Novel α-galactosidase A gene mutation in a Chinese Fabry disease family: A case report.

Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by a deficiency of the enzyme α-galactosidase A.

Herein, we analyzed a four-generation Chinese family. The proband is a 57-year-old woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago. Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm, left ventricular end-diastolic diameter of 63.1 mm, and moderate-to-severe mitral regurgitation. Cardiac magnetic resonance indicated an enlarged left heart and right atrium, decreased left ventricular systolic and diastolic function, a left ventricular ejection fraction of 20%, and thickening of the left ventricular septum. In March 2019, gene and enzyme activity tests confirmed the diagnosis of FD. Her son was diagnosed with FD after gene and enzyme activity assay, and was prescribed agalsidase-β for enzyme replacement therapy in July 2020. Two sisters of the proband were also diagnosed with FD by genetic testing. Both of them had a history of atrial fibrillation.

A novel mutation was identified in a Chinese family with FD, in which the male patient had a low level of enzyme activity, early-onset, and severe organ involvement. Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

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

Herein, we analyzed a

    four-generation Chinese
    FAMILY

 family. The proband is a

    57-year-old
    AGE

    woman
    GENDER

 who was diagnosed with

    left ventricular hypertrophy
    SYMPTOMS

 and

    atrial fibrillation
    SYMPTOMS

 7 years ago.

    Echocardiography
    PARACLINICAL

 showed an

    end-diastolic diameter of the interventricular septum of 19.9 mm
    SYMPTOMS

,

    left ventricular end-diastolic diameter of 63.1 mm
    SYMPTOMS

, and

    moderate-to-severe mitral regurgitation
    SYMPTOMS

.

    Cardiac magnetic resonance
    PARACLINICAL

 indicated an

    enlarged left heart and right atrium
    SYMPTOMS

,

    decreased left ventricular systolic and diastolic function
    SYMPTOMS

, a

    left ventricular ejection fraction of 20%
    SYMPTOMS

, and

    thickening of the left ventricular septum
    SYMPTOMS

. In March 2019,

    gene and enzyme activity tests
    PARACLINICAL

 confirmed the diagnosis of

    FD
    DIAGNOSIS

.

    Her
    GENDER

    son was diagnosed with FD
    FAMILY

 after

    gene and enzyme activity assay
    PARACLINICAL

, and was

    prescribed agalsidase-β for enzyme replacement therapy
    MEDICATION

 in July 2020.

    Two sisters of the proband were also diagnosed with FD
    FAMILY

 by

    genetic testing
    PARACLINICAL

.

    Both of them had a history of atrial fibrillation
    FAMILY

.

A

    novel mutation
    GENETICS

 was identified in a

    Chinese
    ETHNICITY

    family with FD
    FAMILY

, in which the

    male
    GENDER

 patient had a

    low level of enzyme activity
    BIOCHEMICAL

,

    early-onset
    SYMPTOMS

, and

    severe organ involvement
    SYMPTOMS

.

    Comprehensive analysis of clinical phenotype genetic testing
    PARACLINICAL

 and

    enzyme activity testing
    PARACLINICAL

 helped in the diagnosis and treatment of this

    FD
    DIAGNOSIS

 family.

Fabry disease (FD)
lysosomal storage disease
FD
FD


Fabry Nephropathy in a Young Female Patient Presenting with Only Urinary Mulberry Bodies Treated with Chaperone Therapy.

Fabry disease (FD) is an X-linked disorder of the sphingolipid metabolism, caused by deficiency or decreased activity of α-galactosidase A. We report a rare case of Fabry nephropathy (FN) in a 21-year-old Japanese female patient presenting with only urinary mulberry bodies; she was treated with pharmacological chaperone therapy (PCT) after renal biopsy. The patient underwent a detailed examination because her mother was diagnosed with FD in the Division of Community Medicine of our hospital. She did not have renal dysfunction or proteinuria, and only mulberry bodies were detected in the urine. The activity of α-galactosidase A was low, and genetic analysis revealed the R301Q mutation. A percutaneous renal biopsy was performed, and the findings revealed enlargement and vacuolation of glomerular podocytes by light microscopy, and myelin and zebra bodies were detected in podocytes by electron microscopy. She was diagnosed with FN by renal biopsy and gene analysis. PCT was selected as the treatment to prevent cardiac events and renal dysfunction. The present case suggests that renal biopsy may be necessary even for young women with only mulberry bodies for the diagnosis of FN. It could be useful to evaluate the effect of treatment using the counts of mulberry bodies in the urine. In addition, due to its oral administration, PCT may be suitable for patients who are unable to visit the hospital frequently.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disorder of the sphingolipid metabolism
    DIAGNOSIS

, caused by deficiency or decreased activity of α-galactosidase A. We report a rare case of

    Fabry nephropathy (FN)
    DIAGNOSIS

 in a

    21-year-old
    AGE

    Japanese
    ETHNICITY

    female
    GENDER

 patient presenting with

    only urinary mulberry bodies
    MICROSCOPIC

;

    she
    GENDER

 was treated with

    pharmacological chaperone therapy (PCT)
    MEDICATION

 after

    renal biopsy
    PARACLINICAL

. The patient underwent a detailed examination because

    her
    GENDER

    mother was diagnosed with FD
    FAMILY

 in the Division of Community Medicine of our hospital.

    She
    GENDER

    did not have renal dysfunction or proteinuria
    NEG_FINDINGS

, and

    only mulberry bodies were detected in the urine
    MICROSCOPIC

. The

    activity of α-galactosidase A was low
    BIOCHEMICAL

, and

    genetic analysis
    PARACLINICAL

 revealed the

    R301Q mutation
    GENETICS

. A

    percutaneous renal biopsy
    PARACLINICAL

 was performed, and the findings revealed

    enlargement and vacuolation of glomerular podocytes
    MICROSCOPIC

 by

    light microscopy
    PARACLINICAL

, and

    myelin and zebra bodies were detected in podocytes
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

.

    She
    GENDER

 was diagnosed with

    FN
    DIAGNOSIS

 by

    renal biopsy
    PARACLINICAL

 and

    gene analysis
    PARACLINICAL

.

    PCT
    MEDICATION

 was selected as the treatment to prevent

    cardiac events
    SYMPTOMS

 and

    renal dysfunction
    SYMPTOMS

. The present case suggests that

    renal biopsy
    PARACLINICAL

 may be necessary even for

    young
    AGE

    women
    GENDER

 with

    only mulberry bodies
    MICROSCOPIC

 for the diagnosis of

    FN
    DIAGNOSIS

. It could be useful to evaluate the effect of treatment using the

    counts of mulberry bodies in the urine
    MICROSCOPIC

. In addition, due to its

    oral administration
    MEDICATION

,

    PCT
    MEDICATION

 may be suitable for patients who are unable to visit the hospital frequently.

Fabry disease (FD)
disorder of the sphingolipid metabolism
Fabry nephropathy (FN)
FN
FN

pharmacological chaperone therapy (PCT)
PCT
oral administration
PCT


Complete Atrioventricular Block After Kidney Transplantation in a Patient With Fabry Disease Receiving Enzyme Replacement Therapy: A Case Report.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder that results from the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) enzyme. Kidney transplantation is an option for treating end-stage renal disease in patients with FD. However, only a few cases of kidney transplantation have been reported involving patients with FD and end-stage renal disease and cardiomyopathy after enzyme replacement therapy. A 53-year-old man who underwent peritoneal dialysis was referred to our department because his brother was diagnosed with FD. The diagnosis of FD was also confirmed in our patient on account of the reduced leukocyte α-Gal A enzyme activity and mutation in the α-galactosidase A gene (p.Arg301Gln). Though our patient had end-stage renal disease, he received enzyme replacement therapy with 1 mg/kg agalsidase-β every 2 weeks (Fabrazyme; Genzyme Co, Mass, USA) owing to markedly diffuse cardiac hypertrophy. Six years later, he underwent successful deceased-donor kidney transplantation. The post-transplantation course was uneventful, 4 months after transplantation. However, though he showed T-cell-mediated rejection on kidney biopsy, lamellar lysosomal inclusions were not present in vascular endothelial cells. After several months, a permanent pacemaker was inserted owing to a complete atrioventricular block; the patient died of sepsis and candidemia 1 year later. Deceased-donor kidney transplantation was successfully performed in an FD patient with sustained enzyme replacement therapy. However, owing to high cardiac morbidity and infection risks even after enzyme replacement therapy, close monitoring of these risks is essential for increasing patient survival after kidney transplantation.

    Fabry disease (FD)
    DIAGNOSIS

 is a rare

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 that results from the

    deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A) enzyme
    BIOCHEMICAL

.

    Kidney transplantation
    MEDICATION

 is an option for treating

    end-stage renal disease
    DIAGNOSIS

 in patients with

    FD
    DIAGNOSIS

. However, only a few cases of

    kidney transplantation
    MEDICATION

 have been reported involving patients with

    FD
    DIAGNOSIS

 and

    end-stage renal disease
    DIAGNOSIS

 and

    cardiomyopathy
    SYMPTOMS

 after

    enzyme replacement therapy
    MEDICATION

. A

    53-year-old
    AGE

    man
    GENDER

 who underwent

    peritoneal dialysis
    MEDICATION

 was referred to our department

    because his brother was diagnosed with FD
    FAMILY

. The diagnosis of

    FD
    DIAGNOSIS

 was also confirmed in our patient on account of the

    reduced leukocyte α-Gal A enzyme activity
    BIOCHEMICAL

 and

    mutation in the α-galactosidase A gene (p.Arg301Gln)
    GENETICS

. Though our patient had

    end-stage renal disease
    DIAGNOSIS

,

    he
    GENDER

 received

    enzyme replacement therapy with 1 mg/kg agalsidase-β every 2 weeks (Fabrazyme; Genzyme Co, Mass, USA)
    MEDICATION

 owing to

    markedly diffuse cardiac hypertrophy
    SYMPTOMS

. Six years later,

    he
    GENDER

 underwent

    successful deceased-donor kidney transplantation
    MEDICATION

. The

    post-transplantation course was uneventful
    SYMPTOMS

, 4 months after

    transplantation
    MEDICATION

. However, though he showed

    T-cell-mediated rejection
    MICROSCOPIC

 on

    kidney biopsy
    PARACLINICAL

,

    lamellar lysosomal inclusions were not present in vascular endothelial cells
    MICROSCOPIC

. After

    several months
    MEDICATION

, a

    permanent pacemaker was inserted
    MEDICATION

 owing to a

    complete atrioventricular block
    SYMPTOMS

; the patient

    died
    SYMPTOMS

 of

    sepsis
    SYMPTOMS

 and

    candidemia
    DIAGNOSIS

 1 year later.

    Deceased-donor kidney transplantation
    MEDICATION

 was successfully performed in an

    FD
    DIAGNOSIS

 patient with

    sustained enzyme replacement therapy
    MEDICATION

. However, owing to high

    cardiac morbidity
    SYMPTOMS

 and

    infection risks
    SYMPTOMS

 even after

    enzyme replacement therapy
    MEDICATION

, close monitoring of these risks is essential for increasing patient survival after

    kidney transplantation
    MEDICATION

.

Fabry disease (FD)
lysosomal storage disorder
end-stage renal disease
FD
FD
end-stage renal disease
FD
end-stage renal disease
candidemia
FD


Humoral Immune Response to SARS-CoV-2 Vaccination after a Booster Vaccine Dose in Two Kidney Transplant Recipients with Fabry Disease and Variable Secondary Immunosuppressive Regimens.

The urgent need to fight the COVID-19 pandemic has accelerated the development of vaccines against SARS-CoV-2 and approval processes. Initial analysis of two-dose regimens with mRNA vaccines reported up to 95% efficacy against the original strain of the SARS-CoV-2 virus. Challenges arose with the appearance of new strains of the virus, and reports that solid organ transplant recipients may have reduced vaccination success rates after a two-dose mRNA vaccination regimen encouraged health authorities to recommend a booster in immunocompromised patients. Fabry disease is an X-linked inherited lysosomal disorder, which may lead to chronic end-stage renal disease. We report on two patients with advanced Fabry disease, renal graft and adjunctive immunosuppressive therapies who exhibited variable humoral vaccination-related immune responses against SARS-CoV-2 after three vaccine doses. The first patient developed mild COVID-19 infection, while the second patient did not seroconvert after three shots of an mRNA vaccine. Both cases emphasize that patients with Fabry disease and renal graft are susceptible to develop a weak response to COVID-19 vaccination and highlight the importance of maintaining barrier protection measures. Vaccination of family members should be encouraged to lower the risk of viral transmission to immunocompromised, transplanted patients, including vaccinated ones.

The urgent need to fight the

    COVID-19 pandemic
    DIAGNOSIS

 has accelerated the development of

    vaccines against SARS-CoV-2
    MEDICATION

 and approval processes. Initial analysis of

    two-dose regimens with mRNA vaccines
    MEDICATION

 reported up to 95% efficacy against the original

    strain of the SARS-CoV-2 virus
    DIAGNOSIS

. Challenges arose with the appearance of new strains of the virus, and reports that

    solid organ transplant recipients
    MEDICATION

 may have

    reduced vaccination success rates
    SYMPTOMS

 after a

    two-dose mRNA vaccination regimen
    MEDICATION

 encouraged health authorities to recommend a

    booster
    MEDICATION

 in

    immunocompromised
    AGE

 patients.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

    lysosomal disorder
    DIAGNOSIS

, which may lead to

    chronic end-stage renal disease
    DIAGNOSIS

. We report on two patients with

    advanced Fabry disease
    DIAGNOSIS

,

    renal graft
    MEDICATION

 and

    adjunctive immunosuppressive therapies
    MEDICATION

 who exhibited

    variable humoral vaccination-related immune responses against SARS-CoV-2
    BIOCHEMICAL

 after

    three vaccine doses
    MEDICATION

. The first patient developed

    mild COVID-19 infection
    DIAGNOSIS

, while the second patient

    did not seroconvert after three shots of an mRNA vaccine
    NEG_FINDINGS

. Both cases emphasize that patients with

    Fabry disease
    DIAGNOSIS

 and

    renal graft
    SYMPTOMS

 are susceptible to develop a

    weak response to COVID-19 vaccination
    NEG_FINDINGS

 and highlight the importance of maintaining

    barrier protection measures
    MEDICATION

. Vaccination of family members should be encouraged to lower the risk of viral transmission to immunocompromised, transplanted patients, including vaccinated ones.

COVID-19 pandemic
strain of the SARS-CoV-2 virus
Fabry disease
lysosomal disorder
chronic end-stage renal disease
advanced Fabry disease
mild COVID-19 infection
Fabry disease

vaccines against SARS-CoV-2
two-dose regimens with mRNA vaccines
solid organ transplant recipients
two-dose mRNA vaccination regimen
booster
renal graft
adjunctive immunosuppressive therapies
three vaccine doses
barrier protection measures

reduced vaccination success rates
renal graft


Migalastat Treatment in a Kidney-Transplanted Patient with Fabry Disease and N215S Mutation: The First Case Report.

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and, consequently, to glycosphingolipid accumulation in a wide variety of cells. Fabry disease due to N215S (c.644A>G, p.Asn215Ser) missense mutation usually results in a late-onset phenotype presenting with isolated cardiac involvement. We herein present the case of a patient with N215S mutation with cardiac involvement, namely left ventricular hypertrophy and ventricular arrhythmias, and end-stage renal disease requiring kidney transplantation. To the best of our knowledge, this is the first report of a kidney-transplanted Fabry patient treated with oral pharmacologic chaperone migalastat.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations in the GLA gene
    GENETICS

, leading to

    deficient α-galactosidase A activity
    BIOCHEMICAL

 and, consequently, to

    glycosphingolipid accumulation in a wide variety of cells
    MICROSCOPIC

.

    Fabry disease
    DIAGNOSIS

 due to

    N215S (c.644A>G, p.Asn215Ser) missense mutation
    GENETICS

 usually results in a late-onset phenotype presenting with

    isolated cardiac involvement
    SYMPTOMS

. We herein present the case of a patient with

    N215S mutation
    GENETICS

 with

    cardiac involvement
    SYMPTOMS

, namely

    left ventricular hypertrophy
    SYMPTOMS

 and

    ventricular arrhythmias
    SYMPTOMS

, and

    end-stage renal disease
    DIAGNOSIS

 requiring

    kidney transplantation
    MEDICATION

. To the best of our knowledge, this is the first report of a

    kidney-transplanted
    MEDICATION

    Fabry
    DIAGNOSIS

 patient treated with

    oral pharmacologic chaperone migalastat
    MEDICATION

.

Fabry disease
lysosomal storage disorder
Fabry disease
end-stage renal disease
Fabry

isolated cardiac involvement
cardiac involvement
left ventricular hypertrophy
ventricular arrhythmias

kidney transplantation
kidney-transplanted
oral pharmacologic chaperone migalastat


Autopsy Findings of Heterozygous Fabry Disease with the Severe Phenotype: A Case Report.

Fabry disease (FD) is an inherited X-linked lysosomal storage disorder, with hemizygous males being more severely affected than heterozygous females. Herein, we report a rare case of FD in a heterozygous female with a severe phenotype. The patient had obesity and hyperlipidemia and had her first cerebral infarction at the age of 33 years. She underwent renal biopsy and was diagnosed with FD with morphological features of focal segmental glomerulosclerosis nephropathy at the age of 34 years. Her leukocyte alpha-galactosidase A activity was 2.3 Agal/U (normal: >20 Agal/U), and genetic analysis revealed the presence of the classical phenotype. Enzyme replacement therapy (ERT) was initiated at the age of 35 years; however, peritoneal dialysis owing to end-stage renal failure occurred at the age of 37 years. The patient died of a cerebral hemorrhage at the age of 44 years. Her Mainz Severity Score Index at the time of death was 48/76, suggestive of the severe phenotype. Autopsy findings revealed remarkable globotriaosylceramide accumulation on electron microscopy, particularly in the major organs and their vascular smooth muscle cells. Regarding the vertebral arteries which sourced the cerebral hemorrhage, the effects of FD-induced vascular thickening and long-term renal failure-induced atherosclerosis were confirmed. Furthermore, the patient's vascular sclerosis was modified with acquired factors such as lifestyle-related disease associated with obesity. We recommend intensified treatment for metabolic factors simultaneous with ERT to help in delaying the progression of FD.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    inherited X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, with

    hemizygous males
    GENETICS

 being more severely affected than

    heterozygous
    GENETICS

    females
    GENDER

. Herein, we report a rare case of

    FD
    DIAGNOSIS

 in a

    heterozygous
    GENETICS

    female
    GENDER

 with a severe phenotype. The patient had

    obesity
    SYMPTOMS

 and

    hyperlipidemia
    SYMPTOMS

 and had

    her
    GENDER

 first

    cerebral infarction
    SYMPTOMS

 at the

    age of 33 years
    AGE

.

    She
    GENDER

 underwent

    renal biopsy
    PARACLINICAL

 and was diagnosed with

    FD
    DIAGNOSIS

 with

    morphological features of focal segmental glomerulosclerosis nephropathy
    SYMPTOMS

 at the

    age of 34 years
    AGE

.

    Her
    GENDER

    leukocyte alpha-galactosidase A activity was 2.3 Agal/U (normal: >20 Agal/U)
    BIOCHEMICAL

, and

    genetic analysis
    PARACLINICAL

 revealed the

    presence of the classical phenotype
    GENETICS

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 was initiated at the

    age of 35 years
    AGE

; however,

    peritoneal dialysis
    MEDICATION

 owing to

    end-stage renal failure
    SYMPTOMS

 occurred at the

    age of 37 years
    AGE

. The patient

    died
    SYMPTOMS

 of a

    cerebral hemorrhage
    SYMPTOMS

 at the

    age of 44 years
    AGE

.

    Her
    GENDER

    Mainz Severity Score Index
    SYMPTOMS

 at the time of

    death
    SYMPTOMS

    was 48/76
    SYMPTOMS

, suggestive of the

    severe phenotype
    SYMPTOMS

.

    Autopsy findings
    PARACLINICAL

 revealed

    remarkable globotriaosylceramide accumulation on electron microscopy
    MICROSCOPIC

    , particularly in the major organs and their vascular smooth muscle cells
    MICROSCOPIC

. Regarding the

    vertebral arteries
    SYMPTOMS

 which sourced the

    cerebral hemorrhage
    SYMPTOMS

, the effects of

    FD-induced vascular thickening
    SYMPTOMS

 and

    long-term renal failure-induced atherosclerosis
    SYMPTOMS

 were confirmed. Furthermore, the patient's

    vascular sclerosis
    SYMPTOMS

 was modified with acquired factors such as

    lifestyle-related disease associated with obesity
    SYMPTOMS

. We recommend

    intensified treatment for metabolic factors
    MEDICATION

 simultaneous with

    ERT
    MEDICATION

 to help in delaying the progression of

    FD
    DIAGNOSIS

.

Fabry disease (FD)
lysosomal storage disorder
FD
FD
FD

inherited X-linked
hemizygous males
heterozygous
heterozygous
presence of the classical phenotype


Fabry Disease: A Atypical Presentation.

Fabry Disease (FD) is a rare X-linked recessive disease caused by mutations in the GLA gene that lead to a decrease or lack of activity of the enzyme alpha galactosyl A. This lysosomal storage disorder results in progressive damage and dysfunction of several organs and, depending on the type of mutation and gender of the patient, and it may have different manifestations. As FD is a multisystem disease with a progressive character and varying severity, the diagnosis can be challenging, especially when it comes to non-classical forms. As this is a hereditary disease, its diagnosis impacts not only the patient but also his family, making an accurate and timely diagnosis even more important. We present the case of a 59-years-old man diagnosed with non-classical FD, with previous neurological and psychiatric complaints, who was admitted to the Emergency Department (ED) with a generalized tonic-clonic seizure that required orotracheal intubation for airway protection and transferred to an Intensive Care Unit (ICU).

    Fabry Disease (FD)
    DIAGNOSIS

 is a

    rare X-linked recessive disease
    GENETICS

 caused by

    mutations in the GLA gene
    GENETICS

 that lead to a decrease or lack of activity of the enzyme alpha galactosyl A. This

    lysosomal storage disorder
    DIAGNOSIS

 results in

    progressive damage and dysfunction of several organs
    SYMPTOMS

 and, depending on the type of mutation and gender of the patient, and it may have different manifestations. As

    FD
    DIAGNOSIS

 is a

    multisystem disease
    DIAGNOSIS

 with a progressive character and varying severity, the diagnosis can be challenging, especially when it comes to non-classical forms. As this is a

    hereditary disease
    GENETICS

, its diagnosis impacts not only the patient but also his family, making an accurate and timely diagnosis even more important. We present the case of a

    59-years-old
    AGE

    man
    GENDER

 diagnosed with

    non-classical FD
    DIAGNOSIS

, with

    previous neurological and psychiatric complaints
    SYMPTOMS

, who was admitted to the

    Emergency Department (ED)
    PARACLINICAL

 with a

    generalized tonic-clonic seizure
    SYMPTOMS

 that required

    orotracheal intubation
    MEDICATION

    for airway protection
    MEDICATION

 and

    transferred to an Intensive Care Unit (ICU)
    MEDICATION

.

Fabry Disease (FD)
lysosomal storage disorder
FD
multisystem disease
non-classical FD

rare X-linked recessive disease
mutations in the GLA gene
hereditary disease


Renal involvement in a patient with the chronic visceral subtype of acid sphingomyelinase deficiency resembles Fabry disease.

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease (LSD) in which sphingomyelin accumulates due to deficient acid sphingomyelinase. In the chronic visceral subtype, organ manifestations are generally limited to the spleen, liver, and lungs. We report a male patient with the chronic visceral subtype who developed proteinuria and renal insufficiency at the age of 49. In renal tissue, foam cells were observed in the glomeruli as well as sphingomyelin accumulation within podocytes, mesangial cells, endothelial cells, and tubular epithelial cells. Although macrophages are the primary storage cells in both ASMD and Gaucher disease, comparison to the histopathological findings in Gaucher and Fabry disease revealed a diffuse storage pattern in multiple renal cell types, closer resembling the pattern found in Fabry disease.

    Acid sphingomyelinase deficiency (ASMD)
    BIOCHEMICAL

 is a

    lysosomal storage disease (LSD)
    DIAGNOSIS

 in which

    sphingomyelin accumulates
    MICROSCOPIC

 due to

    deficient acid sphingomyelinase
    BIOCHEMICAL

. In the

    chronic visceral subtype
    DIAGNOSIS

,

    organ manifestations
    SYMPTOMS

 are generally

    limited to the spleen, liver, and lungs
    SYMPTOMS

. We report a

    male
    GENDER

 patient with the

    chronic visceral subtype
    DIAGNOSIS

 who developed

    proteinuria
    BIOCHEMICAL

 and

    renal insufficiency
    SYMPTOMS

 at the

    age of 49
    AGE

.

    In renal tissue
    MICROSCOPIC

,

    foam cells were observed in the glomeruli
    MICROSCOPIC

 as well as

    sphingomyelin accumulation within podocytes, mesangial cells, endothelial cells, and tubular epithelial cells
    MICROSCOPIC

. Although

    macrophages are the primary storage cells
    MICROSCOPIC

 in both

    ASMD
    DIAGNOSIS

 and

    Gaucher disease
    DIAGNOSIS

, comparison to the histopathological findings in

    Gaucher
    MICROSCOPIC

 and

    Fabry disease
    DIAGNOSIS

 revealed a

    diffuse storage pattern in multiple renal cell types, closer resembling the pattern found in Fabry disease
    MICROSCOPIC

.

Acid sphingomyelinase deficiency (ASMD)
deficient acid sphingomyelinase
proteinuria

lysosomal storage disease (LSD)
chronic visceral subtype
chronic visceral subtype
ASMD
Gaucher disease
Fabry disease

organ manifestations
limited to the spleen, liver, and lungs
renal insufficiency


Pericardial effusion in the course of Fabry disease cardiomyopathy: a case report.

Fabry disease (FD) is an X-chromosome-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity.

A 51-year-old Japanese woman with a previous diagnosis of FD presented with pericardial effusion. The exudative pericardial fluid contained globotriaosylsphingosine. Left ventricular hypertrophy progressed despite regular administration of agalsidase alfa every 2 weeks over a 7-year period, with increases in plasma levels of globotriaosylsphingosine and interleukin (IL)-18. In addition, the IL-6 level in the pericardial fluid was markedly higher than that in plasma.

This case suggests that elevated IL-6 and IL-18 levels in pericardial fluid and plasma indicate the severity of FD cardiomyopathy.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-chromosome-linked inherited
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 due to

    deficient or absent lysosomal α-galactosidase A activity
    BIOCHEMICAL

.

A

    51-year-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

 with a previous diagnosis of

    FD
    DIAGNOSIS

 presented with

    pericardial effusion
    SYMPTOMS

. The

    exudative pericardial fluid contained globotriaosylsphingosine
    MICROSCOPIC

.

    Left ventricular hypertrophy
    SYMPTOMS

 progressed

    despite regular administration of agalsidase alfa every 2 weeks over a 7-year period
    NEG_FINDINGS

, with

    increases in plasma levels of globotriaosylsphingosine and interleukin (IL)-18
    BIOCHEMICAL

. In addition,

    the IL-6 level in the pericardial fluid was markedly higher than that in plasma
    BIOCHEMICAL

.

This case suggests that

    elevated IL-6 and IL-18 levels in pericardial fluid and plasma
    BIOCHEMICAL

 indicate the severity of

    FD cardiomyopathy
    DIAGNOSIS

.

pericardial effusion
Left ventricular hypertrophy


Angiokeratoma corporis diffusum with severe acroparesthesia, an endothelial abnormality, and inconspicuous genetic findings.

Angiokeratoma corporis diffusum (ACD) was long thought to be a specific dermal sign of Fabry disease (FD, X-linked alpha-galactosidase A [GLA] deficiency). However, other lysosomal storage diseases (LSDs) have also been identified as triggers of ACD. Generalized vasculopathy is an important pathogenetic factor in FD and may also lead to the acroparesthesia (AP) often predominant in FD. We report on an 85-year-old woman with ACD present since her youth and associated with severe AP. Ultrastructure of the dermal lesion showed no lysosomal involvement, but the absence of the basement membrane of the endothelial cells of the capillary vessels was noteworthy. Repeated analyses of the GLA gene revealed no evidence of FD. Whole-exome sequencing was negative for FD and other LSDs, and allowed us to also study FD-related intronic regions of the GLA gene. This is the first report of a patient with FD-like ACD with an endothelial abnormality, otherwise unexplained vasculopathy and severe AP, which are not due to FD or another LSD. Based on family history, another genetic, yet unidentified, defect may cause the disease in this patient. In unexplained ACD, extended genetic analysis is required to exclude particular pathogenic variants of the GLA gene and other genes.

    Angiokeratoma corporis diffusum (ACD)
    SYMPTOMS

 was long thought to be a specific dermal sign of

    Fabry disease (FD
    DIAGNOSIS

,

    X-linked alpha-galactosidase A [GLA] deficiency
    GENETICS

). However, other

    lysosomal storage diseases (LSDs)
    DIAGNOSIS

 have also been identified as triggers of

    ACD
    DIAGNOSIS

.

    Generalized vasculopathy
    SYMPTOMS

 is an important pathogenetic factor in

    FD
    DIAGNOSIS

 and may also lead to the

    acroparesthesia (AP)
    SYMPTOMS

 often predominant in

    FD
    DIAGNOSIS

. We report on an

    85-year-old
    AGE

    woman
    GENDER

 with

    ACD
    DIAGNOSIS

 present

    since her youth
    AGE

 and associated with

    severe AP
    SYMPTOMS

.

    Ultrastructure of the dermal lesion
    PARACLINICAL

 showed

    no lysosomal involvement
    NEG_FINDINGS

, but the

    absence of the basement membrane of the endothelial cells of the capillary vessels
    MICROSCOPIC

 was noteworthy.

    Repeated analyses of the GLA gene
    PARACLINICAL

 revealed

    no evidence of FD
    NEG_FINDINGS

.

    Whole-exome sequencing was negative for FD and other LSDs
    NEG_FINDINGS

, and allowed us to also

    study FD-related intronic regions of the GLA gene
    PARACLINICAL

. This is the first report of a patient with

    FD-like ACD
    DIAGNOSIS

 with an

    endothelial abnormality
    SYMPTOMS

,

    otherwise unexplained vasculopathy
    SYMPTOMS

 and

    severe AP
    SYMPTOMS

, which are

    not due to FD or another LSD
    NEG_FINDINGS

. Based on

    family history
    FAMILY

, another genetic, yet unidentified, defect may cause the disease in this patient. In

    unexplained ACD
    DIAGNOSIS

,

    extended genetic analysis
    PARACLINICAL

 is required to exclude

    particular pathogenic variants of the GLA gene and other genes
    GENETICS

.

Angiokeratoma corporis diffusum (ACD)
Generalized vasculopathy
acroparesthesia (AP)
severe AP
endothelial abnormality
otherwise unexplained vasculopathy
severe AP

Fabry disease (FD
lysosomal storage diseases (LSDs)
ACD
FD
FD
ACD
FD-like ACD
unexplained ACD


Severe manifestations and treatment of COVID-19 in a transplanted patient with Fabry disease.

Fabry disease is an X linked disease caused by pathogenic variants in the GLA gene. The cardiovascular and renal systems are most affected in Fabry patients and may require heart or kidney transplants in the late stages of the disease depending on severity of manifestations. Enzyme replacement therapy (ERT) has proven to delay progression of Fabry disease considerably, especially when started early in life. Current research has shown that individuals who have received cardiac or renal transplants or are currently on dialysis have the greatest probability of developing severe manifestations of COVID-19. It has also been shown that people who contract COVID-19 experience a rapid increase in cytokine levels which can lead to a prothrombotic state and have a greater risk in the presence of comorbidities. A history of cardiac or renal transplants as well as the naturally elevated cytokine levels in Fabry disease make it likely that COVID-19 could have a greater impact on the health of these patients. We report the case of a 67-year-old male with diabetes mellitus, history of kidney transplant, and Fabry disease treated late in progression of the disease first with agalsidase beta ERT, then oral migalastat who developed severe manifestations of COVID-19. The autopsy findings showed acute and organizing hyaline membrane disease consistent with COVID-19 pneumonia and secondary invasive bronchopulmonary aspergillosis with cavitary lesion formation. The sections of the heart showed scattered subendocardial fibrosis, and the transplanted kidneys showed thyroidization and interstitial nephritis potentially secondary to COVID-19, in addition to his long-standing renal disease. This case report serves to chronicle complications in a complex patient with late stage Fabry disease and multiple COVID-19 related complications who succumbed from respiratory failure despite the advanced management for the COVID-19 infection.

    Fabry disease
    DIAGNOSIS

 is an

    X linked disease
    GENETICS

 caused by

    pathogenic variants in the GLA gene
    GENETICS

. The

    cardiovascular and renal systems
    SYMPTOMS

 are most affected in

    Fabry
    DIAGNOSIS

 patients and may require

    heart or kidney transplants
    MEDICATION

 in the late stages of the disease depending on severity of manifestations.

    Enzyme replacement therapy (ERT)
    MEDICATION

 has proven to delay progression of

    Fabry disease
    DIAGNOSIS

 considerably, especially when started

    early in life
    AGE

. Current research has shown that individuals who have

    received cardiac or renal transplants
    MEDICATION

 or are

    currently on dialysis
    MEDICATION

 have the greatest probability of developing

    severe manifestations of COVID-19
    SYMPTOMS

. It has also been shown that people who contract

    COVID-19
    DIAGNOSIS

 experience a

    rapid increase in cytokine levels
    BIOCHEMICAL

 which can lead to a

    prothrombotic state
    BIOCHEMICAL

 and have a greater risk in the presence of comorbidities. A

    history of cardiac or renal transplants
    MEDICATION

 as well as the

    naturally elevated cytokine levels
    BIOCHEMICAL

 in

    Fabry disease
    DIAGNOSIS

 make it likely that

    COVID-19
    DIAGNOSIS

 could have a greater impact on the health of these patients. We report the case of a

    67-year-old
    AGE

    male
    GENDER

 with

    diabetes mellitus
    DIAGNOSIS

,

    history of kidney transplant
    MEDICATION

, and

    Fabry disease
    DIAGNOSIS

 treated late in progression of the disease first with

    agalsidase beta ERT, then oral migalastat
    MEDICATION

 who developed

    severe manifestations of COVID-19
    SYMPTOMS

. The

    autopsy findings
    PARACLINICAL

 showed

    acute and organizing hyaline membrane disease consistent with COVID-19 pneumonia
    MICROSCOPIC

 and

    secondary invasive bronchopulmonary aspergillosis
    DIAGNOSIS

 with

    cavitary lesion formation
    SYMPTOMS

. The

    sections of the heart
    PARACLINICAL

 showed

    scattered subendocardial fibrosis
    SYMPTOMS

, and the

    transplanted kidneys
    PARACLINICAL

 showed

    thyroidization
    MICROSCOPIC

 and

    interstitial nephritis potentially secondary to COVID-19
    DIAGNOSIS

, in addition to his

    long-standing renal disease
    SYMPTOMS

. This case report serves to chronicle complications in a complex patient with

    late stage Fabry disease
    DIAGNOSIS

 and

    multiple COVID-19 related complications
    DIAGNOSIS

 who succumbed from

    respiratory failure
    SYMPTOMS

    despite the advanced management for the COVID-19 infection
    NEG_FINDINGS

.

X linked disease
pathogenic variants in the GLA gene

cardiovascular and renal systems
severe manifestations of COVID-19
severe manifestations of COVID-19
cavitary lesion formation
scattered subendocardial fibrosis
long-standing renal disease
respiratory failure

rapid increase in cytokine levels
prothrombotic state
naturally elevated cytokine levels


Fabry disease associated with multiple myeloma: a case report.

Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked genetic
    GENETICS

    lysosomal disorder
    DIAGNOSIS

 caused by

    alpha-galactosidase A (GLA) deficiency
    BIOCHEMICAL

.

    Multiple myeloma (MM)
    DIAGNOSIS

 predominately affects

    older adults
    AGE

, which ranks as the second commonest

    hematological malignancy
    DIAGNOSIS

. Their overlap has rarely been reported. We present a case of the

    coexistence of FD and MM
    DIAGNOSIS

 in a patient. We report the case of a

    68-year-old
    AGE

    woman
    GENDER

 who was referred to our hospital for the evaluation of

    thoracic spine tumor with bone destruction
    SYMPTOMS

. On admission,

    her
    GENDER

 serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL.

    Bone marrow aspiration
    PARACLINICAL

 revealed

    MM
    DIAGNOSIS

.

    Renal biopsy
    PARACLINICAL

 showed

    myeloma cast nephropathy
    DIAGNOSIS

, which was the primary cause of

    acute kidney injury
    SYMPTOMS

.

    Renal pathology
    PARACLINICAL

 also showed

    podocyte swelling
    MICROSCOPIC

 and

    tubule myeloid bodies in a mosaic pattern compatible with female FD
    MICROSCOPIC

. Consequently, the patient was diagnosed as

    FD
    DIAGNOSIS

 based on the

    germ line mutation in GLA
    GENETICS

. The patient was treated with

    bortezomib and dexamethasone therapy
    MEDICATION

, which

    significantly improved the renal function
    SYMPTOMS

. This is the second case demonstrating a

    potential pathogenic relationship between FD and MM
    SYMPTOMS

. Since

    FD
    DIAGNOSIS

 is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of

    FD
    DIAGNOSIS

 is high. If an

    MM
    DIAGNOSIS

 patient has

    multiple organ abnormalities
    SYMPTOMS

 or any

    familial history
    FAMILY

, the physician should suspect

    FD
    DIAGNOSIS

.

Fabry disease (FD)
lysosomal disorder
Multiple myeloma (MM)
hematological malignancy
coexistence of FD and MM
MM
myeloma cast nephropathy
FD
FD
FD
MM
FD

X-linked genetic
germ line mutation in GLA


A Case of a 49-Year-Old Man with Nonclassical Fabry Disease Diagnosed by Renal Biopsy.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficiency of α-GLA activity, leading to major organ failure and premature mortality. According to different disease courses, FD can be divided into classical and nonclassical phenotypes. The nonclassical FD phenotype is always absent of characteristic symptoms, which makes identifying it challenging. This article presents a 49-year-old man with a 10-year history of proteinuria and decreased glomerular filtration rate. An electrocardiogram showed a complete right bundle branch block and abnormal Q waves in high lateral, accompanied by dramatically elevated ST segment. Consequently, a renal biopsy was performed. Vacuolation was found in many podocytes in light microscopic examinations. Similarly, a myelin-like structure was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, genetic analysis, p.R301Q (c.902G>A [p.Arg301Gln]), confirmed the FD diagnosis. Angiotensin receptor blocker and traditional Chinese medicine, but not enzyme replacement therapy, were prescribed due to financial constraints. The patient had stabilization of kidney disease 6 months later. The case showed that renal biopsy should be performed in patients with cardiac and renal symptoms, which could contribute toward the correct diagnosis for nonclassical FD type.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    mutations in the galactosidase A (GLA) gene
    GENETICS

 that result in

    deficiency of α-GLA activity
    BIOCHEMICAL

, leading to

    major organ failure
    SYMPTOMS

 and

    premature mortality
    SYMPTOMS

. According to different disease courses,

    FD
    DIAGNOSIS

 can be divided into classical and nonclassical phenotypes. The

    nonclassical FD
    DIAGNOSIS

 phenotype is always

    absent of characteristic symptoms
    NEG_FINDINGS

, which makes identifying it challenging. This article presents a

    49-year-old
    AGE

    man
    GENDER

 with a 10-year history of

    proteinuria
    BIOCHEMICAL

 and

    decreased glomerular filtration rate
    BIOCHEMICAL

. An

    electrocardiogram
    PARACLINICAL

 showed a

    complete right bundle branch block
    SYMPTOMS

 and

    abnormal Q waves in high lateral
    SYMPTOMS

, accompanied by

    dramatically elevated ST segment
    SYMPTOMS

. Consequently, a

    renal biopsy
    PARACLINICAL

 was performed.

    Vacuolation was found in many podocytes
    MICROSCOPIC

 in

    light microscopic examinations
    PARACLINICAL

. Similarly,

    a myelin-like structure was detected
    MICROSCOPIC

 by

    electron microscopy
    PARACLINICAL

. Pathological findings were most consistent with

    FD
    DIAGNOSIS

. Consequently,

    genetic analysis
    PARACLINICAL

,

    p.R301Q (c.902G>A [p.Arg301Gln])
    GENETICS

, confirmed the

    FD
    DIAGNOSIS

 diagnosis.

    Angiotensin receptor blocker
    MEDICATION

 and

    traditional Chinese medicine
    MEDICATION

,

    but not enzyme replacement therapy
    NEG_FINDINGS

, were prescribed due to financial constraints. The patient had

    stabilization of kidney disease
    SYMPTOMS

 6 months later. The case showed that

    renal biopsy
    PARACLINICAL

 should be performed in patients with

    cardiac and renal symptoms
    SYMPTOMS

, which could contribute toward the correct diagnosis for

    nonclassical FD type
    DIAGNOSIS

.

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

deficiency of α-GLA activity
proteinuria
decreased glomerular filtration rate

major organ failure
premature mortality
complete right bundle branch block
abnormal Q waves in high lateral
dramatically elevated ST segment
stabilization of kidney disease
cardiac and renal symptoms

absent of characteristic symptoms
but not enzyme replacement therapy

Angiotensin receptor blocker
traditional Chinese medicine


[Solitary angiokeratoma of the tongue].

A 41-year-old woman, who was referred with a reddish purple like lesion on the left side of the tongue, appeared to have an angiokeratoma after histopathological examination. Because of the benign character of this lesion and the absence of any complaints, no adjuvant treatment after excisional biopsy was indicated. Angiokeratomas rarely appear as solitary oral lesions. More often they are seen as part of an underlying systemic disease, mostly Fabry disease. Due to widespread skin involvement of angiokeratomas with Fabry disease, referral to a dermatologist is indicated when oral lesions are encountered. Esthetically unpleasing or painful angiokeratomas can be locally excised or treated by laser- or cryotherapy.

A

    41-year-old
    AGE

    woman
    GENDER

, who was referred with a

    reddish purple like lesion on the left side of the tongue
    SYMPTOMS

, appeared to have an

    angiokeratoma
    DIAGNOSIS

 after

    histopathological examination
    PARACLINICAL

. Because of the benign character of this lesion and the

    absence of any complaints
    NEG_FINDINGS

,

    no adjuvant treatment after excisional biopsy
    NEG_FINDINGS

 was indicated.

    Angiokeratomas
    SYMPTOMS

 rarely appear as

    solitary oral lesions
    SYMPTOMS

. More often they are seen as part of an underlying

    systemic disease
    DIAGNOSIS

, mostly

    Fabry disease
    DIAGNOSIS

. Due to

    widespread skin involvement of angiokeratomas
    SYMPTOMS

 with

    Fabry disease
    DIAGNOSIS

, referral to a

    dermatologist
    PARACLINICAL

 is indicated when

    oral lesions
    SYMPTOMS

 are encountered.

    Esthetically unpleasing or painful angiokeratomas
    SYMPTOMS

 can be

    locally excised
    MEDICATION

 or treated by

    laser- or cryotherapy
    MEDICATION

.

angiokeratoma
systemic disease
Fabry disease
Fabry disease


Rare presentation of Fabry disease as 'burnt-out' hypertrophic cardiomyopathy.

We herein report the case of a 53-year-old man who was historically diagnosed with hypertrophic cardiomyopathy (HCM) and was lost to follow-up, before presenting with end-stage heart failure. This was initially suspected as dilated cardiomyopathy and then 'burnt-out phase' of HCM but subsequently the underlying diagnosis was Fabry disease. Fabry disease is an uncommon lysosomal-storage disease due to reduced or absent activity of the alpha-galactosidase A enzyme. Cardiac involvement most frequently comprises left ventricular hypertrophy. Early treatment of the underlying condition with enzyme replacement therapy may prevent the progression to end-stage heart failure. Fabry disease should be considered in all patients presenting with a clinical phenotype of HCM and a historical diagnosis should be re-evaluated in light of new diagnostic tools. Untreated Fabry can progress to a 'burnt out' phase, whereby initial hypertrophy undergoes eccentric remodelling to a dilated, severely impaired left ventricle.

We herein report the case of a

    53-year-old
    AGE

    man
    GENDER

 who was historically diagnosed with

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 and was

    lost to follow-up
    NEG_FINDINGS

, before presenting with

    end-stage heart failure
    SYMPTOMS

. This was initially suspected as

    dilated cardiomyopathy
    DIAGNOSIS

 and then

    'burnt-out phase' of HCM
    DIAGNOSIS

 but subsequently the underlying diagnosis was

    Fabry disease
    DIAGNOSIS

.

    Fabry disease
    DIAGNOSIS

 is an uncommon

    lysosomal-storage disease
    DIAGNOSIS

 due to

    reduced or absent activity of the alpha-galactosidase A enzyme
    BIOCHEMICAL

.

    Cardiac involvement
    SYMPTOMS

 most frequently comprises

    left ventricular hypertrophy
    SYMPTOMS

.

    Early treatment of
    MEDICATION

 the underlying condition with

    enzyme replacement therapy
    MEDICATION

 may prevent the progression to

    end-stage heart failure
    SYMPTOMS

.

    Fabry disease
    DIAGNOSIS

 should be considered in all patients presenting with a clinical phenotype of

    HCM
    DIAGNOSIS

 and a historical diagnosis should be re-evaluated in light of new diagnostic tools.

    Untreated Fabry
    DIAGNOSIS

 can progress to a '

    burnt out' phase
    DIAGNOSIS

, whereby

    initial hypertrophy undergoes eccentric remodelling to a dilated, severely impaired left ventricle
    SYMPTOMS

.

hypertrophic cardiomyopathy (HCM)
dilated cardiomyopathy
'burnt-out phase' of HCM
Fabry disease
Fabry disease
lysosomal-storage disease
Fabry disease
HCM
Untreated Fabry
burnt out' phase

Early treatment of
enzyme replacement therapy


Corrigendum to: Rapidly progressive aortic stenosis treated with transcatheter aortic valve implantation in a patient with Fabry disease: a case report.

[This corrects the article DOI: 10.1093/ehjcr/ytab124.][This corrects the article DOI: 10.1093/ehjcr/ytab124.].


Application of Genetic Testing in Unveiling the Diagnosis of Fabry Disease in a Patient with Hypertrophic Cardiomyopathy.

Fabry disease (FD) is a lysosomal storage disorder with an X-linked genetic pattern. It is caused by the genetic mutations in the galactosidase alpha gene on the long arm of the X-chromosome, resulting in the deficiency of the alpha-galactosidase A enzyme activity. This leads to an accumulation of globotriaosylceramide in a variety of cells, including cells in the heart. Left ventricular hypertrophy is one of the most common manifestations of FD involving the heart. Further cardiac disease progression portends significant morbidity and mortality. The early initiation of enzyme replacement therapy is associated with reversal or halting of the disease's progression and an improved clinical outcome. Here, we present the case of a 40-year-old male patient with left ventricular hypertrophy based on the results of a transthoracic echocardiogram and advanced cardiac imaging. He was later diagnosed with FD with the assistance of genetic testing. We also briefly outline the diagnostic challenges and treatment of FD.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 with an

    X-linked genetic pattern
    GENETICS

. It is caused by the

    genetic mutations in the galactosidase alpha gene on the long arm of the X-chromosome
    GENETICS

, resulting in the

    deficiency of the alpha-galactosidase A enzyme activity
    BIOCHEMICAL

. This leads to an

    accumulation of globotriaosylceramide in a variety of cells, including cells in the heart
    MICROSCOPIC

.

    Left ventricular hypertrophy
    SYMPTOMS

 is one of the most common manifestations of

    FD
    DIAGNOSIS

    involving the heart
    SYMPTOMS

. Further

    cardiac disease progression
    SYMPTOMS

 portends significant morbidity and mortality. The

    early initiation of enzyme replacement therapy
    MEDICATION

 is associated with

    reversal or halting of the disease's progression
    SYMPTOMS

 and an improved clinical outcome. Here, we present the case of a

    40-year-old
    AGE

    male
    GENDER

 patient with

    left ventricular hypertrophy
    SYMPTOMS

 based on the results of a

    transthoracic echocardiogram
    PARACLINICAL

 and

    advanced cardiac imaging
    PARACLINICAL

.

    He
    GENDER

 was later diagnosed with

    FD
    DIAGNOSIS

 with the assistance of

    genetic testing
    PARACLINICAL

. We also briefly outline the diagnostic challenges and treatment of

    FD
    DIAGNOSIS

.


Generation of an induced pluripotent stem cell line (ZJUi007-A) from a 11-year-old patient of Fabry disease.

PBMCs were collected from a patient with a novel GLA gene mutation (c.140G > A) which contributed to Fabry disease. Subsequently, an induced pluripotent stem cell (iPSC) line was derived using an episomal reprogramming method that transfer the reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28 and L-MYC into the PBMCs. The expected mutation in the iPSC line was confirmed by Sanger sequencing, while the pluripotency status was validated by immunofluorescence assay and flow cytometry for pluripotency markers, as well as teratoma formation.

PBMCs were collected from a patient with a

    novel GLA gene mutation (c.140G > A)
    GENETICS

 which contributed to

    Fabry disease
    DIAGNOSIS

. Subsequently, an

    induced pluripotent stem cell (iPSC) line
    MICROSCOPIC

 was derived using an

    episomal reprogramming method
    MEDICATION

 that

    transfer the reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28 and L-MYC
    MEDICATION

    into the PBMCs
    MICROSCOPIC

. The

    expected mutation in the iPSC line
    GENETICS

 was confirmed by

    Sanger sequencing
    PARACLINICAL

, while the pluripotency status was validated by

    immunofluorescence assay
    PARACLINICAL

 and

    flow cytometry for
    PARACLINICAL

 pluripotency markers, as well as

    teratoma formation
    MICROSCOPIC

.

novel GLA gene mutation (c.140G > A)
expected mutation in the iPSC line


First 2 Fabry Cases with Novel Mutation and Their Associated Clusters in Malaysia.

BACKGROUND No cases of Fabry disease (FD) have been reported thus far in Malaysia. We aimed to report the demographic characteristics, clinical manifestations, molecular results, and treatment outcomes of 2 FD cases. This study was a retrospective review of 2 family clusters of FD on follow-up in Sarawak, Malaysia. CASE REPORT Two index patients were confirmed to have FD. Index patient 1, who had nephrotic-range proteinuria and cornea verticillata, carried a variant within exon 4 of the GLA gene: c.610 T>C (p.Trp204Arg). Agalsidase beta (Fabrazyme®) enzyme replacement therapy was initiated, with the absence of neutralizing antibody after 24 months. No hypersensitivity or adverse reactions were reported. The patient's proteinuria and renal function remained stable. Other family members who carried the same mutation were asymptomatic. Index patient 2, who had residual activity of alpha-galactosidase A and a normal globotriaosylsphingosine level, carried a novel GLA mutation of c.548-5T>A. He was diagnosed with end-stage renal disease on regular dialysis and had nonspecific headache with 1 episode of seizure a few years prior to FD genetic screening. One brother had chronic neuropathic pain but refused further investigations. Other family members who had the same mutation were asymptomatic. This mutation has never been reported in literature, and its pathogenicity warrants further studies. CONCLUSIONS It is of utmost importance to increase awareness of FD among clinicians, so that appropriate screening may be done to determine its true prevalence and prompt treatment can be initiated early.

BACKGROUND No cases of

    Fabry disease (FD)
    DIAGNOSIS

 have been reported thus far in

    Malaysia
    ETHNICITY

. We aimed to report the demographic characteristics, clinical manifestations, molecular results, and treatment outcomes of 2

    FD
    DIAGNOSIS

 cases. This study was a retrospective review of 2 family clusters of

    FD
    DIAGNOSIS

 on follow-up in

    Sarawak
    ETHNICITY

,

    Malaysia
    ETHNICITY

. CASE REPORT Two index patients were confirmed to have

    FD
    DIAGNOSIS

. Index patient 1, who had

    nephrotic-range proteinuria
    BIOCHEMICAL

 and

    cornea verticillata
    SYMPTOMS

, carried a

    variant within exon 4 of the GLA gene: c.610 T>C (p.Trp204Arg)
    GENETICS

.

    Agalsidase beta (Fabrazyme®) enzyme replacement therapy
    MEDICATION

 was initiated, with the

    absence of neutralizing antibody after 24 months
    NEG_FINDINGS

.

    No hypersensitivity or adverse reactions were reported
    NEG_FINDINGS

. The patient's

    proteinuria and renal function remained stable
    BIOCHEMICAL

. Other

    family members who carried the same mutation
    FAMILY

    were asymptomatic
    NEG_FINDINGS

. Index patient 2, who had

    residual activity of alpha-galactosidase A
    BIOCHEMICAL

 and a

    normal globotriaosylsphingosine level
    NEG_FINDINGS

, carried a novel GLA mutation of c.548-5T>A.

    He
    GENDER

 was diagnosed with

    end-stage renal disease
    DIAGNOSIS

 on

    regular dialysis
    MEDICATION

 and had

    nonspecific headache with 1 episode of seizure
    SYMPTOMS

 a few years prior to

    FD genetic screening
    PARACLINICAL

.

    One brother had chronic neuropathic pain
    FAMILY

 but

    refused further investigations
    NEG_FINDINGS

.

    Other family members who had the same mutation
    FAMILY

    were asymptomatic
    NEG_FINDINGS

. This mutation has never been reported in literature, and its pathogenicity warrants further studies. CONCLUSIONS It is of utmost importance to increase awareness of

    FD
    DIAGNOSIS

 among clinicians, so that appropriate screening may be done to determine its true prevalence and prompt treatment can be initiated early.

Fabry disease (FD)
FD
FD
FD
end-stage renal disease
FD


Rapidly progressive aortic stenosis treated with transcatheter aortic valve implantation in a patient with Fabry disease: a case report.

Fabry disease (FD) is a rare lysosomal storage disease, caused by mutations in the gene encoding the enzyme α-galactosidase A (α-Gal A). Cardiac involvement is one of the main causes of death and it is characterized by progressive concentric left ventricular hypertrophy (LVH), which in most cases is symmetric. Mild thickening of the left-sided valves is seen in as many as a quarter of patients. Severe aortic stenosis is an extremely rare disorder in FD.

In this report, we describe the case of a 57-year-old male, who was diagnosed with a cardiac variant of FD 10 years ago. Since the patient had severe LVH, he was started on enzyme replacement therapy when he was 47 years old with an intravenous infusion of 0.2 mg/kg of agalsidase alpha every 14 days. The patient remained stable and asymptomatic for 9 years, until he presented with dyspnoea in New York Heart Association functional class II-III and severe aortic stenosis (aortic valve area: 0.97 cm2) together with severe systolic dysfunction [ejection fraction (EF): 29%]. Because of the patient's comorbidities and high surgical risk, he underwent successful transfemoral transcatheter aortic valve implantation (TAVI). At 2 months following TAVI, the patient was asymptomatic and, in spite of his Fabry cardiomyopathy, the EF had increased to 45%.

To our knowledge, this is the first case in the literature to demonstrate a rapid progression of aortic stenosis with severe impairment of left ventricular function and worsening in functional class in a patient with FD, who following TAVI improved his EF, with disappearance of symptoms and ventricular arrhythmias.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare lysosomal storage disease
    DIAGNOSIS

, caused by

    mutations in the gene encoding the enzyme α-galactosidase A (α-Gal A)
    GENETICS

.

    Cardiac involvement
    SYMPTOMS

 is one of the main causes of

    death
    SYMPTOMS

 and it is characterized by

    progressive concentric left ventricular hypertrophy (LVH)
    SYMPTOMS

, which in most cases is symmetric.

    Mild thickening of the left-sided valves
    SYMPTOMS

 is seen in as many as a quarter of patients.

    Severe aortic stenosis
    SYMPTOMS

 is an extremely rare disorder in

    FD
    DIAGNOSIS

.

In this report, we describe the case of a

    57-year-old
    AGE

    male
    GENDER

, who was diagnosed with a

    cardiac variant of FD
    DIAGNOSIS

 10 years ago. Since the patient had

    severe LVH
    SYMPTOMS

,

    he
    GENDER

 was started on

    enzyme replacement therapy
    MEDICATION

 when

    he
    GENDER

 was

    47 years old
    AGE

    with an intravenous infusion of 0.2 mg/kg of agalsidase alpha every 14 days
    MEDICATION

. The patient remained stable and

    asymptomatic
    NEG_FINDINGS

 for 9 years, until

    he
    GENDER

 presented with

    dyspnoea in New York Heart Association functional class II-III
    SYMPTOMS

 and

    severe aortic stenosis (aortic valve area: 0.97 cm2)
    SYMPTOMS

 together with

    severe systolic dysfunction [ejection fraction (EF): 29%]
    SYMPTOMS

. Because of the patient's comorbidities and high surgical risk,

    he
    GENDER

 underwent

    successful transfemoral transcatheter aortic valve implantation (TAVI)
    MEDICATION

. At 2 months following

    TAVI
    MEDICATION

, the patient was

    asymptomatic
    NEG_FINDINGS

 and, in spite of his

    Fabry cardiomyopathy
    DIAGNOSIS

, the

    EF had increased to 45%
    SYMPTOMS

.

To our knowledge, this is the first case in the literature to demonstrate a

    rapid progression of aortic stenosis
    SYMPTOMS

 with

    severe impairment of left ventricular function
    SYMPTOMS

 and

    worsening in functional class
    SYMPTOMS

 in a patient with

    FD
    DIAGNOSIS

, who following

    TAVI
    MEDICATION

    improved his EF
    SYMPTOMS

, with

    disappearance of symptoms and ventricular arrhythmias
    SYMPTOMS

.

Fabry disease (FD)
rare lysosomal storage disease
FD
cardiac variant of FD
Fabry cardiomyopathy
FD


Anderson-Fabry disease presenting with atrial fibrillation as earlier sign in a young patient: A case report.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder that results from a deficiency of α-galactosidase A enzyme activity in which glycosphingolipids gradually accumulate in multi-organ systems. Cardiac manifestations are the leading cause of mortality in patients with AFD. Among them, arrhythmias comprise a large portion of the heart disease cases in AFD, most of which are characterized by conduction disorders. However, atrial fibrillation as a presenting sign at the young age group diagnosed with AFD is uncommon.

We report a case of a 26-year-old man who was admitted with chest discomfort. Left ventricular hypertrophy was fulfilled in the criteria by the Sokolow-Lyon index and atrial fibrillation on the 12 Leads-electrocardiography (ECG) that was documented in the emergency room. After spontaneously restored to normal sinus rhythm, relationships between P and R waves, including a shorter PR interval on the ECG, were revealed. The echocardiographic findings showed thickened interventricular septal and left posterior ventricular walls. Based on the clues mentioned earlier, we realized the possibility of AFD. Additionally, we noticed the associated symptoms and signs, including bilateral mild hearing loss, neuropathic pain, anhidrosis, and angiokeratoma on the trunk and hands. He was finally diagnosed with classical AFD, which was confirmed by the gene mutation and abnormal enzyme activity of α-galactosidase A.

This case is a rare case of AFD as a presentation with atrial fibrillation at a young age. Confirming the relationship between P and Q waves on the ECG through sinus rhythm conversion may help in differential diagnosis of the cause of atrial fibrillation and hypertrophic myocardium.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 that results from a

    deficiency of α-galactosidase A enzyme activity
    BIOCHEMICAL

 in which

    glycosphingolipids gradually accumulate in multi-organ systems
    MICROSCOPIC

.

    Cardiac manifestations
    SYMPTOMS

 are the leading cause of mortality in patients with

    AFD
    DIAGNOSIS

. Among them,

    arrhythmias
    SYMPTOMS

 comprise a large portion of the

    heart disease
    DIAGNOSIS

 cases in

    AFD
    DIAGNOSIS

, most of which are characterized by

    conduction disorders
    DIAGNOSIS

. However,

    atrial fibrillation
    SYMPTOMS

 as a presenting sign at the

    young age group
    AGE

 diagnosed with

    AFD
    DIAGNOSIS

 is uncommon.

We report a case of a

    26-year-old
    AGE

    man
    GENDER

 who was admitted with

    chest discomfort
    SYMPTOMS

.

    Left ventricular hypertrophy
    SYMPTOMS

 was fulfilled in the criteria by the Sokolow-Lyon index and

    atrial fibrillation on the 12 Leads-electrocardiography (ECG)
    SYMPTOMS

 that was documented in the emergency room. After

    spontaneously restored to normal sinus rhythm
    SYMPTOMS

,

    relationships between P and R waves, including a shorter PR interval on the ECG
    SYMPTOMS

, were revealed. The echocardiographic findings showed

    thickened interventricular septal and left posterior ventricular walls
    SYMPTOMS

. Based on the clues mentioned earlier, we realized the possibility of

    AFD
    DIAGNOSIS

. Additionally, we noticed the associated symptoms and signs, including

    bilateral mild hearing loss
    SYMPTOMS

,

    neuropathic pain
    SYMPTOMS

,

    anhidrosis
    SYMPTOMS

, and

    angiokeratoma on the trunk and hands
    SYMPTOMS

.

    He
    GENDER

 was finally diagnosed with

    classical AFD
    DIAGNOSIS

, which was confirmed by the

    gene mutation
    GENETICS

 and abnormal enzyme activity of α-galactosidase A.

This case is a rare case of

    AFD
    DIAGNOSIS

 as a presentation with

    atrial fibrillation
    SYMPTOMS

 at a

    young age
    AGE

. Confirming the

    relationship between P and Q waves on the ECG
    SYMPTOMS

 through sinus rhythm conversion may help in

    differential diagnosis
    PARACLINICAL

 of the cause of

    atrial fibrillation
    DIAGNOSIS

 and

    hypertrophic myocardium
    DIAGNOSIS

.

Anderson-Fabry disease (AFD)
lysosomal storage disorder
AFD
heart disease
AFD
conduction disorders
AFD
AFD
classical AFD
AFD
atrial fibrillation
hypertrophic myocardium


Lupus Nephritis and Hydroxychloroquine-Associated Zebra Bodies: Not Just in Fabry Disease.

Zebra bodies in kidney biopsy specimens are widely accepted as a specific feature of Fabry disease but they can also be present in a drug-induced mimic of Fabry disease, phospholipidosis. Chloroquine and hydroxychloroquine may both induce zebra body formation and kidney phospholipidosis. However, the frequency and clinical significance of such changes remain unknown. We report 5 serial kidney biopsy cases diagnosed as lupus nephritis during hydroxychloroquine administration. All 5 patients exhibited a few, but varying amounts, of zebra bodies in glomerular intrinsic cells, that is, podocytes, parietal epithelial cells, mesangial cells, and endothelial cells. Most of the zebra bodies detected were subtle, though certainly recognizable; these zebra bodies were much smaller than those observed in Fabry disease. Zebra bodies were not observed in patients with lupus nephritis in the absence of chloroquine or hydroxychloroquine administration. All patients with lupus nephritis who received hydroxychloroquine achieved complete remission during continuous use of hydroxychloroquine, though kidney toxicity of drug-induced phospholipidosis might be masked by immunosuppression. Based on this small series of cases, we speculate that the hydroxychloroquine-associated manifestation of zebra bodies and phospholipidosis in the kidney may be frequent phenomena and may have only a subclinical influence on kidney function, at least in the short term.

    Zebra bodies in kidney biopsy specimens
    MICROSCOPIC

 are widely accepted as a specific feature of

    Fabry disease
    DIAGNOSIS

 but they can also be present in a

    drug-induced mimic of Fabry disease
    DIAGNOSIS

,

    phospholipidosis
    DIAGNOSIS

.

    Chloroquine
    MEDICATION

 and

    hydroxychloroquine
    MEDICATION

 may both induce

    zebra body formation
    MICROSCOPIC

 and

    kidney phospholipidosis
    MICROSCOPIC

. However, the frequency and clinical significance of such changes remain unknown. We report 5

    serial kidney biopsy
    PARACLINICAL

 cases diagnosed as

    lupus nephritis
    DIAGNOSIS

 during

    hydroxychloroquine administration
    MEDICATION

. All 5 patients exhibited

    a few, but varying amounts, of zebra bodies in glomerular intrinsic cells, that is, podocytes, parietal epithelial cells, mesangial cells, and endothelial cells
    MICROSCOPIC

. Most

    of the zebra bodies detected
    MICROSCOPIC

 were subtle, though certainly recognizable; these

    zebra bodies
    MICROSCOPIC

    were much smaller than those observed in Fabry disease
    SYMPTOMS

.

    Zebra bodies
    MICROSCOPIC

 were not observed in patients with

    lupus nephritis
    DIAGNOSIS

 in the

    absence of chloroquine or hydroxychloroquine administration
    NEG_FINDINGS

. All patients with

    lupus nephritis
    DIAGNOSIS

 who received

    hydroxychloroquine
    MEDICATION

 achieved

    complete remission
    SYMPTOMS

 during

    continuous use of hydroxychloroquine
    MEDICATION

, though

    kidney toxicity of drug-induced phospholipidosis
    SYMPTOMS

 might be

    masked by immunosuppression
    NEG_FINDINGS

. Based on this small series of cases, we speculate that the

    hydroxychloroquine
    DIAGNOSIS

-associated

    manifestation of zebra bodies and phospholipidosis in the kidney
    MICROSCOPIC

 may be frequent phenomena and may have only a

    subclinical influence on kidney function
    NEG_FINDINGS

, at least in the short term.

Fabry disease
drug-induced mimic of Fabry disease
phospholipidosis
lupus nephritis
lupus nephritis
lupus nephritis
hydroxychloroquine

Chloroquine
hydroxychloroquine
hydroxychloroquine administration
hydroxychloroquine
continuous use of hydroxychloroquine


Myeloid bodies caused by COQ2 mutation: a case of concurrent COQ2 nephropathy and IgA nephropathy.

Immunoglobulin A (IgA) nephropathy, in the presence of myeloid bodies, has been reported in Fabry disease (FD). In this case, we excluded the diagnosis of FD by demonstrating the absence of mutation in the α-galactosidase A（GLA）gene. Our patient also denied any history of use of cationic amphiphilic drugs. Interestingly, we identified a novel missense mutation for Coenzyme Q2（COQ2） , which is known to cause COQ2 mutation-associated nephropathy. We also found heteromorphic mitochondria and good treatment response in our patient following coenzyme Q10 supplementation. In light of our findings, our patient was diagnosed with COQ2 nephropathy and IgA nephropathy. To our knowledge, this is the first case report of COQ2 nephropathy with pathologic manifestations of myeloid bodies in podocytes.

    Immunoglobulin A (IgA) nephropathy
    DIAGNOSIS

, in the

    presence of myeloid bodies
    MICROSCOPIC

, has been reported in

    Fabry disease (FD)
    DIAGNOSIS

. In this case, we

    excluded the diagnosis of FD
    NEG_FINDINGS

 by demonstrating the

    absence of mutation in the α-galactosidase A（GLA）gene
    NEG_FINDINGS

. Our patient also

    denied any history of use of cationic amphiphilic drugs
    NEG_FINDINGS

. Interestingly, we identified a

    novel missense mutation for Coenzyme Q2（COQ2） , which is
    GENETICS

 known to cause

    COQ2 mutation-associated nephropathy
    GENETICS

. We also found

    heteromorphic mitochondria
    MICROSCOPIC

 and

    good treatment response
    SYMPTOMS

 in our patient following

    coenzyme Q10 supplementation
    MEDICATION

. In light of our findings, our patient was diagnosed with

    COQ2 nephropathy
    DIAGNOSIS

 and

    IgA nephropathy
    DIAGNOSIS

. To our knowledge, this is the first case report of

    COQ2 nephropathy
    DIAGNOSIS

 with

    pathologic manifestations of myeloid bodies in podocytes
    MICROSCOPIC

.

Immunoglobulin A (IgA) nephropathy
Fabry disease (FD)
COQ2 nephropathy
IgA nephropathy
COQ2 nephropathy


LMX1B-associated nephropathy that showed myelin figures on electron microscopy.

The mutation of LIM homeodomain transcription factor LMX1B gene leads to nail-patella syndrome (NPS), which is characterized by dysplastic nails, hypoplastic patellae, iliac horns and nephropathy. The characteristic renal histological finding of NPS nephropathy is irregular thickening of the glomerular basement membrane with patchy lucent areas, including deposits of bundles of type III collagen fibrils revealed by electron microscopy (EM). Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A activity, and the characteristic EM finding is a lamellated membrane structure (myelin figures). We present the case of a male with LMX1B-associated nephropathy (LAN) who showed focal segmental glomerulosclerosis (FSGS) on light microscopy, and myelin figures and slight deposits of collagen fibrils on EM, without findings of glomerular basement membrane abnormality suggestive for NPS. A 21-year-old Japanese-Brazilian man was admitted to hospital for an investigation of the cause of proteinuria and decreased renal function. A renal biopsy was performed to investigate the cause of renal damage. Fabry disease was initially considered, based on the presence of myelin figures on EM, but since he had normal α-galactosidase A activity, this initial diagnosis was denied, and the patient was subsequently diagnosed with FSGS. At 22 years after that renal biopsy, the patient was incidentally diagnosed with LAN when NM_002316:3c.746G > A:p.(Arg249Gln) LMX1B variant was identified in his older brother by a pre-transplantation examination, and the same mutation was confirmed in the patient. Myelin figures revealed by EM might become one of the clues for the diagnosis of LAN.

The

    mutation of LIM homeodomain transcription factor LMX1B gene
    GENETICS

 leads to

    nail-patella syndrome (NPS)
    DIAGNOSIS

, which is characterized by

    dysplastic nails
    SYMPTOMS

,

    hypoplastic patellae
    SYMPTOMS

,

    iliac horns
    SYMPTOMS

 and

    nephropathy
    DIAGNOSIS

. The characteristic renal histological finding of

    NPS nephropathy
    DIAGNOSIS

 is

    irregular thickening of the glomerular basement membrane with patchy lucent areas
    MICROSCOPIC

, including

    deposits of bundles of type III collagen fibrils
    MICROSCOPIC

 revealed by

    electron microscopy (EM)
    PARACLINICAL

.

    Fabry disease
    DIAGNOSIS

 is a

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of α-galactosidase A activity
    BIOCHEMICAL

, and the characteristic EM finding is a

    lamellated membrane structure (myelin figures)
    MICROSCOPIC

. We present the case of a

    male
    GENDER

 with

    LMX1B-associated nephropathy (LAN)
    DIAGNOSIS

 who showed

    focal segmental glomerulosclerosis (FSGS)
    DIAGNOSIS

 on

    light microscopy
    PARACLINICAL

, and

    myelin figures
    MICROSCOPIC

 and

    slight deposits of collagen fibrils
    MICROSCOPIC

 on

    EM
    PARACLINICAL

,

    without findings of glomerular basement membrane abnormality suggestive for NPS
    NEG_FINDINGS

. A

    21-year-old
    AGE

    Japanese-Brazilian
    ETHNICITY

    man
    GENDER

 was admitted to hospital for an investigation of the cause of

    proteinuria
    BIOCHEMICAL

 and

    decreased renal function
    BIOCHEMICAL

. A

    renal biopsy
    PARACLINICAL

 was performed to investigate the cause of

    renal damage
    SYMPTOMS

.

    Fabry disease
    NEG_FINDINGS

 was initially considered, based on the

    presence of myelin figures
    MICROSCOPIC

 on

    EM
    MICROSCOPIC

, but since

    he
    GENDER

 had

    normal α-galactosidase A activity
    NEG_FINDINGS

,

    this initial diagnosis was denied
    NEG_FINDINGS

, and the patient was subsequently diagnosed with

    FSGS
    DIAGNOSIS

. At 22 years after that

    renal biopsy
    PARACLINICAL

, the patient was incidentally diagnosed with

    LAN
    DIAGNOSIS

 when

    NM_002316:3c.746G > A:p.(Arg249Gln) LMX1B variant was identified in his older brother
    GENETICS

 by a

    pre-transplantation examination
    PARACLINICAL

, and the same mutation was confirmed in the patient.

    Myelin figures
    MICROSCOPIC

 revealed by

    EM
    PARACLINICAL

 might become one of the clues for the diagnosis of

    LAN
    DIAGNOSIS

.

dysplastic nails
hypoplastic patellae
iliac horns
renal damage


Case Report: First Two Identified Cases of Fabry Disease in Central Asia.

Background: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked inherited, genetic disease due to the functional deficiency of lysosomal α-galactosidase (α-GAL) that leads to the accumulation of glycosphingolipids (mainly globotriaosylceramide or Gb3) and its derivative globotriaosylsphingosine or lyso-Gb3. Classic FD is a multisystem disorder which initially presents in childhood with neuropathic pain and dermatological, gastrointestinal, ocular, and cochleo-vestibular manifestations. Over time, end-organ damage such as renal failure, cardiac arrhythmia and early stroke may develop leading to reduced life expectancy in the absence of specific treatment. Case presentation: We describe two Kazakh patients who presented in adulthood with a delayed diagnosis. We conducted also a family screening through cascade genotyping. Conclusion: This is the first description of cases of Fabry disease in Central Asia. An extensive family pedigree enabled the identification of ten additional family members. Patients with rare genetic diseases often experience substantial delays in diagnosis due to their rarity and non-specific symptoms, which can negatively impact their management and delay treatment. FD may be difficult to diagnose because of the non-specificity of its early and later-onset symptoms and its X-linked inheritance. Raising awareness of clinicians is important for earlier diagnosis and optimal outcome of specific therapies.

Background:

    Fabry disease (FD
    DIAGNOSIS

, OMIM #

    301500)
    DIAGNOSIS

 is a

    rare, progressive
    DIAGNOSIS

,

    X-linked inherited
    GENETICS

,

    genetic disease
    GENETICS

 due to the

    functional deficiency of lysosomal α-galactosidase (α-GAL)
    BIOCHEMICAL

 that leads to the

    accumulation of glycosphingolipids (mainly globotriaosylceramide or Gb3) and its derivative globotriaosylsphingosine or lyso-Gb3
    MICROSCOPIC

. Classic

    FD
    DIAGNOSIS

 is a

    multisystem disorder
    DIAGNOSIS

 which initially presents in

    childhood
    AGE

 with

    neuropathic pain
    SYMPTOMS

 and

    dermatological, gastrointestinal, ocular, and cochleo-vestibular manifestations
    SYMPTOMS

. Over time,

    end-organ damage
    SYMPTOMS

 such as

    renal failure
    SYMPTOMS

,

    cardiac arrhythmia
    SYMPTOMS

 and

    early stroke
    SYMPTOMS

 may develop leading to

    reduced life expectancy
    SYMPTOMS

 in the

    absence of specific treatment
    NEG_FINDINGS

. Case presentation: We describe two

    Kazakh
    ETHNICITY

 patients who presented in

    adulthood
    AGE

 with a delayed diagnosis. We conducted also a

    family screening
    PARACLINICAL

 through

    cascade genotyping
    PARACLINICAL

. Conclusion: This is the first description of cases of

    Fabry disease
    DIAGNOSIS

 in

    Central Asia
    ETHNICITY

. An

    extensive family pedigree
    FAMILY

 enabled the identification of

    ten additional family members
    FAMILY

. Patients with

    rare genetic diseases
    DIAGNOSIS

 often experience substantial delays in diagnosis due to their rarity and

    non-specific symptoms
    NEG_FINDINGS

, which can negatively impact their management and delay treatment.

    FD
    DIAGNOSIS

 may be difficult to diagnose because of the

    non-specificity of its early and later-onset symptoms
    SYMPTOMS

 and its

    X-linked inheritance
    GENETICS

. Raising awareness of clinicians is important for earlier diagnosis and optimal outcome of specific therapies.

Fabry disease (FD
301500)
rare, progressive
FD
multisystem disorder
Fabry disease
rare genetic diseases
FD

X-linked inherited
genetic disease
X-linked inheritance

absence of specific treatment
non-specific symptoms


Fabry disease with cardiovascular manifestation in a patient with end-stage renal disease.

Fabry disease is a rare X-linked hereditary storage disease caused by a mutation of the gene encoding alpha-galactosidase A. The clinical manifestation of the classical disease form is variable depending on the degree of individual organs involvement, including especially kidney, myocardium, central nervous system (CNS) and skin. We report a case of a 51-year-old man whose diagnostic manifestation was cardiac involvement leading to endomyocardial biopsy, which significantly contributed to the diagnosis. Although at that time he was already 9 years dependent on dialysis with terminal renal failure.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked hereditary
    GENETICS

    storage disease
    DIAGNOSIS

 caused by a mutation of the gene encoding alpha-galactosidase A. The clinical manifestation of the classical disease form is variable depending on the degree of individual organs involvement, including especially

    kidney, myocardium, central nervous system (CNS)
    SYMPTOMS

 and skin. We report a case of a

    51-year-old
    AGE

    man
    GENDER

 whose diagnostic manifestation was

    cardiac involvement
    SYMPTOMS

 leading to

    endomyocardial biopsy
    PARACLINICAL

, which significantly contributed to the diagnosis. Although at that time

    he
    GENDER

 was

    already 9 years dependent on dialysis
    MEDICATION

 with

    terminal renal failure
    SYMPTOMS

.


Fabry Disease p.M290I Mutation is Related to Organ Involvement: A Case Report.

Fabry disease (FD) is an X-linked hereditary disease. It results from mutations in the GLA gene, leading to deficient activity of the enzyme alpha-galactosidase A (α-Gal A) and progressive accumulation of undegraded glycosphingolipids in cell lysosomes. Enzyme replacement therapy (ERT) can improve the natural course of this disease, but an early diagnosis is crucial for a successful treatment. We describe the case of a female diagnosed with chronic proteinuric kidney disease in the postpartum period. Despite receiving optimal medical treatment, the disease progressed and she started renal replacement therapy (RRT) with peritoneal dialysis (PD). Five years later, she was enrolled in a pilot screening study for FD, and the heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon six of the GLA gene was found. The family screening revealed the presence of this mutation in the patient's father and daughter. The proband did not meet the criteria for a definitive FD diagnosis, but she remained under follow-up at our nephrology metabolic diseases consultation, as the mutation was described as pathogenic and associated with a classic FD phenotype. Later that same year, reassessment exams revealed a worsening left ventricle mass index (LVMi), a new ischemic cerebral lesion, and a substantial increase in serum globotriaosylsphingosine (LysoGb3) levels. These clinical changes led to a decision to initiate ERT. p.M290I is a previously known but poorly described GLA mutation. To our knowledge, this is the first report of p.M290I mutation-associated disease activity that offers strong evidence of its pathogenicity.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked hereditary disease
    GENETICS

. It results from

    mutations in the GLA gene
    GENETICS

, leading to

    deficient activity of the enzyme alpha-galactosidase A (α-Gal A)
    BIOCHEMICAL

 and

    progressive accumulation of undegraded glycosphingolipids in cell lysosomes
    MICROSCOPIC

.

    Enzyme replacement therapy (ERT)
    MEDICATION

 can improve the natural course of this disease, but an early diagnosis is crucial for a successful treatment. We describe the case of a

    female
    GENDER

 diagnosed with

    chronic proteinuric kidney disease
    DIAGNOSIS

 in the

    postpartum
    AGE

    period
    AGE

.

    Despite receiving optimal medical treatment
    NEG_FINDINGS

, the disease progressed and

    she
    GENDER

 started

    renal replacement therapy (RRT) with peritoneal dialysis (PD)
    MEDICATION

. Five years later,

    she
    GENDER

 was enrolled in a pilot screening study for

    FD
    DIAGNOSIS

, and the

    heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon six of the GLA gene
    GENETICS

 was found. The

    family screening
    PARACLINICAL

 revealed

    the presence of this mutation in the patient's father and daughter
    FAMILY

. The

    proband did not meet the criteria for a definitive FD diagnosis
    NEG_FINDINGS

, but

    she
    GENDER

 remained under

    follow-up
    PARACLINICAL

 at our

    nephrology metabolic diseases consultation
    PARACLINICAL

, as the mutation was described as pathogenic and associated with a classic

    FD
    DIAGNOSIS

 phenotype. Later that same year,

    reassessment exams
    PARACLINICAL

 revealed a

    worsening left ventricle mass index (LVMi)
    SYMPTOMS

, a

    new ischemic cerebral lesion
    SYMPTOMS

, and a

    substantial increase in serum globotriaosylsphingosine (LysoGb3) levels
    BIOCHEMICAL

. These clinical changes led to a decision to initiate

    ERT
    MEDICATION

.

    p.M290I
    GENETICS

 is a previously known but poorly described

    GLA mutation
    GENETICS

. To our knowledge, this is the first report of

    p.M290I mutation-associated disease activity
    GENETICS

 that offers strong evidence of its pathogenicity.

Fabry disease (FD)
chronic proteinuric kidney disease
FD
FD


Progression of electrocardiogram changes in an untreated fabry disease: a case report.

Fabry disease (FD) is a rare lysosomal storage disorder with multiorgan manifestation and associated with an increased morbidity and mortality. Fabry cardiomyopathy includes left ventricular 'hypertrophy' (LVH), cardiac arrhythmias, and heart failure. We report a case of an untreated FD with characteristic findings in electrocardiogram (ECG) over a follow-up period of 10 years.

A 53-year-old man with FD presented to our outpatient department. He suffered from symptomatic ventricular extrasystoles. Echocardiography detected LVH and reduced global longitudinal strain. Twelve years ago, first examination was conducted due to ventricular arrhythmias. Electrocardiogram showed a short PQ minus P-wave (PendQ) interval and negative T-waves. Over time, the number of leads with negative T-waves increased. Moreover, the echocardiography revealed a thickened left ventricular wall. Without any further examinations at that time, the patient was treated for arterial hypertension with proteinuria. Ten years after first symptoms appeared, FD was diagnosed utilizing cardiac magnetic resonance imaging and genetic tests. Hence, enzyme replacement therapy was initiated.

The ECG is a fast diagnostic method and it may - even without additional organ manifestations - provide preliminary suspicion of FD. In particular, as shown in our case, a short PendQ and QT interval indicate FD. Over time, disease progression can be detected through ECG changes. T-waves correlate with an increasing LVH and a reduction in longitudinal function in echocardiographic examinations. Unexplained LVH must be followed by differential diagnosis. In case of confirmed FD, patients should be treated by multidisciplinary teams in experienced centres.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare lysosomal storage disorder
    DIAGNOSIS

 with

    multiorgan manifestation
    SYMPTOMS

 and associated with an increased morbidity and mortality.

    Fabry cardiomyopathy
    DIAGNOSIS

 includes

    left ventricular 'hypertrophy' (LVH)
    SYMPTOMS

,

    cardiac arrhythmias
    SYMPTOMS

, and

    heart failure
    SYMPTOMS

. We report a case of an

    untreated FD
    DIAGNOSIS

 with

    characteristic findings in electrocardiogram (ECG)
    SYMPTOMS

 over a

    follow-up period of 10 years
    PARACLINICAL

.

A

    53-year-old
    AGE

    man
    GENDER

 with

    FD
    DIAGNOSIS

 presented to our outpatient department.

    He
    GENDER

 suffered from

    symptomatic ventricular extrasystoles
    SYMPTOMS

.

    Echocardiography
    PARACLINICAL

 detected

    LVH
    SYMPTOMS

 and

    reduced global longitudinal strain
    SYMPTOMS

. Twelve years ago, first examination was conducted due to

    ventricular arrhythmias
    SYMPTOMS

.

    Electrocardiogram
    PARACLINICAL

 showed a

    short PQ minus P-wave (PendQ) interval
    SYMPTOMS

 and

    negative T-waves
    SYMPTOMS

. Over time, the

    number of leads with negative T-waves increased
    SYMPTOMS

. Moreover, the

    echocardiography
    PARACLINICAL

 revealed a

    thickened left ventricular wall
    SYMPTOMS

.

    Without any further examinations
    NEG_FINDINGS

 at that time, the patient was treated for

    arterial hypertension
    SYMPTOMS

 with

    proteinuria
    BIOCHEMICAL

. Ten years after first symptoms appeared,

    FD
    DIAGNOSIS

 was diagnosed utilizing

    cardiac magnetic resonance imaging
    PARACLINICAL

 and

    genetic tests
    PARACLINICAL

. Hence,

    enzyme replacement therapy
    MEDICATION

 was initiated.

The

    ECG
    PARACLINICAL

 is a fast diagnostic method and it may - even

    without additional organ manifestations
    NEG_FINDINGS

 - provide preliminary suspicion of

    FD
    DIAGNOSIS

. In particular, as shown in our case, a

    short PendQ and QT interval
    SYMPTOMS

 indicate

    FD
    DIAGNOSIS

. Over time, disease progression can be detected through

    ECG changes
    SYMPTOMS

.

    T-waves correlate with an increasing LVH
    SYMPTOMS

 and a

    reduction in longitudinal function
    SYMPTOMS

 in

    echocardiographic examinations
    PARACLINICAL

.

    Unexplained LVH
    SYMPTOMS

 must be followed by

    differential diagnosis
    PARACLINICAL

. In case of confirmed

    FD
    DIAGNOSIS

, patients should be treated by multidisciplinary teams in experienced centres.

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

Without any further examinations
without additional organ manifestations


New mutation in Fabry disease: c.448delG, first phenotypic description.

Fabry disease (FD) (Anderson-Fabry disease, OMIM 301500) is a genetic disorder caused by a pathogenic variant in the GLA gene on chromosome Xq22 that produces a deficiency in the lysosomal enzyme alpha-galactosidase A. It is transmitted as an X-linked trait, although de novo mutations have been described. The objective of this report is to describe the clinical characteristics of a patient with FD who is a carrier of a mutation not previously studied, in order to provide information on the genotype-phenotype correlation in this pathology. 38-year-old patient who consulted Neurology for positional vertigo. He also reported acroparesthesia, anhidrosis, heat intolerance and episodes of abdominal pain, with postprandial discomfort from 10 years of age. Physical examination showed horizonto-rotatory nystagmus in both looks, the rest of the neurological evaluation did not present abnormalities. The presence of umbilical and thighs angiokeratomas was identified. Determination of Alpha-Galactosidase in blood was requested: 0.34 μmol/l/h (2.10-10.51 μmol/l/h). Genetic analysis detected a deletion of a guanine at position 448, in exon 3 of the GLA gene (c.448delG). This mutation was considered to be pathogenic, confirming the diagnosis of FD, although it is not described in the data bases. Genetic counseling and a family pedifree study were performed without finding relatives with this variant of the GLA gene or a family history of FD, which suggests a de novo mutation.

    Fabry disease (FD)
    DIAGNOSIS

 (

    Anderson-Fabry disease
    DIAGNOSIS

,

    OMIM 301500
    GENETICS

) is a

    genetic disorder
    GENETICS

 caused by a

    pathogenic variant in the GLA gene on chromosome Xq22
    GENETICS

 that produces a deficiency in the lysosomal enzyme alpha-galactosidase A. It is

    transmitted as an X-linked trait
    GENETICS

, although

    de novo mutations
    GENETICS

 have been described. The objective of this report is to describe the clinical characteristics of a patient with

    FD
    DIAGNOSIS

 who is a carrier of a mutation not previously studied, in order to provide information on the genotype-phenotype correlation in this pathology.

    38-year-old
    AGE

 patient who consulted

    Neurology
    PARACLINICAL

 for

    positional vertigo
    SYMPTOMS

.

    He
    GENDER

 also reported

    acroparesthesia
    SYMPTOMS

,

    anhidrosis
    SYMPTOMS

,

    heat intolerance
    SYMPTOMS

 and

    episodes of abdominal pain
    SYMPTOMS

, with

    postprandial discomfort
    SYMPTOMS

 from

    10 years of age
    AGE

.

    Physical examination
    PARACLINICAL

 showed

    horizonto-rotatory nystagmus in both looks
    SYMPTOMS

, the

    rest of the neurological evaluation did not present abnormalities
    NEG_FINDINGS

. The

    presence of umbilical and thighs angiokeratomas
    SYMPTOMS

 was identified.

    Determination of Alpha-Galactosidase in blood was requested: 0.34 μmol/l/h (2.10-10.51 μmol/l/h)
    BIOCHEMICAL

.

    Genetic analysis
    PARACLINICAL

 detected a

    deletion of a guanine at position 448, in exon 3 of the GLA gene (c.448delG)
    GENETICS

. This mutation was considered to be pathogenic, confirming the diagnosis of

    FD
    DIAGNOSIS

, although it is not described in the data bases.

    Genetic counseling
    MEDICATION

 and a

    family pedifree study
    PARACLINICAL

 were performed

    without finding relatives with this variant of the GLA gene or a family history of FD
    NEG_FINDINGS

, which suggests a

    de novo mutation
    GENETICS

.

Fabry disease (FD)
Anderson-Fabry disease
FD
FD


Novel GLA T194A variant causes Fabry disease.

Fabry disease (FD) is an X-linked, systemic lysosomal deposition disease caused by alpha-galactosidase A (AGAL) enzyme deficiency deriving out of changes on the GLA gene. Though several mutations have been described, one must consider that even a specific mutation may present with variable clinical expression within the same family. Typically described as a disease that affects hemizygous men with no residual AGAL activity, we describe a novel FD mutation (first case of GLA T194A variant worldwide) in a 49-year-old woman presenting with a classic phenotype of FD. The patient investigation highlighted a previously not described mutation in exon 4 of the GLA gene, as for the substitution of threonine for alanine. The same mutation was identified in her children, one of them presenting with end-stage kidney disease (ESKD) in early adulthood.

    Fabry disease (FD)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

,

    systemic lysosomal deposition disease
    DIAGNOSIS

 caused by

    alpha-galactosidase A (AGAL) enzyme deficiency
    BIOCHEMICAL

 deriving out of

    changes on the GLA gene
    GENETICS

. Though several mutations have been described, one must consider that even a specific mutation may present with variable clinical expression within the same family. Typically described as a disease that affects

    hemizygous men
    GENETICS

 with

    no residual AGAL activity
    NEG_FINDINGS

, we describe a

    novel FD mutation
    GENETICS

 (first case of

    GLA T194A variant
    GENETICS

 worldwide) in a

    49-year-old
    AGE

    woman
    GENDER

 presenting with a

    classic phenotype of FD
    SYMPTOMS

. The patient investigation highlighted a

    previously not described mutation in exon 4 of the GLA gene, as for the substitution of threonine for alanine
    GENETICS

. The same mutation was identified in

    her
    GENDER

    children
    AGE

, one of them presenting with

    end-stage kidney disease (ESKD)
    DIAGNOSIS

 in

    early adulthood
    AGE

.

Fabry disease (FD)
systemic lysosomal deposition disease
end-stage kidney disease (ESKD)