Fabry disease. A case report.

Fabry disease is an under-recognized X-linked recessive lysosomal storage disorder resulting from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A). The first case of Fabry disease in Slovenia was diagnosed in 1991. This 46 year-old male was referred for dermatologic evaluation of a purpura on his abdomen. He was being treated for proteinuria and cardiac symptoms. The diagnosis of angiokeratoma corporis diffusa (Fabry disease) was made clinically and confirmed by demonstration of the deficient leukocyte alpha-Gal A activity. The patient subsequently developed cerebrovascular symptoms, coronary disease, and renal failure, and died from a recurrent myocardial infarction. Family studies identified several other affected males and carrier female relatives with this X-linked recessive disorder. This case illustrates the typical multi-manifestations of this inherited disease which now can be safely and effectively treated by enzyme replacement therapy. Early diagnosis is important for the most effective treatment of this disease.

    Fabry disease
    DIAGNOSIS

 is an under-recognized

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 resulting from the

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

. The first case of

    Fabry disease
    DIAGNOSIS

 in

    Slovenia
    ETHNICITY

 was diagnosed in 1991. This

    46 year-old
    AGE

    male
    GENDER

 was referred for

    dermatologic evaluation
    PARACLINICAL

 of a

    purpura on his abdomen
    SYMPTOMS

.

    He
    GENDER

 was being treated for

    proteinuria
    BIOCHEMICAL

 and

    cardiac symptoms
    SYMPTOMS

. The diagnosis of

    angiokeratoma corporis diffusa
    DIAGNOSIS

 (

    Fabry disease)
    DIAGNOSIS

 was made clinically and confirmed by demonstration of the

    deficient leukocyte alpha-Gal A activity
    BIOCHEMICAL

. The patient subsequently developed

    cerebrovascular symptoms
    SYMPTOMS

,

    coronary disease
    SYMPTOMS

, and

    renal failure
    SYMPTOMS

, and

    died
    SYMPTOMS

 from a

    recurrent myocardial infarction
    SYMPTOMS

.

    Family studies identified several other affected males and carrier female relatives with this X-linked recessive disorder
    FAMILY

. This case illustrates the typical

    multi-manifestations
    SYMPTOMS

 of this

    inherited disease
    DIAGNOSIS

 which now can be safely and effectively treated by

    enzyme replacement therapy
    MEDICATION

. Early diagnosis is important for the most effective treatment of this disease.

Fabry disease
lysosomal storage disorder
Fabry disease
angiokeratoma corporis diffusa
Fabry disease)
inherited disease

purpura on his abdomen
cardiac symptoms
cerebrovascular symptoms
coronary disease
renal failure
died
recurrent myocardial infarction
multi-manifestations


Renal variant of Anderson-Fabry disease and bilateral renal cell carcinoma.

Anderson-Fabry disease (AFd) is an X-linked metabolic disease with clinical manifestations secondary to accumulation of glycosphingolipids in various tissues. We report the first case in which a patient with renal variant of AFd and chronic renal failure developed bilateral conventional renal cell carcinoma. His metabolic disorder was diagnosed only after histopathologic study of the kidney specimen resected because of the tumoral lesion. There is no clear etiologic relation between the metabolic and neoplastic disease. As AFd is not common or well known and its clinical manifestations tend to be nonspecific, the disorder is often unrecognized, misdiagnosed, or diagnosed late in life. The pathologist should be aware of this disorder when evaluating a kidney specimen from patients with chronic renal failure of unknown cause.

    Anderson-Fabry disease (AFd)
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    metabolic disease
    DIAGNOSIS

 with clinical manifestations secondary to

    accumulation of glycosphingolipids in various tissues
    MICROSCOPIC

. We report the first case in which a patient with

    renal variant of AFd
    DIAGNOSIS

 and

    chronic renal failure
    SYMPTOMS

 developed

    bilateral conventional renal cell carcinoma
    DIAGNOSIS

. His

    metabolic disorder
    DIAGNOSIS

 was diagnosed only after

    histopathologic study of the kidney specimen resected
    PARACLINICAL

 because of the

    tumoral lesion
    SYMPTOMS

. There is

    no clear etiologic relation between the metabolic and neoplastic disease
    NEG_FINDINGS

. As

    AFd
    DIAGNOSIS

 is not common or well known and its clinical manifestations tend to be nonspecific, the disorder is often unrecognized, misdiagnosed, or diagnosed late in life. The pathologist should be aware of this disorder when evaluating a

    kidney specimen
    PARACLINICAL

 from patients with

    chronic renal failure of unknown cause
    SYMPTOMS

.

chronic renal failure
tumoral lesion
chronic renal failure of unknown cause


Atrioventricular conduction disturbances in a young patient with Fabry's disease without other signs of cardiac involvement.

A 30 year-old male patient with a history of Fabry's disease, was referred to hospital with symptoms of dizziness, hypotension and weakness. Fabry's disease had been diagnosed 2 years before, based on angiokeratoma and hypohidrosis on physical examination and complete lack of alpha-galactosidase A on laboratory examination. The ECG on admission demonstrated sinus bradycardia, with a poor response to atropine administration. Echocardiograms on admission and 2 years before were normal, as well as Holter ambulatory ECG recording. Subsequent electrophysiological study demonstrated mild AV conduction disturbances at a site proximal to His, and the patient was simply advised to be regularly followed up. It can therefore be concluded that even young patients with Fabry's disease and normal echocardiograms might develop cardiac symptoms due to AV conduction abnormalities.

A

    30 year-old
    AGE

    male
    GENDER

 patient with a history of

    Fabry's disease
    DIAGNOSIS

, was referred to hospital with symptoms of

    dizziness
    SYMPTOMS

,

    hypotension
    SYMPTOMS

 and

    weakness
    SYMPTOMS

.

    Fabry's disease
    DIAGNOSIS

 had been diagnosed 2 years before, based on

    angiokeratoma
    SYMPTOMS

 and

    hypohidrosis
    SYMPTOMS

 on physical examination and

    complete lack of alpha-galactosidase A
    BIOCHEMICAL

 on

    laboratory examination
    PARACLINICAL

. The

    ECG
    PARACLINICAL

 on admission demonstrated

    sinus bradycardia
    SYMPTOMS

, with a

    poor response to atropine administration
    NEG_FINDINGS

.

    Echocardiograms on admission and 2 years before were normal
    NEG_FINDINGS

, as well as

    Holter ambulatory ECG recording
    PARACLINICAL

. Subsequent

    electrophysiological study
    PARACLINICAL

 demonstrated

    mild AV conduction disturbances at a site proximal to His
    SYMPTOMS

, and the patient was simply advised to be regularly followed up. It can therefore be concluded that even

    young
    AGE

 patients with

    Fabry's disease
    DIAGNOSIS

 and

    normal echocardiograms
    NEG_FINDINGS

 might develop

    cardiac symptoms
    SYMPTOMS

 due to

    AV conduction abnormalities
    SYMPTOMS

.

Fabry's disease
Fabry's disease
Fabry's disease


Beta-mannosidosis with angiokeratoma corporis diffusum.

Beta-mannosidosis is a lysosomal disorder which is caused by a deficiency of beta-mannosidase. This disorder was first described in goats. Twelve human cases have already been reported. We present the first case in Japan in whom the diagnosis was reached from angiokeratoma corporis diffusum. Futhermore, mental retardation, hearing loss, and renal failure were also detected. Pseudoxanthoma elasticum was also present, but whether it is a complication of beta-mannosidosis or not remains unknown. The activity level of beta-mannosidase in the patient's plasma was only 2% of the normal range, while that in the patient's mother was 40%. We suggest that beta-mannosidosis should be one of the differential diagnoses when lysosomal enzyme disorders are suspected in cases of angiokeratoma corporis diffusum.

    Beta-mannosidosis
    DIAGNOSIS

 is a

    lysosomal disorder
    DIAGNOSIS

 which is caused by a

    deficiency of beta-mannosidase
    BIOCHEMICAL

. This disorder was first described in

    goats
    ETHNICITY

. Twelve human cases have already been reported. We present the first case in

    Japan
    ETHNICITY

 in whom the diagnosis was reached from

    angiokeratoma corporis diffusum
    SYMPTOMS

. Futhermore,

    mental retardation
    SYMPTOMS

,

    hearing loss
    SYMPTOMS

, and

    renal failure
    SYMPTOMS

 were also detected.

    Pseudoxanthoma elasticum
    SYMPTOMS

 was also present, but whether it is a complication of

    beta-mannosidosis
    DIAGNOSIS

 or not remains unknown. The

    activity level of beta-mannosidase in the patient's plasma was only 2% of the normal range
    BIOCHEMICAL

,

    while that in the patient's mother was 40%
    BIOCHEMICAL

. We suggest that

    beta-mannosidosis
    DIAGNOSIS

 should be one of the

    differential diagnoses
    PARACLINICAL

 when

    lysosomal enzyme disorders
    DIAGNOSIS

 are suspected in cases of

    angiokeratoma corporis diffusum
    SYMPTOMS

.

Beta-mannosidosis
lysosomal disorder
beta-mannosidosis
beta-mannosidosis
lysosomal enzyme disorders

angiokeratoma corporis diffusum
mental retardation
hearing loss
renal failure
Pseudoxanthoma elasticum
angiokeratoma corporis diffusum


Recurrence of Fabry disease as a result of paternal germline mosaicism for alpha-galactosidase a gene mutation.

We present two sisters with a severe form of Fabry disease, who both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X). Each of the sisters developed renal failure in the third decade of life; the older sibling underwent renal transplantation at 40 years of age. The severe phenotype of the siblings correlates with results of the X-inactivation study: examination of methylation status in human androgene receptor (HUMARA) gene suggests preferential inactivation of the wild-type allele in both patients. Patients' parents had no symptoms of Fabry disease and were tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells. Genotype analysis using DXS7424 marker showed paternal origin of the mutation. The father's sperm was then tested for presence of the mutation to examine the possibility of the germline mosaicism. Both mutant and wild-type alleles were found in DNA isolated from father's sperm. The apparent explanation of these findings is germline mosaicism due to mutation event during the embryonic development of sperm producing cells (spermatogonia). This is the first case of germline mosaicism in Fabry disease reported in the literature.

We present two

    sisters with a severe form of Fabry disease
    FAMILY

, who

    both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X)
    FAMILY

.

    Each of the sisters developed renal failure
    FAMILY

    in the third decade of life
    AGE

; the

    older sibling underwent renal transplantation
    FAMILY

 at

    40 years of age
    AGE

. The

    severe phenotype of the siblings
    FAMILY

 correlates with results of the

    X-inactivation study
    PARACLINICAL

:

    examination of methylation status in human androgene receptor (HUMARA) gene
    PARACLINICAL

 suggests

    preferential inactivation of the wild-type allele
    GENETICS

 in both patients. Patients'

    parents had no symptoms of Fabry disease
    FAMILY

 and were

    tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells
    NEG_FINDINGS

.

    Genotype analysis using DXS7424 marker
    PARACLINICAL

 showed

    paternal origin of the mutation
    GENETICS

. The

    father's sperm was then tested for presence of the mutation
    PARACLINICAL

 to examine the possibility of the

    germline mosaicism
    GENETICS

.

    Both mutant and wild-type alleles were found in DNA isolated from father's sperm
    GENETICS

. The apparent explanation of these findings is

    germline mosaicism
    GENETICS

 due to

    mutation event during the embryonic development of sperm producing cells (spermatogonia)
    GENETICS

. This is the first case of

    germline mosaicism
    GENETICS

 in

    Fabry disease
    DIAGNOSIS

 reported in the literature.


Chloroquine-induced lipidosis mimicking Fabry disease.

Intracellular accumulation of phospholipids may be a consequence of inherited or acquired metabolic disorders. In Fabry disease, deficiency of alpha-galactosidase A results in storage of globotriasylceramide in numerous cells including endothelium, striated muscle (skeletal, cardiac), smooth muscle, and renal epithelium among others; the ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material ('zebra bodies' or myeline figures). Chloroquine therapy may result in storage of biochemically and ultrastructurally similar inclusions in many of the same cells as Fabry disease and often results in similar clinical manifestations. We report a 56-year-old woman with rheumatoid arthritis treated with chloroquine, who developed muscle weakness and renal insufficiency; information regarding therapy was not emphasized at the time of renal biopsy, leading to initial erroneous interpretation of Fabry disease. Following muscle biopsy, genetic and enzyme evaluation, and additional studies on the kidney biopsy, a diagnosis of chloroquine toxicity was established. One year following cessation of chloroquine, renal and muscle dysfunction greatly improved. In chloroquine toxicity, inclusions in glomeruli are not only in visceral epithelial, endothelial and mesangial cells but are in infiltrating monocytes/macrophages, which are most commonly present in the mesangium. Curvilinear bodies, the ultrastructural features of chloroquine toxicity in striated muscle, are not present in renal cells. This report documents differences in appearance, cells affected and morphological differential diagnostic features to distinguish these two entities.

    Intracellular accumulation of phospholipids
    MICROSCOPIC

 may be a consequence of

    inherited
    GENETICS

 or

    acquired metabolic disorders
    GENETICS

. In

    Fabry disease
    DIAGNOSIS

,

    deficiency of alpha-galactosidase A
    BIOCHEMICAL

 results in

    storage of globotriasylceramide in numerous cells including endothelium, striated muscle (skeletal, cardiac), smooth muscle, and renal epithelium
    MICROSCOPIC

 among others; the

    ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material ('zebra bodies' or myeline figures)
    MICROSCOPIC

.

    Chloroquine therapy
    MEDICATION

 may result in

    storage of biochemically and ultrastructurally similar inclusions in many of the same cells as Fabry disease
    MICROSCOPIC

 and often results in similar clinical manifestations. We report a

    56-year-old
    AGE

    woman
    GENDER

 with

    rheumatoid arthritis
    DIAGNOSIS

    treated with chloroquine
    MEDICATION

, who developed

    muscle weakness
    SYMPTOMS

 and

    renal insufficiency
    SYMPTOMS

; information regarding

    therapy was not emphasized
    NEG_FINDINGS

 at the time of

    renal biopsy
    PARACLINICAL

, leading to

    initial erroneous interpretation of Fabry disease
    NEG_FINDINGS

. Following

    muscle biopsy
    PARACLINICAL

,

    genetic and enzyme evaluation
    PARACLINICAL

, and additional

    studies on the kidney biopsy
    PARACLINICAL

, a diagnosis of

    chloroquine toxicity
    DIAGNOSIS

 was established. One year following

    cessation of chloroquine
    MEDICATION

,

    renal and muscle dysfunction greatly improved
    SYMPTOMS

. In

    chloroquine toxicity
    DIAGNOSIS

,

    inclusions in glomeruli are not only in visceral epithelial, endothelial and mesangial cells but are in infiltrating monocytes/macrophages, which are most commonly present in the mesangium
    MICROSCOPIC

.

    Curvilinear bodies
    MICROSCOPIC

, the

    ultrastructural features of chloroquine toxicity in striated muscle
    MICROSCOPIC

, are

    not present in renal cells
    NEG_FINDINGS

. This report documents differences in appearance, cells affected and morphological differential diagnostic features to distinguish these two entities.

Fabry disease
rheumatoid arthritis
chloroquine toxicity
chloroquine toxicity

Chloroquine therapy
treated with chloroquine
cessation of chloroquine


Psychiatric findings in four female carriers of Fabry disease.

Anderson-Fabry disease (AFD) is an X-linked recessive disorder of glycosphingolipid metabolism. Most female carriers are clinically symptomatic; however, psychiatric diagnoses have not been reported in this population. We describe four female carriers of AFD disease who met DSM-IV criteria for major depression. All cases had a score above 26 on the Hamilton Rating Scale for Depression, indicating severe depression. This was independent of the severity or number of symptoms of AFD disease. Excessive guilt, fatigue, occupational difficulty, suicidal ideation and depressed mood were findings in all cases. In conclusion, the common presence of depression in carriers of AFD implies the need for a multidisciplinary approach, including psychiatry, in management of these patients. Further studies are recommended to establish the etiology of psychiatric complications, as well as the incidence and the response to pharmacotherapy and psychotherapy.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

. Most

    female
    GENDER

 carriers are clinically symptomatic; however,

    psychiatric diagnoses
    DIAGNOSIS

 have not been reported in this population. We describe four

    female
    GENDER

 carriers of

    AFD disease
    DIAGNOSIS

 who met DSM-IV criteria for

    major depression
    DIAGNOSIS

. All cases had a score

    above 26 on the Hamilton Rating Scale for Depression
    SYMPTOMS

, indicating

    severe depression
    SYMPTOMS

. This was independent of the severity or number of

    symptoms of AFD disease
    NEG_FINDINGS

.

    Excessive guilt
    SYMPTOMS

,

    fatigue
    SYMPTOMS

,

    occupational difficulty
    SYMPTOMS

,

    suicidal ideation
    SYMPTOMS

 and

    depressed mood
    SYMPTOMS

 were findings in all cases. In conclusion, the common presence of

    depression
    DIAGNOSIS

 in carriers of

    AFD
    DIAGNOSIS

 implies the need for a

    multidisciplinary approach
    MEDICATION

, including

    psychiatry
    PARACLINICAL

, in management of these patients. Further studies are recommended to establish the etiology of

    psychiatric complications
    SYMPTOMS

, as well as the incidence and the response to pharmacotherapy and

    psychotherapy
    MEDICATION

.


A novel alpha-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease.

A 65-year-old man presented to our institution for workup of proteinuria. His serum creatinine level was 1.7 mg/dL (130 micromol/L), and he had proteinuria with protein of almost 5 g/24 h. Fabry disease was diagnosed by means of kidney biopsy and low serum and leukocyte levels of alpha-galactosidase A. Review of his history, family history, physical examinations, and diagnostic studies did not show other findings typical of this disease. His renal function continued to decline, and he eventually underwent a living unrelated renal transplantation 5 years later. Three years after transplantation, his creatinine level is 1.7 mg/dL (130 micromol/L), and corrected iothalamate clearance is 53 mL/min/1.73 m2 . Genetic studies showed that he has a novel missense mutation (M42L) in exon 1. Methionine at codon 42 is highly conserved in eukaryotic alpha-galactosidase A orthologues. This genotype predicts a minor misfolding of alpha-galactosidase A because of a small difference in hydrophobicity between methionine and leucine. His mutation resulted in a very low, but detectable, serum level of alpha-galactosidase A (0.002 U/L; normal range, 0.016 to 0.2 U/L). Cases of Fabry disease that present with predominantly renal manifestations are rare and require a high index of suspicion for diagnosis. Because treatment for Fabry disease recently has become available, it is important for clinicians to be aware of this disease and pursue the diagnosis in cases of otherwise unexplained renal dysfunction.

A

    65-year-old
    AGE

    man
    GENDER

 presented to our institution for workup of

    proteinuria
    BIOCHEMICAL

. His

    serum creatinine level was 1.7 mg/dL (130 micromol/L)
    BIOCHEMICAL

, and

    he
    GENDER

 had proteinuria with protein of almost 5 g/24 h.

    Fabry disease
    DIAGNOSIS

 was diagnosed by means of

    kidney biopsy
    PARACLINICAL

 and low serum and leukocyte levels of alpha-galactosidase A. Review of his history, family history, physical examinations, and diagnostic studies

    did not show other findings typical of this disease
    NEG_FINDINGS

. His

    renal function continued to decline
    SYMPTOMS

, and

    he
    GENDER

 eventually

    underwent a living unrelated renal transplantation
    MEDICATION

 5 years later. Three years after

    transplantation
    MEDICATION

, his

    creatinine level is 1.7 mg/dL (130 micromol/L)
    BIOCHEMICAL

, and

    corrected iothalamate clearance is 53 mL/min/1.73 m2
    BIOCHEMICAL

 .

    Genetic studies
    PARACLINICAL

 showed that

    he
    GENDER

 has a

    novel missense mutation (M42L) in exon 1. Methionine at codon 42 is highly conserved in eukaryotic alpha-galactosidase A orthologues
    GENETICS

. This

    genotype predicts a minor misfolding of alpha-galactosidase A because of a small difference in hydrophobicity between methionine and leucine
    GENETICS

.

    His
    GENDER

 mutation resulted in a

    very low, but detectable, serum level of alpha-galactosidase A (0.002 U/L; normal range, 0.016 to 0.2 U/L)
    BIOCHEMICAL

. Cases of

    Fabry disease
    DIAGNOSIS

 that present with

    predominantly renal manifestations
    SYMPTOMS

 are rare and require a high index of suspicion for diagnosis. Because treatment for

    Fabry disease
    DIAGNOSIS

 recently has become available, it is important for clinicians to be aware of this disease and pursue the diagnosis in cases of otherwise unexplained

    renal dysfunction
    SYMPTOMS

.

Fabry disease
Fabry disease
Fabry disease

renal function continued to decline
predominantly renal manifestations
renal dysfunction


Neuropathy and Fabry's disease.

Fabry's disease is a multisystem disorder that is commonly associated with a painful, debilitating neuropathy. The common coexistence of arthralgias and an elevated erythrocyte sedimentation rate may lead to the misdiagnosis of a rheumatic condition. We report a 38-year-old man who was evaluated for progressive neuropathy and limb pain in the setting of longstanding arthralgias, presumed juvenile rheumatoid arthritis, and past renal transplantation. Histopathologic assessment of nerve and muscle biopsy specimens led to the diagnosis of Fabry's disease, thus allowing the patient to receive enzyme replacement therapy that may slow progression and preserve the transplanted kidney.

    Fabry's disease
    DIAGNOSIS

 is a

    multisystem disorder
    DIAGNOSIS

 that is commonly associated with a

    painful, debilitating neuropathy
    SYMPTOMS

. The common coexistence of

    arthralgias
    SYMPTOMS

 and an

    elevated erythrocyte sedimentation rate
    BIOCHEMICAL

 may lead to the misdiagnosis of a

    rheumatic condition
    DIAGNOSIS

. We report a

    38-year-old
    AGE

    man
    GENDER

 who was evaluated for

    progressive neuropathy
    SYMPTOMS

 and

    limb pain
    SYMPTOMS

 in the setting of

    longstanding arthralgias
    SYMPTOMS

,

    presumed juvenile rheumatoid arthritis
    DIAGNOSIS

, and

    past renal transplantation
    MEDICATION

.

    Histopathologic assessment of nerve and muscle biopsy specimens
    PARACLINICAL

 led to the diagnosis of

    Fabry's disease
    DIAGNOSIS

, thus allowing the patient to receive

    enzyme replacement therapy that may slow progression and preserve the transplanted kidney
    MEDICATION

.

Fabry's disease
multisystem disorder
rheumatic condition
presumed juvenile rheumatoid arthritis
Fabry's disease

painful, debilitating neuropathy
arthralgias
progressive neuropathy
limb pain
longstanding arthralgias


Effect of enzyme-replacement therapy on gastrointestinal symptoms in Fabry disease.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by deficiency of lysosomal alpha-galactosidase A. The disease affects not only kidney, myocardium, central nervous system and the skin but also, in many patients, the gastrointestinal tract. The recent advent of enzyme-replacement therapy has been reported to show beneficial effects on cardiomyopathy, renal function and autonomous nervous function. We report on a 34-year-old patient with Fabry disease in whom gastrointestinal symptoms were major complaints. Enzyme replacements led to remarkable improvement of diarrhoea and constipation. Abdominal pain, the feeling of fullness and meteorism improved, and metoclopramide, which previously had been used regularly, could be discontinued. There were also marked improvements of appetite, body weight, body mass index, physical activity and overall wellbeing. This observation should prompt further investigations into the pathophysiology of gastrointestinal manifestations in Fabry disease and the mechanisms of enzyme-replacement effects on gut function.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by deficiency of lysosomal alpha-galactosidase A. The disease affects not only

    kidney, myocardium, central nervous system and the skin
    SYMPTOMS

 but also, in many patients, the

    gastrointestinal tract
    SYMPTOMS

. The recent advent of

    enzyme-replacement therapy
    MEDICATION

 has been reported to show beneficial effects on

    cardiomyopathy, renal function
    SYMPTOMS

 and

    autonomous nervous function
    SYMPTOMS

. We report on a

    34-year-old
    AGE

 patient with

    Fabry disease
    DIAGNOSIS

 in whom

    gastrointestinal symptoms
    SYMPTOMS

 were major complaints.

    Enzyme replacements
    MEDICATION

 led to

    remarkable improvement of diarrhoea and constipation
    SYMPTOMS

.

    Abdominal pain
    SYMPTOMS

,

    the feeling of fullness
    SYMPTOMS

 and

    meteorism improved
    SYMPTOMS

, and

    metoclopramide, which previously had been used regularly, could be discontinued
    NEG_FINDINGS

. There were also

    marked improvements of appetite, body weight
    SYMPTOMS

,

    body mass index
    SYMPTOMS

,

    physical activity
    SYMPTOMS

 and

    overall wellbeing
    SYMPTOMS

. This observation should prompt further investigations into the pathophysiology of

    gastrointestinal manifestations
    SYMPTOMS

 in

    Fabry disease
    DIAGNOSIS

 and the mechanisms of

    enzyme-replacement
    MEDICATION

 effects on gut function.

Fabry disease
lysosomal storage disorder
Fabry disease
Fabry disease

enzyme-replacement therapy
Enzyme replacements
enzyme-replacement


Enzyme replacement therapy in severe Fabry disease with renal failure: a 1-year follow-up.

We present here the course of clinical response of a 53-year-old haemodialysed Fabry patient who received recombinant human alpha-galactosidase A at a dose of 1 mg/kg every other week over a period of 1 year. The therapy was well tolerated by the patient, who revealed an impressive favourable cutaneous, gastrointestinal, neurological and psychiatric response and a dramatic improvement in his quality of life, but no improvement in cardiac and renal function.

We present here the course of clinical response of a

    53-year-old
    AGE

    haemodialysed
    MEDICATION

    Fabry
    DIAGNOSIS

 patient who

    received recombinant human alpha-galactosidase A at a dose of 1 mg/kg every other week over a period of 1 year
    MEDICATION

. The therapy was well tolerated by the patient, who revealed an

    impressive favourable cutaneous, gastrointestinal, neurological and psychiatric response
    SYMPTOMS

 and a

    dramatic improvement in his quality of life
    SYMPTOMS

, but

    no improvement in cardiac and renal function
    NEG_FINDINGS

.


Fabry disease female proband with clinical manifestations similar to hypertrophic cardiomyopathy.

Fabry's disease is an X-linked inborn error of glycosphingolipid catabolism, resulting from a deficiency in alpha-galactosidase A (alpha-Gal A). A 56-year-old Japanese woman was at first suspected of having hypertrophic cardiomyopathy. The patient and her son had alpha-Gal A activity in leukocytes that was remarkably below the limit of controls. DNA analysis of the alpha-Gal A gene revealed a novel missense mutation at codon 19 in exon 1, resulting in leucine-to-proline substitution. As a result she was confirmed as a classic Fabry heterozygote. Recent advances in enzyme replacement therapy can reverse the storage of glycosphingolipids in Fabry's disease. Thus, in patients with cardiac hypertrophy, it is important to differentiate Fabry's disease from other causes of hypertrophy. Therefore, it is necessary to measure alpha-Gal A activity in all suspected cases and to analyze genetic abnormalities in heterozygotes.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked inborn error of glycosphingolipid catabolism
    GENETICS

, resulting from a

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

. A

    56-year-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

 was at first suspected of having

    hypertrophic cardiomyopathy
    DIAGNOSIS

. The patient and

    her
    GENDER

 son had

    alpha-Gal A activity in leukocytes that was remarkably below the limit of controls
    BIOCHEMICAL

.

    DNA analysis of the alpha-Gal A gene
    PARACLINICAL

 revealed a

    novel missense mutation at codon 19 in exon 1, resulting in leucine-to-proline substitution
    GENETICS

. As a result

    she
    GENDER

 was confirmed as a classic

    Fabry heterozygote
    GENETICS

. Recent advances in

    enzyme replacement therapy
    MEDICATION

 can

    reverse the storage of glycosphingolipids
    MICROSCOPIC

 in

    Fabry's disease
    MICROSCOPIC

. Thus, in patients with

    cardiac hypertrophy
    SYMPTOMS

, it is important to differentiate

    Fabry's disease
    DIAGNOSIS

 from other causes of

    hypertrophy
    SYMPTOMS

. Therefore, it is necessary to measure

    alpha-Gal A activity
    BIOCHEMICAL

 in all suspected cases and to analyze

    genetic abnormalities
    GENETICS

 in

    heterozygotes
    GENETICS

.

Fabry's disease
hypertrophic cardiomyopathy
Fabry's disease


Intermittent claudication -- atypical presentation, diagnosis and treatment.

A unique case of a man with Fabry's disease and associated small vessel vasculopathy manifesting as recurrent episodes of intermittent claudication is described. The case highlights the concept that microvascular involvement due to local accumulation of glycosphingolipid in the smooth muscle fibres of vessel walls may be responsible for claudicant symptoms in such patients rather than the more classical macrovascular insufficiency.

A unique case of a

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 and associated

    small vessel vasculopathy
    SYMPTOMS

 manifesting as

    recurrent episodes of intermittent claudication
    SYMPTOMS

 is described. The case highlights the concept that

    microvascular involvement
    SYMPTOMS

 due to

    local accumulation of glycosphingolipid in the smooth muscle fibres of vessel walls
    MICROSCOPIC

 may be responsible for

    claudicant symptoms
    SYMPTOMS

 in such patients rather than the more classical

    macrovascular insufficiency
    SYMPTOMS

.


Comparative in vitro expression study of four Fabry disease causing mutations at glutamine 279 of the alpha-galactosidase A protein.

Fabry disease is an X-linked lysosomal storage disorder caused by the deficiency of alpha-galactosidase A that results in the accumulation of neutral sphingolipids. We report a novel point mutation in exon 6, Q279K, carried by an asymptomatic child with a family history of classic Fabry disease. Moreover, we comparatively study the in vitro expression and enzyme activity of Q279K and three other already described mutants in glutamine 279. The Q279K, Q279H and Q279R mutants transfected in COS-1 cells expressed no activity while the residual enzyme activity of the Q279E mutant represented 10% of wild type value. Western blot analysis demonstrated a differential behavior of the mutant proteins: Q279K and Q279H persisted as the inactive 50-kD precursor, indicating that these mutations may affect the normal processing of the enzyme, while the Q279R mutant was not detected probably due to an unstable protein which is rapidly degraded. The in vitro expression studies of the novel Q279K mutation were confirmed by Western blot analysis performed in the patient's lymphocytes which revealed the alpha-galactosidase A precursor of 50 kD but not the processed form.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 caused by the

    deficiency of alpha-galactosidase A
    BIOCHEMICAL

 that results in the

    accumulation of neutral sphingolipids
    MICROSCOPIC

. We report a

    novel point mutation in exon 6, Q279K
    GENETICS

, carried by an

    asymptomatic child
    FAMILY

    with a family history of classic Fabry disease
    FAMILY

. Moreover, we comparatively study the in vitro expression and enzyme activity of

    Q279K
    GENETICS

 and three other already described

    mutants in glutamine 279
    GENETICS

. The

    Q279K
    GENETICS

,

    Q279H
    GENETICS

 and

    Q279R
    GENETICS

 mutants transfected in COS-1 cells

    expressed no activity
    NEG_FINDINGS

 while the

    residual enzyme activity of
    BIOCHEMICAL

 the

    Q279E mutant represented 10% of wild type value
    GENETICS

.

    Western blot analysis
    PARACLINICAL

 demonstrated a differential behavior of the mutant proteins:

    Q279K and Q279H
    GENETICS

 persisted as the

    inactive 50-kD precursor
    BIOCHEMICAL

, indicating that these mutations may affect the normal processing of the enzyme, while the

    Q279R mutant
    GENETICS

 was not detected probably due to an unstable protein which is rapidly degraded. The in vitro expression studies of the

    novel Q279K mutation
    GENETICS

 were confirmed by

    Western blot analysis
    PARACLINICAL

 performed in the patient's lymphocytes which revealed the

    alpha-galactosidase A precursor of 50 kD but not the processed form
    BIOCHEMICAL

.

Fabry disease
lysosomal storage disorder


Monitoring the clinical and biochemical response to enzyme replacement therapy in three children with Fabry disease.

Fabry disease is an X-linked disorder of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A. This leads to the progressive accumulation of glycosphingolipids in lysosomes of most visceral tissues and in body fluids. Following successful clinical trials in adults, two recombinant enzyme preparations of alpha-galactosidase have recently been licensed in Europe for the treatment of Fabry disease and treatment in children has commenced. We now report the clinical findings and the levels of globotriaosylceramide in plasma and urine in three boys who have been treated with enzyme replacement therapy (agalsidase beta, Fabrazyme), 1 mg/kg for 2 years. In one boy there was a rapid improvement in all the clinical and biochemical parameters measured. This has been maintained. In the other two boys, who are siblings, there was no measurable clinical improvement after 1 year and the levels of globotriaosylceramide in plasma and urine, although lower than before treatment, were still considerably elevated. There was no evidence of blocking or neutralising antibodies so the dose of enzyme was increased to 2 mg/kg at 74 weeks of therapy. At 2 years their pain scores had improved but this was not accompanied by any reduction in the plasma or urine globotriaosylceramide levels.

Measurement of globotriaosylceramide in plasma and urine may not be the most appropriate marker to monitor the progression of treatment by enzyme replacement therapy in all patients. Certainly the subjective clinical improvement in the two brothers in this report outweighed the objective biochemical findings.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked
    GENETICS

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A. This leads to the

    progressive accumulation of glycosphingolipids in lysosomes of most visceral tissues and in body fluids
    MICROSCOPIC

. Following successful clinical trials in adults, two

    recombinant enzyme preparations of alpha-galactosidase
    MEDICATION

 have recently been licensed in Europe for the treatment of

    Fabry disease
    DIAGNOSIS

 and treatment in

    children
    AGE

 has commenced. We now report the clinical findings and the

    levels of globotriaosylceramide in plasma and urine
    BIOCHEMICAL

 in three

    boys
    GENDER

 who have been

    treated with enzyme replacement therapy (agalsidase beta, Fabrazyme), 1 mg/kg for 2 years
    MEDICATION

. In one

    boy
    GENDER

 there was a

    rapid improvement in all the clinical and biochemical parameters
    SYMPTOMS

 measured. This has been maintained. In the other two

    boys
    GENDER

, who are

    siblings
    GENDER

, there was

    no measurable clinical improvement
    NEG_FINDINGS

 after 1 year and the

    levels of globotriaosylceramide in plasma and urine, although lower than before treatment, were still considerably elevated
    BIOCHEMICAL

. There was

    no evidence of blocking or neutralising antibodies
    NEG_FINDINGS

 so the

    dose of enzyme was increased to 2 mg/kg at 74 weeks of therapy
    MEDICATION

. At 2 years their

    pain scores had improved
    SYMPTOMS

 but this was

    not accompanied by any reduction in the plasma or urine globotriaosylceramide levels
    NEG_FINDINGS

.

    Measurement of globotriaosylceramide in plasma and urine
    PARACLINICAL

 may not be the most appropriate marker to monitor the progression of treatment by

    enzyme replacement therapy
    MEDICATION

 in all patients. Certainly the

    subjective clinical improvement
    SYMPTOMS

 in the two

    brothers
    GENDER

 in this report outweighed the

    objective biochemical findings
    SYMPTOMS

.


Neurologic manifestations of Kanzaki disease.

We describe the neurologic findings in a patient with alpha-N-acetylgalactosaminidase deficiency (Kanzaki disease). Clinical and electrophysiologic studies revealed sensory-motor polyneuropathy, and sural nerve pathology showed decreased density of myelinated fibers with axonal degeneration. The patient had mildly impaired intellectual function with abnormal brain MRI and sensory-neuronal hearing impairment with repeated episodes of vertigo attacks. These findings suggest that Kanzaki disease may develop neurologic complications in the CNS and peripheral nervous system.

We describe the neurologic findings in a patient with

    alpha-N-acetylgalactosaminidase deficiency
    BIOCHEMICAL

 (

    Kanzaki disease)
    DIAGNOSIS

.

    Clinical and electrophysiologic studies
    PARACLINICAL

 revealed

    sensory-motor polyneuropathy
    SYMPTOMS

, and

    sural nerve pathology
    PARACLINICAL

 showed

    decreased density of myelinated fibers with axonal degeneration
    MICROSCOPIC

. The patient had

    mildly impaired intellectual function
    SYMPTOMS

 with

    abnormal brain MRI
    SYMPTOMS

 and

    sensory-neuronal hearing impairment
    SYMPTOMS

 with

    repeated episodes of vertigo attacks
    SYMPTOMS

. These findings suggest that

    Kanzaki disease
    DIAGNOSIS

 may develop

    neurologic complications in the CNS and peripheral nervous system
    SYMPTOMS

.


The co-existence of Fabry and celiac diseases: a case report.

We present a patient with Fabry disease with remarkable diagnostic findings and gluten-sensitive enteropathy. An 11-year-old girl was admitted to hospital with weight loss, anorexia, nausea, vomiting, flank pain, acroparesthesia, and painful extremities. Her mother had end-stage renal failure secondary to Fabry disease. On physical examination, she had growth retardation. Ophthalmological examination showed characteristic whorl-like corneal opacities and Fabry disease was confirmed with low alpha-galactosidase A (alpha-gal A) activity. Her painful attacks were treated with carbamazepine, but vomiting and nausea continued. Laboratory studies revealed positive serum anti-endomysium and anti-gliadin antibodies. Small intestinal biopsy showed subtotal villous atrophy compatible with gluten-sensitive enteropathy. Following treatment with a gluten-free diet, her gastrointestinal symptoms completely disappeared within a few weeks and then she had catch-up growth. In her long-term follow-up, proteinuria appeared and renal involvement was confirmed by characteristic renal biopsy findings. Following these clinicopathological findings, enzyme replacement therapy was started. In conclusion, although heterozygous females can be asymptomatic or are expected to have a mild course of the disease, a severe clinical course in our patient in the 2nd decade is of particular interest. In addition, Fabry disease occurring with gluten-sensitive enteropathy, a very rare co-existence, is emphasized.

We present a patient with

    Fabry disease
    DIAGNOSIS

 with remarkable diagnostic findings and

    gluten-sensitive enteropathy
    DIAGNOSIS

. An

    11-year-old
    AGE

    girl
    GENDER

 was admitted to hospital with

    weight loss
    SYMPTOMS

,

    anorexia
    SYMPTOMS

,

    nausea
    SYMPTOMS

,

    vomiting
    SYMPTOMS

,

    flank pain
    SYMPTOMS

,

    acroparesthesia
    SYMPTOMS

, and

    painful extremities
    SYMPTOMS

.

    Her
    GENDER

    mother had end-stage renal failure secondary to Fabry disease
    FAMILY

. On physical examination,

    she
    GENDER

 had

    growth retardation
    SYMPTOMS

.

    Ophthalmological examination
    PARACLINICAL

 showed

    characteristic whorl-like corneal opacities
    SYMPTOMS

 and

    Fabry disease
    DIAGNOSIS

 was confirmed with

    low alpha-galactosidase A (alpha-gal A) activity
    BIOCHEMICAL

.

    Her
    GENDER

    painful attacks
    SYMPTOMS

 were

    treated with carbamazepine
    NEG_FINDINGS

, but

    vomiting
    SYMPTOMS

 and

    nausea
    SYMPTOMS

 continued.

    Laboratory studies
    PARACLINICAL

 revealed

    positive serum anti-endomysium and anti-gliadin antibodies
    BIOCHEMICAL

.

    Small intestinal biopsy
    PARACLINICAL

 showed

    subtotal villous atrophy
    SYMPTOMS

 compatible with

    gluten-sensitive enteropathy
    DIAGNOSIS

. Following

    treatment with a gluten-free diet
    MEDICATION

,

    her
    GENDER

    gastrointestinal symptoms completely disappeared within a few weeks
    SYMPTOMS

 and then

    she
    GENDER

 had

    catch-up growth
    SYMPTOMS

. In her long-term

    follow-up
    PARACLINICAL

,

    proteinuria appeared
    BIOCHEMICAL

 and

    renal involvement
    SYMPTOMS

 was confirmed by characteristic

    renal biopsy findings
    SYMPTOMS

. Following these clinicopathological findings,

    enzyme replacement therapy
    MEDICATION

 was started. In conclusion, although

    heterozygous
    GENETICS

    females
    GENDER

 can be

    asymptomatic
    NEG_FINDINGS

 or are expected to have a mild course of the disease, a severe clinical course in our patient in the

    2nd decade
    AGE

 is of particular interest. In addition,

    Fabry disease occurring with gluten-sensitive enteropathy
    DIAGNOSIS

, a very rare co-existence, is emphasized.

treatment with a gluten-free diet
enzyme replacement therapy


A nonsense mutation (R220X) in the alpha-galactosidase A gene causes typical Fabry disease in both genders.

Fabry disease is an X-linked recessive disorder resulting from a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). Chronic renal failure is an important cause of death in patients with Fabry disease. We report on patients with Fabry disease (a hemizygous male and his mother) due to a nonsense mutation (R220X) in the alpha-Gal A gene.

The proband, a 41-year-old man, and his 71-year-old mother presented with renal and cardiac manifestations of Fabry disease. Histological examination and molecular analysis of the alpha-Gal A gene were performed.

Typical histological findings of Fabry disease were observed in a renal biopsy specimen from the proband and in renal and myocardial necropsy specimens from the mother. Sequencing of a full-length alpha-Gal A cDNA from the proband indicated a C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X). Examination of genomic alpha-Gal A DNA revealed that the proband was a hemizygote and the mother was a heterozygous carrier for the mutation.

This is the first detailed report of family members with Fabry disease due to a nonsense mutation (R220X) in the alpha-Gal A gene. Our study indicates that this mutation causes the typical disease in both genders.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive disorder
    GENETICS

 resulting from a

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

.

    Chronic renal failure
    SYMPTOMS

 is an important cause of

    death
    SYMPTOMS

 in patients with

    Fabry disease
    DIAGNOSIS

. We report on patients with

    Fabry disease
    DIAGNOSIS

 (a

    hemizygous male
    GENETICS

    and his mother
    FAMILY

) due to a

    nonsense mutation (R220X) in the alpha-Gal A gene
    GENETICS

.

The

    proband
    GENDER

, a

    41-year-old
    AGE

    man
    GENDER

, and

    his
    GENDER

    71-year-old
    AGE

    mother
    GENDER

 presented with

    renal and cardiac manifestations
    SYMPTOMS

 of

    Fabry disease
    DIAGNOSIS

.

    Histological examination
    PARACLINICAL

 and

    molecular analysis of the alpha-Gal A gene
    PARACLINICAL

 were performed.

    Typical histological findings of Fabry disease
    MICROSCOPIC

 were observed in a

    renal biopsy specimen
    PARACLINICAL

 from the proband and in

    renal and myocardial necropsy specimens
    PARACLINICAL

 from the mother.

    Sequencing of a full-length alpha-Gal A cDNA from the proband
    PARACLINICAL

 indicated a

    C-T transition at codon 220, resulting in substitution of the predictable termination for arginine (R220X)
    GENETICS

.

    Examination of genomic alpha-Gal A DNA
    PARACLINICAL

 revealed that the

    proband was a hemizygote
    FAMILY

 and

    the mother was a heterozygous carrier for the mutation
    FAMILY

.

This is the first detailed report of

    family members with Fabry disease
    FAMILY

 due to a

    nonsense mutation (R220X) in the alpha-Gal A gene
    GENETICS

. Our study indicates that this mutation causes the typical disease in both

    genders
    GENDER

.

Fabry disease
Fabry disease
Fabry disease
Fabry disease

Chronic renal failure
death
renal and cardiac manifestations


Fabry's disease presenting as stroke in a young female.

Fabry's disease is an X-linked disorder, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A which results in the accumulation of the glycosphingolipid, ceramide trihexose in the vascular endothelium and can lead to cerebral infarction. Male hemizygotes are generally more severely affected than heterozygote females. Clinical disease in females is thought to be due to unequal X chromosome inactivation.

A 19-year-old woman, who was previously well, presented with neurological deficits secondary to basal ganglia and pontine infarction. Extensive cardiac, arterial and hematologic investigations did not identify the etiology of her stroke. Muscle biopsy revealed endothelial lysosomal aggregates most consistent with a diagnosis of Fabry's disease. The diagnosis was confirmed on the basis of molecular genotype analysis.

Inherited causes of stroke such as Fabry's disease should be considered in young patients with stroke if an etiologic diagnosis is not reached after complete investigations. Muscle biopsy can assist with the diagnosis and guide further investigations. This report summarizes the biochemical and histological features of Fabry's disease and the associated genetic abnormalities.

    Fabry's disease
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

, caused by a

    deficiency of the lysosomal enzyme alpha-galactosidase A
    BIOCHEMICAL

 which results in the

    accumulation of the glycosphingolipid, ceramide trihexose in the vascular endothelium
    MICROSCOPIC

 and can lead to

    cerebral infarction
    SYMPTOMS

.

    Male
    GENDER

    hemizygotes
    GENETICS

 are generally more severely affected than

    heterozygote
    GENETICS

    females
    GENDER

. Clinical disease in

    females
    GENDER

 is thought to be due to

    unequal X chromosome inactivation
    GENETICS

.

A

    19-year-old
    AGE

    woman
    GENDER

, who was

    previously well
    NEG_FINDINGS

, presented with

    neurological deficits
    SYMPTOMS

 secondary to

    basal ganglia and pontine infarction
    SYMPTOMS

.

    Extensive cardiac, arterial and hematologic investigations did not identify the etiology of her stroke
    NEG_FINDINGS

.

    Muscle biopsy
    PARACLINICAL

 revealed

    endothelial lysosomal aggregates
    MICROSCOPIC

 most consistent with a diagnosis of

    Fabry's disease
    DIAGNOSIS

. The diagnosis was confirmed on the basis of

    molecular genotype analysis
    PARACLINICAL

.

    Inherited
    GENETICS

 causes of

    stroke
    SYMPTOMS

 such as

    Fabry's disease
    DIAGNOSIS

 should be considered in

    young
    AGE

 patients with

    stroke
    SYMPTOMS

 if an

    etiologic diagnosis is not reached after complete investigations
    NEG_FINDINGS

.

    Muscle biopsy
    PARACLINICAL

 can assist with the diagnosis and guide further investigations. This report summarizes the biochemical and histological features of

    Fabry's disease
    DIAGNOSIS

 and the associated

    genetic abnormalities
    GENETICS

.

Fabry's disease
Fabry's disease
Fabry's disease
Fabry's disease

X-linked disorder
hemizygotes
heterozygote
unequal X chromosome inactivation
Inherited
genetic abnormalities

cerebral infarction
neurological deficits
basal ganglia and pontine infarction
stroke
stroke


Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion.

Generalized angiokeratoma are associated with three lysosomal storage disorders, one of which is Fabry disease (alpha-galactosidase A deficiency). Treatment for Fabry disease with supplementation of recombinant enzyme is available in the European Union and subsequently physicians' awareness may rise. A patient who was erroneously diagnosed with Fabry disease is presented.

    Generalized angiokeratoma
    SYMPTOMS

 are associated with three

    lysosomal storage disorders
    DIAGNOSIS

, one of which is

    Fabry disease (alpha-galactosidase A deficiency)
    DIAGNOSIS

. Treatment for

    Fabry disease
    DIAGNOSIS

 with

    supplementation of recombinant enzyme
    MEDICATION

 is available in the European Union and subsequently physicians' awareness may rise. A patient who was

    erroneously diagnosed with Fabry disease
    NEG_FINDINGS

 is presented.


The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy.

Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system--the Mainz Severity Score Index (MSSI)--to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty-nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT-related treatment effects.

    Anderson-Fabry disease (AFD)
    DIAGNOSIS

 is an

    X-linked disorder
    GENETICS

 caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. The availability of

    enzyme replacement therapy (ERT)
    MEDICATION

 for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system--the Mainz Severity Score Index (MSSI)--to measure the severity of

    AFD
    DIAGNOSIS

 and to monitor the clinical course of the disease in response to

    ERT
    MEDICATION

. Thirty-nine patients (24

    males
    GENDER

 and 15

    females
    GENDER

) with

    AFD
    DIAGNOSIS

 were

    assessed using the MSSI
    PARACLINICAL

 immediately before and 1 year after commencing

    agalsidase alfa ERT
    MEDICATION

. Control data were obtained from 23 patients in whom

    AFD was excluded
    NEG_FINDINGS

. The MSSI of patients with

    AFD
    DIAGNOSIS

 was significantly higher than that of patients with other

    severe debilitating diseases
    DIAGNOSIS

. The

    MSSI
    PARACLINICAL

 indicated that, although more

    men
    GENDER

 than

    women
    GENDER

 had

    symptoms classified as severe
    SYMPTOMS

, overall, the median total severity scores were not significantly different between

    male
    GENDER

 and

    female
    GENDER

 patients.

    One year of ERT with agalsidase alfa
    MEDICATION

 led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the

    MSSI score
    PARACLINICAL

 may be a useful, specific measure for objectively assessing the severity of

    AFD
    DIAGNOSIS

 and for monitoring ERT-related treatment effects.

Anderson-Fabry disease (AFD)
AFD
AFD
AFD
severe debilitating diseases
AFD

enzyme replacement therapy (ERT)
ERT
agalsidase alfa ERT
One year of ERT with agalsidase alfa


Acute myeloid leukaemia with t(8;21) associated with "occult" mastocytosis. Report of an unusual case and review of the literature.

Approximately 20% of patients with systemic mastocytosis (SM) have an associated haematological, clonal, non-mast cell lineage disease, and most exhibit an associated myelogenous neoplasm. This report describes a 48 year old man with acute myeloid leukaemia (AML) and a type t(8;21) cytogenetic abnormality. Associated bone marrow mastocytosis (a defined subtype of SM) was only detected after successful polychemotherapy in the state of bone marrow aplasia, and persisted after complete remission of AML. The diagnosis of mastocytosis was based on the demonstration of a multifocal dense mastocytic infiltrate. The atypical mast cells showed prominent spindling and an aberrant immunophenotype, with coexpression of tryptase, chymase, KIT, and CD25-which is expressed only on neoplastic (not normal) mast cells. In addition, the transforming somatic mutation D816V of the c-kit gene was detected. Re-examination of the pretherapeutic (initial) bone marrow revealed a slight diffuse increase in partially spindle shaped mast cells also exhibiting an abnormal immunophenotype, with CD25 expression, although compact mastocytic infiltrates were not detected. Because the D816V mutation was detected in the initial bone marrow specimen, strict application of three minor diagnostic criteria (spindling, CD25, D816V) enabled a diagnosis of SM-AML to be confirmed retrospectively in the initial bone marrow tissue.

Approximately 20% of patients with

    systemic mastocytosis (SM)
    DIAGNOSIS

 have an associated

    haematological, clonal, non-mast cell lineage disease
    DIAGNOSIS

, and most exhibit an associated

    myelogenous neoplasm
    DIAGNOSIS

. This report describes a

    48 year old
    AGE

    man
    GENDER

 with

    acute myeloid leukaemia (AML)
    DIAGNOSIS

 and a

    type t(8;21) cytogenetic abnormality
    GENETICS

.

    Associated bone marrow mastocytosis
    MICROSCOPIC

 (a defined subtype

    of SM
    DIAGNOSIS

) was only detected after

    successful polychemotherapy
    MEDICATION

 in the state of

    bone marrow aplasia
    NEG_FINDINGS

, and persisted after

    complete remission of AML
    MEDICATION

. The diagnosis of

    mastocytosis
    DIAGNOSIS

 was based on the demonstration of a

    multifocal dense mastocytic infiltrate
    MICROSCOPIC

. The

    atypical mast cells
    MICROSCOPIC

 showed

    prominent spindling
    MICROSCOPIC

 and an

    aberrant immunophenotype
    MICROSCOPIC

, with

    coexpression of tryptase, chymase, KIT, and CD25
    BIOCHEMICAL

-which is expressed only on neoplastic (not normal)

    mast cells
    MICROSCOPIC

. In addition, the

    transforming somatic mutation D816V of the c-kit gene
    GENETICS

 was detected.

    Re-examination of the pretherapeutic (initial) bone marrow
    PARACLINICAL

 revealed a

    slight diffuse increase in partially spindle shaped mast cells also exhibiting an abnormal immunophenotype, with CD25 expression
    MICROSCOPIC

, although

    compact mastocytic infiltrates were not detected
    NEG_FINDINGS

. Because the

    D816V mutation
    GENETICS

 was detected in the

    initial bone marrow specimen
    PARACLINICAL

, strict application of three minor diagnostic criteria (spindling, CD25, D816V) enabled a diagnosis of

    SM-AML
    DIAGNOSIS

 to be confirmed retrospectively in the

    initial bone marrow tissue
    PARACLINICAL

.

successful polychemotherapy
complete remission of AML


[Intravenous enzyme substitution therapy in children with Fabry's disease].

Fabry's disease is a X-linked lysosomal storage disorder with accumulation of globotriaosylceramide primarily in vascular endothelial cells, affecting mainly skin, kidney, heart and brain. Symptoms may appear in 7-8-year-old children as burning pain in hands and feet; organ damage usually becomes evident in adult age. Intravenous enzyme replacement therapy has recently become available.

Two brothers, 13.5 and 15 years old, had typical symptoms with acroparesthesia, fever, abdominal pain and diarrhoea. There were high levels of urinary globotriaosylceramide, low levels of alfagalactosidase A in leukocytes, and a single-nucleotide deletion in position 10671 of the alfagalactosidase gene (GLA). Both brothers showed slightly abnormal echocardiography and one had typical changes on cerebral MRI. Enzyme replacement therapy with alfagalactosidase A (Replagal) was started in November 2001. After one year of therapy there was clearly clinical improvement with no fever and diarrhoea and less pain. The urinary excretion of globotriaosylceramide was reduced. No adverse effects were recorded.

During 12 months of intravenous enzyme replacement therapy in two adolescent subjects with Fabry's disease we observed clinical improvement and no adverse effects. We recommend greater awareness of Fabry's disease in paediatrics as well as in adult medicine.

    Fabry's disease
    DIAGNOSIS

 is a

    X-linked
    GENETICS

    lysosomal storage disorder
    DIAGNOSIS

 with

    accumulation of globotriaosylceramide primarily in vascular endothelial cells, affecting mainly skin, kidney, heart and brain
    MICROSCOPIC

. Symptoms may appear in

    7-8-year-old
    AGE

    children
    AGE

 as

    burning pain in hands and feet
    SYMPTOMS

;

    organ damage
    SYMPTOMS

 usually becomes evident in

    adult age
    AGE

.

    Intravenous enzyme replacement therapy
    MEDICATION

 has recently become available.

Two

    brothers
    GENDER

,

    13.5 and 15 years old
    AGE

, had typical symptoms with

    acroparesthesia
    SYMPTOMS

,

    fever
    SYMPTOMS

,

    abdominal pain
    SYMPTOMS

 and

    diarrhoea
    SYMPTOMS

. There were

    high levels of urinary globotriaosylceramide
    BIOCHEMICAL

,

    low levels of alfagalactosidase A in leukocytes
    BIOCHEMICAL

, and a

    single-nucleotide deletion in position 10671 of the alfagalactosidase gene (GLA)
    GENETICS

. Both

    brothers
    GENDER

 showed

    slightly abnormal echocardiography
    SYMPTOMS

 and one had

    typical changes on cerebral MRI
    SYMPTOMS

.

    Enzyme replacement therapy with alfagalactosidase A (Replagal)
    MEDICATION

 was started in November 2001. After

    one year of therapy
    MEDICATION

 there was

    clearly clinical improvement
    SYMPTOMS

 with

    no fever and diarrhoea
    SYMPTOMS

 and

    less pain
    SYMPTOMS

. The

    urinary excretion of globotriaosylceramide was reduced
    BIOCHEMICAL

.

    No adverse effects
    NEG_FINDINGS

 were recorded.

During

    12 months of intravenous enzyme replacement therapy
    MEDICATION

 in two

    adolescent
    AGE

 subjects with

    Fabry's disease
    DIAGNOSIS

 we observed

    clinical improvement
    SYMPTOMS

 and

    no adverse effects
    NEG_FINDINGS

. We recommend greater awareness of

    Fabry's disease
    DIAGNOSIS

 in paediatrics as well as in

    adult
    AGE

 medicine.

Fabry's disease
lysosomal storage disorder
Fabry's disease
Fabry's disease

burning pain in hands and feet
organ damage
acroparesthesia
fever
abdominal pain
diarrhoea
slightly abnormal echocardiography
typical changes on cerebral MRI
clearly clinical improvement
no fever and diarrhoea
less pain
clinical improvement


Fabry disease: renal involvement limited to podocyte pathology and proteinuria in a septuagenarian cardiac variant. Pathologic and therapeutic implications.

In men with classical Fabry disease (alpha-galactosidase A [alpha-Gal A] deficiency), kidney failure occurs as early as the second decade of life. In contrast, men with the mild "cardiac variant" have late-onset cardiac involvement and proteinuria but usually do not have renal failure. To investigate the nature of renal involvement in the cardiac variant of Fabry disease, the renal function and morphology were assessed in a 75-year-old affected man. He had mild congestive heart failure, a reduced left ventricular ejection fraction, and hypercholesterolemia but lacked the classical Fabry disease manifestations, including angiokeratoma, acroparesthesias, corneal and lenticular opacities, and hypohidrosis. At age 75 years, he had significant proteinuria, and mildly decreased renal function (serum creatinine, 1.8 mg/dL [159 micromol/L]), presumably secondary to hypertensive arteriosclerosis. He had about 4% residual alpha-Gal A activity in leukocytes, and mutation analysis identified the N215S missense mutation, the common lesion in cardiac variants. Histologic and ultrastructural studies of kidney tissue showed that lysosomal glycosphingolipid deposition was extensive in podocytes, rare in tubular epithelial cells, and absent in mesangial, interstitial, and vascular endothelial and smooth muscle cells. This cardiac variant serves as an "experiment of nature" showing that the residual alpha-Gal A activity precludes glycosphingolipid deposition in the renal endothelial and other cells that lead to early renal failure in classically affected men, whereas marked podocyte accumulation is associated with proteinuria and possibly late-onset renal dysfunction. These findings have important implications for the renal effectiveness of enzyme replacement therapy in classically affected patients and for the aggressive treatment of proteinuria in Fabry disease.

In

    men
    GENDER

 with

    classical Fabry disease
    DIAGNOSIS

 (

    alpha-galactosidase A [alpha-Gal A] deficiency
    BIOCHEMICAL

    )
    DIAGNOSIS

,

    kidney failure
    SYMPTOMS

 occurs as

    early as the second decade of life
    AGE

. In contrast,

    men
    GENDER

 with the

    mild "cardiac variant
    DIAGNOSIS

" have

    late-onset cardiac involvement
    SYMPTOMS

 and

    proteinuria
    BIOCHEMICAL

 but usually do

    not have renal failure
    NEG_FINDINGS

. To investigate the nature of

    renal involvement
    SYMPTOMS

 in the

    cardiac variant of Fabry disease
    DIAGNOSIS

, the

    renal function and morphology
    PARACLINICAL

 were assessed in a

    75-year-old
    AGE

 affected

    man
    GENDER

.

    He
    GENDER

 had

    mild congestive heart failure
    SYMPTOMS

, a

    reduced left ventricular ejection fraction
    SYMPTOMS

, and

    hypercholesterolemia
    SYMPTOMS

 but

    lacked the classical Fabry disease manifestations
    NEG_FINDINGS

, including

    angiokeratoma
    SYMPTOMS

,

    acroparesthesias
    SYMPTOMS

,

    corneal and lenticular opacities
    SYMPTOMS

, and

    hypohidrosis
    SYMPTOMS

. At

    age 75 years
    AGE

,

    he
    GENDER

 had

    significant proteinuria
    BIOCHEMICAL

, and

    mildly decreased renal function (serum creatinine, 1.8 mg/dL [159 micromol/L])
    BIOCHEMICAL

, presumably secondary to

    hypertensive arteriosclerosis
    DIAGNOSIS

.

    He
    GENDER

 had

    about 4% residual alpha-Gal A activity in leukocytes
    BIOCHEMICAL

, and

    mutation analysis
    PARACLINICAL

 identified the

    N215S missense mutation, the common lesion in cardiac variants
    GENETICS

.

    Histologic and ultrastructural studies of kidney tissue
    PARACLINICAL

 showed that

    lysosomal glycosphingolipid deposition was extensive in podocytes, rare in tubular epithelial cells, and absent in mesangial, interstitial, and vascular endothelial and smooth muscle cells
    MICROSCOPIC

. This

    cardiac variant
    DIAGNOSIS

 serves as an "experiment of nature" showing that the

    residual alpha-Gal A activity precludes glycosphingolipid deposition in the renal endothelial and other cells
    BIOCHEMICAL

 that lead to

    early renal failure
    SYMPTOMS

 in classically affected

    men
    GENDER

, whereas

    marked podocyte accumulation
    MICROSCOPIC

 is associated with

    proteinuria
    BIOCHEMICAL

 and possibly

    late-onset renal dysfunction
    SYMPTOMS

. These findings have important implications for the renal effectiveness of

    enzyme replacement therapy
    MEDICATION

 in classically affected patients and for the

    aggressive treatment
    MEDICATION

 of

    proteinuria
    BIOCHEMICAL

 in

    Fabry disease
    DIAGNOSIS

.

classical Fabry disease
)
mild "cardiac variant
cardiac variant of Fabry disease
hypertensive arteriosclerosis
cardiac variant
Fabry disease

enzyme replacement therapy
aggressive treatment


An unusual cause of dyspnea.

The case of a 71-year-old woman who presented with dyspnea and palpitations is presented. Workup yielded a diagnosis of Fabry's disease, and the patient was referred for therapy. Fabry's disease is a disorder of glycosphingolipid metabolism and has forms that are limited to the myocardium. There is evidence that it has been underrecognized as a cause of cardiac hypertrophy. Because screening can be done with a simple blood test and new treatment options appear promising, we recommend consideration of Fabry's disease in the workup of patients with cardiac hypertrophy.

The case of a

    71-year-old
    AGE

    woman
    GENDER

 who presented with

    dyspnea
    SYMPTOMS

 and

    palpitations
    SYMPTOMS

 is presented. Workup yielded a diagnosis of

    Fabry's disease
    DIAGNOSIS

, and the patient was referred for

    therapy
    MEDICATION

.

    Fabry's disease
    DIAGNOSIS

 is a

    disorder of glycosphingolipid metabolism
    DIAGNOSIS

 and has forms that are

    limited to the myocardium
    SYMPTOMS

. There is evidence that it has been underrecognized as a cause of

    cardiac hypertrophy
    SYMPTOMS

. Because screening can be done with a simple blood test and new treatment options appear promising, we recommend consideration of

    Fabry's disease
    DIAGNOSIS

 in the workup of patients with

    cardiac hypertrophy
    SYMPTOMS

.

dyspnea
palpitations
limited to the myocardium
cardiac hypertrophy
cardiac hypertrophy


[Fabry's disease, glomerulonephritis with crescentic and granulomatous interstitial nephritis. Case of one family].

A 26-year-old female patient was admitted to the hospital because of fever of unknown origin and renal failure. Diagnosis of Fabry's disease, extracapillary proliferative (crescentic) glomerulonephritis and granulomatous interstitial nephritis was made by histological, immunohistochemical and electron microscopical diagnosis in a kidney biopsy and confirmed by further investigations. Years ago the brother of the patient had a kidney biopsy diagnosed as metabolic disease. The re-evaluation of this biopsy confirmed Fabry's disease while in this patient an association with tubulointerstitial nephritis occurred. To our knowledge this is the first family with two members having Fabry's disease combined with further kidney diseases.

A

    26-year-old
    AGE

    female
    GENDER

 patient was admitted to the hospital because of

    fever of unknown origin
    SYMPTOMS

 and

    renal failure
    SYMPTOMS

. Diagnosis of

    Fabry's disease
    DIAGNOSIS

,

    extracapillary proliferative (crescentic) glomerulonephritis
    DIAGNOSIS

 and

    granulomatous interstitial nephritis
    DIAGNOSIS

 was made by

    histological, immunohistochemical and electron microscopical diagnosis in a kidney biopsy
    PARACLINICAL

 and confirmed by further investigations. Years ago the

    brother of the patient had a kidney biopsy diagnosed as metabolic disease
    FAMILY

. The

    re-evaluation of this biopsy
    PARACLINICAL

 confirmed

    Fabry's disease
    DIAGNOSIS

 while in this patient an

    association with tubulointerstitial nephritis
    DIAGNOSIS

 occurred. To our knowledge this is the first

    family with two members having Fabry's disease combined with further kidney diseases
    FAMILY

.


[Loss of visual acuity due to choroidal ischemia in Fabry's disease].

We report a case of a 21-year-old man with Fabry's disease who presented with a sudden decrease in visual acuity to 20/200 in the left eye. Pale areas with a lobular choroidal distribution were seen on fundus examination. No retinal vascular causes were found on further evaluation. With anticoagulation treatment, the patient's subsequent course was good, with visual recovery to 20/25 and normalization of the funduscopic appearance. Recovery of both visual acuity and the pale, lobular areas suggested a choroidal etiology, probably ischemic because of the sudden onset. Choroidian ischemia is therefore a cause of visual acuity loss in Fabry's disease, so far not described in the literature.

We report a case of a

    21-year-old
    AGE

    man
    GENDER

 with

    Fabry's disease
    DIAGNOSIS

 who presented with a

    sudden decrease in visual acuity to 20/200 in the left eye
    SYMPTOMS

.

    Pale areas with a lobular choroidal distribution
    SYMPTOMS

 were seen on

    fundus examination
    PARACLINICAL

.

    No retinal vascular causes were found
    NEG_FINDINGS

 on further evaluation. With

    anticoagulation treatment
    MEDICATION

, the patient's subsequent course was good, with

    visual recovery to 20/25
    SYMPTOMS

 and

    normalization of the funduscopic appearance
    SYMPTOMS

.

    Recovery of both visual acuity and the pale, lobular areas
    SYMPTOMS

 suggested a

    choroidal etiology
    SYMPTOMS

, probably

    ischemic
    SYMPTOMS

 because of the

    sudden onset
    SYMPTOMS

.

    Choroidian ischemia
    SYMPTOMS

 is therefore a cause of

    visual acuity loss
    SYMPTOMS

 in

    Fabry's disease
    DIAGNOSIS

, so far not described in the literature.


Fabry disease in a renal allograft.

Incidental findings of rare diseases in organ donors can be seen in allograft biopsies that may have profound implications for the recipient and for the donor and their family. Fabry disease is an X-linked recessive lipid storage disease with cardiovascular, renal and lenticular abnormalities. Phenotypic expression in female heterozygote carriers depends on lyonization. Minimal data exists on outcomes of transplanted kidneys from carriers of Fabry disease. We report a patient with ESRD secondary to focal sclerosis who received a HLA-identical transplant from her sister whose pretransplant donor work up was completely negative. Post-transplant, while pregnant, the recipient developed increasing proteinuria and was biopsied. The biopsy showed extensive myelin figures consistent with Fabry disease. Subsequent genetic, enzymatic and pedigree analysis confirmed the diagnosis in the recipient, the donor and the donor's son. Two years post-transplant the patient continues to have non-nephrotic range proteinuria with normal serum creatinine.

Incidental findings of

    rare diseases
    DIAGNOSIS

 in

    organ donors
    PARACLINICAL

 can be seen in

    allograft biopsies
    PARACLINICAL

 that may have profound implications for the recipient and for the donor and their family.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked recessive
    GENETICS

    lipid storage disease
    DIAGNOSIS

 with

    cardiovascular, renal and lenticular abnormalities
    SYMPTOMS

. Phenotypic expression in

    female
    GENDER

    heterozygote carriers
    GENETICS

 depends on lyonization. Minimal data exists on outcomes of

    transplanted kidneys
    MEDICATION

 from carriers of

    Fabry disease
    DIAGNOSIS

. We report a patient with

    ESRD
    DIAGNOSIS

 secondary to

    focal sclerosis
    DIAGNOSIS

 who

    received a HLA-identical transplant from her sister
    MEDICATION

 whose

    pretransplant donor work up was completely negative
    NEG_FINDINGS

.

    Post-transplant
    MEDICATION

, while

    pregnant
    MEDICATION

, the recipient developed

    increasing proteinuria
    BIOCHEMICAL

 and was

    biopsied
    PARACLINICAL

. The

    biopsy
    PARACLINICAL

 showed

    extensive myelin figures consistent with Fabry disease
    MICROSCOPIC

. Subsequent

    genetic, enzymatic and pedigree analysis
    PARACLINICAL

 confirmed the diagnosis in the recipient, the donor and the donor's son. Two years post

    -transplant
    MEDICATION

 the patient continues to have

    non-nephrotic range proteinuria
    BIOCHEMICAL

 with

    normal serum creatinine
    NEG_FINDINGS

.

rare diseases
Fabry disease
lipid storage disease
Fabry disease
ESRD
focal sclerosis

X-linked recessive
heterozygote carriers

increasing proteinuria
non-nephrotic range proteinuria


[HbH disease--a rare differential diagnosis in a patient with anemia and abdominal pain].

A 45-year-old Vietnamese male was admitted to hospital with severe hypochromic anemia and acute abdominal pain. The peripheral blood smear showed extreme anisocytosis and poikilocytosis as well as teardrops and target cells. Hemoglobin electrophoresis and brilliant cresyl blue staining revealed hemoglobin H (HbH) disease with an infection-associated hemolytic crisis.

In the diagnostic workup of hemolytic and hypochromic anemia, HbH disease as a special type of alpha-thalassemia should be considered early. In patients from Eastern Asia with a mean corpuscular hemoglobin (MCH) < 25 pg, hemoglobin analysis should be performed in order to avoid unnecessary diagnostic procedures. The prognosis of HbH disease is generally favorable, and symptomatic treatment is only recommended during hemolytic crises in association with, e.g., infections or pregnancy.

A

    45-year-old
    AGE

    Vietnamese
    ETHNICITY

    male
    GENDER

 was admitted to hospital with

    severe hypochromic anemia
    BIOCHEMICAL

 and

    acute abdominal pain
    SYMPTOMS

. The

    peripheral blood smear
    PARACLINICAL

 showed

    extreme anisocytosis and poikilocytosis as well as teardrops and target cells
    BIOCHEMICAL

.

    Hemoglobin electrophoresis
    PARACLINICAL

 and

    brilliant cresyl blue staining
    PARACLINICAL

 revealed

    hemoglobin H (HbH) disease with an infection-associated hemolytic crisis
    DIAGNOSIS

.

In the diagnostic workup of

    hemolytic and hypochromic anemia
    BIOCHEMICAL

,

    HbH disease
    DIAGNOSIS

 as a

    special type of alpha-thalassemia
    DIAGNOSIS

 should be considered early. In patients from

    Eastern Asia
    ETHNICITY

 with a

    mean corpuscular hemoglobin (MCH) < 25 pg
    BIOCHEMICAL

,

    hemoglobin analysis
    PARACLINICAL

 should be performed in order to avoid unnecessary diagnostic procedures. The prognosis of

    HbH disease
    DIAGNOSIS

 is generally favorable, and

    symptomatic treatment
    MEDICATION

 is only recommended during

    hemolytic crises
    SYMPTOMS

 in association with, e.g.,

    infections
    SYMPTOMS

 or

    pregnancy
    SYMPTOMS

.

acute abdominal pain
hemolytic crises
infections
pregnancy


Fabry disease: novel alpha-galactosidase A 3'-terminal mutations result in multiple transcripts due to aberrant 3'-end formation.

Mutations in the gene that encodes the lysosomal exoglycohydrolase, alpha-galactosidase A (alpha-GalA), cause Fabry disease, an X-linked recessive inborn error of glycosphingolipid catabolism. Human alpha-GalA is one of the rare mammalian genes that has its polyadenylation signal in the coding sequence and lacks a 3' untranslated region (UTR). We identified two novel frameshift mutations, 1277delAA (del2) and 1284delACTT (del4), in unrelated men with classical Fabry disease. Both mutations occurred in the 3' terminus of the coding region and obliterated the termination codon, and del2 also altered the polyadenylation signal. To characterize these mutations, 3' rapid amplification of cDNA ends (RACE) and polymerase chain reactions (PCR) were performed, and the amplicons were subcloned and sequenced. Both mutations generated multiple transcripts with various lengths of 3' terminal sequences, some elongating approximately 1 kb. Mutant transcripts were classified as follows: type I transcripts had terminal in-frame thymidines that created termination codons when polyadenylated, type II had downstream termination codons within the elongated alpha-GalA sequence, and type III, the most abundant, lacked termination codons at their 3' ends. To determine if the type III transcripts were degraded by the recently described cytosolic messenger RNA degradation pathway for messages lacking termination codons, northern blot analysis was performed. However, the finding of similar levels of nuclear and cytoplasmic alpha-GalA mRNA in normal and patient lymphoblasts suggested that mRNA degradation did not result from either mutation. Expression of representative transcript types revealed differences in intracellular localization and/or protein stability and catalytic activity, with most mutant proteins being nonfunctional. Characterization of these 3' mutations identified a novel molecular mechanism causing classical Fabry disease.

    Mutations in the gene that encodes the lysosomal exoglycohydrolase, alpha-galactosidase A (alpha-GalA)
    GENETICS

, cause

    Fabry disease
    DIAGNOSIS

, an

    X-linked recessive
    GENETICS

    inborn error of glycosphingolipid catabolism
    DIAGNOSIS

.

    Human alpha-GalA
    GENETICS

 is one of the

    rare mammalian genes
    GENETICS

 that has

    its polyadenylation signal in the coding sequence and lacks a 3' untranslated region (UTR)
    GENETICS

. We identified two

    novel frameshift mutations, 1277delAA (del2) and 1284delACTT (del4)
    GENETICS

, in unrelated

    men
    GENDER

 with

    classical Fabry disease
    DIAGNOSIS

.

    Both mutations occurred in the 3' terminus of the coding region and obliterated the termination codon
    GENETICS

, and

    del2 also altered the polyadenylation signal
    GENETICS

. To characterize these mutations,

    3' rapid amplification of cDNA ends (RACE) and polymerase chain reactions (PCR)
    PARACLINICAL

 were performed, and the amplicons were

    subcloned and sequenced
    PARACLINICAL

. Both mutations generated

    multiple transcripts with various lengths of 3' terminal sequences
    MICROSCOPIC

, some elongating approximately 1 kb. Mutant transcripts were classified as follows:

    type I transcripts
    MICROSCOPIC

 had

    terminal in-frame thymidines that created termination codons when polyadenylated
    GENETICS

,

    type II
    MICROSCOPIC

 had

    downstream termination codons within the elongated alpha-GalA sequence
    GENETICS

, and

    type III
    MICROSCOPIC

, the most abundant,

    lacked termination codons at their 3' ends
    GENETICS

. To determine if the

    type III transcripts
    MICROSCOPIC

 were degraded by the recently described

    cytosolic messenger RNA degradation pathway
    BIOCHEMICAL

 for messages

    lacking termination codons
    GENETICS

,

    northern blot analysis
    PARACLINICAL

 was performed. However, the finding of similar

    levels of nuclear and cytoplasmic alpha-GalA mRNA
    BIOCHEMICAL

 in normal and patient

    lymphoblasts
    MICROSCOPIC

 suggested that

    mRNA degradation
    GENETICS

 did not result from either mutation. Expression of representative transcript types revealed differences in intracellular localization and/or protein stability and catalytic activity, with most mutant proteins being nonfunctional. Characterization of these

    3' mutations
    GENETICS

 identified a novel molecular mechanism causing

    classical Fabry disease
    DIAGNOSIS

.


Anderson-Fabry disease in Austria.

Fabry disease is an X-linked inherited inborn error of glycosphingolipid catabolism. The deficiency of alpha-galactosidase A leads to the deposition of glycosphingolipids primarily in lysosomes of blood vessel cells. In classically affected hemizygotes clinical manifestations include pain in the extremities, vessel ectasia (angiokeratoma) in skin and mucous membranes, ophthalmological abnormalities, and hypohidrosis. As disease progresses there is renal, cardiac, cerebral and vascular involvement, with most patients experiencing renal insufficiency, cardiac hypertrophy or stroke. Many female carriers of Fabry disease also have symptoms. Recently available enzyme replacement therapy has the potential to control or even reverse disease progression. The present analysis reports on five Austrian families with Fabry disease, cared for by nephrologists in June 2002. Furthermore we discuss potential indications for enzyme replacement therapy in patients maintained on renal replacement therapy.

    Fabry disease
    DIAGNOSIS

 is an

    X-linked inherited inborn error of glycosphingolipid catabolism
    GENETICS

. The

    deficiency of alpha-galactosidase A
    BIOCHEMICAL

 leads to the

    deposition of glycosphingolipids primarily in lysosomes of blood vessel cells
    MICROSCOPIC

. In classically affected

    hemizygotes
    GENETICS

 clinical manifestations include

    pain in the extremities
    SYMPTOMS

,

    vessel ectasia (angiokeratoma) in skin and mucous membranes
    SYMPTOMS

,

    ophthalmological abnormalities
    SYMPTOMS

, and

    hypohidrosis
    SYMPTOMS

. As disease progresses there is

    renal, cardiac, cerebral and vascular involvement
    SYMPTOMS

, with most patients experiencing

    renal insufficiency
    SYMPTOMS

,

    cardiac hypertrophy
    SYMPTOMS

 or

    stroke
    SYMPTOMS

. Many

    female
    GENDER

 carriers of

    Fabry disease
    DIAGNOSIS

 also have

    symptoms
    SYMPTOMS

. Recently available

    enzyme replacement therapy
    MEDICATION

 has the potential to control or even reverse disease progression. The present analysis reports on five

    Austrian
    ETHNICITY

 families with

    Fabry disease
    DIAGNOSIS

, cared for by

    nephrologists
    PARACLINICAL

 in June 2002. Furthermore we discuss potential indications for

    enzyme replacement therapy
    MEDICATION

 in patients

    maintained on renal replacement therapy
    MEDICATION

.

Fabry disease
Fabry disease
Fabry disease

enzyme replacement therapy
enzyme replacement therapy
maintained on renal replacement therapy


Renal involvement in Anderson-Fabry disease.

Anderson-Fabry disease (AFd) is a rare X-linked lisosomal storage disorder of glycosphingolipid (GL) metabolism, caused by a deficiency of the activity of alpha-galactosidase A (alpha-gal A). The progressive accumulation of GL in tissues results in the clinical manifestations of the disease, that are more evident in hemizygous males, and include characteristic skin lesions (angiokeratomas), neurological symptoms (acroparesthesia), ocular features (cornea verticillata), cardiac involvement (left ventricular enlargement, conduction abnormalities), cerebrovascular manifestations (thromboses, hemorrhage, etc.), and kidney involvement with progression to end-stage renal failure (ESRF). ESRF is a common manifestation in hemizygous males (3rd-5th decade) and death occurs around the 5th decade of life because of severe cardiac and/or cerebrovascular complications. Heterozygous females have an attenuated form of this systemic disease. In the kidney, accumulation of GL occurs in the endothelial cells of every vessel, in the epithelial cells of every tubular segment, and in all kinds of glomerular cells. The broad spectrum of renal lesions is a pathophysiological continuum with progressive impairment in the renal function related to continuous intracellular deposition of GL. Electron microscopic study of renal biopsies shows typical osmiophilic inclusion bodies in the cytoplasm of all kind of renal cells, characterized by concentric lamellation of clear and dark layers (35-50 A of periodicity). ESRF is treated by dialysis and kidney transplantation: neither treatment modifies the progression of the cardiovascular and cerebrovascular lesions due to progressive GL deposition. The outcome of kidney transplantation seems to be similar to that found in other non-diabetic patients, but the survival rate on dialysis is lower than in patients with other causes of ESRF. Nowadays, treatment with enzyme replacement infusion with purified alpha-Gal A, produced by a genetically engineered human cell line or Chinese hamster ovocytes, seems to be effective and safe.

    Anderson-Fabry disease (AFd)
    DIAGNOSIS

 is a

    rare X-linked
    GENETICS

    lisosomal storage disorder of glycosphingolipid (GL) metabolism
    DIAGNOSIS

, caused by a

    deficiency of the activity of alpha-galactosidase A (alpha-gal A)
    BIOCHEMICAL

. The

    progressive accumulation of GL in tissues
    MICROSCOPIC

 results in the clinical manifestations of the disease, that are more evident in

    hemizygous males
    GENETICS

, and include

    characteristic skin lesions (angiokeratomas)
    SYMPTOMS

,

    neurological symptoms
    SYMPTOMS

 (

    acroparesthesia)
    SYMPTOMS

,

    ocular features (cornea verticillata)
    SYMPTOMS

,

    cardiac involvement
    SYMPTOMS

 (

    left ventricular enlargement
    SYMPTOMS

,

    conduction abnormalities)
    SYMPTOMS

,

    cerebrovascular manifestations (thromboses, hemorrhage, etc.)
    SYMPTOMS

, and

    kidney involvement
    SYMPTOMS

 with

    progression to end-stage renal failure (ESRF)
    SYMPTOMS

.

    ESRF
    DIAGNOSIS

 is a common manifestation in

    hemizygous males
    GENETICS

 (

    3rd-5th decade)
    AGE

 and

    death
    SYMPTOMS

 occurs

    around the 5th decade of life
    AGE

 because of

    severe cardiac and/or cerebrovascular complications
    SYMPTOMS

.

    Heterozygous
    GENETICS

    females
    GENDER

 have an attenuated form of this

    systemic disease
    DIAGNOSIS

.

    In the kidney
    MICROSCOPIC

,

    accumulation of GL occurs in the endothelial cells of every vessel, in the epithelial cells of every tubular segment, and in all kinds of glomerular cells
    MICROSCOPIC

. The broad spectrum of

    renal lesions
    SYMPTOMS

 is a pathophysiological continuum with

    progressive impairment in the renal function
    SYMPTOMS

 related to

    continuous intracellular deposition of GL
    MICROSCOPIC

.

    Electron microscopic study of renal biopsies
    PARACLINICAL

 shows

    typical osmiophilic inclusion bodies in the cytoplasm of all kind of renal cells, characterized by concentric lamellation of clear and dark layers (35-50 A of periodicity)
    MICROSCOPIC

.

    ESRF
    DIAGNOSIS

 is treated by

    dialysis
    MEDICATION

 and

    kidney transplantation
    MEDICATION

:

    neither treatment modifies the progression of the cardiovascular and cerebrovascular lesions
    NEG_FINDINGS

 due to

    progressive GL deposition
    MICROSCOPIC

. The outcome of

    kidney transplantation
    MEDICATION

 seems to be similar to that found in other non-

    diabetic
    DIAGNOSIS

 patients, but the survival rate on

    dialysis
    MEDICATION

 is lower than in patients with other causes of

    ESRF
    DIAGNOSIS

. Nowadays,

    treatment with enzyme replacement infusion with purified alpha-Gal A,
    MEDICATION

 produced by a genetically engineered

    human cell line or Chinese hamster ovocytes
    MICROSCOPIC

, seems to be effective and safe.

rare X-linked
hemizygous males
hemizygous males
Heterozygous


A novel 6 bp insertion in exon 7 associated with an unusual phenotype in a family with Fabry disease.

A male patient presented with oligosymptomatic Fabry disease (end stage renal failure and non-obstructive cardiomyopathy) at around 30 years of age. His leukocyte alpha-galactosidase activity (alpha-gal) was 2.6% of controls. A 50-year-old sister had similar cardiac symptoms and her asymptomatic heterozygous daughter (33 years) had normal enzyme activity. All three patients carried a novel, 6bp insertion on exon 7 of the AGAL gene. The majority of male Fabry patients carrying mutations in exon 7 have residual alpha-gal below 1% and suffer from neuropathic pain. Comparable oligosymptomatic phenotypes in Caucasian patients carry a common mutation on exon 6 (R301Q) and have a significantly later onset. The course of the disease is likely to be altered by recombinant enzyme therapy in the future. Therefore, a thorough documentation of phenotypes, residual activities and underlying genotypes is of current interest.

A

    male
    GENDER

 patient presented with

    oligosymptomatic Fabry disease
    DIAGNOSIS

 (

    end stage renal failure
    SYMPTOMS

 and

    non-obstructive cardiomyopathy
    SYMPTOMS

) at

    around 30 years of age
    AGE

.

    His
    GENDER

    leukocyte alpha-galactosidase activity (alpha-gal) was 2.6% of controls
    BIOCHEMICAL

. A

    50-year-old
    AGE

    sister had similar cardiac symptoms
    FAMILY

 and

    her
    GENDER

    asymptomatic heterozygous daughter (33 years) had normal enzyme activity
    FAMILY

. All three patients carried a

    novel, 6bp insertion on exon 7 of the AGAL gene
    GENETICS

. The majority of

    male
    GENDER

    Fabry
    DIAGNOSIS

 patients carrying

    mutations in exon 7
    GENETICS

 have

    residual alpha-gal below 1%
    BIOCHEMICAL

 and suffer from

    neuropathic pain
    SYMPTOMS

. Comparable

    oligosymptomatic phenotypes
    SYMPTOMS

 in

    Caucasian
    ETHNICITY

 patients carry a

    common mutation on exon 6 (R301Q)
    GENETICS

 and have a significantly later onset. The course of the disease is likely to be altered by

    recombinant enzyme therapy
    MEDICATION

 in the future. Therefore, a thorough documentation of phenotypes, residual activities and underlying genotypes is of current interest.

end stage renal failure
non-obstructive cardiomyopathy
neuropathic pain
oligosymptomatic phenotypes


[Atypical symptoms of Fabry's disease: sudden bilateral deafness, lymphoedema and Lown-Ganong-Levine syndrome].

A 40-year-old man with Fabry disease, confirmed by decreased leukocyte alpha-galactosidase A activity in 2001, complained of sudden bilateral deafness, as evidenced by clinical history and audiometry. Magnetic resonance of the brain revealed features typical of Fabry disease. Other clinical manifestations of the disease included: angiokeratoma, mild proteinuria with normal renal function, lymphoedema of the lower limbs, pre-excitation syndrome, myocardial hypertrophy.

A

    40-year-old
    AGE

    man
    GENDER

 with

    Fabry disease
    DIAGNOSIS

, confirmed by

    decreased leukocyte alpha-galactosidase A activity
    BIOCHEMICAL

 in 2001, complained of

    sudden bilateral deafness
    SYMPTOMS

, as evidenced by

    clinical history
    PARACLINICAL

 and

    audiometry
    PARACLINICAL

.

    Magnetic resonance of the brain
    PARACLINICAL

 revealed features typical of

    Fabry disease
    DIAGNOSIS

. Other clinical manifestations of the disease included:

    angiokeratoma
    SYMPTOMS

,

    mild proteinuria
    BIOCHEMICAL

 with

    normal renal function
    NEG_FINDINGS

,

    lymphoedema of the lower limbs
    SYMPTOMS

,

    pre-excitation syndrome
    SYMPTOMS

,

    myocardial hypertrophy
    SYMPTOMS

.

sudden bilateral deafness
angiokeratoma
lymphoedema of the lower limbs
pre-excitation syndrome
myocardial hypertrophy


Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.

A 46-year-old female patient with Sjögren's syndrome, hypertension, and stable chronic renal insufficiency (creatinine [CR], 1.9 to 2.1 mg/dL) had a progressive worsening of renal function (CR, 5.0 mg/dL) after 11 months of chloroquine therapy (155 mg/day; cumulative dose of approximately 51 g). Light microscopy revealed nonspecific angionephrosclerosis. Electron microscopy showed accumulations of lamellated myelinoid material and occasionally also of curvilinear bodies, especially in the glomerular podocytes and to a lesser extent in vascular myothelial and endothelial cells. In the tubular system, mainly protein droplets were stored. Activity of alpha-galactosidase A was normal in isolated leukocytes (56 nmol/mg; range, 33.2 to 109 nmol/mg), ruling out Fabry's disease. Clinical, morphological, and biochemical findings were consistent with chloroquine-associated deterioration of renal function that improved considerably after discontinuation of chloroquine treatment. Adverse effects of chloroquine may aggravate preexisting renal disease. Electron microscopy is a worthwhile tool for establishing the correct diagnosis.

A

    46-year-old
    AGE

    female
    GENDER

 patient with

    Sjögren's syndrome
    DIAGNOSIS

,

    hypertension
    SYMPTOMS

, and

    stable chronic renal insufficiency (creatinine [CR], 1.9 to 2.1 mg/dL)
    BIOCHEMICAL

 had a

    progressive worsening of renal function (CR, 5.0 mg/dL)
    SYMPTOMS

 after

    11 months of chloroquine therapy (155 mg/day; cumulative dose of approximately 51 g)
    MEDICATION

.

    Light microscopy
    PARACLINICAL

 revealed

    nonspecific angionephrosclerosis
    MICROSCOPIC

.

    Electron microscopy
    PARACLINICAL

 showed

    accumulations of lamellated myelinoid material and occasionally also of curvilinear bodies, especially in the glomerular podocytes and to a lesser extent in vascular myothelial and endothelial cells
    MICROSCOPIC

.

    In the tubular system, mainly protein droplets were stored
    MICROSCOPIC

.

    Activity of alpha-galactosidase A was normal in isolated leukocytes (56 nmol/mg; range, 33.2 to 109 nmol/mg)
    NEG_FINDINGS

,

    ruling out Fabry's disease
    NEG_FINDINGS

. Clinical, morphological, and biochemical findings were consistent with

    chloroquine-associated deterioration of renal function
    DIAGNOSIS

 that improved considerably after

    discontinuation of chloroquine treatment
    MEDICATION

.

    Adverse effects of chloroquine
    SYMPTOMS

 may aggravate

    preexisting renal disease
    DIAGNOSIS

.

    Electron microscopy
    PARACLINICAL

 is a worthwhile tool for establishing the correct diagnosis.