.

    Hydroxychloroquine treatment
    MEDICATION

 started 2 years ago, and

    proteinuria
    BIOCHEMICAL

 and

    hematuria increased
    BIOCHEMICAL

.

    Renal biopsy
    PARACLINICAL

 demonstrated

    renal phospholipidosis
    MICROSCOPIC

.

    Zebra bodies and myelin figures
    MICROSCOPIC

 were found by

    renal electron microscopy
    PARACLINICAL

 and were

    initially thought to be indicators of Fabry disease
    NEG_FINDINGS

. A

    genetic analysis of the patient and her family members did not reveal mutations in the GLA gene
    NEG_FINDINGS

, supporting a diagnosis of

    hydroxychloroquine-induced renal phospholipidosis
    DIAGNOSIS

.

This report reveals one of the adverse effects of

    hydroxychloroquine
    MEDICATION

. We should pay more attention to

    hydroxychloroquine-induced renal phospholipidosis
    DIAGNOSIS

.

hydroxychloroquine
Hydroxychloroquine treatment
hydroxychloroquine


A Case of Fabry Disease Presenting with Young Stroke and Fever.

Although it is known that Fabry disease should be included in the differential diagnosis of young stroke and fever of unknown origin, it has not been reported in the literature of stroke with fever as the presentation of Fabry disease. This is relevant because stroke with fever may misguide the differential diagnosis. Here we present a young stroke patient with fever. DWI of brain MRI revealed acute multiple infarctions. Due to the fever, infectious and inflammatory origins such as infective endocarditis and autoimmune diseases were examined first. However, we could not identify the source of fever after fever workup. The fever did not respond to one week of acetaminophen and antibiotics, but responded promptly to steroid. Our patient is also a case of de novo mutation rather than being inherited that further complicates the diagnosis of this patient. Because of the rare combined presentation of stroke with fever, Fabry disease should also be considered in stroke with fever, even without family history of Fabry disease.

Although it is known that

    Fabry disease
    DIAGNOSIS

 should be included in the

    differential diagnosis
    PARACLINICAL

 of

    young stroke
    SYMPTOMS

 and

    fever of unknown origin
    SYMPTOMS

, it has not been reported in the literature of

    stroke with fever
    SYMPTOMS

 as the presentation of

    Fabry disease
    DIAGNOSIS

. This is relevant because

    stroke
    SYMPTOMS

 with

    fever
    SYMPTOMS

 may misguide the

    differential diagnosis
    PARACLINICAL

. Here we present a

    young
    AGE

    stroke
    SYMPTOMS

 patient with

    fever
    SYMPTOMS

.

    DWI of brain MRI
    PARACLINICAL

 revealed

    acute multiple infarctions
    SYMPTOMS

. Due to the

    fever
    SYMPTOMS

,

    infectious and inflammatory origins
    SYMPTOMS

 such as

    infective endocarditis
    DIAGNOSIS

 and

    autoimmune diseases
    DIAGNOSIS

 were examined first. However,

    we could not identify the source of fever after fever workup
    NEG_FINDINGS

. The

    fever did not respond to one week of acetaminophen and antibiotics
    NEG_FINDINGS

, but responded promptly to

    steroid
    MEDICATION

. Our patient is also a case of

    de novo mutation rather than being inherited
    GENETICS

 that further complicates the diagnosis of this patient. Because of the rare combined presentation of

    stroke with fever
    SYMPTOMS

,

    Fabry disease
    DIAGNOSIS

 should also be considered in

    stroke with fever
    SYMPTOMS

, even

    without family history of Fabry disease
    NEG_FINDINGS

.

Fabry disease
Fabry disease
infective endocarditis
autoimmune diseases
Fabry disease

young stroke
fever of unknown origin
stroke with fever
stroke
fever
stroke
fever
acute multiple infarctions
fever
infectious and inflammatory origins
stroke with fever
stroke with fever


Effectiveness of immunosuppressive therapy for nephrotic syndrome in a patient with late-onset Fabry disease: a case report and literature review.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene, followed by deficiency in α-galactosidase A (α-gal) activity. Nephrotic syndrome, as the renal phenotype of FD, is unusual. Here, we report the rare case of a patient with FD with nephrotic syndrome whose proteinuria disappeared by immunotherapy.

A 67-year-old Japanese man was admitted to our hospital because of emesis, abdominal pain, and facial edema due to nephrotic syndrome. The patient was diagnosed with focal segmental glomerulosclerosis (FSGS) by renal biopsy before being diagnosed with FD, and immunotherapy was initiated. After treatment, the kidney biopsy results showed typical glycosphingolipid accumulation in the podocytes of this patient. The white blood cell α-gal activity was very low, and genetic analysis revealed a GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD. Immunotherapy (steroids and cyclosporine A) dramatically improved the massive proteinuria. Currently, he has been undergoing enzyme replacement therapy, and his proteinuria has further decreased. There is the possibility that other nephrotic syndromes, such as minimal change nephrotic syndrome or FSGS, may co-exist in this patient.

We experienced the rare case of a FD patient whose nephrotic syndrome disappeared by immunotherapy. These findings suggest that immunosuppressive treatment may be considered if nephrotic syndrome develops, even in patients with FD.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations of the GLA gene
    GENETICS

, followed by

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

.

    Nephrotic syndrome
    DIAGNOSIS

, as the renal phenotype of

    FD
    DIAGNOSIS

, is unusual. Here, we report the rare case of a patient with

    FD
    DIAGNOSIS

 with

    nephrotic syndrome
    DIAGNOSIS

 whose

    proteinuria disappeared
    BIOCHEMICAL

 by

    immunotherapy
    MEDICATION

.

A

    67-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 was admitted to our hospital because of

    emesis
    SYMPTOMS

,

    abdominal pain
    SYMPTOMS

, and

    facial edema
    SYMPTOMS

 due to

    nephrotic syndrome
    DIAGNOSIS

. The patient was diagnosed with

    focal segmental glomerulosclerosis (FSGS)
    DIAGNOSIS

 by

    renal biopsy
    PARACLINICAL

 before being diagnosed with

    FD
    DIAGNOSIS

, and

    immunotherapy
    MEDICATION

 was initiated. After treatment, the

    kidney biopsy
    PARACLINICAL

 results showed

    typical glycosphingolipid accumulation in the podocytes
    MICROSCOPIC

 of this patient. The

    white blood cell α-gal activity was very low
    BIOCHEMICAL

, and

    genetic analysis
    PARACLINICAL

 revealed a

    GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD
    GENETICS

.

    Immunotherapy (steroids and cyclosporine A)
    MEDICATION

    dramatically improved the massive proteinuria
    BIOCHEMICAL

. Currently,

    he
    GENDER

 has been undergoing

    enzyme replacement therapy
    MEDICATION

, and his

    proteinuria has further decreased
    BIOCHEMICAL

. There is the possibility that other

    nephrotic syndromes
    DIAGNOSIS

, such as

    minimal change nephrotic syndrome
    DIAGNOSIS

 or

    FSGS
    DIAGNOSIS

, may co-exist in this patient.

We experienced the rare case of a

    FD
    DIAGNOSIS

 patient whose

    nephrotic syndrome
    DIAGNOSIS

 disappeared by

    immunotherapy
    MEDICATION

. These findings suggest that

    immunosuppressive treatment
    MEDICATION

 may be considered if

    nephrotic syndrome
    DIAGNOSIS

 develops, even in patients with

    FD
    DIAGNOSIS

.


IgA nephropathy suspected to be combined with Fabry disease or Alport syndrome: a case report.

Immunoglobulin A (IgA) nephropathy is the most common glomerular disease, and it often manifests as persistent microscopic hematuria or gross hematuria. Fabry disease and Alport syndrome are hereditary diseases caused by mutation of genes, and these diseases are rare in China. At present, patients can be diagnosed with IgA nephropathy by clinical manifestations and laboratory examinations, but there is still controversy about the simultaneous diagnosis of Alport syndrome and Fabry disease in patients with IgA nephropathy. The present case was a 17-year-old girl with hematuria and proteinuria who underwent a renal biopsy. Light microscopy and immunofluorescence showed that IgA was deposited in the mesangium. Under electron microscopy, zebra bodies with a lamellated structure were detected. A gene test showed a COL4A3 gene mutation. The patient was administered prednisone 40 mg once a day and dispersible tablets of mycophenolate mofetil 0.75 g two times a day. The patient's condition showed a trend of remission. The findings in our case emphasize the importance of renal biopsy and gene detection in hereditary kidney disease, especially for Fabry disease and its rare coexistence with Alport syndrome.

    Immunoglobulin A (IgA) nephropathy
    DIAGNOSIS

 is the most common

    glomerular disease
    DIAGNOSIS

, and it often manifests as

    persistent microscopic hematuria
    BIOCHEMICAL

 or

    gross hematuria
    BIOCHEMICAL

.

    Fabry disease
    DIAGNOSIS

 and

    Alport syndrome
    DIAGNOSIS

 are

    hereditary diseases
    GENETICS

 caused by

    mutation of genes
    GENETICS

, and these diseases are rare in

    China
    ETHNICITY

. At present, patients can be diagnosed with

    IgA nephropathy
    DIAGNOSIS

 by clinical manifestations and

    laboratory examinations
    PARACLINICAL

, but there is still controversy about the simultaneous diagnosis of

    Alport syndrome and Fabry disease
    DIAGNOSIS

 in patients with

    IgA nephropathy
    DIAGNOSIS

. The present case was a

    17-year-old
    AGE

    girl
    GENDER

 with

    hematuria
    BIOCHEMICAL

 and

    proteinuria
    BIOCHEMICAL

 who underwent a

    renal biopsy
    PARACLINICAL

.

    Light microscopy
    PARACLINICAL

 and

    immunofluorescence
    PARACLINICAL

 showed that

    IgA was deposited in the mesangium
    MICROSCOPIC

. Under

    electron microscopy
    PARACLINICAL

,

    zebra bodies with a lamellated structure were detected
    MICROSCOPIC

. A

    gene test
    PARACLINICAL

 showed a

    COL4A3 gene mutation
    GENETICS

. The patient was administered

    prednisone 40 mg once a day and dispersible tablets of mycophenolate mofetil 0.75 g two times a day
    MEDICATION

. The patient's condition showed a

    trend of remission
    SYMPTOMS

. The findings in our case emphasize the importance of

    renal biopsy
    PARACLINICAL

 and

    gene detection
    PARACLINICAL

 in

    hereditary kidney disease
    DIAGNOSIS

, especially for

    Fabry disease
    DIAGNOSIS

 and its

    rare coexistence with Alport syndrome
    DIAGNOSIS

.

Immunoglobulin A (IgA) nephropathy
glomerular disease
Fabry disease
Alport syndrome
IgA nephropathy
Alport syndrome and Fabry disease
IgA nephropathy
hereditary kidney disease
Fabry disease
rare coexistence with Alport syndrome

persistent microscopic hematuria
gross hematuria
hematuria
proteinuria

hereditary diseases
mutation of genes
COL4A3 gene mutation


Early initiation of enzyme replacement therapy in classical Fabry disease normalizes biomarkers in clinically asymptomatic pediatric patients.

Fabry disease is an X-linked lysosomal storage disorder which often presents with renal, cardiac, gastrointestinal, and nervous system abnormalities. Available enzyme replacement therapies have demonstrated efficacy at significantly reducing elevated biomarkers associated with increased disease activity, while improving the clinical symptoms associated with Fabry disease. In two cases with classical Fabry disease, we demonstrate that the initiation of enzyme replacement therapy prior to the onset of overt clinical disease is well tolerated and effectively reduces elevated biomarkers, mitigating unnecessary organ damage that may occur prior to the onset of clinical manifestations of disease. This proactive approach should be considered as a best-practice management strategy which has the potential to significantly improve health outcomes in patients with classical Fabry patients, particularly in the context of newborn screening for Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 which often presents with

    renal
    SYMPTOMS

,

    cardiac
    SYMPTOMS

,

    gastrointestinal
    SYMPTOMS

, and

    nervous system abnormalities
    SYMPTOMS

. Available

    enzyme replacement therapies
    MEDICATION

 have demonstrated efficacy at

    significantly reducing elevated biomarkers associated with increased disease activity
    BIOCHEMICAL

, while

    improving the clinical symptoms associated with Fabry disease
    SYMPTOMS

. In two cases with

    classical Fabry disease
    DIAGNOSIS

, we demonstrate that the

    initiation of enzyme replacement therapy prior to the onset of overt clinical disease
    MEDICATION

 is well tolerated and

    effectively reduces elevated biomarkers
    BIOCHEMICAL

,

    mitigating unnecessary organ damage
    SYMPTOMS

 that may occur prior to the onset

    of clinical manifestations of disease
    SYMPTOMS

. This

    proactive approach
    MEDICATION

 should be considered as a best-practice management strategy which has the potential to significantly improve health outcomes in patients with

    classical Fabry
    DIAGNOSIS

 patients, particularly in the context of

    newborn
    AGE

 screening for

    Fabry disease
    DIAGNOSIS

.

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


p.G360R Is a Pathogenic GLA Gene Mutation Responsible for a Classic Phenotype of Fabry Disease.

The authors report the case of a classic phenotype of Fabry disease in a 60-year-old male patient presenting with left ventricular hypertrophy and stroke. Genetic analysis revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more GLA gene variants in a Fabry patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the p.G360R mutation is pathogenic and responsible for a classic phenotype of Fabry disease. The clinical improvement following the initiation of enzyme replacement therapy reinforces the importance of Fabry disease awareness and diagnosis in patients exhibiting red flags, such as left ventricular hypertrophy and stroke.

The authors report the case of a classic phenotype of

    Fabry disease
    DIAGNOSIS

 in a

    60-year-old
    AGE

    male
    GENDER

 patient presenting with

    left ventricular hypertrophy
    SYMPTOMS

 and

    stroke
    SYMPTOMS

.

    Genetic analysis
    PARACLINICAL

 revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more

    GLA gene variants
    GENETICS

 in a

    Fabry
    DIAGNOSIS

 patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the

    p.G360R mutation
    GENETICS

 is pathogenic and responsible for a classic phenotype of

    Fabry disease
    DIAGNOSIS

. The

    clinical improvement
    SYMPTOMS

 following the

    initiation of enzyme replacement therapy
    MEDICATION

 reinforces the importance of

    Fabry disease
    DIAGNOSIS

 awareness and diagnosis in patients exhibiting red flags, such as

    left ventricular hypertrophy
    SYMPTOMS

 and

    stroke
    SYMPTOMS

.

Fabry disease
Fabry
Fabry disease
Fabry disease

left ventricular hypertrophy
stroke
clinical improvement
left ventricular hypertrophy
stroke


Ocular manifestations in a patient with de novo Fabry disease.

Fabry disease (FD) is an X-linked, recessively inherited, rare, progressive, disorder of glycosphingolipid metabolism affecting multiple organs resulting in organ dysfunction. It is rare to find only one FD affected subject with a de novo mutation. Here we report a case of a 41-year-old Asian male diagnosed with de novo FD. Comprehensive ophthalmological evaluation was performed using slit lamp, color fundus photography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography. On slit lamp examination, cornea verticillata and slightly tortuous, and aneurysmal dilatation of inferior bulbar conjunctival vessels were observed. Other imaging modalities showed unremarkable findings. Cornea verticillata and inferior bulbar conjunctival vascular abnormalities may be detected earlier than other ocular abnormalities in de novo FDs like hereditary FDs.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked, recessively inherited
    GENETICS

,

    rare, progressive, disorder of glycosphingolipid metabolism
    DIAGNOSIS

    affecting multiple organs
    SYMPTOMS

 resulting in

    organ dysfunction
    SYMPTOMS

. It is rare to find only one

    FD
    DIAGNOSIS

 affected subject with a

    de novo mutation
    GENETICS

. Here we report a case of a

    41-year-old
    AGE

    Asian
    ETHNICITY

    male
    GENDER

 diagnosed with

    de novo FD
    DIAGNOSIS

.

    Comprehensive ophthalmological evaluation
    PARACLINICAL

 was performed using

    slit lamp
    PARACLINICAL

,

    color fundus photography
    PARACLINICAL

,

    optical coherence tomography
    PARACLINICAL

,

    fluorescein angiography
    PARACLINICAL

, and

    indocyanine green angiography
    PARACLINICAL

. On

    slit lamp examination
    PARACLINICAL

,

    cornea verticillata
    SYMPTOMS

 and

    slightly tortuous, and aneurysmal dilatation of inferior bulbar conjunctival vessels
    SYMPTOMS

 were observed.

    Other imaging modalities showed unremarkable findings
    NEG_FINDINGS

.

    Cornea verticillata
    SYMPTOMS

 and

    inferior bulbar conjunctival vascular abnormalities
    SYMPTOMS

 may be detected earlier than other

    ocular abnormalities
    SYMPTOMS

 in

    de novo FDs
    DIAGNOSIS

 like

    hereditary FDs
    DIAGNOSIS

.

X-linked, recessively inherited
de novo mutation


Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease.

Fabry disease (FD) is a rare and underdiagnosed X-linked disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A, which leads to storage of complex glycosphingolipids inside of lysosomes in critical organs and tissues, impairing their functions and consequently resulting in a progressive multisystem disease. FD is caused by mutations in the GLA gene, and only 4.6% of described mutations are located in the splice site regions. RNA splicing is an essential step to the formation of functional proteins, and mutations in splice site regions can cause formation of aberrant transcripts leading to disease. Here we report a novel GLA insertion at position c.801+3 in intron 5 (c.801+2_801+3insT) in a Brazilian family with suspicion of FD. The index case, a 46-year-old male, presented undetectable α-galactosidase A activity. Analysis of blood cDNA found two aberrant GLA transcripts. In the first transcript, a novel donor splice site was created promoting formation of an intron inclusion with 37 bp. The splice site was not recognized in the second transcript and the intron 5 was not excised. The wild-type transcript was not formed and both aberrant transcripts lead to a premature stop codon. Despite not being in the canonical site, this new mutation disrupts existing 5' splice site and produces two aberrant transcripts leading to FD.

    Fabry disease (FD)
    DIAGNOSIS

 is a rare and underdiagnosed

    X-linked disorder
    GENETICS

 resulting from the

    deficient activity of the lysosomal hydrolase α-galactosidase A
    BIOCHEMICAL

, which leads to

    storage of complex glycosphingolipids inside of lysosomes in critical organs and tissues, impairing their functions
    MICROSCOPIC

 and consequently resulting in a

    progressive multisystem disease
    DIAGNOSIS

.

    FD
    DIAGNOSIS

 is caused by

    mutations in the GLA gene
    GENETICS

, and only 4.6% of described mutations are located in the splice site regions. RNA splicing is an essential step to the formation of functional proteins, and mutations in splice site regions can cause formation of aberrant transcripts leading to disease. Here we report a

    novel GLA insertion at position c.801+3 in intron 5 (c.801+2_801+3insT)
    GENETICS

 in a

    Brazilian
    ETHNICITY

    family with suspicion of FD
    FAMILY

. The index case, a

    46-year-old
    AGE

    male
    GENDER

, presented

    undetectable α-galactosidase A activity
    BIOCHEMICAL

.

    Analysis of blood cDNA
    PARACLINICAL

 found two

    aberrant GLA transcripts
    GENETICS

. In the first transcript, a

    novel donor splice site was created promoting formation of an intron inclusion with 37 bp. The splice site was not recognized in the second transcript and the intron 5 was not excised. The wild-type transcript was not formed and both aberrant transcripts lead to a premature stop codon
    GENETICS

. Despite not being in the canonical site, this

    new mutation disrupts existing 5' splice site and produces two aberrant transcripts
    GENETICS

 leading to

    FD
    DIAGNOSIS

.

Fabry disease (FD)
progressive multisystem disease
FD
FD


Restrictive cardiomyopathy in a patient with systemic sclerosis and Fabry disease: a case-based review.

Systemic sclerosis (SSc) is a rare immune-mediated vasculopathy characterized by fibrosis of the skin and internal organs. Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene producing α-galactosidase-A enzyme (α-Gal A) deficiency. Being a systemic disease, cardiac involvement in FD has a high mortality rate due to heart failure and arrhythmia. The coexistence of these two entities has not been reported previously. We describe the case of a female patient with limited SSc (lcSSc), a diagnosis based on the presence of sclerodactyly, Raynaud phenomenon, microvascular involvement, and positive anti-centromere antibodies. On follow-up, she developed chest pain, a second-degree A-V block, and restrictive cardiomyopathy (without cardiovascular risk factors). Although heart involvement is common in these two entities, the abnormal thickening of lateral and inferior wall, the infiltration pattern and the conduction system disorders presented herein are more characteristic in a heterozygous female with a cardiac variant of FD. The diagnosis of FD was confirmed with high globotriaosylsphingosine (Lyso-Gb3) levels and identification of GLA gene mutation. The patient was treated with enzymatic replacement (agalsidase alpha) following mild improvement in ventricular mass at 6th month, without clinical deterioration. The related literature on SSc associated with FD is also reviewed.

    Systemic sclerosis (SSc)
    DIAGNOSIS

 is a

    rare immune-mediated vasculopathy
    DIAGNOSIS

 characterized by

    fibrosis of the skin and internal organs
    SYMPTOMS

.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations in the GLA gene
    GENETICS

 producing

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

. Being a

    systemic disease
    DIAGNOSIS

,

    cardiac involvement
    SYMPTOMS

 in

    FD
    DIAGNOSIS

 has a high mortality rate due to

    heart failure
    SYMPTOMS

 and

    arrhythmia
    SYMPTOMS

. The coexistence of these two entities has not been reported previously. We describe the case of a

    female
    GENDER

 patient with

    limited SSc (lcSSc)
    DIAGNOSIS

, a diagnosis based on the presence of

    sclerodactyly
    SYMPTOMS

,

    Raynaud phenomenon
    SYMPTOMS

,

    microvascular involvement
    SYMPTOMS

, and

    positive anti-centromere antibodies
    BIOCHEMICAL

. On

    follow-up
    PARACLINICAL

,

    she
    GENDER

 developed

    chest pain
    SYMPTOMS

, a

    second-degree A-V block
    SYMPTOMS

, and

    restrictive cardiomyopathy
    SYMPTOMS

 (

    without cardiovascular risk factors)
    NEG_FINDINGS

. Although

    heart involvement
    SYMPTOMS

 is common in these two entities, the

    abnormal thickening of lateral and inferior wall
    SYMPTOMS

, the

    infiltration pattern
    SYMPTOMS

 and the

    conduction system disorders
    SYMPTOMS

 presented herein are more characteristic in a

    heterozygous
    GENETICS

    female
    GENDER

 with a

    cardiac variant of FD
    DIAGNOSIS

. The diagnosis of

    FD
    DIAGNOSIS

 was confirmed with

    high globotriaosylsphingosine (Lyso-Gb3) levels
    BIOCHEMICAL

 and identification of

    GLA gene mutation
    GENETICS

. The patient was treated with

    enzymatic replacement (agalsidase alpha)
    MEDICATION

 following

    mild improvement in ventricular mass
    SYMPTOMS

 at 6th month,

    without clinical deterioration
    NEG_FINDINGS

. The related literature on

    SSc associated with FD
    DIAGNOSIS

 is also reviewed.

Systemic sclerosis (SSc)
rare immune-mediated vasculopathy
Fabry disease (FD)
lysosomal storage disorder
systemic disease
FD
limited SSc (lcSSc)
cardiac variant of FD
FD
SSc associated with FD

X-linked
mutations in the GLA gene
heterozygous
GLA gene mutation

without cardiovascular risk factors)
without clinical deterioration


Coexistence of Fabry disease with IgM nephropathy: A case report.

Coexistence of Fabry disease and IgM nephropathy is rare. The varying severity and unapparent clinical manifestation of Fabry disease makes it difficult to recognize when coexisting with another more prevalent cause of nephropathy requiring electron microscopy and genetic testing to confirm their coexistence.

A 54-year-old female presented with proteinuria without any clinical signs or family history of Fabry disease.

Immunostaining of the renal biopsy identified mesangial IgM deposition diagnosing it as IgM nephropathy. The light microscopy indicated prominent vacuolization of podocytes. Further examination of toluidine blue stained semi-thin sections and electron microscopy revealed blue bodies and myelin bodies in the cytoplasm of podocytes, respectively. Mutation analysis detected missense mutation establishing the diagnosis of coexisting Fabry disease.

The patient was treated with angiotensin-converting enzyme inhibitors. Enzyme replacement therapy was not administered due to financial constraints.

After 2 months of treatment the patient demonstrated urine protein to creatinine ratio of 0.21 g/g.

Identifying coexistence of Fabry disease with other nephropathy requires meticulous pathologic investigations including electron microscopy especially when Fabry disease presents with atypical phenotype.

    Coexistence of Fabry disease and IgM nephropathy
    DIAGNOSIS

 is rare. The varying severity and unapparent clinical manifestation of

    Fabry disease
    DIAGNOSIS

 makes it difficult to recognize when coexisting with another more prevalent cause of

    nephropathy
    DIAGNOSIS

 requiring

    electron microscopy
    PARACLINICAL

 and

    genetic testing
    PARACLINICAL

 to confirm their coexistence.

A

    54-year-old
    AGE

    female
    GENDER

 presented with

    proteinuria
    BIOCHEMICAL

    without any clinical signs or family history of Fabry disease
    NEG_FINDINGS

.

    Immunostaining of the renal biopsy
    PARACLINICAL

 identified

    mesangial IgM deposition
    MICROSCOPIC

 diagnosing it as

    IgM nephropathy
    DIAGNOSIS

. The

    light microscopy
    PARACLINICAL

 indicated

    prominent vacuolization of podocytes
    MICROSCOPIC

. Further

    examination of toluidine blue stained semi-thin sections
    PARACLINICAL

 and

    electron microscopy
    PARACLINICAL

 revealed

    blue bodies and myelin bodies in the cytoplasm of podocytes, respectively
    MICROSCOPIC

.

    Mutation analysis
    PARACLINICAL

 detected

    missense mutation
    GENETICS

 establishing the diagnosis of

    coexisting Fabry disease
    DIAGNOSIS

.

The patient was

    treated with angiotensin-converting enzyme inhibitors
    MEDICATION

.

    Enzyme replacement therapy was not administered due to financial constraints
    NEG_FINDINGS

.

    After 2 months of treatment
    MEDICATION

 the patient demonstrated

    urine protein to creatinine ratio of 0.21 g/g.
    BIOCHEMICAL

Identifying

    coexistence of Fabry disease with other nephropathy
    DIAGNOSIS

 requires

    meticulous pathologic investigations
    PARACLINICAL

 including

    electron microscopy
    PARACLINICAL

 especially when

    Fabry disease presents with atypical phenotype
    SYMPTOMS

.


Ocular findings in Fabry disease in Colombian patients

Fabry disease is a rare X-linked disorder caused by an alpha-galactosidase enzyme deficiency, which leads to a progressive lysosomal glycosphingolipids accumulation, mainly globotriaosylceramide, in multiple organism tissues including the eye. This case series describes the first ophthalmological Colombian report of Fabry disease highlighting the importance of ocular signs as markers of the disease, useful in diagnosis and treatment to avoid long-term complications that lead to a morbi-mortality increment. We describe five cases of Fabry disease from Bogotá, Colombia, including a complete clinical history, ophthalmologic, optometric examination, and photographs. We found that all patients had refractive defects and that in all cases corneal verticillata pattern was found. Four patients presented with posterior capsule lens brown-beige deposits and four patients had conjunctival and retinal tortuous vessels. A complete ophthalmologic examination is important for prompt diagnosis, which is key to starting a multidisciplinary treatment and reducing morbi-mortality.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked disorder
    GENETICS

 caused by an

    alpha-galactosidase enzyme deficiency
    BIOCHEMICAL

, which leads to a

    progressive lysosomal glycosphingolipids accumulation, mainly globotriaosylceramide, in multiple organism tissues including the eye
    MICROSCOPIC

. This case series describes the first

    ophthalmological
    PARACLINICAL

    Colombian
    ETHNICITY

 report of

    Fabry disease
    DIAGNOSIS

 highlighting the importance of

    ocular signs
    SYMPTOMS

 as markers of the disease, useful in diagnosis and treatment to avoid

    long-term complications
    SYMPTOMS

 that lead to a morbi-mortality increment. We describe five cases of

    Fabry disease
    DIAGNOSIS

 from

    Bogotá
    ETHNICITY

,

    Colombia
    ETHNICITY

, including a

    complete clinical history
    PARACLINICAL

,

    ophthalmologic, optometric examination
    PARACLINICAL

, and

    photographs
    PARACLINICAL

. We found that all patients had

    refractive defects
    SYMPTOMS

 and that in all cases

    corneal verticillata pattern
    SYMPTOMS

 was found. Four patients presented with

    posterior capsule lens brown-beige deposits
    SYMPTOMS

 and four patients had

    conjunctival and retinal tortuous vessels
    SYMPTOMS

. A

    complete ophthalmologic examination
    PARACLINICAL

 is important for prompt diagnosis, which is key to starting a

    multidisciplinary treatment
    MEDICATION

 and reducing morbi-mortality.

Fabry disease
Fabry disease
Fabry disease


A novel association between angiokeratoma corporis diffusum and acid sphingomyelinase deficiency.

Angiokeratoma corporis diffusum refers to symmetrical clusters of minute red papules in a "bathing trunk" distribution and is considered the cutaneous hallmark of Fabry disease. Acid sphingomyelinase deficiency is an autosomal recessive sphingolipidosis, which presents with massive hepatosplenomegaly, pulmonary infiltrates, and skeletal abnormalities. We present the unusual case of a 12-year-old girl with acid sphingomyelinase deficiency who developed characteristic lesions of angiokeratoma corporis diffusum.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 refers to

    symmetrical clusters of minute red papules in a "bathing trunk" distribution
    SYMPTOMS

 and is considered the cutaneous hallmark of

    Fabry disease
    DIAGNOSIS

.

    Acid sphingomyelinase deficiency
    BIOCHEMICAL

 is an

    autosomal recessive
    GENETICS

    sphingolipidosis
    DIAGNOSIS

, which presents with

    massive hepatosplenomegaly
    SYMPTOMS

,

    pulmonary infiltrates
    SYMPTOMS

, and

    skeletal abnormalities
    SYMPTOMS

. We present the unusual case of a

    12-year-old
    AGE

    girl
    GENDER

 with

    acid sphingomyelinase deficiency
    BIOCHEMICAL

 who developed

    characteristic lesions of angiokeratoma corporis diffusum
    SYMPTOMS

.

Acid sphingomyelinase deficiency
acid sphingomyelinase deficiency


Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C>T/p.Arg118Cys: A family study.

Fabry disease (FD) has an extensive phenotypic expression associated with GLA gene variants. The GLA gene variant c.352C>T/p.Arg118Cys was considered with uncertain pathogenicity because of the finding of high residual alpha-galactosidase A (α-Gal A) enzyme activity, the absence of Mendelian segregation with an FD phenotype with many individuals remaining asymptomatic at old ages and the lack of globotriaosylceramide (Gb3) deposits in tissues. Gb3 deposits are found in kidneys before the progression to overt microalbuminuria and decreased glomerular filtration.

We describe a family with c.352C>T/p.Arg118Cys variant and pathognomonic signs of FD renal damage in masculine children.

The proband died of end-stage renal failure and we analyzed GLA gene in his offspring and found the variant in all daughters and five of seven grandchildren. In patients who we measure plasma and urinary Gb3, α-Gal A enzyme activity, and plasma globotriaosylsphingosine (Lyso-Gb3), these were normal or almost normal. A kidney biopsy was performed in two boys and one girl with normal renal function and characteristic signs of FD as enlarged and vacuolated epithelial cells, myelin figures, myelin-like figures, lamellated structures in podocytes and endothelial cells, were found in boys. These boys received agalsidase beta 1 mg/kg IV infusion every other week to prevent further renal damage.

This is the first report that shows a link between FD renal Gb3 deposits and c.352C>T/p.Arg118Cys variant, supporting pathogenicity of a variant considered until now with uncertain pathogenicity.

    Fabry disease (FD)
    DIAGNOSIS

 has an extensive phenotypic expression associated with

    GLA gene variants
    GENETICS

. The

    GLA gene variant c.352C>T/p.Arg118Cys
    GENETICS

 was considered with uncertain pathogenicity because of the finding of

    high residual alpha-galactosidase A (α-Gal A) enzyme activity
    BIOCHEMICAL

, the

    absence of Mendelian segregation with an FD phenotype
    NEG_FINDINGS

 with many individuals

    remaining asymptomatic at old ages
    NEG_FINDINGS

 and the

    lack of globotriaosylceramide (Gb3) deposits in tissues
    NEG_FINDINGS

.

    Gb3 deposits are found in kidneys
    MICROSCOPIC

 before the progression to

    overt microalbuminuria
    BIOCHEMICAL

 and

    decreased glomerular filtration
    BIOCHEMICAL

.

We describe a

    family with c.352C>T/p.Arg118Cys variant
    FAMILY

 and

    pathognomonic signs of FD renal damage
    SYMPTOMS

 in

    masculine children
    AGE

.

The

    proband
    GENDER

    died
    SYMPTOMS

 of

    end-stage renal failure
    SYMPTOMS

 and we

    analyzed GLA gene in his offspring
    FAMILY

 and

    found the variant in all daughters and five of seven grandchildren
    FAMILY

. In patients who we measure

    plasma and urinary Gb3, α-Gal A enzyme activity
    BIOCHEMICAL

, and

    plasma globotriaosylsphingosine (Lyso-Gb3)
    BIOCHEMICAL

,

    these were normal or almost normal
    NEG_FINDINGS

. A

    kidney biopsy
    PARACLINICAL

 was performed in two

    boys
    GENDER

 and one

    girl
    GENDER

 with

    normal renal function
    NEG_FINDINGS

 and

    characteristic signs of FD
    MICROSCOPIC

 as

    enlarged and vacuolated epithelial cells, myelin figures, myelin-like figures, lamellated structures in podocytes and endothelial cells
    MICROSCOPIC

, were found in

    boys
    GENDER

. These

    boys
    GENDER

 received

    agalsidase beta 1 mg/kg IV infusion every other week
    MEDICATION

 to prevent further

    renal damage
    SYMPTOMS

.

This is the first report that shows a link between

    FD renal Gb3 deposits
    MICROSCOPIC

 and

    c.352C>T/p.Arg118Cys variant
    GENETICS

, supporting pathogenicity of a variant considered until now with uncertain pathogenicity.

GLA gene variants
GLA gene variant c.352C>T/p.Arg118Cys
c.352C>T/p.Arg118Cys variant

pathognomonic signs of FD renal damage
died
end-stage renal failure
renal damage


A case of female Fabry disease revealed by renal biopsy.

Fabry disease (FD) is an X-linked inherited glycosphingolipid metabolism disorder, therefore, heterozygous female FD patients display highly variable clinical symptoms, disease severity, and pathological findings. This makes it very challenging to diagnosing female patients with FD. A 69-year-old Japanese female was introduced to the nephrologist for the evaluation of proteinuria. A renal biopsy was performed. Although the light microscopic examinations revealed that most of the glomeruli showed minor glomerular abnormalities, however, vacuolation was apparently found in the tubular epithelial cells. Immunofluorescence staining for globotriaosylceramide was positively detected in some podocytes and distal tubular epithelial cells. In addition, myelin-like structure (zebra body) was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, biochemical and genetic analysis confirmed the diagnosis of female FD. Enzyme replacement therapy was performed in conjunction with renin-angiotensin aldosterone system inhibitors and beta-blockers. The patient's family members received the analysis, and the same DNA missense mutation was detected in the patient's grandson. The enzyme replacement therapy was introduced to the grandson. The present case showed that renal biopsy can contribute towards a correct diagnosis for FD. Particularly, in female FD patients, careful examination of pathological changes is essential, for example, vacuolation of any type of renal cells may be a clue for the diagnosis.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

    glycosphingolipid metabolism disorder
    DIAGNOSIS

, therefore,

    heterozygous
    GENETICS

    female
    GENDER

    FD
    DIAGNOSIS

 patients display highly variable clinical symptoms, disease severity, and pathological findings. This makes it very challenging to diagnosing

    female
    GENDER

 patients with

    FD
    DIAGNOSIS

. A

    69-year-old
    AGE

    Japanese
    ETHNICITY

    female
    GENDER

 was introduced to the

    nephrologist
    PARACLINICAL

 for the evaluation of

    proteinuria
    BIOCHEMICAL

. A

    renal biopsy
    PARACLINICAL

 was performed. Although the light microscopic examinations revealed that

    most of the glomeruli showed minor glomerular abnormalities
    NEG_FINDINGS

, however,

    vacuolation was apparently found in the tubular epithelial cells
    MICROSCOPIC

.

    Immunofluorescence staining for globotriaosylceramide was positively detected in some podocytes and distal tubular epithelial cells
    MICROSCOPIC

. In addition,

    myelin-like structure (zebra body) was detected
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. Pathological findings were most consistent with

    FD
    DIAGNOSIS

. Consequently,

    biochemical and genetic analysis
    PARACLINICAL

 confirmed the diagnosis of

    female
    GENDER

    FD
    DIAGNOSIS

.

    Enzyme replacement therapy was performed in conjunction with renin-angiotensin aldosterone system inhibitors and beta-blockers
    MEDICATION

. The patient's

    family members received the analysis
    FAMILY

, and the

    same DNA missense mutation was detected in the patient's grandson
    FAMILY

. The

    enzyme replacement therapy was introduced to the grandson
    MEDICATION

. The present case showed that

    renal biopsy
    PARACLINICAL

 can contribute towards a correct diagnosis for

    FD
    DIAGNOSIS

. Particularly, in

    female
    GENDER

    FD
    DIAGNOSIS

 patients, careful examination of

    pathological changes
    PARACLINICAL

 is essential, for example,

    vacuolation of any type of renal cells
    MICROSCOPIC

 may be a clue for the diagnosis.

Fabry disease (FD)
glycosphingolipid metabolism disorder
FD
FD
FD
FD
FD
FD