Bilateral multifocal retinal arteriolar sheathing as the only ocular finding in hereditary amyloidosis.

To report the early ocular findings in hereditary amyloidosis.

Case report of a visually asymptomatic, 52-year-old Mexican man with systemic manifestations of amyloidosis (peripheral neuropathy, restrictive cardiomyopathy), with a positive family history, and with amyloid on an endomyocardial biopsy specimen, who had bilateral multifocal sheathing or cuffing of the peripheral retinal arterioles.

An extensive evaluation for retinal vasculitis was discontinued when hereditary amyloidosis was diagnosed.

Focal retinal periarteriolar plaques of amyloid may be the earliest and only ocular finding of hereditary amyloidosis.

To report the

    early ocular findings
    SYMPTOMS

 in

    hereditary amyloidosis
    DIAGNOSIS

.

Case report of a

    visually asymptomatic
    SYMPTOMS

,

    52-year-old
    AGE

    Mexican
    ETHNICITY

    man
    GENDER

 with

    systemic manifestations of amyloidosis
    SYMPTOMS

 (

    peripheral neuropathy
    SYMPTOMS

,

    restrictive cardiomyopathy)
    SYMPTOMS

,

    with a positive family history
    FAMILY

, and with

    amyloid
    SYMPTOMS

    on an endomyocardial biopsy specimen
    PARACLINICAL

, who had

    bilateral multifocal sheathing or cuffing of the peripheral retinal arterioles
    SYMPTOMS

.

An

    extensive evaluation for retinal vasculitis
    NEG_FINDINGS

 was

    discontinued
    NEG_FINDINGS

 when

    hereditary amyloidosis
    DIAGNOSIS

 was diagnosed.

    Focal retinal periarteriolar plaques of amyloid
    SYMPTOMS

 may be the earliest and only ocular finding of

    hereditary amyloidosis
    DIAGNOSIS

.

hereditary amyloidosis
hereditary amyloidosis
hereditary amyloidosis


Three siblings of familial amyloid cardiomyopathy with isoleucine-50 transthyretin mutation.

We herein describe three siblings with familial amyloid cardiomyopathy in a Japanese family, who demonstrated an Ile-50 mutation in the transthyretin gene. In their clinical course, the symptoms started at from 50 to 55 years of age, and two cases died within 5 years. However, one case is still alive seven years after onset probably due to either the implantation of a pacemaker for a complete atrio-ventricular block or the administration of dimethylsulphoxide. Based on our findings, some differences were observed not only in the mutation of the transthyretin gene but also in the clinical course between our cases and the previously reported cases.

We herein describe three

    siblings with familial amyloid cardiomyopathy
    FAMILY

 in a

    Japanese
    ETHNICITY

    family
    FAMILY

, who demonstrated an

    Ile-50 mutation in the transthyretin gene
    GENETICS

. In their clinical course, the symptoms started at

    from 50 to 55 years of age
    AGE

, and two cases

    died
    SYMPTOMS

    within 5 years
    AGE

. However, one case is still alive seven years after onset probably due to either the

    implantation of a pacemaker for a complete atrio-ventricular block
    MEDICATION

 or the administration of

    dimethylsulphoxide
    MEDICATION

. Based on our findings, some differences were observed not only in the

    mutation of the transthyretin gene
    GENETICS

 but also in the clinical course between our cases and the previously reported cases.


[Liver transplantation in familial amyloid polyneuropathy. Case report and review of the literature].

A 59-year old male of German origin noticed exercise-independent cardiac arrhythmia two years before admission. An alanine 47 transthyretin variant of Familial Amyloid Polyneuropathy with hypertrophic cardiomyopathy, peripheral sensory-motor polyneuropathy, I, degree AV heart block was diagnosed. To diminish production and deposition of mutant transthyretin and to prevent disease progression orthotopic liver transplantation was performed. Prior to transplant the patient complained of inappetence. Postoperatively, he received a chemically defined enteral nutrition regime that was discontinued after 30 months until return of appetite and weight gain indicated marked improvement. However, a duodenal biopsy still demonstrated amyloid deposits 24 months after transplantation. Echocardiographic findings remained unchanged. Neurologic examination showed an improvement of sensory-motor polyneuropathy with regression of electromyographic changes. Only traces of variant transthyretin were detectable in plasma samples taken 12 months after the operation. During the 3 year follow-up, no additional symptoms have occurred and progression of amyloidosis was prevented. Currently, orthotopic liver transplantation is the only specific treatment to prevent progression of familial amyloid polyneuropathy.

A

    59-year old
    AGE

    male
    GENDER

 of

    German
    ETHNICITY

 origin noticed

    exercise-independent cardiac arrhythmia
    SYMPTOMS

 two years before admission. An

    alanine 47 transthyretin variant of Familial Amyloid Polyneuropathy
    DIAGNOSIS

 with

    hypertrophic cardiomyopathy
    DIAGNOSIS

,

    peripheral sensory-motor polyneuropathy, I, degree AV heart block
    SYMPTOMS

 was diagnosed. To

    diminish production and deposition of mutant transthyretin
    BIOCHEMICAL

 and to prevent disease progression

    orthotopic liver transplantation
    MEDICATION

 was performed. Prior to

    transplant
    MEDICATION

 the patient complained of

    inappetence
    SYMPTOMS

.

    Postoperatively
    MEDICATION

,

    he
    GENDER

 received a

    chemically defined enteral nutrition regime that was discontinued after 30 months
    MEDICATION

 until

    return of appetite
    SYMPTOMS

 and

    weight gain
    SYMPTOMS

 indicated

    marked improvement
    SYMPTOMS

. However, a

    duodenal biopsy
    PARACLINICAL

 still demonstrated

    amyloid deposits
    MICROSCOPIC

 24 months after

    transplantation
    MEDICATION

.

    Echocardiographic findings remained unchanged
    NEG_FINDINGS

.

    Neurologic examination
    PARACLINICAL

 showed an

    improvement of sensory-motor polyneuropathy
    SYMPTOMS

 with

    regression of electromyographic changes
    SYMPTOMS

.

    Only traces of variant transthyretin were detectable in plasma samples
    BIOCHEMICAL

 taken 12 months after the operation. During the 3 year follow-up,

    no additional symptoms
    NEG_FINDINGS

 have occurred and

    progression of amyloidosis
    DIAGNOSIS

 was prevented. Currently,

    orthotopic liver transplantation
    MEDICATION

 is the only specific treatment to prevent progression of

    familial amyloid polyneuropathy
    DIAGNOSIS

.


Scan findings of various myocardial SPECT agents in a case of amyloid polyneuropathy with suspected myocardial involvement.

A 31-year-old male having familial amyloid polyneuropathy underwent a Tc-99m(V)-DMSA study to evaluate the myocardial involvement. The patient also underwent T1-201, I-123-BMIPP and I-123-MIBG myocardial SPECT studies to evaluate blood perfusion, fatty acid metabolism and sympathetic function of the heart, respectively. Tc-99m(V)-DMSA SPECT showed uptake to the myocardium indicating myocardial involvement of amyloidosis. Both T1-201 and I-123-BMIPP studies showed normal uptake indicating normal blood perfusion and fatty acid metabolism but I-123-MIBG SPECT showed no uptake to the heart, indicating severe impairment of sympathetic function.

A

    31-year-old
    AGE

    male
    GENDER

 having

    familial amyloid polyneuropathy
    DIAGNOSIS

 underwent a

    Tc-99m(V)-DMSA study
    PARACLINICAL

 to evaluate the

    myocardial involvement
    SYMPTOMS

. The patient also underwent

    T1-201, I-123-BMIPP and I-123-MIBG myocardial SPECT studies
    PARACLINICAL

 to evaluate

    blood perfusion, fatty acid metabolism
    PARACLINICAL

 and sympathetic function of the

    heart
    SYMPTOMS

, respectively.

    Tc-99m(V)-DMSA SPECT
    PARACLINICAL

 showed

    uptake to the myocardium
    SYMPTOMS

 indicating

    myocardial involvement of amyloidosis
    SYMPTOMS

. Both

    T1-201 and I-123-BMIPP studies
    NEG_FINDINGS

 showed

    normal uptake
    NEG_FINDINGS

 indicating

    normal blood perfusion and fatty acid metabolism
    NEG_FINDINGS

 but

    I-123-MIBG SPECT
    PARACLINICAL

 showed

    no uptake to the heart
    NEG_FINDINGS

, indicating

    severe impairment of sympathetic function
    SYMPTOMS

.


A new isoleucine substitution of Val-20 in transthyretin tetramers selectively impairs dimer-dimer contacts and causes systemic amyloidosis.

The most frequent form of inherited amyloidoses is associated with mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex. Amyloid fibrils containing the variant and to a lesser extent the wild-type form of the TTR molecule are deposited in various organs, including peripheral nerves and the myocardium, with polyneuropathy and cardiomyopathy as major clinical manifestations. So far, more than 40 distinct amino acid substitutions distributed throughout the TTR sequence over 30 positions have been found to be correlated with an increased amyloidogenicity of TTR. Most of these amyloidogenic amino acid substitutions are suspected to alter the conformation and stability of the monomer. Here we identify and characterize by protein and DNA analysis a novel amyloidogenic Val-20 to Ile mutation in a German three-generation family. The index patient suffered from severe amyloid cardiomyopathy at the age of 60. Conformational stability and unfolding behavior of the Ile-20 monomer in urea gradients was found to be almost indistinguishable from that of wild-type TTR. In contrast, tetramer stability was significantly reduced in agreement with the expected change in the interactions between the two opposing dimers via the side chain of Ile-20. Our observations provide strong evidence for the view that amyloidogenic amino acid substitutions in TTR facilitate the conversion of tetrameric TTR complexes into those conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential.

The most frequent form of

    inherited amyloidoses
    GENETICS

 is associated with

    mutations in the transthyretin (TTR) gene coding for 127-amino acid residues of four
    GENETICS

 identical, noncovalently linked subunits that form a pair of dimers in the plasma protein complex.

    Amyloid fibrils containing the variant and
    MICROSCOPIC

 to a lesser extent

    the wild-type form of the TTR molecule are deposited in various organs, including peripheral nerves and the myocardium
    MICROSCOPIC

, with

    polyneuropathy
    DIAGNOSIS

 and

    cardiomyopathy
    SYMPTOMS

 as major clinical manifestations. So far, more than 40 distinct

    amino acid substitutions distributed throughout the TTR sequence
    GENETICS

 over 30 positions have been found to be correlated with an

    increased amyloidogenicity of TTR
    MICROSCOPIC

. Most of these

    amyloidogenic amino acid substitutions
    GENETICS

 are suspected to alter the conformation and stability of the monomer. Here we identify and characterize by

    protein and DNA analysis
    PARACLINICAL

 a

    novel amyloidogenic Val-20 to Ile mutation
    GENETICS

 in a

    German
    ETHNICITY

    three-generation family
    FAMILY

. The index patient suffered from

    severe amyloid cardiomyopathy
    DIAGNOSIS

 at the

    age of 60
    AGE

. Conformational stability and

    unfolding behavior of the Ile-20 monomer in urea gradients
    BIOCHEMICAL

 was found to be almost indistinguishable from that of wild-type TTR. In contrast,

    tetramer stability was significantly reduced
    BIOCHEMICAL

 in agreement with the expected

    change in the interactions between the two opposing dimers via the side chain of Ile-20
    GENETICS

. Our observations provide strong evidence for the view that

    amyloidogenic amino acid substitutions in TTR
    GENETICS

 facilitate the

    conversion of tetrameric TTR complexes
    MICROSCOPIC

 into those conformational intermediates of the TTR folding pathway that have an intrinsic amyloidogenic potential.

polyneuropathy
severe amyloid cardiomyopathy


Technetium-99m (Tc-99m) diphosphono-propanedicarboxylic acid bone tracer uptake and Tc-99m sestamibi distribution in cardiac amyloidosis--a case report.

It has long been recognised that significant bone tracer localisation in the myocardium is a good indicator for amyloid involvement of the heart in the clinical context of systemic amyloidosis. In this case report, although myocardial tissue diagnosis of amyloidosis was not made, the massive myocardial uptake of bone tracer strongly suggested the presence of amyloid infiltration in the heart, and this finding eventually led to the histological diagnosis of familial amyloid polyneuropathy by skin and sural nerve biopsy. Interesting findings were noted in the single photon emission computerised tomography (SPECT) studies of the myocardium with Technetium-99m diphosphono-propanedicarboxylic acid bone agent and Technetium-99m sestamibi myocardial perfusion agent. Such findings suggest that there is a lack of correlation between the intensity of myocardial uptake of bone tracer and viability of the myocardium, and that amyloid will not deposit in infarcted myocardial tissue.

It has long been recognised that

    significant bone tracer localisation in the myocardium
    MICROSCOPIC

 is a good indicator for

    amyloid involvement of the heart
    SYMPTOMS

 in the clinical context of

    systemic amyloidosis
    DIAGNOSIS

. In this case report, although

    myocardial tissue diagnosis of amyloidosis was not made
    NEG_FINDINGS

, the

    massive myocardial uptake of bone tracer
    MICROSCOPIC

 strongly suggested the presence of

    amyloid infiltration in the heart
    MICROSCOPIC

, and this finding eventually led to the histological diagnosis of

    familial amyloid polyneuropathy
    DIAGNOSIS

 by

    skin and sural nerve biopsy
    PARACLINICAL

. Interesting findings were noted in the

    single photon emission computerised tomography (SPECT) studies of the myocardium with Technetium-99m diphosphono-propanedicarboxylic acid bone agent and Technetium-99m sestamibi myocardial perfusion agent
    PARACLINICAL

. Such findings suggest that there is a

    lack of correlation between the intensity of myocardial uptake of bone tracer and viability of the myocardium
    NEG_FINDINGS

, and that amyloid will

    not deposit in infarcted myocardial tissue
    NEG_FINDINGS

.

systemic amyloidosis
familial amyloid polyneuropathy


A new transthyretin variant (Ser 24) associated with familial amyloid polyneuropathy.

An American kindred with systemic amyloidosis presenting with carpal tunnel syndrome, peripheral neuropathy, and cardiomyopathy is reported. The transthyretin gene of a patient was analysed by direct DNA sequencing and both cytosine and thymine were present at the first base of codon 24. This new point mutation in exon 2 results in the amino acid substitution of serine for proline in the A-B loop of the transthyretin molecule. DNA testing for this mutant allele by restriction fragment length polymorphism analysis based on the polymerase chain reaction is described.

An

    American
    ETHNICITY

    kindred with systemic amyloidosis
    FAMILY

 presenting with

    carpal tunnel syndrome
    SYMPTOMS

,

    peripheral neuropathy
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

 is reported.

    The transthyretin gene
    PARACLINICAL

 of a patient was

    analysed by direct DNA sequencing
    PARACLINICAL

 and

    both cytosine and thymine were present at the first base of codon 24
    GENETICS

. This

    new point mutation in exon 2 results in the amino acid substitution of serine for proline in the A-B loop of the transthyretin molecule
    GENETICS

.

    DNA testing
    PARACLINICAL

 for this

    mutant allele
    GENETICS

    by restriction fragment length polymorphism analysis based on the polymerase chain reaction
    PARACLINICAL

 is described.

carpal tunnel syndrome
peripheral neuropathy
cardiomyopathy


[Cardiac amyloidosis secondary to multiple myeloma detected by echocardiography].

The authors present the clinical history of a 70-year-old male with arterial hypertension who sought medical advice because of dyspnea on exertion, orthopnea and episodes of paroxysmal nocturnal dyspnea. The electrocardiogram showed left arterial hemiblock and abnormalities of ventricular repolarization compatible with a left lateral endocardiac lesion. Echocardiography revealed a hypertrophied left ventricle with a small ventricular cavity, compatible with an infiltrative-restrictive myopathy. Blood chemistry showed creatinine 4.9 mg/dl, BUN 133 mg/dl and alkaline phosphatase 204 i.v. The patient expired because of intractable heart failure. The histopathological examination of a piece of myocardium (authorized by the family) stained with Congo red confirmed the presence of abundant, diffuse deposits of amyloid, as had been suspected because of the echocardiographic findings.

The authors present the clinical history of a

    70-year-old
    AGE

    male
    GENDER

 with

    arterial hypertension
    SYMPTOMS

 who sought medical advice because of

    dyspnea on exertion
    SYMPTOMS

,

    orthopnea
    SYMPTOMS

 and

    episodes of paroxysmal nocturnal dyspnea
    SYMPTOMS

. The

    electrocardiogram
    PARACLINICAL

 showed

    left arterial hemiblock
    SYMPTOMS

 and

    abnormalities of ventricular repolarization compatible with a left lateral endocardiac lesion
    SYMPTOMS

.

    Echocardiography
    PARACLINICAL

 revealed a

    hypertrophied left ventricle with a small ventricular cavity
    SYMPTOMS

, compatible with an

    infiltrative-restrictive myopathy
    DIAGNOSIS

.

    Blood chemistry
    PARACLINICAL

 showed

    creatinine 4.9 mg/dl
    BIOCHEMICAL

,

    BUN 133 mg/dl
    BIOCHEMICAL

 and

    alkaline phosphatase 204 i.v
    BIOCHEMICAL

. The patient

    expired
    SYMPTOMS

 because of

    intractable heart failure
    SYMPTOMS

. The

    histopathological examination of a piece of myocardium (authorized
    PARACLINICAL

 by the family)

    stained with Congo red
    PARACLINICAL

 confirmed the presence of

    abundant, diffuse deposits of amyloid
    MICROSCOPIC

, as had been suspected because of the echocardiographic findings.

creatinine 4.9 mg/dl
BUN 133 mg/dl
alkaline phosphatase 204 i.v


[Contribution of myocardial biopsy and immunohistochemistry to the prognostic evaluation of cardiac amyloidosis].

The authors report four cases of cardiac amyloidosis, the diagnosis of which was confirmed by endomyocardial biopsy. They underline the value of immuno-histological studies with labelling of the biopsy fragments with anti-transthyretin and anti-light chain immunoglobulin antibodies. This approach provides a more precise typing of amyloidosis and a more accurate evaluation of the prognosis.

The authors report four cases of

    cardiac amyloidosis
    DIAGNOSIS

, the diagnosis of which was confirmed by

    endomyocardial biopsy
    PARACLINICAL

. They underline the value of

    immuno-histological studies
    PARACLINICAL

 with

    labelling of the biopsy fragments
    PARACLINICAL

 with

    anti-transthyretin and anti-light chain immunoglobulin antibodies
    BIOCHEMICAL

. This approach provides a more precise typing of

    amyloidosis
    DIAGNOSIS

 and a more accurate evaluation of the prognosis.


Amyloid deposits inside myocardial fibers in transthyretin-Met30 familial amyloidotic polyneuropathy. A histological and biochemical study.

A case of severe cardiac involvement is reported in a patient affected with familial amyloidotic polyneuropathy due to the Portuguese type I variant (Val-->Met30) of the transthyretin (prealbumin) molecule. Echocardiographic and hemodynamic studies suggested the presence of a progressive infiltrative cardiomyopathy that was later confirmed by endomyocardial biopsy. Amyloid deposits were found in both intra- and extra-myofiber location and thought to be related to primary involvement of the heart. Norepinephrine content of myocardial bioptic specimens was about threefold lower than normal, indicating that autonomic denervation may contribute to the maintenance and progression of cardiomyopathy. A sample obtained from the sural nerve showed a loss of myelinated fibers along with accumulation of amyloid masses in the endoneurial space. This histopathologic pattern correlated with a sharp decrease in the activity of the enzyme subserving electrochemical conduction through the axonal membrane, Na+, K(+)-ATPase.

A case of

    severe cardiac involvement
    SYMPTOMS

 is reported in a patient affected with

    familial amyloidotic polyneuropathy
    DIAGNOSIS

 due to the

    Portuguese type I variant (Val-->Met30) of the transthyretin (prealbumin) molecule
    GENETICS

.

    Echocardiographic and hemodynamic studies
    PARACLINICAL

 suggested the presence of a

    progressive infiltrative cardiomyopathy
    DIAGNOSIS

 that was later confirmed by

    endomyocardial biopsy
    PARACLINICAL

.

    Amyloid deposits were found in both intra- and extra-myofiber location
    MICROSCOPIC

 and thought to be related to

    primary involvement of the heart
    SYMPTOMS

.

    Norepinephrine content of myocardial bioptic specimens was about threefold lower than normal
    BIOCHEMICAL

, indicating that

    autonomic denervation
    SYMPTOMS

 may contribute to the maintenance and progression of

    cardiomyopathy
    SYMPTOMS

. A

    sample obtained from the sural nerve
    PARACLINICAL

 showed a

    loss of myelinated fibers
    MICROSCOPIC

 along with

    accumulation of amyloid masses in the endoneurial space
    MICROSCOPIC

. This histopathologic pattern correlated with a

    sharp decrease in the activity of the enzyme subserving electrochemical conduction through the axonal membrane, Na+, K(+)-ATPase.
    BIOCHEMICAL

severe cardiac involvement
primary involvement of the heart
autonomic denervation
cardiomyopathy

familial amyloidotic polyneuropathy
progressive infiltrative cardiomyopathy


[A sporadic case of late onset familial amyloidotic polyneuropathy preceded by cardiac involvement].

We report a 65-year-old man with amyloidotic polyneuropathy, who first suffered from heart failure at the age of 57, 3 years before the onset of neurological symptoms. He had no obvious family history. We analysed the transthyretin gene of the patient and 6 asymptomatic family members using polymerase chain reaction (PCR). The single amino acid substitution of a methionine for valine at position 30, which is a common mutation of Japanese type I FAP patients, was found from the patient and his sister of 47 years. Though Type I FAP patients often have cardiac conduction block, they rarely have signs of heart failure until the end stage of the disease. This is the first report of Type I FAP with severe myocardial involvement, in which TTR mutation at position 30 was confirmed. The result revealed the clinical variation of Type I FAP.

We report a

    65-year-old
    AGE

    man
    GENDER

 with

    amyloidotic polyneuropathy
    DIAGNOSIS

, who first suffered from

    heart failure
    SYMPTOMS

 at the

    age of 57
    AGE

, 3 years before the onset of

    neurological symptoms
    SYMPTOMS

.

    He
    GENDER

 had

    no obvious family history
    NEG_FINDINGS

. We

    analysed the transthyretin gene of the patient and 6 asymptomatic family members
    PARACLINICAL

 using

    polymerase chain reaction (PCR)
    PARACLINICAL

. The

    single amino acid substitution of a methionine for valine at position 30, which is a common mutation of Japanese
    GENETICS

    type I FAP
    DIAGNOSIS

 patients, was found from the patient

    and his sister of 47 years
    FAMILY

. Though

    Type I FAP
    DIAGNOSIS

 patients often have

    cardiac conduction block
    SYMPTOMS

, they rarely have

    signs of heart failure
    NEG_FINDINGS

 until the end stage of the disease. This is the first report of

    Type I FAP
    DIAGNOSIS

 with

    severe myocardial involvement
    SYMPTOMS

, in which

    TTR mutation at position 30
    GENETICS

 was confirmed. The result revealed the clinical variation of

    Type I FAP
    DIAGNOSIS

.

amyloidotic polyneuropathy
type I FAP
Type I FAP
Type I FAP
Type I FAP

heart failure
neurological symptoms
cardiac conduction block
severe myocardial involvement

no obvious family history
signs of heart failure


Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant.

Cardiac amyloidosis is caused by amyloid deposits derived from different human plasma proteins. It can lead to cardiac conduction disturbances, restrictive cardiomyopathy, and low output heart failure. The heart is variably involved during the development of systemic amyloidosis and seems to be more frequently affected in immunoglobulin (primary) than in reactive (secondary) amyloidosis. Amyloid is common in the elderly. Isolated atrial amyloid, for which a major subunit is the atrial natriuretic peptide, seems to be three times more frequent than senile cardiac amyloid, which is derived from normal prealbumin (transthyretin). Like polyneuropathy, cardiac amyloidosis is a prominent clinical feature of hereditary amyloidosis, namely of the autosomal dominant transthyretin (TTR) type. All 28 cases of TTR amyloidoses reported so far were heterozygotes for a single nucleotide change in the gene for TTR that resulted in amino acid substitutions in the mature protein. A new TTR genetic variant is reported in a German family where the index patient presented at the age of 63 with anginal pain and arrhythmia. Electrocardiography was suggestive of a pseudoinfarction pattern, and echocardiography and cardiac catheterisation showed signs of hypertrophic nonobstructive cardiomyopathy with increased ventricular filling pressures and a prominent "a" wave. Amyloid of the TTR type was identified by immunohistochemistry in the endomyocardial biopsy specimen. Hybrid isoelectric focusing established heterozygosity by showing normal TTR protein and an electrically neutral TTR variant differing from all known TTR variants so far. The patient died in an accident before investigations were complete. Electrophoretic analysis of the plasma from his first degree relatives (son, daughter, brother, and mother) identified the asymptomatic 22 year old son as an apparently heterozygous carrier of the mutant TTR protein. Comparative tryptic peptide mapping and sequencing showed that isoleucine at position 68 of the amino acid sequence was replaced by leucine.

    Cardiac amyloidosis
    DIAGNOSIS

 is caused by

    amyloid deposits derived from different human plasma proteins
    MICROSCOPIC

. It can lead to

    cardiac conduction disturbances
    SYMPTOMS

,

    restrictive cardiomyopathy
    SYMPTOMS

, and

    low output heart failure
    SYMPTOMS

. The heart is variably involved during the development of

    systemic amyloidosis
    DIAGNOSIS

 and seems to be more frequently affected in

    immunoglobulin (primary)
    DIAGNOSIS

 than in

    reactive (secondary) amyloidosis
    DIAGNOSIS

.

    Amyloid
    DIAGNOSIS

 is common in the

    elderly
    AGE

.

    Isolated atrial amyloid
    DIAGNOSIS

, for which a major subunit is the

    atrial natriuretic peptide
    BIOCHEMICAL

, seems to be three times more frequent than

    senile cardiac amyloid
    DIAGNOSIS

, which is derived from

    normal prealbumin (transthyretin)
    BIOCHEMICAL

. Like

    polyneuropathy
    DIAGNOSIS

,

    cardiac amyloidosis
    DIAGNOSIS

 is a prominent clinical feature of

    hereditary amyloidosis
    DIAGNOSIS

, namely

    of the autosomal dominant transthyretin (TTR) type
    DIAGNOSIS

. All 28 cases of

    TTR amyloidoses
    DIAGNOSIS

 reported so far were

    heterozygotes for a single nucleotide change in the gene for TTR that resulted in amino acid substitutions in the mature protein
    GENETICS

. A

    new TTR genetic variant
    GENETICS

 is reported in a

    German
    ETHNICITY

 family where the index patient presented at the

    age of 63
    AGE

 with

    anginal pain
    SYMPTOMS

 and

    arrhythmia
    SYMPTOMS

.

    Electrocardiography
    PARACLINICAL

 was

    suggestive of a pseudoinfarction pattern
    SYMPTOMS

, and

    echocardiography
    PARACLINICAL

 and

    cardiac catheterisation
    PARACLINICAL

 showed

    signs of hypertrophic nonobstructive cardiomyopathy
    SYMPTOMS

 with

    increased ventricular filling pressures and a prominent "a" wave
    SYMPTOMS

.

    Amyloid of the TTR type
    MICROSCOPIC

 was identified by

    immunohistochemistry in the endomyocardial biopsy specimen
    PARACLINICAL

.

    Hybrid isoelectric focusing
    PARACLINICAL

 established

    heterozygosity
    GENETICS

 by showing

    normal TTR protein
    BIOCHEMICAL

 and an

    electrically neutral TTR variant
    BIOCHEMICAL

 differing from all known TTR variants so far. The patient

    died in an accident
    SYMPTOMS

 before investigations were complete.

    Electrophoretic analysis of the plasma from his first degree relatives (son, daughter, brother, and mother)
    PARACLINICAL

 identified the

    asymptomatic 22 year old son as an apparently heterozygous carrier of the mutant TTR protein
    FAMILY

.

    Comparative tryptic peptide mapping and sequencing
    PARACLINICAL

 showed that

    isoleucine at position 68 of the amino acid sequence was replaced by leucine
    GENETICS

.

atrial natriuretic peptide
normal prealbumin (transthyretin)
normal TTR protein
electrically neutral TTR variant


Amyloid polyneuropathy with transthyretin Arg50 in a Japanese case from Osaka.

A Japanese patient with systemic amyloidosis associated with a transthyretin (TTR) variant Arg50 is presented. This 41-year-old man became impotent and developed decreased pain sensation in his hands, and then sensory loss and muscle wasting in his lower legs, and cardiomyopathy appeared. The symptoms progressed and he died of congestive heart failure at age 46. There were amyloid deposits in all organs studied and massive amyloid deposition was seen in the peripheral nerves and cardiac muscles. Amyloid fibrils extracted from heart tissue contained TTR. A genetic mutation, causing a Ser50-->Arg substitution of the TTR molecule, was identified in another family member. Plasma TTR was shown to be a mixture of normal TTR Ser50 and mutant TTR Arg50 in the 2 subjects.

A

    Japanese
    ETHNICITY

 patient with

    systemic amyloidosis
    DIAGNOSIS

 associated with a

    transthyretin (TTR) variant Arg50
    GENETICS

 is presented. This

    41-year-old
    AGE

    man
    GENDER

 became

    impotent
    SYMPTOMS

 and developed

    decreased pain sensation in his hands
    SYMPTOMS

, and then

    sensory loss
    SYMPTOMS

 and

    muscle wasting in his lower legs
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

 appeared. The symptoms progressed and

    he
    GENDER

    died
    SYMPTOMS

 of

    congestive heart failure
    SYMPTOMS

 at

    age 46
    AGE

. There were

    amyloid deposits in all organs studied
    MICROSCOPIC

 and

    massive amyloid deposition was seen in the peripheral nerves and cardiac muscles
    MICROSCOPIC

.

    Amyloid fibrils extracted from heart tissue contained TTR
    MICROSCOPIC

. A

    genetic mutation, causing a Ser50-->Arg substitution of the TTR molecule
    GENETICS

,

    was identified in another family member
    FAMILY

.

    Plasma TTR
    BIOCHEMICAL

 was shown to be a mixture of

    normal TTR Ser50 and mutant TTR Arg50
    GENETICS

 in the 2 subjects.

impotent
decreased pain sensation in his hands
sensory loss
muscle wasting in his lower legs
cardiomyopathy
died
congestive heart failure


Familial amyloid polyneuropathy related to transthyretin Gly42 in a Japanese family.

A Japanese family is described in which 6 persons showed familial amyloid polyneuropathy (FAP). Mean ages of onset were 38 for 4 males and 54 for 2 females. Three of the 6 became emaciated and died after 4 to 10 years. In 5, muscular weakness and autonomic dysfunction were the initial symptoms followed by sensory disturbances. Amyloidotic cardiomyopathy was present in 3 of the subjects. Amyloid deposits showed an immunohistological relation to transthyretin (TTR). Analysis of 1 patient's TTR gene revealed a single base change (A----G) that led to amino acid substitution (Glu42----Gly). This base change produced a new restriction site for endonuclease Cfr13 I in exon 2. Polymorphic analysis of the length of the Cfr13 I-restriction fragment confirmed the base change, and made it possible to detect the mutant TTR Gly42 gene in the FAP subjects. Amino acid sequencing analysis showed a variant of TTR Gly42 in 1 patient's serum.

A

    Japanese
    ETHNICITY

 family is described in which 6 persons showed

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

.

    Mean ages of onset were 38
    AGE

 for 4

    males
    GENDER

 and

    54
    AGE

 for 2

    females
    GENDER

. Three of the 6 became

    emaciated
    SYMPTOMS

 and

    died
    SYMPTOMS

    after 4 to 10 years
    AGE

. In 5,

    muscular weakness
    SYMPTOMS

 and

    autonomic dysfunction
    SYMPTOMS

 were the initial symptoms followed by

    sensory disturbances
    SYMPTOMS

.

    Amyloidotic cardiomyopathy
    DIAGNOSIS

 was present in 3 of the subjects.

    Amyloid deposits showed an immunohistological relation to transthyretin (TTR)
    MICROSCOPIC

.

    Analysis of 1 patient's TTR gene
    PARACLINICAL

 revealed a

    single base change (A----G) that led to amino acid substitution (Glu42----Gly)
    GENETICS

. This

    base change produced a new restriction site for endonuclease Cfr13 I in exon 2
    GENETICS

.

    Polymorphic analysis of the length of the Cfr13 I-restriction fragment
    PARACLINICAL

 confirmed the

    base change
    GENETICS

, and made it possible to detect the

    mutant TTR Gly42 gene
    GENETICS

 in the

    FAP
    DIAGNOSIS

 subjects.

    Amino acid sequencing analysis
    PARACLINICAL

 showed a

    variant of TTR Gly42
    GENETICS

 in 1 patient's

    serum
    BIOCHEMICAL

.

familial amyloid polyneuropathy (FAP)
Amyloidotic cardiomyopathy
FAP

emaciated
died
muscular weakness
autonomic dysfunction
sensory disturbances


Senile cardiac amyloidosis associated with homozygosity for a transthyretin variant (ILE-122).

Senile cardiac amyloidosis, also known as senile systemic amyloidosis, is a sporadic disease of late onset but with increasing incidence with age. Recently it has been shown in one case that amyloid deposits contained a transthyretin variant with an isoleucine for valine substitution at position 122. A second case with the transthyretin isoleucine 122 variant is reported here. This individual, who died with restrictive cardiomyopathy, was found to be homozygous for this transthyretin variant and his son heterozygous for the variant. A brother of the propositus was also homozygous for the variant but died of a cerebral vascular accident without being evaluated for amyloidosis. These studies show genetic transmission of the isoleucine-122 transthyretin variant associated with this form of cardiac amyloidosis.

    Senile cardiac amyloidosis
    DIAGNOSIS

, also known as

    senile systemic amyloidosis
    DIAGNOSIS

, is a sporadic disease of late onset but with increasing incidence with age. Recently it has been shown in one case that

    amyloid deposits
    MICROSCOPIC

 contained a

    transthyretin variant with an isoleucine for valine substitution at position 122
    GENETICS

. A second case with the

    transthyretin isoleucine 122 variant
    GENETICS

 is reported here. This individual, who

    died
    SYMPTOMS

 with

    restrictive cardiomyopathy
    DIAGNOSIS

,

    was found to be homozygous for this transthyretin variant and his son heterozygous for the variant
    FAMILY

. A

    brother of the propositus was also homozygous for the variant but died of a cerebral vascular accident
    FAMILY

    without being evaluated for amyloidosis
    NEG_FINDINGS

. These studies show

    genetic transmission of the isoleucine-122 transthyretin variant
    GENETICS

 associated with this form of

    cardiac amyloidosis
    DIAGNOSIS

.

Senile cardiac amyloidosis
senile systemic amyloidosis
restrictive cardiomyopathy
cardiac amyloidosis


Familial restrictive cardiomyopathy with atrioventricular block and skeletal myopathy.

Five generations of an Italian family with an autosomal dominant restrictive cardiomyopathy are described. Members of four generations were examined. Symptoms usually developed in the third or fourth decade but the disease did occur in childhood. Initially the condition was characterised by normal ventricular size and systolic function with increased diastolic filling pressures in both ventricles and consequent bi-atrial enlargement. Cardiac catheterisation showed a left ventricular filling pattern of "dip and plateau". The electrocardiogram typically showed non-specific changes in the ST segment and T wave and changes indicating considerable atrial enlargement, which were confirmed by echocardiography. Light microscopy of two endocardial biopsy specimens showed no specific features but excluded the endomyocardial fibrosis of eosinophilic heart disease, amyloid, and specific heart muscle diseases. At necropsy in one case examined under light microscopy extensive patchy fibrosis was found throughout the endocardium, myocardium, and subepicardium, but there were no features typical of eosinophilic heart disease. Histopathological and biochemical examination of skeletal muscle identified no abnormality. The disease often had an insidious course over five to ten years after presentation. Bundle branch blocks, leading to complete atrioventricular block, however, often occurred and may be the first manifestation. Some individuals who survived into the fifth decade developed a progressive, non-wasting skeletal myopathy.

Five generations of an

    Italian
    ETHNICITY

    family with an autosomal dominant restrictive cardiomyopathy
    FAMILY

 are described. Members of four generations were examined. Symptoms usually developed

    in the third or fourth decade
    AGE

 but the disease did occur in

    childhood
    AGE

. Initially the condition was characterised by

    normal ventricular size and systolic function
    NEG_FINDINGS

 with

    increased diastolic filling pressures in both ventricles
    SYMPTOMS

 and consequent

    bi-atrial enlargement
    SYMPTOMS

.

    Cardiac catheterisation
    PARACLINICAL

 showed a

    left ventricular filling pattern of "dip and plateau"
    SYMPTOMS

. The electrocardiogram typically showed

    non-specific changes in the ST segment and T wave
    SYMPTOMS

 and

    changes indicating considerable atrial enlargement
    SYMPTOMS

, which were confirmed by

    echocardiography
    PARACLINICAL

.

    Light microscopy of two endocardial biopsy specimens
    PARACLINICAL

 showed

    no specific features
    NEG_FINDINGS

 but

    excluded the endomyocardial fibrosis of eosinophilic heart disease, amyloid, and specific heart muscle diseases
    NEG_FINDINGS

. At

    necropsy
    PARACLINICAL

 in one case examined under

    light microscopy
    PARACLINICAL

    extensive patchy fibrosis was found throughout the endocardium, myocardium, and subepicardium
    MICROSCOPIC

, but there were

    no features typical of eosinophilic heart disease
    NEG_FINDINGS

.

    Histopathological and biochemical examination of skeletal muscle
    PARACLINICAL

 identified

    no abnormality
    NEG_FINDINGS

. The disease often had an insidious course over five to ten years after presentation.

    Bundle branch blocks
    SYMPTOMS

, leading to

    complete atrioventricular block
    SYMPTOMS

, however, often occurred and may be the first manifestation. Some individuals who survived into the

    fifth decade
    AGE

 developed a

    progressive, non-wasting skeletal myopathy
    DIAGNOSIS

.


Familial amyloidotic polyneuropathy in Hokkaido: a case report.

A 54-year-old man began to feel numbness in his hands at the age of 42 (1975). His condition became progressively worse accompanied by muscle weakness of the lower limbs and glove and stocking paresthesia of the extremities. The patient was admitted to our hospital on March 23, 1987. Neurological examination revealed distal dominant muscle weakness, sensory disturbance and areflexia. Electrocardiogram and ultrasound-cardiogram strongly suggested cardiomyopathy. A biopsy of the rectal wall and the cardiac muscle revealed amyloid deposits. The patient, his elder brother and one of his daughters had abnormal serum transthyretin (TTR, a protein referred as prealbumin). Therefore, the diagnosis of familial amyloidotic polyneuropathy (FAP) was confirmed. The patients's brother and daughter mentioned above, however, had no abnormal findings on physical examination and they were thus considered to be asymptomatic carriers. There may be more cases of asymptomatic carriers, if examination of abnormal TTR is more frequently analyzed.

A

    54-year-old
    AGE

    man
    GENDER

 began to feel

    numbness in his hands
    SYMPTOMS

 at the

    age of 42
    AGE

 (1975). His condition became progressively worse accompanied by

    muscle weakness of the lower limbs
    SYMPTOMS

 and

    glove and stocking paresthesia of the extremities
    SYMPTOMS

. The patient was admitted to our hospital on March 23, 1987.

    Neurological examination
    PARACLINICAL

 revealed

    distal dominant muscle weakness
    SYMPTOMS

,

    sensory disturbance
    SYMPTOMS

 and

    areflexia
    SYMPTOMS

.

    Electrocardiogram
    PARACLINICAL

 and

    ultrasound-cardiogram
    PARACLINICAL

 strongly suggested

    cardiomyopathy
    DIAGNOSIS

. A

    biopsy of the rectal wall and the cardiac muscle
    PARACLINICAL

 revealed

    amyloid deposits
    MICROSCOPIC

. The patient, his

    elder brother and one of his daughters
    FAMILY

 had

    abnormal serum transthyretin (TTR, a protein referred as prealbumin)
    BIOCHEMICAL

. Therefore, the diagnosis of

    familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 was confirmed. The patients's

    brother and daughter
    FAMILY

 mentioned above, however, had

    no abnormal findings on physical examination
    NEG_FINDINGS

 and they were thus considered to be

    asymptomatic carriers
    NEG_FINDINGS

. There may be more cases of asymptomatic carriers, if

    examination of abnormal TTR
    PARACLINICAL

 is more frequently analyzed.


[Noninvasive diagnosis of cardiac involvement by technetium-99m-pyrophosphate (Tc-99m PYP) myocardial scintigraphy in 2 cases of familial amyloid polyneuropathy and 1 case of secondary amyloidosis].

To validate the significance of technetium-99m-pyrophosphate (Tc-99m PYP) myocardial scintigraphy in diagnosing cardiac amyloidosis, 2 patients with familial amyloid polyneuropathy (FAP) and 1 patient with amyloidosis secondary to chronic rheumatic arthritis were studied. All three patients had echocardiographic abnormalities, which were increased wall thickness of the interventricular septum and the left ventricular posterior wall, and granular sparkling appearance in the septum. In 2 patients with FAP, abnormal myocardial uptake of Tc-99m PYP was diffusely detected in Tc-99m PYP SPECT. In the remaining 1 patient with secondary amyloidosis, however, Tc-99m PYP SPECT showed no abnormality, although we had confirmed the presence of myocardial amyloid deposits (type AA amyloid protein) with high amount in the histological examination. Thus, these results indicate that Tc-99m PYP scintigraphy may have a limitation in detecting cardiac involvement in secondary amyloidosis although it is useful in FAP.

To validate the significance of

    technetium-99m-pyrophosphate (Tc-99m PYP) myocardial scintigraphy
    PARACLINICAL

 in diagnosing

    cardiac amyloidosis
    DIAGNOSIS

, 2 patients with

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 and 1 patient with

    amyloidosis secondary to chronic rheumatic arthritis
    DIAGNOSIS

 were studied. All three patients had

    echocardiographic abnormalities
    SYMPTOMS

, which were

    increased wall thickness of the interventricular septum and the left ventricular posterior wall
    SYMPTOMS

, and

    granular sparkling appearance in the septum
    SYMPTOMS

. In 2 patients with

    FAP
    DIAGNOSIS

,

    abnormal myocardial uptake of Tc-99m PYP was diffusely detected
    SYMPTOMS

 in

    Tc-99m PYP SPECT
    PARACLINICAL

. In the remaining 1 patient with

    secondary amyloidosis
    DIAGNOSIS

, however,

    Tc-99m PYP SPECT
    PARACLINICAL

    showed no abnormality
    NEG_FINDINGS

, although we had confirmed the

    presence of myocardial amyloid deposits (type AA amyloid protein) with high amount
    MICROSCOPIC

 in the

    histological examination
    PARACLINICAL

. Thus, these results indicate that

    Tc-99m PYP scintigraphy
    PARACLINICAL

 may have a limitation in detecting

    cardiac involvement
    SYMPTOMS

 in

    secondary amyloidosis
    DIAGNOSIS

 although it is useful in

    FAP
    DIAGNOSIS

.


Familial atrial standstill caused by amyloidosis.

Three of nine siblings were affected by atrial standstill. Clinical, electrophysiological, and histological findings in two of these cases were studied. Electrophysiological studies showed persistent atrial standstill in one and partial atrial standstill in the other. Biopsy specimens of the right atria showed amyloid deposits, but specimens of the right ventricles and skin did not. Neither patient had peripheral neuropathy, gastrointestinal disorder, or renal dysfunction. Familial atrial standstill is usually associated with peripheral neuropathy. In the two cases studied amyloid deposition mainly affected the atrium, rather than the ventricles or other organs, and caused atrial standstill.

    Three of nine siblings were affected by atrial standstill
    FAMILY

. Clinical, electrophysiological, and histological findings in two of these cases were studied.

    Electrophysiological studies
    PARACLINICAL

 showed

    persistent atrial standstill
    SYMPTOMS

 in one and

    partial atrial standstill
    SYMPTOMS

 in the other.

    Biopsy specimens of the right atria
    PARACLINICAL

 showed

    amyloid deposits
    MICROSCOPIC

, but

    specimens of the right ventricles and skin did not
    PARACLINICAL

. Neither patient had

    peripheral neuropathy, gastrointestinal disorder
    NEG_FINDINGS

, or

    renal dysfunction
    SYMPTOMS

.

    Familial atrial standstill
    SYMPTOMS

 is usually associated with

    peripheral neuropathy
    DIAGNOSIS

. In the two cases studied

    amyloid deposition mainly affected the atrium, rather than the ventricles or other organs
    MICROSCOPIC

, and caused

    atrial standstill
    SYMPTOMS

.

persistent atrial standstill
partial atrial standstill
renal dysfunction
Familial atrial standstill
atrial standstill


[Familial primary disseminated amyloidosis (a new clinical form?)].

This report concerns two siblings we observed, one male the other female, who presented with primary disseminated amyloidosis. Repeated blood and urine examinations failed to demonstrate dysglobulinaemia. The brother developed, at the age of 51, extensive cutaneous amyloidosis with xanthochromia of the entire upper part of his body. His dermis contained a potassium permanganate-resistant amyloid substance. One year later, he presented with amyloid cardiomyopathy confirmed by biopsy. Owing to the intractable cardiac failure, heart transplantation was performed, but the patient died post-operatively. At autopsy, amyloid deposits were found to be present in the heart, liver, spleen and adrenal glands. His sister developed, at the age of 40, cutaneous amyloidosis in the form of yellowish and purpuric papules and plaques disseminated over the upper part of her body. Histological examination and electron microscopy of the skin showed large potassium permanganate-resistant amyloid deposits. In addition, endoscopy and histology demonstrated the presence of amyloid substance deposits in her larynx, oesophagus and rectum. Echocardiography revealed amyloid cardiomyopathy. She now has moderate cardiac failure, and heart transplantation is being contemplated. Like her brother, she has no renal of neurological amyloid lesions. There is no abnormality of serum or urinary globulins, and her SAA protein is present in normal concentrations. These cases do not fit in with the known nosological framework of amyloidosis. Clinically, both patients had disseminated amyloidosis of the AL type, and their disease clearly differed from familial systemic amyloidosis with neuropathy or nephropathy. To our knowledge, no case of familial primary amyloidosis of the AL type without dysglobulinaemia has yet been reported.

This report concerns two siblings we observed, one

    male
    GENDER

 the other

    female
    GENDER

, who presented with

    primary disseminated amyloidosis
    DIAGNOSIS

.

    Repeated blood and urine examinations failed to demonstrate dysglobulinaemia
    NEG_FINDINGS

. The

    brother
    GENDER

 developed, at the

    age of 51
    AGE

,

    extensive cutaneous amyloidosis
    SYMPTOMS

 with

    xanthochromia of the entire upper part of his body
    SYMPTOMS

.

    His
    GENDER

    dermis contained a potassium permanganate-resistant amyloid substance
    MICROSCOPIC

. One year later,

    he
    GENDER

 presented with

    amyloid cardiomyopathy
    DIAGNOSIS

 confirmed by

    biopsy
    PARACLINICAL

. Owing to the

    intractable cardiac failure
    SYMPTOMS

,

    heart transplantation
    MEDICATION

 was performed, but the patient

    died
    SYMPTOMS

 post-operatively. At

    autopsy
    PARACLINICAL

,

    amyloid deposits were found to be present in the heart, liver, spleen and adrenal glands
    MICROSCOPIC

.

    His
    GENDER

    sister developed, at the age of 40
    FAMILY

,

    cutaneous amyloidosis in the form of yellowish and purpuric papules and plaques disseminated over the upper part of her body
    SYMPTOMS

.

    Histological examination
    PARACLINICAL

 and

    electron microscopy of the skin
    PARACLINICAL

 showed

    large potassium permanganate-resistant amyloid deposits
    MICROSCOPIC

. In addition,

    endoscopy and histology
    PARACLINICAL

 demonstrated the

    presence of amyloid substance deposits in her larynx, oesophagus and rectum
    MICROSCOPIC

.

    Echocardiography
    PARACLINICAL

 revealed

    amyloid cardiomyopathy
    DIAGNOSIS

.

    She
    GENDER

 now has

    moderate cardiac failure
    SYMPTOMS

, and

    heart transplantation
    MEDICATION

 is being contemplated. Like

    her
    GENDER

    brother
    GENDER

,

    she
    GENDER

 has

    no renal of neurological amyloid lesions
    NEG_FINDINGS

. There is

    no abnormality of serum or urinary globulins
    NEG_FINDINGS

, and

    her
    GENDER

    SAA protein is present in normal concentrations
    BIOCHEMICAL

. These cases do not fit in with the known nosological framework of

    amyloidosis
    DIAGNOSIS

. Clinically, both patients had

    disseminated amyloidosis of the AL type
    DIAGNOSIS

, and their disease clearly differed from

    familial systemic amyloidosis
    DIAGNOSIS

 with

    neuropathy
    DIAGNOSIS

 or

    nephropathy
    DIAGNOSIS

. To our knowledge, no case of

    familial primary amyloidosis of the AL type
    DIAGNOSIS

    without dysglobulinaemia
    NEG_FINDINGS

 has yet been reported.

heart transplantation
heart transplantation


Hereditary amyloidosis: description of a new American kindred with late onset cardiomyopathy. Appalachian amyloid.

A family with hereditary amyloidosis characterized by peripheral neuropathy and cardiomyopathy is described. Lack of eye involvement sets their disease apart from the Indiana/Swiss familial amyloidotic polyneuropathy type II. The disease is of late onset; affected members die of cardiomyopathy after age 60. The late onset and lack of clinically significant neuropathy in several family members has led to misdiagnosis of the cardiomyopathy. Immunohistochemistry using antiprealbumin antiserum showed staining of amyloid deposits in nerve and heart.

A

    family with hereditary amyloidosis
    FAMILY

 characterized by

    peripheral neuropathy
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

 is described.

    Lack of eye involvement
    NEG_FINDINGS

 sets their disease apart from the

    Indiana/Swiss familial amyloidotic polyneuropathy type II
    ETHNICITY

. The disease is of late onset; affected members

    die of cardiomyopathy
    SYMPTOMS

    after age 60
    AGE

. The

    late onset
    SYMPTOMS

 and

    lack of clinically significant neuropathy in several family members
    NEG_FINDINGS

 has led to

    misdiagnosis of the cardiomyopathy
    NEG_FINDINGS

.

    Immunohistochemistry using antiprealbumin antiserum
    PARACLINICAL

 showed

    staining of amyloid deposits in nerve and heart
    MICROSCOPIC

.

peripheral neuropathy
cardiomyopathy
die of cardiomyopathy
late onset


Familial amyloid polyneuropathy.

Amyloid fibrils were isolated from the myocardium of two patients with familial amyloid polyneuropathy. The solubilized amyloid fibril whole protein shared immunologic determinants with normal human serum prealbumin (transthyretin), but revealed subtle differences on immunoelectrophoresis and radial immunodiffusion. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, amyloid fibril whole protein was resolved into numerous bands that reacted with antitransthyretin on immunoblots. The whole protein also contained peptide fragments of fibronectin, but was devoid of amyloid P protein. An antiserum raised against the whole protein was suitable for immunocytochemistry of amyloid in paraffin sections. In contrast, commercial antitransthyretin, raised against the intact tetrameric protein failed to react with tissue amyloid. Immunochemical and immunocytochemical results support the concept that familial amyloid polyneuropathy with cardiomyopathy is due to infiltration of susceptible tissues by an anomalous transthyretin.

    Amyloid fibrils were isolated from the myocardium
    MICROSCOPIC

 of two patients with

    familial amyloid polyneuropathy
    DIAGNOSIS

. The

    solubilized amyloid fibril whole protein
    MICROSCOPIC

 shared

    immunologic determinants with normal human serum prealbumin (transthyretin)
    SYMPTOMS

, but revealed subtle differences on

    immunoelectrophoresis and radial immunodiffusion
    PARACLINICAL

. On

    sodium dodecyl sulfate-polyacrylamide gel electrophoresis
    PARACLINICAL

,

    amyloid fibril whole protein
    MICROSCOPIC

 was resolved into numerous bands that

    reacted with antitransthyretin
    BIOCHEMICAL

 on

    immunoblots
    BIOCHEMICAL

. The whole protein also contained

    peptide fragments of fibronectin
    BIOCHEMICAL

, but was

    devoid of amyloid P protein
    NEG_FINDINGS

. An

    antiserum raised against the whole protein
    PARACLINICAL

 was suitable for

    immunocytochemistry of amyloid in paraffin sections
    PARACLINICAL

. In contrast,

    commercial antitransthyretin, raised against the intact tetrameric protein failed to react with tissue amyloid
    NEG_FINDINGS

.

    Immunochemical and immunocytochemical
    PARACLINICAL

 results support the concept that

    familial amyloid polyneuropathy
    DIAGNOSIS

 with

    cardiomyopathy
    DIAGNOSIS

 is due to

    infiltration of susceptible tissues by an anomalous transthyretin
    MICROSCOPIC

.

familial amyloid polyneuropathy
familial amyloid polyneuropathy
cardiomyopathy

reacted with antitransthyretin
immunoblots
peptide fragments of fibronectin


[Cardiac involvement in systemic amyloidosis: myocardial scintigraphic evaluation].

To assess the clinical significance of technetium-99m-pyrophosphate (Tc-99m-PYP), -methylene diphosphonate (Tc-99m-MDP) and thallium-201 (Tl-201) myocardial scintigraphy in the diagnosis of cardiac amyloidosis and in the differential diagnosis of cardiac diseases, 12 patients with biopsy-proved systemic amyloidosis (seven with familial amyloid polyneuropathy (FAP) and five with primary amyloidosis) were investigated. The results obtained were as follows: In 10 patients (six with FAP and four with primary amyloidosis) studied by Tc-99m-PYP scintigraphy, two (FAP one, primary amyloidosis one) had diffusely positive myocardial uptake, which was of greater intensity than that of the sternum. Six (four FAP; two primary amyloidosis) also had diffusely positive myocardial uptakes, but the intensity was less than that of the sternum. The remaining two (one FAP; one primary amyloidosis) had only equivocal myocardial uptakes. Two of these patients also had hepatic uptakes and another had both hepatic and thyroid uptakes. The intensity of myocardial uptake of Tc-99m-PYP in patients with echocardiographic left ventricular hypertrophy and/or highly refractile myocardial echoes, so-called granular sparkling appearance (GS) was slightly greater than that in patients with neither myocardial hypertrophy nor GS. FAP had slightly less intensity than primary amyloidosis. In 29 persons with other cardiac diseases and normal subjects examined by Tc-99m-PYP scintigraphy, seven (two dilated cardiomyopathy; two sarcoidosis; three hypertensive heart disease) also had diffusely positive myocardial scans of mild or moderate degree. However, none of them had marked myocardial or other tissue uptakes. Both Tc-99m-PYP and -MDP scintigraphic studies were performed in four patients (three FAP; one primary amyloidosis). In Tc-99m-MDP scintigraphy, diffusely positive myocardial uptakes were observed in two patients with FAP and the remaining two had negative scans. The intensity of Tc-99m-MDP myocardial uptake in each patient was significantly lower than that of Tc-99m-PYP uptake. Tl-201 scintigraphy was carried out in 10 patients (six FAP; four primary amyloidosis). Left ventricular hypertrophy was found in six patients and right ventricular visualization in five. Although electrocardiograms in seven of 10 patients showed QS patterns in the right to mid precordial leads, similar to that seen in antero-septal and extensive anterior myocardial infarctions, neither myocardial perfusion defect nor low uptake on Tl-201 images was detected in nine of them. The scintigrams in another one, which showed low uptake at the apical portion of the left ventricle, were considered normal.(ABSTRACT TRUNCATED AT 400 WORDS)

To assess the clinical significance of

    technetium-99m-pyrophosphate (Tc-99m-PYP), -methylene diphosphonate (Tc-99m-MDP) and thallium-201 (Tl-201) myocardial scintigraphy
    PARACLINICAL

 in the diagnosis of

    cardiac amyloidosis
    DIAGNOSIS

 and in the

    differential diagnosis
    PARACLINICAL

 of

    cardiac diseases
    DIAGNOSIS

, 12 patients with

    biopsy-proved
    DIAGNOSIS

    systemic amyloidosis
    DIAGNOSIS

 (seven with

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 and five with

    primary amyloidosis
    DIAGNOSIS

) were investigated. The results obtained were as follows: In 10 patients (six with

    FAP
    DIAGNOSIS

 and four with

    primary amyloidosis
    DIAGNOSIS

) studied by

    Tc-99m-PYP scintigraphy
    PARACLINICAL

, two (

    FAP
    DIAGNOSIS

 one,

    primary amyloidosis
    DIAGNOSIS

 one) had

    diffusely positive myocardial uptake, which was of greater intensity than that of the sternum
    SYMPTOMS

. Six (four

    FAP
    DIAGNOSIS

; two

    primary amyloidosis
    DIAGNOSIS

) also had

    diffusely positive myocardial uptakes, but the intensity was less than that of the sternum
    SYMPTOMS

. The remaining two (one

    FAP
    DIAGNOSIS

; one

    primary amyloidosis
    DIAGNOSIS

) had

    only equivocal myocardial uptakes
    SYMPTOMS

. Two of these patients also had

    hepatic uptakes
    SYMPTOMS

 and another had

    both hepatic and thyroid uptakes
    SYMPTOMS

. The

    intensity of myocardial uptake of Tc-99m-PYP
    SYMPTOMS

 in patients with

    echocardiographic left ventricular hypertrophy
    SYMPTOMS

 and/or

    highly refractile myocardial echoes, so-called granular sparkling appearance (GS)
    SYMPTOMS

 was slightly greater than that in patients with

    neither myocardial hypertrophy nor GS
    SYMPTOMS

.

    FAP
    DIAGNOSIS

 had slightly less intensity than

    primary amyloidosis
    DIAGNOSIS

. In 29 persons with

    other cardiac diseases
    NEG_FINDINGS

 and normal subjects examined by

    Tc-99m-PYP scintigraphy
    PARACLINICAL

, seven (two

    dilated cardiomyopathy
    DIAGNOSIS

; two

    sarcoidosis
    DIAGNOSIS

; three

    hypertensive heart disease
    DIAGNOSIS

) also had

    diffusely positive myocardial scans of mild or moderate degree
    SYMPTOMS

. However,

    none
    NEG_FINDINGS

 of them had

    marked myocardial or other tissue uptakes
    NEG_FINDINGS

.

    Both Tc-99m-PYP and -MDP scintigraphic studies
    PARACLINICAL

 were performed in four patients (three

    FAP
    DIAGNOSIS

; one

    primary amyloidosis
    DIAGNOSIS

). In

    Tc-99m-MDP scintigraphy
    PARACLINICAL

,

    diffusely positive myocardial uptakes
    SYMPTOMS

 were observed in two patients with

    FAP
    DIAGNOSIS

 and the remaining two had

    negative scans
    NEG_FINDINGS

. The

    intensity of Tc-99m-MDP myocardial uptake in each patient was significantly lower than that of Tc-99m-PYP uptake
    SYMPTOMS

.

    Tl-201 scintigraphy
    PARACLINICAL

 was carried out in 10 patients (six

    FAP
    DIAGNOSIS

; four

    primary amyloidosis
    DIAGNOSIS

).

    Left ventricular hypertrophy
    SYMPTOMS

 was found in six patients and

    right ventricular visualization
    SYMPTOMS

 in five. Although

    electrocardiograms
    PARACLINICAL

 in seven of 10 patients showed

    QS patterns in the right to mid precordial leads, similar to that seen in antero-septal and extensive anterior myocardial infarctions
    SYMPTOMS

,

    neither myocardial perfusion defect nor low uptake on Tl-201 images was detected
    NEG_FINDINGS

 in nine of them. The

    scintigrams
    PARACLINICAL

 in another one, which showed

    low uptake at the apical portion of the left ventricle
    SYMPTOMS

, were considered normal.(ABSTRACT TRUNCATED AT 400 WORDS)

cardiac amyloidosis
cardiac diseases
biopsy-proved
systemic amyloidosis
familial amyloid polyneuropathy (FAP)
primary amyloidosis
FAP
primary amyloidosis
FAP
primary amyloidosis
FAP
primary amyloidosis
FAP
primary amyloidosis
FAP
primary amyloidosis
dilated cardiomyopathy
sarcoidosis
hypertensive heart disease
FAP
primary amyloidosis
FAP
FAP
primary amyloidosis


Echocardiographic aspects of cardiac amyloidosis.

We report the M-mode and two-dimensional echocardiographic findings in a patient with familial amyloidosis. The diagnosis was made by the clinical picture and histologic evidence of amyloid in peripheral nerve biopsy. Though the patient had no clinical sign of heart failure, extensive involvement of the heart was demonstrated by echocardiography. M-mode echocardiography revealed increased right ventricular wall thickness in conjunction with symmetric increase in left ventricular wall thickness. On two-dimensional echocardiography, the entire interventricular septum and the papillary muscles were more dense than normal. These high density echoes had a "granular and sparkling" pattern. This case shows that cardiac amyloidosis can be diagnosed in the pre-clinical, asymptomatic state by M-mode and two-dimensional echocardiography. When symptomatic, confusion with constrictive pericarditis may be avoided non-invasively.

We report the

    M-mode and two-dimensional echocardiographic
    PARACLINICAL

 findings in a patient with

    familial amyloidosis
    DIAGNOSIS

. The diagnosis was made by the clinical picture and histologic evidence of

    amyloid in peripheral nerve biopsy
    MICROSCOPIC

. Though the patient had

    no clinical sign of heart failure
    NEG_FINDINGS

,

    extensive involvement of the heart
    SYMPTOMS

 was demonstrated by

    echocardiography
    PARACLINICAL

.

    M-mode echocardiography
    PARACLINICAL

 revealed

    increased right ventricular wall thickness in conjunction with symmetric increase in left ventricular wall thickness
    SYMPTOMS

. On

    two-dimensional echocardiography
    PARACLINICAL

,

    the entire interventricular septum and the papillary muscles were more dense than normal
    SYMPTOMS

. These

    high density echoes had a "granular and sparkling" pattern
    SYMPTOMS

. This case shows that

    cardiac amyloidosis
    DIAGNOSIS

 can be diagnosed in the pre-clinical, asymptomatic state by

    M-mode and two-dimensional echocardiography
    PARACLINICAL

. When symptomatic, confusion with

    constrictive pericarditis
    DIAGNOSIS

 may be avoided non-invasively.

familial amyloidosis
cardiac amyloidosis
constrictive pericarditis