Fabry disease simulating Crohn's ileitis.

Fabry disease is an inherited (X-linked) lysosomal storage disorder caused by deficiency of α-galactosidase A, leading to accumulation of globotriaosylceramide in various tissues. A 57-year-old male with a family history and laboratory findings of Fabry disease, was consulted for severe abdominal pain, undulating pyrexia, weight loss and diarrhea. The tentative clinical diagnosis of Crohn's ileitis was supported at computed tomographic examination, at laparotomy and at inspection of the resected ileal segment. Histology revealed chronic and acute inflammation, thick-walled occluded vessels, fibrosis and characteristic bi-refringent lamellar deposits of globotriaosylceramide and calcifications. Multi-nucleated giant cells contained phagocytized bi-refringent material. Transmission electron microscopy showed cells with irregular cytoplasmic bodies displaying distinctive zebra-like lamellar structures. It is submitted that the gastrointestinal phenotype of Fabry disease may concur with symptoms resembling abdominal Crohn's disease.

    Fabry disease
    DIAGNOSIS

 is an

    inherited (X-linked)
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    deficiency of α-galactosidase A
    BIOCHEMICAL

, leading to

    accumulation of globotriaosylceramide in various tissues
    MICROSCOPIC

. A

    57-year-old
    AGE

    male
    GENDER

 with a

    family history and laboratory findings of Fabry disease
    FAMILY

, was consulted for

    severe abdominal pain
    SYMPTOMS

,

    undulating pyrexia
    SYMPTOMS

,

    weight loss
    SYMPTOMS

 and

    diarrhea
    SYMPTOMS

. The tentative clinical diagnosis of

    Crohn's ileitis
    DIAGNOSIS

 was supported at

    computed tomographic examination
    PARACLINICAL

, at

    laparotomy
    PARACLINICAL

 and at

    inspection of the resected ileal segment
    PARACLINICAL

.

    Histology
    PARACLINICAL

 revealed

    chronic and acute inflammation
    MICROSCOPIC

,

    thick-walled occluded vessels
    SYMPTOMS

,

    fibrosis
    MICROSCOPIC

 and

    characteristic bi-refringent lamellar deposits of globotriaosylceramide
    MICROSCOPIC

 and

    calcifications
    SYMPTOMS

.

    Multi-nucleated giant cells contained phagocytized bi-refringent material
    MICROSCOPIC

.

    Transmission electron microscopy
    PARACLINICAL

 showed

    cells with irregular cytoplasmic bodies displaying distinctive zebra-like lamellar structures
    MICROSCOPIC

. It is submitted that the

    gastrointestinal phenotype
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

 may concur with

    symptoms resembling abdominal Crohn's disease
    SYMPTOMS

.

Fabry disease
lysosomal storage disorder
Crohn's ileitis
Fabry disease


Comprehensive clinical evaluation of a large Spanish family with Anderson-Fabry disease, novel GLA mutation and severe cardiac phenotype.

Fabry disease is an X-linked multisystemic lysosomal-storage condition. We describe a large family with a novel GLA mutation: p.M187R/g7219 T>G.

Anamnesis/physical-exam, blood/urine analysis, α-Gal-A activity and/or genetic study of at-risk individuals and multidisciplinary evaluation in confirmed cases.

4 males and 13 heterozygous-females displayed the mutation. Cardiac/renal/neurological disease was diagnosed at a mean age of 41/29/39 years in males and 51/56/46 years in females. Onset mean age was 20 years versus 42 years. 9/15 had cardiomyopathy. Delta wave suggestive of accessory pathway was identified in 1 male and 2 females. 1 female had cardiac arrest (ventricular fibrillation, 61 years). 2 females and 1 male died suddenly (63, 64 and 57 years). Cardiac-subscore of Mainz Severity-Score-Index was severe for males and females over 40 years. 4/15(26%) developed early renal disease. 2 males needed dialysis. 1 male died at 69 years in spite of kidney-heart transplant.

We describe the largest genetically confirmed Spanish family using multidisciplinary evaluation and MSSI calculation. The novel mutation p.M187R/g7219 T>G is associated with a particularly malignant cardiac phenotype in males and females over 40 years. Severity was higher than that of the largest Spanish FOS-cohort. Short-PR with delta is being reported for the first time.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    multisystemic lysosomal-storage condition
    DIAGNOSIS

. We describe a large family with a novel GLA mutation: p.M187R/g7219 T>G.

    Anamnesis/physical-exam
    PARACLINICAL

,

    blood/urine analysis
    PARACLINICAL

,

    α-Gal-A activity
    BIOCHEMICAL

 and/or

    genetic study
    PARACLINICAL

 of at-risk individuals and

    multidisciplinary evaluation
    PARACLINICAL

 in confirmed cases.

4

    males
    GENDER

 and 13 heterozygous-

    females
    GENDER

 displayed

    the mutation
    GENETICS

.

    Cardiac/renal/neurological disease
    DIAGNOSIS

 was diagnosed at a

    mean age of 41/29/39 years
    AGE

 in

    males
    GENDER

 and

    51/56/46 years
    AGE

 in

    females
    GENDER

.

    Onset mean age was 20 years versus 42 years
    AGE

. 9/15 had

    cardiomyopathy
    DIAGNOSIS

.

    Delta wave suggestive of accessory pathway
    SYMPTOMS

 was identified in 1

    male
    GENDER

 and 2

    females
    GENDER

. 1

    female
    GENDER

 had

    cardiac arrest (ventricular fibrillation
    SYMPTOMS

,

    61 years
    AGE

). 2

    females
    GENDER

 and 1

    male
    GENDER

    died
    SYMPTOMS

 suddenly (

    63, 64 and 57 years
    AGE

).

    Cardiac-subscore of Mainz Severity-Score-Index was severe
    SYMPTOMS

 for

    males
    GENDER

 and

    females
    GENDER

    over 40 years
    AGE

. 4/15(26%) developed

    early renal disease
    DIAGNOSIS

. 2

    males
    GENDER

 needed

    dialysis
    MEDICATION

. 1

    male
    GENDER

    died
    SYMPTOMS

 at

    69 years
    AGE

 in

    spite of kidney-heart transplant
    NEG_FINDINGS

.

We describe the largest genetically confirmed

    Spanish
    ETHNICITY

 family using

    multidisciplinary evaluation
    PARACLINICAL

 and

    MSSI calculation
    PARACLINICAL

. The

    novel mutation p.M187R/g7219 T>G
    GENETICS

 is associated with a

    particularly malignant cardiac phenotype
    SYMPTOMS

 in

    males
    GENDER

 and

    females
    GENDER

    over 40 years
    AGE

. Severity was higher than that of the largest Spanish FOS-cohort.

    Short-PR with delta
    SYMPTOMS

 is being reported for the first time.

X-linked
the mutation
novel mutation p.M187R/g7219 T>G


Fabry disease presenting as apical left ventricular hypertrophy in a patient carrying the missense mutation R118C.

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by abnormalities of the GLA gene, which encodes the enzyme α-galactosidase A. A deficiency of this enzyme leads to the lysosomal accumulation of glycosphingolipids, which may cause left ventricular hypertrophy that is typically concentric and symmetric. We present the case of a 60-year-old woman with symptoms of dyspnea, atypical chest pain and palpitations, in whom a transthoracic echocardiogram revealed an apical variant of hypertrophic cardiomyopathy. Analysis of specific sarcomeric genetic mutations was negative. The patient underwent a screening protocol for Anderson-Fabry disease, using a dried blood spot test, which was standard at our institution for patients with left ventricular hypertrophy. The enzymatic activity assay revealed reduced α-galactosidase A enzymatic activity. Molecular analysis identified a missense point mutation in the GLA gene (p.R118C). This case report shows that Anderson-Fabry disease may cause an apical form of left ventricular hypertrophy. The diagnosis was only achieved because of systematic screening, which highlights the importance of screening for Anderson-Fabry disease in patients with unexplained left ventricular hypertrophy, including those presenting with more unusual patterns, such as apical variants of left ventricular hypertrophy. This case also supports the idea that the missense mutation R118C is indeed a true pathogenic mutation of Anderson-Fabry disease.

    Anderson-Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    abnormalities of the GLA gene
    GENETICS

, which encodes the enzyme α-galactosidase A. A

    deficiency of this enzyme
    BIOCHEMICAL

 leads to the

    lysosomal accumulation of glycosphingolipids
    MICROSCOPIC

, which may cause

    left ventricular hypertrophy that is typically concentric and symmetric
    SYMPTOMS

. We present the case of a

    60-year-old
    AGE

    woman
    GENDER

 with symptoms of

    dyspnea
    SYMPTOMS

,

    atypical chest pain
    SYMPTOMS

 and

    palpitations
    SYMPTOMS

, in whom a

    transthoracic echocardiogram
    PARACLINICAL

 revealed an

    apical variant of hypertrophic cardiomyopathy
    SYMPTOMS

.

    Analysis of specific sarcomeric genetic mutations was negative
    NEG_FINDINGS

. The patient underwent a screening protocol for

    Anderson-Fabry disease
    DIAGNOSIS

, using a

    dried blood spot test
    PARACLINICAL

, which was standard at our institution for patients with

    left ventricular hypertrophy
    SYMPTOMS

. The

    enzymatic activity assay
    PARACLINICAL

 revealed

    reduced α-galactosidase A enzymatic activity
    BIOCHEMICAL

.

    Molecular analysis
    PARACLINICAL

 identified a

    missense point mutation in the GLA gene (p.R118C)
    GENETICS

. This case report shows that

    Anderson-Fabry disease
    DIAGNOSIS

 may cause an

    apical form of left ventricular hypertrophy
    SYMPTOMS

. The diagnosis was only achieved because of systematic screening, which highlights the importance of screening for

    Anderson-Fabry disease
    DIAGNOSIS

 in patients with

    unexplained left ventricular hypertrophy
    SYMPTOMS

, including those presenting with more unusual patterns, such as

    apical variants of left ventricular hypertrophy
    SYMPTOMS

. This case also supports the idea that the

    missense mutation R118C
    GENETICS

 is indeed a true pathogenic mutation of

    Anderson-Fabry disease
    DIAGNOSIS

.

Anderson-Fabry disease
lysosomal storage disorder
Anderson-Fabry disease
Anderson-Fabry disease
Anderson-Fabry disease
Anderson-Fabry disease


Fabry disease: clinical and genotypic aspects of three cases in first degree relatives.

Fabry disease is an X-linked, lysosomal storage disease caused by the inherited deficiency of the enzyme α-galactosidase A. The diagnosis is usually late, with renal, cardiovascular and/or cerebral complications that reduce life expectancy. Angiokeratomas are asymptomatic lesions present as the initial manifestation and usually less appreciated. Their detection is important for early diagnosis and institution of treatment with enzyme replacement therapy, which prevents late complications reducing morbidity and mortality. We report a case of a male teenager with acroparestesias and angiokeratomas. Family medical research discovered that his mother and brother had similar signs and symptoms and that the three patients had the same mutation in the gene encoding the enzyme, confirming the diagnosis.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

,

    lysosomal storage disease
    DIAGNOSIS

 caused by the inherited deficiency of the enzyme α-galactosidase A. The diagnosis is usually late, with

    renal, cardiovascular and/or cerebral complications
    SYMPTOMS

 that

    reduce life expectancy
    SYMPTOMS

.

    Angiokeratomas
    SYMPTOMS

 are

    asymptomatic lesions
    SYMPTOMS

 present as the initial manifestation and usually less appreciated. Their detection is important for early diagnosis and institution of

    treatment with enzyme replacement therapy
    MEDICATION

, which prevents

    late complications
    SYMPTOMS

 reducing morbidity and mortality. We report a case of a

    male
    GENDER

    teenager
    AGE

 with

    acroparestesias
    SYMPTOMS

 and

    angiokeratomas
    SYMPTOMS

.

    Family medical research
    PARACLINICAL

 discovered that

    his mother and brother had similar signs and symptoms
    FAMILY

 and

    that the three patients had the same mutation in the gene encoding the enzyme
    FAMILY

, confirming the diagnosis.


KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia.

KCNJ2 mutations are associated with a variety of inherited arrhythmia syndromes including catecholaminergic polymorphic ventricular tachycardia 3.

To characterize the detailed cellular mechanisms of the clinically recognized KCNJ2 mutation R67Q.

Kir2.1 current density was measured from COS-1 cells transiently transfected with wild-type human Kir-2.1 (WT-Kir2.1) and/or a heterozygous missense mutation in KCNJ2 (R67Q-Kir2.1) by using the whole-cell voltage clamp technique. Catecholamine activity was simulated with protein kinase A-stimulating cocktail exposure. Phosphorylation-deficient mutants, S425N-Kir2.1 and S425N-Kir2.1/R67Q-S425N-Kir2.1, were used in a separate set of experiments. HA- or Myc-Tag-WT-Kir2.1 and HA-Tag-R67Q-Kir2.1 were used for confocal imaging.

A 33-year-old woman presented with a catecholaminergic polymorphic ventricular tachycardia-like clinical phenotype and was found to have KCNJ2 missense mutation R67Q. Treatment with nadolol and flecainide resulted in the complete suppression of arrhythmias and symptom resolution. Under baseline conditions, R67Q-Kir2.1 expressed alone did not produce inward rectifier current while cells coexpressing WT-Kir2.1 and R67Q-Kir2.1 demonstrated the rectification index (RI) similar to that of WT-Kir2.1. After PKA stimulation, R67Q-Kir2.1/WT-Kir2.1 failed to increase peak outward current density; WT-Kir2.1 increased by 46% (n = 5), while R67Q-Kir2.1/WT-Kir2.1 decreased by 6% (n = 6) (P = .002). Rectification properties in R67Q-Kir2.1/WT-Kir2.1 demonstrated sensitivity to calcium with a decreased RI in the high-calcium pipette solution (RI 20.3% ± 4.1%) than in the low-calcium pipette solution (RI 36.5% ± 5.7%) (P < .05). Immunostaining of WT-Kir2.1 and R67Q-Kir2.1 individually and together showed a normal membrane expression pattern and colocalization by using the Pearson correlation coefficient.

R67Q-Kir2.1 is associated with an adrenergic-dependent clinical and cellular phenotype with rectification abnormality enhanced by increased calcium. These findings are a significant advancement of our knowledge and understanding of the phenotype-genotype relationship of arrhythmia syndromes related to KCNJ2 mutations.

    KCNJ2 mutations
    GENETICS

 are associated with a variety of

    inherited arrhythmia syndromes
    GENETICS

 including

    catecholaminergic polymorphic ventricular tachycardia
    DIAGNOSIS

 3.

Kir2.1 current density was measured from COS-1 cells transiently transfected with wild-type human Kir-2.1 (WT-Kir2.1) and/or a

    heterozygous missense mutation in KCNJ2 (R67Q-Kir2.1)
    GENETICS

 by using the

    whole-cell voltage clamp technique
    PARACLINICAL

.

    Catecholamine activity
    MEDICATION

 was simulated with

    protein kinase A-stimulating cocktail exposure
    MEDICATION

.

    Phosphorylation-deficient mutants
    GENETICS

,

    S425N-Kir2.1 and S425N-Kir2.1/R67Q-S425N-Kir2.1
    GENETICS

, were used in a separate set of experiments. HA- or Myc-Tag-WT-Kir2.1 and HA-Tag-R67Q-Kir2.1 were used for

    confocal imaging
    PARACLINICAL

.

A

    33-year-old
    AGE

    woman
    GENDER

 presented with a

    catecholaminergic polymorphic ventricular tachycardia-like clinical phenotype
    SYMPTOMS

 and was found to have KCNJ2 missense mutation R67Q. Treatment with

    nadolol and flecainide
    MEDICATION

 resulted in the

    complete suppression of arrhythmias
    SYMPTOMS

 and

    symptom resolution
    SYMPTOMS

. Under baseline conditions,

    R67Q-Kir2.1 expressed alone did not produce inward rectifier current
    NEG_FINDINGS

 while cells coexpressing WT

    -Kir2.1 and R67Q-Kir2.1
    GENETICS

 demonstrated the

    rectification index (RI) similar to that
    SYMPTOMS

 of WT-Kir2.1. After

    PKA stimulation
    MEDICATION

,

    R67Q-Kir2.1/WT-Kir2.1 failed to increase peak outward current density
    GENETICS

;

    WT-Kir2.1 increased by 46%
    BIOCHEMICAL

 (n = 5), while

    R67Q-Kir2.1/WT-Kir2.1 decreased by 6%
    GENETICS

 (n = 6) (P = .002). Rectification properties in

    R67Q-Kir2.1/WT-Kir2.1
    GENETICS

 demonstrated sensitivity to calcium with a

    decreased RI in the high-calcium pipette solution (RI 20.3% ± 4.1%
    SYMPTOMS

) than in the low-calcium pipette solution (

    RI 36.5% ± 5.7%)
    SYMPTOMS

 (P < .05).

    Immunostaining
    PARACLINICAL

 of WT-Kir2.1 and R67Q-Kir2.1 individually and together showed a normal membrane expression pattern and colocalization by using the Pearson correlation coefficient.

    R67Q-Kir2.1
    GENETICS

 is associated with an

    adrenergic-dependent clinical and cellular phenotype
    SYMPTOMS

 with

    rectification abnormality enhanced by increased calcium
    SYMPTOMS

. These findings are a significant advancement of our knowledge and understanding of the phenotype-genotype relationship of

    arrhythmia syndromes
    DIAGNOSIS

 related to

    KCNJ2 mutations
    GENETICS

.


De novo mutation in a male patient with Fabry disease: a case report.

Fabry disease is an X-linked inherited metabolic condition where the deficit of the α-galactosidase A enzyme, encoded by the GLA gene, leads to glycosphingolipid storage, mainly globotriaosylceramide. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD, including missense and nonsense mutations, small and large deletions. Such mutations are usually inherited, and cases of de novo onset occur rarely.

In this article we report an interesting case of a 44-year-old male patient suffering from a severe form of Fabry disease, with negative family history. The patient showed signs such as cornea verticillata, angiokeratomas, cardiac and neurological manifestations, an end-stage renal disease and he had low α-galactosidase A activity. We detected, in this subject, the mutation c.493 G > C in the third exon of the GLA gene which causes the amino acid substitution D165H in the protein. This mutation affects the amino acid - belonging to the group of buried residues - involved, probably, in the preservation of the protein folding. Moreover, studies of multiple sequence alignment indicate that this amino acid is highly conserved, thus strengthening the hypothesis that it is a key amino acid to the enzyme functionality.The study of the relatives of the patient showed that, surprisingly, none of the members of his family of origin had this genetic alteration, suggesting a de novo mutation. Only his 11-year-old daughter - showing acroparaesthesias and heat intolerance with reduced enzymatic activity - had the same mutation.

We suggest that a non-inherited mutation of the α-galactosidase A gene is responsible for Fabry disease in the patient who had reduced enzyme activity and classical clinical manifestations of the disease. In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counselling, studying the genealogical tree of the patients and starting enzyme replacement therapy to prevent irreversible vital organ damage that occurs during the course of the disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited
    GENETICS

    metabolic condition
    DIAGNOSIS

 where the

    deficit of the α-galactosidase A enzyme
    BIOCHEMICAL

, encoded by

    the GLA gene
    BIOCHEMICAL

, leads to

    glycosphingolipid storage, mainly globotriaosylceramide
    MICROSCOPIC

. To date, more than 600 mutations have been identified in

    human GLA gene
    GENETICS

 that are responsible for

    FD
    DIAGNOSIS

, including

    missense and nonsense mutations, small and large deletions
    GENETICS

. Such

    mutations are usually inherited
    GENETICS

, and cases of de novo onset occur rarely.

In this article we report an interesting case of a

    44-year-old
    AGE

    male
    GENDER

 patient suffering from a

    severe form of Fabry disease
    DIAGNOSIS

, with

    negative family history
    NEG_FINDINGS

. The patient showed signs such as

    cornea verticillata
    SYMPTOMS

,

    angiokeratomas
    SYMPTOMS

,

    cardiac and neurological manifestations
    SYMPTOMS

, an

    end-stage renal disease
    DIAGNOSIS

 and

    he
    GENDER

 had

    low α-galactosidase A activity
    BIOCHEMICAL

. We detected, in this subject, the

    mutation c.493 G > C in the third exon of the GLA gene
    GENETICS

 which causes the

    amino acid substitution D165H in the protein
    GENETICS

. This

    mutation affects the amino acid - belonging to the group of buried residues - involved
    GENETICS

, probably, in the preservation of the protein folding. Moreover, studies of

    multiple sequence alignment
    PARACLINICAL

 indicate that

    this amino acid is highly conserved
    GENETICS

, thus strengthening the hypothesis that it is a key amino acid to the enzyme functionality.The study of the relatives of the patient showed that, surprisingly,

    none of the members of his family of origin had this genetic alteration
    FAMILY

, suggesting a

    de novo mutation
    GENETICS

. Only

    his
    GENDER

    11-year-old
    FAMILY

    daughter - showing acroparaesthesias
    FAMILY

 and

    heat intolerance with reduced enzymatic activity
    SYMPTOMS

    - had the same mutation
    FAMILY

.

We suggest that a

    non-inherited mutation of the α-galactosidase A gene
    GENETICS

 is responsible for

    Fabry disease
    DIAGNOSIS

 in the patient who had

    reduced enzyme activity
    BIOCHEMICAL

 and

    classical clinical manifestations of the disease
    SYMPTOMS

. In a family, it is rare to find only one

    Fabry disease
    DIAGNOSIS

 affected subject with a

    de novo mutation
    GENETICS

. These findings emphasize the importance of early diagnosis,

    genetic counselling
    MEDICATION

,

    studying the genealogical tree
    PARACLINICAL

 of the patients and starting

    enzyme replacement therapy
    MEDICATION

 to prevent

    irreversible vital organ damage
    SYMPTOMS

 that occurs during the course of the disease.

Fabry disease
metabolic condition
FD
severe form of Fabry disease
end-stage renal disease
Fabry disease
Fabry disease

deficit of the α-galactosidase A enzyme
the GLA gene
low α-galactosidase A activity
reduced enzyme activity

genetic counselling
enzyme replacement therapy


Adult polyglucosan body disease in a patient originally diagnosed with Fabry's disease.

Adult polyglucosan body disease is a rare autosomal recessive disease, caused by glycogen branching enzyme gene mutations, characterised by urinary dysfunction, spastic paraplegia with vibration sense loss, peripheral neuropathy, and cognitive impairment. Fabry's disease is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations; neurological manifestations include cerebrovascular accidents, small-fibre neuropathy and autonomic dysfunction. Here, we report the case of a 44-year-old Sicilian male with stroke-like episodes, hypohidrosis and mild proteinuria, which led to the diagnosis of Fabry's disease after a hemizygous mutation (p.Ala143Thr) in α-galactosidase A gene was detected. Subsequently, he developed progressive walking difficulties and dementia, which were considered atypical for Fabry's disease. Therefore, we performed additional investigations that eventually led to the diagnosis of adult polyglucosan body disease caused by two novel missense mutations (p.Asp413His and p.Gly534Val) in the glycogen branching enzyme gene. Recently, the pathogenic role of the p.Ala143Thr mutation in causing Fabry's disease has been questioned. This case underlines the importance of performing further investigations when facing with atypical features even in the presence of a genetic diagnosis of a rare disease.

    Adult polyglucosan body disease
    DIAGNOSIS

 is a

    rare autosomal recessive disease
    GENETICS

, caused by

    glycogen branching enzyme gene mutations
    GENETICS

, characterised by

    urinary dysfunction
    SYMPTOMS

,

    spastic paraplegia
    SYMPTOMS

 with

    vibration sense loss
    SYMPTOMS

,

    peripheral neuropathy
    SYMPTOMS

, and

    cognitive impairment
    SYMPTOMS

.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by

    α-galactosidase A gene mutations
    GENETICS

;

    neurological manifestations
    SYMPTOMS

 include

    cerebrovascular accidents
    SYMPTOMS

,

    small-fibre neuropathy
    SYMPTOMS

 and

    autonomic dysfunction
    SYMPTOMS

. Here, we report the case of a

    44-year-old
    AGE

    Sicilian
    ETHNICITY

    male
    GENDER

 with

    stroke-like episodes
    SYMPTOMS

,

    hypohidrosis
    SYMPTOMS

 and

    mild proteinuria
    BIOCHEMICAL

, which led to the diagnosis of

    Fabry's disease
    DIAGNOSIS

 after a

    hemizygous mutation (p.Ala143Thr) in α-galactosidase A gene
    GENETICS

 was detected. Subsequently,

    he
    GENDER

 developed

    progressive walking difficulties
    SYMPTOMS

 and

    dementia
    SYMPTOMS

,

    which were considered atypical for Fabry's disease
    NEG_FINDINGS

. Therefore, we performed additional investigations that eventually led to the diagnosis of

    adult polyglucosan body disease
    DIAGNOSIS

 caused by

    two novel missense mutations (p.Asp413His and p.Gly534Val) in the glycogen branching enzyme gene
    GENETICS

. Recently, the pathogenic role of the

    p.Ala143Thr mutation
    GENETICS

 in causing

    Fabry's disease
    DIAGNOSIS

 has been questioned. This case underlines the importance of performing further investigations when facing with atypical features even in the presence of a genetic diagnosis of a rare disease.

Adult polyglucosan body disease
Fabry's disease
lysosomal storage disorder
Fabry's disease
adult polyglucosan body disease
Fabry's disease

urinary dysfunction
spastic paraplegia
vibration sense loss
peripheral neuropathy
cognitive impairment
neurological manifestations
cerebrovascular accidents
small-fibre neuropathy
autonomic dysfunction
stroke-like episodes
hypohidrosis
progressive walking difficulties
dementia


Rare diseases: what do you need to know?

This six-part series on rare diseases aims to increase awareness and offer advice on how nurses can help patients. Part 1 uses a case study to illustrate the complexity of caring for people with rare diseases and provides pointers on how the care of this patient group can be improved.

This six-part series on

    rare diseases
    DIAGNOSIS

 aims to increase awareness and offer advice on how nurses can help patients. Part 1 uses a case study to illustrate the complexity of caring for people with

    rare diseases
    DIAGNOSIS

 and provides pointers on how the care of this patient group can be improved.


Lysosome-associated protein 1 (LAMP-1) and lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease.

This study investigated the potential relationship between the expression levels of lysosome-associated membrane proteins (LAMP) 1 and 2 and responses to enzyme replacement therapy (ERT) in the members of a single family with Fabry disease (FD). LAMP levels were assessed by flow cytometry in leukocytes from 17 FD patients who received an eight-month course of ERT course and 101 healthy individuals. We found that phagocytic cells from the FD patients had higher expression levels of both LAMP-1 and LAMP-2, relative to the levels in phagocytes from the healthy controls (p=0.001). Furthermore, the LAMP-1 and LAMP-2 levels in phagocytes from the FD carriers continuously decreased with ERT administration to reach levels similar to those in healthy controls. We suggest that LAMP-1 and LAMP-2 could be used as additional markers with which to assess ERT effectiveness in FD.

This study investigated the potential relationship between the

    expression levels of lysosome-associated membrane proteins (LAMP) 1 and 2
    BIOCHEMICAL

 and responses to

    enzyme replacement therapy (ERT)
    MEDICATION

 in the members of a single

    family with Fabry disease (FD)
    FAMILY

.

    LAMP levels
    BIOCHEMICAL

 were assessed by

    flow cytometry
    PARACLINICAL

 in leukocytes from 17

    FD
    DIAGNOSIS

 patients who

    received an eight-month course of ERT course
    MEDICATION

 and 101 healthy individuals. We found that

    phagocytic cells from the FD
    MICROSCOPIC

 patients had

    higher expression levels of both LAMP-1 and LAMP-2,
    MICROSCOPIC

 relative to the

    levels in phagocytes
    MICROSCOPIC

 from the healthy controls (p=0.001). Furthermore,

    the LAMP-1 and LAMP-2 levels in phagocytes from the FD
    BIOCHEMICAL

 carriers

    continuously decreased
    BIOCHEMICAL

 with

    ERT administration
    MEDICATION

    to reach levels similar to those in
    BIOCHEMICAL

 healthy controls. We suggest that

    LAMP-1 and LAMP-2
    BIOCHEMICAL

 could be used as additional markers with which to assess

    ERT
    MEDICATION

 effectiveness in

    FD
    DIAGNOSIS

.


An unusual case of familial lymphedema.

A 47-year-old man with stable stage II chronic kidney disease and episodic diarrhea presented with chronic, progressive bilateral lower extremity lymphedema. His mother and 2 brothers had similar acral swelling. Thus, a diagnosis of typical primary familial lymphedema was suspected. Approximately 1 year later, progressive azotemia and proteinuria ensued. A renal biopsy suggested Fabry disease, which was confirmed by enzymatic and genetic testing. In addition, Fabry disease was diagnosed in his mother and 2 male siblings with lower extremity lymphedema. As this case illustrates, Fabry disease is an underappreciated and often unrecognized cause of familial lymphedema.

A

    47-year-old
    AGE

    man
    GENDER

 with

    stable stage II chronic kidney disease
    DIAGNOSIS

 and

    episodic diarrhea
    SYMPTOMS

 presented with

    chronic, progressive bilateral lower extremity lymphedema
    SYMPTOMS

.

    His
    GENDER

    mother and 2 brothers had similar acral swelling
    FAMILY

. Thus, a diagnosis of

    typical primary familial lymphedema
    DIAGNOSIS

 was suspected. Approximately 1 year later,

    progressive azotemia
    BIOCHEMICAL

 and

    proteinuria
    BIOCHEMICAL

 ensued. A

    renal biopsy
    PARACLINICAL

 suggested

    Fabry disease
    DIAGNOSIS

, which was confirmed by

    enzymatic and genetic testing
    PARACLINICAL

. In addition,

    Fabry disease was diagnosed in his mother and 2 male siblings with lower extremity lymphedema
    FAMILY

. As this case illustrates,

    Fabry disease
    DIAGNOSIS

 is an underappreciated and often unrecognized cause of

    familial lymphedema
    DIAGNOSIS

.

stable stage II chronic kidney disease
typical primary familial lymphedema
Fabry disease
Fabry disease
familial lymphedema


Successful treatment of renal failure caused by multiple myeloma with HLA-identical living kidney and bone marrow transplantation: a case report.

Here we have described a successful HLA-identical living allogeneic kidney transplantation after bone marrow transplantation in a patient with end-stag liver disease caused by multiple myeloma (MM). Our case is unique, because this combined transplantation is rarely possible and because of our unique immunosuppressive and management strategies. A 45-year-old man with ESRD MM and κ light-chain nephropathy was diagnosed. Cytostatic treatment resulted in partial remission, so autologous peripheral stem cell transplantation (SCT) was performed leading to a complete remission; however the patient remained anuric. The patient's HLA-identical brother offered to be a donor of peripheral stem cells for collection and cryopreservation. Kidney transplantation was performed with a combination of tacrolimus sirolimuns, and methylprednisolone. With a well-functioning kidney graft, allogeneic SCT was performed in the incipient relapse phase of MM, after total body irradiation. Severe oropharyngeal infections, diarrhea, sepsis, and renal failure. Fearing acute renal rejection, we administered steroid bolus. He experienced therapy with gradual restoration of kidney function. Then, steroid-responsive acute graft-versus-host disease (grade II, predominantly bowel) was diagnosed on the background of diarrhea, which returned once. Later he experienced a left subclavian vein thrombosis at the site of a central venous catheter and sepsis. Having recovered from these events, the patient enjoys good health, with stable kidney function and normal protein excretion. After the steroid was stopped, a bone marrow biopsy revealed full-donor type normocellular hemopoiesis. Because of the chimerism, we gradually discontinued the immunosuppression including, sirolimus and finally tacrolimus, since with minimal trough levels there were no complications. Bone marrow biopsy showed a complete remission. In MM with ESRD HLA-identical combined kidney and bone marrow transplantation from a living donor may offer not only complete remission and good renal function, but also good health without immunosuppression.

Here we have described a successful

    HLA-identical living allogeneic kidney transplantation after bone marrow transplantation
    MEDICATION

 in a patient with

    end-stag liver disease
    DIAGNOSIS

 caused by

    multiple myeloma (MM)
    DIAGNOSIS

. Our case is unique, because this

    combined transplantation
    MEDICATION

 is rarely possible and because of our unique immunosuppressive and management strategies. A

    45-year-old
    AGE

    man
    GENDER

 with

    ESRD MM
    DIAGNOSIS

 and

    κ light-chain nephropathy
    DIAGNOSIS

 was diagnosed.

    Cytostatic treatment
    MEDICATION

 resulted in

    partial remission
    SYMPTOMS

, so

    autologous peripheral stem cell transplantation (SCT)
    MEDICATION

 was performed leading to a

    complete remission
    MEDICATION

; however the patient

    remained anuric
    NEG_FINDINGS

. The patient's

    HLA-identical brother offered to be a donor of peripheral stem cells for collection and cryopreservation
    FAMILY

.

    Kidney transplantation was performed with a combination of tacrolimus sirolimuns, and methylprednisolone
    MEDICATION

. With a

    well-functioning kidney graft
    SYMPTOMS

,

    allogeneic SCT
    MEDICATION

 was performed in the

    incipient relapse phase of MM
    DIAGNOSIS

, after

    total body irradiation
    MEDICATION

.

    Severe oropharyngeal infections
    SYMPTOMS

,

    diarrhea
    SYMPTOMS

,

    sepsis
    SYMPTOMS

, and

    renal failure
    SYMPTOMS

.

    Fearing acute renal rejection
    NEG_FINDINGS

, we administered

    steroid bolus
    MEDICATION

.

    He
    GENDER

 experienced

    therapy with gradual restoration of kidney function
    MEDICATION

. Then,

    steroid-responsive acute graft-versus-host disease (grade II, predominantly bowel)
    DIAGNOSIS

 was diagnosed on the background of

    diarrhea
    SYMPTOMS

, which returned once. Later he experienced a

    left subclavian vein thrombosis at the site of a central venous catheter
    SYMPTOMS

 and

    sepsis
    SYMPTOMS

. Having recovered from these events, the patient enjoys good health, with

    stable kidney function
    SYMPTOMS

 and

    normal protein excretion
    BIOCHEMICAL

. After the

    steroid was stopped
    MEDICATION

, a

    bone marrow biopsy
    PARACLINICAL

 revealed

    full-donor type normocellular hemopoiesis
    MICROSCOPIC

. Because of the

    chimerism
    MEDICATION

, we

    gradually discontinued the immunosuppression including, sirolimus and finally tacrolimus
    MEDICATION

, since with

    minimal trough levels
    BIOCHEMICAL

 there were

    no complications
    NEG_FINDINGS

.

    Bone marrow biopsy
    PARACLINICAL

 showed a

    complete remission
    SYMPTOMS

. In

    MM
    DIAGNOSIS

 with

    ESRD
    DIAGNOSIS

    HLA-identical combined kidney and bone marrow transplantation from a living donor
    MEDICATION

 may offer not only

    complete remission
    SYMPTOMS

 and

    good renal function
    SYMPTOMS

, but also good health

    without immunosuppression
    NEG_FINDINGS

.

remained anuric
Fearing acute renal rejection
no complications
without immunosuppression

normal protein excretion
minimal trough levels


Initially Nondiagnosed Fabry's Disease when Electron Microscopy Is Lacking: The Continuing Story of Focal and Segmental Glomerulosclerosis.

Focal and segmental glomerulosclerosis is classified as either primary or secondary. We present a patient with a past history of biopsy-proven focal and segmental glomerulosclerosis. Despite initial response to dual blockade and steroids, proteinuria raised when steroids were decreased. After the patient was restarted on steroids, proteinuria did not improve. Another biopsy confirmed the previous diagnosis but suggested Fabry's disease, later confirmed by electron microscopy, α-galactosidase A serum and leukocyte deficiency as well as genetic studies. Proteinuria decreased when agalsidase β was prescribed in parallel with steroid tapering, increased with steroid discontinuation and improved with meprednisone administration. This report highlights the relevance of electron microscopy in kidney biopsy. In glomerulosclerosis, despite specific treatment, secondary hemodynamic and immunologic pathways may contribute to the development of proteinuria and accelerate the renal disease progression due to the primary disease. We discuss possible pathophysiologic pathways involved in proteinuria in Fabry's disease according to the biopsy and the therapeutic response.

    Focal and segmental glomerulosclerosis
    DIAGNOSIS

 is classified as either primary or secondary. We present a patient with a past history of

    biopsy-proven focal and segmental glomerulosclerosis
    DIAGNOSIS

.

    Despite initial response to dual blockade and steroids
    NEG_FINDINGS

,

    proteinuria raised
    BIOCHEMICAL

    when steroids were decreased
    NEG_FINDINGS

. After the patient was

    restarted on steroids
    MEDICATION

,

    proteinuria did not improve
    NEG_FINDINGS

.

    Another biopsy
    PARACLINICAL

 confirmed the previous diagnosis but suggested

    Fabry's disease
    DIAGNOSIS

, later confirmed by

    electron microscopy
    PARACLINICAL

,

    α-galactosidase A serum and leukocyte deficiency
    BIOCHEMICAL

 as well as

    genetic studies
    PARACLINICAL

.

    Proteinuria decreased
    BIOCHEMICAL

 when

    agalsidase β was prescribed in parallel with steroid tapering
    MEDICATION

, increased with

    steroid discontinuation
    MEDICATION

 and improved with

    meprednisone administration
    MEDICATION

. This report highlights the relevance of

    electron microscopy
    PARACLINICAL

 in

    kidney biopsy
    PARACLINICAL

. In

    glomerulosclerosis
    DIAGNOSIS

,

    despite specific treatment
    NEG_FINDINGS

,

    secondary hemodynamic and immunologic pathways
    SYMPTOMS

 may contribute to the development of

    proteinuria
    BIOCHEMICAL

 and accelerate the

    renal disease
    SYMPTOMS

 progression due to the primary disease. We discuss possible pathophysiologic pathways involved in

    proteinuria
    BIOCHEMICAL

 in

    Fabry's disease
    DIAGNOSIS

 according to the biopsy and the therapeutic response.


Novel α-galactosidase A mutation in patients with severe cardiac manifestations of Fabry disease.

Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of α-galactosidase A (α-gal A), a lysosomal hydrolase. This inactivation is responsible for the accumulation of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. Fabry is considered a rare disease, with an incidence of 1:40,000; however, there are good reasons to believe that it is often seen but rarely diagnosed. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD. We describe the case of a 54-year-old male patient, who presented with left ventricular hypertrophy, chronic renal failure and acroparaesthesias, which are considered to be specific features of FD. Clinical and instrumental investigations showed several cardiovascular manifestations. The molecular analysis of GLA gene revealed a novel mutation in the fifth exon, called N249K, and the enzymatic analysis showed no α-galactosidase A activity. Family screening detected the same mutation in some relatives and also the enzymatic analysis confirmed the diagnosis of FD. In conclusion, these data suggest that the N249K mutation may be associated with cardiac manifestations of FD combined with other classical features of the disease.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    hereditary
    GENETICS

    metabolic disorder
    DIAGNOSIS

 caused by the

    partial or total inactivation of α-galactosidase A (α-gal A), a lysosomal hydrolase
    BIOCHEMICAL

. This inactivation is responsible for the

    accumulation of undegraded glycosphingolipids in the lysosomes
    MICROSCOPIC

 with subsequent

    cellular and microvascular dysfunction
    MICROSCOPIC

.

    Fabry
    DIAGNOSIS

 is considered a rare disease, with an incidence of 1:40,000; however, there are good reasons to believe that it is often seen but rarely diagnosed. To date, more than 600 mutations have been identified in

    human GLA gene
    GENETICS

 that are responsible for

    FD
    DIAGNOSIS

. We describe the case of a

    54-year-old
    AGE

    male
    GENDER

 patient, who presented with

    left ventricular hypertrophy
    SYMPTOMS

,

    chronic renal failure
    SYMPTOMS

 and

    acroparaesthesias
    SYMPTOMS

, which are considered to be specific features of

    FD
    DIAGNOSIS

.

    Clinical and instrumental investigations
    PARACLINICAL

 showed

    several cardiovascular manifestations
    SYMPTOMS

. The

    molecular analysis of GLA gene
    PARACLINICAL

 revealed a

    novel mutation in the fifth exon, called N249K
    GENETICS

, and the

    enzymatic analysis
    PARACLINICAL

 showed

    no α-galactosidase A activity
    NEG_FINDINGS

.

    Family screening detected the same mutation in some relatives
    FAMILY

 and also the

    enzymatic analysis
    PARACLINICAL

 confirmed the diagnosis of

    FD
    DIAGNOSIS

. In conclusion, these data suggest that the

    N249K mutation
    GENETICS

 may be associated with

    cardiac manifestations
    SYMPTOMS

 of

    FD
    DIAGNOSIS

 combined with other classical features of the disease.

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

left ventricular hypertrophy
chronic renal failure
acroparaesthesias
several cardiovascular manifestations
cardiac manifestations


Angiokeratomas - When is a few too many?

Many patients have a few scattered angiokeratoma and we reassure them that this it is normal; however, if they are numerous, Fabry disease should be considered and the family history should be checked.

Many patients have a

    few scattered angiokeratoma
    SYMPTOMS

 and we reassure them that this it

    is normal
    NEG_FINDINGS

; however, if they are numerous,

    Fabry disease
    DIAGNOSIS

 should be considered and the

    family history
    PARACLINICAL

 should be checked.


Fabry's disease with LVOT obstruction: diagnosis and management.

A 46-year-old male was diagnosed with hypertrophic cardiomyopathy (HCM) and severe left ventricular outflow tract (LVOT) obstruction. Genetic testing revealed that this was a "mimic of HCM" and the true diagnosis was Fabry's disease, although there were no other clinical features of Fabry's. Despite maximal medical therapy he remained symptomatic from the outflow tract gradient and required surgical myectomy for symptom relief. This case illustrates the diagnosis of an HCM mimic by genetic testing.

A

    46-year-old
    AGE

    male
    GENDER

 was diagnosed with

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 and

    severe left ventricular outflow tract (LVOT) obstruction
    SYMPTOMS

.

    Genetic testing
    PARACLINICAL

 revealed that this was a "

    mimic of HCM
    DIAGNOSIS

" and the true diagnosis was

    Fabry's disease
    DIAGNOSIS

, although there were

    no other clinical features of Fabry's
    NEG_FINDINGS

.

    Despite maximal medical therapy
    NEG_FINDINGS

 he

    remained symptomatic from the outflow tract gradient
    SYMPTOMS

 and required

    surgical myectomy
    MEDICATION

 for

    symptom relief
    MEDICATION

. This case illustrates the diagnosis of an

    HCM
    DIAGNOSIS

 mimic by

    genetic testing
    PARACLINICAL

.

hypertrophic cardiomyopathy (HCM)
mimic of HCM
Fabry's disease
HCM

no other clinical features of Fabry's
Despite maximal medical therapy


Intrafamilial phenotypic variability in four families with Anderson-Fabry disease.

We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.

We analysed the clinical history of 16

    hemizygous males
    GENETICS

 affected by

    Anderson-Fabry Disease
    DIAGNOSIS

, from four families, to verify their intrafamilial phenotypic variability. Seven

    male
    GENDER

 patients,

    ranging from 26 to 61 years of age
    AGE

,

    died
    SYMPTOMS

, whereas nine (

    age range 23-55
    AGE

) are alive. Eleven patients have undergone

    enzyme replacement therapy (ERT) for a period of 5-10 years
    MEDICATION

. We have found a wide range of

    intrafamilial phenotypic variability
    SYMPTOMS

 in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of

    intrafamilial phenotypic variability
    SYMPTOMS

 in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.

died
intrafamilial phenotypic variability
intrafamilial phenotypic variability


A case of Fabry nephropathy with histological features of oligonephropathy.

Newborn screening studies indicate the expected high incidence of later-onset Fabry disease with silent Fabry nephropathy while, with recent improved clinical care of premature infants, children with congenital oligonephropathy caused by premature embryonal development of the kidney are thought to be increasing. However, the coexistence of Fabry nephropathy and oligonephropathy has not been reported previously. We present the case of a 13-year-old boy who was diagnosed with Fabry nephropathy accompanied with histological features of oligonephropathy. He was born as a preterm baby, and a renal biopsy was performed because of mild renal dysfunction and mild proteinuria. He had neither characteristic early symptoms nor a family history of Fabry disease. Histologic findings demonstrated diffuse global enlargement and foamy change of podocytes with markedly decreased number and enlargement of the glomeruli. Both his plasma and leukocyte α-galactosidase A (GLA) activities were markedly decreased, and the plasma globotriaosylsphingosine and urine globotriaosylceramide levels were increased. Gene analysis revealed a missense mutation, R112H, in the GLA gene, which had been reported in the later-onset phenotype of Fabry patients. He is now under treatment with enzyme replacement therapy and an angiotensin-converting enzyme inhibitor.

This case indicated the possible co-occurrence of Fabry nephropathy and oligonephropathy. For early diagnosis and timely management, careful examinations for proteinuria and renal function, in addition to establishing an effective screening system for Fabry disease, will be necessary.

Newborn screening studies indicate the expected high incidence of later-onset

    Fabry disease
    DIAGNOSIS

 with

    silent Fabry nephropathy
    DIAGNOSIS

 while, with recent improved clinical care of

    premature infants
    AGE

,

    children
    AGE

 with

    congenital oligonephropathy
    DIAGNOSIS

 caused by

    premature embryonal development of the kidney
    SYMPTOMS

 are thought to be increasing. However, the

    coexistence of Fabry nephropathy
    DIAGNOSIS

 and

    oligonephropathy
    DIAGNOSIS

 has not been reported previously. We present the case of a

    13-year-old
    AGE

    boy
    GENDER

 who was diagnosed with

    Fabry nephropathy
    DIAGNOSIS

 accompanied with

    histological features of oligonephropathy
    SYMPTOMS

.

    He
    GENDER

 was born as a

    preterm baby
    AGE

, and a

    renal biopsy
    PARACLINICAL

 was performed because of

    mild renal dysfunction
    SYMPTOMS

 and

    mild proteinuria
    BIOCHEMICAL

.

    He
    GENDER

 had

    neither characteristic early symptoms nor a family history of Fabry disease
    NEG_FINDINGS

.

    Histologic findings
    PARACLINICAL

 demonstrated

    diffuse global enlargement and foamy change of podocytes with markedly decreased number and enlargement of the glomeruli
    MICROSCOPIC

. Both his

    plasma and leukocyte α-galactosidase A (GLA) activities were markedly decreased
    BIOCHEMICAL

, and the

    plasma globotriaosylsphingosine and urine globotriaosylceramide levels were increased
    BIOCHEMICAL

.

    Gene analysis
    PARACLINICAL

 revealed a

    missense mutation, R112H, in the GLA gene
    GENETICS

, which had been reported in the later-onset phenotype of

    Fabry
    DIAGNOSIS

 patients.

    He
    GENDER

 is now under

    treatment with enzyme replacement therapy and an angiotensin-converting enzyme inhibitor
    MEDICATION

.

This case indicated the possible

    co-occurrence of Fabry nephropathy and oligonephropathy
    DIAGNOSIS

. For early diagnosis and timely management,

    careful examinations for proteinuria and renal function
    PARACLINICAL

, in addition to establishing an effective screening system for

    Fabry disease
    DIAGNOSIS

, will be necessary.


Enzyme replacement therapy in two Japanese siblings with Fabry disease, and its effectiveness on angiokeratoma and neuropathic pain.

Enzyme replacement therapy (ERT) for Fabry disease does not show a clear benefit in angiokeratoma. We describe two Japanese siblings with Fabry disease, who were diagnosed when angiokeratomas were found on the older sibling at the age of 13 years. Neither of the boys complained of pain, while both suffered from hypohidrosis. We evaluated the safety and efficacy of ERT with recombinant human agalsidase alfa (Replagal®, Dainippon-Sumitomo Pharma. Co., Osaka, Japan) in these siblings over a 5-year period. In both siblings, sweating was observed 3 months after the initiation of ERT, which motivated them to adhere to ERT. Pain sensation was regained after 12 to 36 months of ERT, followed by a decrease after 48 to 60 months. Angiokeratomas on the lateral side of the knee of the older sibling partially disappeared after 48 months of ERT. Although the height of both siblings at baseline was lower than the corresponding average age-related heights in the normal Japanese population, during ERT they were within, or close to, the average +1 standard deviation in the non-Fabry population. Their growth rate seemed to indicate catch-up growth. Other clinical symptoms were maintained at baseline levels. Immunoglobulin G anti-agalsidase alfa antibodies were not detected in both sibling during ERT, and no infusion-associated reaction was observed. The treatment was generally well tolerated. ERT was a safe and effective treatment for angiokeratoma and neuropathic pain for these two siblings with Fabry disease.

    Enzyme replacement therapy (ERT)
    MEDICATION

 for

    Fabry disease
    DIAGNOSIS

 does not show a clear benefit in

    angiokeratoma
    DIAGNOSIS

. We describe two

    Japanese
    ETHNICITY

 siblings with

    Fabry disease
    DIAGNOSIS

, who were diagnosed when

    angiokeratomas were found on the older sibling
    SYMPTOMS

 at the

    age of 13 years
    AGE

. Neither of the

    boys
    GENDER

    complained of pain
    NEG_FINDINGS

, while both suffered from

    hypohidrosis
    SYMPTOMS

. We evaluated the safety and efficacy of

    ERT with recombinant human agalsidase alfa (Replagal®
    MEDICATION

, Dainippon-Sumitomo Pharma. Co.,

    Osaka
    ETHNICITY

,

    Japan
    ETHNICITY

    )
    MEDICATION

 in these siblings over a 5-year period. In both siblings,

    sweating
    SYMPTOMS

 was observed 3 months after the initiation

    of ERT
    MEDICATION

, which motivated them to

    adhere to ERT
    MEDICATION

.

    Pain sensation was regained
    SYMPTOMS

 after

    12 to 36 months of ERT
    MEDICATION

, followed by a decrease after

    48 to 60 months
    MEDICATION

.

    Angiokeratomas on the lateral side of the knee of the older sibling partially disappeared
    SYMPTOMS

 after

    48 months of ERT
    MEDICATION

. Although the height of both siblings at baseline

    was lower than the corresponding average age-related heights
    SYMPTOMS

 in the normal

    Japanese
    ETHNICITY

 population, during

    ERT
    MEDICATION

 they were within, or close to, the average +1 standard deviation in the non-

    Fabry
    DIAGNOSIS

 population. Their

    growth rate seemed to indicate catch-up growth
    SYMPTOMS

.

    Other clinical symptoms were maintained at baseline levels
    SYMPTOMS

.

    Immunoglobulin G anti-agalsidase alfa antibodies were not detected in both sibling during ERT
    NEG_FINDINGS

, and

    no infusion-associated reaction
    NEG_FINDINGS

 was observed. The treatment was generally well tolerated.

    ERT
    MEDICATION

 was a safe and effective treatment for

    angiokeratoma
    SYMPTOMS

 and

    neuropathic pain
    SYMPTOMS

 for these two siblings with

    Fabry disease
    DIAGNOSIS

.

Fabry disease
angiokeratoma
Fabry disease
Fabry
Fabry disease


A missense mutation of the α-galactosidase A gene in a Chinese family of Fabry disease with renal failure.

Fabry disease (FD) is a rare disease due to an X-linked recessive inborn error of glycosphingolipid metabolism resulting from the mutations of the α-galactosidase A (α-gal A) gene. FD is rare in Chinese and the data on clinic and genetic features of FD is still limited.

In this study, the α-gal A gene of a Chinese family diagnosed with FD was analyzed for mutations and the genetic features of FD in this family were presented.

The α-gal A activity of the proband in this family was 0.03 nmol/ml/h in the whole blood. By PCR amplification and sequencing of the α-gal A gene exons, a single C-to-T transition was identified in codon 112 of exon 2. This C-to-T transition, mapping to position 334 in the cDNA of the α-gal A gene, was a missense mutation predicting a substitution of arginine to cysteine (p.R112C), which disrupts the normal activity of α-gal A enzyme. No further mutations were found in other exons of the α-gal A gene. In contrast to previous reports, in this family, all of the five male patients developed end-stage renal failure due to this missense mutation.

These findings suggest that the missense mutation, p.R112C, in α-gal A gene ablates its activity and results in the development of FD with the renal damage.

    Fabry disease (FD)
    DIAGNOSIS

 is a

    rare disease
    DIAGNOSIS

 due to an

    X-linked recessive inborn error of glycosphingolipid metabolism
    GENETICS

 resulting from the

    mutations of the α-galactosidase A (α-gal A) gene
    GENETICS

.

    FD
    DIAGNOSIS

 is rare in

    Chinese
    ETHNICITY

 and the data on clinic and genetic features of

    FD
    DIAGNOSIS

 is still limited.

In this study, the

    α-gal A gene
    GENETICS

 of a

    Chinese
    ETHNICITY

    family diagnosed with FD
    FAMILY

    was analyzed for mutations
    PARACLINICAL

 and the genetic features of

    FD
    DIAGNOSIS

 in this family were presented.

The

    α-gal A activity of
    BIOCHEMICAL

 the proband in this family

    was 0.03 nmol/ml/h in the whole blood
    BIOCHEMICAL

. By

    PCR amplification and sequencing of the α-gal A gene exons
    PARACLINICAL

, a

    single C-to-T transition was identified in codon 112 of exon 2
    GENETICS

.

    This C-to-T transition, mapping to position 334 in the cDNA of the α-gal A gene, was a missense mutation predicting a substitution of arginine to cysteine (p.R112C), which disrupts the normal activity of α-gal A enzyme
    GENETICS

.

    No further mutations were found in other exons of the α-gal A gene
    NEG_FINDINGS

. In contrast to previous reports, in this family, all of the five

    male
    GENDER

 patients developed

    end-stage renal failure
    SYMPTOMS

 due to this

    missense mutation
    GENETICS

.

These findings suggest that the

    missense mutation, p.R112C, in α-gal A gene ablates its activity
    GENETICS

 and results in the development of

    FD
    DIAGNOSIS

 with the

    renal damage
    SYMPTOMS

.

Fabry disease (FD)
rare disease
FD
FD
FD
FD

α-gal A activity of
was 0.03 nmol/ml/h in the whole blood


Heart failure in a woman with SLE, anti-phospholipid syndrome and Fabry's disease.

We describe a female patient with systemic lupus erythematosus (SLE) also diagnosed with Fabry's disease and anti-phospholipid antibody syndrome (APS). SLE and Fabry's disease are both systemic diseases with variable clinical presentations. Recent studies have shown a relatively high incidence of late onset Fabry's disease in female heterozygous individuals, suggesting that this condition could be under-diagnosed. We discuss a possible association between SLE and Fabry's disease and consider the role of lipid abnormalities in the pathogenesis of SLE.

We describe a

    female
    GENDER

 patient with

    systemic lupus erythematosus (SLE)
    DIAGNOSIS

 also diagnosed with

    Fabry's disease
    DIAGNOSIS

 and

    anti-phospholipid antibody syndrome (APS)
    DIAGNOSIS

.

    SLE
    DIAGNOSIS

 and

    Fabry's disease
    DIAGNOSIS

 are both

    systemic diseases
    DIAGNOSIS

 with variable clinical presentations. Recent studies have shown a relatively high incidence of

    late onset Fabry's disease
    DIAGNOSIS

 in

    female
    GENDER

    heterozygous individuals
    GENETICS

, suggesting that this condition could be under-diagnosed. We discuss a possible

    association between SLE and Fabry's disease
    DIAGNOSIS

 and consider the role of

    lipid abnormalities
    MICROSCOPIC

 in the pathogenesis of

    SLE
    DIAGNOSIS

.


A single lung transplant in a patient with fabry disease: causality or far-fetched? A case report.

Introduction. Fabry disease is a rare X-linked lysosomal storage disorder, characterized by an α-galactosidase A deficiency resulting in globotriaosylceramide storage within cells. Subsequently, various organ systems are involved, clinically the most important are kidneys, the heart, and the peripheral and central nervous systems. Although obstructive lung disease is a common pathological finding in Fabry disease, pulmonary involvement is a clinically disregarded feature. Case Presentation. We report a patient with a diagnosis of chronic obstructive pulmonary disease (COPD) who received a single lung transplant in 2007. Later, a kidney biopsy revealed the diagnosis of Fabry disease, which was confirmed by enzymatic and genetic testing. Ultrastructural changes in a native lung biopsy were consistent with the diagnosis. Although the association of a lung transplant and Fabry disease appears far-fetched on first sight, respiratory impairment cannot be denied in Fabry disease. Conclusion. With this case presentation, we would like to stimulate discussion about rare differential diagnoses hidden beneath widespread disease and that a correct diagnosis is the base of an optimal treatment strategy for each patient. Overall, the patient might have benefited from specific enzyme replacement therapy, especially in view of the chronic kidney disease.

Introduction.

    Fabry disease
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, characterized by an

    α-galactosidase A deficiency
    BIOCHEMICAL

 resulting in

    globotriaosylceramide storage within cells
    MICROSCOPIC

. Subsequently,

    various organ systems
    SYMPTOMS

 are involved, clinically the most important are

    kidneys, the heart
    SYMPTOMS

, and

    the peripheral and central nervous systems
    SYMPTOMS

. Although

    obstructive lung disease
    SYMPTOMS

 is a common pathological finding in

    Fabry disease
    DIAGNOSIS

,

    pulmonary involvement
    SYMPTOMS

 is a clinically disregarded feature. Case Presentation. We report a patient with a diagnosis of

    chronic obstructive pulmonary disease (COPD)
    DIAGNOSIS

 who

    received a single lung transplant
    MEDICATION

 in 2007. Later, a

    kidney biopsy
    PARACLINICAL

 revealed the diagnosis of

    Fabry disease
    DIAGNOSIS

, which was confirmed by

    enzymatic and genetic testing
    PARACLINICAL

.

    Ultrastructural changes in a native lung biopsy
    MICROSCOPIC

 were consistent with the diagnosis. Although the association of a

    lung transplant
    MEDICATION

 and

    Fabry disease
    DIAGNOSIS

 appears far-fetched on first sight,

    respiratory impairment
    SYMPTOMS

 cannot be denied in

    Fabry disease
    DIAGNOSIS

. Conclusion. With this case presentation, we would like to stimulate discussion about rare differential diagnoses hidden

    beneath widespread disease
    DIAGNOSIS

 and that a correct diagnosis is the base of an optimal treatment strategy for each patient. Overall, the patient might have benefited from

    specific enzyme replacement therapy
    MEDICATION

, especially in view of the

    chronic kidney disease
    DIAGNOSIS

.

received a single lung transplant
lung transplant
specific enzyme replacement therapy


A Case of Cerebral Aneurysmal Subarachnoid Hemorrhage in Fabry's Disease.

We report an unusual case of cerebral aneurysmal subarachnoid hemorrage (SAH) with Fabry's disease. A 42-year-old woman presented with aneurysmal SAH originated from a saccular aneurysm of the right posterior communicating artery. The patient was treated by an endovascular coil embolization of aneurysm. Postoperatively the patient recovered favorably without any neurological deficit. During her admission, the patient had a sign of proteinuria in urine analysis. The pathologic findings of kidney needle biopsy implied nephrosialidosis (mucolipidosis of lysosomal stroage disease), which is consistent with a Fabry's disease. It is uncommon that Fabry's disease is presented with aneurysmal SAH, especially in middle-aged patients, but could be a clinical concern. Further investigations are needed to reveal risk factors, vascular anatomy, and causative mechanisms of Fabry's disease with aneurysmal SAH.

We report an unusual case of

    cerebral aneurysmal subarachnoid hemorrage (SAH)
    SYMPTOMS

 with

    Fabry's disease
    DIAGNOSIS

. A

    42-year-old
    AGE

    woman
    GENDER

 presented with

    aneurysmal SAH originated from a saccular aneurysm of the right posterior communicating artery
    SYMPTOMS

. The patient was treated by an

    endovascular coil embolization of aneurysm
    MEDICATION

. Postoperatively the patient recovered favorably

    without any neurological deficit
    NEG_FINDINGS

. During her admission, the patient had a

    sign of proteinuria in urine analysis
    BIOCHEMICAL

. The pathologic findings of

    kidney needle biopsy
    PARACLINICAL

 implied

    nephrosialidosis (mucolipidosis of lysosomal stroage disease)
    DIAGNOSIS

, which is consistent with a

    Fabry's disease
    DIAGNOSIS

. It is uncommon that

    Fabry's disease
    DIAGNOSIS

 is presented with

    aneurysmal SAH
    SYMPTOMS

, especially in

    middle-aged
    AGE

 patients, but could be a clinical concern. Further investigations are needed to reveal risk factors, vascular anatomy, and causative mechanisms of

    Fabry's disease
    DIAGNOSIS

 with

    aneurysmal SAH
    SYMPTOMS

.


Japanese patients with Fabry disease predominantly showing cardiac and neurological manifestation with novel missense mutation: R220P.

Fabry disease, an X-linked lysosomal sphingolipid storage disorder caused by mutation of the α-galactosidase A (GLA) gene, results in systemic organ damage. However, the age of onset of clinical manifestations and course of the disease are variable even within the same family.

In this study, we evaluated the clinical phenotype and the molecular lesions associated with the GLA gene in a Japanese family with Fabry disease that predominantly showed cardiac and neurological manifestations.

A genetic analysis of the GLA gene using conventional genomic sequencing was performed in all seven members of this family, including four hemizygous males and three heterozygous females. Endomyocardial biopsy was performed in two patients with severe left ventricular (LV) hypertrophy.

A novel missense mutation was identified at codon 220 in exon 5, thus resulting in an arginine to proline substitution (R220P) in all seven family members. The three adult hemizygous males had LV hypertrophy and developed neurological manifestations in their 50s. One of the adult hemizygotes developed complete atrioventricular block. On the other hand, we could not find any organ damage in a young hemizygous male or the three heterozygous females.

We identified a novel missense mutation in a Japanese family with Fabry disease showing cardiac and neurological manifestations. In patients with Fabry disease, advanced organ damage in the heart and brain can be life-threatening, even if renal failure is lacking.

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal sphingolipid storage disorder
    DIAGNOSIS

 caused by

    mutation of the α-galactosidase A (GLA) gene
    GENETICS

, results in

    systemic organ damage
    SYMPTOMS

. However, the age of onset of clinical manifestations and course of the disease are variable even within the same family.

In this study, we evaluated the clinical phenotype and the

    molecular lesions associated with the GLA gene
    GENETICS

 in a

    Japanese
    ETHNICITY

    family with Fabry disease
    FAMILY

 that predominantly showed

    cardiac and neurological manifestations
    SYMPTOMS

.

A

    genetic analysis of the GLA gene
    PARACLINICAL

 using

    conventional genomic sequencing
    PARACLINICAL

 was performed in all seven members of this family, including four

    hemizygous males
    GENETICS

 and three heterozygous

    females
    GENDER

.

    Endomyocardial biopsy
    PARACLINICAL

 was performed in two patients with

    severe left ventricular (LV) hypertrophy
    SYMPTOMS

.

A

    novel missense mutation was identified at codon 220 in exon 5, thus resulting in an arginine to proline substitution (R220P)
    GENETICS

    in all seven family members
    FAMILY

. The three

    adult
    AGE

    hemizygous
    GENETICS

    males
    GENDER

 had

    LV hypertrophy
    SYMPTOMS

 and developed

    neurological manifestations
    SYMPTOMS

    in their 50s
    AGE

. One of the

    adult
    AGE

    hemizygotes
    GENETICS

 developed

    complete atrioventricular block
    SYMPTOMS

. On the other hand, we

    could not find any organ damage in a young hemizygous male
    NEG_FINDINGS

 or the three heterozygous

    females
    GENDER

.

We identified a

    novel missense mutation
    GENETICS

 in a

    Japanese
    ETHNICITY

    family with Fabry disease
    FAMILY

 showing

    cardiac and neurological manifestations
    SYMPTOMS

. In patients with

    Fabry disease
    DIAGNOSIS

,

    advanced organ damage in the heart and brain
    SYMPTOMS

 can be

    life-threatening
    SYMPTOMS

, even if

    renal failure is lacking
    NEG_FINDINGS

.

Fabry disease
lysosomal sphingolipid storage disorder
Fabry disease


[A boy with Fabry disease with the onset at the age of four].

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of α-galactosidase A (GLA). Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme, leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction. Patients of severe cases die young. It has been proved that enzyme replacement therapy is a useful method to treat patients with Fabry disease. But the clinical diagnosis of the patients may often be difficult because of the lack of specific symptoms. In this study, a Chinese boy was diagnosed as Fabry disease at the age of 11 years with episodic pain for 7 years. The boy described the onset, at the age of 4 years, of episodic burning pain in the toes. Generalized aching and pain in the feet became progressive in the past two years and his hands were also affected. Divers analgesics were tried without effects. When he was admitted at the age of 11 years, none of complications was found in his heart, brain, kidneys, skin and eyes by routine laboratory examinations. Significantly decreased GLA activity of peripheral leucocytes [1.0 nmol/(h×mg protein) vs. normal control 24.5 to 86.1 nmol/(h×mg protein)] supported the diagnosis of Fabry disease. A splicing mutation IVS6+2 T>C was identified on his GLA gene. But it was not found in his mother and younger sister. The incidence of Fabry disease is not clear in Mainland China. The patients usually have insidious onset with complex and non-specific clinical manifestations. Stroke, uremia, cardiomyopathy and multiple organ dysfunctions are common at the late stage. Early diagnosis is the key point to reduce the mortality and handicap. GLA enzyme activity is important to the diagnosis of Fabry disease. The mutation analysis of GLA gene is helpful for genetic counseling.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by a

    deficiency of α-galactosidase A (GLA)
    BIOCHEMICAL

.

    Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme
    MICROSCOPIC

, leads to

    severe painful neuropathy
    SYMPTOMS

 with

    progressive renal, cardiovascular, and cerebrovascular dysfunction
    SYMPTOMS

. Patients of severe cases die

    young
    AGE

. It has been proved that

    enzyme replacement therapy
    MEDICATION

 is a useful method to treat patients with

    Fabry disease
    DIAGNOSIS

. But the clinical diagnosis of the patients may often be difficult because of the

    lack of specific symptoms
    NEG_FINDINGS

. In this study, a

    Chinese
    ETHNICITY

    boy
    GENDER

 was diagnosed as

    Fabry disease
    DIAGNOSIS

 at the

    age of 11 years
    AGE

 with

    episodic pain for 7 years
    SYMPTOMS

. The

    boy
    GENDER

 described the onset, at the

    age of 4 years
    AGE

, of

    episodic burning pain in the toes
    SYMPTOMS

.

    Generalized aching and pain in the feet became progressive
    SYMPTOMS

 in the past two years and his

    hands were also affected
    SYMPTOMS

.

    Divers analgesics were tried without effects
    NEG_FINDINGS

. When

    he
    GENDER

 was admitted at the

    age of 11 years
    AGE

,

    none of complications was found in his heart, brain, kidneys, skin and eyes
    NEG_FINDINGS

 by

    routine laboratory examinations
    NEG_FINDINGS

.

    Significantly decreased GLA activity of peripheral leucocytes [1.0 nmol/(h×mg protein) vs. normal control 24.5 to 86.1 nmol/(h×mg protein)]
    BIOCHEMICAL

 supported the diagnosis of

    Fabry disease
    DIAGNOSIS

. A

    splicing mutation IVS6+2 T>C was identified on his GLA gene
    GENETICS

. But

    it was not found in his mother and younger sister
    FAMILY

. The incidence of

    Fabry disease
    DIAGNOSIS

 is not clear in

    Mainland China
    ETHNICITY

. The patients usually have

    insidious onset
    SYMPTOMS

 with

    complex and non-specific clinical manifestations
    SYMPTOMS

.

    Stroke
    SYMPTOMS

,

    uremia
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

 and

    multiple organ dysfunctions
    SYMPTOMS

 are common at the late stage. Early diagnosis is the key point to reduce the mortality and handicap.

    GLA enzyme activity
    BIOCHEMICAL

 is important to the diagnosis of

    Fabry disease
    DIAGNOSIS

. The

    mutation analysis of GLA gene
    PARACLINICAL

 is helpful for

    genetic counseling
    MEDICATION

.

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

enzyme replacement therapy
genetic counseling


Fabry cardiomyopathy.

Fabry disease is a progressive X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the α-galactosidase lysosomal enzyme. The partial or complete deficiency of the lysosomal enzyme leads to an accumulation of neutral glycosphingolipids in the vascular endothelium and visceral tissues throughout the body. In the heart, glycosphingolipids deposition causes progressive left ventricular hypertrophy (LVH). We report a case of Fabry disease which was suspected based upon two-dimensional echocardiographic finding of LVH. A 44-year-old man was admitted to evaluation of aggravated exertional dyspnea of two weeks duration. He had been diagnosed with end-stage renal disease of unknown etiology at age 41 followed by renal transplantation that year. He had been treated with oral immunosuppressive agents. On hospital day two, transthoracic echocardiography revealed concentric LVH. Left ventricular systolic function was preserved but diastolic dysfunction was present. Fabry disease was confirmed by demonstration of a low plasma α-galactosidase A (α-Gal A) activity. Analysis of genomic DNA showed α-Gal A gene mutation. The patient was diagnosed with Fabry disease.

    Fabry disease
    DIAGNOSIS

 is a

    progressive X-linked
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 caused by a

    deficiency of the α-galactosidase lysosomal enzyme
    BIOCHEMICAL

. The

    partial or complete deficiency of the lysosomal enzyme
    BIOCHEMICAL

 leads to an

    accumulation of neutral glycosphingolipids in the vascular endothelium and visceral tissues throughout the body
    MICROSCOPIC

. In the heart,

    glycosphingolipids deposition
    MICROSCOPIC

 causes

    progressive left ventricular hypertrophy (LVH)
    SYMPTOMS

. We report a case of

    Fabry disease
    DIAGNOSIS

 which was suspected based upon

    two-dimensional echocardiographic
    PARACLINICAL

 finding of

    LVH
    SYMPTOMS

. A

    44-year-old
    AGE

    man
    GENDER

 was admitted to evaluation of

    aggravated exertional dyspnea of two weeks duration
    SYMPTOMS

.

    He
    GENDER

 had been diagnosed with

    end-stage renal disease of unknown etiology
    DIAGNOSIS

 at

    age 41
    AGE

 followed by

    renal transplantation
    MEDICATION

 that year.

    He
    GENDER

 had been

    treated with oral immunosuppressive agents
    MEDICATION

. On hospital day two,

    transthoracic echocardiography
    PARACLINICAL

 revealed

    concentric LVH
    SYMPTOMS

.

    Left ventricular systolic function was preserved
    SYMPTOMS

 but

    diastolic dysfunction was present
    SYMPTOMS

.

    Fabry disease
    DIAGNOSIS

 was confirmed by demonstration of a

    low plasma α-galactosidase A (α-Gal A) activity
    BIOCHEMICAL

.

    Analysis of genomic DNA
    PARACLINICAL

 showed

    α-Gal A gene mutation
    GENETICS

. The patient was diagnosed with

    Fabry disease
    DIAGNOSIS

.

progressive X-linked
α-Gal A gene mutation


Segmental cherry angiomas associated with extragenital lichen sclerosus: a report of two cases.

Cherry angiomas (Campbell de Morgan spots) are common acquired red skin papules composed of dilated capillary loops, usually of unknown aetiology. Extragenital lichen sclerosus (LS) presents as porcelain-white scaly atrophic lesions with or without genital involvement. We report two cases of segmental multiple cherry angiomas in association with extragenital LS. Two unrelated women, aged 46 and 66 years, presented with extragenital LS affecting their axillae and lower abdomen. During the examination, both patients were noted to have several hundred red skin papules in a segmental distribution, affecting the left thigh and flank of one woman, and the right abdomen and back of the other. Clinically and histologically, the papules were consistent with cherry angiomas. The striking segmental distribution of multiple cherry angiomas may be due to genetic mosaicism; however, segmental Fabry disease was excluded by sequence analysis of the α-galactosidase A gene. Any causal link between cherry angiomas and LS remains uncertain.

    Cherry angiomas (Campbell de Morgan spots)
    SYMPTOMS

 are common

    acquired red skin papules composed of dilated capillary loops
    SYMPTOMS

, usually of unknown aetiology.

    Extragenital lichen sclerosus (LS)
    DIAGNOSIS

 presents as

    porcelain-white scaly atrophic lesions with or without genital involvement
    SYMPTOMS

. We report two cases of

    segmental multiple cherry angiomas
    SYMPTOMS

 in association with

    extragenital LS
    DIAGNOSIS

. Two unrelated

    women
    GENDER

,

    aged 46 and 66 years
    AGE

, presented with

    extragenital LS affecting their axillae and lower abdomen
    SYMPTOMS

. During the examination, both patients were noted to have

    several hundred red skin papules in a segmental distribution, affecting the left thigh and flank
    SYMPTOMS

 of one

    woman
    GENDER

,

    and the right abdomen and back
    SYMPTOMS

 of the other. Clinically and histologically, the

    papules
    SYMPTOMS

 were consistent with

    cherry angiomas
    SYMPTOMS

. The

    striking segmental distribution of multiple cherry angiomas
    SYMPTOMS

 may be due to

    genetic mosaicism
    GENETICS

; however,

    segmental Fabry disease was excluded
    NEG_FINDINGS

 by

    sequence analysis of the α-galactosidase A gene
    NEG_FINDINGS

. Any causal link between

    cherry angiomas
    SYMPTOMS

 and

    LS
    DIAGNOSIS

 remains uncertain.

Extragenital lichen sclerosus (LS)
extragenital LS
LS


A mutant mRNA expression in an endomyocardial biopsy sample obtained from a patient with a cardiac variant of Fabry disease caused by a novel acceptor splice site mutation in the invariant AG of intron 5 of the α-galactosidase A gene.

We herein describe the case of a 58-year-old man who presented with dilated-phase hypertrophic cardiomyopathy (HCM) and required an implantable cardioverter defibrillator implant. Subsequently, the patient was diagnosed with Fabry disease (FD), which was suspected based on the results of an endomyocardial biopsy and diagnosed following demonstration of deficient α-galactosidase A (GLA) activity. Molecular studies showed a novel point mutation in the 3' splice site consensus sequence of intron 5 in the gene encoding GLA that created a new splicing site, resulting in the expression of mutant mRNA. FD should be considered a cause of HCM in patients with severe tachyarrhythmia without other remarkable manifestations of FD.

We herein describe the case of a

    58-year-old
    AGE

    man
    GENDER

 who presented with

    dilated-phase hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 and required an

    implantable cardioverter defibrillator implant
    MEDICATION

. Subsequently, the patient was diagnosed with

    Fabry disease (FD)
    DIAGNOSIS

, which was suspected based on the results of an

    endomyocardial biopsy
    PARACLINICAL

 and diagnosed following demonstration of

    deficient α-galactosidase A (GLA) activity
    BIOCHEMICAL

.

    Molecular studies
    PARACLINICAL

 showed a

    novel point mutation in the 3' splice site consensus sequence of intron 5 in the gene encoding GLA that created a new splicing site, resulting in the expression of mutant mRNA
    GENETICS

.

    FD
    DIAGNOSIS

 should be considered a cause of

    HCM
    DIAGNOSIS

 in patients with

    severe tachyarrhythmia
    SYMPTOMS

    without other remarkable manifestations of FD
    NEG_FINDINGS

.


What lies beneath: Fabry nephropathy in a female patient with severe cerebrovascular disease.

Fabry disease is an X-linked inborn error of metabolism, which is caused by the deficiency of α-galactosidase A, leading to progressive accumulation of neutral glycosphingolipids and a-galactosyl breakdown products in most body fluids and several tissues, resulting in the clinical manifestations. The onset of Fabry disease symptoms in females is not observed as early as in males. We report a novel presentation of Fabry disease in a female patient with medical history of relapsing strokes and brain magnetic resonance angiography showing signs of microangiopathy and multiple lacunar strokes that were first diagnosed as Moyamoya disease (a chronic progressive cerebrovascular disease). The patient subsequently displayed increased levels of serum creatinine and proteinuria. Diagnosis of Fabry disease was made by a renal biopsy and was confirmed by molecular studies showing a missense mutation: c1066C > T (het) [R356W]. The diagnosis was delayed by 21 years with respect to her first symptom (stroke), probably because her initial clinical presentation was neurological and diagnosed as Moyamoya disease. Other factors that contributed to the delay of the diagnosis were the lack of acute or chronic pain (neuropathic pain) and angiokeratomas. Some similarities in the pathogenic aspects of the patient's vascular lesions lead us to speculate that this patient has Fabry disease, with a phenotype that had not yet been described. It is necessary to be aware of this possibility to avoid misdiagnosis of Fabry disease as Moyamoya disease.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    inborn error of metabolism
    GENETICS

, which is caused by the

    deficiency of α-galactosidase A
    BIOCHEMICAL

, leading to

    progressive accumulation of neutral glycosphingolipids and a-galactosyl breakdown products in most body fluids and several tissues
    MICROSCOPIC

, resulting in the clinical manifestations. The onset of

    Fabry disease
    DIAGNOSIS

 symptoms in

    females
    GENDER

 is not observed as early as in

    males
    GENDER

. We report a novel presentation of

    Fabry disease
    DIAGNOSIS

 in a

    female
    GENDER

 patient with medical history of

    relapsing strokes
    SYMPTOMS

 and

    brain magnetic resonance angiography
    PARACLINICAL

 showing

    signs of microangiopathy
    SYMPTOMS

 and

    multiple lacunar strokes
    SYMPTOMS

 that were first diagnosed as

    Moyamoya disease
    DIAGNOSIS

 (a

    chronic progressive cerebrovascular disease
    DIAGNOSIS

). The patient subsequently displayed

    increased levels of serum creatinine
    BIOCHEMICAL

 and

    proteinuria
    BIOCHEMICAL

. Diagnosis of

    Fabry disease
    DIAGNOSIS

 was made by a

    renal biopsy
    PARACLINICAL

 and was confirmed by

    molecular studies
    PARACLINICAL

 showing a

    missense mutation: c1066C > T (het) [R356W]
    GENETICS

. The diagnosis was delayed by

    21 years
    AGE

 with respect to her first symptom (

    stroke
    SYMPTOMS

), probably because

    her
    GENDER

 initial clinical presentation was

    neurological
    SYMPTOMS

 and diagnosed as

    Moyamoya disease
    DIAGNOSIS

. Other factors that contributed to the delay of the diagnosis were the

    lack of acute or chronic pain (neuropathic pain)
    NEG_FINDINGS

 and

    angiokeratomas
    NEG_FINDINGS

. Some

    similarities in the pathogenic aspects of the patient's vascular lesions
    SYMPTOMS

 lead us to speculate that this patient has

    Fabry disease
    DIAGNOSIS

, with a phenotype that had not yet been described. It is necessary to be aware of this possibility to avoid misdiagnosis of

    Fabry disease
    DIAGNOSIS

 as

    Moyamoya disease
    DIAGNOSIS

.

deficiency of α-galactosidase A
increased levels of serum creatinine
proteinuria


[White matter lesions, young age, female--differential diagnosis of multiple sclerosis and juvenile stroke].

Fabry's disease is an X-chromosomal linked recessive lysosomal storage disease caused by a deficiency of α-galactosidase A. Accumulation of toxic levels of sphingolipids leads to metabolic dysfunction in various cell types (endothelial cells, myocytes, fibroblasts) and organs thus causing a variety of symptoms. Neurological manifestations include recurrent strokes and polyneuropathy, many patients complain of pain or vertigo. The presentation of these polymorphic symptoms mostly at young age often leads to incorrect diagnosis and mistreatment. Here we report two cases of female patients who both were misdiagnosed and thus mistreated for many years. These case-reports aim in increasing the awareness for Fabry's disease as a differential diagnosis, especially in young women presenting with white matter lesions.

    Fabry's disease
    DIAGNOSIS

 is an

    X-chromosomal linked recessive
    GENETICS

    lysosomal storage disease
    DIAGNOSIS

 caused by a deficiency of α-galactosidase A.

    Accumulation of toxic levels of sphingolipids
    MICROSCOPIC

 leads to

    metabolic dysfunction in various cell types (endothelial cells, myocytes, fibroblasts) and organs
    MICROSCOPIC

 thus causing a variety of symptoms.

    Neurological manifestations
    SYMPTOMS

 include

    recurrent strokes
    SYMPTOMS

 and

    polyneuropathy
    SYMPTOMS

, many patients complain of

    pain
    SYMPTOMS

 or

    vertigo
    SYMPTOMS

. The presentation of these

    polymorphic symptoms
    SYMPTOMS

 mostly at

    young age
    AGE

 often leads to incorrect diagnosis and

    mistreatment
    NEG_FINDINGS

. Here we report two cases of

    female
    GENDER

 patients who both were

    misdiagnosed and thus mistreated for many years
    NEG_FINDINGS

. These case-reports aim in increasing the awareness for

    Fabry's disease
    DIAGNOSIS

 as a

    differential diagnosis
    PARACLINICAL

, especially in

    young
    AGE

    women
    GENDER

 presenting with

    white matter lesions
    SYMPTOMS

.

Fabry's disease
lysosomal storage disease
Fabry's disease

Neurological manifestations
recurrent strokes
polyneuropathy
pain
vertigo
polymorphic symptoms
white matter lesions


A Novel Frameshift Mutation of Galactosidase-alpha in Fabry Disease Restricted to Dermatologic Manifestations.

A 28-year-old Asian male was referred for dermatologic evaluation of diffuse bluish-red maculopapules in the lower trunk and genital regions. There was no family history, and with the exception of dispersed skin lesions and hypohidrosis, no other complaints or symptoms were present. Histological evaluation of the skin lesions revealed angiokeratomas. When this combination of clinical and histological findings is observed, Fabry disease is suspected. Biochemical examination performed for definitive diagnosis did not show any activity of the α-galactosidase A enzyme. Through identification of a c.182_183ins(GA) mutation of the GLA gene, Fabry disease was diagnosed. However, there was no particular abnormal finding with regard to the evaluation of non-cutaneous manifestations, a symptom that can occur in the progress of this disease. We reported a case of Fabry disease, restricted to the dermatologic presentation, involving a novel frameshift mutation in the GLA gene.

A

    28-year-old
    AGE

    Asian
    ETHNICITY

    male
    GENDER

 was referred for

    dermatologic evaluation
    PARACLINICAL

 of

    diffuse bluish-red maculopapules in the lower trunk and genital regions
    SYMPTOMS

. There was

    no family history
    NEG_FINDINGS

, and with the exception of

    dispersed skin lesions
    SYMPTOMS

 and

    hypohidrosis
    SYMPTOMS

,

    no other complaints or symptoms
    NEG_FINDINGS

 were present.

    Histological evaluation of the skin lesions
    PARACLINICAL

 revealed

    angiokeratomas
    MICROSCOPIC

. When this combination of clinical and histological findings is observed,

    Fabry disease
    DIAGNOSIS

 is suspected.

    Biochemical examination
    PARACLINICAL

 performed for definitive diagnosis

    did not show any activity of the α-galactosidase A enzyme
    NEG_FINDINGS

. Through identification of a

    c.182_183ins(GA) mutation of the GLA gene
    GENETICS

,

    Fabry disease
    DIAGNOSIS

 was diagnosed. However, there was

    no particular abnormal finding with regard to the evaluation of non-cutaneous manifestations
    NEG_FINDINGS

, a symptom that can occur in the progress of this disease. We reported a case of

    Fabry disease
    DIAGNOSIS

, restricted to the dermatologic presentation, involving a

    novel frameshift mutation in the GLA gene
    GENETICS

.

Fabry disease
Fabry disease
Fabry disease


Female with Fabry Disease Unknowingly Donates Affected Kidney to Sister: A Call for Pre-transplant Genetic Testing.

Fabry disease, an X-linked lysosomal storage disorder, is caused by the deficiency of the alpha-galactosidase A enzyme and the progressive accumulation of globotriaosylceramide in vascular endothelial cells. The multi-systemic manifestations of Fabry disease include cardiac, gastrointestinal, renal, and neuropathic complications. Renal dysfunction and ultimately end-stage renal disease occurs in classically affected males and in about 10-15% of female heterozygotes from classically affected families as a result of progressive glycosphingolipid accumulation. We report a case in which a female with a de novo GLA mutation donated a kidney to her sister prior to the diagnosis of symptomatic Fabry disease. The transplant recipient has progressed to graft failure and has been relisted for transplant. This case report demonstrates the need to screen potential kidney transplant donors and recipients for Fabry disease.

    Fabry disease
    DIAGNOSIS

, an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

, is caused by the

    deficiency of the alpha-galactosidase A enzyme
    BIOCHEMICAL

 and the

    progressive accumulation of globotriaosylceramide in vascular endothelial cells
    MICROSCOPIC

. The

    multi-systemic manifestations
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

 include

    cardiac, gastrointestinal, renal
    SYMPTOMS

, and

    neuropathic complications
    SYMPTOMS

.

    Renal dysfunction
    SYMPTOMS

 and ultimately

    end-stage renal disease
    DIAGNOSIS

 occurs in classically affected

    males
    GENDER

 and in about 10-15% of

    female
    GENDER

    heterozygotes
    GENETICS

 from classically affected families as a result of

    progressive glycosphingolipid accumulation
    MICROSCOPIC

. We report a case in which a

    female
    GENDER

 with a

    de novo GLA mutation
    GENETICS

    donated a kidney to her sister
    MEDICATION

 prior to the diagnosis of

    symptomatic Fabry disease
    DIAGNOSIS

. The

    transplant recipient
    MEDICATION

 has progressed to

    graft failure
    SYMPTOMS

 and has been

    relisted for transplant
    MEDICATION

. This case report demonstrates the need to screen potential

    kidney transplant
    MEDICATION

 donors and recipients for

    Fabry disease
    DIAGNOSIS

.

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

X-linked
heterozygotes
de novo GLA mutation

multi-systemic manifestations
cardiac, gastrointestinal, renal
neuropathic complications
Renal dysfunction
graft failure

donated a kidney to her sister
transplant recipient
relisted for transplant
kidney transplant


Cerebral hemorrhage in a paucisymptomatic young patient with Fabry disease.

Fabry disease is an inborn error of glycosphingolipid catabolism caused by deficient activity of the lysosomal exoglycohydrolase α-galactosidase A. It has an X-linked inheritance and occurs in all ethnic groups, with an incidence of 1 in 40,000 in the general population. The incidence of cerebrovascular accidents in patients affected by Fabry disease is much higher than in the general population. Moreover, there is a greater prevalence of hypertension, cardiac disease, and renal disease in patients affected by Fabry disease that have suffered a stroke. Here we present the case of a paucisymptomatic young man affected by Fabry disease and treated with enzyme replacement therapy who was admitted for hemorrhagic stroke.

    Fabry disease
    DIAGNOSIS

 is an

    inborn error of glycosphingolipid catabolism
    GENETICS

 caused by deficient activity of the lysosomal exoglycohydrolase α-galactosidase A. It has an

    X-linked inheritance
    GENETICS

 and occurs in all ethnic groups, with an incidence of 1 in 40,000 in the general population. The incidence of

    cerebrovascular accidents
    SYMPTOMS

 in patients affected by

    Fabry disease
    DIAGNOSIS

 is much higher than in the general population. Moreover, there is a greater prevalence of

    hypertension
    SYMPTOMS

,

    cardiac disease
    SYMPTOMS

, and

    renal disease
    SYMPTOMS

 in patients affected by

    Fabry disease
    DIAGNOSIS

 that have suffered a

    stroke
    SYMPTOMS

. Here we present the case of a

    paucisymptomatic
    SYMPTOMS

    young
    AGE

    man
    GENDER

 affected by

    Fabry disease
    DIAGNOSIS

 and

    treated with enzyme replacement therapy
    MEDICATION

 who was admitted for

    hemorrhagic stroke
    SYMPTOMS

.

Fabry disease
Fabry disease
Fabry disease
Fabry disease

cerebrovascular accidents
hypertension
cardiac disease
renal disease
stroke
paucisymptomatic
hemorrhagic stroke


Non-syndrome patient with bilateral supernumerary teeth: Case report and 9-year follow-up.

The presence of supernumerary teeth, also known as hyperdontia, is the condition of having teeth in addition to the regular number of teeth. The occurrence of multiple supernumerary teeth is often found in association with syndromes such as Gardner syndrome, Anderson-Fabry disease, Ellis-van Creveld syndrome, Ehlers-Danlos syndrome, incontinentia pigmenti, and Tricho-rhino-phalangeal syndrome. Only a few examples of nonsyndromic multiple supernumerary teeth have been reported in literature. In this report, we present the unusual case and 9-year follow up of a non-syndrome female patient with bilateral supernumerary teeth that occurred with an interval of several years.

The

    presence of supernumerary teeth
    SYMPTOMS

, also known as

    hyperdontia
    SYMPTOMS

, is the condition of

    having teeth in addition to the regular number of teeth
    SYMPTOMS

. The occurrence of

    multiple supernumerary teeth
    SYMPTOMS

 is often found in association with syndromes such as

    Gardner syndrome
    DIAGNOSIS

,

    Anderson-Fabry disease
    DIAGNOSIS

,

    Ellis-van Creveld syndrome
    DIAGNOSIS

,

    Ehlers-Danlos syndrome
    DIAGNOSIS

,

    incontinentia pigmenti
    DIAGNOSIS

, and

    Tricho-rhino-phalangeal syndrome
    DIAGNOSIS

. Only a few examples of

    nonsyndromic multiple supernumerary teeth
    SYMPTOMS

 have been reported in literature. In this report, we present the unusual case and 9-year follow up of a

    non-syndrome
    NEG_FINDINGS

    female
    GENDER

 patient with

    bilateral supernumerary teeth
    SYMPTOMS

 that occurred with an interval of several years.

Gardner syndrome
Anderson-Fabry disease
Ellis-van Creveld syndrome
Ehlers-Danlos syndrome
incontinentia pigmenti
Tricho-rhino-phalangeal syndrome