Left Ventricular Assist Device Support for Fabry Cardiomyopathy: A Case Series.

Patients with restrictive cardiomyopathy due to Fabry disease are often deemed ineligible for left ventricular assist device (LVAD) support due to the risk of suction events with a small LV cavity. We describe the first case series of LVAD support for Fabry disease. LVAD therapy can improve survival, quality of life, and provide clinical stability to start enzyme replacement therapy. Precautions at the time of surgery include rapid treatment of fever to avoid Fabry crises, involvement of a multidisciplinary team, and early initiation of rehabilitation. We describe LVAD support for both bridging and destination therapy.

Patients with

    restrictive cardiomyopathy
    DIAGNOSIS

 due to

    Fabry disease
    DIAGNOSIS

 are often deemed

    ineligible
    NEG_FINDINGS

 for

    left ventricular assist device (LVAD) support
    MEDICATION

 due to the risk of

    suction events with a small LV cavity
    SYMPTOMS

. We describe the first case series of

    LVAD support
    MEDICATION

 for

    Fabry disease
    DIAGNOSIS

.

    LVAD therapy
    MEDICATION

 can

    improve survival
    SYMPTOMS

,

    quality of life
    SYMPTOMS

, and provide

    clinical stability
    SYMPTOMS

 to

    start enzyme replacement therapy
    MEDICATION

. Precautions at the time of

    surgery
    MEDICATION

 include

    rapid treatment of fever
    MEDICATION

 to avoid

    Fabry crises
    SYMPTOMS

,

    involvement of a multidisciplinary team
    MEDICATION

, and

    early initiation of rehabilitation
    MEDICATION

. We describe

    LVAD support for both bridging and destination therapy
    MEDICATION

.

restrictive cardiomyopathy
Fabry disease
Fabry disease

suction events with a small LV cavity
improve survival
quality of life
clinical stability
Fabry crises


Diverse phenotypic expression associated with the same genetic variant in female heterozygote patients of Anderson-Fabry disease: a case series.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder resulting from a mutation of alpha-galactosidase A gene (GLA), causing deficiency in alpha-galactosidase activity. The enzyme deficit can lead to storage of globotriaosylceramide in various organs including heart. Studies suggest that vasospastic angina (VSA) is associated with AFD.

This clinical case series aimed to present two female patients with AFD, including progressive cardiac involvement: a 50-year-old woman (patient number 1) and a 39-year-old woman (patient number 2) who are siblings with a male AFD patient harbouring p. Arg342Glu missense variant in alpha-galactosidase A gene (GLA), who suffered VSA and subsequent ventricular fibrillation. Enzymatic tests and genetic analysis confirmed AFD in both female patients and histological tests revealed globotriaosylceramide deposits in their hearts. In patient number 1, a 12-lead electrocardiography and transthoracic echocardiography revealed cardiac hypertrophy. Coronary angiography revealed no organic coronary artery stenosis and vasospasms was induced by spasm provocation test. In patient number 2, no signs of cardiac hypertrophy were found, and coronary arteries had no organic stenosis with negative spasm provocation test. Both patients received enalapril therapy and enzyme replacement therapy (ERT).

Different phenotype of AFD was occurred even with the same genetic variant in female heterozygote patients. The duration of exposing accumulation of Gb3 might affect cardiac hypertrophy and vasospasms. Coronary angiography with acetylcholine provocation test should be considered in female AFD patient, especially in case with cardiac hypertrophy.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from a

    mutation of alpha-galactosidase A gene (GLA)
    GENETICS

, causing

    deficiency in alpha-galactosidase activity
    BIOCHEMICAL

. The

    enzyme deficit
    BIOCHEMICAL

 can lead to

    storage of globotriaosylceramide in various organs including heart
    MICROSCOPIC

. Studies suggest that

    vasospastic angina (VSA)
    SYMPTOMS

 is associated with

    AFD
    DIAGNOSIS

.

This clinical case series aimed to present two

    female
    GENDER

 patients with

    AFD
    DIAGNOSIS

, including

    progressive cardiac involvement
    SYMPTOMS

: a

    50-year-old
    AGE

    woman
    GENDER

 (patient number 1) and a

    39-year-old
    AGE

    woman
    GENDER

 (patient number 2) who are

    siblings with a male
    FAMILY

    AFD
    DIAGNOSIS

 patient harbouring

    p. Arg342Glu missense variant in alpha-galactosidase A gene (GLA)
    GENETICS

, who suffered

    VSA
    SYMPTOMS

 and subsequent

    ventricular fibrillation
    SYMPTOMS

.

    Enzymatic tests
    PARACLINICAL

 and

    genetic analysis
    PARACLINICAL

 confirmed

    AFD
    DIAGNOSIS

 in both

    female
    GENDER

 patients and

    histological tests
    PARACLINICAL

 revealed

    globotriaosylceramide deposits in their hearts
    MICROSCOPIC

. In patient number 1, a

    12-lead electrocardiography
    PARACLINICAL

 and

    transthoracic echocardiography
    PARACLINICAL

 revealed

    cardiac hypertrophy
    SYMPTOMS

.

    Coronary angiography
    PARACLINICAL

 revealed

    no organic coronary artery stenosis
    NEG_FINDINGS

 and

    vasospasms was induced by spasm provocation test
    SYMPTOMS

. In patient number 2,

    no signs of cardiac hypertrophy
    NEG_FINDINGS

    were found
    NEG_FINDINGS

, and

    coronary arteries had no organic stenosis
    NEG_FINDINGS

 with

    negative spasm provocation test
    NEG_FINDINGS

. Both patients received

    enalapril therapy
    MEDICATION

 and

    enzyme replacement therapy (ERT)
    MEDICATION

.

Different phenotype of

    AFD
    DIAGNOSIS

 was occurred even with the same

    genetic variant
    GENETICS

 in

    female
    GENDER

    heterozygote
    GENETICS

 patients. The duration of

    exposing accumulation of Gb3
    MICROSCOPIC

 might affect

    cardiac hypertrophy
    SYMPTOMS

 and

    vasospasms
    SYMPTOMS

.

    Coronary angiography
    PARACLINICAL

 with

    acetylcholine provocation test
    PARACLINICAL

 should be considered in

    female
    GENDER

    AFD
    DIAGNOSIS

 patient, especially in case with

    cardiac hypertrophy
    SYMPTOMS

.

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

enalapril therapy
enzyme replacement therapy (ERT)


Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.

Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.

We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.

RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.

    Cardiac involvement
    SYMPTOMS

 in

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 can lead to

    arrhythmia
    SYMPTOMS

, including

    ventricular tachycardia (VT)
    SYMPTOMS

. The literature on

    radiofrequency ablation (RFA)
    MEDICATION

 for the treatment of

    VT
    DIAGNOSIS

 in

    AFD disease
    DIAGNOSIS

 is limited.

We discuss

    RFA
    MEDICATION

 of

    drug-refractory VT electrical storm
    SYMPTOMS

 in three

    males
    GENDER

 with

    AFD
    DIAGNOSIS

. The first patient (

    53 years old
    AGE

) had

    extensive involvement of the inferolateral left ventricle (LV)
    SYMPTOMS

 demonstrated with

    cardiac magnetic resonance imaging (CMRI)
    PARACLINICAL

, with a

    left ventricular ejection fraction (LVEF) of 35%
    SYMPTOMS

. Two

    VT ablation procedures
    MEDICATION

 were performed. At the first procedure,

    the inferobasal endocardial LV was ablated
    MEDICATION

. Furthermore,

    VT
    SYMPTOMS

 prompted a second

    ablation, where epicardial and endocardial sites were ablated
    MEDICATION

. The

    acute arrhythmia burden was controlled
    SYMPTOMS

 but

    he
    GENDER

    died
    SYMPTOMS

 4 months later

    despite appropriate implantable cardioverter-defibrillator therapies for VT
    NEG_FINDINGS

. The second patient (

    67 years old
    AGE

) had

    full-thickness inferolateral involvement
    SYMPTOMS

 demonstrated with

    CMRI
    PARACLINICAL

 and

    LVEF of 45%
    SYMPTOMS

.

    RFA of several endocardial left ventricular sites
    MEDICATION

 was performed. Over a 3-year follow-up, only

    brief non-sustained VT
    SYMPTOMS

 was identified, but

    he
    GENDER

 subsequently

    died of cardiac failure
    SYMPTOMS

. Our third patient (

    69 years old
    AGE

), had an

    LVEF of 35%
    SYMPTOMS

.

    He
    GENDER

 had

    RFA of endocardial left ventricular apical disease
    MEDICATION

, but

    died
    SYMPTOMS

 3 weeks later of

    cardiac failure
    SYMPTOMS

.

    RFA
    MEDICATION

 of

    drug-refractory VT
    NEG_FINDINGS

 in

    AFD
    DIAGNOSIS

 is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value.

    VT storm
    SYMPTOMS

 in the context of

    AFD
    DIAGNOSIS

 may be a marker of

    end-stage disease
    DIAGNOSIS

.

Anderson-Fabry disease (AFD)
VT
AFD disease
AFD
AFD
AFD
end-stage disease


Riga-Fede disease associated with Fabry's disease and Niemann-Pick C disease in a boy with microcephaly: A case report.

A 16-month-old Saudi boy has microcephaly and three rare genetic diseases [Riga Fede disease (RFD), Niemann-Pick C disease, and Fabry disease. In the published literature, there is no reported case with these four associations, especially RFD affection of the dorsal surface of the tongue. It is also a clear demonstration of how the proper diagnosis and treatment could provide a better quality of life, ease pain, resources, and money saving. The difficult RDF ulcer was resolved by a conservative treatment, which was accomplished by smoothing sharp edges and removing mamelons of the lower primary incisors using a diamond bur in a high-speed dental handpiece. The aim of this report is to present and discuss steps of diagnosis and the effect of misdiagnosis on the management of a very rare case.

A

    16-month-old
    AGE

    Saudi
    ETHNICITY

    boy
    GENDER

 has

    microcephaly
    SYMPTOMS

 and three

    rare genetic diseases
    GENETICS

 [

    Riga Fede disease (RFD)
    DIAGNOSIS

,

    Niemann-Pick C disease
    DIAGNOSIS

, and

    Fabry disease
    DIAGNOSIS

. In the published literature, there is no reported case with these four associations, especially

    RFD affection of the dorsal surface of the tongue
    DIAGNOSIS

. It is also a clear demonstration of how the proper diagnosis and treatment could provide a better quality of life, ease pain, resources, and money saving. The

    difficult RDF ulcer
    SYMPTOMS

 was resolved by a

    conservative treatment
    MEDICATION

, which was accomplished by

    smoothing sharp edges and removing mamelons of the lower primary incisors using a diamond bur in a high-speed dental handpiece
    MEDICATION

. The aim of this report is to present and discuss steps of diagnosis and the effect of misdiagnosis on the management of a very rare case.


"Protenuria in SLE: Is it always lupus?"

Proteinuria is one of the most typical manifestations of kidney involvement in Systemic Lupus Erythematosus (SLE). We report the case of a 23-year-old woman with a 6-year-long history of SLE presenting with proteinuria after a three-year remission on hydroxychloroquine. Kidney histological examination showed alterations inconsistent with lupus nephritis and suggestive of hydroxychloroquine toxicity or Fabry disease. The latter was confirmed by genetic assay.

    Proteinuria
    BIOCHEMICAL

 is one of the most typical manifestations of

    kidney involvement
    SYMPTOMS

 in

    Systemic Lupus Erythematosus (SLE)
    DIAGNOSIS

. We report the case of a

    23-year-old
    AGE

    woman
    GENDER

 with a

    6-year-long
    AGE

 history of

    SLE
    DIAGNOSIS

 presenting with

    proteinuria
    BIOCHEMICAL

 after a

    three-year remission on hydroxychloroquine
    MEDICATION

.

    Kidney histological examination
    PARACLINICAL

 showed

    alterations inconsistent with lupus nephritis
    MICROSCOPIC

 and suggestive of

    hydroxychloroquine toxicity
    DIAGNOSIS

 or

    Fabry disease
    DIAGNOSIS

. The latter was confirmed by

    genetic assay
    PARACLINICAL

.

Systemic Lupus Erythematosus (SLE)
SLE
hydroxychloroquine toxicity
Fabry disease


Case Report: A Spinal Ischemic Lesion in a 24-Year-Old Patient With Fabry Disease.

While cerebral lesions are common in Fabry disease (FD), spinal lesions have not been described, and their presence was suggested to be indicative of multiple sclerosis. Here, we present a FD patient with histopathological confirmed spinal ischemic stroke.

A patient with genetically and biochemically diagnosed FD and characteristic manifestations (acroparesthesia, angiokeratomas, hypohidrosis, microalbuminuria, myocardial hypertrophy) presented with paraplegia, loss of all sensory modalities below Th9, and loss of bowel and bladder function. While cranial MRI was inconspicuous, spinal MRI showed a T2 hyperintense, non-contrast-enhancing lesion of the thoracic spinal cord. Lumbar puncture revealed mild pleocytosis, increased total protein and lactate levels, decreased glucose ratio, and negative oligoclonal bands. Rheumatic, neoplastic, and infectious disorders were excluded. The patient received intravenous and intrathecal methylprednisolone, plasmapheresis, intravenous immunoglobulins, and cyclophosphamide without clinical improvement. A biopsy of the thoracic lesion was performed. A histopathological examination revealed necrotic tissue consistent with spinal cord ischemia. Diagnostic work-up for stroke etiology clarification was not conspicuous. Two years onward, the patient suffered from a pontine infarction and a transient ischemic attack.

The current case highlights the possible occurrence of spinal ischemic lesions in FD. Thus, the diagnosis of FD should not be prematurely discarded in the presence of spinal lesions.

While

    cerebral lesions
    SYMPTOMS

 are common in

    Fabry disease (FD)
    DIAGNOSIS

,

    spinal lesions
    SYMPTOMS

 have not been described, and their presence was suggested to be indicative of

    multiple sclerosis
    DIAGNOSIS

. Here, we present a

    FD
    DIAGNOSIS

 patient with

    histopathological
    PARACLINICAL

 confirmed

    spinal ischemic stroke
    SYMPTOMS

.

A patient with genetically and biochemically diagnosed

    FD
    DIAGNOSIS

 and characteristic manifestations (

    acroparesthesia
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

,

    microalbuminuria
    BIOCHEMICAL

,

    myocardial hypertrophy
    SYMPTOMS

) presented with

    paraplegia
    SYMPTOMS

,

    loss of all sensory modalities below Th9
    SYMPTOMS

, and

    loss of bowel and bladder function
    SYMPTOMS

. While

    cranial MRI was inconspicuous
    NEG_FINDINGS

,

    spinal MRI
    PARACLINICAL

 showed a

    T2 hyperintense, non-contrast-enhancing lesion of the thoracic spinal cord
    SYMPTOMS

.

    Lumbar puncture
    PARACLINICAL

 revealed

    mild pleocytosis
    BIOCHEMICAL

,

    increased total protein and lactate levels
    BIOCHEMICAL

,

    decreased glucose ratio
    BIOCHEMICAL

, and

    negative oligoclonal bands
    NEG_FINDINGS

.

    Rheumatic, neoplastic, and infectious disorders were excluded
    NEG_FINDINGS

. The patient received

    intravenous and intrathecal methylprednisolone, plasmapheresis, intravenous immunoglobulins
    MEDICATION

, and

    cyclophosphamide
    MEDICATION

    without clinical improvement
    NEG_FINDINGS

. A

    biopsy of the thoracic lesion
    PARACLINICAL

 was performed. A

    histopathological examination
    PARACLINICAL

 revealed

    necrotic tissue consistent with spinal cord ischemia
    SYMPTOMS

.

    Diagnostic work-up for stroke etiology clarification was not conspicuous
    PARACLINICAL

. Two years onward, the patient suffered from a

    pontine infarction
    SYMPTOMS

 and a

    transient ischemic attack
    SYMPTOMS

.

The current case highlights the possible occurrence of

    spinal ischemic lesions
    SYMPTOMS

 in

    FD
    DIAGNOSIS

. Thus, the diagnosis of

    FD
    DIAGNOSIS

 should not be

    prematurely discarded
    NEG_FINDINGS

 in the presence of

    spinal lesions
    SYMPTOMS

.

Fabry disease (FD)
multiple sclerosis
FD
FD
FD
FD


When Frequent (Pandemic) Occurs in a Non-Frequent Disease: COVID-19 and Fabry Disease: Report of Two Cases.

Fabry disease (FD), like COVID-19, can affect multiple organs, including the lungs. Patients with FD are expected to develop severe COVID-19, due to involvement of not only the lungs but also the kidneys and the presence of other comorbidities. We present 2 cases of mild COVID-19 in patients with FD who were infected with the COVID-19 virus. Although it is unknown whether the X chromosome mutation in patients with FD affects the development of severe COVID-19, it is suggested that it may play a protective role against COVID-19 infection. Based on these cases, we suggest that FD is not a risk factor for severe COVID-19.

    Fabry disease (FD)
    DIAGNOSIS

, like

    COVID-19
    DIAGNOSIS

, can

    affect multiple organs, including the lungs
    SYMPTOMS

. Patients with

    FD
    DIAGNOSIS

 are expected to develop

    severe COVID-19
    DIAGNOSIS

, due to

    involvement of not only the lungs but also the kidneys
    SYMPTOMS

 and the presence of other comorbidities. We present 2 cases of

    mild COVID-19
    DIAGNOSIS

 in patients with

    FD
    DIAGNOSIS

 who were infected with the

    COVID-19 virus
    DIAGNOSIS

. Although it is unknown whether the

    X chromosome mutation
    GENETICS

 in patients with

    FD
    DIAGNOSIS

 affects the development of

    severe COVID-19
    DIAGNOSIS

, it is suggested that it may play a protective role against

    COVID-19 infection
    DIAGNOSIS

. Based on these cases, we suggest that

    FD
    DIAGNOSIS

 is not a risk factor for

    severe COVID-19
    DIAGNOSIS

.

Fabry disease (FD)
COVID-19
FD
severe COVID-19
mild COVID-19
FD
COVID-19 virus
FD
severe COVID-19
COVID-19 infection
FD
severe COVID-19


Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations.

Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel GLA variant located in the 5' splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    glycosphingolipidosis
    DIAGNOSIS

 caused by

    mutations in GLA, a gene
    GENETICS

 responsible for encoding

    α-galactosidase A
    BIOCHEMICAL

, an enzyme required for

    degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body
    MICROSCOPIC

.

    FD
    DIAGNOSIS

 patients present a broad spectrum of clinical phenotype and many

    symptoms are shared with other diseases
    SYMPTOMS

, making diagnosis challenging. Here we describe a

    novel GLA variant located in the 5' splice site of the intron 3,
    GENETICS

 in four members of a

    family with neuropsychiatric symptoms
    FAMILY

.

    Analysis of the RNA
    PARACLINICAL

 showed the

    variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts
    GENETICS

. The functional characterization showed

    absence of enzymatic activity in cells expressing both transcripts
    BIOCHEMICAL

, confirming their pathogenicity. The family presents

    mild signs of FD
    SYMPTOMS

, as

    angiokeratoma
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

,

    acroparesthesia
    SYMPTOMS

,

    tinnitus
    SYMPTOMS

,

    vertigo
    SYMPTOMS

, as well as

    accumulation of plasma lyso-Gb3 and urinary Gb3
    BIOCHEMICAL

. Interestingly, the

    man
    GENDER

 and two

    women
    GENDER

 present

    psychiatric symptoms
    SYMPTOMS

, as

    depression
    DIAGNOSIS

 or

    schizophrenia
    DIAGNOSIS

. Although

    psychiatric illnesses
    SYMPTOMS

, especially

    depression
    DIAGNOSIS

, are frequently reported in patients with

    FD
    DIAGNOSIS

 and studies have shown that the

    hippocampus is an affected brain structure
    SYMPTOMS

 in these patients, it is not clear whether the

    Gb3 accumulation in the brain
    MICROSCOPIC

 is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the

    accumulation of Gb3
    MICROSCOPIC

 could produce

    neuronal alterations
    SYMPTOMS

 leading to

    psychiatric symptoms
    SYMPTOMS

.

Fabry disease (FD)
glycosphingolipidosis
FD
depression
schizophrenia
depression
FD


Different Phenotypes of Anderson-Fabry Disease Identified with Cardiac Magnetic Resonance Imaging in a Family with the Same Late-Onset Mutation.

BACKGROUND Cardiac magnetic resonance imaging (CMR) is the only noninvasive test capable of differentiating between hypertrophic cardiomyopathy (HCM) and late-onset Anderson-Fabry disease (AFD). The purpose of this report is to show how CMR led to diagnosis of AFD in 3 family members, 1 of whom previously was misdiagnosed with HCM, and how late-onset AFD can present with different cardiac phenotypes, even in a family with the same pathogenic mutation. CASE REPORT A 60-year-old man was referred because of evidence of left ventricular hypertrophy (LVH) on an electrocardiogram (ECG) that was performed to screen for cardiomyopathy. One of his siblings previously had been diagnosed with HCM and atrial fibrillation. The patient's ECG and echocardiographic findings were suspicious for HCM. CMR showed severe symmetrical LVH but tissue characterization sequences were highly suggestive of AFD cardiomyopathy. Enzymatic and genetic testing confirmed the diagnosis of late-onset AFD (presence of the GLA p.F113.L mutation). The brother of the index patient then was re-evaluated and also diagnosed with late-onset AFD. He was found to have the same pathogenic mutation but with a presentation of asymmetrical septal LVH. The daughter of the index patient was positive for the same mutation but did not have LVH. CONCLUSIONS The fact that patients with late-onset AFD can present with different LVH and fibrosis patterns, even in the presence of the same pathogenic mutation, underscores the importance of including AFD in the differential diagnosis of HCM. CMR is fundamental for differentiating between those 2 entities and defining the pathological phase of AFD. A correct diagnosis can have a substantial impact on patient management, and more so on thier families.

BACKGROUND

    Cardiac magnetic resonance imaging (CMR)
    PARACLINICAL

 is the only noninvasive test capable of differentiating between

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 and

    late-onset Anderson-Fabry disease (AFD)
    DIAGNOSIS

. The purpose of this report is to show how

    CMR
    PARACLINICAL

 led to diagnosis of

    AFD
    DIAGNOSIS

 in 3 family members, 1 of whom previously was

    misdiagnosed with HCM
    NEG_FINDINGS

, and how

    late-onset AFD
    DIAGNOSIS

 can present with different

    cardiac phenotypes
    SYMPTOMS

, even in a

    family with the same pathogenic mutation
    FAMILY

. CASE REPORT A

    60-year-old
    AGE

    man
    GENDER

 was referred because of evidence of

    left ventricular hypertrophy (LVH)
    SYMPTOMS

 on an

    electrocardiogram (ECG)
    PARACLINICAL

 that was performed to screen for

    cardiomyopathy
    DIAGNOSIS

.

    One of his siblings previously had been diagnosed with HCM and atrial fibrillation
    FAMILY

. The patient's

    ECG and echocardiographic findings
    SYMPTOMS

 were suspicious for

    HCM
    SYMPTOMS

.

    CMR
    PARACLINICAL

 showed

    severe symmetrical LVH
    SYMPTOMS

 but

    tissue characterization sequences
    PARACLINICAL

 were highly suggestive of

    AFD cardiomyopathy
    DIAGNOSIS

.

    Enzymatic and genetic testing
    PARACLINICAL

 confirmed the diagnosis of

    late-onset AFD
    DIAGNOSIS

 (

    presence of the GLA p.F113.L mutation)
    GENETICS

. The

    brother
    GENDER

 of the index patient then was re-evaluated and also diagnosed with

    late-onset AFD
    DIAGNOSIS

.

    He
    GENDER

 was found

    to have the same pathogenic mutation
    FAMILY

 but with a presentation of

    asymmetrical septal LVH
    SYMPTOMS

.

    The daughter of the index patient was positive for the same mutation but did not have LVH
    FAMILY

. CONCLUSIONS The fact that patients with

    late-onset AFD
    DIAGNOSIS

 can present with different

    LVH and fibrosis patterns
    SYMPTOMS

, even in the presence of the same pathogenic mutation, underscores the importance of including

    AFD
    DIAGNOSIS

 in the

    differential diagnosis
    PARACLINICAL

 of

    HCM
    DIAGNOSIS

.

    CMR
    PARACLINICAL

 is fundamental for differentiating between those 2 entities and defining the pathological phase of

    AFD
    DIAGNOSIS

. A correct diagnosis can have a substantial impact on patient management, and more so on thier families.

hypertrophic cardiomyopathy (HCM)
late-onset Anderson-Fabry disease (AFD)
AFD
late-onset AFD
cardiomyopathy
AFD cardiomyopathy
late-onset AFD
late-onset AFD
late-onset AFD
AFD
HCM
AFD

cardiac phenotypes
left ventricular hypertrophy (LVH)
ECG and echocardiographic findings
HCM
severe symmetrical LVH
asymmetrical septal LVH
LVH and fibrosis patterns


Fabry Disease in Young Ischemic Stroke Patients in Northern Israel.

The prevalence of Fabry Disease (FD) with cerebrovascular complications varies in different populations. The aim of this study was to estimate the presence of FD among young stroke patients in northern Israel.

We performed a retro-/prospective search for FD in young patients (aged ≤50 years old) admitted to the Department of Neurology due to acute ischemic stroke of any etiology.

Overall, 114 patients were examined for FD. Mean age of patients was 40±7.44 years. There were 75 (65.78%) males. FD was found in 4 (3.5%) patients. None of the FD patients had a cryptogenic stroke.

The results of our study call for a search of FD in young stroke patients of any etiology, and not only among cryptogenic ones.

The prevalence of

    Fabry Disease (FD)
    DIAGNOSIS

 with

    cerebrovascular complications
    SYMPTOMS

 varies in different populations. The aim of this study was to estimate the presence of

    FD
    DIAGNOSIS

 among

    young
    AGE

    stroke
    SYMPTOMS

 patients in

    northern Israel
    ETHNICITY

.

We performed a retro-/prospective search for

    FD
    DIAGNOSIS

 in

    young
    AGE

 patients (

    aged ≤50 years old
    AGE

) admitted to the Department of

    Neurology
    PARACLINICAL

 due to

    acute ischemic stroke of any etiology
    SYMPTOMS

.

Overall, 114 patients were examined for

    FD
    DIAGNOSIS

.

    Mean age of patients was 40±7.44 years
    AGE

. There were 75 (65.78%)

    males
    GENDER

.

    FD
    DIAGNOSIS

 was found in 4 (3.5%) patients.

    None
    NEG_FINDINGS

 of the

    FD
    DIAGNOSIS

 patients had a

    cryptogenic stroke
    NEG_FINDINGS

.

The results of our study call for a search of

    FD
    DIAGNOSIS

 in

    young
    AGE

    stroke
    DIAGNOSIS

 patients of any etiology, and not only among

    cryptogenic
    DIAGNOSIS

 ones.

Fabry Disease (FD)
FD
FD
FD
FD
FD
FD
stroke
cryptogenic

cerebrovascular complications
stroke
acute ischemic stroke of any etiology


A late-onset male Fabry disease patient with somatic mosaicism of a classical GLA mutation: a case report.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA). Male patients of FD develop early sign and symptoms in childhood or adolescence. However, "de novo somatic mosaicism" is rare and might be developed a relatively mild phenotype despite carrying a classic type. A 34-year-old male patient visited with foamy urine. Renal biopsy findings were consistent with FD. Leukocyte α-galactosidase activity was markedly reduced at 5.3 nmol/hr/mg (normal range, 25-126). Sequence analysis of the patient's GLA gene identified mosaicism for the mutation GLA[NM_000169.2] c.820=/G>C. This mutation results in a substitution of the amino acid in position 274 from glycine to arginine. However, no family members showed FD-related symptoms, and the daughter of the patient was also tested for paternity and was identified as a real biological daughter, but DNA sequence analysis for FD showed no mutations. Based on these results, we diagnosed the patients as de novo mutation with somatic mosaicism. Next generation sequencing turned out that 58% of the readings had the mutated allele in buccal cells, 84% in blood, and 85% in urine, when 100% should be expected in a hemizygous affected male confirming the presence of somatic mosaicisms. The patient has been on treatment for enzyme replacement therapy (agalsidase-β, 1.0 mg/kg biweekly) for past 9 years and has maintained normal renal function (serum creatinine 1.0 mg/dL) with mild albuminuria (123 mg/g Cr). Therefore, this case suggests somatic mosaicism is one of important phenotype modifiers.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

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

.

    Male
    GENDER

 patients of

    FD
    DIAGNOSIS

 develop

    early sign and symptoms
    SYMPTOMS

    in childhood or adolescence
    AGE

. However, "

    de novo somatic mosaicism
    GENETICS

" is rare and might be developed a relatively mild phenotype despite carrying a classic type. A

    34-year-old
    AGE

    male
    GENDER

 patient visited with

    foamy urine
    MICROSCOPIC

.

    Renal biopsy
    PARACLINICAL

 findings were consistent with

    FD
    DIAGNOSIS

.

    Leukocyte α-galactosidase activity was markedly reduced at 5.3 nmol/hr/mg (normal range, 25-126)
    BIOCHEMICAL

.

    Sequence analysis of the patient's GLA gene
    PARACLINICAL

 identified mosaicism for the mutation GLA[NM_000169.2] c.820=/G>C. This

    mutation results in a substitution of the amino acid in position 274 from glycine to arginine
    GENETICS

. However,

    no family members showed FD-related symptoms
    NEG_FINDINGS

, and

    the daughter of the patient was also tested for paternity and was identified as a real biological daughter
    FAMILY

, but

    DNA sequence analysis for FD showed no mutations
    NEG_FINDINGS

. Based on these results, we diagnosed the patients as

    de novo mutation with somatic mosaicism
    GENETICS

.

    Next generation sequencing
    PARACLINICAL

 turned out that

    58% of the readings had the mutated allele in buccal cells, 84% in blood, and 85% in urine
    GENETICS

, when 100% should be expected in a

    hemizygous affected male
    GENETICS

 confirming the presence of

    somatic mosaicisms
    GENETICS

. The patient has been

    on treatment for enzyme replacement therapy (agalsidase-β, 1.0 mg/kg biweekly) for past 9 years
    MEDICATION

 and has

    maintained normal renal function (serum creatinine 1.0 mg/dL)
    NEG_FINDINGS

 with

    mild albuminuria (123 mg/g Cr)
    BIOCHEMICAL

. Therefore, this case suggests

    somatic mosaicism
    GENETICS

 is one of important phenotype modifiers.

Fabry disease (FD)
lysosomal storage disorder
FD
FD


Previously Unidentified Gene Variation Associated with Fabry Disease: The Impact on One Family.

Fabry disease is an X-linked lysosomal storage genetic disorder associated with over 1000 mutations in the alpha-galactosidase-A gene region. We report here a 69-year-old male who underwent a kidney biopsy to evaluate progressive renal failure. He was found to have zebra bodies in visceral epithelial cells on biopsy, with electron microscopy showing inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease. An alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50-150 nm/hr/mg). Genetic studies revealed a missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H) that had not been previously associated with Fabry disease. The same variant was detected in two additional family members. The pathologic findings, clinical features, and low alpha-galactosidase level suggest that the c.682 A > C variant is associated with Fabry disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage genetic disorder
    DIAGNOSIS

 associated with over

    1000 mutations in the alpha-galactosidase-A gene region
    GENETICS

. We report here a

    69-year-old
    AGE

    male
    GENDER

 who underwent a

    kidney biopsy
    PARACLINICAL

 to evaluate

    progressive renal failure
    SYMPTOMS

.

    He
    GENDER

 was found to have

    zebra bodies in visceral epithelial cells
    MICROSCOPIC

 on

    biopsy
    PARACLINICAL

, with

    electron microscopy
    PARACLINICAL

 showing

    inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease
    MICROSCOPIC

. An

    alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50-150 nm/hr/mg)
    BIOCHEMICAL

.

    Genetic studies
    PARACLINICAL

 revealed a

    missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H)
    GENETICS

 that had not been previously associated with

    Fabry disease
    DIAGNOSIS

. The same variant was detected in two additional family members. The pathologic findings, clinical features, and

    low alpha-galactosidase level
    BIOCHEMICAL

 suggest that the

    c.682 A > C variant
    GENETICS

 is associated with

    Fabry disease
    DIAGNOSIS

.

Fabry disease
lysosomal storage genetic disorder
Fabry disease
Fabry disease


Fabry disease with early-onset ventricular dilation: A case report.

The most common cardiac involvement of Fabry disease (FD) is left ventricular hypertrophy (LVH), which usually occurs in male patients over the age of 30. In rare cases, it can progress to ventricular dilation in the late stage of the disease.

A 16-year-old boy presenting with recurrent extremity pain and chest distress was admitted to our hospital. Imaging examinations revealed ventricular dilation.

α-Galactosidase A enzyme assay and GLA gene sequencing confirmed the diagnosis of FD and revealed a novel mutation c.76_77insT.

The patient was treated using metoprolol (23.75 mg qd) and angiotensin-converting enzyme inhibitor (fosinopril sodium 5 mg qd). He refused enzyme replacement therapy for financial reasons.

The echocardiography, electrocardiography, renal function, and routine blood and urine tests performed 20 months after the patients discharge from hospital showed no significant changes. The patient reported a slow and gradual decrease in the frequency and degree of pain and chest distress, starting approximately 24 months after discharge.

Cardiac involvement of FD can progress rapidly in some cases. Screening for FD should be considered in patients with unexplained ventricular dilation, especially in those with a history of typical FD manifestations.

The most common

    cardiac involvement
    SYMPTOMS

 of

    Fabry disease (FD)
    DIAGNOSIS

 is

    left ventricular hypertrophy (LVH)
    SYMPTOMS

, which usually occurs in

    male
    GENDER

 patients

    over the age of 30
    AGE

. In rare cases, it can progress to

    ventricular dilation
    SYMPTOMS

 in the late stage of the disease.

A

    16-year-old
    AGE

    boy
    GENDER

 presenting with

    recurrent extremity pain
    SYMPTOMS

 and

    chest distress
    SYMPTOMS

 was admitted to our hospital.

    Imaging examinations
    PARACLINICAL

 revealed

    ventricular dilation
    SYMPTOMS

.

    α-Galactosidase A enzyme assay
    PARACLINICAL

 and

    GLA gene sequencing
    PARACLINICAL

 confirmed the diagnosis of

    FD
    DIAGNOSIS

 and revealed a novel mutation c.76_77insT.

The patient was

    treated using metoprolol (23.75 mg qd) and angiotensin-converting enzyme inhibitor (fosinopril sodium 5 mg qd)
    MEDICATION

.

    He
    GENDER

    refused enzyme replacement therapy for financial reasons
    NEG_FINDINGS

.

The

    echocardiography
    PARACLINICAL

,

    electrocardiography, renal function
    PARACLINICAL

, and

    routine blood and urine tests
    PARACLINICAL

 performed 20 months after the patients discharge from hospital showed

    no significant changes
    NEG_FINDINGS

. The patient reported a

    slow and gradual decrease in the frequency and degree of pain and chest distress
    SYMPTOMS

, starting approximately 24 months after discharge.

    Cardiac involvement
    SYMPTOMS

 of

    FD
    DIAGNOSIS

 can progress rapidly in some cases. Screening for

    FD
    DIAGNOSIS

 should be considered in patients with

    unexplained ventricular dilation
    SYMPTOMS

, especially in those with a

    history of typical FD manifestations
    SYMPTOMS

.


Sudden onset of nephrotic syndrome in an asymptomatic Fabry patient: a case report.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the mutation of the GLA gene, encoding the α-galactosidase, which is responsible for the catabolism of neutral glycosphingolipids. Microalbuminuria or low-grade proteinuria, and continuously progressive renal failure are common manifestations in FD males. However, sudden onset of nephrotic syndrome in FD, is rarely reported.

A 32-year-old Chinese man was admitted to our hospital because of sudden onset of generalized edema due to nephrotic syndrome. He denied hypohidrosis, nocturia, and any history of episodic hand or foot pain. A few scattered angiokeratoma can be found on the low back skin on examination. Except for the similar locating pattern of angiokeratoma, no evident abnormality was found in the laboratory work up and physical examination of his younger brother. The patient was diagnosed with FD companying with minimal change disease by renal biopsy. Genetic analysis on our patient and his sibling revealed a nonsense GLA gene variant (c.707G > A, p.Trp236*), which has been previously reported in FD. Immunotherapy alone (steroids and tacrolimus), but without enzyme replacement therapy, much improved the massive proteinuria. Follow up to date, his 24-h urine protein is stable at about 0.5 g, and renal function keeps normal.

Sudden onset of nephrotic syndrome, although rare, may occur in FD, even as the primary renal manifestation, but this usually suggests additional renal disease. Immunosuppressive treatment should be considered in such FD patient companying with nephrotic syndrome.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by the

    mutation of the GLA gene, encoding the α-galactosidase
    GENETICS

, which is responsible for the

    catabolism of neutral glycosphingolipids
    MICROSCOPIC

.

    Microalbuminuria
    BIOCHEMICAL

 or

    low-grade proteinuria
    BIOCHEMICAL

, and

    continuously progressive renal failure
    SYMPTOMS

 are common manifestations in

    FD
    DIAGNOSIS

    males
    GENDER

. However,

    sudden onset
    SYMPTOMS

 of

    nephrotic syndrome
    DIAGNOSIS

 in

    FD
    DIAGNOSIS

, is rarely reported.

A

    32-year-old
    AGE

    Chinese
    ETHNICITY

    man
    GENDER

 was admitted to our hospital because of

    sudden onset of generalized edema
    SYMPTOMS

 due to

    nephrotic syndrome
    DIAGNOSIS

.

    He
    GENDER

    denied hypohidrosis
    NEG_FINDINGS

,

    nocturia
    NEG_FINDINGS

, and

    any history of episodic hand or foot pain
    NEG_FINDINGS

. A few

    scattered angiokeratoma can be found on the low back skin
    SYMPTOMS

 on examination. Except for the

    similar locating pattern of angiokeratoma
    SYMPTOMS

,

    no evident abnormality was found in the laboratory work up and physical examination of his younger brother
    NEG_FINDINGS

. The patient was diagnosed with

    FD companying with minimal change disease
    DIAGNOSIS

 by

    renal biopsy
    PARACLINICAL

.

    Genetic analysis
    PARACLINICAL

 on our patient and his sibling revealed a

    nonsense GLA gene variant (c.707G > A, p.Trp236*)
    GENETICS

, which has been previously reported in

    FD
    DIAGNOSIS

.

    Immunotherapy alone (steroids and tacrolimus)
    MEDICATION

, but

    without enzyme replacement therapy
    NEG_FINDINGS

, much

    improved the massive proteinuria
    BIOCHEMICAL

. Follow up to date, his

    24-h urine protein is stable at about 0.5 g
    BIOCHEMICAL

, and

    renal function keeps normal
    NEG_FINDINGS

.

    Sudden onset of nephrotic syndrome
    SYMPTOMS

, although rare, may occur in

    FD
    DIAGNOSIS

, even as the primary renal manifestation, but this usually suggests

    additional renal disease
    DIAGNOSIS

.

    Immunosuppressive treatment
    MEDICATION

 should be considered in such

    FD
    DIAGNOSIS

 patient companying with

    nephrotic syndrome
    DIAGNOSIS

.


A classic variant of Fabry disease in a family with the M296I late-onset variant.

Fabry disease is an X-linked recessive disease of glycosphingolipid metabolism caused by deficiency or reduced activity of α-galactosidase A. Fabry disease phenotypes are known to consist of a classic variant and a late-onset variant. In patients with Fabry disease, the phenotype is generally considered to be defined (at least partially) by the genotype. However, patients with the classic variant have been encountered in families with mutations that are expected to produce the late-onset variant. Here, we describe a 4-year-old boy with a classic variant of Fabry disease in a family with the M296I late-onset variant. The patient's grandfather, mother, and aunt experienced late-onset disease, characteristic of the M296I variant. Conversely, the patient experienced typical disease symptoms in childhood. He had symptoms of hypohidrosis and associated heat accumulation. He cried at night due to the occurrence of severe acroparaesthesia. This symptom became more pronounced in warmer climates. Although the patient's family had a late-onset variant mutation of Fabry disease, we determined that the patient's symptoms were similar to those of classic Fabry disease. Therefore, the patient began enzyme replacement therapy, which alleviated his symptoms. Notably, enzyme replacement therapy led to rapid improvement of the patient's subjective symptoms. Thus, we presumed that the patient's symptoms supported a diagnosis of classic Fabry disease. These findings suggest that childhood symptoms may occur in patients with Fabry disease, even in families with late-onset variant mutations. The genotype-phenotype correlation in Fabry disease remains controversial.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive disease of glycosphingolipid metabolism
    GENETICS

 caused by deficiency or reduced activity of α-galactosidase A.

    Fabry disease
    DIAGNOSIS

 phenotypes are known to consist of a classic variant and a

    late-onset variant
    DIAGNOSIS

. In patients with

    Fabry disease
    DIAGNOSIS

, the phenotype is generally considered to be defined (at least partially) by the genotype. However, patients with the classic variant have been encountered in families with

    mutations that are expected to produce the late-onset variant
    GENETICS

. Here, we describe a

    4-year-old
    AGE

    boy
    GENDER

 with a

    classic variant of Fabry disease
    DIAGNOSIS

 in a

    family with the M296I late-onset variant
    FAMILY

. The

    patient's grandfather, mother, and aunt experienced late-onset disease, characteristic of the M296I variant
    FAMILY

. Conversely, the patient experienced

    typical disease symptoms
    SYMPTOMS

 in

    childhood
    AGE

.

    He
    GENDER

 had symptoms of

    hypohidrosis
    SYMPTOMS

 and

    associated heat accumulation
    SYMPTOMS

.

    He
    GENDER

    cried at night
    SYMPTOMS

 due to the occurrence of

    severe acroparaesthesia
    SYMPTOMS

. This symptom became more pronounced in warmer climates.

    Although the patient's family had a late-onset variant mutation of Fabry disease
    FAMILY

, we determined that the patient's

    symptoms were similar to those of classic Fabry disease
    SYMPTOMS

. Therefore, the patient began

    enzyme replacement therapy
    MEDICATION

, which

    alleviated his symptoms
    SYMPTOMS

. Notably,

    enzyme replacement therapy
    MEDICATION

 led to

    rapid improvement of the patient's subjective symptoms
    SYMPTOMS

. Thus, we presumed that the patient's symptoms supported a diagnosis of

    classic Fabry disease
    DIAGNOSIS

. These findings suggest that

    childhood symptoms
    SYMPTOMS

 may occur in patients with

    Fabry disease
    DIAGNOSIS

, even in families with

    late-onset variant mutations
    GENETICS

. The genotype-phenotype correlation in

    Fabry disease
    DIAGNOSIS

 remains controversial.

Fabry disease
Fabry disease
late-onset variant
Fabry disease
classic variant of Fabry disease
classic Fabry disease
Fabry disease
Fabry disease

enzyme replacement therapy
enzyme replacement therapy


Downregulation of megalin, cubilin, ClC-5 and podocin in Fabry nephropathy: potential implications in the decreased effectiveness of enzyme replacement therapy.

Fabry disease is an X-linked disorder due to mutations in α-galactosidase A, resulting in the accumulation of enzyme substrates and cell malfunction. Kidney involvement is frequent, affecting all native kidney cell types. Podocyte damage results in proteinuria and chronic kidney disease. End-stage kidney disease is the rule in middle-aged males and some females with the classic phenotype. In podocytes and kidney proximal tubular cells, megalin is one of the molecules involved in enzyme replacement therapy (ERT) cellular absorption. After podocyte damage, podocin concentration is decreased and contributes to progressive proteinuria. We report in a male and a female patient the decreased expression of megalin, cubilin, ClC-5 and podocin compared to controls and chronic kidney disease (CKD) biopsies. Moreover, the decrease in ClC-5, a molecule engaged in endosomal-lysosomal acidification, could also affect ERT. These findings may partially explain some of the dysfunctions described in Fabry nephropathy and could highlight possible alterations in the pharmacokinetics of the delivered enzyme.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

 due to

    mutations in α-galactosidase A
    GENETICS

, resulting in the

    accumulation of enzyme substrates
    MICROSCOPIC

 and

    cell malfunction
    MICROSCOPIC

.

    Kidney involvement
    SYMPTOMS

 is frequent, affecting

    all native kidney cell types
    MICROSCOPIC

.

    Podocyte damage
    MICROSCOPIC

 results in

    proteinuria
    BIOCHEMICAL

 and

    chronic kidney disease
    DIAGNOSIS

.

    End-stage kidney disease
    DIAGNOSIS

 is the rule in

    middle-aged
    AGE

    males
    GENDER

 and some

    females
    GENDER

 with the classic phenotype. In

    podocytes and kidney proximal tubular cells
    MICROSCOPIC

,

    megalin
    GENETICS

 is one of the molecules involved in

    enzyme replacement therapy (ERT) cellular absorption
    MEDICATION

. After

    podocyte damage
    BIOCHEMICAL

,

    podocin concentration is decreased
    BIOCHEMICAL

 and contributes to

    progressive proteinuria
    BIOCHEMICAL

. We report in a

    male
    GENDER

 and a

    female
    GENDER

 patient the

    decreased expression of megalin, cubilin, ClC-5 and podocin
    BIOCHEMICAL

 compared to controls and

    chronic kidney disease (CKD) biopsies
    DIAGNOSIS

. Moreover, the

    decrease in ClC-5, a molecule engaged in endosomal-lysosomal acidification
    BIOCHEMICAL

, could also affect

    ERT
    MEDICATION

. These findings may partially explain some of the dysfunctions described in

    Fabry nephropathy
    DIAGNOSIS

 and could highlight possible alterations in the pharmacokinetics of the delivered enzyme.

Fabry disease
chronic kidney disease
End-stage kidney disease
chronic kidney disease (CKD) biopsies
Fabry nephropathy

X-linked disorder
mutations in α-galactosidase A
megalin


Analysis of the alpha galactosidase gene: mutation profile and description of two novel mutations with extensive literature review in Turkish population.

Objectives Fabry disease (FD, OMIM #301500) is a rare and progressive X-linked lysosomal storage disorder. FD is caused by mutations in the GLA gene on chromosome Xq22. Methods In this article, we aimed to present the largest sample of GLA mutation spectrum including common and novel variants in Turkish population. GLA gene sequence analysis was performed on the subjects who applied to the department of medical genetics with the preliminary diagnosis of FD between 2013 and 2018. Results We detected 22 different mutations as two novel [(p.F69S(c.206T>C), p.P205A (c.613C>G)] and 20 previously reported GLA mutations in 47 individuals from 22 unrelated families. These mutations included 14 missense mutations, four nonsense mutations, two small deletions, one small deletion/insertion and one small insertion. Major clinical findings of the female case with p.F69S(c.206T>C) mutation were cornea verticillata, acroparesthesia, angiokeratoma, psychiatric and gastrointestinal symptoms. Other novel mutation (p.P205A [c.613C>G]) was carried by a male case presenting gastrointestinal symptoms. Conclusions We described clinical findings of two cases that had novel mutations to provide more insight in genotype-phenotype correlation. We presented the largest mutation spectrum in Turkish population and reviewed previous mutations in this article.

Objectives

    Fabry disease (FD
    DIAGNOSIS

, OMIM #

    301500)
    DIAGNOSIS

 is a

    rare and progressive X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

.

    FD
    DIAGNOSIS

 is caused by

    mutations in the GLA gene on chromosome Xq22
    GENETICS

. Methods In this article, we aimed to present the largest sample of GLA mutation spectrum including common and novel variants in

    Turkish
    ETHNICITY

 population.

    GLA gene sequence analysis
    PARACLINICAL

 was performed on the subjects who applied to the department of

    medical genetics
    PARACLINICAL

 with the preliminary diagnosis of

    FD
    DIAGNOSIS

 between 2013 and 2018. Results We detected

    22 different mutations as two novel [(p.F69S(c.206T>C), p.P205A (c.613C>G)]
    GENETICS

 and 20 previously reported

    GLA mutations
    GENETICS

 in 47 individuals from 22 unrelated families. These mutations included

    14 missense mutations
    GENETICS

,

    four nonsense mutations
    GENETICS

,

    two small deletions, one small deletion/insertion and one small insertion
    GENETICS

. Major clinical findings of the

    female
    GENDER

 case with

    p.F69S(c.206T>C) mutation
    GENETICS

 were

    cornea verticillata
    SYMPTOMS

,

    acroparesthesia
    SYMPTOMS

,

    angiokeratoma
    SYMPTOMS

,

    psychiatric
    SYMPTOMS

 and

    gastrointestinal symptoms
    SYMPTOMS

. Other

    novel mutation (p.P205A [c.613C>G])
    GENETICS

 was carried by a

    male
    GENDER

 case presenting

    gastrointestinal symptoms
    SYMPTOMS

. Conclusions We described clinical findings of two cases that had

    novel mutations
    GENETICS

 to provide more insight in genotype-phenotype correlation. We presented the largest mutation spectrum in

    Turkish
    ETHNICITY

 population and reviewed previous mutations in this article.

Fabry disease (FD
301500)
lysosomal storage disorder
FD
FD

cornea verticillata
acroparesthesia
angiokeratoma
psychiatric
gastrointestinal symptoms
gastrointestinal symptoms


Recurrent fever of unknown origin: An overlooked symptom of Fabry disease.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to the absent or deficient activity of lysosomal hydrolase a-galactosidase A (α-Gal A), which leads to the accumulation of its substrates in various organs and tissues. Classic clinical manifestations include angiokeratomas, proteinuria, renal failure, neuropathic pain, and left ventricular hypertrophy. Fever is one of the rare symptoms that may occur during FD.

Three Chinese Han patients with FD referred to Peking Union Medical College Hospital were reported. The complete medical records were established, and detailed data were collected. Whole-exome sequencing by next-generation sequencing and α-Gal A enzyme activity assay were performed to confirm the diagnosis.

These three patients all presented with recurrent fever of unknown origin initially, accompanied with arthralgia/arthritis and other symptoms. We identified two known variants in the GLA gene, c.1176_1179delGAAG and c.782G>A (p.G261D), and a novel variant c.440G>A (p.G147E) which is likely pathogenic in our patient.

FD should be considered as a rare cause of recurrent fever of unknown origin. The coexistence of gene variants related to systemic autoinflammatory diseases may make the clinical phenotypes of FD more complex and prone to recurrent fever.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 due to the

    absent or deficient activity of lysosomal hydrolase a-galactosidase A (α-Gal A)
    BIOCHEMICAL

, which leads to the

    accumulation of its substrates in various organs and tissues
    MICROSCOPIC

. Classic clinical manifestations include

    angiokeratomas
    SYMPTOMS

,

    proteinuria
    BIOCHEMICAL

,

    renal failure
    SYMPTOMS

,

    neuropathic pain
    SYMPTOMS

, and

    left ventricular hypertrophy
    SYMPTOMS

.

    Fever
    SYMPTOMS

 is one of the rare symptoms that may occur during

    FD
    DIAGNOSIS

.

Three

    Chinese Han
    ETHNICITY

 patients with

    FD
    DIAGNOSIS

 referred to Peking Union Medical College Hospital were reported. The complete medical records were established, and detailed data were collected.

    Whole-exome sequencing by next-generation sequencing
    PARACLINICAL

 and

    α-Gal A enzyme activity assay
    PARACLINICAL

 were performed to confirm the diagnosis.

These three patients all presented with

    recurrent fever of unknown origin
    SYMPTOMS

 initially, accompanied with

    arthralgia/arthritis
    SYMPTOMS

 and other symptoms. We identified

    two known variants in the GLA gene, c.1176_1179delGAAG and c.782G>A (p.G261D)
    GENETICS

, and a

    novel variant c.440G>A (p.G147E) which is likely pathogenic
    GENETICS

 in our patient.

    FD
    DIAGNOSIS

 should be considered as a rare cause of

    recurrent fever of unknown origin
    SYMPTOMS

. The

    coexistence of gene variants related to systemic autoinflammatory diseases
    GENETICS

 may make the clinical phenotypes of

    FD
    DIAGNOSIS

 more complex and prone to

    recurrent fever
    SYMPTOMS

.

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

angiokeratomas
renal failure
neuropathic pain
left ventricular hypertrophy
Fever
recurrent fever of unknown origin
arthralgia/arthritis
recurrent fever of unknown origin
recurrent fever


Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report.

Genetic changes in the LIM homeobox transcription factor 1 beta (LMX1B) have been associated with focal segmental glomerulosclerosis (FSGS) without the extra-renal or ultrastructural manifestations of Nail-patella syndrome (NPS) known as Nail-patella-like renal disease (NPLRD). Fabry disease (FD) is an X-linked lysosomal disease caused by the deficiency of alpha-galactosidase A. The classic form of the disease is characterized by acroparesthesia, angiokeratomas, cornea verticillata, hypertrophic cardiomyopathy, strokes, and chronic kidney disease. Podocyte myelin bodies on ultrastructural examination of kidney tissue are very characteristic of FD; however some medications and other conditions may mimic this finding.

Here, we report on a female patient with chronic kidney disease (CKD), positive family history for kidney disease and kidney biopsy showing a FSGS lesion and presence of focal myelin figures within podocytes concerning for FD. However, genetic testing for FD was negative. After comprehensive clinical, biochemical, and genetic evaluation, including whole exome and RNA sequencing, she was ultimately diagnosed with NPLRD.

This case illustrates the difficulties of diagnosing atypical forms of rare Mendelian kidney diseases and the role of a multidisciplinary team in an individualized medicine clinic setting in combination with state-of-the-art sequencing technologies to reach a definitive diagnosis.

    Genetic changes in the LIM homeobox transcription factor 1 beta (LMX1B)
    GENETICS

 have been associated with

    focal segmental glomerulosclerosis (FSGS)
    DIAGNOSIS

    without the extra-renal or ultrastructural manifestations
    NEG_FINDINGS

 of

    Nail-patella syndrome (NPS)
    DIAGNOSIS

 known as

    Nail-patella-like renal disease (NPLRD)
    DIAGNOSIS

.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal disease
    DIAGNOSIS

 caused by the deficiency of alpha-galactosidase A. The classic form of the disease is characterized by

    acroparesthesia
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    cornea verticillata
    SYMPTOMS

,

    hypertrophic cardiomyopathy
    SYMPTOMS

,

    strokes
    SYMPTOMS

, and

    chronic kidney disease
    DIAGNOSIS

.

    Podocyte myelin bodies
    MICROSCOPIC

 on

    ultrastructural examination of kidney tissue
    PARACLINICAL

 are very characteristic of

    FD
    DIAGNOSIS

; however some medications and other conditions may mimic this finding.

Here, we report on a

    female
    GENDER

 patient with

    chronic kidney disease (CKD)
    DIAGNOSIS

,

    positive family history for kidney disease
    FAMILY

 and

    kidney biopsy
    PARACLINICAL

 showing a

    FSGS lesion
    MICROSCOPIC

 and

    presence of focal myelin figures within podocytes
    MICROSCOPIC

 concerning for

    FD
    MICROSCOPIC

. However,

    genetic testing for FD was negative
    NEG_FINDINGS

. After comprehensive

    clinical, biochemical, and genetic evaluation
    PARACLINICAL

, including

    whole exome and RNA sequencing
    PARACLINICAL

,

    she
    GENDER

 was ultimately diagnosed with

    NPLRD
    DIAGNOSIS

.

This case illustrates the difficulties of diagnosing

    atypical forms
    DIAGNOSIS

 of

    rare Mendelian kidney diseases
    DIAGNOSIS

 and the role of a multidisciplinary team in an

    individualized medicine
    MEDICATION

 clinic setting in combination with state-of-the-art sequencing technologies to reach a definitive diagnosis.

acroparesthesia
angiokeratomas
cornea verticillata
hypertrophic cardiomyopathy
strokes


Ventricular Septal Myectomy for the Treatment of Left Ventricular Outflow Tract Obstruction Due to Fabry Disease.

Fabry cardiomyopathy can cause symptomatic left ventricular outflow tract obstruction. We review a case of Fabry cardiomyopathy mimicking hypertrophic cardiomyopathy on echocardiography with severe left ventricular outflow tract obstruction treated with ventricular septal myectomy.

    Fabry cardiomyopathy
    DIAGNOSIS

 can cause

    symptomatic left ventricular outflow tract obstruction
    SYMPTOMS

. We review a case of

    Fabry cardiomyopathy mimicking hypertrophic cardiomyopathy
    DIAGNOSIS

 on

    echocardiography
    PARACLINICAL

 with

    severe left ventricular outflow tract obstruction
    SYMPTOMS

 treated with

    ventricular septal myectomy
    MEDICATION

.


Massive accumulation of globotriaosylceramide in various tissues from a Fabry patient with a high antibody titer against alpha-galactosidase A after 6 years of enzyme replacement therapy.

Fabry disease is an X-linked metabolic disorder due to a pathogenic mutation of the GLA gene. The accumulation of globotriaosylceramide (Gb3) damages multiple organs, including the heart, kidney and nervous system, especially in classical type Fabry disease. Enzyme replacement therapy (ERT) using recombinant alpha-galactosidase A has been shown to remove Gb3 from organs and to improve the prognosis of Fabry disease. We herein report the case of a 67-year-old classical type Fabry patient who had been treated with ERT for 6 years and who continuously showed a high antibody titer against recombinant alpha-galactosidase A during therapy. A post-mortem examination was performed after sudden death. A histological examination revealed the massive accumulation of Gb3 in various organs, even after long term ERT. In addition to the typical pathological findings as reported in tissue biopsy samples, the serious accumulation of Gb3 in the cardiac conduction system and the endocrine system was detected. Since the start of ERT for this patient might be too late to improve organ damage and prognosis, ERT should be started before the appearance of major organ involvement for the effective elimination of Gb3 and changes in the therapeutic strategy might be considered if the patient shows a high antibody titer against recombinant alpha-galactosidase A.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    metabolic disorder
    DIAGNOSIS

 due to a

    pathogenic mutation of the GLA gene
    GENETICS

. The

    accumulation of globotriaosylceramide (Gb3) damages multiple organs, including the heart, kidney and nervous system
    MICROSCOPIC

, especially in

    classical type Fabry disease
    DIAGNOSIS

.

    Enzyme replacement therapy (ERT) using recombinant alpha-galactosidase A
    MEDICATION

 has been shown to

    remove Gb3 from organs
    MICROSCOPIC

 and to improve the prognosis of

    Fabry disease
    DIAGNOSIS

. We herein report the case of a

    67-year-old
    AGE

    classical type Fabry
    DIAGNOSIS

 patient who had been

    treated with ERT for 6 years
    MEDICATION

 and who continuously showed a

    high antibody titer against recombinant alpha-galactosidase A
    BIOCHEMICAL

 during therapy. A

    post-mortem examination
    PARACLINICAL

 was performed after

    sudden death
    SYMPTOMS

. A

    histological examination
    PARACLINICAL

 revealed the

    massive accumulation of Gb3 in various organs
    MICROSCOPIC

,

    even after long term ERT
    NEG_FINDINGS

. In addition to the typical pathological findings as reported in

    tissue biopsy samples
    PARACLINICAL

, the

    serious accumulation of Gb3 in the cardiac conduction system and the endocrine system
    MICROSCOPIC

 was detected. Since the start of

    ERT
    MEDICATION

 for this patient might be too late to improve

    organ damage
    SYMPTOMS

 and prognosis,

    ERT
    MEDICATION

 should be started before the appearance of

    major organ involvement
    SYMPTOMS

 for the effective

    elimination of Gb3
    BIOCHEMICAL

 and changes in the therapeutic strategy might be considered if the patient shows a high antibody titer against recombinant alpha-galactosidase A.

Fabry disease
metabolic disorder
classical type Fabry disease
Fabry disease
classical type Fabry

X-linked
pathogenic mutation of the GLA gene

sudden death
organ damage
major organ involvement


A case of latent heterozygous Fabry disease in a female living kidney donor candidate.

A 52-year-old woman had been found to have hematuria at her annual checkup 5 years in a row. She hoped to donate her kidney to her husband, so we performed a percutaneous kidney biopsy at our department. It was difficult for us to detect apparent abnormalities under a light microscopic examination, and she was determined to meet the eligibility criteria for living kidney transplantation. However, the sample for electron microscopy was not evaluated before kidney donation. She subsequently underwent living kidney transplantation as a donor. A 1-h biopsy revealed swelling and obvious vacuolation of the glomerular podocytes, which were characteristic of Fabry disease. Her medical history and examinations were reviewed. No findings or episodes were observed. Pre-donation electronmicroscopy revealed numerous zebra bodies in the podocytes. A definite diagnosis of heterozygous Fabry disease was made based on the GLA gene mutation despite the normal range of leukocyte α-Gal A activity. Based on the pathological deposition of GL-3, chaperone therapy was initiated to suppress the progression of organ damage. In this case, we could not confirm a diagnosis of Fabry disease despite performing a renal biopsy prior to kidney donation. Kidney donor candidates may sometimes have factors that cannot be assumed based on medical or family history. Thus, it is important to perform a renal biopsy before kidney donation when necessary, and to always conduct a detailed evaluation including electron microscopy.

A

    52-year-old
    AGE

    woman
    GENDER

 had been found to have

    hematuria
    SYMPTOMS

 at her annual checkup 5 years in a row.

    She
    GENDER

 hoped to

    donate her kidney to her husband
    MEDICATION

, so we performed a

    percutaneous kidney biopsy
    PARACLINICAL

 at our department. It was

    difficult for us to detect apparent abnormalities
    NEG_FINDINGS

 under a

    light microscopic examination
    NEG_FINDINGS

, and

    she
    GENDER

 was determined to meet the eligibility criteria for

    living kidney transplantation
    MEDICATION

. However, the

    sample for electron microscopy was not evaluated
    NEG_FINDINGS

 before

    kidney donation
    MEDICATION

.

    She
    GENDER

 subsequently underwent

    living kidney transplantation as a donor
    MEDICATION

. A

    1-h biopsy
    PARACLINICAL

 revealed

    swelling and obvious vacuolation of the glomerular podocytes
    MICROSCOPIC

, which were characteristic of

    Fabry disease
    MICROSCOPIC

.

    Her
    GENDER

 medical history and examinations were reviewed.

    No findings or episodes were observed
    NEG_FINDINGS

.

    Pre-donation electronmicroscopy
    PARACLINICAL

 revealed

    numerous zebra bodies in the podocytes
    MICROSCOPIC

. A definite diagnosis of

    heterozygous Fabry disease
    DIAGNOSIS

 was made based on the

    GLA gene mutation
    GENETICS

 despite the

    normal range of leukocyte α-Gal A activity
    NEG_FINDINGS

. Based on the

    pathological deposition of GL-3
    MICROSCOPIC

,

    chaperone therapy
    MEDICATION

 was initiated to

    suppress the progression of organ damage
    SYMPTOMS

. In this case, we

    could not confirm a diagnosis of Fabry disease
    NEG_FINDINGS

 despite performing a

    renal biopsy
    PARACLINICAL

 prior to

    kidney donation
    MEDICATION

. Kidney donor candidates may sometimes have factors that cannot be assumed based on medical or family history. Thus, it is important to perform a

    renal biopsy
    PARACLINICAL

 before

    kidney donation
    MEDICATION

 when necessary, and to always conduct a detailed evaluation including

    electron microscopy
    PARACLINICAL

.


Rare Etiology of Renal Failure in a 25-Year-Old Caucasian Man: Fabry Disease With a Novel Mutation of GLA Gene.

Fabry disease (FD) is an X-linked recessive lysosomal storage disease caused by a mutation of the galactosidase alpha (GLA) gene, leading to deficiency of α-galactosidase A (alpha-Gal A). This deficiency results in a progressive, multiorgan accumulation of glycolipids, most notably globotriaosylceramide (Gb3), leading to multiorgan failure and subsequently premature death. Gb3 accumulation in the podocytes, epithelial, and mesangial cells of the glomeruli results in progressive renal disease and eventually renal failure and hemodialysis (HD). There are two types of FD: early-onset classical type 1 and late-onset type 2. Although nearly a thousand mutations of the GLA gene have been identified, the majority of them are of unknown significance. Herein we report the case of a 25-year-old Caucasian male with no significant medical history who presented with peripheral neuropathy and end-stage renal failure, requiring HD. He was diagnosed with FD based on the electron microscopy findings of renal biopsy and severely reduced alpha-Gal A activity (<0.4 nmol/mL/hour). A novel mutation of c.281G>T; p.Cys94Phe was identified. On discharge from our facility, he was referred to a renal transplant center and genetic counseling.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a

    mutation of the galactosidase alpha (GLA) gene
    GENETICS

, leading to

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

. This

    deficiency
    BIOCHEMICAL

 results in a

    progressive, multiorgan accumulation of glycolipids, most notably globotriaosylceramide (Gb3)
    MICROSCOPIC

, leading to

    multiorgan failure
    SYMPTOMS

 and subsequently

    premature death
    SYMPTOMS

.

    Gb3 accumulation in the podocytes, epithelial, and mesangial cells of the glomeruli
    MICROSCOPIC

 results in

    progressive renal disease
    SYMPTOMS

 and eventually

    renal failure
    SYMPTOMS

 and

    hemodialysis (HD)
    MEDICATION

. There are two types of

    FD
    DIAGNOSIS

:

    early-onset classical type 1
    DIAGNOSIS

 and

    late-onset type 2
    DIAGNOSIS

. Although nearly a thousand

    mutations of the GLA gene
    GENETICS

 have been identified, the majority of them are of unknown significance. Herein we report the case of a

    25-year-old
    AGE

    Caucasian
    ETHNICITY

    male
    GENDER

 with

    no significant medical history
    NEG_FINDINGS

 who presented with

    peripheral neuropathy
    SYMPTOMS

 and

    end-stage renal failure
    SYMPTOMS

, requiring

    HD
    MEDICATION

.

    He
    GENDER

 was diagnosed with

    FD
    DIAGNOSIS

 based on the

    electron microscopy findings of renal biopsy
    PARACLINICAL

 and

    severely reduced alpha-Gal A activity (<0.4 nmol/mL/hour)
    BIOCHEMICAL

. A

    novel mutation of c.281G>T; p.Cys94Phe
    GENETICS

 was identified. On discharge from our facility,

    he
    GENDER

 was

    referred to a renal transplant center and genetic counseling
    MEDICATION

.

Fabry disease (FD)
lysosomal storage disease
FD
early-onset classical type 1
late-onset type 2
FD

multiorgan failure
premature death
progressive renal disease
renal failure
peripheral neuropathy
end-stage renal failure


Cornea Verticillata in classical Fabry disease, first from Sri Lanka: a case report.

Fabry disease is a rare inborn error of metabolism with profound clinical consequences if untreated. It is caused by the deficiency of α galactosidase A enzyme and is the only lysosomal storage disorder with an X linked inheritance. Confirmation requires genetic analysis of Galactosidase Alpha (GLA) Gene, which is often a challenge in resource-poor settings. Despite these technological limitations, specific clinical features in this condition can establish the diagnosis.

We report on a 13-year old male who presented with an afebrile convulsion with a background history of chronic burning sensation of hands and feet and anhidrosis for 2 years duration with a similar history of episodic acroparesthesia in the other male sibling. The early clinical diagnosis was based on the history and detection of Cornea Verticillata on eye examination. Biochemical confirmation was established with detection of low α galactosidase A enzyme levels and a missense mutation of the Galactosidase Alpha (GLA) Gene (c.136C > T) established the genetic confirmation.

This is the first case of Fabry disease reported in Sri Lanka. Awareness of specific clinical features aided clinical diagnosis long before access to genetic confirmation was available.

    Fabry disease
    DIAGNOSIS

 is a

    rare inborn error of metabolism
    DIAGNOSIS

 with profound clinical consequences if untreated. It is caused by the

    deficiency of α galactosidase A enzyme
    BIOCHEMICAL

 and is the only

    lysosomal storage disorder
    DIAGNOSIS

 with an

    X linked inheritance
    GENETICS

. Confirmation requires

    genetic analysis of Galactosidase Alpha (GLA) Gene
    PARACLINICAL

, which is often a challenge in resource-poor settings. Despite these technological limitations, specific clinical features in this condition can establish the diagnosis.

We report on a

    13-year old
    AGE

    male
    GENDER

 who presented with an

    afebrile convulsion
    SYMPTOMS

 with a background history of

    chronic burning sensation of hands and feet
    SYMPTOMS

 and

    anhidrosis for 2 years duration
    SYMPTOMS

 with a

    similar history of episodic acroparesthesia in the other male sibling
    FAMILY

. The early clinical diagnosis was based on the history and detection of

    Cornea Verticillata
    SYMPTOMS

 on

    eye examination
    PARACLINICAL

.

    Biochemical confirmation
    PARACLINICAL

 was established with detection of

    low α galactosidase A enzyme levels
    BIOCHEMICAL

 and a

    missense mutation of the Galactosidase Alpha (GLA) Gene (c.136C > T)
    GENETICS

 established the

    genetic confirmation
    PARACLINICAL

.

This is the first case of

    Fabry disease
    DIAGNOSIS

 reported in

    Sri Lanka
    ETHNICITY

. Awareness of specific clinical features aided clinical diagnosis long before access to

    genetic confirmation
    PARACLINICAL

 was available.

Fabry disease
rare inborn error of metabolism
lysosomal storage disorder
Fabry disease

deficiency of α galactosidase A enzyme
low α galactosidase A enzyme levels


Therapeutic challenges in two adolescent male patients with Fabry disease and high antibody titres.

Enzyme replacement therapy (ERT) has been shown to stabilize certain aspects of Fabry disease (FD). However, in some patients on ERT, high antibody titres have been documented, with limited clinical improvement in systemic manifestations and often with significant adverse drug reactions. We present two related adolescent males with a 4.5 kb GLA deletion, not amenable to chaperone therapy, leading to profound reduction in α-galactosidase A (α-gal A) enzyme activity. Over a 3-year period of ERT, increasing IgG antibody titres against α-gal A were noted. After starting ERT serial urine globotriaosylceramide (Gb3) measurements showed an upward trend from 333 to 2260 μg/mmol creatinine for patient 1 and 1165 to 2260 μg/mmol creatinine for patient 2. Markedly increased levels of urine and plasma globotriaosylsphingosine (Lyso-Gb3) analogues were also found. The patients experienced recurrent infusion-associated reactions necessitating premedication and prolonged infusion times. Over the 3-year period of ERT, the patients experienced continued malaise, gastrointestinal symptoms and neuropathic pain. In addition, they had increasing anxiety related to their disease and apparent lack of response to ERT which led to a decision to ultimately stop ERT. No other approved treatment options are currently available for these patients. It is possible that the rapid development of the high antidrug neutralizing antibody (ADA) titres is related to the large GLA deletion leading to virtually absent enzyme activity. It remains unclear if their symptomatology during the period of receiving ERT is related to lack of its efficacy, the rising ADA titres, or both. These two patients highlight the need for further research into the management of antidrug antibodies and additional therapeutic approaches for FD.

The development of very high antidrug antibody titres in response to ERT in two related adolescent males with FD highlight the need for other therapeutic options for patients in whom ERT or other currently approved therapies does not meet their treatment needs.

    Enzyme replacement therapy (ERT)
    MEDICATION

 has been shown to stabilize certain aspects of

    Fabry disease (FD)
    DIAGNOSIS

. However, in some patients on

    ERT
    MEDICATION

,

    high antibody titres
    BIOCHEMICAL

 have been documented, with

    limited clinical improvement in systemic manifestations
    SYMPTOMS

 and often with

    significant adverse drug reactions
    SYMPTOMS

. We present two related

    adolescent
    AGE

    males
    GENDER

 with a

    4.5 kb GLA deletion
    GENETICS

,

    not amenable to chaperone therapy
    NEG_FINDINGS

, leading to

    profound reduction in α-galactosidase A (α-gal A) enzyme activity
    BIOCHEMICAL

. Over a

    3-year period of ERT
    MEDICATION

,

    increasing IgG antibody titres against α-gal A
    BIOCHEMICAL

 were noted. After starting

    ERT
    MEDICATION

    serial urine globotriaosylceramide (Gb3) measurements showed an upward trend from 333 to 2260 μg/mmol creatinine
    BIOCHEMICAL

 for patient 1 and

    1165 to 2260 μg/mmol creatinine
    BIOCHEMICAL

 for patient 2.

    Markedly increased levels of urine and plasma globotriaosylsphingosine (Lyso-Gb3) analogues were also found
    BIOCHEMICAL

. The patients experienced

    recurrent infusion-associated reactions
    SYMPTOMS

 necessitating

    premedication and prolonged infusion times
    MEDICATION

. Over the

    3-year period of ERT
    MEDICATION

, the patients experienced

    continued malaise
    SYMPTOMS

,

    gastrointestinal symptoms
    SYMPTOMS

 and

    neuropathic pain
    SYMPTOMS

. In addition, they had

    increasing anxiety related to their disease
    SYMPTOMS

 and

    apparent lack of response to ERT
    NEG_FINDINGS

 which led to a decision to ultimately

    stop ERT
    MEDICATION

. No other approved treatment options are currently available for these patients. It is possible that the

    rapid development of the high antidrug neutralizing antibody (ADA) titres
    BIOCHEMICAL

 is related to the

    large GLA deletion
    GENETICS

 leading to

    virtually absent enzyme activity
    BIOCHEMICAL

. It remains unclear if their symptomatology during the period of receiving

    ERT
    MEDICATION

 is related to

    lack of its efficacy
    NEG_FINDINGS

, the

    rising ADA titres
    BIOCHEMICAL

, or both. These two patients highlight the need for further research into the management of

    antidrug antibodies
    BIOCHEMICAL

 and additional therapeutic approaches for

    FD
    DIAGNOSIS

.

The development of

    very high antidrug antibody titres in response to ERT
    BIOCHEMICAL

 in two related

    adolescent
    AGE

    males
    GENDER

 with

    FD
    DIAGNOSIS

 highlight the need for other therapeutic options for patients in whom

    ERT or other currently approved therapies does not
    NEG_FINDINGS

 meet their treatment needs.


First phenotypic description of a female patient with c.610 T > C variant of GLA: a renal-predominant presentation of Fabry disease.

Fabry disease (FD) is an X-linked lysosomal storage disorder due to deficient alpha-galactosidase activity leading to intracellular glycosphingolipid accumulation. Multiple variants have been reported in the GLA gene coding for alpha-galactosidase, and the question of the pathogenicity of rare variants needs to be addressed, especially in patients with mild phenotypes.

The patient, a 37-year-old female, presented with a persistent proteinuria after an otherwise uncomplicated first pregnancy. Renal biopsy showed both mild mesangial IgA deposits, and a striking vacuolization of podocytes and tubular cells consistent with Fabry disease. On electron microscopy, discrete but characteristic pseudo-myelinic lamellar inclusions were observed in the podocytes' lysosomes. A more detailed physical examination revealed an angiokeratoma, and medical history ancient acroparesthesia. There was no cardiac or cerebral involvement of Fabry disease on magnetic resonance imaging. While blood enzymatic activity of alpha-ga lactosidase was normal in this patient, lysoGb3 was elevated (3 N), and a rare heterozygous variant called c.610 T > C was documented in GLA gene. The patient was treated with an ACE inhibitor, with a rapid decrease in proteinuria. After a 5-year follow-up, her renal function has remained normal, with mild proteinuria, and normal cardiac echography.

We report and phenotypically describe the first case of a Fabry disease female patient carrying the GLA c.610 T > C variant associated with a renal-predominant clinical presentation.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 due to

    deficient alpha-galactosidase activity
    BIOCHEMICAL

 leading to

    intracellular glycosphingolipid accumulation
    MICROSCOPIC

.

    Multiple variants
    GENETICS

 have been reported

    in the GLA gene coding for alpha-galactosidase
    GENETICS

, and the question of the pathogenicity of rare variants needs to be addressed, especially in patients with mild phenotypes.

The patient, a

    37-year-old
    AGE

    female
    GENDER

, presented with a

    persistent proteinuria
    BIOCHEMICAL

 after an

    otherwise uncomplicated first pregnancy
    NEG_FINDINGS

.

    Renal biopsy
    PARACLINICAL

 showed both

    mild mesangial IgA deposits
    MICROSCOPIC

, and a

    striking vacuolization of podocytes and tubular cells consistent with Fabry disease
    MICROSCOPIC

. On

    electron microscopy
    PARACLINICAL

,

    discrete but characteristic pseudo-myelinic lamellar inclusions were observed in the podocytes' lysosomes
    MICROSCOPIC

. A more detailed physical examination revealed an

    angiokeratoma
    SYMPTOMS

, and medical history ancient

    acroparesthesia
    SYMPTOMS

. There was

    no cardiac or cerebral involvement of Fabry disease on magnetic resonance imaging
    NEG_FINDINGS

.

    While blood enzymatic activity of alpha-ga lactosidase was normal
    NEG_FINDINGS

 in this patient,

    lysoGb3 was elevated (3 N)
    BIOCHEMICAL

, and a

    rare heterozygous variant called c.610 T > C was documented in GLA gene
    GENETICS

. The patient was treated with an

    ACE inhibitor
    MEDICATION

, with a

    rapid decrease in proteinuria
    BIOCHEMICAL

. After a 5-year follow-up,

    her
    GENDER

    renal function has remained normal
    NEG_FINDINGS

, with

    mild proteinuria
    BIOCHEMICAL

, and

    normal cardiac echography
    NEG_FINDINGS

.

We report and phenotypically describe the first case of a

    Fabry disease
    DIAGNOSIS

    female
    GENDER

 patient carrying the

    GLA c.610 T > C variant
    GENETICS

 associated with a

    renal-predominant clinical presentation
    SYMPTOMS

.

Fabry disease (FD)
lysosomal storage disorder
Fabry disease

deficient alpha-galactosidase activity
persistent proteinuria
lysoGb3 was elevated (3 N)
rapid decrease in proteinuria
mild proteinuria

angiokeratoma
acroparesthesia
renal-predominant clinical presentation


Fabry disease due to G171S GLA mutation: An atypical small nerve fiber sparing variant?

To describe the ocular manifestations and in vivo confocal microscopic findings in a patient carrying the recently described hemizygous G171S GLA gene mutation.

A 63-year-old Albanian male patient was evaluated for cataract surgery. Anamnesis showed pacemaker implantation in left ventricular hypertrophy, chronic kidney disease, family history for kidney transplantation, and late onset of sporadic acroparesthesias. Bilateral cornea verticillata, and increased tortuosity in conjunctival and retinal vessels were present. In vivo confocal microscopy revealed clusters of hyper-reflective corneal epithelial cells centripetally extending from the limbus. Interestingly, the nerve fiber number, density, and length in the corneal sub-basal nerve plexus were preserved. Alpha-galactosidase A activity was almost absent and hemizygous c.511G>A mutation (G171S - p.Gly171Ser) of the GLA gene was identified. The patient was referred for initiation of enzyme replacement therapy, and genetic counseling was recommended for at-risk family members.

This is the third reported case of Fabry disease due to GLA G171S mutation. All patients are of Albanian descent. Cornea verticillata and vascular anomalies remain common ocular manifestations, as well as cardiac and renal involvement. Confirming its pathogenicity, this mutation results in a "classic" Fabry disease phenotype, but it seems to be associated with a relative small nerve fiber sparing that may delay a correct diagnosis. The diagnosis of Fabry disease still remains challenging due to its clinical heterogeneity, but a thorough ophthalmological examination can promote early detection and, consequently, early initiation of enzyme replacement therapy.

To describe the

    ocular manifestations
    SYMPTOMS

 and

    in vivo confocal microscopic findings
    PARACLINICAL

 in a patient carrying the

    recently described hemizygous G171S GLA gene mutation
    GENETICS

.

A

    63-year-old
    AGE

    Albanian
    ETHNICITY

    male
    GENDER

 patient was evaluated for

    cataract surgery
    MEDICATION

. Anamnesis showed

    pacemaker implantation in left ventricular hypertrophy
    MEDICATION

,

    chronic kidney disease
    DIAGNOSIS

,

    family history for kidney transplantation
    FAMILY

, and

    late onset of sporadic acroparesthesias
    SYMPTOMS

.

    Bilateral cornea verticillata
    SYMPTOMS

, and

    increased tortuosity in conjunctival and retinal vessels
    SYMPTOMS

 were present.

    In vivo confocal microscopy
    PARACLINICAL

 revealed

    clusters of hyper-reflective corneal epithelial cells centripetally extending from the limbus
    MICROSCOPIC

. Interestingly, the

    nerve fiber number, density, and length in the corneal sub-basal nerve plexus were preserved
    SYMPTOMS

.

    Alpha-galactosidase A activity was almost absent
    BIOCHEMICAL

 and

    hemizygous c.511G>A mutation (G171S - p.Gly171Ser) of the GLA gene was identified
    GENETICS

. The patient was referred for

    initiation of enzyme replacement therapy
    MEDICATION

, and

    genetic counseling
    MEDICATION

 was recommended for at-risk family members.

This is the third reported case of

    Fabry disease
    DIAGNOSIS

 due to

    GLA G171S mutation
    GENETICS

. All patients are of

    Albanian descent
    ETHNICITY

.

    Cornea verticillata
    SYMPTOMS

 and

    vascular anomalies
    SYMPTOMS

 remain common

    ocular manifestations
    SYMPTOMS

, as well as

    cardiac and renal involvement
    SYMPTOMS

. Confirming its pathogenicity, this mutation results in a

    "classic" Fabry disease
    SYMPTOMS

 phenotype, but it seems to be associated with a

    relative small nerve fiber sparing
    SYMPTOMS

 that may delay a correct diagnosis. The diagnosis of

    Fabry disease
    DIAGNOSIS

 still remains challenging due to its clinical heterogeneity, but a thorough

    ophthalmological examination
    PARACLINICAL

 can promote early detection and, consequently,

    early initiation of enzyme replacement therapy
    MEDICATION

.

chronic kidney disease
Fabry disease
Fabry disease


Angiokeratomas and treatment with enzyme replacement therapy in a patient with Fabry disease.

Angiokeratomas are the cutaneous hallmark of Fabry disease. Although it is well established that enzyme replacement therapy (ERT) prevents or slows the progression of disease on target organs in the majority of patients, the long-term effect of ERT on angiokeratomas remains unknown. We present a patient diagnosed with Fabry disease at age 11, with rapid progression of new angiokeratomas in typical regions before beginning treatment with ERT. To date, our patient has been treated with ERT for 10 years. During the treatment period, new angiokeratomas have not arisen nor have existing ones enlarged during puberty, adolescence, and early adulthood. Furthermore, partial regression of the angiokeratomas has occurred in association with regression of left ventricular hypertrophy and anhidrosis. Overall, this case suggests that long-term ERT could stop the progression of angiokeratomas and induce their partial regression but does not produce complete resolution. Importantly, regression of angiokeratomas might be a marker of systemic target-organ efficacy of ERT.

    Angiokeratomas
    SYMPTOMS

 are the cutaneous hallmark of

    Fabry disease
    DIAGNOSIS

. Although it is well established that

    enzyme replacement therapy (ERT)
    MEDICATION

 prevents or

    slows the progression of disease on target organs
    SYMPTOMS

 in the majority of patients, the long-term effect of

    ERT
    MEDICATION

 on

    angiokeratomas
    SYMPTOMS

 remains unknown. We present a patient diagnosed with

    Fabry disease
    DIAGNOSIS

 at

    age 11
    AGE

, with

    rapid progression of new angiokeratomas in typical regions
    SYMPTOMS

 before beginning

    treatment with ERT
    MEDICATION

. To date, our patient has been

    treated with ERT for 10 years
    MEDICATION

. During the treatment period,

    new angiokeratomas have not arisen nor have existing ones enlarged
    SYMPTOMS

 during

    puberty
    AGE

,

    adolescence
    AGE

, and

    early adulthood
    AGE

. Furthermore,

    partial regression of the angiokeratomas
    SYMPTOMS

 has occurred in association with

    regression of left ventricular hypertrophy
    SYMPTOMS

 and

    anhidrosis
    SYMPTOMS

. Overall, this case suggests that

    long-term ERT
    MEDICATION

 could

    stop the progression of angiokeratomas
    SYMPTOMS

 and

    induce their partial regression
    SYMPTOMS

 but does not produce

    complete resolution
    SYMPTOMS

. Importantly,

    regression of angiokeratomas
    SYMPTOMS

 might be a marker of

    systemic target-organ
    SYMPTOMS

 efficacy of

    ERT
    MEDICATION

.

enzyme replacement therapy (ERT)
ERT
treatment with ERT
treated with ERT for 10 years
long-term ERT
ERT


Post-transplant de-novo renal phospholipidosis in a kidney transplant recipient: Fabry disease or something else?

Renal phospholipidosis is a rare cause of proteinuria and kidney dysfunction. We describe a kidney transplant recipient who presented with slowly rising serum creatinine, nephrotic range proteinuria, and lower extremity edema 10 years post transplant. He was diagnosed with renal phospholipidosis on the transplant kidney biopsy. Patient did not have prior history or current symptoms or signs of Fabry disease. Serum α-galactosidase level was normal. The etiology was suspected to be due to chronic use of sertraline, a previously reported cause of drug-induced renal phospholipidosis. Sertraline was discontinued, and proteinuria declined with stabilization of kidney function at 6-months follow-up.

    Renal phospholipidosis
    DIAGNOSIS

 is a rare cause of

    proteinuria
    BIOCHEMICAL

 and

    kidney dysfunction
    SYMPTOMS

. We describe a

    kidney transplant recipient
    MEDICATION

 who presented with

    slowly rising serum creatinine
    BIOCHEMICAL

,

    nephrotic range proteinuria
    BIOCHEMICAL

, and

    lower extremity edema
    SYMPTOMS

 10 years

    post transplant
    MEDICATION

.

    He
    GENDER

 was diagnosed with

    renal phospholipidosis
    DIAGNOSIS

 on the

    transplant kidney biopsy
    PARACLINICAL

. Patient

    did not have prior history or current symptoms or signs of Fabry disease
    NEG_FINDINGS

.

    Serum α-galactosidase level was normal
    NEG_FINDINGS

. The etiology was suspected to be due to

    chronic use of sertraline
    MEDICATION

, a previously reported cause of

    drug-induced renal phospholipidosis
    DIAGNOSIS

.

    Sertraline was discontinued
    MEDICATION

, and

    proteinuria declined
    BIOCHEMICAL

 with

    stabilization of kidney function
    SYMPTOMS

 at

    6-months follow-up
    PARACLINICAL

.

Renal phospholipidosis
renal phospholipidosis
drug-induced renal phospholipidosis

proteinuria
slowly rising serum creatinine
nephrotic range proteinuria
proteinuria declined

kidney dysfunction
lower extremity edema
stabilization of kidney function

kidney transplant recipient
post transplant
chronic use of sertraline
Sertraline was discontinued


AA amyloidosis associated with Fabry disease.

Fabry disease (FD) is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could cause inflammation and, subsequently, AA amyloidosis (AAA). Our aim was to describe AAA cases occurring in the course of FD.

We described two patients displaying both AAA and FD and an additional case from the literature.

Three female patients originating from Europe (n = 2) and Algeria (n = 1) harboured heterozygous GLA mutations. The median age at AAA diagnosis was 61 years old. The diagnosis of Fabry was made before the diagnosis of AAA (n = 1) or concomitantly (n = 2). At AAA diagnosis, two patients displayed a nephrotic syndrome; all had inflammation.

Fabry disease can be associated with AAA, suggesting that an inflammatory component could exist in this genetic disease.

    Fabry disease (FD)
    DIAGNOSIS

 is the second most common

    lysosomal storage disorder
    DIAGNOSIS

, carrying a large morbidity and mortality. It has been recently reported that

    lysosomal storage disorders
    DIAGNOSIS

 could cause

    inflammation
    SYMPTOMS

 and, subsequently,

    AA amyloidosis (AAA)
    DIAGNOSIS

. Our aim was to describe

    AAA
    DIAGNOSIS

 cases occurring in the course of

    FD
    DIAGNOSIS

.

We described two patients displaying

    both AAA and FD
    DIAGNOSIS

 and an additional case from the literature.

Three

    female
    GENDER

 patients originating from

    Europe
    ETHNICITY

 (n = 2) and

    Algeria
    ETHNICITY

 (n = 1) harboured

    heterozygous GLA mutations
    GENETICS

. The

    median age at AAA
    AGE

 diagnosis

    was 61 years old
    AGE

. The diagnosis of

    Fabry
    DIAGNOSIS

 was made before the diagnosis of

    AAA
    DIAGNOSIS

 (n = 1) or concomitantly (n = 2). At

    AAA
    DIAGNOSIS

 diagnosis, two patients displayed a

    nephrotic syndrome
    DIAGNOSIS

; all had

    inflammation
    SYMPTOMS

.

    Fabry disease
    DIAGNOSIS

 can be associated with

    AAA
    DIAGNOSIS

, suggesting that an inflammatory component could exist in this

    genetic disease
    GENETICS

.

Fabry disease (FD)
lysosomal storage disorder
lysosomal storage disorders
AA amyloidosis (AAA)
AAA
FD
both AAA and FD
Fabry
AAA
AAA
nephrotic syndrome
Fabry disease
AAA

heterozygous GLA mutations
genetic disease