Noninvasive diagnosis of hereditary transthyretin-related cardiac amyloidosis: A case report.

Cardiac transthyretin amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of clinical manifestations, routine electrocardiogram, echocardiography and the traditional requirement for endomyocardial biopsy confirmation.

A 68-year-old female had suffered from lumbago for 5 years with progressive weakness, numbness in both lower limb.

The patient's clinical signs were not specific, but cardiac amyloidosis was suspected based on relative left ventricular apical sparing of longitudinal strain on echocardiography and continuous elevated serum levels of cardiac biomarkers (ultrasensitive cardiac troponin I and NT-proBNP). She was finally diagnosed hereditary transthyretin-related cardiac amylodosis by specific findings of cardiovascular magnetic resonance imaging (CMR), -technetium pyrophosphate (Tc-PYP) scintigraphy and genetic testing.

The patient received medications including diuretics, beta-blockers and angiotensin-converting enzyme inhibitors at the time of hospitalization. Ultimately, however, she refused further treatments and requested discharge from our hospital.

A series of noninvasive technique enables the diagnosis of hereditary transthyretin-related cardiac amyloidosis.

While endomyocardial biopsy is not able to performed, this case demonstrates that a combination of noninvasive techniques, especially CMR, nuclear imaging, and genetic testing, may help us to make a correct diagnosis of hereditary transthyretin-related cardiac amyloidosis.

    Cardiac transthyretin amyloidosis
    DIAGNOSIS

 is a

    progressive
    DIAGNOSIS

 and fatal

    cardiomyopathy
    DIAGNOSIS

 for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of clinical manifestations,

    routine electrocardiogram
    PARACLINICAL

,

    echocardiography
    PARACLINICAL

 and the traditional requirement for

    endomyocardial biopsy confirmation
    PARACLINICAL

.

A

    68-year-old
    AGE

    female
    GENDER

 had suffered from

    lumbago for 5 years
    SYMPTOMS

 with

    progressive weakness
    SYMPTOMS

,

    numbness in both lower limb
    SYMPTOMS

.

The patient's

    clinical signs were not specific
    SYMPTOMS

, but

    cardiac amyloidosis
    DIAGNOSIS

 was suspected based on

    relative left ventricular apical sparing of longitudinal strain
    SYMPTOMS

 on

    echocardiography
    PARACLINICAL

 and

    continuous elevated serum levels of cardiac biomarkers (ultrasensitive cardiac troponin I and NT-proBNP)
    BIOCHEMICAL

.

    She
    GENDER

 was finally diagnosed

    hereditary transthyretin-related cardiac amylodosis
    DIAGNOSIS

 by specific findings of

    cardiovascular magnetic resonance imaging (CMR)
    PARACLINICAL

,

    -technetium pyrophosphate (Tc-PYP) scintigraphy
    PARACLINICAL

 and

    genetic testing
    PARACLINICAL

.

The patient received

    medications including diuretics, beta-blockers and angiotensin-converting enzyme inhibitors
    MEDICATION

 at the time of

    hospitalization
    MEDICATION

. Ultimately, however,

    she
    GENDER

    refused further treatments
    NEG_FINDINGS

 and requested

    discharge from our hospital
    MEDICATION

.

A series of noninvasive technique enables the diagnosis of

    hereditary transthyretin-related cardiac amyloidosis
    DIAGNOSIS

.

While

    endomyocardial biopsy
    PARACLINICAL

 is not able to performed, this case demonstrates that a combination of noninvasive techniques, especially

    CMR
    PARACLINICAL

,

    nuclear imaging
    PARACLINICAL

, and

    genetic testing
    PARACLINICAL

, may help us to make a correct diagnosis of

    hereditary transthyretin-related cardiac amyloidosis
    DIAGNOSIS

.


Extremely Early Onset Transthyretin Familial Amyloid Polyneuropathy with a Leu55Pro Mutation: A Pediatric Case Report and Literature Review.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant disease caused by the deposition of amyloid fibrils composed of TTR proteins. Symptoms of this disease include progressive sensorimotor neuropathy, cardiomyopathy, and involvement of other organs. We described a pediatric case of extremely early onset TTR-FAP with a TTR Leu55Pro mutation. A 17-year-old boy began to suffer from lower limb weakness, gait disturbance, and decreased sensation from 14 years of age onward. He presented with hypertrophic cardiomyopathy, periorbital and scleral ecchymosis, anhidrosis, orthostatic intolerance, and gastrointestinal autonomic dysfunction including nausea, vomiting, and diarrhea alternating with constipation. The patient's older sister had developed similar gastrointestinal symptoms from 20 years of age onward and was diagnosed as having hypertrophic cardiomyopathy. The boy's biopsy results showed infiltrated amyloid deposition on subcutaneous fat tissue and endocardium. Genetic analysis of the TTR gene demonstrated that both the patient and his sister had a pathogenic mutation, c.224T > C (Leu55Pro). Both patients were prescribed tafamidis, a TTR stabilizing agent. Although a majority of TTR-FAPs occur during adulthood, it should be suspected, even in pediatric populations, when symmetric length dependent neuropathy occurs in conjunction with a family history of neuropathy, autonomic neuropathy, and/or cardiomyopathy.

    Transthyretin familial amyloid polyneuropathy (TTR-FAP)
    DIAGNOSIS

 is a life-threatening

    autosomal dominant disease
    GENETICS

 caused by the

    deposition of amyloid fibrils composed of TTR proteins
    MICROSCOPIC

. Symptoms of this disease include

    progressive sensorimotor neuropathy
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

, and

    involvement of other organs
    SYMPTOMS

. We described a

    pediatric
    AGE

 case of

    extremely early onset TTR-FAP
    DIAGNOSIS

 with a

    TTR Leu55Pro mutation
    GENETICS

. A

    17-year-old
    AGE

    boy
    GENDER

 began to suffer from

    lower limb weakness
    SYMPTOMS

,

    gait disturbance
    SYMPTOMS

, and

    decreased sensation
    SYMPTOMS

 from

    14 years of age
    AGE

 onward.

    He
    GENDER

 presented with

    hypertrophic cardiomyopathy
    SYMPTOMS

,

    periorbital and scleral ecchymosis
    SYMPTOMS

,

    anhidrosis
    SYMPTOMS

,

    orthostatic intolerance
    SYMPTOMS

, and

    gastrointestinal autonomic dysfunction
    SYMPTOMS

 including

    nausea
    SYMPTOMS

,

    vomiting
    SYMPTOMS

, and

    diarrhea
    SYMPTOMS

    alternating with constipation
    SYMPTOMS

. The patient's

    older sister had developed similar gastrointestinal symptoms
    FAMILY

    from 20 years of age
    FAMILY

 onward and was diagnosed as having

    hypertrophic cardiomyopathy
    DIAGNOSIS

. The

    boy
    GENDER

's

    biopsy results
    PARACLINICAL

 showed

    infiltrated amyloid deposition on subcutaneous fat tissue and endocardium
    MICROSCOPIC

.

    Genetic analysis of the TTR gene
    PARACLINICAL

 demonstrated that

    both the patient and his sister had a pathogenic mutation, c.224T > C (Leu55Pro)
    FAMILY

. Both patients were prescribed

    tafamidis, a TTR stabilizing agent
    MEDICATION

. Although a majority of

    TTR-FAPs
    DIAGNOSIS

 occur during

    adulthood
    AGE

, it should be suspected, even in

    pediatric
    AGE

 populations, when

    symmetric length dependent neuropathy
    SYMPTOMS

 occurs in conjunction with a

    family history of neuropathy
    FAMILY

,

    autonomic neuropathy
    SYMPTOMS

, and/or

    cardiomyopathy
    SYMPTOMS

.

autosomal dominant disease
TTR Leu55Pro mutation

progressive sensorimotor neuropathy
cardiomyopathy
involvement of other organs
lower limb weakness
gait disturbance
decreased sensation
hypertrophic cardiomyopathy
periorbital and scleral ecchymosis
anhidrosis
orthostatic intolerance
gastrointestinal autonomic dysfunction
nausea
vomiting
diarrhea
alternating with constipation
symmetric length dependent neuropathy
autonomic neuropathy
cardiomyopathy


[Problems of diagnostics and treatment of transtiretinum amyloidosis with destruction of the heart in the elderly: Clinical experience.]

The article presents a modern understanding of the treatment of cardiac amyloidosis, provides data on the frequency of occurrence, classification and variants of clinical manifestations of transthyretin amyloidosis. This pathology is a slowly progressive disease, the symptoms of which usually appear in the elderly and senile age. This diagnosis may become more common in the future as the population ages and diagnostic methods improve. As an illustration, a description of the clinical case of transtritin amyloidosis of the heart in a 77-year-old patient, which occurred with a primary lesion of the heart and symptoms of chronic heart failure, is given. It shows the difficulties in the lifetime diagnosis of transthyretin amyloidosis.

The article presents a modern understanding of the treatment of

    cardiac amyloidosis
    DIAGNOSIS

, provides data on the frequency of occurrence, classification and variants of clinical manifestations of

    transthyretin amyloidosis
    DIAGNOSIS

. This pathology is a

    slowly progressive
    DIAGNOSIS

 disease, the symptoms of which usually appear in the

    elderly
    AGE

 and

    senile age
    AGE

. This diagnosis may become more common in the future as the population ages and diagnostic methods improve. As an illustration, a description of the clinical case of

    transtritin amyloidosis of the heart
    DIAGNOSIS

 in a

    77-year-old
    AGE

 patient, which occurred with a

    primary lesion of the heart
    SYMPTOMS

 and

    symptoms of chronic heart failure
    SYMPTOMS

, is given. It shows the difficulties in the lifetime diagnosis of

    transthyretin amyloidosis
    DIAGNOSIS

.

cardiac amyloidosis
transthyretin amyloidosis
slowly progressive
transtritin amyloidosis of the heart
transthyretin amyloidosis

primary lesion of the heart
symptoms of chronic heart failure


Hereditary ATTR Amyloidosis with Cardiomyopathy Caused by the Novel Variant Transthyretin Y114S (p.Y134S).

We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.

We report the clinical features of a patient with

    hereditary transthyretin (ATTR) amyloidosis
    DIAGNOSIS

 associated with a

    novel mutation (Y114S, p.Y134S)
    GENETICS

. A

    65-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 was admitted to our hospital after a 3-year history of

    progressive dyspnea on exertion
    SYMPTOMS

. Five years previously,

    he
    GENDER

 presented

    dysesthesia in both hands
    SYMPTOMS

 caused by

    carpal tunnel syndrome
    SYMPTOMS

. A

    genetic analysis
    PARACLINICAL

 revealed a

    base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C)
    GENETICS

. The clinical characteristics were

    progressive cardiomyopathy with a poor vital prognosis
    SYMPTOMS

,

    late onset
    SYMPTOMS

,

    sporadic
    DIAGNOSIS

 case,

    bilateral carpal tunnel syndrome
    SYMPTOMS

,

    hypothyroidism
    SYMPTOMS

, and

    small fiber neuropathy
    SYMPTOMS

.


Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type.

For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

For the first time, we report of a

    Swedish
    ETHNICITY

    family of
    FAMILY

 five individuals with a

    TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene
    GENETICS

. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the

    Swedish
    ETHNICITY

 population is

    TTRVal30Met
    GENETICS

 and is mostly found in the Northern part of

    Sweden
    ETHNICITY

. Interestingly, the

    TTRGlu54Leu mutation
    GENETICS

 was found in the same endemic area. The main phenotype of the

    TTR Glu54Leu
    GENETICS

 patients is

    severe cardiomyopathy
    SYMPTOMS

, which resulted in

    heart transplantation for the
    MEDICATION

 index person. As previously seen for

    ATTR amyloidosis
    DIAGNOSIS

 patients with

    mainly cardiomyopathy
    DIAGNOSIS

,

    the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species
    MICROSCOPIC

. However,

    western blot analyses
    PARACLINICAL

 detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual

    type A band pattern
    SYMPTOMS

.

severe cardiomyopathy
type A band pattern


Transthyretin Amyloidosis Presenting With Upper-Extremity Neuropathy and Paucity of Autonomic Impairment.

We report a 73-year-old man with Val142Ile transthyretin (TTR) amyloidosis and an atypical clinical presentation of upper-extremity-predominant neuropathy without significant autonomic or cardiac involvement. TTR familial amyloid polyneuropathy commonly presents as length-dependent sensorimotor polyneuropathy with marked and early autonomic involvement. Multiple pathogenic mutations in TTR gene have been identified, of which Val50Met is commonly associated with TTR familial amyloid polyneuropathy, and Val142Ile is commonly associated with familial amyloid cardiomyopathy. Our patient is from a nonendemic region, without family history for amyloidosis. Predominant upper-extremity neuropathy, without significant cardiac or autonomic involvement, distinguishes this case from previously reported Val142Ile-mutated TTR amyloidosis.

We report a

    73-year-old
    AGE

    man
    GENDER

 with

    Val142Ile transthyretin (TTR) amyloidosis
    DIAGNOSIS

 and an atypical clinical presentation of

    upper-extremity-predominant neuropathy
    SYMPTOMS

    without significant autonomic or cardiac involvement
    NEG_FINDINGS

.

    TTR familial amyloid polyneuropathy
    DIAGNOSIS

 commonly presents as

    length-dependent sensorimotor polyneuropathy
    SYMPTOMS

 with

    marked and early autonomic involvement
    SYMPTOMS

.

    Multiple pathogenic mutations in TTR gene
    GENETICS

 have been identified, of which

    Val50Met
    GENETICS

 is commonly associated with

    TTR familial amyloid polyneuropathy
    DIAGNOSIS

, and

    Val142Ile
    GENETICS

 is commonly associated with

    familial amyloid cardiomyopathy
    DIAGNOSIS

. Our patient is from a

    nonendemic region
    ETHNICITY

,

    without family history for amyloidosis
    NEG_FINDINGS

.

    Predominant upper-extremity neuropathy
    SYMPTOMS

,

    without significant cardiac or autonomic involvement
    NEG_FINDINGS

, distinguishes this case from previously reported

    Val142Ile-mutated TTR amyloidosis
    DIAGNOSIS

.


Case series: clinical outcomes of the transthyretin valine-to-isoleucine mutation in a brother-sister pair.

Approximately 4% of the African-American population possess a valine-to-isoleucine (V122I) substitution within the transthyretin protein that results in a tendency for a normally tetrameric protein to dissociate into misfolded, monomeric subunits. These misfolded proteins can then accumulate pathologically and cause an autosomal dominant amyloid cardiomyopathy. Homozygous patients are infrequently documented in case reports, and though there are larger studies among heterozygous patients, there is a lack of studies or reports comparing disease within a family.

In this case series, we discuss a 61-year-old African-American male who succumbed to heart failure secondary to cardiac amyloidosis while awaiting orthotopic heart transplantation. We compare his case with that of his sister, a 65-year-old African-American woman with a history of recurrent supraventricular tachycardia requiring radiofrequency ablation, and intermittent chest pain with chronically elevated troponin despite no evidence of coronary artery disease. The sister in question was found to be homozygous for the transthyretin (TTR) V122I mutation with evidence of infiltrative process on cardiac magnetic resonance imaging, while clinical testing verified a heterozygous genotype in the brother. Here, we compare the clinical course and imaging data for the aforementioned brother-sister pair in the context of the amyloidogenic transthyretin V122I gene variant.

Through this familial report, we aim to highlight the variations in expression both within this family and in comparison, to the population. We also hope to emphasize the importance of genetic testing of families at risk for this specific transthyretin variant within the African-American community especially as novel therapies begin to emerge.

Approximately 4% of the

    African-American
    ETHNICITY

 population possess a

    valine-to-isoleucine (V122I) substitution within the transthyretin protein
    GENETICS

 that results in a tendency for a

    normally tetrameric protein to dissociate into misfolded, monomeric subunits
    MICROSCOPIC

. These

    misfolded proteins
    MICROSCOPIC

 can then

    accumulate pathologically
    MICROSCOPIC

 and cause an

    autosomal dominant amyloid cardiomyopathy
    DIAGNOSIS

.

    Homozygous
    GENETICS

 patients are infrequently documented in case reports, and though there are larger studies among

    heterozygous
    GENETICS

 patients, there is a lack of studies or reports comparing disease within a family.

In this case series, we discuss a

    61-year-old
    AGE

    African-American
    ETHNICITY

    male
    GENDER

 who succumbed to

    heart failure
    SYMPTOMS

 secondary to

    cardiac amyloidosis
    DIAGNOSIS

 while awaiting

    orthotopic heart transplantation
    MEDICATION

. We compare his case with that of his

    sister
    GENDER

, a

    65-year-old
    AGE

    African-American
    ETHNICITY

    woman
    GENDER

 with a history of

    recurrent supraventricular tachycardia
    SYMPTOMS

 requiring

    radiofrequency ablation
    MEDICATION

, and

    intermittent chest pain
    SYMPTOMS

 with

    chronically elevated troponin
    BIOCHEMICAL

 despite

    no evidence of coronary artery disease
    NEG_FINDINGS

. The

    sister in question was found to be homozygous for the transthyretin (TTR) V122I mutation
    FAMILY

 with

    evidence of infiltrative process
    SYMPTOMS

 on

    cardiac magnetic resonance imaging
    PARACLINICAL

, while

    clinical testing
    PARACLINICAL

    verified a heterozygous genotype in the brother
    FAMILY

. Here, we compare the clinical course and imaging data for the aforementioned

    brother-sister pair
    FAMILY

 in the context of the

    amyloidogenic transthyretin V122I gene variant
    GENETICS

.

Through this familial report, we aim to highlight the variations in expression both within this family and in comparison, to the population. We also hope to emphasize the importance of

    genetic testing
    PARACLINICAL

 of families at risk for this specific

    transthyretin variant
    GENETICS

 within the

    African-American
    ETHNICITY

 community especially as novel therapies begin to emerge.

African-American African-American African-American African-American

heart failure
recurrent supraventricular tachycardia
intermittent chest pain
evidence of infiltrative process

orthotopic heart transplantation
radiofrequency ablation


Cardiac amyloidosis: A case report and review of literature.

Cardiac amyloidosis, a disease caused by the precipitation of amyloid proteins in the myocardial extracellular matrix has been historically difficult to diagnose due to lack of specific clinical manifestations and necessity of biopsy to demonstrate amyloid deposition. However, advances in cardiovascular imaging techniques have facilitated earlier recognition of this disease. In addition, while once thought of as incurable, treatment strategies are emerging for cardiac amyloidosis, making early diagnosis essential.

We outline the case of a 73 years old African American female who was admitted with sudden onset shortness of breath and found to be in cardiogenic shock. Cardiac amyloidosis was suspected due to discordance between electrocardiogram and echocardiogram findings and this was subsequently confirmed with the aid of scintigraphy and an endomyocardial biopsy.

Our objective is to highlight the diagnostic evaluation and clinical implications of cardiac amyloidosis.

    Cardiac amyloidosis
    DIAGNOSIS

, a disease caused by the

    precipitation of amyloid proteins in the myocardial extracellular matrix
    MICROSCOPIC

 has been historically difficult to diagnose due to lack of specific clinical manifestations and necessity of

    biopsy
    PARACLINICAL

 to demonstrate

    amyloid deposition
    BIOCHEMICAL

. However, advances in cardiovascular imaging techniques have facilitated earlier recognition of this disease. In addition, while once thought of as

    incurable
    NEG_FINDINGS

, treatment strategies are emerging for

    cardiac amyloidosis
    DIAGNOSIS

, making early diagnosis essential.

We outline the case of a

    73 years old
    AGE

    African American
    ETHNICITY

    female
    GENDER

 who was admitted with

    sudden onset shortness of breath
    SYMPTOMS

 and found to be in

    cardiogenic shock
    SYMPTOMS

.

    Cardiac amyloidosis
    DIAGNOSIS

 was suspected due to

    discordance between electrocardiogram and echocardiogram findings
    SYMPTOMS

 and this was subsequently confirmed with the aid of

    scintigraphy
    PARACLINICAL

 and an

    endomyocardial biopsy
    PARACLINICAL

.

Our objective is to highlight the diagnostic evaluation and clinical implications of

    cardiac amyloidosis
    DIAGNOSIS

.

Cardiac amyloidosis
cardiac amyloidosis
Cardiac amyloidosis
cardiac amyloidosis


Demyelinating Neuropathy in a Patient Treated With Revusiran for Transthyretin (Thr60Ala) Amyloidosis.

Transthyretin amyloidosis patients develop length-dependent peripheral neuropathy, autonomic dysfunction, and restrictive cardiomyopathy associated with deposition of amyloid fibrils in these tissues. Despite advances in management over the past decade, this disorder causes profound debilitation and ultimately proves fatal. In this report, we describe a man with late-onset cardiac amyloidosis due to a transthyretin Thr60Ala mutation who was treated with an investigational RNAi therapeutic, revusiran, which targets hepatic transthyretin production. Sixteen months into treatment, he developed bilateral lower-extremity weakness and numbness, worsening balance, difficulty manipulating objects with his hands, and finger numbness. Nerve conduction studies were consistent with multifocal demyelinating neuropathy. Intravenous immunoglobulin therapy improved sensation in his hands and feet, and improved hand dexterity. A sural nerve biopsy demonstrated demyelination with substantial axonal loss in the absence of histologically detectable endoneurial amyloid deposition. This case expands the clinicopathologic spectrum of transthyretin amyloidosis and may represent complex disease and treatment effects.

    Transthyretin amyloidosis
    DIAGNOSIS

 patients develop

    length-dependent peripheral neuropathy
    SYMPTOMS

,

    autonomic dysfunction
    SYMPTOMS

, and

    restrictive cardiomyopathy
    SYMPTOMS

 associated with

    deposition of amyloid fibrils in these tissues
    MICROSCOPIC

. Despite advances in management over the past decade, this disorder causes

    profound debilitation
    SYMPTOMS

 and ultimately proves fatal. In this report, we describe a

    man
    GENDER

 with

    late-onset cardiac amyloidosis
    DIAGNOSIS

 due to a

    transthyretin Thr60Ala mutation
    GENETICS

 who was treated with an

    investigational RNAi therapeutic, revusiran
    MEDICATION

, which

    targets hepatic transthyretin production
    BIOCHEMICAL

. Sixteen months into treatment,

    he
    GENDER

 developed

    bilateral lower-extremity weakness and numbness
    SYMPTOMS

,

    worsening balance
    SYMPTOMS

,

    difficulty manipulating objects with his hands
    SYMPTOMS

, and

    finger numbness
    SYMPTOMS

.

    Nerve conduction studies
    PARACLINICAL

 were consistent with

    multifocal demyelinating neuropathy
    DIAGNOSIS

.

    Intravenous immunoglobulin therapy
    MEDICATION

    improved sensation in his hands and feet
    SYMPTOMS

, and

    improved hand dexterity
    SYMPTOMS

. A

    sural nerve biopsy
    PARACLINICAL

 demonstrated

    demyelination with substantial axonal loss
    SYMPTOMS

 in the

    absence of histologically detectable endoneurial amyloid deposition
    NEG_FINDINGS

. This case expands the clinicopathologic spectrum of

    transthyretin amyloidosis
    DIAGNOSIS

 and may represent complex disease and treatment effects.

Transthyretin amyloidosis
late-onset cardiac amyloidosis
multifocal demyelinating neuropathy
transthyretin amyloidosis


Amyloid Cardiomyopathy in the Rare Transthyretin Tyr78Phe Mutation.

Tyr78Phe is a rare pathogenic transthyretin (TTR) mutation. Few previous reports described a late-onset hereditary transthyretin-related amyloidosis (ATTR-m) form with a variable phenotype, mainly dominated by neurological manifestations. We describe the case of a 69-year-old male with massive but asymptomatic cardiac infiltration and only subclinical neurological involvement, and review the literature to depict characteristics of the Tyr78Phe TTR mutation.

    Tyr78Phe
    GENETICS

 is a

    rare pathogenic transthyretin (TTR) mutation
    GENETICS

. Few previous reports described a

    late-onset hereditary transthyretin-related amyloidosis (ATTR-m) form
    DIAGNOSIS

 with a variable phenotype, mainly dominated by

    neurological manifestations
    SYMPTOMS

. We describe the case of a

    69-year-old
    AGE

    male
    GENDER

 with

    massive but asymptomatic cardiac infiltration
    SYMPTOMS

 and

    only subclinical neurological involvement
    SYMPTOMS

, and review the literature to depict characteristics of the

    Tyr78Phe TTR mutation
    GENETICS

.


Hereditary cardiac amyloidosis associated with Pro24Ser transthyretin mutation: a case report.

Transthyretin amyloidosis is a systemic disorder caused by extracellular deposition of insoluble amyloid fibrils in peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs. Hereditary transthyretin amyloidosis is an autosomal dominant disease. More than 120 mutations have been reported in the transthyretin gene with considerable phenotypic heterogeneity and geographic diversity. Among them, a sporadic case of hereditary transthyretin amyloidosis with cardiac-predominant phenotype is very rare, progressive, and potentially fatal if left undiagnosed. However, a clinical diagnosis of cardiac amyloidosis still remains challenging due to non-specific symptoms, and less sensitivity and specificity of medical examinations.

A 60-year-old Japanese man with a history of embolic stroke and hypertrophic cardiomyopathy visited our department for heart failure. The present case exhibited only cardiomyopathy without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome, polyneuropathy, or autonomic dysfunction. An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. Technetium pyrophosphate scintigraphy indicated marked diffuse myocardial uptake of technetium pyrophosphate, strongly suggesting transthyretin cardiac amyloidosis, which was firmly confirmed by a left ventricular endomyocardial biopsy. Genetic analysis demonstrated a transthyretin C70T (Pro24Ser) heterozygous mutation. Tafamidis, a transthyretin stabilizer, was started. His cardiac symptoms remained unchanged for 12 months.

Here we report the case of a patient with hereditary cardiac amyloidosis associated with a Pro24Ser mutation in transthyretin, which is the first case reported in Japan. Technetium pyrophosphate scintigraphy was extremely useful for definitive diagnosis. Thus, we propose that the nuclear imaging technique should be taken into account even for an exploratory diagnosis of transthyretin cardiac amyloidosis.

    Transthyretin amyloidosis
    DIAGNOSIS

 is a

    systemic disorder
    DIAGNOSIS

 caused by

    extracellular deposition of insoluble amyloid fibrils in peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs
    MICROSCOPIC

.

    Hereditary transthyretin amyloidosis
    DIAGNOSIS

 is an

    autosomal dominant disease
    GENETICS

. More than 120 mutations have been reported

    in the transthyretin gene
    GENETICS

 with considerable phenotypic heterogeneity and geographic diversity. Among them, a sporadic case of

    hereditary transthyretin amyloidosis
    DIAGNOSIS

 with

    cardiac-predominant phenotype
    SYMPTOMS

 is very rare, progressive, and potentially fatal if

    left undiagnosed
    NEG_FINDINGS

. However, a clinical diagnosis of

    cardiac amyloidosis
    DIAGNOSIS

 still remains challenging due to

    non-specific symptoms
    NEG_FINDINGS

, and less sensitivity and specificity of medical examinations.

A

    60-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 with a history of

    embolic stroke
    SYMPTOMS

 and

    hypertrophic cardiomyopathy
    SYMPTOMS

 visited our department for

    heart failure
    SYMPTOMS

. The present case exhibited only

    cardiomyopathy
    DIAGNOSIS

    without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome
    NEG_FINDINGS

,

    polyneuropathy
    DIAGNOSIS

, or

    autonomic dysfunction
    SYMPTOMS

. An

    echocardiogram
    PARACLINICAL

 revealed

    severe asymmetric left ventricular hypertrophy
    SYMPTOMS

,

    biatrial dilatation
    SYMPTOMS

,

    pericardial effusion
    SYMPTOMS

, and

    preserved left ventricular ejection fraction of 50%
    SYMPTOMS

 with

    severe diastolic dysfunction
    SYMPTOMS

.

    Technetium pyrophosphate scintigraphy
    PARACLINICAL

 indicated

    marked diffuse myocardial uptake of technetium pyrophosphate
    MICROSCOPIC

, strongly suggesting

    transthyretin cardiac amyloidosis
    DIAGNOSIS

, which was firmly confirmed by a

    left ventricular endomyocardial biopsy
    PARACLINICAL

.

    Genetic analysis
    PARACLINICAL

 demonstrated a

    transthyretin C70T (Pro24Ser) heterozygous mutation
    GENETICS

.

    Tafamidis, a transthyretin stabilizer
    MEDICATION

, was started. His

    cardiac symptoms remained unchanged for 12 months
    NEG_FINDINGS

.

Here we report the case of a patient with

    hereditary cardiac amyloidosis
    DIAGNOSIS

 associated with a

    Pro24Ser mutation in transthyretin
    GENETICS

, which is the first case reported in

    Japan
    ETHNICITY

.

    Technetium pyrophosphate scintigraphy
    PARACLINICAL

 was extremely useful for definitive diagnosis. Thus, we propose that the

    nuclear imaging technique
    PARACLINICAL

 should be taken into account even for an exploratory diagnosis of

    transthyretin cardiac amyloidosis
    DIAGNOSIS

.

Transthyretin amyloidosis
systemic disorder
Hereditary transthyretin amyloidosis
hereditary transthyretin amyloidosis
cardiac amyloidosis
cardiomyopathy
polyneuropathy
transthyretin cardiac amyloidosis
hereditary cardiac amyloidosis
transthyretin cardiac amyloidosis


Monitoring treatment response to tafamidis by serial native T1 and extracellular volume in transthyretin amyloid cardiomyopathy.

Tafamidis meglumine, a transthyretin (TTR) stabilizer, is effective in delaying the progression of neuropathy in TTR amyloidosis with Val30Met mutations. However, its efficacy in TTR amyloid cardiomyopathy is not fully elucidated. Herein, we report a 73-year-old Japanese man with a diagnosis of TTR amyloid cardiomyopathy with Val30Met mutation treated with tafamidis. To evaluate treatment response, cardiac magnetic resonance imaging was performed before and after 12 months of tafamidis treatment. Native T1, extracellular volume, and left ventricular mass showed no obvious worsening, and findings of other diagnostic studies also supported the efficacy of tafamidis to delay the progression of amyloid cardiomyopathy. Our case suggests that serial native T1 and extracellular volume may be novel non-invasive imaging methods to monitor the treatment response to TTR stabilizers in cardiac amyloidosis and also that tafamidis may be effective in suppressing cardiac progression in TTR amyloid cardiomyopathy with Val30Met mutation.

    Tafamidis meglumine, a transthyretin (TTR) stabilizer
    MEDICATION

, is effective in delaying the progression of

    neuropathy
    SYMPTOMS

 in

    TTR amyloidosis
    DIAGNOSIS

 with

    Val30Met mutations
    GENETICS

. However, its efficacy in

    TTR amyloid cardiomyopathy
    DIAGNOSIS

 is not fully elucidated. Herein, we report a

    73-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 with a diagnosis of

    TTR amyloid cardiomyopathy
    DIAGNOSIS

 with

    Val30Met mutation
    GENETICS

 treated with

    tafamidis
    MEDICATION

. To evaluate treatment response,

    cardiac magnetic resonance imaging was performed before and after 12 months of tafamidis treatment
    PARACLINICAL

.

    Native T1, extracellular volume, and left ventricular mass
    SYMPTOMS

 showed

    no obvious worsening
    NEG_FINDINGS

, and findings of other diagnostic studies also supported the efficacy of

    tafamidis
    MEDICATION

 to

    delay the progression of amyloid cardiomyopathy
    SYMPTOMS

. Our case suggests that

    serial native T1 and extracellular volume
    PARACLINICAL

 may be novel non-invasive imaging methods to monitor the treatment response to

    TTR stabilizers
    MEDICATION

 in

    cardiac amyloidosis
    DIAGNOSIS

 and also that

    tafamidis
    MEDICATION

 may be effective in

    suppressing cardiac progression
    SYMPTOMS

 in

    TTR amyloid cardiomyopathy
    DIAGNOSIS

 with

    Val30Met mutation
    GENETICS

.

TTR amyloidosis
TTR amyloid cardiomyopathy
TTR amyloid cardiomyopathy
cardiac amyloidosis
TTR amyloid cardiomyopathy

Val30Met mutations
Val30Met mutation
Val30Met mutation


Late-onset Transthyretin (TTR)-familial Amyloid Polyneuropathy (FAP) with a Long Disease Duration from Non-endemic Areas in Japan.

We herein report the case of an 84-year-old woman with transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP-ATTR Val30Met), representing a very old case. The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation. Esophagogastroduodenoscopy revealed mucosal amyloid deposits, positive in anti-TTR antibody staining. A TTR gene analysis isolated the Val30Met mutation. More than a few cases of FAP-ATTR develop late, like our own, and their familial histories are often obscure in non-endemic areas, which might make a diagnosis difficult.

We herein report the case of an

    84-year-old
    AGE

    woman
    GENDER

 with

    transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP-ATTR Val30Met)
    DIAGNOSIS

, representing a

    very old
    AGE

 case. The patient had

    muscle weakness
    SYMPTOMS

 and

    sensory disturbances in her extremities
    SYMPTOMS

 caused by

    severe peripheral neuropathy
    SYMPTOMS

.

    She
    GENDER

 also had

    vitreous opacity
    SYMPTOMS

 and

    orthostatic hypotension
    SYMPTOMS

, and

    pyrophosphate scintigraphy
    PARACLINICAL

 showed a

    myocardial accumulation
    SYMPTOMS

.

    Esophagogastroduodenoscopy
    PARACLINICAL

 revealed

    mucosal amyloid deposits, positive in anti-TTR antibody staining
    MICROSCOPIC

. A

    TTR gene analysis
    PARACLINICAL

 isolated the

    Val30Met mutation
    GENETICS

. More than a few cases of

    FAP-ATTR
    DIAGNOSIS

 develop late, like our own, and their

    familial histories
    FAMILY

 are often obscure in non-endemic areas, which might make a diagnosis difficult.

muscle weakness
sensory disturbances in her extremities
severe peripheral neuropathy
vitreous opacity
orthostatic hypotension
myocardial accumulation


Failure of Tafamidis to Halt Progression of Ala36Pro TTR Oculomeningovascular Amyloidosis.

Oculomeningovascular amyloidosis is a variant of transthyretin (TTR) amyloidotic polyneuropathy, which is associated with blindness and brain ischemia, microhemorrages, and siderosis due to prominent production of the abnormal TTR in the eye and in the choroid plexuses. Tafamidis is a TTR stabilizer that is orally administered and, by interfering with amyloid fibril formation and deposition, is capable of slowing progression of TTR polyneuropathy and of early-stage cardiomyopathy. However, the ocular manifestations of amyloid deposition progressed despite tafamidis therapy in Val30Met TTR amyloidosis, and the effects of tafamidis on meningovascular amyloidosis are unknown. We observed failure of tafamidis to halt progression of oculomeningovascular amyloid deposition in a patient with familial Ala36Pro TTR amyloidosis. She received molecular diagnosis at age 24 and presented at age 26 with paresthesias of the lower limbs and bowel dysfunction. Echography showed minimal amyloid opacities in the corpus vitreum. Treatment with tafamidis meglumine was started. Sixteen months later, she complained of severe headache followed by left hemiparesthesias and numbness lasting 20 minutes. Magnetic resonance imaging showed multiple focal and diffuse hemosiderin deposits compatible with microbleeds and early siderosis. Echography showed a marked increase of "vitreal opacities." Our observation confirms that tafamidis fails in halting increase of vitreal amyloid deposits and indicates that it is presumably ineffective in preventing clinical onset due to progression of meningovascular amyloidosis. These failures may be due to the incapability of tafamidis to cross the blood-retina and blood-brain barriers. Therapeutic options targeting oculomeningovascular TTR amyloidoses in humans are required.

    Oculomeningovascular amyloidosis
    DIAGNOSIS

 is a variant of

    transthyretin (TTR) amyloidotic polyneuropathy
    DIAGNOSIS

, which is associated with

    blindness
    SYMPTOMS

 and

    brain ischemia
    SYMPTOMS

,

    microhemorrages
    SYMPTOMS

, and

    siderosis
    SYMPTOMS

 due to

    prominent production of the abnormal TTR in the eye and in the choroid plexuses
    MICROSCOPIC

.

    Tafamidis
    MEDICATION

 is a

    TTR stabilizer
    MEDICATION

 that is

    orally administered
    MEDICATION

 and, by

    interfering with amyloid fibril formation and deposition
    MICROSCOPIC

, is capable of slowing progression of

    TTR polyneuropathy
    DIAGNOSIS

 and of

    early-stage cardiomyopathy
    DIAGNOSIS

. However, the

    ocular manifestations of amyloid deposition
    SYMPTOMS

 progressed

    despite tafamidis therapy
    NEG_FINDINGS

 in

    Val30Met TTR amyloidosis
    DIAGNOSIS

, and the effects of

    tafamidis
    MEDICATION

 on

    meningovascular amyloidosis
    DIAGNOSIS

 are unknown. We observed

    failure of tafamidis to halt progression of oculomeningovascular amyloid deposition
    NEG_FINDINGS

 in a patient with

    familial Ala36Pro TTR amyloidosis
    GENETICS

.

    She
    GENDER

 received

    molecular diagnosis
    PARACLINICAL

 at

    age 24
    AGE

 and presented at

    age 26
    AGE

 with

    paresthesias of the lower limbs
    SYMPTOMS

 and

    bowel dysfunction
    SYMPTOMS

.

    Echography
    PARACLINICAL

 showed

    minimal amyloid opacities in the corpus vitreum
    SYMPTOMS

.

    Treatment with tafamidis meglumine
    MEDICATION

 was started. Sixteen months later,

    she
    GENDER

 complained of

    severe headache
    SYMPTOMS

 followed by

    left hemiparesthesias
    SYMPTOMS

 and

    numbness lasting 20 minutes
    SYMPTOMS

.

    Magnetic resonance imaging
    PARACLINICAL

 showed

    multiple focal and diffuse hemosiderin deposits compatible with microbleeds
    SYMPTOMS

 and

    early siderosis
    SYMPTOMS

.

    Echography
    PARACLINICAL

 showed a

    marked increase of "vitreal opacities
    SYMPTOMS

.

    "
    SYMPTOMS

 Our observation confirms that

    tafamidis fails in halting increase of vitreal amyloid deposits
    NEG_FINDINGS

 and indicates that it is presumably

    ineffective in preventing clinical onset due to progression of meningovascular amyloidosis
    NEG_FINDINGS

. These failures may be due to the

    incapability of tafamidis to cross the blood-retina and blood-brain barriers
    NEG_FINDINGS

. Therapeutic options targeting

    oculomeningovascular TTR amyloidoses
    DIAGNOSIS

 in humans are required.

Tafamidis
TTR stabilizer
orally administered
tafamidis
Treatment with tafamidis meglumine


Amyloid cardiomyopathy: a hidden heart failure cause that is often misdiagnosed.

Congestive heart failure (CHF) is a very common condition, especially in the elderly, characterized by dyspnea, orthopnea, nocturnal paroxysmal dyspnea, and peripheral edema.

We report the case of a 76-year-old with CHF symptoms for the last 3 months. The ECG and transthoracic echocardiogram were suggestive of CHF due to amyloid cardiomyopathy. After cardiac MRI, a positive Congo red staining of subcutaneous fat aspiration and a negative genetic testing for mutant transthyretin, senile amyloid cardiomyopathy (ATTRw) was expected.

Cardiac amyloidosis is remarkably underdiagnosed. Mostly, the treatment is supportive and differs from other typical causes of CHF, and thus, a high index of suspicion is required.

    Congestive heart failure (CHF)
    DIAGNOSIS

 is a very common condition, especially in the

    elderly
    AGE

, characterized by

    dyspnea
    SYMPTOMS

,

    orthopnea
    SYMPTOMS

,

    nocturnal paroxysmal dyspnea
    SYMPTOMS

, and

    peripheral edema
    SYMPTOMS

.

We report the case of a

    76-year-old
    AGE

 with

    CHF symptoms for the last 3 months
    SYMPTOMS

. The

    ECG
    PARACLINICAL

 and

    transthoracic echocardiogram
    PARACLINICAL

 were suggestive of

    CHF
    DIAGNOSIS

 due to

    amyloid cardiomyopathy
    DIAGNOSIS

. After

    cardiac MRI
    PARACLINICAL

, a

    positive Congo red staining of subcutaneous fat aspiration
    PARACLINICAL

 and a

    negative genetic testing for mutant transthyretin
    NEG_FINDINGS

,

    senile amyloid cardiomyopathy (ATTRw)
    DIAGNOSIS

 was expected.

    Cardiac amyloidosis
    DIAGNOSIS

 is remarkably underdiagnosed. Mostly, the treatment is supportive and differs from other typical causes of

    CHF
    DIAGNOSIS

, and thus, a high index of suspicion is required.

Congestive heart failure (CHF)
CHF
amyloid cardiomyopathy
senile amyloid cardiomyopathy (ATTRw)
Cardiac amyloidosis
CHF

dyspnea
orthopnea
nocturnal paroxysmal dyspnea
peripheral edema
CHF symptoms for the last 3 months


Recurrent Syncope, a Clue in Amyloid Cardiomyopathy.

Infiltrative cardiomyopathies include a variety of disorders that lead to myocardial thickening resulting in a constellation of clinical manifestations and eventually heart failure that could be the first clue to reach the diagnosis. Among the more described infiltrative diseases of the heart is amyloid cardiomyopathy. The disease usually presents with subtle, nonspecific symptoms. Herein, we illustrate a case of recurrent syncope as the initial presenting symptom for systemic amyloid with polyneuropathy and cardiomyopathy as a cause of syncope. The article illustrates the role of advanced cardiac imaging in the diagnosis of the disease with a focused literature review. We also highlight the role of early, shared decision-making between patient, family, and medical team in the management of cardiac amyloidosis.

    Infiltrative cardiomyopathies
    DIAGNOSIS

 include a variety of disorders that lead to

    myocardial thickening
    SYMPTOMS

 resulting in a

    constellation of clinical manifestations
    SYMPTOMS

 and eventually

    heart failure
    SYMPTOMS

 that could be the first clue to reach the diagnosis. Among the more described

    infiltrative diseases of the heart
    DIAGNOSIS

 is

    amyloid cardiomyopathy
    DIAGNOSIS

. The disease usually presents with

    subtle, nonspecific symptoms
    SYMPTOMS

. Herein, we illustrate a case of

    recurrent syncope
    SYMPTOMS

 as the initial presenting symptom for

    systemic amyloid with polyneuropathy
    DIAGNOSIS

 and

    cardiomyopathy
    SYMPTOMS

 as a cause of

    syncope
    SYMPTOMS

. The article illustrates the role of

    advanced cardiac imaging
    PARACLINICAL

 in the diagnosis of the disease with a focused literature review. We also highlight the role of early, shared decision-making between patient, family, and medical team in the management of

    cardiac amyloidosis
    DIAGNOSIS

.

Infiltrative cardiomyopathies
infiltrative diseases of the heart
amyloid cardiomyopathy
systemic amyloid with polyneuropathy
cardiac amyloidosis


Coronary ectasia in amyloid cardiomyopathy and neuropathy due to the transthyretin mutation c.323A>G.

atrial fibrillation(AF) is a frequent manifestation of cardiac involvement in genetic and wild-type transthyretin-related familial amyloidosis(TTR-FA). However, ectasia of coronary arteries and ablation for AF have not been reported in TTR-FA.

A 65yo male developed progressive sensori-motor polyneuropathy since age 59y. At age 60y bifascicular block and myocardial thickening were recognised. At age 62y heart failure developed and work-up with cardiac MRI suggested amyloidosis but biopsy was non-informative. Coronary angiography revealed ectasias of the coronary arteries. At age 65y AF developed, neither responding to electrical cardioversion nor ablation. Work-up for polyneuropathy revealed the point mutation c.323A>G (p.His108Arg) in the TTR-gene. Tafamidis was started but did not exhibit a beneficial effect after 7 months.

TTR-FA may manifest in the coronary arteries with ectasia. Ablation for AF in TTR-FA may be unsuccessful. Tafamidis has been unsuccessful for cardiac or nerve involvement after the first seven months.

    atrial fibrillation(AF)
    DIAGNOSIS

 is a frequent manifestation of

    cardiac involvement
    SYMPTOMS

 in

    genetic and wild-type transthyretin-related familial amyloidosis(TTR-FA)
    GENETICS

. However,

    ectasia of coronary arteries
    SYMPTOMS

 and

    ablation for AF
    MEDICATION

 have not been reported in

    TTR-FA
    DIAGNOSIS

.

A

    65yo
    AGE

    male
    GENDER

 developed

    progressive sensori-motor polyneuropathy
    SYMPTOMS

 since

    age 59y
    AGE

. At

    age 60y
    AGE

    bifascicular block
    SYMPTOMS

 and

    myocardial thickening
    SYMPTOMS

 were recognised. At

    age 62y
    AGE

    heart failure
    SYMPTOMS

 developed and

    work-up with cardiac MRI
    PARACLINICAL

 suggested

    amyloidosis
    DIAGNOSIS

 but

    biopsy was non-informative
    NEG_FINDINGS

.

    Coronary angiography
    PARACLINICAL

 revealed

    ectasias of the coronary arteries
    SYMPTOMS

. At

    age 65y
    AGE

    AF
    SYMPTOMS

 developed,

    neither responding to electrical cardioversion nor ablation
    NEG_FINDINGS

.

    Work-up
    PARACLINICAL

 for

    polyneuropathy
    DIAGNOSIS

 revealed the

    point mutation c.323A>G (p.His108Arg) in the TTR-gene
    GENETICS

.

    Tafamidis
    MEDICATION

 was started but

    did not exhibit a beneficial effect after 7 months
    NEG_FINDINGS

.

    TTR-FA
    DIAGNOSIS

 may

    manifest in the coronary arteries with ectasia
    SYMPTOMS

.

    Ablation for AF
    NEG_FINDINGS

 in

    TTR-FA
    DIAGNOSIS

    may be unsuccessful
    NEG_FINDINGS

.

    Tafamidis has been unsuccessful for cardiac or nerve involvement
    NEG_FINDINGS

 after the first seven

    months
    NEG_FINDINGS

.

atrial fibrillation(AF)
TTR-FA
amyloidosis
polyneuropathy
TTR-FA
TTR-FA


Late-onset Familial Amyloidotic Polyneuropathy with Bence Jones Proteinuria and Cardiomyopathy.

Familial amyloidotic polyneuropathy is a genetically determined disease characterized by deposition of an anomalous transthyretin. A high index of suspicion is needed for this multisymptomatic and lethal disease to be diagnosed. The patient was a 70-year-old male examined due to hypesthesia in the hands and feet, plus difficulty walking. A neurophysiological study delivered the diagnosis of axonal sensorimotor polyneuropathy. He later developed cardiac symptoms and diarrhea. Urine laboratory analyses revealed a monoclonal spike of light chains (kappa). Biopsies of abdominal fat and bone marrow yielded normal results. The genetic study was compatible with a heterozygous Val30Met-transthyretin mutation. Very few case studies have described an association between familial amyloidotic polyneuropathy and monoclonal gammopathy. We stress that genetic confirmation is important regardless of the type of amyloid deposition revealed by the biopsy.

    Familial amyloidotic polyneuropathy
    DIAGNOSIS

 is a

    genetically determined
    GENETICS

 disease characterized by

    deposition of an anomalous transthyretin
    MICROSCOPIC

. A high index of suspicion is needed for this

    multisymptomatic
    DIAGNOSIS

 and lethal disease to be diagnosed. The patient was a

    70-year-old
    AGE

    male
    GENDER

 examined due to

    hypesthesia in the hands and feet
    SYMPTOMS

, plus

    difficulty walking
    SYMPTOMS

. A

    neurophysiological study
    PARACLINICAL

 delivered the diagnosis of

    axonal sensorimotor polyneuropathy
    DIAGNOSIS

.

    He
    GENDER

 later developed

    cardiac symptoms
    SYMPTOMS

 and

    diarrhea
    SYMPTOMS

.

    Urine laboratory analyses
    PARACLINICAL

 revealed a

    monoclonal spike of light chains (kappa)
    BIOCHEMICAL

.

    Biopsies of abdominal fat and bone marrow yielded normal results
    PARACLINICAL

. The

    genetic study
    PARACLINICAL

 was compatible with a

    heterozygous Val30Met-transthyretin mutation
    GENETICS

. Very few case studies have described an association between

    familial amyloidotic polyneuropathy
    DIAGNOSIS

 and

    monoclonal gammopathy
    DIAGNOSIS

. We stress that

    genetic confirmation
    PARACLINICAL

 is important regardless of the type of amyloid deposition revealed by the biopsy.

Familial amyloidotic polyneuropathy
multisymptomatic
axonal sensorimotor polyneuropathy
familial amyloidotic polyneuropathy
monoclonal gammopathy

hypesthesia in the hands and feet
difficulty walking
cardiac symptoms
diarrhea


A novel ATTR L32V mutation causes familial amyloid polyneuropathy in a Bolivian family.

We report a new transthyretin (ATTR) gene c.272C>G mutation and variant protein, p.Leu32Val, in a kindred of Bolivian origin with a rapid progressive peripheral neuropathy and cardiomyopathy. Three individuals from a kindred with peripheral nerve and cardiac amyloidosis were examined. Analysis of the TTR gene was performed by Sanger direct sequencing. Neuropathologic examination was obtained on the index patient with mass spectrometry study of the ATTR deposition. Direct DNA sequence analysis of exons 2, 3, and 4 of the TTR gene demonstrated a c.272 C>G mutation in exon 2 (p.L32V). Sural nerve biopsy revealed massive amyloid deposition in the perineurium, endoneurium and vasa nervorum. Mass spectrometric analyses of ATTR immunoprecipitated from nerve biopsy showed the presence of both wild-type and variant proteins. The observed mass results for the wild-type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. The ATTR L32V is associated with a severe course. This has implications for treatment of affected individuals and counseling of family members.

We report a

    new transthyretin (ATTR) gene c.272C>G mutation and variant protein, p.Leu32Val
    GENETICS

, in a

    kindred
    FAMILY

 of

    Bolivian
    ETHNICITY

 origin with a

    rapid progressive peripheral neuropathy
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

. Three individuals from a

    kindred
    FAMILY

 with

    peripheral nerve and cardiac amyloidosis
    DIAGNOSIS

 were examined.

    Analysis of the TTR gene
    PARACLINICAL

 was performed by

    Sanger direct sequencing
    PARACLINICAL

.

    Neuropathologic examination
    PARACLINICAL

 was obtained on the index patient with

    mass spectrometry study of the ATTR deposition
    PARACLINICAL

.

    Direct DNA sequence analysis of exons 2, 3, and 4 of the TTR gene
    PARACLINICAL

 demonstrated a

    c.272 C>G mutation in exon 2 (p.L32V)
    GENETICS

.

    Sural nerve biopsy
    PARACLINICAL

 revealed

    massive amyloid deposition in the perineurium, endoneurium and vasa nervorum
    MICROSCOPIC

.

    Mass spectrometric analyses of ATTR immunoprecipitated from nerve biopsy
    PARACLINICAL

 showed the

    presence of both wild-type and variant proteins
    BIOCHEMICAL

. The observed mass results for the wild-type and variant proteins were consistent with the predicted values calculated from the genetic analysis data. The

    ATTR L32V
    GENETICS

 is associated with a severe course. This has implications for treatment of affected individuals and counseling of family members.

rapid progressive peripheral neuropathy
cardiomyopathy


Transthyretin amyloidosis: a phenocopy of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder that affects over one in 500 persons worldwide. The autosomal dominant transmission of HCM implies that many relatives are at risk for HCM associated morbidity and mortality, therefore genetic testing and counselling is of great importance. However, in only 50-60% of the patients a mutation is found, which hampers predictive genetic testing in relatives. In HCM patients in whom the causal mutation has not been identified (yet), phenocopies of HCM - i.e. diseases that mimic HCM - could be responsible for the HCM phenotype. One of the HCM phenocopies is transthyretin amyloidosis (ATTR), caused by mutations in the transthyretin (TTR) gene.

From 697 HCM index patients referred to our cardiogenetics outpatient clinic and tested for HCM associated genes between January 1997 and December 2012, we selected the ones without a detected causal mutation (n = 345). In these patients, additional DNA analysis of the TTR gene was performed.

In four patients (1.2%), a TTR mutation was detected (E7G, V30M, T119M, V122I). The E7G mutation is probably a non-pathogenic mutation. The T119M mutation is a known TTR mutation, but does not cause a cardiac phenotype. So in two (0.6%) patients, TTR analysis identified the cause of their HCM.

ATTR should always be considered in patients with unexplained HCM, especially because of the great benefit of an early diagnosis regarding treatment and prognosis.

    Hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 is an

    inherited cardiac disorder
    GENETICS

 that affects over one in 500 persons worldwide. The

    autosomal dominant transmission of HCM
    GENETICS

 implies that many relatives are at risk for

    HCM
    SYMPTOMS

 associated morbidity and mortality, therefore

    genetic testing
    PARACLINICAL

 and

    counselling
    MEDICATION

 is of great importance. However, in only 50-60% of the patients a mutation is found, which hampers

    predictive genetic testing
    PARACLINICAL

 in relatives. In

    HCM
    DIAGNOSIS

 patients in whom the causal

    mutation has not been identified
    NEG_FINDINGS

 (yet),

    phenocopies of HCM
    SYMPTOMS

 - i.e.

    diseases that mimic HCM
    SYMPTOMS

 - could be responsible for the

    HCM
    SYMPTOMS

 phenotype. One of the

    HCM
    DIAGNOSIS

 phenocopies is

    transthyretin amyloidosis (ATTR)
    DIAGNOSIS

, caused by

    mutations in the transthyretin (TTR) gene
    GENETICS

.

From 697

    HCM
    DIAGNOSIS

 index patients referred to our

    cardiogenetics
    PARACLINICAL

 outpatient clinic and tested for

    HCM associated genes
    GENETICS

 between January 1997 and December 2012, we selected the ones

    without a detected causal mutation
    NEG_FINDINGS

 (n = 345). In these patients,

    additional DNA analysis of the TTR gene
    PARACLINICAL

 was performed.

In four patients (1.2%), a

    TTR mutation
    GENETICS

 was detected

    (E7G, V30M, T119M, V122I)
    GENETICS

. The

    E7G mutation is probably a non-pathogenic mutation
    GENETICS

. The

    T119M mutation
    GENETICS

 is a

    known TTR mutation
    GENETICS

, but

    does not cause a cardiac phenotype
    NEG_FINDINGS

. So in two (0.6%) patients,

    TTR analysis
    PARACLINICAL

 identified the cause of their

    HCM
    DIAGNOSIS

.

    ATTR
    DIAGNOSIS

 should always be considered in patients with

    unexplained HCM
    SYMPTOMS

, especially because of the great benefit of an early diagnosis regarding treatment and prognosis.

Hypertrophic cardiomyopathy (HCM)
HCM
HCM
transthyretin amyloidosis (ATTR)
HCM
HCM
ATTR

HCM
phenocopies of HCM
diseases that mimic HCM
HCM
unexplained HCM

mutation has not been identified
without a detected causal mutation
does not cause a cardiac phenotype


Late onset cardiomyopathy as presenting sign of ATTR A45G amyloidosis caused by a novel TTR mutation (p.A65G).

The clinical description of a novel TTR gene mutation characterized by a late onset amyloid cardiomyopathy.

A 78-year-old man of Dutch origin with recent surgery for bilateral carpal tunnel syndrome (CTS) was admitted to our hospital because of heart failure with preserved ejection fraction (55%). Cardiac ultrasound showed thickened biventricular walls, and cardiac magnetic resonance imaging also showed late gadolinium enhancement. Early signs of a polyneuropathy were found by neurophysiological testing. A few months later, his 72-year-old sister was admitted to an affiliated hospital because of heart failure caused by a restrictive cardiomyopathy. In both patients, a subcutaneous abdominal fat aspirate was stained with Congo red and DNA was analyzed by direct sequencing of exons 1 to 4 of the transthyretin (TTR) gene. Both fat aspirates revealed transthyretin-derived (ATTR) amyloid. 99mTc-diphosphonate scintigraphy further confirmed cardiac ATTR amyloidosis in the male patient. DNA analysis of both patients showed a novel TTR mutation c.194C>G that encodes for the gene product TTR (p.A65G) ending up as the mature protein TTR A45G. The 56-year-old daughter of the male patient had the same TTR mutation. A full diagnostic workup did not reveal any signs of amyloidosis yet.

A novel amyloidogenic TTR mutation was found in a Dutch family. The clinical presentation of ATTR A45G amyloidosis in the affected family members was heart failure due to a late-onset cardiomyopathy. The systemic nature of this disease was reflected by bilateral CTS and by early signs of a polyneuropathy in the index patient.

The clinical description of a

    novel TTR gene mutation
    GENETICS

 characterized by a

    late onset amyloid cardiomyopathy
    SYMPTOMS

.

A

    78-year-old
    AGE

    man
    GENDER

 of

    Dutch origin
    ETHNICITY

 with

    recent surgery
    MEDICATION

 for

    bilateral carpal tunnel syndrome (CTS)
    SYMPTOMS

 was admitted to our hospital because of

    heart failure with preserved ejection fraction (55%)
    SYMPTOMS

.

    Cardiac ultrasound
    PARACLINICAL

 showed

    thickened biventricular walls
    SYMPTOMS

, and

    cardiac magnetic resonance imaging
    PARACLINICAL

 also showed

    late gadolinium enhancement
    SYMPTOMS

.

    Early signs of a polyneuropathy
    SYMPTOMS

 were found by

    neurophysiological testing
    PARACLINICAL

. A few months later,

    his
    GENDER

    72-year-old
    AGE

 sister was admitted to an affiliated hospital because of

    heart failure
    SYMPTOMS

 caused by a

    restrictive cardiomyopathy
    SYMPTOMS

. In both patients, a

    subcutaneous abdominal fat aspirate was stained with Congo red
    PARACLINICAL

 and

    DNA was analyzed by direct sequencing of exons 1 to 4 of the transthyretin (TTR) gene
    PARACLINICAL

. Both

    fat aspirates
    PARACLINICAL

 revealed

    transthyretin-derived (ATTR) amyloid
    MICROSCOPIC

.

    99mTc-diphosphonate scintigraphy
    PARACLINICAL

 further confirmed

    cardiac ATTR amyloidosis
    DIAGNOSIS

 in the

    male
    GENDER

 patient.

    DNA analysis
    PARACLINICAL

 of both patients showed a novel TTR mutation c.194C>G that encodes for the gene product TTR (p.A65G) ending up as the mature protein TTR A45G. The

    56-year-old
    FAMILY

    daughter of the male
    FAMILY

    patient had the same TTR mutation
    FAMILY

. A

    full diagnostic workup did not reveal any signs of amyloidosis yet
    NEG_FINDINGS

.

A

    novel amyloidogenic TTR mutation
    GENETICS

 was found in a

    Dutch
    ETHNICITY

 family. The clinical presentation of

    ATTR A45G amyloidosis
    DIAGNOSIS

 in the affected family members was

    heart failure due to a late-onset cardiomyopathy
    SYMPTOMS

. The systemic nature of this disease was reflected by

    bilateral CTS
    SYMPTOMS

 and by

    early signs of a polyneuropathy
    SYMPTOMS

 in the index patient.

novel TTR gene mutation
novel amyloidogenic TTR mutation

cardiac ATTR amyloidosis
ATTR A45G amyloidosis


Familial amyloid cardiomyopathy masquerading as chronic Guillain-Barre syndrome: things are not always what they seem.

Familial amyloid cardiomyopathy is a challenging condition that mimics many other diseases, particularly in patients with pronounced neurological presentations and unexplained or equivocal cardiac abnormalities. In this case, a 57-year-old man was admitted for outpatient cardiological evaluation of progressive right heart failure and limb paraesthesias. The patient presented with hypertension, chronic Guillain-Barre syndrome, and sick sinus syndrome. Transthoracic echocardiograms showed a thickened ventricular wall and enlarged atrium. Tissue Doppler showed a restrictive filling pattern. Transthyretin (TTR)-associated amyloidosis, which was revealed by abdominal fat-pad biopsy and DNA analysis, explained the concurrence of independent pathological features, including neuropathy and cardiac involvement. Genetic testing identified a G > T mutation in exon 4 of the transthyretin (TTR) gene. This mutation resulted in the alanine-to-serine substitution at amino acid position 117. Moreover, genetic testing confirmed that the patient's asymptomatic son carried the same amyloidogenic TTR mutation. Given these findings, the diagnosis of familial amyloid cardiomyopathy, which was misdiagnosed as chronic Guillain-Barre syndrome, was proposed.

    Familial amyloid cardiomyopathy
    DIAGNOSIS

 is a challenging condition that mimics many other diseases, particularly in patients with

    pronounced neurological presentations
    SYMPTOMS

 and

    unexplained or equivocal cardiac abnormalities
    SYMPTOMS

. In this case, a

    57-year-old
    AGE

    man
    GENDER

 was admitted for

    outpatient cardiological evaluation
    PARACLINICAL

 of

    progressive right heart failure
    SYMPTOMS

 and

    limb paraesthesias
    SYMPTOMS

. The patient presented with

    hypertension
    SYMPTOMS

,

    chronic Guillain-Barre syndrome
    DIAGNOSIS

, and

    sick sinus syndrome
    SYMPTOMS

.

    Transthoracic echocardiograms
    PARACLINICAL

 showed a

    thickened ventricular wall and enlarged atrium
    SYMPTOMS

.

    Tissue Doppler
    PARACLINICAL

 showed a

    restrictive filling pattern
    SYMPTOMS

.

    Transthyretin (TTR)-associated amyloidosis
    DIAGNOSIS

, which was revealed by

    abdominal fat-pad biopsy
    PARACLINICAL

 and

    DNA analysis
    PARACLINICAL

, explained the

    concurrence of independent pathological features
    SYMPTOMS

, including

    neuropathy and cardiac involvement
    SYMPTOMS

.

    Genetic testing
    PARACLINICAL

 identified a

    G > T mutation in exon 4 of the transthyretin (TTR) gene
    GENETICS

. This

    mutation resulted in the alanine-to-serine substitution at amino acid position 117
    GENETICS

. Moreover,

    genetic testing
    PARACLINICAL

 confirmed

    that the patient's asymptomatic son carried the same amyloidogenic TTR mutation
    FAMILY

. Given these findings, the diagnosis of

    familial amyloid cardiomyopathy
    DIAGNOSIS

, which was

    misdiagnosed as chronic Guillain-Barre syndrome
    NEG_FINDINGS

, was proposed.


Cardiac Amyloidosis Phenotype Associated With a Glu89Lys Transthyretin Mutation.

We report a 45-year-old man with rapidly progressive cardiac amyloidosis, who required heart transplantation within 2 years of symptomatic onset. Hematologic testing and initial tissue biopsy results confirmed amyloid infiltration but were inconclusive for the amyloidogenic protein source. Mass spectroscopy and transthyretin (TTR) sequencing were required to reach a diagnosis of TTR amyloidosis resulting from a Glu89Lys mutation. Although a predominantly neuropathic phenotype has previously been described with this mutation, the present kinship documents a primarily cardiac presentation. This case report highlights the diagnostic challenge of TTR amyloidosis and the marked variability of the genotype-phenotype correlation.

We report a

    45-year-old
    AGE

    man
    GENDER

 with

    rapidly progressive cardiac amyloidosis
    DIAGNOSIS

, who required

    heart transplantation
    MEDICATION

 within 2 years of symptomatic onset.

    Hematologic testing
    PARACLINICAL

 and

    initial tissue biopsy results
    PARACLINICAL

 confirmed

    amyloid infiltration
    MICROSCOPIC

 but

    were inconclusive for the amyloidogenic protein source
    NEG_FINDINGS

.

    Mass spectroscopy
    PARACLINICAL

 and

    transthyretin (TTR) sequencing
    PARACLINICAL

 were required to reach a diagnosis of

    TTR amyloidosis
    DIAGNOSIS

 resulting from a

    Glu89Lys mutation
    GENETICS

. Although a

    predominantly neuropathic phenotype
    SYMPTOMS

 has previously been described with this mutation, the present kinship documents a

    primarily cardiac presentation
    SYMPTOMS

. This case report highlights the diagnostic challenge of

    TTR amyloidosis
    DIAGNOSIS

 and the marked variability of the genotype-phenotype correlation.

rapidly progressive cardiac amyloidosis
TTR amyloidosis
TTR amyloidosis

predominantly neuropathic phenotype
primarily cardiac presentation


PET-CT evaluation of amyloid systemic involvement with [18F]-florbetaben in patient with proved cardiac amyloidosis: a case report.

One of the most frequent disorders which lead to cardiac amyloidosis is transthyretin-related amyloidosis (ATTR). Some PET radio-pharmaceuticals for the detection of beta-amyloid deposits within the brain have shown to be able to detect also cardiac amyloid deposits. We present a case of a man with ATTR studied with [18F]-florbetaben PET-CT.

Total-body scan showed a moderate uptake in the bone marrow, especially in correspondence of the vertebral column, while no significant myocardial uptake was present. Cardiac-focused scans showed low mean cardiac SUV values confirming the absence of significant myocardial uptake. Brain scan showed a significant cortical brain uptake of the radio-pharmaceutical more evident in correspondence of frontal and temporal lobes.

Distinct subtypes of amyloidosis show different uptake of the radiotracer. Brain amyloid deposition in the presence of a systemic disease could not be caused by the same amyloid precursor.

One of the most frequent disorders which lead to

    cardiac amyloidosis
    DIAGNOSIS

 is

    transthyretin-related amyloidosis (ATTR)
    DIAGNOSIS

. Some

    PET radio-pharmaceuticals
    PARACLINICAL

 for the detection of

    beta-amyloid deposits within the brain
    MICROSCOPIC

 have shown to be able to detect also

    cardiac amyloid deposits
    SYMPTOMS

. We present a case of a

    man
    GENDER

 with

    ATTR
    DIAGNOSIS

 studied with

    [18F]-florbetaben PET-CT
    PARACLINICAL

.

    Total-body scan
    PARACLINICAL

 showed a

    moderate uptake in the bone marrow, especially in correspondence of the vertebral column
    MICROSCOPIC

, while

    no significant myocardial uptake was present
    NEG_FINDINGS

.

    Cardiac-focused scans
    PARACLINICAL

 showed

    low mean cardiac SUV values
    NEG_FINDINGS

 confirming the

    absence of significant myocardial uptake
    NEG_FINDINGS

.

    Brain scan
    PARACLINICAL

 showed a

    significant cortical brain uptake of the radio-pharmaceutical more evident in correspondence of frontal and temporal lobes
    SYMPTOMS

.

Distinct subtypes of

    amyloidosis
    DIAGNOSIS

 show different uptake of the radiotracer.

    Brain amyloid deposition
    SYMPTOMS

 in the presence of a

    systemic disease
    DIAGNOSIS

 could

    not be caused by the same amyloid precursor
    NEG_FINDINGS

.


Tafamidis for the Treatment of Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report.

Tafamidis meglumine is a novel medicine that has been shown to slow the progression of peripheral neurological impairment in patients with hereditary transthyretin amyloidosis (ATTR). However, the efficacy of tafamidis against ATTR-related cardiac amyloidosis remains unclear. A 72-year-old woman had cardiac hypertrophy and axonopathy in her lower legs. Endomyocardial biopsy revealed an infiltrative cardiomyopathy consistent with amyloidosis. Immunostaining and genetic studies confirmed the diagnosis of ATTR, and tafamidis was started subsequently. Two years after the initiation of tafamidis treatment, electromyography demonstrated no change in the axonopathy in her lower legs; however, electrocardiography displayed QRS prolongation, and echocardiography disclosed an increase in interventricular septal thickness. Endomyocardial biopsy indicated that transthyretin amyloid infiltration of the myocardium was not reduced. In this case, there was no apparent progression of axonopathy, although there were signs of worsening amyloid cardiomyopathy during the treatment with tafamidis.

    Tafamidis meglumine
    MEDICATION

 is a

    novel medicine
    MEDICATION

 that has been shown to slow the progression of

    peripheral neurological impairment
    SYMPTOMS

 in patients with

    hereditary transthyretin amyloidosis (ATTR)
    DIAGNOSIS

. However, the efficacy of

    tafamidis
    MEDICATION

 against

    ATTR-related cardiac amyloidosis
    DIAGNOSIS

 remains unclear. A

    72-year-old
    AGE

    woman
    GENDER

 had

    cardiac hypertrophy
    SYMPTOMS

 and

    axonopathy in her lower legs
    SYMPTOMS

.

    Endomyocardial biopsy
    PARACLINICAL

 revealed an

    infiltrative cardiomyopathy consistent with amyloidosis
    DIAGNOSIS

.

    Immunostaining and genetic studies
    PARACLINICAL

 confirmed the diagnosis of

    ATTR
    DIAGNOSIS

, and

    tafamidis
    MEDICATION

 was started subsequently. Two years after the initiation of

    tafamidis treatment
    MEDICATION

,

    electromyography
    PARACLINICAL

 demonstrated

    no change in the axonopathy in her lower legs
    NEG_FINDINGS

; however,

    electrocardiography
    PARACLINICAL

 displayed

    QRS prolongation
    SYMPTOMS

, and

    echocardiography
    PARACLINICAL

 disclosed an

    increase in interventricular septal thickness
    SYMPTOMS

.

    Endomyocardial biopsy
    PARACLINICAL

 indicated that

    transthyretin amyloid infiltration of the myocardium was not reduced
    MICROSCOPIC

. In this case, there was

    no apparent progression of axonopathy
    NEG_FINDINGS

, although there were

    signs of worsening amyloid cardiomyopathy
    SYMPTOMS

 during the

    treatment with tafamidis
    MEDICATION

.

Tafamidis meglumine
novel medicine
tafamidis
tafamidis
tafamidis treatment
treatment with tafamidis


Hereditary Amyloidosis with Recurrent Lung Infiltrates.

BACKGROUND Amyloidosis is a protein conformational disorder characterized by extracellular deposition of amyloid fibrils in extracellular tissue. Lung involvement is most commonly caused by secondary AL amyloidosis. The familial autosomal-dominant senile transthyretin (ATTR) disease manifests mainly as polyneuropathy and restrictive cardiomyopathy denoting the name familial amyloidotic polyneuropathy (FAP). Rarely, this form manifests with clinical and radiologically relevant respiratory tract symptoms and lung involvement. CASE REPORT A 51-year-old male former smoker presented with progressive lower-extremity weakness of several months' duration. He was ultimately diagnosed with chronic demyelinating polyneuropathy and treated with intravenous immunoglobulin therapy. Subsequently, he was admitted with heart failure symptoms and pulmonary infiltrates and his echocardiogram showed a 'myocardial speckled pattern', prompting an endomyocardial biopsy, which showed transthyretin amyloid deposition. He was started on diflunisal. Additionally, serial radiographic imaging of his chest over 3 different admissions for cough, dyspnea, hypoxemia, and lethargy demonstrated recurrent pulmonary infiltrates. A fiberoptic bronchoscopy with trans-bronchial biopsies revealed amyloid deposition in the lung tissue. CONCLUSIONS The clinical presentation of recurrent or persistent pulmonary symptoms and fleeting infiltrates on imaging in a patient with familial amyloidotic polyneuropathy is not common; when present, it should raise the suspicion of respiratory tract involvement.

BACKGROUND

    Amyloidosis
    DIAGNOSIS

 is a

    protein conformational disorder
    DIAGNOSIS

 characterized by

    extracellular deposition of amyloid fibrils in extracellular tissue
    MICROSCOPIC

.

    Lung involvement
    SYMPTOMS

 is most commonly caused by

    secondary AL amyloidosis
    DIAGNOSIS

. The

    familial autosomal-dominant senile transthyretin (ATTR) disease
    DIAGNOSIS

 manifests mainly as

    polyneuropathy
    DIAGNOSIS

 and

    restrictive cardiomyopathy
    DIAGNOSIS

 denoting the name

    familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

. Rarely, this form manifests with

    clinical and radiologically relevant respiratory tract symptoms
    SYMPTOMS

 and

    lung involvement
    SYMPTOMS

. CASE REPORT A

    51-year-old
    AGE

    male
    GENDER

    former smoker
    MEDICATION

 presented with

    progressive lower-extremity weakness of several months' duration
    SYMPTOMS

.

    He
    GENDER

 was ultimately diagnosed with

    chronic demyelinating polyneuropathy
    DIAGNOSIS

 and treated with

    intravenous immunoglobulin therapy
    MEDICATION

. Subsequently,

    he
    GENDER

 was admitted with

    heart failure symptoms
    SYMPTOMS

 and

    pulmonary infiltrates
    SYMPTOMS

 and his

    echocardiogram
    PARACLINICAL

 showed a

    'myocardial speckled pattern'
    SYMPTOMS

, prompting an

    endomyocardial biopsy
    PARACLINICAL

, which showed

    transthyretin amyloid deposition
    MICROSCOPIC

.

    He
    GENDER

 was

    started on diflunisal
    MEDICATION

. Additionally,

    serial radiographic imaging of his chest
    PARACLINICAL

 over 3 different admissions for

    cough
    SYMPTOMS

,

    dyspnea
    SYMPTOMS

,

    hypoxemia
    SYMPTOMS

, and

    lethargy
    SYMPTOMS

 demonstrated

    recurrent pulmonary infiltrates
    SYMPTOMS

. A

    fiberoptic bronchoscopy with trans-bronchial biopsies
    PARACLINICAL

 revealed

    amyloid deposition in the lung tissue
    MICROSCOPIC

. CONCLUSIONS The clinical presentation of

    recurrent or persistent pulmonary symptoms
    SYMPTOMS

 and

    fleeting infiltrates
    SYMPTOMS

 on

    imaging
    SYMPTOMS

 in a patient with

    familial amyloidotic polyneuropathy
    DIAGNOSIS

 is not common; when present, it should raise the suspicion of

    respiratory tract involvement
    SYMPTOMS

.

former smoker
intravenous immunoglobulin therapy
started on diflunisal


[Transthyretin familial amyloid polyneuropathy - three Hungarian cases with rare mutations (His88Arg and Phe33Leu)].

Introduction - Transthyretin familial amyloid polyneuropathy is a rare autosomal dominant progressive systemic disesase of adults caused by endoneural amyloid deposition due to point mutations of the transthyretin gene. It is the most severe form among hereditary polyneuropathies, being fatal within 10 years if left untreated. The disease is underdiagnosed, the late onset forms (above the age of 50) being probably more widespread than previously thought. Early diagnosis is essential as the early introduction of causal therapy (tafamidis) slows progression and prolongs survival. Patients - We report here three non-related Hungarian cases of transthyretin familial amyloid polyneuropathy with non-Val30Met mutations (His88Arg in two cases, Phe33Leu in one case). They were all characterized by late-onset, progressive, length-dependent, axonal, sensorimotor polyneuropathy and the simultaneous presentation of severe restrictive cardiomyopathy. In all three cases, clinical and electrophysiological signs of myopathy were also present, suggesting the involvement of skeletal muscles as well. In two cases, high resolution ultrasound of the peripheral nerves was also performed, which showed segmental structural alterations (change or loss of fascicular structure) and some increase of echogenicity of the interfascicular epineurium, without substantial enlargement of the nerves. Conclusion - In Hungary, mainly the rare, non-Val30Met mutation forms of transthyretin familial amyloid polyneuropathy are encountered, as in our cases. As opposed to the Val30Met forms, these mutations are characterized by late onset and simultaneous presentation of severe cardiomyopathy. Our report highlights the importance of considering transthyretin familial amyloid polyneuropathy in the differential diagnosis of late-onset, progressive, axonal polyneuropathies of unknown etiology, particularly if associated with cardiac disease.

Introduction -

    Transthyretin familial amyloid polyneuropathy
    DIAGNOSIS

 is a

    rare autosomal dominant progressive systemic disesase
    DIAGNOSIS

 of

    adults
    AGE

 caused by

    endoneural amyloid deposition
    MICROSCOPIC

 due to

    point mutations of the transthyretin gene
    GENETICS

. It is the most severe form among

    hereditary polyneuropathies
    DIAGNOSIS

, being

    fatal
    SYMPTOMS

 within 10 years if left untreated. The disease is underdiagnosed, the late onset forms (

    above the age of 50
    AGE

) being probably more widespread than previously thought. Early diagnosis is essential as the early introduction of

    causal therapy (tafamidis)
    MEDICATION

 slows progression and prolongs survival. Patients - We report here three non-related

    Hungarian
    ETHNICITY

 cases of

    transthyretin familial amyloid polyneuropathy
    DIAGNOSIS

 with

    non-Val30Met mutations (His88Arg
    GENETICS

 in two cases,

    Phe33Leu
    GENETICS

 in one case). They were all characterized by

    late-onset, progressive, length-dependent, axonal, sensorimotor polyneuropathy
    SYMPTOMS

 and the simultaneous presentation of

    severe restrictive cardiomyopathy
    SYMPTOMS

. In all three cases,

    clinical and electrophysiological signs of myopathy
    SYMPTOMS

 were also present, suggesting the

    involvement of skeletal muscles
    SYMPTOMS

 as well. In two cases,

    high resolution ultrasound of the peripheral nerves
    PARACLINICAL

 was also performed, which showed

    segmental structural alterations (change or loss of fascicular structure)
    SYMPTOMS

 and

    some increase of echogenicity of the interfascicular epineurium
    SYMPTOMS

,

    without substantial enlargement of the nerves
    NEG_FINDINGS

. Conclusion - In

    Hungary
    ETHNICITY

, mainly the rare,

    non-Val30Met mutation
    GENETICS

 forms of

    transthyretin familial amyloid polyneuropathy
    DIAGNOSIS

 are encountered, as in our cases. As opposed to the

    Val30Met
    GENETICS

 forms, these mutations are characterized by

    late onset
    SYMPTOMS

 and simultaneous presentation of

    severe cardiomyopathy
    SYMPTOMS

. Our report highlights the importance of considering

    transthyretin familial amyloid polyneuropathy
    DIAGNOSIS

 in the

    differential diagnosis
    PARACLINICAL

 of

    late-onset, progressive, axonal polyneuropathies
    DIAGNOSIS

    of unknown etiology
    NEG_FINDINGS

, particularly if associated with

    cardiac disease
    SYMPTOMS

.


Acute cardiac failure secondary to senile systemic amyloidosis.

Hereditary or senile transthyretin (TTR) cardiac amyloidosis is a rare and underestimated cause of heart failure in old patients. New diagnostic methods, particularly cardiac MRI and proteomic analysis, have been recently developed that enable both earlier identification and development of specific treatments.We report a case of cardiac amyloidosis revealed through late-onset heart failure.

    Hereditary or senile transthyretin (TTR) cardiac amyloidosis
    DIAGNOSIS

 is a rare and underestimated cause of

    heart failure
    SYMPTOMS

 in

    old
    AGE

 patients. New diagnostic methods, particularly

    cardiac MRI
    PARACLINICAL

 and

    proteomic analysis
    PARACLINICAL

, have been recently developed that enable both earlier identification and development of specific treatments.We report a case of

    cardiac amyloidosis
    DIAGNOSIS

 revealed through

    late-onset heart failure
    SYMPTOMS

.


Clinical and echocardiographic characteristics for differentiating between transthyretin-related and light-chain cardiac amyloidoses.

Differential diagnosis between transthyretin (TTR) and immunoglobulin light-chain (AL) cardiac amyloidoses is essential due to significantly different prognoses and therapeutic options. Therefore, clinical characteristics of patients with biopsy-proven cardiac amyloidosis were investigated to differentiate TTR from AL amyloidosis. From September 2006 to May 2014, 46 patients were confirmed to have cardiac amyloidosis (TTR, n = 28; AL, n = 18) in our institute. The median age of patients with TTR amyloidosis was 78 years (range 61-90) with 27 (96 %) males, while that of patients with AL amyloidosis was 66 (range 52-76) with 12 (67 %) males. There were no statistically significant differences in echocardiographic findings regarding left ventricular (LV) systolic function or diastolic dysfunction between the two groups. Interestingly, serum brain natriuretic peptide (BNP) levels in patients with AL amyloidosis were significantly higher than those in TTR amyloidosis patients. In contrast, the LV wall was significantly thicker in patients with TTR amyloidosis than in those with AL amyloidosis. Therefore, the ratio of BNP to LV mass index (LVMI) at presentation in AL amyloidosis patients was significantly higher than that in TTR patients (6.7 vs 2.9, p = 0.0006). A BNP-LVMI ratio of less than 3.5 had a diagnostic sensitivity and specificity for TTR amyloidosis of 71 and 83 %, respectively. One-year overall survival was 88.7 % in the patients with TTR amyloidosis and 23.7 % in the patients with AL amyloidosis. Our analysis indicates that the BNP-LVMI ratio, as well as age and sex, may be useful parameters for distinguishing TTR from AL cardiac amyloidosis.

    Differential diagnosis
    PARACLINICAL

 between

    transthyretin (TTR) and immunoglobulin light-chain (AL) cardiac amyloidoses
    DIAGNOSIS

 is essential due to significantly different prognoses and therapeutic options. Therefore, clinical characteristics of patients with

    biopsy-proven cardiac amyloidosis
    DIAGNOSIS

 were investigated to differentiate

    TTR
    DIAGNOSIS

 from

    AL amyloidosis
    DIAGNOSIS

. From September 2006 to May 2014, 46 patients were confirmed to have

    cardiac amyloidosis (TTR,
    DIAGNOSIS

 n = 28;

    AL
    DIAGNOSIS

, n = 18) in our institute. The

    median age
    AGE

 of patients with

    TTR amyloidosis
    DIAGNOSIS

    was 78 years (range 61-90)
    AGE

 with 27 (96 %)

    males
    GENDER

, while that of patients with

    AL amyloidosis
    DIAGNOSIS

    was 66 (range 52-76)
    AGE

 with 12 (67 %)

    males
    GENDER

. There were

    no statistically significant differences in echocardiographic findings regarding left ventricular (LV) systolic function or diastolic dysfunction
    NEG_FINDINGS

 between the two groups. Interestingly,

    serum brain natriuretic peptide (BNP) levels
    BIOCHEMICAL

 in patients with

    AL amyloidosis
    DIAGNOSIS

    were significantly higher than those
    BIOCHEMICAL

 in

    TTR amyloidosis
    DIAGNOSIS

 patients. In contrast,

    the LV wall was significantly thicker
    SYMPTOMS

 in patients with

    TTR amyloidosis
    DIAGNOSIS

 than in those with

    AL amyloidosis
    DIAGNOSIS

. Therefore, the

    ratio of BNP to LV mass index (LVMI)
    SYMPTOMS

 at presentation in

    AL amyloidosis
    DIAGNOSIS

 patients was significantly higher than that in

    TTR patients
    DIAGNOSIS

 (6.7 vs 2.9, p = 0.0006). A

    BNP-LVMI ratio of less than 3.5
    BIOCHEMICAL

 had a diagnostic sensitivity and specificity for

    TTR amyloidosis
    DIAGNOSIS

 of 71 and 83 %, respectively. One-year overall survival was 88.7 % in the patients with

    TTR amyloidosis
    DIAGNOSIS

 and 23.7 % in the patients with

    AL amyloidosis
    DIAGNOSIS

. Our analysis indicates that the

    BNP-LVMI ratio
    BIOCHEMICAL

, as well as age and sex, may be useful parameters for distinguishing

    TTR from AL cardiac amyloidosis
    DIAGNOSIS

.

the LV wall was significantly thicker
ratio of BNP to LV mass index (LVMI)


Personalized medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type transthyretin amyloidosis (cardiomyopathy).

Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently, Pfizer, Inc. is enrolling a 400-person clinical trial to test the efficacy of 20 or 80 mg of tafamidis to ameliorate transthyretin (TTR)-associated cardiomyopathy using clinical endpoints. Herein, we provide guidance for how to optimize the dose of tafamidis for each WT TTR cardiomyopathy patient using its mechanism of action as the key readout, i.e. we identify the dose of tafamidis that maximally kinetically stabilizes TTR in the blood. Tetramer dissociation is rate limiting for TTR aggregation, which appears to drive the pathology of the TTR amyloidoses. Hence, we measure the TTR tetramer dissociation rate (kinetic stability) in the patient's plasma as a function of tafamidis dose to optimize the dose employed to maximize kinetic stability. Historical data tell us that a subset of patients exhibiting higher tafamidis plasma concentrations are maximally kinetically stabilized at the 20-mg tafamidis dose, whereas the patient studied herein required a 60 mg once daily dose to achieve maximum kinetic stabilization. We anticipate that establishing the dose of tafamidis that achieves maximal TTR kinetic stabilization will translate into a maximal clinical effect, but that remains to be demonstrated.

Placebo-controlled clinical trials are useful for identifying the dose of a drug candidate that produces a meaningful clinical response in a patient population. Currently, Pfizer, Inc. is enrolling a

    400-person
    MEDICATION

 clinical trial to test the efficacy of

    20 or 80 mg of tafamidis
    MEDICATION

 to ameliorate

    transthyretin (TTR)-associated cardiomyopathy
    DIAGNOSIS

 using clinical endpoints. Herein, we provide guidance for how to optimize the dose of

    tafamidis
    MEDICATION

 for each WT

    TTR cardiomyopathy
    DIAGNOSIS

 patient using its mechanism of action as the key readout, i.e. we identify the dose of

    tafamidis
    MEDICATION

 that maximally

    kinetically stabilizes TTR in the blood
    BIOCHEMICAL

.

    Tetramer dissociation
    BIOCHEMICAL

 is rate limiting for

    TTR aggregation
    BIOCHEMICAL

, which appears to drive the pathology of the

    TTR amyloidoses
    DIAGNOSIS

. Hence, we measure the

    TTR tetramer dissociation rate (kinetic stability) in the patient's plasma
    BIOCHEMICAL

 as a function of

    tafamidis
    MEDICATION

 dose to optimize the dose employed to maximize kinetic stability. Historical data tell us that a subset of patients exhibiting

    higher tafamidis plasma concentrations are maximally kinetically stabilized
    BIOCHEMICAL

 at the

    20-mg tafamidis dose
    MEDICATION

, whereas the patient studied herein required a

    60 mg once daily dose
    MEDICATION

 to achieve maximum

    kinetic stabilization
    BIOCHEMICAL

. We anticipate that establishing the dose of

    tafamidis
    MEDICATION

 that achieves maximal

    TTR kinetic stabilization
    BIOCHEMICAL

 will translate into a maximal clinical effect, but that remains to be demonstrated.

400-person
20 or 80 mg of tafamidis
tafamidis
tafamidis
tafamidis
20-mg tafamidis dose
60 mg once daily dose
tafamidis


Myopathy in a patient with systemic AA amyloidosis possibly induced by psoriasis vulgaris: An autopsy case.

Amyloid myopathy is a rare manifestation of primary systemic amyloid light-chain (AL) amyloidosis, but it has not been reported to occur in secondary amyloid A (AA) amyloidosis.

We describe a 46-year-old man with psoriasis vulgaris who presented with idiopathic upper and lower limb weakness and was eventually diagnosed with hypertrophic cardiomyopathy. Muscle biopsy findings were compatible with mild inflammatory myopathy. He died of cardiopulmonary arrest, and an autopsy was performed.

The autopsy revealed amyloid plaques immunopositive for AA (but not AL or transthyretin) in the perimysial, perivascular, and endomysial regions of the iliopsoas muscle. The final diagnosis was systemic AA amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris.

This is an extremely rare autopsy case of myopathy in a patient with systemic AA amyloidosis. The reason for the unusually large amount of amyloid deposition in muscle blood vessel walls remains unclear.

    Amyloid myopathy
    DIAGNOSIS

 is a rare manifestation of

    primary systemic amyloid light-chain (AL) amyloidosis
    DIAGNOSIS

, but it has not been reported to occur in

    secondary amyloid A (AA) amyloidosis
    DIAGNOSIS

.

We describe a

    46-year-old
    AGE

    man
    GENDER

 with

    psoriasis vulgaris
    DIAGNOSIS

 who presented with

    idiopathic upper and lower limb weakness
    SYMPTOMS

 and was eventually diagnosed with

    hypertrophic cardiomyopathy
    DIAGNOSIS

.

    Muscle biopsy
    PARACLINICAL

 findings were compatible with

    mild inflammatory myopathy
    DIAGNOSIS

.

    He
    GENDER

    died
    SYMPTOMS

 of

    cardiopulmonary arrest
    SYMPTOMS

, and an

    autopsy
    PARACLINICAL

 was performed.

The

    autopsy
    PARACLINICAL

 revealed

    amyloid plaques immunopositive for AA (but not AL or transthyretin) in the perimysial, perivascular, and endomysial regions of the iliopsoas muscle
    MICROSCOPIC

. The final diagnosis was

    systemic AA amyloidosis with muscle amyloid angiopathy
    DIAGNOSIS

, possibly induced by

    psoriasis vulgaris
    DIAGNOSIS

.

This is an extremely rare

    autopsy
    PARACLINICAL

 case of

    myopathy
    DIAGNOSIS

 in a patient with

    systemic AA amyloidosis
    DIAGNOSIS

. The reason for the

    unusually large amount of amyloid deposition in muscle blood vessel walls
    MICROSCOPIC

 remains unclear.


Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy.

Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment.

    Hereditary transthyretin amyloidosis (ATTR)
    DIAGNOSIS

 is a genetically and clinically heterogeneous disease manifesting with

    predominant peripheral and autonomic neuropathy
    SYMPTOMS

;

    cardiomyopathy
    SYMPTOMS

, or both.

    ATTR V122I
    GENETICS

 is the most common variant associated with

    non-neuropathic familial amyloid cardiomyopathy
    DIAGNOSIS

. We present an unusual case of

    V122I amyloidosis
    DIAGNOSIS

 with features of

    amyloid neuropathy
    DIAGNOSIS

 and

    myopathy
    SYMPTOMS

, supported by

    histological confirmation
    PARACLINICAL

 in both sites and

    diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy
    SYMPTOMS

    throughout skeletal and cardiac muscle
    SYMPTOMS

. A

    64 year old
    AGE

    Jamaican
    ETHNICITY

    man
    GENDER

 presented with

    cardiac failure
    SYMPTOMS

.

    Cardiac MR
    PARACLINICAL

 revealed

    infiltrative cardiomyopathy
    DIAGNOSIS

;

    abdominal fat aspirate
    PARACLINICAL

 confirmed the

    presence of amyloid
    MICROSCOPIC

, and

    he
    GENDER

 was

    homozygous for the V122I variant of transthyretin
    GENETICS

.

    He
    GENDER

 also described

    general weakness
    SYMPTOMS

 and

    EMG
    PARACLINICAL

 demonstrated

    myopathic features
    SYMPTOMS

.

    Sural nerve and vastus lateralis biopsy
    PARACLINICAL

 showed

    TTR amyloid
    MICROSCOPIC

. The patient is being

    treated with diflunisal, an oral TTR stabilising agent
    MEDICATION

.

    Symptomatic myopathy and neuropathy
    SYMPTOMS

 with confirmation of

    tissue amyloid deposition
    SYMPTOMS

 has not previously been described.

    Extracardiac amyloidosis
    DIAGNOSIS

 has implications for diagnosis and treatment.