Extracorporeal membrane oxygenation as bridge-to-decision in acute heart failure due to systemic light-chain amyloidosis.

Female, 58.

Acute hear failure.

Dispnoea • edema • fatigue.

Bone marrow biopsy • endomyocardial biopsy • abdominal subcutaneous fat biopsy under ECMO support.

Cardiology.

Rare disease.

Cardiac amyloidosis results from the amyloid deposition in heart tissue, either in the context of a systemic disease or as a localized form. Several pro-amyloid proteins can produce amyloid deposits in the heart. Each of these amyloidoses has characteristic clinical (cardiac and extracardiac) features, and a specific diagnosis and treatment.

A 58-year-old woman who presented with acute heart failure and echocardiographic findings strongly suggestive of infiltrative cardiomyopathy needed percutaneous veno-arterial extracorporeal membrane oxygenation (ECMO) as bridge-to-decision. Amyloid deposition was found on endomyocardial and bone marrow biopsies. Bone marrow plasma cell infiltrate with acute renal lesion and hypercalcemia confirmed the diagnosis of multiple myeloma-associated systemic light-chain amyloidosis (AL). Refractory shock with multi-organic failure syndrome persisted and no improvements in left ventricular function and structure were seen. After extensive discussion by a multidisciplinary team, and with the patients' family, she was not considered eligible for high-dose chemotherapy and/or autologous stem cell transplantation, heart transplantation, or sequential heart with autologous stem cell transplantation. The patient died a few hours after ECMO withdrawal. During the 14 days of ECMO support no major bleeding or thrombotic complications occurred.

The clinician must consider a diagnosis of cardiac amyloidosis in patients with heart failure, a restrictive type of cardiomyopathy with ventricular hypertrophy in the absence of valve abnormalities, or uncontrolled arterial hypertension. Although developments in chemotherapy have greatly improved the outcomes in AL amyloidosis, the prognosis of patients with severe cardiac involvement remains very poor. ECMO is potentially a reliable bridge-to-diagnosis and bridge-to-decision in these patients. An experienced ECMO team, careful patient selection, and rigorous management protocols with objective criteria to wean or stop ECMO are needed.

    Dispnoea
    SYMPTOMS

 •

    edema
    SYMPTOMS

 •

    fatigue
    SYMPTOMS

.

    Bone marrow biopsy
    PARACLINICAL

 •

    endomyocardial biopsy
    PARACLINICAL

 •

    abdominal subcutaneous fat biopsy
    PARACLINICAL

 under

    ECMO support
    MEDICATION

.

    Cardiac amyloidosis
    DIAGNOSIS

 results from the

    amyloid deposition in heart tissue
    MICROSCOPIC

, either in the context of a

    systemic disease
    DIAGNOSIS

 or as a localized form. Several

    pro-amyloid proteins
    MICROSCOPIC

 can produce

    amyloid deposits in the heart
    MICROSCOPIC

. Each of these

    amyloidoses
    DIAGNOSIS

 has characteristic clinical

    (cardiac and extracardiac)
    SYMPTOMS

 features, and a specific diagnosis and treatment.

A

    58-year-old
    AGE

    woman
    GENDER

 who presented with

    acute heart failure
    SYMPTOMS

 and

    echocardiographic findings strongly suggestive of infiltrative cardiomyopathy
    SYMPTOMS

 needed

    percutaneous veno-arterial extracorporeal membrane oxygenation (ECMO) as bridge-to-decision
    MEDICATION

.

    Amyloid deposition
    MICROSCOPIC

 was found on

    endomyocardial and bone marrow biopsies
    PARACLINICAL

.

    Bone marrow plasma cell infiltrate
    MICROSCOPIC

 with

    acute renal lesion
    MICROSCOPIC

 and

    hypercalcemia
    BIOCHEMICAL

 confirmed the diagnosis of

    multiple myeloma-associated systemic light-chain amyloidosis (AL)
    DIAGNOSIS

.

    Refractory shock with multi-organic failure syndrome persisted
    SYMPTOMS

 and

    no improvements in left ventricular function and structure were seen
    NEG_FINDINGS

. After extensive discussion by a multidisciplinary team, and with the patients' family,

    she
    GENDER

 was

    not considered eligible for high-dose chemotherapy and/or autologous stem cell transplantation, heart transplantation, or sequential heart with autologous stem cell transplantation
    NEG_FINDINGS

. The patient

    died
    SYMPTOMS

 a few hours after

    ECMO withdrawal
    MEDICATION

. During the

    14 days of ECMO support
    MEDICATION

    no major bleeding or thrombotic complications
    NEG_FINDINGS

 occurred.

The clinician must consider a diagnosis of

    cardiac amyloidosis
    DIAGNOSIS

 in patients with

    heart failure
    SYMPTOMS

, a

    restrictive type of cardiomyopathy with ventricular hypertrophy
    SYMPTOMS

 in the

    absence of valve abnormalities
    NEG_FINDINGS

, or

    uncontrolled arterial hypertension
    SYMPTOMS

. Although developments in

    chemotherapy
    MEDICATION

 have greatly improved the outcomes in

    AL amyloidosis
    DIAGNOSIS

, the prognosis of patients with

    severe cardiac involvement
    SYMPTOMS

 remains very poor.

    ECMO
    MEDICATION

 is potentially a reliable

    bridge-to-diagnosis and bridge-to-decision
    MEDICATION

 in these patients. An

    experienced ECMO team
    MEDICATION

, careful patient selection, and rigorous management protocols with objective criteria to

    wean or stop ECMO
    MEDICATION

 are needed.


Case report: isolated cardiac amyloidosis: an enigma unravelled.

Amyloidosis is a rare, multisystem disease characterized by deposition of fibrils in extracellular tissue involving kidney, liver, heart, autonomic nervous system, and several other organs. This report discusses a 75-year-old male who presented with worsening dyspnea on exertion, orthopnea, and lower-extremity edema. On physical exam, he had elevated jugular venous pressure and lower-extremity edema. Electrocardiogram depicted low voltage in limb leads and a prolonged PR interval. Echocardiogram revealed left ventricular hypertrophy, severe biatrial dilatation, and restrictive filling physiology. Coronary angiography showed absence of significant epicardial coronary artery disease. On right heart catheterization, a "dip-and-plateau sign" was noted on right ventricular pressure tracings. A diagnosis of cardiac amyloidosis was considered, but a complete hematology work-up for systemic amyloidosis was negative. Cardiac magnetic resonance imaging was pursued, showing delayed gadolinium enhancement, and this ultimately led to the myocardial biopsy confirming the diagnosis of isolated cardiac amyloidosis. Further genetic analyses confirmed isolated cardiac amyloid caused by mutant transthyretin protein (Val-122-Ile). Isolated cardiac amyloidosis is an extremely rare entity, and diagnosis may be difficult despite the use of multimodality imaging. If the index of suspicion is high, then myocardial biopsy should be considered.

    Amyloidosis
    DIAGNOSIS

 is a rare,

    multisystem disease
    DIAGNOSIS

 characterized by

    deposition of fibrils in extracellular tissue involving kidney, liver, heart, autonomic nervous system, and several other organs
    MICROSCOPIC

. This report discusses a

    75-year-old
    AGE

    male
    GENDER

 who presented with

    worsening dyspnea on exertion
    SYMPTOMS

,

    orthopnea
    SYMPTOMS

, and

    lower-extremity edema
    SYMPTOMS

. On physical exam,

    he
    GENDER

 had

    elevated jugular venous pressure
    SYMPTOMS

 and

    lower-extremity edema
    SYMPTOMS

.

    Electrocardiogram
    PARACLINICAL

 depicted

    low voltage in limb leads and a prolonged PR interval
    SYMPTOMS

.

    Echocardiogram
    PARACLINICAL

 revealed

    left ventricular hypertrophy
    SYMPTOMS

,

    severe biatrial dilatation
    SYMPTOMS

, and

    restrictive filling physiology
    SYMPTOMS

.

    Coronary angiography
    PARACLINICAL

 showed

    absence of significant epicardial coronary artery disease
    NEG_FINDINGS

. On

    right heart catheterization
    PARACLINICAL

, a

    "dip-and-plateau sign" was noted on right ventricular pressure tracings
    SYMPTOMS

. A diagnosis of

    cardiac amyloidosis
    DIAGNOSIS

 was considered, but

    a complete hematology work-up for systemic amyloidosis was negative
    NEG_FINDINGS

.

    Cardiac magnetic resonance imaging
    PARACLINICAL

 was pursued, showing

    delayed gadolinium enhancement
    SYMPTOMS

, and this ultimately led to the

    myocardial biopsy
    PARACLINICAL

 confirming the diagnosis of

    isolated cardiac amyloidosis
    DIAGNOSIS

. Further

    genetic analyses
    PARACLINICAL

 confirmed

    isolated cardiac amyloid
    DIAGNOSIS

 caused by

    mutant transthyretin protein (Val-122-Ile)
    GENETICS

.

    Isolated cardiac amyloidosis
    DIAGNOSIS

 is an extremely rare entity, and diagnosis may be difficult despite the use of

    multimodality imaging
    PARACLINICAL

. If the index of suspicion is high, then

    myocardial biopsy
    PARACLINICAL

 should be considered.

Amyloidosis
multisystem disease
cardiac amyloidosis
isolated cardiac amyloidosis
isolated cardiac amyloid
Isolated cardiac amyloidosis


A genealogical and clinical study of the phenotypical variation within the Swedish transthyretin His88Arg (p. His108Arg) amyloidosis family.

In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (≥ 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44.

the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

In 2005 we reported the first case of

    transthyretin His88Arg (p. His108Arg) amyloidosis
    DIAGNOSIS

, a mutation characterised by

    cardiomyopathy
    DIAGNOSIS

. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in

    Sweden
    ETHNICITY

, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the

    transthyretin (TTR) His88Arg mutation
    GENETICS

.

    Genealogical studies of church records
    PARACLINICAL

 were used to identify the individuals with the disease and their families.

    Routine clinical investigations of neurological and heart manifestation
    PARACLINICAL

 of the disease were utilised. We found that

    genealogically all seven individuals were related and originated from the same
    FAMILY

 region in

    Sweden
    ETHNICITY

.

    Amyloid deposits were demonstrated in biopsies
    MICROSCOPIC

 and the

    TTR His88Arg mutation
    GENETICS

 was identified in all patients. Patients had a

    late onset disease
    AGE

 (

    ≥ 50 years of age
    AGE

) and all exhibited a

    severe amyloid cardiomyopathy
    DIAGNOSIS

. A

    pronounced peripheral axonal neuropathy
    SYMPTOMS

 was with certainty demonstrated in one patient only, who also was operated for a

    magnetic resonance confirmed spinal stenosis
    PARACLINICAL

, however,

    without any effect on his neurological symptoms
    NEG_FINDINGS

. Five of the patients had

    carpal tunnel syndrome
    DIAGNOSIS

. The first reported case is now deceased from

    cardiac failure
    SYMPTOMS

. One patient has had a

    sequential heart and liver transplantation
    MEDICATION

. One gene carrier had

    no symptoms or findings of disease
    NEG_FINDINGS

 on latest evaluation at the

    age of 44
    AGE

.

the

    Swedish
    ETHNICITY

    TTRHis88Arg
    GENETICS

 patients all have a common

    Swedish founder
    ETHNICITY

.

    Cardiomyopathy with heart failure
    SYMPTOMS

, as well as

    carpal tunnel syndrome
    SYMPTOMS

 and

    spinal stenosis
    SYMPTOMS

 were early signs of disease; but

    peripheral neuropathy
    SYMPTOMS

 was present in one patient before symptoms of

    cardiomyopathy
    SYMPTOMS

 so the phenotypical presentation of this mutation is variable.

transthyretin (TTR) His88Arg mutation
TTR His88Arg mutation
TTRHis88Arg

pronounced peripheral axonal neuropathy
cardiac failure
Cardiomyopathy with heart failure
carpal tunnel syndrome
spinal stenosis
peripheral neuropathy
cardiomyopathy


Cardiac amyloidosis in a heart transplant patient - A case report and retrospective analysis of amyloidosis evolution.

Cardiac amyloidosis is a very rare cause of heart failure in heart transplant recipients but an important differential diagnosis in cases of progressive cardiac failure. We report a 72-year-old male patient with the diagnosis of senile systemic amyloidosis (SSA) in a transplanted heart 15 years after transplantation by the initial diagnosis of the dilated cardiomyopathy. Additionally performed immunohistochemical analysis with anti-transthyretin antibody of the cardiac biopsies of the last 15 years enabled the possibility to show the evolution of this disease with characteristic biphasic pattern.

    Cardiac amyloidosis
    DIAGNOSIS

 is a very rare cause of

    heart failure
    SYMPTOMS

 in

    heart transplant recipients
    MEDICATION

 but an important

    differential diagnosis
    PARACLINICAL

 in cases of

    progressive cardiac failure
    SYMPTOMS

. We report a

    72-year-old
    AGE

    male
    GENDER

 patient with the diagnosis of

    senile systemic amyloidosis (SSA)
    DIAGNOSIS

 in a

    transplanted heart
    MEDICATION

 15 years after

    transplantation
    MEDICATION

 by the initial diagnosis of the

    dilated cardiomyopathy
    DIAGNOSIS

. Additionally performed

    immunohistochemical analysis with anti-transthyretin antibody of the cardiac biopsies of the last 15 years
    PARACLINICAL

 enabled the possibility to show the evolution of this disease with characteristic

    biphasic pattern
    MICROSCOPIC

.

Cardiac amyloidosis
senile systemic amyloidosis (SSA)
dilated cardiomyopathy

heart failure
progressive cardiac failure

heart transplant recipients
transplanted heart
transplantation


Amyloid polyneuropathy caused by wild-type transthyretin.

Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene.

We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis.

The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elderly patients with cardiomyopathy, but a few cases of polyneuropathy have been reported.

This entity is especially noteworthy in light of emerging treatment options for hereditary transthyretin amyloidosis, which are likely to also be beneficial in wild-type disease.

    Amyloidosis derived from transthyretin (TTR) molecules
    MICROSCOPIC

 is typically caused by

    mutations of the TTR gene
    GENETICS

.

We describe an

    elderly
    AGE

 patient with a

    severe length-dependent polyneuropathy
    DIAGNOSIS

 that unexpectedly proved to be caused by

    wild-type transthyretin amyloidosis
    DIAGNOSIS

.

The diagnosis was made by

    muscle biopsy
    PARACLINICAL

, because

    no amyloid deposits were found in the biopsied nerve segment
    NEG_FINDINGS

. Most cases of

    wild-type transthyretin amyloidosis
    DIAGNOSIS

 occur in

    elderly
    AGE

 patients with

    cardiomyopathy
    DIAGNOSIS

, but a few cases of

    polyneuropathy
    DIAGNOSIS

 have been reported.

This entity is especially noteworthy in light of emerging treatment options for

    hereditary transthyretin amyloidosis
    DIAGNOSIS

, which are likely to also be beneficial in

    wild-type disease
    DIAGNOSIS

.

severe length-dependent polyneuropathy
wild-type transthyretin amyloidosis
wild-type transthyretin amyloidosis
cardiomyopathy
polyneuropathy
hereditary transthyretin amyloidosis
wild-type disease


Transthyretin cardiac amyloidosis: an under-diagnosed cause of heart failure.

Cardiac amyloidosis is the most common cause of infiltrative cardiomyopathy and is associated with a poor prognosis. Transthyretin cardiac amyloidosis, particularly the type caused by the mutation that replaces the amino acid valine with the amino acid isoleucine at position 122 (Val122Ile), is most common among African- Americans above 65 years of age. Evidence suggests that this mutation is an important, though under-diagnosed, cause of heart failure in this population.

A 74-year-old African American male with a diagnosis of non-ischemic cardiomyopathy for several years, presented with gradually worsening dyspnea on exertion and lower extremity edema. There is no known cardiac disease in his family. An echocardiogram was done showing a decrease in ejection fraction to 30% from 45% in the span of a year. An endomyocardial biopsy analysis identified transthyretin amyloid with the Val122Ile mutation, confirming the diagnosis of familial transthyretin cardiomyopathy.

Systemic amyloidosis is a group of diseases caused by the deposition of an abnormally folded, insoluble protein that can accumulate in multiple organs causing progressive and irreversible dysfunction. The mutations that most commonly induce variant transthyretin cardiac amyloidosis are Val122Ile, Val30Met and Thr60Ala. The Val122Ile mutation has been found to be present in 3-4% of the African American/Caribbean population.

Familial amyloid cardiomyopathy is an uncommonly recognized cause of heart failure in the population, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. Patients that meet the high-risk profile criteria - male gender, age 65 years and older, heart failure symptoms, symmetric left ventricular (LV) hypertrophy, and moderately depressed LV function - should likely undergo additional testing for cardiac amyloidosis.

    Cardiac amyloidosis
    DIAGNOSIS

 is the most common cause of

    infiltrative cardiomyopathy
    DIAGNOSIS

 and is associated with a poor prognosis.

    Transthyretin cardiac amyloidosis
    DIAGNOSIS

, particularly the type caused by the

    mutation that replaces the amino acid valine with the amino acid isoleucine at position 122 (Val122Ile)
    GENETICS

, is most common among

    African- Americans
    ETHNICITY

    above 65 years of age
    AGE

. Evidence suggests that this mutation is an important, though under-diagnosed, cause of

    heart failure
    SYMPTOMS

 in this population.

A

    74-year-old
    AGE

    African American
    ETHNICITY

    male
    GENDER

 with a diagnosis of

    non-ischemic cardiomyopathy
    DIAGNOSIS

 for several years, presented with

    gradually worsening dyspnea on exertion
    SYMPTOMS

 and

    lower extremity edema
    SYMPTOMS

. There is

    no known cardiac disease in his family
    FAMILY

. An

    echocardiogram
    PARACLINICAL

 was done showing a

    decrease in ejection fraction to 30% from 45% in the span of a year
    SYMPTOMS

. An

    endomyocardial biopsy analysis
    PARACLINICAL

 identified

    transthyretin amyloid with the Val122Ile mutation
    MICROSCOPIC

, confirming the diagnosis of

    familial transthyretin cardiomyopathy
    DIAGNOSIS

.

    Systemic amyloidosis
    DIAGNOSIS

 is a group of diseases caused by the

    deposition of an abnormally folded, insoluble protein that can accumulate in multiple organs
    MICROSCOPIC

 causing

    progressive and irreversible dysfunction
    SYMPTOMS

. The mutations that most commonly induce

    variant transthyretin cardiac amyloidosis
    DIAGNOSIS

 are

    Val122Ile
    GENETICS

,

    Val30Met
    GENETICS

 and

    Thr60Ala
    GENETICS

. The

    Val122Ile mutation
    GENETICS

 has been found to be present in 3-4% of the

    African American/Caribbean
    ETHNICITY

 population.

    Familial amyloid cardiomyopathy
    DIAGNOSIS

 is an uncommonly recognized cause of

    heart failure
    DIAGNOSIS

 in the population, and patients may wait several years before accurate diagnosis, risking additional

    significant irreversible deterioration
    SYMPTOMS

. Patients that meet the high-risk profile criteria -

    male
    GENDER

    gender
    GENDER

,

    age 65 years and older
    AGE

,

    heart failure symptoms
    SYMPTOMS

,

    symmetric left ventricular (LV) hypertrophy
    SYMPTOMS

, and

    moderately depressed LV function
    SYMPTOMS

 - should likely undergo additional testing for

    cardiac amyloidosis
    DIAGNOSIS

.

African- Americans
African American
African American/Caribbean


Facing the challenges of ventricular hypertrophy: the eyes don't lie.

We describe the case of a 47-year-old man with new-onset heart failure who was found to have severe biventricular wall thickening. We present comprehensive data from invasive and non-invasive multimodality imaging, genetic and histologic tests, and briefly describe their importance in the final diagnosis. To our knowledge, this is the first case of the Portuguese variant of familial amyloid polyneuropathy presenting with heart failure in the fifth decade of life. This is an unusual case report, but also an illustration of how to approach any patient with suspected infiltrative cardiomyopathy.

We describe the case of a

    47-year-old
    AGE

    man
    GENDER

 with

    new-onset heart failure
    SYMPTOMS

 who was found to have

    severe biventricular wall thickening
    SYMPTOMS

. We present comprehensive data from

    invasive and non-invasive multimodality imaging
    PARACLINICAL

,

    genetic and histologic tests
    PARACLINICAL

, and briefly describe their importance in the final diagnosis. To our knowledge, this is the first case of the Portuguese variant of

    familial amyloid polyneuropathy
    DIAGNOSIS

 presenting with

    heart failure
    SYMPTOMS

 in the

    fifth decade of life
    AGE

. This is an unusual case report, but also an illustration of how to approach any patient with suspected

    infiltrative cardiomyopathy
    DIAGNOSIS

.

new-onset heart failure
severe biventricular wall thickening
heart failure

familial amyloid polyneuropathy
infiltrative cardiomyopathy


Isolated heart transplantation for familial transthyretin (TTR) V122I cardiac amyloidosis.

Transthyretin (TTR) cardiac amyloidosis is characterized by deposition of either mutant or wild type TTR amyloid protein in the myocardium ultimately leading to progressive cardiomyopathy and heart failure. The most common TTR gene mutation that leads to TTR cardiac amyloidosis is the valine-to-isoleucine substitution at position 122 (V122I or Ile122). Currently, the only definitive treatment suggested for mutant TTR cardiac amyloidosis is the combined or sequential liver-heart transplantation in eligible patients, since liver is the source of TTR production. Here, we report a case of heterozygous Val122L mutated TTR-related cardiac amyloidosis treated with isolated heart transplantation with no recurrence of amyloid in the cardiac allograft and no systemic abnormalities 5 years after heart transplantation. Abbreviations MMF mycophenolate mofetil NYHA New York Heart Association TTR transthyretin VE minute ventilation.

    Transthyretin (TTR) cardiac amyloidosis
    DIAGNOSIS

 is characterized by

    deposition of either mutant or wild type TTR amyloid protein in the myocardium
    MICROSCOPIC

 ultimately leading to

    progressive cardiomyopathy
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

. The most common

    TTR gene mutation
    GENETICS

 that leads to

    TTR cardiac amyloidosis
    DIAGNOSIS

 is the

    valine-to-isoleucine substitution at position 122 (V122I or Ile122)
    GENETICS

. Currently, the only definitive treatment suggested for

    mutant TTR cardiac amyloidosis
    DIAGNOSIS

 is the

    combined or sequential liver-heart transplantation
    MEDICATION

 in eligible patients, since liver is the source of

    TTR production
    BIOCHEMICAL

. Here, we report a case of

    heterozygous Val122L mutated TTR-related cardiac amyloidosis
    GENETICS

 treated with

    isolated heart transplantation
    MEDICATION

 with

    no recurrence of amyloid in the cardiac allograft
    NEG_FINDINGS

 and

    no systemic abnormalities
    NEG_FINDINGS

 5

    years after heart transplantation
    NEG_FINDINGS

. Abbreviations

    MMF mycophenolate mofetil
    MEDICATION

 NYHA New York Heart Association

    TTR transthyretin VE minute ventilation
    BIOCHEMICAL

.

Transthyretin (TTR) cardiac amyloidosis
TTR cardiac amyloidosis
mutant TTR cardiac amyloidosis

progressive cardiomyopathy
heart failure

TTR production
TTR transthyretin VE minute ventilation


[Perioperative management for liver transplant in a patient with familial amyloid polyneuropathy with heart involvement].

Familial amyloid polyneuropathy (FAP) is a systemic amyloidosis caused by mutated transthyretin. Cardiac amyloidosis, the major prognostic determinant in systemic amyloidosis, is characterized by infiltration of the myocardium, leading to cardiomyopathy and conduction disturbances. Liver transplantation is the only curative option for patients with FAP. The case is presented of a 36-year-old patient with type i FAP with cardiac involvement, proposed for liver transplant surgery, which was successfully performed without any preoperative event of interest.

    Familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 is a

    systemic amyloidosis
    DIAGNOSIS

 caused by

    mutated transthyretin
    GENETICS

.

    Cardiac amyloidosis
    DIAGNOSIS

, the major prognostic determinant in

    systemic amyloidosis
    DIAGNOSIS

, is characterized by

    infiltration of the myocardium
    MICROSCOPIC

, leading to

    cardiomyopathy
    SYMPTOMS

 and

    conduction disturbances
    SYMPTOMS

.

    Liver transplantation
    MEDICATION

 is the only curative option for patients with

    FAP
    DIAGNOSIS

. The case is presented of a

    36-year-old
    AGE

 patient with

    type i FAP
    DIAGNOSIS

 with

    cardiac involvement
    SYMPTOMS

, proposed for

    liver transplant surgery
    MEDICATION

, which was successfully performed

    without any preoperative event of interest
    NEG_FINDINGS

.

Familial amyloid polyneuropathy (FAP)
systemic amyloidosis
Cardiac amyloidosis
systemic amyloidosis
FAP
type i FAP

cardiomyopathy
conduction disturbances
cardiac involvement

Liver transplantation
liver transplant surgery


[Sequential heart and liver transplantation for familial amyloid polyneuropathy].

Combined heart and liver transplantation for familial amyloid polyneuropathy (FAP) is currently the best treatment for patients with cardiomyopathy related to FAP. However, its optimal timing and the possibility of domino liver transplantation in this setting remain under discussion. Most such cases in the medical literature have been performed simultaneously, although many of them have required the use of veno-venous bypass and the majority have not used the liver as a graft for domino liver transplantation.

We report 3 cases of non-Val30Met mutation that underwent sequential heart and domino liver transplantation at our institution.

We describe the 3 cases and the medical literature, with special attention to the reason for sequential heart and liver transplantation, the role of transient elastography in this setting, and the feasibility of domino liver transplantation.

In our experience, combined heart and liver transplantation is a feasible but challenging procedure for patients with FAP. Performing the procedure sequentially rather than simultaneously seems safer and easier, both technically and hemodynamically. More importantly, such an approach allows the use of livers from FAP patients as grafts for domino liver transplantation.

    Combined heart and liver transplantation
    MEDICATION

 for

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 is currently the best treatment for patients with

    cardiomyopathy
    DIAGNOSIS

 related to

    FAP
    DIAGNOSIS

. However, its optimal timing and the possibility of

    domino liver transplantation
    MEDICATION

 in this setting remain under discussion. Most such cases in the medical literature have been performed simultaneously, although many of them have required the

    use of veno-venous bypass
    MEDICATION

 and the majority have

    not used the liver as a graft for domino liver transplantation
    MEDICATION

.

We report 3 cases of

    non-Val30Met mutation
    GENETICS

 that

    underwent sequential heart and domino liver transplantation
    MEDICATION

 at our institution.

We describe the 3 cases and the medical literature, with special attention to the reason for

    sequential heart and liver transplantation
    MEDICATION

, the role of

    transient elastography
    PARACLINICAL

 in this setting, and the feasibility of

    domino liver transplantation
    MEDICATION

.

In our experience,

    combined heart and liver transplantation
    MEDICATION

 is a feasible but challenging procedure for patients with

    FAP
    DIAGNOSIS

.

    Performing the procedure
    MEDICATION

 sequentially rather than simultaneously seems safer and easier, both technically and hemodynamically. More importantly, such an approach allows the use of livers from

    FAP
    DIAGNOSIS

 patients as

    grafts for domino liver transplantation
    MEDICATION

.

familial amyloid polyneuropathy (FAP)
cardiomyopathy
FAP
FAP
FAP


Structure-based analysis of A19D, a variant of transthyretin involved in familial amyloid cardiomyopathy.

Transthyretin (TTR) is a tetrameric beta-sheet-rich protein. Its deposits have been implicated in four different amyloid diseases. Although aggregation of the wild-type sequence is responsible for the senile form of the disease, more than one hundred variants have been described thus far, most of which confer a more amyloidogenic character to TTR, mainly because they compromise the stability of the protein in relation to monomer formation, which upon misfolding is intrinsically aggregation-prone. We report the case of a Brazilian patient suffering from a severe cardiomyopathy who carries a rare mutation in exon 2 of the TTR gene that results in an Ala to Asp substitution at position 19 (A19D). The putative pathogenic mechanisms of this variant were analyzed in silico. We constructed a structural model for the A19D tetramer from which its thermodynamic stability was compared to that displayed by the V30M (more amyloidogenic than WT-TTR) and T119M (non-amyloidogenic) variants. The FoldX force field predicted that A19D and V30M are 10.88 and 8.07 kCal/mol less stable than the WT-TTR, while T119M is 5.15 kCal/mol more stable, which is consistent with the aggregation propensities exhibited by these variants. We analyzed the step in which the tetramer-dimer-monomer-unfolded monomer equilibrium might contribute the most to the increased or decreased amyloidogenicity in each variant. Our results suggest that the concentration of four non-native negative charges occur inside thyroxine-binding channels, and the loss of contacts at both the tetrameric and dimeric interfaces would account for an overall decreased stability of the tetramer and the consequent enhanced amyloidogenicity of the A19D variant. As far as we know, this is the first description of a non-V30M mutation in Brazil.

    Transthyretin (TTR)
    DIAGNOSIS

 is a

    tetrameric beta-sheet-rich
    MICROSCOPIC

 protein. Its deposits have been implicated in four different

    amyloid diseases
    DIAGNOSIS

. Although

    aggregation of
    MICROSCOPIC

 the wild-type sequence is responsible for the senile form of the disease, more than one hundred variants have been described thus far, most of which confer a more amyloidogenic character to TTR, mainly because they compromise the stability of the protein in relation to monomer formation, which upon misfolding is intrinsically

    aggregation-prone
    MICROSCOPIC

. We report the case of a

    Brazilian
    ETHNICITY

 patient suffering from a

    severe cardiomyopathy
    DIAGNOSIS

 who carries a

    rare mutation in exon 2 of the TTR gene that results in an Ala to Asp substitution at position 19 (A19D)
    GENETICS

. The putative pathogenic mechanisms of this variant were analyzed in silico. We constructed a structural model for the A19D tetramer from which its thermodynamic stability was compared to that displayed by the

    V30M (more amyloidogenic than WT-TTR
    GENETICS

) and

    T119M (non-amyloidogenic
    GENETICS

) variants. The

    FoldX force field
    PARACLINICAL

 predicted that

    A19D and V30M
    GENETICS

 are 10.88 and 8.07 kCal/mol less stable than the WT-TTR, while

    T119M
    GENETICS

 is 5.15 kCal/mol more stable, which is consistent with the aggregation propensities exhibited by these variants. We analyzed the step in which the tetramer-dimer-monomer-unfolded monomer equilibrium might contribute the most to the increased or decreased amyloidogenicity in each variant. Our results suggest that the

    concentration of four non-native negative charges occur inside thyroxine-binding channels
    GENETICS

, and the

    loss of contacts at both the tetrameric and dimeric interfaces
    SYMPTOMS

 would account for an overall

    decreased stability of
    BIOCHEMICAL

 the tetramer and the consequent enhanced amyloidogenicity of the

    A19D variant
    GENETICS

. As far as we know, this is the first description of a

    non-V30M mutation
    GENETICS

 in

    Brazil
    ETHNICITY

.

Transthyretin (TTR)
amyloid diseases
severe cardiomyopathy


Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life.

Individuals heterozygous for the V122I mutation in transthyretin (TTR) tend to develop cardiac amyloidosis, often after the seventh decade of life. Although homozygotes have been reported, these have typically been single case reports. We report a cohort of 13 V122I homozygotes. TTR gene sequencing results from the Mayo Clinic Molecular Genetics Laboratory between September 2004 and January 2013 were reviewed; 177 heterozygotes and 13 homozygotes for the V122I alteration were identified. Detailed clinical history was available for the 24 heterozygotes seen at Mayo Clinic. We compared age at onset of disease for this group to homozygotes, both alone and pooled with the 11 homozygotes from the literature. Individuals with homozygous V122I manifested symptoms a mean of 10 years earlier than heterozygotes (63.8 ± 5.7 versus 72 ± 8.1 yrs, P = 0.0002). Further, males were significantly overrepresented in both heterozygous and homozygous individuals. There was a trend for an even higher male bias in the homozygous group. All 24 homozygotes were African American, whereas four of the heterozygotes were reported as white. Two novel V122I compound heterozygotes were also identified, with clinical presentation in the late fifth or early sixth decade of life. This study is the largest homozygous V122I cohort reported and demonstrates association with earlier age at onset. It also highlights the uncertain penetrance, particularly with respect to sex.

Individuals

    heterozygous for the V122I mutation in transthyretin (TTR)
    GENETICS

 tend to develop

    cardiac amyloidosis
    DIAGNOSIS

, often

    after the seventh decade of life
    AGE

. Although

    homozygotes
    GENETICS

 have been reported, these have typically been single case reports. We report a cohort of 13

    V122I homozygotes
    GENETICS

.

    TTR gene sequencing results
    PARACLINICAL

 from the Mayo Clinic

    Molecular Genetics Laboratory
    PARACLINICAL

 between September 2004 and January 2013 were reviewed; 177

    heterozygotes
    GENETICS

 and 13 homozygotes for the

    V122I alteration
    GENETICS

 were identified. Detailed clinical history was available for the 24

    heterozygotes
    GENDER

 seen at Mayo Clinic. We compared

    age at onset
    AGE

 of disease for this group to homozygotes, both alone and pooled with the 11 homozygotes from the literature. Individuals with

    homozygous V122I
    GENETICS

 manifested symptoms

    a mean of 10 years earlier
    AGE

 than

    heterozygotes
    GENETICS

    (63.8 ± 5.7 versus 72 ± 8.1 yrs
    AGE

, P = 0.0002). Further,

    males
    GENDER

 were significantly overrepresented in both heterozygous and homozygous individuals. There was a trend for an even higher

    male
    GENDER

 bias in the homozygous group. All 24 homozygotes were

    African American
    ETHNICITY

, whereas four of the

    heterozygotes
    GENETICS

 were reported as

    white
    ETHNICITY

. Two

    novel V122I compound heterozygotes
    GENETICS

 were also identified, with clinical presentation in the

    late fifth or early sixth decade of life
    AGE

. This study is the largest

    homozygous V122I
    GENETICS

 cohort reported and demonstrates association with

    earlier age at onset
    AGE

. It also highlights the uncertain penetrance, particularly with respect to sex.


A novel variant mutation of transthyretin Ile73Val-related amyloidotic polyneuropathy in Taiwanese.

Familial amyloidotic polyneuropathy (FAP) is an inherited disease caused by deposition of mutant amyloid proteins in the peripheral nerves. Abnormal transthyretin (TTR) accounts for protein aggregation in the majority of FAP. Val30Met is the most common TTR gene-mutation reported in different ethnic populations. In Taiwan, Ala97Ser mutation is probably a major hot-spot of TTR mutations. On the other hand, Ile73Val mutation was only reported in one Bangladeshi family. We reported here the first patient of amyloidotic polyneuropathy with Ile73Val TTR mutation in Taiwan.

This patient had symptoms and signs of sensory motor polyneuropathy and early gastrointestinal autonomic dysfunction since around 50 years old. A nerve conduction velocity (NCV) study showed typical axonal sensory-motor polyneuropathy. A standard autonomic function test revealed orthostatic hypotension and was compatible with cardiovascular autonomic dysfunction. There was also impaired sudomotor activity. An echocardiogram study suggested amyloidotic restrictive cardiomyopathy. A genetic analysis revealed Ile73Val TTRR mutation.

We reported the first patient with Ile73Val TTR mutation in Taiwan, who had earlier gastrointestinal dysfunction. Similar to the Bangladeshi patient reported in the previous article, painful neuropathy, a feature typically presented in more common TTR gene mutations, is absent.

    Familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 is an

    inherited disease
    GENETICS

 caused by

    deposition of mutant amyloid proteins in the peripheral nerves
    MICROSCOPIC

.

    Abnormal transthyretin (TTR)
    BIOCHEMICAL

 accounts for

    protein aggregation
    MICROSCOPIC

 in the majority of

    FAP
    DIAGNOSIS

.

    Val30Met
    GENETICS

 is the most common

    TTR gene-mutation
    GENETICS

 reported in different ethnic populations. In

    Taiwan
    ETHNICITY

,

    Ala97Ser mutation
    GENETICS

 is probably a major

    hot-spot of TTR mutations
    GENETICS

. On the other hand,

    Ile73Val mutation
    GENETICS

 was only reported in one

    Bangladeshi
    ETHNICITY

 family. We reported here the first patient of

    amyloidotic polyneuropathy
    DIAGNOSIS

 with

    Ile73Val TTR mutation
    GENETICS

 in

    Taiwan
    ETHNICITY

.

This patient had

    symptoms and signs of sensory motor polyneuropathy
    SYMPTOMS

 and

    early gastrointestinal autonomic dysfunction
    SYMPTOMS

 since

    around 50 years old
    AGE

. A

    nerve conduction velocity (NCV) study
    PARACLINICAL

 showed typical

    axonal sensory-motor polyneuropathy
    DIAGNOSIS

. A

    standard autonomic function test
    PARACLINICAL

 revealed

    orthostatic hypotension
    SYMPTOMS

 and was compatible with

    cardiovascular autonomic dysfunction
    SYMPTOMS

. There was also

    impaired sudomotor activity
    SYMPTOMS

. An

    echocardiogram study
    PARACLINICAL

 suggested

    amyloidotic restrictive cardiomyopathy
    DIAGNOSIS

. A

    genetic analysis
    PARACLINICAL

 revealed

    Ile73Val TTRR mutation
    GENETICS

.

We reported the first patient with

    Ile73Val TTR mutation
    GENETICS

 in

    Taiwan
    ETHNICITY

, who had earlier

    gastrointestinal dysfunction
    SYMPTOMS

. Similar to the

    Bangladeshi
    ETHNICITY

 patient reported in the previous article,

    painful neuropathy
    SYMPTOMS

, a feature typically presented in more common

    TTR gene mutations
    GENETICS

, is absent.

inherited disease
Val30Met
TTR gene-mutation
Ala97Ser mutation
hot-spot of TTR mutations
Ile73Val mutation
Ile73Val TTR mutation
Ile73Val TTRR mutation
Ile73Val TTR mutation
TTR gene mutations

Taiwan Bangladeshi Taiwan Taiwan Bangladeshi


Severe heart disease in an unusual case of familial amyloid polyneuropathy type I.

Familial amyloid polyneuropathy type I (FAP type I) is a rare hereditary systemic amyloidosis caused by the Val30Met mutation in the transthyretin (TTR) gene. The clinical onset and spectrum are variable and depend on phenotypic heterogeneity. Cardiac complications (dysrhythmias and conduction disturbances, cardiomyopathy and dysautonomia) indicate a poor prognosis, even after liver transplantation. We report an atypical case of FAP type I, highlighting the severe cardiac involvement and its complications. Early diagnosis of amyloid heart disease is increasingly important in the context of several clinical trials of promising new and experimental drugs.

    Familial amyloid polyneuropathy type I (FAP type I)
    DIAGNOSIS

 is a

    rare hereditary systemic amyloidosis
    DIAGNOSIS

 caused by the

    Val30Met mutation in the transthyretin (TTR) gene
    GENETICS

. The clinical onset and spectrum are variable and depend on phenotypic heterogeneity.

    Cardiac complications
    SYMPTOMS

 (

    dysrhythmias and conduction disturbances
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

 and

    dysautonomia
    SYMPTOMS

) indicate a poor prognosis, even after

    liver transplantation
    MEDICATION

. We report an atypical case of

    FAP type I
    DIAGNOSIS

, highlighting the

    severe cardiac involvement
    SYMPTOMS

 and

    its complications
    SYMPTOMS

. Early diagnosis of

    amyloid heart disease
    DIAGNOSIS

 is increasingly important in the context of several clinical trials of promising new and experimental drugs.


Diagnosis of systemic amyloidosis and amyloidosis mediated cardiomyopathy by VATS pleural biopsy for chronic pleural effusion.

Amyloidosis is a family of diseases characterized by the extracellular accumulation of amyloid protein, causing altered physiology based on its abnormal deposition in an organ. The etiology of persistent pleural effusions in patients with systemic amyloidosis is unknown. Endomyocardial biopsy is the gold standard of diagnosis for patients with cardiac involvement in systemic amyloidosis. We present the case of a patient with systemic amyloidosis whose diagnosis was made by pleural pathology collected via video-assisted thoracic surgery after a false negative endomyocardial biopsy.

    Amyloidosis
    DIAGNOSIS

 is a family of diseases characterized by the

    extracellular accumulation of amyloid protein
    MICROSCOPIC

, causing

    altered physiology
    SYMPTOMS

 based on its

    abnormal deposition in an organ
    MICROSCOPIC

. The etiology of

    persistent pleural effusions
    SYMPTOMS

 in patients with

    systemic amyloidosis
    DIAGNOSIS

 is unknown.

    Endomyocardial biopsy
    PARACLINICAL

 is the gold standard of diagnosis for patients with

    cardiac involvement
    SYMPTOMS

 in

    systemic amyloidosis
    DIAGNOSIS

. We present the case of a patient with

    systemic amyloidosis
    DIAGNOSIS

 whose diagnosis was made by

    pleural pathology collected
    PARACLINICAL

 via

    video-assisted thoracic surgery
    MEDICATION

 after a

    false negative endomyocardial biopsy
    NEG_FINDINGS

.

Amyloidosis
systemic amyloidosis
systemic amyloidosis
systemic amyloidosis

altered physiology
persistent pleural effusions
cardiac involvement


Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome.

Mutations in SLC29A3 lead to pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy plus syndrome. We report a new association of PHID syndrome with severe systemic inflammation, scleroderma-like changes, and cardiomyopathy. A 12-year-old girl with PHID syndrome presented with shortness of breath, hepatosplenomegaly, and raised erythrocyte sedimentation rate and C-reactive protein. An echocardiogram showed biventricular myocardial hypertrophy, and cardiac magnetic resonance imaging showed circumferential late gadolinium enhancement of the myocardium. No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan. Abdominal ultrasound revealed intra-abdominal fat surrounding the solid organs, suggesting a possibility of evolving lipodystrophy with visceral adiposity. PHID syndrome is a novel monogenic autoinflammatory syndrome (AIS) associated with severe elevation of serum amyloid. Lipodystrophy, cutaneous sclerodermatous changes, and cardiomyopathy were also present in this case. In contrast to other AIS, blockade of interleukin-1 and tumor necrosis-α was ineffective.

    Mutations in SLC29A3
    GENETICS

 lead to

    pigmentary hypertrichosis
    SYMPTOMS

 and

    non-autoimmune insulin-dependent diabetes mellitus (PHID)
    DIAGNOSIS

 and

    H syndromes
    DIAGNOSIS

,

    familial Rosai-Dorfman disease
    DIAGNOSIS

, and

    histiocytosis-lymphadenopathy plus syndrome
    DIAGNOSIS

. We report a new association of

    PHID syndrome
    DIAGNOSIS

 with

    severe systemic inflammation
    SYMPTOMS

,

    scleroderma-like changes
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

. A

    12-year-old
    AGE

    girl
    GENDER

 with

    PHID syndrome
    DIAGNOSIS

 presented with

    shortness of breath
    SYMPTOMS

,

    hepatosplenomegaly
    SYMPTOMS

, and

    raised erythrocyte sedimentation rate and C-reactive protein
    BIOCHEMICAL

. An

    echocardiogram
    PARACLINICAL

 showed

    biventricular myocardial hypertrophy
    SYMPTOMS

, and

    cardiac magnetic resonance imaging
    PARACLINICAL

 showed

    circumferential late gadolinium enhancement of the myocardium
    SYMPTOMS

.

    No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan
    NEG_FINDINGS

.

    Abdominal ultrasound
    PARACLINICAL

 revealed

    intra-abdominal fat surrounding the solid organs
    SYMPTOMS

, suggesting a possibility of

    evolving lipodystrophy with visceral adiposity
    SYMPTOMS

.

    PHID syndrome
    DIAGNOSIS

 is a

    novel monogenic autoinflammatory syndrome (AIS)
    DIAGNOSIS

 associated with

    severe elevation of serum amyloid
    BIOCHEMICAL

.

    Lipodystrophy
    SYMPTOMS

,

    cutaneous sclerodermatous changes
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

 were also present in this case. In contrast to other

    AIS
    DIAGNOSIS

,

    blockade of interleukin-1 and tumor necrosis-α was ineffective
    NEG_FINDINGS

.


High 99mTc-DPD myocardial uptake in a patient with apolipoprotein AI-related amyloidotic cardiomyopathy.

Amyloidotic cardiomyopathy is still a widely underdiagnosed condition that usually requires endomyocardial biopsy (EMB) for a definite diagnosis. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has proven highly sensitive for detecting amyloidotic cardiomyopathy due to transthyretin-related amyloid deposition. Herein we report the first description of the (99mTc-DPD scintigraphy profile in a patient with suspected amyloidotic cardiomyopathy and a final EMB- and genetically-proven diagnosis of familial apolipoprotein AI amyloidosis due to Leu174Ser variant.

    Amyloidotic cardiomyopathy
    DIAGNOSIS

 is still a widely underdiagnosed condition that usually requires

    endomyocardial biopsy (EMB)
    PARACLINICAL

 for a definite diagnosis.

    99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD)
    PARACLINICAL

 has proven highly sensitive for detecting

    amyloidotic cardiomyopathy
    DIAGNOSIS

 due to

    transthyretin-related amyloid deposition
    DIAGNOSIS

. Herein we report the first description of the

    (99mTc-DPD scintigraphy profile
    PARACLINICAL

 in a patient with suspected

    amyloidotic cardiomyopathy
    DIAGNOSIS

 and a final

    EMB- and genetically-proven
    PARACLINICAL

 diagnosis of

    familial apolipoprotein AI amyloidosis due to Leu174Ser variant
    DIAGNOSIS

.


Inclusion body myositis coexisting with hypertrophic cardiomyopathy: an autopsy study.

Inclusion body myositis is an inflammatory myopathy characterized pathologically by rimmed vacuoles and the accumulation of amyloid-related proteins. Autopsy studies in these patients, including histochemical examinations of multiple skeletal muscles, have not yet been published. In this paper, we describe the autopsy findings of a patient with inclusion body myositis and hypertrophic cardiomyopathy. A 69-year-old man, who was a human T lymphotropic virus type 1 carrier, exhibited slowly progressive muscle weakness and atrophy, predominantly affecting the scapular, quadriceps femoris, and forearm flexor muscles. His disease course was more rapidly progressive than that typically observed; the patient died suddenly of arrhythmia 5 years after diagnosis. Autopsy findings revealed that multiple muscles, including the respiratory muscles, were involved. Longitudinal studies revealed an increased frequency of rimmed vacuoles and p62/sequestosome 1- and/or TAR DNA-binding protein 43-positive deposits in autopsied muscles, although the amount of inflammatory infiltrate appeared to be decreased. We speculated that muscle degeneration may be more closely involved in disease progression compared with autoimmunity. Genetic analysis revealed a myosin binding protein C3 mutation, which is reportedly responsible for familial hypertrophic cardiomyopathy. This mutation and human T lymphotropic virus type 1 infection may have affected the skeletal muscles of this patient.

    Inclusion body myositis
    DIAGNOSIS

 is an

    inflammatory myopathy
    DIAGNOSIS

 characterized pathologically by

    rimmed vacuoles
    MICROSCOPIC

 and the

    accumulation of amyloid-related proteins
    MICROSCOPIC

.

    Autopsy studies
    PARACLINICAL

 in these patients, including

    histochemical examinations of multiple skeletal muscles
    PARACLINICAL

, have not yet been published. In this paper, we describe the

    autopsy
    PARACLINICAL

 findings of a patient with

    inclusion body myositis
    DIAGNOSIS

 and

    hypertrophic cardiomyopathy
    DIAGNOSIS

. A

    69-year-old
    AGE

    man
    GENDER

, who was a

    human T lymphotropic virus type 1 carrier
    DIAGNOSIS

, exhibited

    slowly progressive muscle weakness and atrophy
    SYMPTOMS

,

    predominantly affecting the scapular, quadriceps femoris, and forearm flexor muscles
    SYMPTOMS

.

    His
    GENDER

 disease course was

    more rapidly progressive
    SYMPTOMS

 than that typically observed; the patient

    died suddenly of arrhythmia
    SYMPTOMS

 5 years after diagnosis.

    Autopsy findings
    PARACLINICAL

 revealed that

    multiple muscles, including the respiratory muscles, were involved
    SYMPTOMS

.

    Longitudinal studies
    PARACLINICAL

 revealed an

    increased frequency of rimmed vacuoles and p62/sequestosome 1- and/or TAR DNA-binding protein 43-positive deposits in autopsied muscles
    MICROSCOPIC

, although the

    amount of inflammatory infiltrate appeared to be decreased
    NEG_FINDINGS

. We speculated that

    muscle degeneration
    DIAGNOSIS

 may be more closely involved in disease progression compared with

    autoimmunity
    DIAGNOSIS

.

    Genetic analysis
    PARACLINICAL

 revealed a

    myosin binding protein C3 mutation
    GENETICS

, which is reportedly responsible for

    familial hypertrophic cardiomyopathy
    DIAGNOSIS

. This mutation and

    human T lymphotropic virus type 1 infection
    DIAGNOSIS

 may have affected the

    skeletal muscles
    SYMPTOMS

 of this patient.


The first Caucasian patient with p.Val122Ile mutated-transthyretin cardiac amyloidosis treated with isolated heart transplantation.

Effective treatments for mutated transthyretin (TTR)-related cardiac amyloidosis are limited. Heart transplantation or combined liver-heart transplantation are the most successful options, although results rely on underline mechanism and systemic nature of the disease. In this report, we present the first case of a Caucasian patient with the p.Val122Ile mutated TTR-related cardiac amyloidosis treated with heart transplantation due to this gene mutation frequent in Afro-Americans with a prevalent isolated heart involvement. The choice of isolated heart transplantation instead of combined heart and liver transplantations was based on (1) severe and progressive cardiac disease, (2) evidence of a gene mutation generally associated with isolated cardiac disease and (3) absence of relevant extra-cardiac involvement (with the possible exception of mild peripheral neuropathy). In any case, the very short post-transplant observation period of 10 months does not allow any conclusions on the long-term course of the presented strategy. Finally, it is the first European Caucasian family with the p.Val122Ile TTR mutation that has been described. Till now, very few Caucasian cases of p.Val122Ile mutated TTR-related cardiac amyloidosis have been reported. The patient and some members of his family also had mild peripheral neuropathy suggesting a regional phenotypic heterogeneity of European Caucasian TTR p.Val122Ile.

Effective treatments for

    mutated transthyretin (TTR)-related cardiac amyloidosis
    DIAGNOSIS

 are limited.

    Heart transplantation
    MEDICATION

 or

    combined liver-heart transplantation
    MEDICATION

 are the most successful options, although results rely on underline mechanism and systemic nature of the disease. In this report, we present the first case of a

    Caucasian
    ETHNICITY

 patient with the

    p.Val122Ile mutated TTR-related cardiac amyloidosis
    GENETICS

 treated with

    heart transplantation
    MEDICATION

 due to this

    gene mutation
    GENETICS

 frequent in

    Afro-Americans
    ETHNICITY

 with a prevalent

    isolated heart involvement
    SYMPTOMS

. The choice of

    isolated heart transplantation
    MEDICATION

 instead of

    combined heart and liver transplantations
    MEDICATION

 was based on (1)

    severe and progressive cardiac disease
    SYMPTOMS

, (2) evidence of a

    gene mutation generally associated with isolated cardiac disease
    GENETICS

 and (3)

    absence of relevant extra-cardiac involvement
    NEG_FINDINGS

 (with the possible exception of

    mild peripheral neuropathy)
    NEG_FINDINGS

. In any case, the very short

    post-transplant
    MEDICATION

 observation period of 10 months does not allow any conclusions on the long-term course of the presented strategy. Finally, it is the first

    European Caucasian
    ETHNICITY

 family with the

    p.Val122Ile TTR mutation
    GENETICS

 that has been described. Till now, very few

    Caucasian
    ETHNICITY

 cases of

    p.Val122Ile mutated TTR-related cardiac amyloidosis
    GENETICS

 have been reported. The patient and

    some members of his family also had mild peripheral neuropathy
    FAMILY

 suggesting a regional phenotypic heterogeneity of

    European Caucasian
    ETHNICITY

    TTR p.Val122Ile
    GENETICS

.

Caucasian
Afro-Americans
European Caucasian
Caucasian
European Caucasian

isolated heart involvement
severe and progressive cardiac disease


Direct tissue evaluation via immunofluorescence: in the diagnosis of hereditary transthyretin cardiac amyloidosis.

Multiple precursor proteins have been shown to cause cardiac amyloidosis. The most common forms are due either to immunoglobulin light chains or to transthyretin proteins (either wild-type or mutant forms). Correct subclassification of the amyloid is paramount because treatment differs in accordance with the type of amyloidosis. Indirect diagnostic methods, including serologic analysis, can lead to misdiagnosis. Definitive diagnosis often requires analysis of amyloid in the tissue. We present a case of a woman who was diagnosed with hereditary transthyretin cardiac amyloidosis by means of immunofluorescence and genetic analysis. This case highlights the importance-in the diagnostic algorithm of cardiac amyloidosis-of direct evaluation of the tissue with immunofluorescence and of genetic testing.

Multiple precursor proteins have been shown to cause

    cardiac amyloidosis
    DIAGNOSIS

. The most common forms are due either to

    immunoglobulin light chains
    DIAGNOSIS

 or to transthyretin proteins (either wild-type or mutant forms). Correct subclassification of the amyloid is paramount because treatment differs in accordance with the type of

    amyloidosis
    DIAGNOSIS

.

    Indirect
    PARACLINICAL

 diagnostic methods, including

    serologic analysis
    PARACLINICAL

, can lead to misdiagnosis. Definitive diagnosis often requires

    analysis of amyloid in the tissue
    PARACLINICAL

. We present a case of a

    woman
    GENDER

 who was diagnosed with

    hereditary transthyretin cardiac amyloidosis
    DIAGNOSIS

 by means of

    immunofluorescence
    PARACLINICAL

 and

    genetic analysis
    PARACLINICAL

. This case highlights the importance-in the diagnostic algorithm of

    cardiac amyloidosis
    DIAGNOSIS

-of

    direct evaluation of the tissue with immunofluorescence
    PARACLINICAL

 and of

    genetic testing
    PARACLINICAL

.


Two siblings diagnosed to have transthyretin-related familial amyloid cardiomyopathy around the same time at different hospitals.

Mutation in the transthyretin (TTR) gene may clinically manifest as cardiomyopathy. Here, we describe 69-year-old and 72-year-old brothers who were diagnosed as having TTR-related familial amyloid cardiomyopathy by endomyocardial biopsy at different hospitals at around the same time. They were not from an endemic area of familial amyloid polyneuropathy. Genetic analysis showed a base change in the TTR gene leading to a p.Val30Met mutation in both patients. Screening of family members, as well as detailed family history taking, is important for the diagnosis of cardiomyopathy of unknown etiology.

    Mutation in the transthyretin (TTR) gene
    GENETICS

 may clinically manifest as

    cardiomyopathy
    DIAGNOSIS

. Here, we describe

    69-year-old
    AGE

 and

    72-year-old
    AGE

    brothers
    GENDER

 who were diagnosed as having

    TTR-related familial amyloid cardiomyopathy
    DIAGNOSIS

 by

    endomyocardial biopsy
    PARACLINICAL

 at different hospitals at around the same time. They were

    not from an endemic area of familial amyloid polyneuropathy
    NEG_FINDINGS

.

    Genetic analysis
    PARACLINICAL

 showed a

    base change in the TTR gene leading to a p.Val30Met mutation
    GENETICS

 in both patients.

    Screening of family members
    PARACLINICAL

, as well as

    detailed family history taking
    PARACLINICAL

, is important for the diagnosis of

    cardiomyopathy of unknown etiology
    DIAGNOSIS

.


Transthyretin cardiac amyloidoses in older North Americans.

The amyloidoses are a group of hereditary or acquired disorders caused by the extracellular deposition of insoluble protein fibrils that impair tissue structure and function. All amyloidoses result from protein misfolding, a common mechanism for disorders in older persons, including Alzheimer's disease and Parkinson's disease. Abnormalities in the protein transthyretin (TTR), a serum transporter of thyroxine and retinol, is the most common cause of cardiac amyloidoses in elderly adults. Mutations in TTR can result in familial amyloidotic cardiomyopathy, and wild-type TTR can result in senile cardiac amyloidosis. These underdiagnosed disorders are much more common than previously thought. The resulting restrictive cardiomyopathy can cause congestive heart failure, arrhythmias, and advanced conduction system disease. Although historically difficult to make, the diagnosis of TTR cardiac amyloidosis has become easier in recent years with advances in cardiac imaging and more widespread use of genetic analysis. Although therapy has largely involved supportive medical care, avoidance of potentially toxic agents, and rarely organ transplantation, the near future brings the possibility of targeted pharmacotherapies designed to prevent TTR misfolding and amyloid deposition. Because these disease-modifying agents are designed to prevent disease progression, it has become increasingly important that older persons with TTR amyloidosis be expeditiously identified and considered for enrollment in clinical registries and trials.

The

    amyloidoses
    DIAGNOSIS

 are a group of

    hereditary
    GENETICS

 or acquired disorders caused by the

    extracellular deposition of insoluble protein fibrils
    MICROSCOPIC

 that

    impair tissue structure and function
    SYMPTOMS

. All

    amyloidoses
    DIAGNOSIS

 result from

    protein misfolding
    MICROSCOPIC

, a common mechanism for disorders in

    older persons
    AGE

, including

    Alzheimer's disease
    DIAGNOSIS

 and

    Parkinson's disease
    DIAGNOSIS

.

    Abnormalities in the protein transthyretin (TTR
    GENETICS

), a

    serum transporter of thyroxine and retinol
    BIOCHEMICAL

, is the most common cause of

    cardiac amyloidoses
    DIAGNOSIS

 in

    elderly adults
    AGE

.

    Mutations in TTR
    GENETICS

 can result in

    familial amyloidotic cardiomyopathy
    DIAGNOSIS

, and

    wild-type TTR
    GENETICS

 can result in

    senile cardiac amyloidosis
    DIAGNOSIS

. These underdiagnosed disorders are much more common than previously thought. The resulting

    restrictive cardiomyopathy
    SYMPTOMS

 can cause

    congestive heart failure
    SYMPTOMS

,

    arrhythmias
    SYMPTOMS

, and

    advanced conduction system disease
    SYMPTOMS

. Although historically difficult to make, the diagnosis of

    TTR cardiac amyloidosis
    DIAGNOSIS

 has become easier in recent years with advances in

    cardiac imaging
    PARACLINICAL

 and more widespread use of

    genetic analysis
    PARACLINICAL

. Although therapy has largely involved

    supportive medical care
    MEDICATION

,

    avoidance of potentially toxic agents
    MEDICATION

, and

    rarely organ transplantation
    MEDICATION

, the near future brings the possibility of

    targeted pharmacotherapies
    MEDICATION

 designed to prevent

    TTR misfolding and amyloid deposition
    BIOCHEMICAL

. Because these

    disease-modifying agents
    MEDICATION

 are designed to prevent disease progression, it has become increasingly important that

    older persons
    AGE

 with

    TTR amyloidosis
    DIAGNOSIS

 be expeditiously identified and considered for enrollment in clinical registries and trials.

amyloidoses
amyloidoses
Alzheimer's disease
Parkinson's disease
cardiac amyloidoses
familial amyloidotic cardiomyopathy
senile cardiac amyloidosis
TTR cardiac amyloidosis
TTR amyloidosis

impair tissue structure and function
restrictive cardiomyopathy
congestive heart failure
arrhythmias
advanced conduction system disease

supportive medical care
avoidance of potentially toxic agents
rarely organ transplantation
targeted pharmacotherapies
disease-modifying agents


Technetium pyrophosphate myocardial uptake and peripheral neuropathy in a rare variant of familial transthyretin (TTR) amyloidosis (Ser23Asn): a case report and literature review.

We report the fourth case of transthyretin amyloidosis (ATTR) Ser23Asn in a 41-year-old Ecuadorian male. He has a pedigree that spans seven generations and involves 24 family members who suffered early cardiac death. Salient presenting symptoms were fatigue, shortness of breath, and peripheral neuropathy. The diagnosis of cardiac amyloid was confirmed by immunohistochemical staining of an endomyocardial biopsy, genotyping and by technetium pyrophosphate ((99m)Tc-PYP) scintigraphy, which remains to be established as a reliable tool to visualize myocardial amyloid involvement in patients with the Ser23Asn transthyretin (TTR) variant. The patient underwent successful combined heart and liver transplant. We add to the current ATTR literature that in patients with the rare Ser23Asn mutation, peripheral nerve in addition to cardiac involvement can occur and (99m)Tc-PYP scintigraphy can be used as an imaging modality to visualize myocardial amyloid.

We report the fourth case of

    transthyretin amyloidosis (ATTR) Ser23Asn
    DIAGNOSIS

 in a

    41-year-old
    AGE

    Ecuadorian
    ETHNICITY

    male
    GENDER

.

    He
    GENDER

    has a pedigree that spans seven generations and involves 24 family members who suffered early cardiac death
    FAMILY

. Salient presenting symptoms were

    fatigue
    SYMPTOMS

,

    shortness of breath
    SYMPTOMS

, and

    peripheral neuropathy
    SYMPTOMS

. The diagnosis of

    cardiac amyloid
    DIAGNOSIS

 was confirmed by

    immunohistochemical staining of an endomyocardial biopsy
    PARACLINICAL

,

    genotyping
    PARACLINICAL

 and by

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

, which remains to be established as a reliable tool to visualize

    myocardial amyloid involvement
    SYMPTOMS

 in patients with the

    Ser23Asn transthyretin (TTR) variant
    GENETICS

. The patient underwent

    successful combined heart and liver transplant
    MEDICATION

. We add to the current ATTR literature that in patients with the

    rare Ser23Asn mutation
    GENETICS

,

    peripheral nerve in addition to cardiac involvement
    SYMPTOMS

 can occur and

    (99m)Tc-PYP scintigraphy
    PARACLINICAL

 can be used as an imaging modality to visualize

    myocardial amyloid
    SYMPTOMS

.

Ser23Asn transthyretin (TTR) variant
rare Ser23Asn mutation


Familial amyloidotic polyneuropathy with muscle, vitreous, leptomeningeal, and cardiac involvement: phenotypic, pathological, and MRI description.

Familial amyloidotic polyneuropathy (FAN type 1) is a rare systemic disease that causes severe and disabling peripheral neuropathy. We describe the phenotypic, radiological, and pathological characteristics of a patient with familial amyloid polyneuropathy type 1 who had evidence of motor-sensory-autonomic neuropathy, ocular vitreous deposits, diffuse leptomeningeal involvement, and hypertrophic cardiomyopathy. Muscle involvement, an infrequently reported feature, was also observed. Early recognition of the disease has significant therapeutic implications.

    Familial amyloidotic polyneuropathy (FAN type 1)
    DIAGNOSIS

 is a

    rare systemic disease
    DIAGNOSIS

 that causes

    severe and disabling peripheral neuropathy
    SYMPTOMS

. We describe the phenotypic, radiological, and pathological characteristics of a patient with

    familial amyloid polyneuropathy type 1
    DIAGNOSIS

 who had evidence of

    motor-sensory-autonomic neuropathy
    SYMPTOMS

,

    ocular vitreous deposits
    SYMPTOMS

,

    diffuse leptomeningeal involvement
    SYMPTOMS

, and

    hypertrophic cardiomyopathy
    SYMPTOMS

.

    Muscle involvement
    SYMPTOMS

, an infrequently reported feature, was also observed. Early recognition of the disease has significant therapeutic implications.


A case of familial amyloid polyneuropathy due to Phe33Val TTR with vitreous involvement as the initial manifestation.

We report a 61-year-old Japanese woman with transthyretin (TTR) Val33-related familial amyloid polyneuropathy (FAP). She presented with late-onset, vitreous involvement as the initial manifestation, slow development of polyneuropathy, cardiomyopathy, and severe autonomic failure without carpal tunnel syndrome. Liver transplantation was performed and her postoperative course was stable. Taken together with previous reports, vitreous opacities seem to be common to Val33 FAP. Vitreous amyloidosis is usually seen in combination with the involvement of other visceral organs. The findings in the present case emphasize that vitreous opacities could be the first manifestation of FAP.

We report a

    61-year-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

 with

    transthyretin (TTR) Val33-related
    GENETICS

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

.

    She
    GENDER

 presented with

    late-onset
    SYMPTOMS

,

    vitreous involvement
    SYMPTOMS

 as the initial manifestation,

    slow development of polyneuropathy
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

, and

    severe autonomic failure
    SYMPTOMS

    without carpal tunnel syndrome
    NEG_FINDINGS

.

    Liver transplantation
    MEDICATION

 was performed and

    her
    GENDER

 postoperative course was stable. Taken together with previous reports,

    vitreous opacities
    SYMPTOMS

 seem to be common to

    Val33 FAP
    DIAGNOSIS

.

    Vitreous amyloidosis
    SYMPTOMS

 is usually seen in combination with the

    involvement of other visceral organs
    SYMPTOMS

. The findings in the present case emphasize that

    vitreous opacities
    SYMPTOMS

 could be the first manifestation of

    FAP
    DIAGNOSIS

.

familial amyloid polyneuropathy (FAP)
Val33 FAP
FAP

late-onset
vitreous involvement
slow development of polyneuropathy
cardiomyopathy
severe autonomic failure
vitreous opacities
Vitreous amyloidosis
involvement of other visceral organs
vitreous opacities


How I treat amyloidosis.

Amyloidosis is an uncommon disorder in which proteins change conformation, aggregate, and form fibrils that infiltrate tissues, leading to organ failure and death. The most frequent types are light-chain (AL) derived from monoclonal B-cell disorders producing amyloidogenic immunoglobulin light chains, and the hereditary and "senile systemic" (ATTR) variants from mutant and wild-type transthyretin (TTR). Diagnosis requires tissue biopsy. AL is more frequent and causes more organ disease than ATTR. Although both can cause cardiomyopathy and heart failure, AL progresses more quickly, so survival depends on timely diagnosis. Typing is usually based on clinical and laboratory findings with monoclonal gammopathy evaluation and, if indicated, TTR gene testing. Direct tissue typing is required when one patient has 2 potential amyloid-forming proteins. In coming years, widespread use of definitive proteomics will improve typing. New therapies are in testing for ATTR, whereas those for AL have followed multiple myeloma, leading to improved survival. Challenges of diagnosing and caring for patients with amyloidosis include determination of type, counseling, and delivery of prompt therapy often while managing multisystem disease. Recent advances grew from clinical research and advocacy in many countries, and global husbandry of such efforts will reap future benefits for families and patients with amyloidosis.

    Amyloidosis
    DIAGNOSIS

 is an uncommon disorder in which

    proteins change conformation, aggregate, and form fibrils that infiltrate tissues
    MICROSCOPIC

, leading to

    organ failure
    SYMPTOMS

 and

    death
    SYMPTOMS

. The most frequent types are

    light-chain (AL)
    DIAGNOSIS

 derived from

    monoclonal B-cell disorders
    DIAGNOSIS

 producing

    amyloidogenic immunoglobulin light chains
    BIOCHEMICAL

, and the

    hereditary
    GENETICS

    and "senile systemic" (ATTR)
    DIAGNOSIS

 variants from

    mutant and wild-type transthyretin (TTR)
    GENETICS

. Diagnosis requires

    tissue biopsy
    PARACLINICAL

.

    AL
    DIAGNOSIS

 is more frequent and causes more

    organ disease
    DIAGNOSIS

 than

    ATTR
    DIAGNOSIS

. Although both can cause

    cardiomyopathy
    SYMPTOMS

 and

    heart failure
    SYMPTOMS

,

    AL
    DIAGNOSIS

 progresses more quickly, so survival depends on timely diagnosis. Typing is usually based on clinical and laboratory findings with

    monoclonal gammopathy evaluation
    PARACLINICAL

 and, if indicated,

    TTR gene testing
    PARACLINICAL

.

    Direct tissue typing
    PARACLINICAL

 is required when one patient has 2 potential

    amyloid-forming proteins
    MICROSCOPIC

. In coming years, widespread use of definitive proteomics will improve typing. New therapies are in testing for

    ATTR
    DIAGNOSIS

, whereas those for

    AL
    DIAGNOSIS

 have followed

    multiple myeloma
    DIAGNOSIS

, leading to improved survival. Challenges of diagnosing and caring for patients with

    amyloidosis
    DIAGNOSIS

 include determination of type,

    counseling
    MEDICATION

, and delivery of

    prompt therapy
    MEDICATION

 often while managing

    multisystem disease
    DIAGNOSIS

. Recent advances grew from clinical research and advocacy in many countries, and global husbandry of such efforts will reap future benefits for families and patients with

    amyloidosis
    DIAGNOSIS

.

Amyloidosis
light-chain (AL)
monoclonal B-cell disorders
and "senile systemic" (ATTR)
AL
organ disease
ATTR
AL
ATTR
AL
multiple myeloma
amyloidosis
multisystem disease
amyloidosis

organ failure
death
cardiomyopathy
heart failure


Cardiomyopathy in a Japanese family with the Glu61Lys transthyretin variant: a new phenotype.

We report a Japanese family with transthyretin (TTR) amyloidosis caused by ATTRGlu61Lys that was associated with progressive cardiomyopathy, peripheral neuropathy, and bilateral carpal tunnel syndrome. Amyloidotic polyneuropathy in association with ATTRGlu61Lys was previously described in a Japanese family by Shiomi et al., (Biochem Biophys Res Commun 1993;194:1090-1096), and the main clinical features of that family were late-onset sensorimotor polyneuropathy and severe autonomic disturbance. However, there have been no descriptions of either cardiac involvement or carpal tunnel syndrome. The Japanese family, we present here, had severe cardiomyopathy as a cardinal symptom, which is a new phenotype of the TTR amyloidosis with ATTRGlu61Lys. This report, alongwith a previous one, demonstrates the clinical variety of TTR amyloidosis caused by ATTRGlu61Lys.

We report a

    Japanese
    ETHNICITY

 family with

    transthyretin (TTR) amyloidosis
    DIAGNOSIS

 caused by

    ATTRGlu61Lys
    GENETICS

 that was associated with

    progressive cardiomyopathy
    SYMPTOMS

,

    peripheral neuropathy
    SYMPTOMS

, and

    bilateral carpal tunnel syndrome
    SYMPTOMS

.

    Amyloidotic polyneuropathy in association with ATTRGlu61Lys
    DIAGNOSIS

 was previously described in a

    Japanese
    ETHNICITY

 family by Shiomi et al., (Biochem Biophys Res Commun 1993;194:1090-1096), and the main clinical features of that family were

    late-onset sensorimotor polyneuropathy
    SYMPTOMS

 and

    severe autonomic disturbance
    SYMPTOMS

. However, there have been no descriptions of either

    cardiac involvement
    SYMPTOMS

 or

    carpal tunnel syndrome
    NEG_FINDINGS

. The

    Japanese
    ETHNICITY

 family, we present here, had

    severe cardiomyopathy
    SYMPTOMS

 as a cardinal symptom, which is a new phenotype of the

    TTR amyloidosis with ATTRGlu61Lys
    DIAGNOSIS

. This report, alongwith a previous one, demonstrates the clinical variety of

    TTR amyloidosis
    DIAGNOSIS

 caused by

    ATTRGlu61Lys
    DIAGNOSIS

.

progressive cardiomyopathy
peripheral neuropathy
bilateral carpal tunnel syndrome
late-onset sensorimotor polyneuropathy
severe autonomic disturbance
cardiac involvement
severe cardiomyopathy


Cardiac amyloidosis, a monoclonal gammopathy and a potentially misleading mutation.

A 46-year-old Afro-Caribbean man presented with progressive dyspnea and recurrent syncope. Clinical examination revealed evidence of biventricular failure.

Electrocardiography, echocardiography, cardiac biopsy, measurement of serum levels of free light chain, scintigraphy with radiolabeled serum amyloid P component, transthyretin gene sequencing and immunohistochemistry.

Cardiac acquired monoclonal immunoglobulin-light-chain amyloidosis with the incidental presence of the amyloidogenic transthyretin Val122Ile mutation.

The patient was referred for consideration of urgent cardiac transplantation and subsequent autologous stem cell transplantation. Unfortunately, he died suddenly within a few weeks of referral.

A

    46-year-old
    AGE

    Afro-Caribbean
    ETHNICITY

    man
    GENDER

 presented with

    progressive dyspnea
    SYMPTOMS

 and

    recurrent syncope
    SYMPTOMS

.

    Clinical examination
    PARACLINICAL

 revealed

    evidence of biventricular failure
    SYMPTOMS

.

    Electrocardiography
    PARACLINICAL

,

    echocardiography
    PARACLINICAL

,

    cardiac biopsy
    PARACLINICAL

,

    measurement of serum levels of free light chain
    PARACLINICAL

,

    scintigraphy with radiolabeled serum amyloid P component
    PARACLINICAL

,

    transthyretin gene sequencing
    PARACLINICAL

 and

    immunohistochemistry
    PARACLINICAL

.

    Cardiac acquired monoclonal immunoglobulin-light-chain amyloidosis
    DIAGNOSIS

 with the

    incidental presence of the amyloidogenic transthyretin Val122Ile mutation
    GENETICS

.

The patient was referred for

    consideration of urgent cardiac transplantation and subsequent autologous stem cell transplantation
    MEDICATION

. Unfortunately,

    he
    GENDER

    died
    SYMPTOMS

    suddenly
    SYMPTOMS

 within a few weeks of referral.

progressive dyspnea
recurrent syncope
evidence of biventricular failure
died
suddenly


Atrioventicular block in familial amyloidosis; revisiting an old debate.

Familial amyloidosis with polyneuropathy (FAP) is the rarest of the cardiac amyloidoses, with less than 200 cases diagnosed each year. In this disease, cardiac involvement is characterized by extracellular amyloid infiltration throughout the heart, usually resulting in sinoatrial nodal dysfunction, cardiomyopathy, and congestive heart failure. While cardiac conduction disturbances are a common feature of FAP, the mechanism of these disturbances seems to be a point of contention among researchers. We present a case of a 78-year-old man with a history of FAP admitted with the diagnosis of atrial fibrillation/flutter. After failing to convert to normal sinus rhythm despite medical therapy, an electrical cardioversion was performed. Following the procedure, the patient converted to symptomatic Mobitz type two second-degree atrioventricular block and required dual chamber pacemaker placement. Our case emphasizes the potential consequences of cardioversion in this progressive condition and the need for further studies on the pathophysiology of cardiac involvement in FAP.

    Familial amyloidosis with polyneuropathy (FAP)
    DIAGNOSIS

 is the rarest of the

    cardiac amyloidoses
    DIAGNOSIS

, with less than 200 cases diagnosed each year. In this disease,

    cardiac involvement
    SYMPTOMS

 is characterized by

    extracellular amyloid infiltration throughout the heart
    MICROSCOPIC

, usually resulting in

    sinoatrial nodal dysfunction
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

, and

    congestive heart failure
    SYMPTOMS

. While

    cardiac conduction disturbances
    SYMPTOMS

 are a common feature of

    FAP
    DIAGNOSIS

, the mechanism of these disturbances seems to be a point of contention among researchers. We present a case of a

    78-year-old
    AGE

    man
    GENDER

 with a history of

    FAP
    DIAGNOSIS

 admitted with the diagnosis of

    atrial fibrillation/flutter
    SYMPTOMS

. After

    failing to convert to normal sinus rhythm despite medical therapy
    NEG_FINDINGS

, an

    electrical cardioversion
    MEDICATION

 was performed. Following the procedure, the patient converted to

    symptomatic Mobitz type two second-degree atrioventricular block
    SYMPTOMS

 and required

    dual chamber pacemaker placement
    MEDICATION

. Our case emphasizes the potential consequences of

    cardioversion
    MEDICATION

 in this progressive condition and the need for further studies on the pathophysiology of

    cardiac involvement
    SYMPTOMS

 in

    FAP
    DIAGNOSIS

.

electrical cardioversion
dual chamber pacemaker placement
cardioversion


Heart transplantation for homozygous familial transthyretin (TTR) V122I cardiac amyloidosis.

Heart failure is the usual cause of death in patients with amyloid cardiomyopathy. The commonest form of hereditary cardiac amyloidosis is associated with the Val122Ile variant of transthyretin (TTR), which is carried by 3-4% of the African American population. Here, we report the outcome of the first cardiac transplantation in a patient with TTR V122I. A 59-year-old Caribbean man presented with biventricular failure. Other than previous bilateral carpel tunnel syndrome, he had been well and had no evidence of extracardiac amyloidosis. An endomyocardial biopsy demonstrated amyloid of TTR type. Sequencing of TTR gene indicated homozygosity for V122I. He underwent cardiac transplantation and 3 years later, remains well with no evidence of allograft or systemic amyloid deposition.

    Heart failure
    SYMPTOMS

 is the usual cause of

    death
    SYMPTOMS

 in patients with

    amyloid cardiomyopathy
    DIAGNOSIS

. The commonest form of

    hereditary cardiac amyloidosis
    DIAGNOSIS

 is associated with the

    Val122Ile variant of transthyretin (TTR)
    GENETICS

, which is carried by 3-4% of the

    African American
    ETHNICITY

 population. Here, we report the outcome of the first

    cardiac transplantation
    MEDICATION

 in a patient with TTR V122I. A

    59-year-old
    AGE

    Caribbean
    ETHNICITY

    man
    GENDER

 presented with

    biventricular failure
    SYMPTOMS

. Other than previous

    bilateral carpel tunnel syndrome
    NEG_FINDINGS

,

    he
    GENDER

 had been well and had

    no evidence of extracardiac amyloidosis
    NEG_FINDINGS

. An

    endomyocardial biopsy
    PARACLINICAL

 demonstrated

    amyloid of TTR type
    MICROSCOPIC

.

    Sequencing of TTR gene
    PARACLINICAL

 indicated homozygosity for V122I.

    He
    GENDER

 underwent

    cardiac transplantation
    MEDICATION

 and 3 years later, remains well with

    no evidence of allograft or systemic amyloid deposition
    NEG_FINDINGS

.

Heart failure
death
biventricular failure

amyloid cardiomyopathy
hereditary cardiac amyloidosis

cardiac transplantation
cardiac transplantation


Accelerating restrictive cardiomyopathy after liver transplantation in a patient with familial amyloidotic polyneuropathy: a case report.

Hereditary amyloidodis is a rare disease process with a propensity to cause polyneuropathies, autonomic dysfunction, and restrictive cardiomyopathy. It is transmitted in an autosomal dominant manner, with disease onset usually in the 20s-40s. The most common hereditary amyloidogenic protein, transthyretin, is synthesized in the liver and lies on Chromosome 18. Over 80 amyloidogenic transthyretin mutations have been described, the majority of which are neuropathic and hence the common name, Familial Amyloidotic Polyneuropathy. Until 1990, the disease was intractable with a 5-15 year survival after diagnosis. The prognosis changed after the implementation of orthotropic liver transplantation as a treatment strategy which halts the synthesis of amyloidogenic transthyretin. This has now has been performed over 1300 times in 67 centers.

We describe the case of a man of Irish ancestry with Familial Amyloidotic Polyneuropathy and no clinical history of cardiac involvement. Shortly after orthotropic liver transplantation, he developed congestive heart failure. He was subsequently diagnosed with an accelerating post-transplant restrictive cardiomyopathy due to amyloid infiltration.

A liver transplant induced cardiomyopathy in Familial Amyloidotic Polyneuropathy can be observed in patients without any history of cardiac symptoms. All patients with Familial Amyloidotic Polyneuropathy should be followed after transplantation to assess for a deterioration in cardiac function.

    Hereditary amyloidodis
    DIAGNOSIS

 is a rare disease process with a propensity to cause

    polyneuropathies
    SYMPTOMS

,

    autonomic dysfunction
    SYMPTOMS

, and

    restrictive cardiomyopathy
    SYMPTOMS

. It is

    transmitted in an autosomal dominant manner
    GENETICS

, with disease onset usually

    in the 20s-40s
    AGE

. The most common

    hereditary amyloidogenic protein
    GENETICS

,

    transthyretin
    BIOCHEMICAL

, is synthesized in the liver and

    lies on Chromosome 18
    GENETICS

. Over 80

    amyloidogenic transthyretin mutations
    GENETICS

 have been described, the majority of which are

    neuropathic
    DIAGNOSIS

 and hence the common name,

    Familial Amyloidotic Polyneuropathy
    DIAGNOSIS

. Until 1990, the disease was intractable with a 5-15 year survival after diagnosis. The prognosis changed after the implementation of

    orthotropic liver transplantation
    MEDICATION

 as a treatment strategy which

    halts the synthesis of amyloidogenic transthyretin
    BIOCHEMICAL

. This has now has been performed over 1300 times in 67 centers.

We describe the case of a

    man
    GENDER

 of

    Irish ancestry
    ETHNICITY

 with

    Familial Amyloidotic Polyneuropathy
    DIAGNOSIS

 and

    no clinical history of cardiac involvement
    NEG_FINDINGS

. Shortly after

    orthotropic liver transplantation
    MEDICATION

,

    he
    GENDER

 developed

    congestive heart failure
    SYMPTOMS

.

    He
    GENDER

 was subsequently diagnosed with an

    accelerating post-transplant restrictive cardiomyopathy
    DIAGNOSIS

 due to

    amyloid infiltration
    MICROSCOPIC

.

A

    liver transplant induced cardiomyopathy
    DIAGNOSIS

 in

    Familial Amyloidotic Polyneuropathy
    DIAGNOSIS

 can be observed in patients

    without any history of cardiac symptoms
    NEG_FINDINGS

. All patients with

    Familial Amyloidotic Polyneuropathy
    DIAGNOSIS

 should be followed after

    transplantation
    MEDICATION

 to assess for a

    deterioration in cardiac function
    SYMPTOMS

.

polyneuropathies
autonomic dysfunction
restrictive cardiomyopathy
congestive heart failure
deterioration in cardiac function

orthotropic liver transplantation
orthotropic liver transplantation
transplantation


Identification of a novel TTR Gly67Glu mutant and the first case series of familial transthyretin amyloidosis in Hong Kong Chinese.

Familial transthyretin amyloidosis (ATTR), caused by mutant transthyretin deposition, is mainly characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. There are few reports among the Chinese population. We previously described the TTR mutation (Val30Ala) in the first Hong Kong Chinese family with ATTR. In this study, we report the progress of this family and describe another three unrelated Chinese kinships newly diagnosed with ATTR. The second proband presented mainly with peripheral neuropathy, and genetic analysis of the TTR gene showed alanine-to-serine substitution at amino acid 97. The third proband complained of autonomic dysfunction, and a novel missense mutation of glycine-to-glutamate substitution at amino acid 67 was found. The fourth patient presented with peripheral neuropathy and diastolic cardiomyopathy with the mutation threonine-to-lysine at codon 59. Diagnosis was delayed for more than 2 years. We performed DNA analysis in 46 subjects and detected a total of 21 patients, including the four probands, affected with ATTR, 15 of whom were still at a symptom-free stage at the time of writing. We conclude that ATTR remains largely underdiagnosed in the Chinese population. A high clinical suspicion is crucial for a timely diagnosis and can thus lead to a significant decrease in morbidity and mortality.

    Familial transthyretin amyloidosis (ATTR)
    DIAGNOSIS

, caused by

    mutant transthyretin deposition
    MICROSCOPIC

, is mainly characterized by

    peripheral neuropathy
    SYMPTOMS

,

    autonomic dysfunction
    SYMPTOMS

, and

    cardiomyopathy
    SYMPTOMS

. There are few reports among the

    Chinese
    ETHNICITY

 population. We previously described the

    TTR mutation (Val30Ala)
    GENETICS

 in the first

    Hong Kong Chinese
    ETHNICITY

 family with

    ATTR
    DIAGNOSIS

. In this study, we report the progress of this family and describe another three unrelated

    Chinese
    ETHNICITY

    kinships
    FAMILY

 newly diagnosed with

    ATTR
    DIAGNOSIS

. The second proband presented mainly with

    peripheral neuropathy
    SYMPTOMS

, and

    genetic analysis of the TTR gene
    PARACLINICAL

 showed

    alanine-to-serine substitution at amino acid 97
    GENETICS

. The third proband complained of

    autonomic dysfunction
    SYMPTOMS

, and a

    novel missense mutation of glycine-to-glutamate substitution at amino acid 67
    GENETICS

 was found. The fourth patient presented with

    peripheral neuropathy
    SYMPTOMS

 and

    diastolic cardiomyopathy
    SYMPTOMS

 with the

    mutation threonine-to-lysine at codon 59
    GENETICS

. Diagnosis was delayed for more than 2 years. We performed

    DNA analysis
    PARACLINICAL

 in 46 subjects and detected a total of 21 patients, including the four probands, affected with

    ATTR
    DIAGNOSIS

, 15 of whom were still at a

    symptom-free stage
    NEG_FINDINGS

 at the time of writing. We conclude that

    ATTR
    DIAGNOSIS

 remains largely underdiagnosed in the

    Chinese
    ETHNICITY

 population. A high clinical suspicion is crucial for a timely diagnosis and can thus lead to a significant decrease in morbidity and mortality.

peripheral neuropathy
autonomic dysfunction
cardiomyopathy
peripheral neuropathy
autonomic dysfunction
peripheral neuropathy
diastolic cardiomyopathy

Chinese
Hong Kong Chinese
Chinese
Chinese


A new ATTR Phe64Ile mutation with late-onset multiorgan involvement.

We describe a novel transthyretin mutation in which phenylalanine is replaced with isoleucine in exon 3 at codon 64: Phe64Ile. The mutation was found in an isolated patient and it was not possible to perform a family study. The phenotype included heart and peripheral nerve involvement associated with a possible gastrointestinal and renal involvement.

We describe a

    novel transthyretin mutation in which phenylalanine is replaced with isoleucine in exon 3 at codon 64: Phe64Ile
    GENETICS

. The mutation was found in an isolated patient and it was

    not possible to perform a family study
    NEG_FINDINGS

. The phenotype included

    heart and peripheral nerve involvement
    SYMPTOMS

 associated with a possible

    gastrointestinal and renal involvement
    SYMPTOMS

.

heart and peripheral nerve involvement
gastrointestinal and renal involvement


Transthyretin valine-94-alanine, a novel variant associated with late-onset systemic amyloidosis with cardiac involvement.

A 63-year-old Caucasian male, diagnosed with dilated cardiomyopathy in 1993, remained clinically stable for several years. In 2003, a marked increase of N-terminal pro-natriuretic peptide serum level (611 ng/ml to 4926 ng/ml) was observed; left ventricular (LV) septum thickness was 10 mm. In addition, sensorimotor polyneuropathy and autonomic dysfunction occurred. Further progression of heart failure occurred despite unchanged systolic LV function. Endomyocardial biopsy in 2006 revealed transthyretin amyloidosis by Congo red and immunohistochemical staining, as well as Val94Ala substitution by transthyretin gene analysis. Cardiac amyloid deposition was quantified by technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. Mutational search of the relatives (n = 1) was unremarkable. The transthyretin Val94Ala mutation is characterized by sensorimotor polyneuropathy, autonomic dysfunction, and gastrointestinal and cardiac involvement with amyloid. This mutation is an addition to the growing spectrum of transthyretin mutations with late onset of clinical symptoms, but noteworthy because of progressive, finally disabling disease course. Final clinical assessment of severity of cardiac involvement in the present patient is rendered complex by possible concomitant or preceding idiopathic dilated cardiomyopathy.

A

    63-year-old
    AGE

    Caucasian
    ETHNICITY

    male
    GENDER

, diagnosed with

    dilated cardiomyopathy
    DIAGNOSIS

 in 1993,

    remained clinically stable for several years
    NEG_FINDINGS

. In 2003, a

    marked increase of N-terminal pro-natriuretic peptide serum level (611 ng/ml to 4926 ng/ml)
    BIOCHEMICAL

 was observed;

    left ventricular (LV) septum thickness was 10 mm
    SYMPTOMS

. In addition,

    sensorimotor polyneuropathy
    SYMPTOMS

 and

    autonomic dysfunction
    SYMPTOMS

 occurred.

    Further progression of heart failure
    SYMPTOMS

 occurred

    despite unchanged systolic LV function
    NEG_FINDINGS

.

    Endomyocardial biopsy
    PARACLINICAL

 in 2006 revealed

    transthyretin amyloidosis
    DIAGNOSIS

 by

    Congo red and immunohistochemical staining
    PARACLINICAL

, as well as

    Val94Ala substitution
    GENETICS

 by

    transthyretin gene analysis
    PARACLINICAL

.

    Cardiac amyloid deposition
    MICROSCOPIC

 was quantified by

    technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy
    PARACLINICAL

.

    Mutational search of the relatives (n = 1) was unremarkable
    NEG_FINDINGS

. The

    transthyretin Val94Ala mutation
    GENETICS

 is characterized by

    sensorimotor polyneuropathy
    DIAGNOSIS

,

    autonomic dysfunction
    SYMPTOMS

, and

    gastrointestinal and cardiac involvement with amyloid
    SYMPTOMS

. This mutation is an addition to the growing spectrum of

    transthyretin mutations
    GENETICS

 with

    late onset of clinical symptoms
    SYMPTOMS

, but noteworthy because of progressive,

    finally disabling disease course
    SYMPTOMS

. Final clinical assessment of severity of

    cardiac involvement
    SYMPTOMS

 in the present patient is rendered complex by possible concomitant or preceding

    idiopathic dilated cardiomyopathy
    DIAGNOSIS

.

dilated cardiomyopathy
transthyretin amyloidosis
sensorimotor polyneuropathy
idiopathic dilated cardiomyopathy

Val94Ala substitution
transthyretin Val94Ala mutation
transthyretin mutations