Intravenous Thrombolysis For Acute Ischemic Stroke in Fabry Disease.

Fabry is a rare X-linked recessive genetic disease caused by α-galactosidase A deficiency. Cerebrovascular events occur in ∼13% of patients, whereas stroke may be the presenting clinical manifestation. There are very limited case reports of tissue plasminogen activator administration for acute ischemic stroke in patients with Fabry disease.

A 46-year-old man presented with right-sided hemiparesis with a National Institutes of Health Stroke Scale score of 3. Brain computed tomography showed a hyperdense lesion resembling carvenous angioma. The patient received intravenous thrombolysis 265 minutes after symptom onset, with clinical improvement (discharge National Institutes of Health Stroke Scale score of 1). Brain magnetic resonance imaging disclosed acute thalamic infarction, cavernous angioma, and multiple cerebral microbleeds. The presence of skin angiokeratomas and cardiac hypertrophy prompted further positive investigation for Fabry disease (nondetectable α-galactosidase activity, excessively elevated lyso-Gb3, and pathogenic deletion in the GLA gene).

The present case supports the scarce data underscoring the safety of intravenous thrombolysis for acute ischemic stroke in Fabry disease patients even when cerebral microbleeds are present.

    Fabry
    DIAGNOSIS

 is a

    rare X-linked recessive genetic disease
    GENETICS

 caused by

    α-galactosidase A deficiency
    BIOCHEMICAL

.

    Cerebrovascular events
    SYMPTOMS

 occur in ∼13% of patients, whereas

    stroke
    SYMPTOMS

 may be the presenting clinical manifestation. There are very limited case reports of

    tissue plasminogen activator administration
    MEDICATION

 for

    acute ischemic stroke
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

.

A

    46-year-old
    AGE

    man
    GENDER

 presented with

    right-sided hemiparesis
    SYMPTOMS

 with a

    National Institutes of Health Stroke Scale score of 3
    SYMPTOMS

.

    Brain computed tomography
    PARACLINICAL

 showed a

    hyperdense lesion resembling carvenous angioma
    SYMPTOMS

. The patient received

    intravenous thrombolysis
    MEDICATION

 265 minutes after symptom onset, with

    clinical improvement
    SYMPTOMS

 (

    discharge National Institutes of Health Stroke Scale score of 1)
    SYMPTOMS

.

    Brain magnetic resonance imaging
    PARACLINICAL

 disclosed

    acute thalamic infarction
    SYMPTOMS

,

    cavernous angioma
    SYMPTOMS

, and

    multiple cerebral microbleeds
    SYMPTOMS

. The presence of

    skin angiokeratomas
    SYMPTOMS

 and

    cardiac hypertrophy
    SYMPTOMS

 prompted further positive investigation for

    Fabry disease
    DIAGNOSIS

 (

    nondetectable α-galactosidase activity
    BIOCHEMICAL

,

    excessively elevated lyso-Gb3
    BIOCHEMICAL

, and

    pathogenic deletion in the GLA gene
    GENETICS

).

The present case supports the scarce data underscoring the safety of

    intravenous thrombolysis
    MEDICATION

 for

    acute ischemic stroke
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 patients even when

    cerebral microbleeds
    SYMPTOMS

 are present.

Fabry
Fabry disease
Fabry disease
Fabry disease

rare X-linked recessive genetic disease
pathogenic deletion in the GLA gene

α-galactosidase A deficiency
nondetectable α-galactosidase activity
excessively elevated lyso-Gb3


Strong increase of leukocyte apha-galactosidase A activity in two male patients with Fabry disease following oral chaperone therapy.

Fabry disease (OMIM 301500) is an X-linked disorder caused by alpha-galactosidase A (α-Gal A) deficiency. The administration of a pharmacologic chaperone (migalastat) in Fabry patients with amenable mutations has been reported to improve or stabilize organ damages and reduce lyso-Gb3 plasma level. An increase of α-Gal A activity has been observed in vitro in cells expressing amenable GLA mutations when incubated with migalastat. The impact of the drug on α-Gal A in vivo activity has been poorly studied.

We conducted a retrospective analysis of two unrelated male Fabry patients with p.Asn215Ser (p.N215S) variant.

We report the important increase of α-Gal A activity in blood leukocytes reaching normal ranges of activity after about 1 year of treatment with migalastat. Cardiac parameters improved or stabilized with the treatment.

We confirm in vivo the effects of migalastat that have been observed in N215S carriers in vitro. The increase of α-Gal A activity may be the strongest marker for biochemical efficacy. The normalization of enzyme activity could become the new therapeutic target to achieve.

    Fabry disease
    DIAGNOSIS

 (

    OMIM 301500
    GENETICS

) is an

    X-linked disorder
    GENETICS

 caused by

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

. The

    administration of a pharmacologic chaperone (migalastat)
    MEDICATION

 in

    Fabry
    DIAGNOSIS

 patients with

    amenable mutations
    GENETICS

 has been reported to

    improve or stabilize organ damages
    SYMPTOMS

 and

    reduce lyso-Gb3 plasma level
    BIOCHEMICAL

. An

    increase of α-Gal A activity
    BIOCHEMICAL

 has been observed in vitro in cells expressing

    amenable GLA mutations
    GENETICS

 when incubated with

    migalastat
    MEDICATION

. The impact of the drug on

    α-Gal A in vivo activity
    BIOCHEMICAL

 has been poorly studied.

We conducted a retrospective analysis of two unrelated

    male
    GENDER

    Fabry
    DIAGNOSIS

 patients with

    p.Asn215Ser (p.N215S) variant
    GENETICS

.

We report the

    important increase of α-Gal A activity in blood leukocytes reaching normal ranges of activity
    BIOCHEMICAL

 after

    about 1 year of treatment with migalastat
    MEDICATION

.

    Cardiac parameters improved or stabilized
    SYMPTOMS

 with the treatment.

We confirm in vivo the effects of

    migalastat
    MEDICATION

 that have been observed in

    N215S carriers
    GENETICS

 in vitro. The

    increase of α-Gal A activity
    BIOCHEMICAL

 may be the strongest marker for biochemical efficacy. The

    normalization of enzyme activity
    BIOCHEMICAL

 could become the new therapeutic target to achieve.

OMIM 301500
X-linked disorder
amenable mutations
amenable GLA mutations
p.Asn215Ser (p.N215S) variant
N215S carriers


Successful Combined Heart and Kidney Transplantation in Patient With Fabry's Disease: A Case Report.

Fabry's disease is a X-linked hereditary disease that causes the accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart. This can result in both chronic kidney disease and cardiac dysfunction, including arrhythmias and heart failure. We describe a case of a 62-year-old male with Fabry's disease undergoing successful combined heart and kidney transplantation for chronic renal failure and low-output systolic heart failure. The patient has normal cardiac function and normal renal function 7 years after transplantation, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A. Fabry's disease is not a contraindication for organ transplantation, even in patients presenting with both renal failure and heart failure.

    Fabry's disease
    DIAGNOSIS

 is a

    X-linked hereditary disease
    GENETICS

 that causes the

    accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart
    MICROSCOPIC

. This can result in both

    chronic kidney disease
    DIAGNOSIS

 and

    cardiac dysfunction
    SYMPTOMS

, including

    arrhythmias
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

. We describe a case of a

    62-year-old
    AGE

    male
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 undergoing

    successful combined heart and kidney transplantation
    MEDICATION

 for

    chronic renal failure
    SYMPTOMS

 and

    low-output systolic heart failure
    SYMPTOMS

. The patient has

    normal cardiac function and normal renal function 7 years after transplantation
    NEG_FINDINGS

, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A.

    Fabry's disease
    DIAGNOSIS

 is not a contraindication for

    organ transplantation
    MEDICATION

, even in patients presenting with

    both renal failure and heart failure
    SYMPTOMS

.

Fabry's disease
chronic kidney disease
Fabry's disease
Fabry's disease

cardiac dysfunction
arrhythmias
heart failure
chronic renal failure
low-output systolic heart failure
both renal failure and heart failure


Fabry disease and immunoglobulin A nephropathy presenting with Alport syndrome-like findings: A case report.

Fabry's disease is an X-linked inherited syndrome. Herein, we presented an unusual case of Fabry disease coexisting with immunoglobulin A nephropathy (IgAN) presenting with Alport syndrome-like pathological findings.

We report a 30-year-old male who presented with proteinuria and elevated serum creatinine and for whom the initial pathologic diagnosis supported Alport syndrome.

A diagnosis of Fabry disease with immunoglobulin A nephropathy (IgAN) was finally made after further examination.

After the initial diagnosis the patient was treated with herbal medications and mecobalamin.

The patient was discharged 1 week later. He was maintained on these treatments and received regular follow-up in our hospital.

FD coexisting with IgAN is rare and may have nonspecific clinical presentations. Laboratory examination and genetic diagnosis is needed for confirmation. Timely diagnosis and reproductive intervention is needed for therapy.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked inherited syndrome
    GENETICS

. Herein, we presented an unusual case of

    Fabry disease coexisting with immunoglobulin A nephropathy (IgAN)
    DIAGNOSIS

 presenting with

    Alport syndrome-like pathological findings
    SYMPTOMS

.

We report a

    30-year-old
    AGE

    male
    GENDER

 who presented with

    proteinuria
    BIOCHEMICAL

 and

    elevated serum creatinine
    BIOCHEMICAL

 and for whom the initial

    pathologic diagnosis
    PARACLINICAL

 supported

    Alport syndrome
    DIAGNOSIS

.

A diagnosis of

    Fabry disease with immunoglobulin A nephropathy (IgAN)
    DIAGNOSIS

 was finally made after further examination.

After the initial diagnosis the patient was treated with

    herbal medications
    MEDICATION

 and

    mecobalamin
    MEDICATION

.

The patient was discharged 1 week later.

    He
    GENDER

 was

    maintained on these treatments
    MEDICATION

 and received

    regular follow-up
    MEDICATION

 in our hospital.

    FD coexisting with IgAN
    DIAGNOSIS

 is rare and may have

    nonspecific clinical presentations
    SYMPTOMS

.

    Laboratory examination
    PARACLINICAL

 and

    genetic diagnosis
    PARACLINICAL

 is needed for confirmation. Timely diagnosis and

    reproductive intervention
    MEDICATION

 is needed for therapy.

herbal medications
mecobalamin
maintained on these treatments
regular follow-up
reproductive intervention


Multiple sclerosis and Fabry disease - diagnostic "mixup".

A common disease like multiple sclerosis (MS) usually dominates the arena of demyelinating disorders; however, when a red flag such as a first relative family history of neurologic disease other than MS is present, the diagnostics may be more challenging. Recently, we have come across an intriguing clinical and diagnostic dilemma requiring extensive literature search and finally, decision making. Namely, initial presentation in our patient was that of a frequent condition such as optic neuritis and demyelinating CNS lesions, and then unexpected additional information during the usual diagnostic process, in the matter of first relative being diagnosed with a rare disease - Anderson-Fabry disease, oriented us in another direction. Almost paradoxically, the rare diagnosis being genetically confirmed, initiated treatment first. Furthermore, multitude of published data instigated clinical, radiological and laboratory uncertainty in our minds urging us to use a "wait and see" approach for the potential second diagnosis in order to prevent causing harm or labeling our patient wrongly by a potential misdiagnosis. However, further clinical course, a follow-up MRI, comparison with initial findings, and multi-disciplinary consultation safely directed us to a frequent diagnosis of multiple sclerosis. Our patient is currently treated for both conditions.

A common disease like

    multiple sclerosis (MS)
    DIAGNOSIS

 usually dominates the arena of

    demyelinating disorders
    DIAGNOSIS

; however, when a red flag such as a

    first relative family history of neurologic disease other than MS
    FAMILY

 is present, the diagnostics may be more challenging. Recently, we have come across an intriguing clinical and diagnostic dilemma requiring extensive literature search and finally, decision making. Namely, initial presentation in our patient was that of a frequent condition such as

    optic neuritis
    SYMPTOMS

 and

    demyelinating CNS lesions
    SYMPTOMS

, and then unexpected additional information during the usual diagnostic process, in the matter of

    first relative being diagnosed with a rare disease - Anderson-Fabry disease
    FAMILY

, oriented us in another direction. Almost paradoxically, the rare diagnosis being genetically confirmed, initiated treatment first. Furthermore, multitude of published data instigated clinical, radiological and laboratory uncertainty in our minds urging us to use a "wait and see" approach for the potential second diagnosis in order to prevent causing harm or labeling our patient wrongly by a potential misdiagnosis. However, further clinical course, a

    follow-up MRI
    PARACLINICAL

, comparison with initial findings, and multi-disciplinary consultation safely directed us to a frequent diagnosis of

    multiple sclerosis
    DIAGNOSIS

. Our patient is currently treated for both conditions.

multiple sclerosis (MS)
demyelinating disorders
multiple sclerosis

optic neuritis
demyelinating CNS lesions


Fabry Disease with Pacemaker Implantation as the Initial Event.

Fabry disease (FD) is a rare X-linked hereditary disorder (Xq22) caused by a deficiency in alpha-galactosidase activity. A 34-year-old man was referred to our hospital because of renal dysfunction. He had previously undergone pacemaker implantation at 24 years of age. Investigations revealed undetectable alpha-galactosidase A activity levels. Renal biopsy results indicated vacuolization of podocytes. A genetic analysis revealed that the patient carried the W340X mutation. Enzyme replacement therapy with agalsidase beta was started. This case is novel because most cases of FD nephropathy precede cardiac disease. In our patient, the cardiac event was the initial event, and renal impairment followed.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked hereditary disorder (Xq22)
    GENETICS

 caused by a

    deficiency in alpha-galactosidase activity
    BIOCHEMICAL

. A

    34-year-old
    AGE

    man
    GENDER

 was referred to our hospital because of

    renal dysfunction
    SYMPTOMS

.

    He
    GENDER

 had

    previously undergone pacemaker implantation at 24 years of age
    MEDICATION

. Investigations revealed

    undetectable alpha-galactosidase A activity levels
    BIOCHEMICAL

.

    Renal biopsy
    PARACLINICAL

 results indicated

    vacuolization of podocytes
    MICROSCOPIC

. A

    genetic analysis
    PARACLINICAL

 revealed that the patient

    carried the W340X mutation
    GENETICS

.

    Enzyme replacement therapy with agalsidase beta
    MEDICATION

 was started. This case is novel because most cases of

    FD nephropathy
    DIAGNOSIS

 precede

    cardiac disease
    SYMPTOMS

. In our patient, the

    cardiac event
    SYMPTOMS

 was the initial event, and

    renal impairment
    SYMPTOMS

 followed.

renal dysfunction
cardiac disease
cardiac event
renal impairment


Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males.

The α-galactosidase gene (GLA) c.337T>C/p.Phe113Leu variant was originally described in patients with late-onset cardiac forms of Fabry disease (FD), who had residual α-galactosidase activity. It has since emerged as the most commonly reported GLA variant in Portuguese subjects diagnosed with FD but is also prevalent in the Italian population, where two boys carrying the GLA Leu113 allele were identified in a large-scale newborn screening program, the variant allele segregating in both cases with the same surrounding haplotype. To further delineate the genotype-phenotype correlations of this GLA variant, we have reviewed the natural history and clinical phenotypes of 11 symptomatic Portuguese males, from 10 unrelated families originating from several different areas in mainland Portugal and Madeira Island, who were diagnosed with FD associated with the GLA Leu113 allele in a diversity of clinical and screening settings. Nine of the patients were the probands of their respective families. To test whether the GLA Leu113 allele inherited by the 10 Portuguese and the two Italian families resulted from independent mutational events, we have additionally performed a haplotype analysis with 5 highly polymorphic, closely linked microsatellite markers surrounding the GLA gene.

Hemizygosity for the GLA Leu113 variant allele is associated with a late-onset form of FD, invariably presenting with severe cardiac involvement. Clinically relevant cerebrovascular and kidney involvement may also occur in some patients but the pathogenic relationship between the incomplete α-galactosidase deficiency and the risks of stroke and of chronic kidney disease is not straightforward. The observation that the Leu113 allele segregated within the same GLA microsatellite haplotype in both the Portuguese and Italian families suggests its inheritance from a common ancestor.

The

    α-galactosidase gene (GLA) c.337T>C/p.Phe113Leu variant
    GENETICS

 was originally described in patients with

    late-onset cardiac forms of Fabry disease (FD)
    DIAGNOSIS

, who had

    residual α-galactosidase activity
    BIOCHEMICAL

. It has since emerged as the most commonly reported

    GLA variant
    GENETICS

 in

    Portuguese
    ETHNICITY

 subjects diagnosed with

    FD
    DIAGNOSIS

 but is also prevalent in the

    Italian
    ETHNICITY

 population, where two

    boys
    GENDER

 carrying the

    GLA Leu113 allele
    GENETICS

 were identified in a large-scale newborn screening program,

    the variant allele segregating in both cases with the same surrounding haplotype
    GENETICS

. To further delineate the genotype-phenotype correlations of this GLA variant, we have reviewed the natural history and clinical phenotypes of 11 symptomatic

    Portuguese
    ETHNICITY

    males
    GENDER

, from 10 unrelated families originating from several different areas in

    mainland Portugal
    ETHNICITY

 and

    Madeira Island
    ETHNICITY

, who were diagnosed with

    FD
    DIAGNOSIS

 associated with the

    GLA Leu113 allele
    GENETICS

 in a diversity of clinical and screening settings. Nine of the patients were the probands of their respective families. To test whether the

    GLA Leu113 allele inherited
    GENETICS

 by the 10

    Portuguese
    ETHNICITY

 and the two

    Italian
    ETHNICITY

 families resulted from independent mutational events, we have additionally performed a

    haplotype analysis with 5 highly polymorphic, closely linked microsatellite markers surrounding the GLA gene
    PARACLINICAL

.

    Hemizygosity for the GLA Leu113 variant allele
    GENETICS

 is associated with a

    late-onset form of FD
    DIAGNOSIS

, invariably presenting with

    severe cardiac involvement
    SYMPTOMS

.

    Clinically relevant cerebrovascular and kidney involvement
    SYMPTOMS

 may also occur in some patients but the pathogenic relationship between the

    incomplete α-galactosidase deficiency
    BIOCHEMICAL

 and the risks of

    stroke
    SYMPTOMS

 and of

    chronic kidney disease
    DIAGNOSIS

 is not straightforward. The observation that

    the Leu113 allele segregated within the same GLA microsatellite haplotype
    GENETICS

 in both the

    Portuguese
    ETHNICITY

 and

    Italian
    ETHNICITY

 families suggests its

    inheritance from a common ancestor
    FAMILY

.

residual α-galactosidase activity
incomplete α-galactosidase deficiency

Portuguese
Italian
Portuguese
mainland Portugal
Madeira Island
Portuguese
Italian
Portuguese
Italian


Why systematic literature reviews in Fabry disease should include all published evidence.

Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

,

    progressive disorder of lipid metabolism
    DIAGNOSIS

 resulting from the

    deficient activity of the enzyme α-galactosidase
    BIOCHEMICAL

.

    Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa
    MEDICATION

, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of

    ERT
    MEDICATION

. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of

    ERT
    MEDICATION

 on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of

    ERT
    MEDICATION

 in patients with

    Fabry disease
    DIAGNOSIS

; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods,

    ERT
    MEDICATION

 regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of

    ERT
    MEDICATION

 outcomes in

    Fabry disease
    DIAGNOSIS

, highlighting that in a

    rare genetic disorder
    DIAGNOSIS

 like

    Fabry disease
    DIAGNOSIS

, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.


Central nervous system vasculopathy caused by Fabry disease: a case report.

Fabry disease is rare, and the diagnosis is often delayed. Here, we describe a case of Fabry disease resulting in vasculopathy of the central nervous system. Magnetic resonance (MR) black-blood sequence (three-dimensional T1 volumetric isotropic turbo spin echo acquisition), with the unique advantage of imaging the vascular wall, facilitated a clear identification of the vasculopathy.

A 27-year-old man visited our hospital for the treatment of " double vision 6d." After a series of examinations, the patient was diagnosed with Fabry disease, which caused vasculopathy of the central nervous system. Subsequently, the patient was treated with corticosteroids and his symptoms were attenuated. Two months after the initial treatment, the initial lesion in the vascular vessel disappeared, however, a new lesion appeared. Similarly, four months after the initial treatment, although the previous lesion disappeared, a new lesion appeared.

This case highlights that clinicians should use MR black-blood sequence scan in a timely manner in case of young patients with migratory lesions of brain. In case of detection of a vascular lesion in combination with other systemic lesions, the possibility of Fabry disease should be considered.

    Fabry disease
    DIAGNOSIS

 is rare, and the diagnosis is often delayed. Here, we describe a case of

    Fabry disease
    DIAGNOSIS

 resulting in

    vasculopathy of the central nervous system
    SYMPTOMS

.

    Magnetic resonance (MR) black-blood sequence
    PARACLINICAL

 (three-dimensional T1 volumetric isotropic turbo spin echo acquisition), with the unique advantage of

    imaging the vascular wall
    PARACLINICAL

, facilitated a clear identification of the

    vasculopathy
    SYMPTOMS

.

A

    27-year-old
    AGE

    man
    GENDER

 visited our hospital for the treatment of "

    double vision 6d
    SYMPTOMS

." After a series of examinations, the patient was diagnosed with

    Fabry disease
    DIAGNOSIS

, which caused

    vasculopathy of the central nervous system
    SYMPTOMS

. Subsequently, the patient was treated with

    corticosteroids
    MEDICATION

 and his

    symptoms were attenuated
    SYMPTOMS

. Two months after the initial treatment,

    the initial lesion in the vascular vessel disappeared, however, a new lesion appeared
    SYMPTOMS

. Similarly, four months after the initial treatment,

    although the previous lesion disappeared, a new lesion appeared
    SYMPTOMS

.

This case highlights that clinicians should use

    MR black-blood sequence scan
    PARACLINICAL

 in a timely manner in case of

    young
    AGE

 patients with

    migratory lesions of brain
    SYMPTOMS

. In case of detection of a

    vascular lesion in combination with other systemic lesions
    SYMPTOMS

, the possibility of

    Fabry disease
    DIAGNOSIS

 should be considered.

Fabry disease
Fabry disease
Fabry disease
Fabry disease


MULTIPLE SCLEROSIS OR FABRY DISEASE - PROS AND CONS.

- Fabry disease is a rare X-linked inherited lysosomal storage disease affecting multiple organ systems, presenting in the central nervous system (CNS) as white matter lesions with underlying cerebral vasculopathy and autoinflammatory changes of the choroid plexus and leptomeninges. We present a young female patient (age 36 years) admitted to our department due to visual loss on the left eye. Magnetic resonance imaging (MRI) showed demyelinating lesions in the frontal and parietal lobe, periventricularly, in mesencephalon and right cerebellar hemisphere, and left optic neuritis; MR angiography was normal. Her medical history revealed renal dysfunction, hypothyroidism, and miscarriage in the 6th month of pregnancy due to eclampsia and Fabry disease in the family (mother). Cerebrospinal fluid analysis showed mild pleocytosis, normal blood brain barrier function and oligoclonal bands type 3. Visual evoked potentials showed prechiasmal dysfunction of the left optic nerve. Genetical testing for Fabry disease was positive (two heterozygous mutations), with decreased alpha galactosidase activity values and increased Lyso GB3 values. The patient received corticosteroid therapy (methylprednisolone) 1 g for 5 days, which led to regression of visual disturbances on the left eye. After this acute treatment, there was a question of definitive diagnosis and further treatment of the underlying cause. Considering renal dysfunction, miscarriage, arterial hypertension, positive genetic and biochemical testing for Fabry disease, as well as MRI findings showing lesions in posterior circulation, we concluded that the patient probably had Fabry disease with autoinflammatory changes in the CNS and should be treated with enzyme replacement therapy. Still, there was a question of optic neuritis on the left eye and positive oligoclonal bands favoring the diagnosis of multiple sclerosis. Therefore, further clinical and neuroradiological follow up was needed to distinguish multiple sclerosis and Fabry disease in this patient.

-

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked inherited
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

    affecting multiple organ systems
    SYMPTOMS

,

    presenting in the central nervous system (CNS)
    SYMPTOMS

 as

    white matter lesions with underlying cerebral vasculopathy
    SYMPTOMS

 and

    autoinflammatory changes of the choroid plexus and leptomeninges
    SYMPTOMS

. We present a

    young
    AGE

    female
    GENDER

 patient (

    age 36 years
    AGE

) admitted to our department due to

    visual loss on the left eye
    SYMPTOMS

.

    Magnetic resonance imaging (MRI)
    PARACLINICAL

 showed

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

, and

    left optic neuritis
    SYMPTOMS

;

    MR angiography was normal
    NEG_FINDINGS

.

    Her
    GENDER

 medical history revealed

    renal dysfunction
    SYMPTOMS

,

    hypothyroidism
    SYMPTOMS

, and

    miscarriage in the 6th month of pregnancy
    SYMPTOMS

 due to

    eclampsia
    DIAGNOSIS

 and

    Fabry disease in the family (mother)
    FAMILY

.

    Cerebrospinal fluid analysis
    PARACLINICAL

 showed

    mild pleocytosis
    BIOCHEMICAL

,

    normal blood brain barrier function
    NEG_FINDINGS

 and

    oligoclonal bands type 3
    BIOCHEMICAL

. Visual evoked potentials showed

    prechiasmal dysfunction of the left optic nerve
    SYMPTOMS

.

    Genetical testing for Fabry disease was positive (two heterozygous mutations)
    GENETICS

, with

    decreased alpha galactosidase activity values
    BIOCHEMICAL

 and

    increased Lyso GB3 values
    BIOCHEMICAL

. The patient received

    corticosteroid therapy (methylprednisolone) 1 g for 5 days
    MEDICATION

, which led to

    regression of visual disturbances on the left eye
    SYMPTOMS

. After this

    acute treatment
    MEDICATION

, there was a question of definitive diagnosis and further treatment of the underlying cause. Considering

    renal dysfunction
    SYMPTOMS

,

    miscarriage
    SYMPTOMS

,

    arterial hypertension
    SYMPTOMS

,

    positive genetic and biochemical testing for Fabry disease
    SYMPTOMS

, as well as

    MRI
    PARACLINICAL

 findings showing

    lesions in posterior circulation
    SYMPTOMS

, we concluded that the patient probably had

    Fabry disease
    DIAGNOSIS

 with

    autoinflammatory changes in the CNS
    SYMPTOMS

 and should be treated with

    enzyme replacement therapy
    MEDICATION

. Still, there was a question of

    optic neuritis on the left eye
    SYMPTOMS

 and

    positive oligoclonal bands
    BIOCHEMICAL

 favoring the diagnosis of

    multiple sclerosis
    DIAGNOSIS

. Therefore,

    further clinical and neuroradiological follow up
    PARACLINICAL

 was needed to distinguish

    multiple sclerosis
    DIAGNOSIS

 and

    Fabry disease
    DIAGNOSIS

 in this patient.

Fabry disease
lysosomal storage disease
eclampsia
Fabry disease
multiple sclerosis
multiple sclerosis
Fabry disease

MR angiography was normal
normal blood brain barrier function


Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder.

Lysosomal storage disorders (LSDs) collectively constitute a significant public health burden in developing countries. Commoner LSDs include Gaucher, Fabry, and Niemann-Pick disease (NPD), but many cases remain undiagnosed. With the high incidence of consanguineous marriages, South East Asian countries are expected to have high prevalence of these LSDs. Here we report 4 cases of NPD type A/B in 3 families presenting with hepatosplenomegaly and cytopenias including one family with two sibs having hypertension and mitral valve prolapse. The diagnosis of NPD was proven by mutation analysis with identification of novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the SMPD1 gene. We also had two cases of NPD type C, confirmed on mutation analysis.

    Lysosomal storage disorders (LSDs)
    DIAGNOSIS

 collectively constitute a significant public health burden in developing countries. Commoner

    LSDs
    DIAGNOSIS

 include

    Gaucher
    DIAGNOSIS

,

    Fabry
    DIAGNOSIS

, and

    Niemann-Pick disease (NPD)
    DIAGNOSIS

, but many cases remain undiagnosed. With the high incidence of

    consanguineous marriages
    GENETICS

,

    South East Asian
    ETHNICITY

 countries are expected to have high prevalence of these

    LSDs
    DIAGNOSIS

. Here we report 4 cases of

    NPD type A/B
    DIAGNOSIS

 in 3 families presenting with

    hepatosplenomegaly
    SYMPTOMS

 and

    cytopenias
    BIOCHEMICAL

 including one

    family with two sibs having hypertension and mitral valve prolapse
    FAMILY

. The diagnosis of

    NPD
    DIAGNOSIS

 was proven by

    mutation analysis
    PARACLINICAL

 with identification of

    novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the SMPD1 gene
    GENETICS

. We also had two cases of

    NPD type C
    DIAGNOSIS

, confirmed on

    mutation analysis
    PARACLINICAL

.

Lysosomal storage disorders (LSDs)
LSDs
Gaucher
Fabry
Niemann-Pick disease (NPD)
LSDs
NPD type A/B
NPD
NPD type C


Hydroxychloroquine-induced podocytopathy mimicking Fabry disease.

Hydroxychloroquine (HCQ) is largely prescribed as an immunomodulator to prevent systemic diseases flares in patients with systemic lupus erythematous, rheumatoid arthritis, Sjogren's disease. Among reported side effects, HCQ can accumulate in lysosomes and induced phospholipidosis. Here, we report an HCQ-induced podocytopathy mimicking Fabry disease (FD). They share the same histological lesions: cytoplasmic vacuolisation of the podocytes and zebra bodies on light and electronic microscopy. FD has been ruled out by measuring enzymatic activity and genetic test. The persistence of proteinuria after immunological remission of a systemic disease treated with HCQ could suggest this HCQ-induced podocytopathy.

    Hydroxychloroquine (HCQ)
    MEDICATION

 is largely prescribed as an

    immunomodulator
    MEDICATION

 to prevent

    systemic diseases flares
    SYMPTOMS

 in patients with

    systemic lupus erythematous
    DIAGNOSIS

,

    rheumatoid arthritis
    DIAGNOSIS

,

    Sjogren's disease
    DIAGNOSIS

. Among reported side effects,

    HCQ
    MEDICATION

 can

    accumulate in lysosomes and induced phospholipidosis
    MICROSCOPIC

. Here, we report an

    HCQ-induced podocytopathy mimicking Fabry disease (FD)
    DIAGNOSIS

. They share the same

    histological lesions
    MICROSCOPIC

:

    cytoplasmic vacuolisation of the podocytes
    MICROSCOPIC

 and

    zebra bodies
    MICROSCOPIC

 on

    light and electronic microscopy
    PARACLINICAL

.

    FD has been ruled out by measuring enzymatic activity and genetic test
    NEG_FINDINGS

. The

    persistence of proteinuria
    BIOCHEMICAL

    after immunological remission
    NEG_FINDINGS

 of a

    systemic disease
    DIAGNOSIS

 treated with

    HCQ
    MEDICATION

 could suggest this

    HCQ-induced podocytopathy
    DIAGNOSIS

.

Hydroxychloroquine (HCQ)
immunomodulator
HCQ
HCQ


Genotype⁻Phenotype Correlation in a New Fabry-Disease-Causing Mutation.

Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical activity, and periodic cardiac arrhythmia. Echocardiography revealed left ventricular hypertrophy with normal diastolic function. The patient had experienced acroparesthesia in her upper limbs and abdominal pain since childhood, and in the last decade had experienced mild proteinuria without renal failure. Her renal biopsy was typical for Fabry disease. The patient's brain magnetic resonance imaging (MRI) (T2 flair) showed white matter hyperintensities lesions. DNA sequencing of the proband, her mother and one of her sons showed a novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp). All three patients had decreased α-galactosidase A activity and specific FD manifestations. Conclusion: A novel GLA mutation, c.270C>G (p.Cys90Trp), was found in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac involvement. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.

Background:

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare X-linked inherited
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    α-galactosidase A deficiency
    BIOCHEMICAL

 leading to

    intracellular glycosphingolipid accumulation
    MICROSCOPIC

.

    FD
    DIAGNOSIS

 manifestation is

    multisystem
    SYMPTOMS

, and can differ depending on

    disease-related genetic variants
    GENETICS

. Currently, more than 700 different

    FD-causing mutations
    GENETICS

 have been identified in the

    human GLA gene
    GENETICS

. We identified a

    novel mutation
    GENETICS

 in a

    Lithuanian
    ETHNICITY

    family with classical manifestations of Fabry disease
    FAMILY

, revealing

    severe effects to the cardiovascular systems
    SYMPTOMS

 of

    heterozygous
    GENETICS

    women
    GENDER

. Case presentation: A

    49-year-old
    AGE

    woman
    GENDER

 underwent

    echocardiography
    PARACLINICAL

 due to

    progressive dyspnea that lasted seven years
    SYMPTOMS

,

    reduced physical activity
    SYMPTOMS

, and

    periodic cardiac arrhythmia
    SYMPTOMS

.

    Echocardiography
    PARACLINICAL

 revealed

    left ventricular hypertrophy
    SYMPTOMS

 with

    normal diastolic function
    NEG_FINDINGS

. The patient had experienced

    acroparesthesia in her upper limbs
    SYMPTOMS

 and

    abdominal pain
    SYMPTOMS

 since

    childhood
    AGE

, and in the last decade had experienced

    mild proteinuria
    BIOCHEMICAL

    without renal failure
    NEG_FINDINGS

.

    Her
    GENDER

    renal biopsy
    PARACLINICAL

 was typical for

    Fabry disease
    DIAGNOSIS

. The patient's

    brain magnetic resonance imaging (MRI) (T2 flair)
    PARACLINICAL

 showed

    white matter hyperintensities lesions
    SYMPTOMS

.

    DNA sequencing of the proband, her mother and one of her sons
    PARACLINICAL

 showed a

    novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp)
    GENETICS

. All three patients had

    decreased α-galactosidase A activity
    BIOCHEMICAL

 and

    specific FD manifestations
    SYMPTOMS

. Conclusion: A

    novel GLA mutation, c.270C>G (p.Cys90Trp)
    GENETICS

, was found in a

    Lithuanian
    ETHNICITY

    family with a classical form of Fabry disease
    FAMILY

 in

    heterozygous
    GENETICS

    women
    GENDER

 with

    predominant cardiac involvement
    SYMPTOMS

. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.

Fabry disease (FD)
lysosomal storage disorder
FD
Fabry disease

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

normal diastolic function
without renal failure


A Case of a 50-Year-Old Woman with Typical Fabry Disease Who Showed Serial Electrocardiographic and Echocardiographic Changes over a 17-Year Period.

Fabry disease (FD) is a progressive, X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A activity. Affected individuals accumulate globotriaosylceramide and glycosphingolipids in the lysosomes and cytoplasm of cells throughout the body, leading to major organ failure and premature death. Cardiac involvement includes left ventricular hypertrophy, arrhythmia, endothelial dysfunction at vascular wall, and cardiomyopathy. The diagnosis of FD can be difficult and there is often a long lag time between symptoms and diagnosis. Here, we present a case of a 50-year-old woman with typical Fabry disease who showed serial electrocardiographic and echocardiographic changes over 17 years prior to diagnosis with Fabry disease.

    Fabry disease (FD)
    DIAGNOSIS

 is a progressive,

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of α-galactosidase A activity
    BIOCHEMICAL

. Affected individuals

    accumulate globotriaosylceramide and glycosphingolipids in the lysosomes and cytoplasm of cells throughout the body
    MICROSCOPIC

, leading to

    major organ failure
    SYMPTOMS

 and

    premature death
    SYMPTOMS

.

    Cardiac involvement
    SYMPTOMS

 includes

    left ventricular hypertrophy
    SYMPTOMS

,

    arrhythmia
    SYMPTOMS

,

    endothelial dysfunction at vascular wall
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

. The diagnosis of

    FD
    DIAGNOSIS

 can be difficult and there is often a long lag time between symptoms and diagnosis. Here, we present a case of a

    50-year-old
    AGE

    woman
    GENDER

 with typical

    Fabry disease
    DIAGNOSIS

 who showed

    serial electrocardiographic and echocardiographic changes
    SYMPTOMS

 over 17 years prior to diagnosis with

    Fabry disease
    DIAGNOSIS

.

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


Ventricular tachycardia: a presentation of Fabry disease case report.

Fabry disease is an inherited rare metabolic disease caused by mutation in the GLA gene, encoding lysosomal enzyme alpha-galactosidase A. The disorder is a systemic disease that manifests as cerebrovascular and cardiac disease, chronic renal failure, skin lesion, peripheral neuropathy, and other abnormalities. Ventricular tachycardia as a Fabry disease presentation is very rare.

A 36-year-old man self-presented to a general practitioner complaining of episodes of shortness of breath together with a 6-month history of malaise. The 12-lead electrocardiogram (ECG) prompted a decision to transfer him immediately to a percutaneous coronary intervention (PCI) capable hospital under the suspicion of acute coronary syndrome. Whilst awaiting transport, he experienced acute onset of dyspnoea together with non-specific chest heaviness. A repeat ECG monitor strip showed ventricular tachycardia transforming to ventricular fibrillation. The patient was successfully defibrillated. Coronary angiography was performed upon arrival at hospital and demonstrated unobstructed coronary arteries. Transthoracic echocardiography revealed concentric left ventricular hypertrophy (LVH) and normal systolic function, with severe diastolic dysfunction. Magnetic resonance imaging (MRI) confirmed the LVH, and did not demonstrate any late gadolinium enhancement.

Our case illustrates the pivotal role of critical clinical thinking in the diagnosis of rare but treatable hereditary cardiomyopathy. The uncommon cardiac presentation of Fabry disease promotes further research linking different phenotypes of Fabry disease with different pathogenic mutations.

    Fabry disease
    DIAGNOSIS

 is an

    inherited rare metabolic disease
    GENETICS

 caused by mutation in the GLA gene, encoding lysosomal enzyme alpha-galactosidase A. The disorder is a

    systemic disease
    DIAGNOSIS

 that manifests as

    cerebrovascular and cardiac disease
    SYMPTOMS

,

    chronic renal failure
    SYMPTOMS

,

    skin lesion
    SYMPTOMS

,

    peripheral neuropathy
    SYMPTOMS

, and other

    abnormalities
    SYMPTOMS

.

    Ventricular tachycardia
    SYMPTOMS

 as a

    Fabry disease
    DIAGNOSIS

 presentation is very rare.

A

    36-year-old
    AGE

    man
    GENDER

 self-presented to a

    general practitioner
    PARACLINICAL

 complaining of

    episodes of shortness of breath
    SYMPTOMS

 together with a

    6-month history of malaise
    SYMPTOMS

. The

    12-lead electrocardiogram (ECG)
    PARACLINICAL

 prompted a decision to transfer

    him
    GENDER

 immediately to a

    percutaneous coronary intervention (PCI) capable hospital
    MEDICATION

 under the suspicion of

    acute coronary syndrome
    DIAGNOSIS

. Whilst awaiting transport,

    he
    GENDER

 experienced

    acute onset of dyspnoea
    SYMPTOMS

 together with

    non-specific chest heaviness
    SYMPTOMS

. A

    repeat ECG monitor strip
    PARACLINICAL

 showed

    ventricular tachycardia transforming to ventricular fibrillation
    SYMPTOMS

. The patient was successfully

    defibrillated
    MEDICATION

.

    Coronary angiography
    PARACLINICAL

 was performed upon arrival at hospital and demonstrated

    unobstructed coronary arteries
    NEG_FINDINGS

.

    Transthoracic echocardiography
    PARACLINICAL

 revealed

    concentric left ventricular hypertrophy (LVH)
    SYMPTOMS

 and

    normal systolic function
    NEG_FINDINGS

, with

    severe diastolic dysfunction
    SYMPTOMS

.

    Magnetic resonance imaging (MRI)
    PARACLINICAL

 confirmed the

    LVH
    DIAGNOSIS

, and

    did not demonstrate any late gadolinium enhancement
    NEG_FINDINGS

.

Our case illustrates the pivotal role of critical clinical thinking in the diagnosis of

    rare
    DIAGNOSIS

 but treatable

    hereditary cardiomyopathy
    DIAGNOSIS

. The

    uncommon cardiac presentation
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

 promotes further research linking different phenotypes of

    Fabry disease
    DIAGNOSIS

 with different pathogenic mutations.

Fabry disease
systemic disease
Fabry disease
acute coronary syndrome
LVH
rare
hereditary cardiomyopathy
Fabry disease
Fabry disease


New Fabry disease mutation confirms cardiomyopathy aetiology: a case report.

Aetiologic diagnosis should be a priority in cardiomyopathy patients, as some of them may benefit from efficient specific treatment. To achieve this, the best approach is to look for clinical and paraclinical 'red flags'.

A 55-year-old woman was referred to our centre with the diagnoses of hypertrophic cardiomyopathy (HCM), high blood pressure and dyslipidaemia. The only symptom she declared was long-term acroparesthaesia with an otherwise normal clinical exam. Lab work-up showed slightly above normal values of troponin and brain natriuretic peptide (BNP), and chronic kidney disease Stage IIIA. Both the electrocardiogram (ECG) and the echocardiography showed signs of biventricular HCM, with short PR interval on the ECG and longitudinal systolic dysfunction on the echo. Family history revealed that her son and brother had been diagnosed with Fabry disease (FD). She was then tested for FD and the results confirmed the diagnosis. Alpha-galactosidase (AGAL) levels were low and she had a severe mutation on the GLA gene (gross deletion of 3' region of the GLA gene including coding parts of exon 7), not described before. The patient was started on specific enzyme therapy.

Fabry disease is a rare X-linked disease caused by mutations on the GLA gene, which leads to low levels of AGAL and accumulation of globotriaosylceramide in the lysosomes of most tissues. Even though FD is X-linked, current medical knowledge states that most females are not mere carriers, but often present with a milder or later-onset phenotype.

    Aetiologic diagnosis
    PARACLINICAL

 should be a priority in

    cardiomyopathy
    DIAGNOSIS

 patients, as some of them may benefit from efficient specific treatment. To achieve this, the best approach is to look for clinical and paraclinical 'red flags'.

A

    55-year-old
    AGE

    woman
    GENDER

 was referred to our centre with the diagnoses of

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

,

    high blood pressure
    SYMPTOMS

 and

    dyslipidaemia
    BIOCHEMICAL

. The only symptom

    she
    GENDER

 declared was

    long-term acroparesthaesia
    SYMPTOMS

 with an

    otherwise normal clinical exam
    NEG_FINDINGS

.

    Lab work-up
    PARACLINICAL

 showed

    slightly above normal values of troponin and brain natriuretic peptide (BNP)
    BIOCHEMICAL

, and

    chronic kidney disease Stage IIIA
    DIAGNOSIS

. Both the

    electrocardiogram (ECG)
    PARACLINICAL

 and the

    echocardiography
    PARACLINICAL

 showed

    signs of biventricular HCM, with short PR interval on the ECG and longitudinal systolic dysfunction on the echo
    SYMPTOMS

.

    Family history revealed that her son and brother had been diagnosed with Fabry disease (FD)
    FAMILY

.

    She
    GENDER

 was then tested for

    FD
    DIAGNOSIS

 and the results confirmed the diagnosis.

    Alpha-galactosidase (AGAL) levels were low
    BIOCHEMICAL

 and

    she
    GENDER

 had a

    severe mutation on the GLA gene (gross deletion of 3' region of the GLA gene including coding parts of exon 7)
    GENETICS

, not described before. The patient was started on

    specific enzyme therapy
    MEDICATION

.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked disease
    GENETICS

 caused by

    mutations on the GLA gene
    GENETICS

, which leads to

    low levels of AGAL
    BIOCHEMICAL

 and

    accumulation of globotriaosylceramide in the lysosomes of most tissues
    MICROSCOPIC

. Even though

    FD
    DIAGNOSIS

    is X-linked
    GENETICS

, current medical knowledge states that most

    females
    GENDER

 are not mere carriers, but often present with a milder or later-onset phenotype.

cardiomyopathy
hypertrophic cardiomyopathy (HCM)
chronic kidney disease Stage IIIA
FD
Fabry disease
FD


Progressive cardiac involvement in a compound heterozygote Fabry patient: a case report.

Fabry disease is an X-linked lysosomal storage disorder due to mutations in the gene encoding for alpha-galactosidase A, with subsequent accumulation of complex sphingolipids in multiple organs, including the heart. Female heterozygotes can develop cardiac involvement although this is usually milder and slower to progress compared with male hemizygotes.

A 71-year-old woman with two separate pathological Fabry mutations (N215S, C202R; compound heterozygote) presented with progressive cardiac involvement despite enzyme replacement therapy (ERT) with Replagal, as demonstrated by troponin elevation and cardiovascular magnetic resonance (CMR) findings: moderate segmental left ventricular dysfunction with wall thinning, low myocardial native T1, and extensive late gadolinium enhancement with co-located increased T2.

We report for the first time, a detailed cardiac phenotype using CMR in a compound heterozygote Fabry patient with progressive cardiac involvement despite ERT.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 due to

    mutations in the gene encoding for alpha-galactosidase A
    GENETICS

, with subsequent

    accumulation of complex sphingolipids in multiple organs, including the heart
    MICROSCOPIC

.

    Female
    GENDER

    heterozygotes
    GENETICS

 can develop

    cardiac involvement
    SYMPTOMS

 although this is usually milder and slower to progress compared with

    male
    GENDER

    hemizygotes
    GENETICS

.

A

    71-year-old
    AGE

    woman
    GENDER

    with two separate pathological Fabry mutations (N215S, C202R; compound heterozygote)
    GENETICS

 presented with

    progressive cardiac involvement
    SYMPTOMS

    despite enzyme replacement therapy (ERT) with Replagal
    NEG_FINDINGS

, as demonstrated by

    troponin elevation
    BIOCHEMICAL

 and

    cardiovascular magnetic resonance (CMR) findings
    PARACLINICAL

:

    moderate segmental left ventricular dysfunction with wall thinning
    SYMPTOMS

,

    low myocardial native T1
    SYMPTOMS

, and extensive late gadolinium enhancement with co-located increased T2.

We report for the first time, a detailed cardiac phenotype using

    CMR
    PARACLINICAL

 in a

    compound heterozygote
    GENETICS

    Fabry
    DIAGNOSIS

 patient with

    progressive cardiac involvement
    SYMPTOMS

    despite ERT
    NEG_FINDINGS

.

Fabry disease
lysosomal storage disorder
Fabry


Dysregulated DNA methylation of GLA gene was associated with dysfunction of autophagy.

Lysosomes are an essential organ for cellular metabolism and play an important role in autophagy. We examined the association between methylation and autophagy in a severely affected female patient with Fabry disease, which is caused by mutation of the GLA gene on the X chromosome, and her two sisters, who had few symptoms. We confirmed autophagic flux by LC3 turnover assay using fibroblasts from each sister. In the severe female patient, autophagic flux showed abnormal while her two sisters with few symptoms had normal autophagic flux, revealing the direct relationship between symptoms and autophagic flux. Furthermore, we observed the levels of p62, which is a substrate for autophagy, and lysosome morphology. In the severe patient of this family, lysosomes were enlarged and p62 was accumulated. The methylated allele of the GLA gene in the severe patient had a high proportion of wild alleles; conversely, the sisters' methylated allele had a high proportion of mutant alleles. Therefore, we examined the mRNA expression level of the mutant allele by allele-specific PCR. It was high in the severe patient and low in the siblings with few symptoms. That is, the correlation between the mRNA expression level of the mutant allele and disease severity was confirmed. We showed a correlation between severe symptoms, dysfunction of autophagy and methylation of wild alleles in Fabry disease. It was suggested that allele-specific PCR may lead to a diagnosis and help to determine the prognosis of female patients with Fabry disease.

    Lysosomes
    MICROSCOPIC

 are an essential organ for

    cellular metabolism
    MICROSCOPIC

 and play an important role in

    autophagy
    MICROSCOPIC

. We examined the

    association between methylation and autophagy
    MICROSCOPIC

 in a severely affected

    female
    GENDER

 patient with

    Fabry disease
    DIAGNOSIS

, which is caused by

    mutation of the GLA gene on the X chromosome
    GENETICS

, and

    her two sisters, who had few symptoms
    FAMILY

. We confirmed

    autophagic flux
    MICROSCOPIC

 by

    LC3 turnover assay using fibroblasts from each sister
    PARACLINICAL

. In the severe

    female
    GENDER

 patient,

    autophagic flux showed abnormal
    MICROSCOPIC

 while

    her two sisters with few symptoms had normal autophagic flux
    FAMILY

, revealing the direct relationship between symptoms and

    autophagic flux
    MICROSCOPIC

. Furthermore, we observed the

    levels of p62
    BIOCHEMICAL

, which is a

    substrate for autophagy
    BIOCHEMICAL

, and

    lysosome morphology
    MICROSCOPIC

. In the severe patient of this family,

    lysosomes were enlarged
    MICROSCOPIC

 and

    p62 was accumulated
    MICROSCOPIC

.

    The methylated allele of the GLA gene in the severe patient had a high proportion of wild alleles
    GENETICS

;

    conversely, the sisters' methylated allele had a high proportion of mutant alleles
    FAMILY

. Therefore, we examined the

    mRNA expression level of the mutant allele
    GENETICS

 by

    allele-specific PCR
    PARACLINICAL

.

    It was high in the severe patient and low in the siblings with few symptoms
    GENETICS

. That is, the correlation between the

    mRNA expression level of the mutant allele
    GENETICS

 and disease severity was confirmed. We showed a correlation between

    severe symptoms
    SYMPTOMS

,

    dysfunction of autophagy
    MICROSCOPIC

 and

    methylation of wild alleles
    GENETICS

 in

    Fabry disease
    DIAGNOSIS

. It was suggested that

    allele-specific PCR
    PARACLINICAL

 may lead to a diagnosis and help to determine the prognosis of

    female
    GENDER

 patients with

    Fabry disease
    DIAGNOSIS

.

Fabry disease
Fabry disease
Fabry disease


The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts.

Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations.

We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients.

Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes.

ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.

    Enzyme replacement therapy (ERT) with recombinant human α-galactosidase
    MEDICATION

 has been available for the treatment of

    Fabry disease
    DIAGNOSIS

 since 2001 in

    Europe
    ETHNICITY

 and 2003 in the USA. Treatment outcomes with

    ERT
    MEDICATION

 are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations.

We conducted a comprehensive systematic literature review of all original articles on

    ERT
    MEDICATION

 in the treatment of

    Fabry disease
    DIAGNOSIS

 published up until January 2017. This article presents the findings in

    adult
    AGE

    male
    GENDER

 patients.

Clinical evidence for the efficacy of

    ERT
    MEDICATION

 in

    adult
    AGE

    male
    GENDER

 patients was available from 166 publications including 36 clinical trial publications.

    ERT
    MEDICATION

 significantly

    decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types
    BIOCHEMICAL

, slows the

    decline in estimated glomerular filtration rate
    BIOCHEMICAL

, and

    reduces/stabilizes left ventricular mass and cardiac wall thickness
    SYMPTOMS

.

    ERT
    MEDICATION

 also

    improves nervous system, gastrointestinal, pain, and quality of life outcomes
    SYMPTOMS

.

    ERT
    MEDICATION

 is a disease-specific treatment for patients with

    Fabry disease
    DIAGNOSIS

 that may provide

    clinical benefits on several outcomes and organ systems
    SYMPTOMS

. Better outcomes may be observed when treatment is started at an

    early age
    AGE

 prior to the development of

    organ damage
    SYMPTOMS

 such as

    chronic kidney disease
    DIAGNOSIS

 or

    cardiac fibrosis
    SYMPTOMS

. Consolidated evidence suggests a dose effect. Data described in

    male
    GENDER

 patients, together with

    female
    GENDER

 and

    paediatric
    AGE

 data, informs clinical practice and therapeutic goals for individualized treatment.

Fabry disease
Fabry disease
Fabry disease
chronic kidney disease


[The unusual couple: a clinical case of coexistence between aHUS and Fabry's disease].

Atypical hemolytic-uremic syndrome (aHUS) is a rare, potentially lethal (1-4) systemic disorder, capable of affecting both adults and children, causing thrombotic microangiopathy (TMA) (5) that leads to the formation of thrombus within small blood vessels with multiple organ failure. The pathogenesis of the aHUS is part of a sort of chronic and uncontrolled activation of the complement system by genetic mutation of some proteins usually responsible for its self-regulation (6,7). Today, the rapid diagnosis of the disease and the timely start of treatment with eculizumab, improve outcomes of renal failure, stroke and heart attack (8-10). Fabry disease is a rare tesaurismosis, X linked, due to the deficiency of the lysosomal enzyme alpha-galactosidase A (11-13), necessary for the physiological catabolism of glycosphingolipids. Multisystem clinical manifestations lead to a serious degenerative pathology. The diagnostic suspicion based on anamnesis and careful research of the symptoms and then confirmed by the enzymatic dosage of alpha galactosidase or by molecular analysis, allows the early treatment of the patient with enzyme replacement therapy, guaranteeing the resolution and/or slowing down the evolution of the disease, especially in the brain, heart and kidneys. In this report, we describe the clinical case of a patient who is a carrier of both rare diseases.

    Atypical hemolytic-uremic syndrome (aHUS)
    DIAGNOSIS

 is a rare, potentially lethal (1-4)

    systemic disorder
    DIAGNOSIS

, capable of affecting both

    adults
    AGE

 and

    children
    AGE

, causing

    thrombotic microangiopathy (TMA)
    DIAGNOSIS

 (5) that leads to the

    formation of thrombus within small blood vessels
    SYMPTOMS

 with

    multiple organ failure
    SYMPTOMS

. The pathogenesis of the

    aHUS
    DIAGNOSIS

 is part of a sort of chronic and

    uncontrolled activation of the complement system
    BIOCHEMICAL

 by

    genetic mutation of some proteins usually responsible for its self-regulation
    GENETICS

 (6,7). Today, the rapid diagnosis of the disease and the timely start of

    treatment with eculizumab
    MEDICATION

, improve outcomes of

    renal failure
    SYMPTOMS

,

    stroke
    SYMPTOMS

 and

    heart attack
    SYMPTOMS

 (8-10).

    Fabry disease
    DIAGNOSIS

 is a

    rare tesaurismosis
    DIAGNOSIS

,

    X linked
    GENETICS

, due to the

    deficiency of the lysosomal enzyme alpha-galactosidase A
    BIOCHEMICAL

 (11-13), necessary for the

    physiological catabolism of glycosphingolipids
    BIOCHEMICAL

.

    Multisystem clinical manifestations
    SYMPTOMS

 lead to a

    serious degenerative pathology
    SYMPTOMS

. The diagnostic suspicion based on

    anamnesis
    PARACLINICAL

 and careful research of the symptoms and then confirmed by the

    enzymatic dosage of alpha galactosidase
    PARACLINICAL

 or by

    molecular analysis
    PARACLINICAL

, allows the

    early treatment
    MEDICATION

 of the patient with

    enzyme replacement therapy
    MEDICATION

, guaranteeing the

    resolution and/or slowing down the evolution of the disease, especially in the brain, heart and kidneys
    SYMPTOMS

. In this report, we describe the clinical case of a patient who is a

    carrier of both rare diseases
    FAMILY

.

treatment with eculizumab
early treatment
enzyme replacement therapy


Misdiagnosis of multiple sclerosis in a female heterozygote with Fabry's disease.

Fabry's disease is an X-linked disorder of enzyme alpha-galactosidase A which leads to an accumulation of the glycolipids in lysosomes in vessels and organs. The disorder is rare with an estimated incidence of 1 in 40,000 and disease occurs more rarely in women than men. Paresthesias, hearing loss, and stroke are the typical neurological manifestations. Brain magnetic resonance imaging abnormalities may mimic those seen in multiple sclerosis (MS). Reported here is one of the rarely reported cases of Fabry's disease in a female heterozygote mistaken for MS.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disorder of enzyme alpha-galactosidase A
    DIAGNOSIS

 which leads to an

    accumulation of the glycolipids in lysosomes in vessels and organs
    MICROSCOPIC

. The disorder is rare with an estimated incidence of 1 in 40,000 and disease occurs more rarely in

    women
    GENDER

 than

    men
    GENDER

.

    Paresthesias
    SYMPTOMS

,

    hearing loss
    SYMPTOMS

, and

    stroke
    SYMPTOMS

 are the typical

    neurological manifestations
    SYMPTOMS

.

    Brain magnetic resonance imaging abnormalities may mimic those seen in multiple sclerosis (MS)
    SYMPTOMS

. Reported here is one of the rarely reported cases of

    Fabry's disease
    DIAGNOSIS

 in a

    female
    GENDER

    heterozygote
    GENETICS

    mistaken for MS
    NEG_FINDINGS

.


High Lyso-Gb3 Plasma Levels Associated with Decreased miR-29 and miR-200 Urinary Excretion in Young Non-Albuminuric Male Patient with Classic Fabry Disease.

Renal involvement is associated with a greater morbidity and mortality in Fabry disease. Pathological albuminuria, the first Fabry nephropathy clinical manifestation, can occur from early childhood, although histological lesions such as tubulo-interstitial fibrosis and glomerulosclerosis are present or may precede the onset of pathological albuminuria. In renal cells, exposure to Lyso-Gb3 is correlated with increased expression of Transforming Growth Factor-βeta (TGF-β). miR-21, miR-192, and miR-433 that promote fibrosis are activated by TGF-β, and miR-29 and miR-200 that suppress fibrosis are inhibited by TGF-β. A 23-year-old male was diagnosed with FD. αGalA decreased enzyme activity: 0.1 nmol/hour/liter; genotype: [c.317T>G (p.L106R)]; GFR: 104.4 mL/min/m2; urinary albumin excretion: 6.00 mg/day; plasma Lyso-Gb3: 124.5 nmol/L. A decrease urinary excretion of miR-29 and miR-200 was found (p <0.005) compared to controls. In addition to its usefulness as a phenotype marker, Lyso-Gb3 has been proposed as an indicator of therapeutic response. We detect an association of high Lyso-Gb3 plasma values with decreased urinary excretion of miRNAs with known antifibrotic effect (miR-29 and miR-200). Although the present work is a case report, it could be hypothesized that one of the harmful Lyso-Gb3 effects could be the miRNAs regulation through changes in TGF-β expression.

    Renal involvement
    SYMPTOMS

 is associated with a greater morbidity and mortality in

    Fabry disease
    DIAGNOSIS

.

    Pathological albuminuria
    BIOCHEMICAL

, the first

    Fabry nephropathy
    DIAGNOSIS

 clinical manifestation, can occur from

    early childhood
    AGE

, although

    histological lesions
    SYMPTOMS

 such as

    tubulo-interstitial fibrosis
    MICROSCOPIC

 and

    glomerulosclerosis
    SYMPTOMS

 are present or may precede the onset of

    pathological albuminuria
    BIOCHEMICAL

.

    In renal cells
    MICROSCOPIC

,

    exposure to Lyso-Gb3
    MICROSCOPIC

 is correlated with

    increased expression of Transforming Growth Factor-βeta (TGF-β)
    BIOCHEMICAL

.

    miR-21
    GENETICS

,

    miR-192
    GENETICS

, and

    miR-433
    GENETICS

 that

    promote fibrosis
    SYMPTOMS

 are

    activated by TGF-β
    BIOCHEMICAL

, and

    miR-29
    GENETICS

 and

    miR-200
    GENETICS

 that

    suppress fibrosis
    SYMPTOMS

 are

    inhibited by TGF-β
    BIOCHEMICAL

. A

    23-year-old
    AGE

    male
    GENDER

 was diagnosed with

    FD
    DIAGNOSIS

.

    αGalA decreased enzyme activity: 0.1 nmol/hour/liter
    BIOCHEMICAL

;

    genotype: [c.317T>G (p.L106R)]
    GENETICS

;

    GFR: 104.4 mL/min/m2
    BIOCHEMICAL

;

    urinary albumin excretion: 6.00 mg/day
    BIOCHEMICAL

; plasma Lyso-Gb3: 124.5 nmol/L. A

    decrease urinary excretion of miR-29 and miR-200 was found
    BIOCHEMICAL

 (p <0.005) compared to controls. In addition to its usefulness as a phenotype marker,

    Lyso-Gb3
    BIOCHEMICAL

 has been proposed as an indicator of therapeutic response. We detect an

    association of high Lyso-Gb3 plasma values with decreased urinary excretion of miRNAs with known antifibrotic effect (miR-29 and miR-200)
    BIOCHEMICAL

. Although the present work is a case report, it could be hypothesized that one of the harmful

    Lyso-Gb3
    BIOCHEMICAL

 effects could be the

    miRNAs regulation through changes in TGF-β expression
    GENETICS

.

Renal involvement
histological lesions
glomerulosclerosis
promote fibrosis
suppress fibrosis


[Neuropathy and Fabry's disease. Report of five cases].

Fabry's disease is an X-linked multisistemic lisosomal storage disorder caused by deficiency or absence in α-Galatosidase A. Symptoms develop early in childhood with small fiber neuropathy, autonomic disorders and skin lesions (angiokeratomas). More severe in males, patients develop over years heart disease (hypertrophic cardiomyopathy, bradycardia), proteinuria, renal failure, transient ischemic attacks and stroke, associated with decreased life expectancy. We report five patients with Fabry's disease aged between 21 to 56 years and with family history. Neuropathic symptoms are described and neurophysiological testing findings of nerve conduction studies, quantitative sensory testing, autonomic testing and sympathetic skin response are presented.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    multisistemic lisosomal storage disorder
    DIAGNOSIS

 caused by deficiency or absence in α-Galatosidase A. Symptoms develop

    early in childhood
    AGE

 with

    small fiber neuropathy
    SYMPTOMS

,

    autonomic disorders
    SYMPTOMS

 and

    skin lesions (angiokeratomas)
    SYMPTOMS

. More severe in

    males
    GENDER

, patients develop over years

    heart disease (hypertrophic cardiomyopathy, bradycardia)
    DIAGNOSIS

,

    proteinuria
    BIOCHEMICAL

,

    renal failure
    SYMPTOMS

,

    transient ischemic attacks
    SYMPTOMS

 and

    stroke
    SYMPTOMS

, associated with

    decreased life expectancy
    SYMPTOMS

. We report five patients with

    Fabry's disease
    DIAGNOSIS

    aged between 21 to 56 years
    AGE

 and with

    family history
    FAMILY

.

    Neuropathic symptoms
    SYMPTOMS

 are described and

    neurophysiological testing findings of nerve conduction studies
    PARACLINICAL

,

    quantitative sensory testing
    PARACLINICAL

,

    autonomic testing
    PARACLINICAL

 and

    sympathetic skin response
    PARACLINICAL

 are presented.

small fiber neuropathy
autonomic disorders
skin lesions (angiokeratomas)
renal failure
transient ischemic attacks
stroke
decreased life expectancy
Neuropathic symptoms


Monogenic mimics of Behçet's disease in the young.

Monogenic autoinflammatory disorders (AID) and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet's disease (BD). We aimed to retrospectively describe the clinical and laboratory features of 11 paediatric cases referred for suspected BD who turned out to have an alternative, monogenic disease mimicking BD.

Retrospective, paediatric BD specialist multicentre case series. Next generation sequencing (NGS) or conventional candidate gene screening approaches were utilized, facilitated in some cases by functional assays.

Eleven children referred with suspected BD underwent genetic screening because of atypical BD features, and/or presentation before age 5 years. Eight patients (73%) were Caucasian, two were Pakistani and one was Turkish; 55% were female. A positive family history of BD was reported in 54% cases. The median age of disease onset was 0.6 (range 0.2-2.3) years. All had systemic inflammation and oral ulceration; 5/11 had genital ulceration; 3/11 had ocular involvement; and 9/11 had cutaneous manifestations. Nine/11 had known disease-causing genetic mutations in: TNFAIP3 (n = 2), WDR1 (n = 2), NCF1, AP1S3, LYN, MEFV and GLA. The remaining two cases each had novel variants in STAT1 and TNFRSF1A.

Rare monogenic diseases can mimic BD, particularly when presenting early in life. These observations are now informing a strategy to explore screening for genetic mimics of BD in a UK cohort of children and adults to better understand the proportion of UK BD patients who may in fact have an underlying monogenetic diagnosis.

    Monogenic autoinflammatory disorders (AID)
    DIAGNOSIS

 and

    primary immunodeficiencies
    DIAGNOSIS

 can present

    early in life
    AGE

 with features that may be

    mistaken for Behçet's disease (BD)
    NEG_FINDINGS

. We aimed to retrospectively describe the clinical and laboratory features of 11

    paediatric
    AGE

 cases referred for suspected

    BD
    DIAGNOSIS

 who turned out to have an alternative,

    monogenic disease mimicking BD
    DIAGNOSIS

.

Retrospective,

    paediatric
    AGE

    BD
    DIAGNOSIS

 specialist multicentre case series.

    Next generation sequencing (NGS)
    PARACLINICAL

 or

    conventional candidate gene screening approaches
    PARACLINICAL

 were utilized, facilitated in some cases by

    functional assays
    PARACLINICAL

.

Eleven

    children
    AGE

 referred with suspected

    BD
    DIAGNOSIS

 underwent

    genetic screening
    PARACLINICAL

 because of

    atypical BD features
    SYMPTOMS

, and/or presentation

    before age 5 years
    AGE

. Eight patients (73%) were

    Caucasian
    ETHNICITY

, two were

    Pakistani
    ETHNICITY

 and one was

    Turkish
    ETHNICITY

; 55% were

    female
    GENDER

. A

    positive family history of BD
    FAMILY

 was reported in 54% cases. The

    median age of disease onset was 0.6 (range 0.2-2.3) years
    AGE

. All had

    systemic inflammation
    SYMPTOMS

 and

    oral ulceration
    SYMPTOMS

; 5/11 had

    genital ulceration
    SYMPTOMS

; 3/11 had

    ocular involvement
    SYMPTOMS

; and 9/11 had

    cutaneous manifestations
    SYMPTOMS

. Nine/11 had

    known disease-causing genetic mutations in: TNFAIP3
    GENETICS

 (n = 2)

    , WDR1
    GENETICS

 (n = 2)

    , NCF1, AP1S3, LYN, MEFV and GLA
    GENETICS

. The remaining two cases each had novel variants in STAT1 and TNFRSF1A.

    Rare monogenic diseases
    GENETICS

 can mimic

    BD
    DIAGNOSIS

, particularly when presenting

    early in life
    AGE

. These observations are now informing a strategy to explore screening for

    genetic mimics of BD
    DIAGNOSIS

 in a UK cohort of

    children
    AGE

 and

    adults
    AGE

 to better understand the proportion of UK

    BD
    DIAGNOSIS

 patients who may in fact have an underlying monogenetic diagnosis.

atypical BD features
systemic inflammation
oral ulceration
genital ulceration
ocular involvement
cutaneous manifestations


Angiokeratomas, not everything is Fabry disease.

Angiokeratoma corporis diffusum are benign capillary malformations typically associated with Fabry disease and other lysosomal storage disorders. Only in a few cases they appear in healthy individuals.

We carried out an exhaustive review of the literature on angiokeratomas and their main clinical, dermoscopy and histological features. Additionally, we reviewed the cases of healthy subjects illustrating the limitations of each case and comparing these results with our case.

Angiokeratoma corporis diffusum is mostly related to Fabry disease and other lysosomal storage disorders. However, some cases may occur in apparently healthy individuals. Therefore, there is a increasing interest in its etiology, pathogenesis and clinical evaluation.

This is an academic-clinical review on angiokeratomas and their main implications in daily dermatological practice. Additionally, we report the first case in the literature of angiokeratoma corporis diffusum in a healthy patient with up-to-date laboratory methods currently available. The clinician should remember that not all angiokeratoma corporis diffusum occurs with lysosomal storage disorders.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 are

    benign capillary malformations
    SYMPTOMS

 typically associated with

    Fabry disease
    DIAGNOSIS

 and other

    lysosomal storage disorders
    DIAGNOSIS

. Only in a few cases they appear in healthy individuals.

We carried out an exhaustive review of the literature on

    angiokeratomas
    DIAGNOSIS

 and their main clinical, dermoscopy and histological features. Additionally, we reviewed the cases of healthy subjects illustrating the limitations of each case and comparing these results with our case.

    Angiokeratoma corporis diffusum
    SYMPTOMS

 is mostly related to

    Fabry disease
    DIAGNOSIS

 and other

    lysosomal storage disorders
    DIAGNOSIS

. However, some cases may occur in apparently healthy individuals. Therefore, there is a increasing interest in its etiology, pathogenesis and clinical evaluation.

This is an academic-clinical review on

    angiokeratomas
    SYMPTOMS

 and their main implications in daily dermatological practice. Additionally, we report the first case in the literature of

    angiokeratoma corporis diffusum
    SYMPTOMS

 in a healthy patient with up-to-date laboratory methods currently available. The clinician should remember that not all

    angiokeratoma corporis diffusum
    SYMPTOMS

 occurs with

    lysosomal storage disorders
    DIAGNOSIS

.

Angiokeratoma corporis diffusum
benign capillary malformations
Angiokeratoma corporis diffusum
angiokeratomas
angiokeratoma corporis diffusum
angiokeratoma corporis diffusum

Fabry disease
lysosomal storage disorders
angiokeratomas
Fabry disease
lysosomal storage disorders
lysosomal storage disorders


Acute Decompensated Heart Failure After Initiation of Amiodarone in a Patient With Anderson-Fabry Disease.

A 54-year-old man with the lysosomal storage disorder Anderson-Fabry disease (AFD) and cardiac involvement was placed on amiodarone for treatment of symptomatic paroxysmal atrial fibrillation. Shortly thereafter, he developed symptoms of acute decompensated heart failure, requiring hospital admission. Endomyocardial biopsy demonstrated findings consistent with AFD and possible amiodarone toxicity. Amiodarone was discontinued, and the patient's heart failure resolved with return to baseline status. Amiodarone is known to alter lysosomal pH and enzyme activity, and this case illustrates how it should be used with considerable caution in patients with AFD.

A

    54-year-old
    AGE

    man
    GENDER

 with the

    lysosomal storage disorder Anderson-Fabry disease (AFD)
    DIAGNOSIS

 and

    cardiac involvement
    SYMPTOMS

 was

    placed on amiodarone
    MEDICATION

 for treatment of

    symptomatic paroxysmal atrial fibrillation
    SYMPTOMS

. Shortly thereafter,

    he
    GENDER

 developed

    symptoms of acute decompensated heart failure
    SYMPTOMS

, requiring

    hospital admission
    MEDICATION

.

    Endomyocardial biopsy
    PARACLINICAL

 demonstrated findings consistent with

    AFD
    DIAGNOSIS

 and possible

    amiodarone toxicity
    SYMPTOMS

.

    Amiodarone was discontinued
    MEDICATION

, and the patient's

    heart failure resolved with return to baseline status
    SYMPTOMS

.

    Amiodarone
    MEDICATION

 is known to

    alter lysosomal pH and enzyme activity
    BIOCHEMICAL

, and this case illustrates how it should be used with considerable caution in patients with

    AFD
    DIAGNOSIS

.

placed on amiodarone
hospital admission
Amiodarone was discontinued
Amiodarone


Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease.

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.

    Anderson-Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by

    α-galactosidase A (α-GalA) gene variants
    GENETICS

 and characterized by a

    large genotypic and phenotypic spectrum
    SYMPTOMS

.

    Enzyme replacement therapy (ERT) using recombinant α-GalA
    MEDICATION

 has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for

    cardiac manifestations
    SYMPTOMS

 has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of

    ERT
    MEDICATION

. We report the differences in the clinical effects of

    ERT continued for > 10 years
    MEDICATION

 in three patients with the same genotype.

    Left ventricular hypertrophy
    SYMPTOMS

 and

    myocardial dysfunction
    SYMPTOMS

 progressed in the

    heterozygote proband
    GENETICS

    even under ERT
    NEG_FINDINGS

,

    although disease progression was prevented in two sons of Case 1
    FAMILY

.

Anderson-Fabry disease
lysosomal storage disease

large genotypic and phenotypic spectrum
cardiac manifestations
Left ventricular hypertrophy
myocardial dysfunction


[Acquired facial angiokeratoma].

Angiokeratomas are vascular dilations (telangiectasic papules) with keratotic surface caused by capillary dilation in the dermal papilla due to venous hyperpression, vascular malformation or a capillary fragility. They most commonly are benign and just unsightly and they may sometimes reveal a dreaded overload disease known as Fabry Disease. Here we report the case of a 56-year old patient, with no notable medical history, presenting with nontraumatic, nonpruritic, bleeding on contact, grouped cluster erythematous papules without extracutaneous manifestations on the left malar region, that had occurred 4 months before. Diascopy revealed partially emptied papules with keratotic surface. Kaposi syndrome, melanoma, carcinoma or angiokeratoma were suspected. Histological examination revealed angiokeratoma. Treatment based on electrocoagulation was proposed to the patient.

    Angiokeratomas
    SYMPTOMS

 are

    vascular dilations (telangiectasic papules) with keratotic surface
    SYMPTOMS

 caused by

    capillary dilation in the dermal papilla
    SYMPTOMS

 due to

    venous hyperpression
    SYMPTOMS

,

    vascular malformation
    SYMPTOMS

 or a

    capillary fragility
    SYMPTOMS

. They most commonly are

    benign
    NEG_FINDINGS

 and just unsightly and they may sometimes reveal a dreaded overload disease known as

    Fabry Disease
    DIAGNOSIS

. Here we report the case of a

    56-year old
    AGE

 patient,

    with no notable medical history
    NEG_FINDINGS

, presenting with

    nontraumatic, nonpruritic, bleeding on contact, grouped cluster erythematous papules
    SYMPTOMS

    without extracutaneous manifestations
    NEG_FINDINGS

    on the left malar region
    SYMPTOMS

, that had occurred 4 months before.

    Diascopy
    PARACLINICAL

 revealed

    partially emptied papules with keratotic surface
    SYMPTOMS

.

    Kaposi syndrome
    NEG_FINDINGS

,

    melanoma
    NEG_FINDINGS

,

    carcinoma
    NEG_FINDINGS

 or

    angiokeratoma
    DIAGNOSIS

 were suspected.

    Histological examination
    PARACLINICAL

 revealed

    angiokeratoma
    DIAGNOSIS

.

    Treatment based on electrocoagulation
    MEDICATION

 was proposed to the patient.

benign
with no notable medical history
without extracutaneous manifestations
Kaposi syndrome
melanoma
carcinoma

Fabry Disease
angiokeratoma
angiokeratoma


Limited effects of long-term enzyme replacement therapy on the cardiac conduction system in Fabry disease.

The long-term effects of enzyme replacement therapy (ERT) on cardiac function and the conduction system in Fabry disease are not clearly understood. We report a case of a 48-year-old man with non-classical Fabry disease treated with ERT for 11 years. He was diagnosed with Fabry disease at age 27 years based on the presence of decreased alpha-galactosidase A activity in the peripheral leukocytes and of the causal alpha-galactosidase A mutation (Val339Gln). Subsequently, peritoneal dialysis was initiated for renal failure at age 35 years. ERT was initiated at age 39 years to halt the progression of cardiac dysfunction. Electrical conduction disturbances progressed gradually to complete atrioventricular block with atrial standstill during 9 years of ERT despite the lack of progression of ventricular hypertrophy. Although he underwent permanent pacemaker implantation to prevent sudden cardiac death, the atrioventricular junctional rhythm remained, thereby lowering the ventricular pacing rate. Based on this case, we recognize that the effects of ERT are limited for inhibiting the progression of Fabry disease and especially for inhibiting arrhythmia and conduction disturbances. Early diagnosis of Fabry disease and early initiation of ERT might be the key to further improvements in this disease and its associated conditions. <Learning objective: We encountered a patient with Fabry disease treated with long-term enzyme replacement therapy (ERT) in whom conduction disturbances progressed without progression of left ventricular hypertrophy. This case suggests that ERT is limited for inhibiting the progression of Fabry disease and especially of arrhythmia and conduction disturbances. Early diagnosis of Fabry disease and initiation of ERT may be important for providing further improvements of this condition.>.

The long-term effects of

    enzyme replacement therapy (ERT)
    MEDICATION

 on cardiac function and the conduction system in

    Fabry disease
    DIAGNOSIS

 are not clearly understood. We report a case of a

    48-year-old
    AGE

    man
    GENDER

 with

    non-classical Fabry disease
    DIAGNOSIS

    treated with ERT for 11 years
    MEDICATION

.

    He
    GENDER

 was diagnosed with

    Fabry disease
    DIAGNOSIS

 at

    age 27 years
    AGE

 based on the presence of

    decreased alpha-galactosidase A activity in the peripheral leukocytes
    BIOCHEMICAL

 and of the

    causal alpha-galactosidase A mutation (Val339Gln)
    GENETICS

. Subsequently,

    peritoneal dialysis
    MEDICATION

 was initiated for

    renal failure
    SYMPTOMS

 at

    age 35 years
    AGE

.

    ERT
    MEDICATION

 was initiated at

    age 39 years
    AGE

 to halt the progression of

    cardiac dysfunction
    SYMPTOMS

.

    Electrical conduction disturbances
    SYMPTOMS

 progressed gradually to

    complete atrioventricular block with atrial standstill
    SYMPTOMS

 during

    9 years of ERT
    MEDICATION

    despite the lack of progression of ventricular hypertrophy
    NEG_FINDINGS

.

    Although he underwent permanent pacemaker implantation to prevent sudden cardiac death, the atrioventricular junctional rhythm remained, thereby lowering the ventricular pacing rate
    NEG_FINDINGS

. Based on this case, we recognize that the

    effects of ERT are limited for inhibiting the progression of Fabry disease and especially for inhibiting arrhythmia and conduction disturbances
    NEG_FINDINGS

. Early diagnosis of

    Fabry disease
    DIAGNOSIS

 and

    early initiation of ERT
    MEDICATION

 might be the key to further improvements in this disease and its associated conditions. <Learning objective: We encountered a patient with

    Fabry disease
    DIAGNOSIS

 treated with

    long-term enzyme replacement therapy (ERT)
    MEDICATION

 in whom

    conduction disturbances progressed
    SYMPTOMS

    without progression of left ventricular hypertrophy
    NEG_FINDINGS

. This case suggests that

    ERT
    NEG_FINDINGS

 is limited for inhibiting the progression of

    Fabry disease
    DIAGNOSIS

 and especially of

    arrhythmia
    SYMPTOMS

 and

    conduction disturbances
    SYMPTOMS

. Early diagnosis of

    Fabry disease
    DIAGNOSIS

 and

    initiation of ERT
    MEDICATION

 may be important for providing further improvements of this condition.>.

Fabry disease
non-classical Fabry disease
Fabry disease
Fabry disease
Fabry disease
Fabry disease
Fabry disease


Multiple sclerosis and fabry Disease, two sides of the coin? The case of an Italian family.

Multiple Sclerosis (MS) is considered among possible differential diagnosis of Fabry Disease (FD), especially in early stages when findings are suggestive but not diagnostic for MS. We report the case of a family in which FD and MS coexist, offering an overview on clues for differential diagnosis and speculating on shared etiopathogenic mechanisms for these conditions.

Taking as starting point the diagnosis of FD in a dialysis patient during a screening programme, we retrospectively rebuilt his family history and revised clinical and imaging examinations of his five siblings, two of which with previous diagnosis of MS.

After genetic testing, two subjects were found positive to a new α-galactosidase A mutation, probably causative for FD classical variant. The two subjects meeting diagnostic criteria for MS were found negative to any GLA gene mutation, therefore initial diagnosis was confirmed. The remaining two siblings resulted unaffected, with neither clinical nor instrumental evidence of FD and MS.

Differential diagnosis between FD and MS may be challenging, especially in early clinical stages when only extensive clinical evaluation and correct MRI interpretation may reduce the risk of misdiagnosis. Moreover this report allows speculating on potential etiological and pathogenic mechanisms, common both to FD and MS.

    Multiple Sclerosis (MS)
    DIAGNOSIS

 is considered among possible

    differential diagnosis
    PARACLINICAL

 of

    Fabry Disease (FD)
    DIAGNOSIS

, especially in early stages when findings are suggestive but

    not diagnostic for MS
    NEG_FINDINGS

. We report the case of a

    family in which FD and MS coexist
    FAMILY

, offering an overview on clues for

    differential diagnosis
    PARACLINICAL

 and speculating on shared etiopathogenic mechanisms for these conditions.

Taking as starting point the diagnosis of

    FD
    DIAGNOSIS

 in a

    dialysis
    MEDICATION

 patient during a screening programme, we retrospectively rebuilt his

    family history and revised clinical and imaging examinations of his five siblings, two of which with previous diagnosis of MS
    FAMILY

.

After

    genetic testing
    PARACLINICAL

, two subjects were found

    positive to a new α-galactosidase A mutation, probably causative for FD classical variant
    GENETICS

. The two subjects

    meeting diagnostic criteria for MS
    NEG_FINDINGS

 were found

    negative to any GLA gene mutation
    NEG_FINDINGS

, therefore initial diagnosis was confirmed. The remaining two siblings resulted unaffected, with

    neither clinical nor instrumental evidence of FD and MS
    NEG_FINDINGS

.

    Differential diagnosis
    PARACLINICAL

 between

    FD
    DIAGNOSIS

 and

    MS
    DIAGNOSIS

 may be challenging, especially in early clinical stages when only extensive clinical evaluation and correct

    MRI interpretation
    PARACLINICAL

 may reduce the risk of misdiagnosis. Moreover this report allows speculating on potential etiological and pathogenic mechanisms, common both to

    FD
    DIAGNOSIS

 and

    MS
    DIAGNOSIS

.

Multiple Sclerosis (MS)
Fabry Disease (FD)
FD
FD
MS
FD
MS


[A case of Anderson-Fabry disease: a multidisciplinary approach for diagnosis and follow up].

Fabry disease (also known as Anderson-Fabry disease, angiocheratoma corporis diffusum, diffuse angiocheratoma) is a rare tesaurismosis linked to the deficiency of the lysosomal enzyme alpha-galactosidase A, required for the physiological catabolism of glycosphingolipids. The related clinical signs show a multisystemic feature and define a degenerative and disabling pathology, whose approach requires a close multidisciplinary specialist collaboration. Currently, the renewed interest in the disease is aimed at the need to provide an early diagnosis, in order to early begin the enzyme replacement therapy and to slow down or avoid the establishment of irreparable organ damage. For this reason, the diagnostic suspicion becomes crucial and arises from the careful observation and research of the symptoms, together with the anamnesis and the overall clinical evaluation of the patient.

    Fabry disease
    DIAGNOSIS

 (also known as

    Anderson-Fabry disease
    DIAGNOSIS

,

    angiocheratoma corporis diffusum
    DIAGNOSIS

,

    diffuse angiocheratoma
    DIAGNOSIS

) is a

    rare tesaurismosis
    DIAGNOSIS

 linked to the

    deficiency of the lysosomal enzyme alpha-galactosidase A
    BIOCHEMICAL

, required for the

    physiological catabolism of glycosphingolipids
    BIOCHEMICAL

. The related clinical signs show a

    multisystemic feature
    SYMPTOMS

 and define a

    degenerative and disabling pathology
    SYMPTOMS

, whose approach requires a

    close multidisciplinary specialist collaboration
    PARACLINICAL

. Currently, the renewed interest in the disease is aimed at the need to provide an early diagnosis, in order to

    early begin the enzyme replacement therapy
    MEDICATION

 and to slow down or avoid the establishment of

    irreparable organ damage
    SYMPTOMS

. For this reason, the diagnostic suspicion becomes crucial and arises from the careful observation and research of the symptoms, together with the

    anamnesis
    PARACLINICAL

 and the

    overall clinical evaluation
    PARACLINICAL

 of the patient.

Fabry disease
Anderson-Fabry disease
angiocheratoma corporis diffusum
diffuse angiocheratoma
rare tesaurismosis

multisystemic feature
degenerative and disabling pathology
irreparable organ damage


Fabry disease. A potential pitfall A family with a novel intronic mutation.

Fabry disease is a genetic disorder characterized by the accumulation of globotriaosylceramide in cell lysosomes resulting from an X-linked deficiency of α-galactosidase A activity. It presents with multiorgan manifestations, including progressive renal disease, cardiomyopathy and premature demise. Recently, its prevalence has been reported to be higher in hemodialysis (HD) patients than in the general population. We report two cases of homozygous patients with an intronic alpha-galactosidase gene mutation and a classic phenotype of the disease. One of the patients had a kidney transplant and the donor was his brother, before Fabry disease were diagnose.

    Fabry disease
    DIAGNOSIS

 is a

    genetic disorder
    GENETICS

 characterized by the

    accumulation of globotriaosylceramide in cell lysosomes
    MICROSCOPIC

 resulting from an

    X-linked
    GENETICS

    deficiency of α-galactosidase A activity
    BIOCHEMICAL

. It presents with

    multiorgan manifestations
    SYMPTOMS

, including

    progressive renal disease
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

 and

    premature demise
    SYMPTOMS

. Recently, its prevalence has been reported to be higher in

    hemodialysis (HD)
    MEDICATION

 patients than in the general population. We report two cases of

    homozygous
    GENETICS

 patients with an

    intronic alpha-galactosidase gene mutation
    GENETICS

 and a

    classic phenotype of the disease
    SYMPTOMS

. One of the patients had a

    kidney transplant
    MEDICATION

 and the

    donor was his brother
    FAMILY

, before

    Fabry disease
    DIAGNOSIS

 were diagnose.

multiorgan manifestations
progressive renal disease
cardiomyopathy
premature demise
classic phenotype of the disease