Familial amyloidosis in a large Spanish kindred resulting from a D38V mutation in the transthyretin gene.

Transthyretin amyloidosis, also known as familial amyloidotic polyneuropathy, is an autosomal dominant disorder that results from a mutation in the gene encoding plasma transthyretin (TTR). Distinct clinical presentations of the disease have been related so far to different point mutations, polyneuropathy being the predominant clinical feature in the majority of cases. Nevertheless, misdiagnosis of familial forms of amyloidosis is still common.

A 71-year-old man was admitted to our hospital for heart failure. He had been previously diagnosed of AL amyloidosis with predominant polyneuropathic, cardiac and laryngeal involvement on the basis of clinical data and amyloid deposition in tissue specimens. During admission, suspicion of transthyretin amyloidosis was raised due to the absence of renal involvement, monoclonal protein and plasma cell dyscrasia. Complete clinical evaluation and sequence analysis of the TTR gene of the patient and his family were performed.

Gene sequence analysis revealed a rare A-to-T transition in exon 2 resulting in the substitution of aspartic acid by valine at position 38 (D38V) in the index case and in two other members of the family. Clinical study of the kindred showed a predominant late-onset heart involvement with variable polyneuropathy.

Here we report a large pedigree from Spain with three members affected by a severe late-onset form of amyloidosis due to a rare D38V TTR mutation. The variations on the natural history of this form of amyloidosis may have important consequences on genetic counselling, follow-up, and therapeutic approaches for these patients.

    Transthyretin amyloidosis
    DIAGNOSIS

, also known as

    familial amyloidotic polyneuropathy
    DIAGNOSIS

, is an

    autosomal dominant disorder
    GENETICS

 that results from a

    mutation in the gene encoding plasma transthyretin (TTR)
    GENETICS

. Distinct clinical presentations of the disease have been related so far to different

    point mutations
    GENETICS

,

    polyneuropathy
    DIAGNOSIS

 being the predominant clinical feature in the majority of cases. Nevertheless, misdiagnosis of

    familial forms of amyloidosis
    DIAGNOSIS

 is still common.

A

    71-year-old
    AGE

    man
    GENDER

 was admitted to our hospital for

    heart failure
    SYMPTOMS

.

    He
    GENDER

 had been previously diagnosed of

    AL amyloidosis
    DIAGNOSIS

 with

    predominant polyneuropathic, cardiac and laryngeal involvement
    SYMPTOMS

 on the basis of clinical data and

    amyloid deposition in tissue specimens
    MICROSCOPIC

. During admission, suspicion of

    transthyretin amyloidosis
    DIAGNOSIS

 was raised due to the

    absence of renal involvement
    NEG_FINDINGS

,

    monoclonal protein
    BIOCHEMICAL

 and

    plasma cell dyscrasia
    BIOCHEMICAL

.

    Complete clinical evaluation
    PARACLINICAL

 and

    sequence analysis of the TTR gene of the patient and his family
    PARACLINICAL

 were performed.

    Gene sequence analysis
    PARACLINICAL

 revealed a

    rare A-to-T transition in exon 2 resulting in the substitution of aspartic acid by valine at position 38 (D38V)
    GENETICS

    in the index case and in two other members of the family
    FAMILY

.

    Clinical study
    PARACLINICAL

 of the kindred showed a

    predominant late-onset heart involvement
    SYMPTOMS

 with

    variable polyneuropathy
    SYMPTOMS

.

Here we report a large pedigree from

    Spain
    ETHNICITY

    with three members affected by a severe late-onset form of amyloidosis
    FAMILY

 due to a

    rare D38V TTR mutation
    GENETICS

. The variations on the natural history of this form of

    amyloidosis
    DIAGNOSIS

 may have important consequences on

    genetic counselling
    MEDICATION

, follow-up, and therapeutic approaches for these patients.

Transthyretin amyloidosis
familial amyloidotic polyneuropathy
polyneuropathy
familial forms of amyloidosis
AL amyloidosis
transthyretin amyloidosis
amyloidosis

monoclonal protein
plasma cell dyscrasia


A new transthyretin variant (Glu61Gly) associated with cardiomyopathy.

We report the identification of a new transthyretin (TTR) gene mutation and variant protein, Glu61Gly, in a 55-year-old man with progressive cardiomyopathy, mild peripheral neuropathy and bilateral carpal tunnel syndrome. A diagnosis of TTR-associated familial amyloidosis (ATTR) was considered after an endomyocardial biopsy revealed amyloid deposits in the heart of a patient who had no family history of amyloidosis and no evidence of a plasma cell dyscrasia. Serum screening for a TTR variant by isoelectric focusing (IEF) was positive and prompted further studies to identify the genetic abnormality and to characterize the amyloidogenic protein. Direct DNA sequence analysis of all four coding regions in the TTR gene demonstrated heterozygosity in exon 3. Near equal amounts of guanine (G) and adenine (A) were observed at the second base position of codon 61. The wild-type (GAG) and mutated (GGG) sequences found in codon 61 correspond to glutamic acid (Glu) and glycine (Gly) residues, amino acids which differ in mass by -72 Da. Mass spectrometric analyses of TTR immunoprecipitated from serum 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.

We report the identification of a

    new transthyretin (TTR) gene mutation and variant protein, Glu61Gly
    GENETICS

, in a

    55-year-old
    AGE

    man
    GENDER

 with

    progressive cardiomyopathy
    SYMPTOMS

,

    mild peripheral neuropathy
    SYMPTOMS

 and

    bilateral carpal tunnel syndrome
    SYMPTOMS

. A diagnosis of

    TTR-associated familial amyloidosis (ATTR)
    DIAGNOSIS

 was considered after an

    endomyocardial biopsy
    PARACLINICAL

 revealed

    amyloid deposits in the heart
    MICROSCOPIC

 of a patient who had

    no family history of amyloidosis
    NEG_FINDINGS

 and

    no evidence of a plasma cell dyscrasia
    NEG_FINDINGS

.

    Serum screening for a TTR variant
    PARACLINICAL

    by isoelectric focusing (IEF)
    PARACLINICAL

 was positive and prompted further studies to identify the genetic abnormality and to characterize the amyloidogenic protein.

    Direct DNA sequence analysis of all four coding regions in the TTR gene
    PARACLINICAL

 demonstrated

    heterozygosity in exon 3
    GENETICS

.

    Near equal amounts of guanine (G) and adenine (A) were observed at the second base position of codon 61
    GENETICS

.

    The wild-type (GAG) and mutated (GGG) sequences found in codon 61 correspond to glutamic acid (Glu) and glycine (Gly) residues, amino acids which differ in mass by -72 Da
    GENETICS

.

    Mass spectrometric analyses of TTR immunoprecipitated from serum
    PARACLINICAL

 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
    PARACLINICAL

.

progressive cardiomyopathy
mild peripheral neuropathy
bilateral carpal tunnel syndrome

no family history of amyloidosis
no evidence of a plasma cell dyscrasia


Severe congestive heart failure with cardiac liver cirrhosis 10 years after orthotopic liver transplantation for familial amyloidotic polyneuropathy.

Reported herein is an autopsy case of familial amyloidotic polyneuropathy (FAP) with cardiac liver cirrhosis associated with amyloid cardiomyopathy after liver transplantation. At 47 years of age a Japanese woman with a transthyretin Val30Met mutation and sensorimotor polyneuropathy underwent liver transplantation; no postoperative deterioration related to the graft or polyneuropathy occurred. However, cardiovascular dysfunction associated with amyloid deposition gradually worsened. Pacemaker implantation and diuretics were ineffective against the heart failure; 10 years after transplantation the patient died. Autopsy revealed massive pleural and pericardial effusions and amyloid cardiomyopathy, especially in the right atrium and cardiac conduction system. Amyloid deposition was slight in all organs except the heart, but liver cirrhosis with reversed lobulation and centrilobular hemorrhagic necrosis was prominent. There was no histological evidence for chronic liver graft rejection. These findings suggest that liver transplantation effectively stopped amyloid deposition and ameliorated clinical FAP symptoms but that amyloid cardiomyopathy after liver transplantation in advanced clinical stages may lead to severe congestive heart failure and cardiac liver cirrhosis.

Reported herein is an

    autopsy
    PARACLINICAL

 case of

    familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 with

    cardiac liver cirrhosis
    SYMPTOMS

 associated with

    amyloid cardiomyopathy
    DIAGNOSIS

 after

    liver transplantation
    MEDICATION

. At

    47 years of age
    AGE

 a

    Japanese
    ETHNICITY

    woman
    GENDER

 with a

    transthyretin Val30Met mutation
    GENETICS

 and

    sensorimotor polyneuropathy
    DIAGNOSIS

 underwent

    liver transplantation
    MEDICATION

;

    no postoperative deterioration related to the graft or polyneuropathy
    NEG_FINDINGS

 occurred. However,

    cardiovascular dysfunction associated with amyloid deposition
    SYMPTOMS

 gradually worsened.

    Pacemaker implantation and diuretics were ineffective against the heart failure
    NEG_FINDINGS

; 10 years after

    transplantation
    MEDICATION

 the patient

    died
    SYMPTOMS

.

    Autopsy
    PARACLINICAL

 revealed

    massive pleural and pericardial effusions
    SYMPTOMS

 and

    amyloid cardiomyopathy, especially in the right atrium and cardiac conduction system
    SYMPTOMS

.

    Amyloid deposition was slight in all organs except the heart
    MICROSCOPIC

, but

    liver cirrhosis with reversed lobulation
    SYMPTOMS

 and

    centrilobular hemorrhagic necrosis
    SYMPTOMS

 was prominent. There was

    no histological evidence for chronic liver graft rejection
    NEG_FINDINGS

. These findings suggest that

    liver transplantation
    MEDICATION

 effectively

    stopped amyloid deposition
    BIOCHEMICAL

 and

    ameliorated clinical FAP symptoms
    SYMPTOMS

 but that

    amyloid cardiomyopathy
    DIAGNOSIS

 after

    liver transplantation
    MEDICATION

 in advanced clinical stages may lead to

    severe congestive heart failure
    SYMPTOMS

 and

    cardiac liver cirrhosis
    SYMPTOMS

.

liver transplantation
liver transplantation
transplantation
liver transplantation
liver transplantation


A Swedish family with the rare Phe33Leu transthyretin mutation.

Familial amyloidotic polyneuropathy (FAP) designates TTR mutations where the phenotype is dominated by a peripheral sensory-motor polyneuropathy. The most common mutation is ATTR Val30Met. FAP in association with ATTR Phe33Leu has been described previously in two American families, one of Polish-Lithuanian descent and the other of Polish-American. In this study, we report the phenotype of the ATTR Phe33Leu in a Swedish family. The proband is a 48 year-old patient from northern Sweden, whose father died with symptoms suggestive of FAP. Characteristic clinical features included polyneuropathy, carpal tunnel syndrome and asymptomatic, but echocardiographic examination diagnosed cardiomyopathy. The family history supports an early intervention with orthotopic liver transplantation in patients with FAP associated with the TTR Phe33Leu, and the patient was submitted for liver transplantation.

    Familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 designates

    TTR mutations
    GENETICS

 where the phenotype is dominated by a

    peripheral sensory-motor polyneuropathy
    SYMPTOMS

. The most common mutation is

    ATTR Val30Met
    GENETICS

.

    FAP
    DIAGNOSIS

 in association with

    ATTR Phe33Leu
    GENETICS

 has been described previously in two

    American
    ETHNICITY

 families, one of

    Polish-Lithuanian descent
    ETHNICITY

 and the other of

    Polish-American
    ETHNICITY

. In this study, we report the phenotype of the

    ATTR Phe33Leu
    GENETICS

 in a

    Swedish
    ETHNICITY

 family. The proband is a

    48 year-old
    AGE

 patient from

    northern Sweden
    ETHNICITY

, whose

    father died with symptoms suggestive of FAP
    FAMILY

. Characteristic clinical features included

    polyneuropathy
    SYMPTOMS

,

    carpal tunnel syndrome
    SYMPTOMS

 and

    asymptomatic
    SYMPTOMS

, but

    echocardiographic examination
    PARACLINICAL

 diagnosed

    cardiomyopathy
    SYMPTOMS

. The family history supports an

    early intervention with orthotopic liver transplantation
    MEDICATION

 in patients with

    FAP associated with
    DIAGNOSIS

 the

    TTR Phe33Leu
    GENETICS

, and the patient was submitted for

    liver transplantation
    MEDICATION

.

TTR mutations
ATTR Val30Met
ATTR Phe33Leu
ATTR Phe33Leu
TTR Phe33Leu

peripheral sensory-motor polyneuropathy
polyneuropathy
carpal tunnel syndrome
asymptomatic
cardiomyopathy

American
Polish-Lithuanian descent
Polish-American
Swedish
northern Sweden


Cardiomyopathy in Swedish patients with the Gly53Glu and His88Arg transthyretin variants.

We report two new amyloidogenic transthyretin (TTR) variants detected in the Swedish population. One variant was previously unknown, while the other has been described in a French family. In Swedish patients, both variants have caused late-onset cardiac amyloidosis characterised by heart failure. In both cases, the diagnosis was determined by the detection of amyloid deposits in skin and/or rectal biopsies and identification of TTR mutations by genetic analysis. The index case of the previously unknown mutation (ATTR His88Arg) was a 66-year-old Swedish man, who sought medical attention for increasing dyspnea. Echocardiographic examination disclosed a restrictive cardiomyopathy, and subsequent examinations disclosed TTR amyloidosis. The patient is alive with moderate symptoms one year after the onset of disease. The index case for the new Swedish mutation (ATTR Gly53Glu) is a woman who sought medical attention at the age of 57 because of increasing dyspnea. Echocardiographic examination disclosed a hypertrophic cardiomyopathy with diastolic impairment. The diagnosis of systemic amyloidosis was made by fat aspiration biopsy and histopathology. The patient developed severe intractable heart failure, with pulmonary effusion and ascites. She died four years after the onset of her disease of intractable heart and kidney failure. Post mortem examination of biopsy specimens and blood revealed TTR amyloid deposits and the ATTR Gly53Glu mutation was detected.

We report two new

    amyloidogenic transthyretin (TTR) variants
    GENETICS

 detected in the

    Swedish
    ETHNICITY

 population. One variant was previously unknown, while the other has been described in a

    French
    ETHNICITY

 family. In

    Swedish
    ETHNICITY

 patients, both variants have caused

    late-onset cardiac amyloidosis
    DIAGNOSIS

 characterised by

    heart failure
    SYMPTOMS

. In both cases, the diagnosis was determined by the detection of

    amyloid deposits in skin and/or rectal biopsies
    MICROSCOPIC

 and identification of

    TTR mutations
    GENETICS

 by

    genetic analysis
    PARACLINICAL

. The index case of the

    previously unknown mutation (ATTR His88Arg)
    GENETICS

 was a

    66-year-old
    AGE

    Swedish
    ETHNICITY

    man
    GENDER

, who sought medical attention for

    increasing dyspnea
    SYMPTOMS

.

    Echocardiographic examination
    PARACLINICAL

 disclosed a

    restrictive cardiomyopathy
    SYMPTOMS

, and subsequent examinations disclosed

    TTR amyloidosis
    DIAGNOSIS

. The patient is alive with

    moderate symptoms
    SYMPTOMS

 one year after the onset of disease. The index case for the

    new Swedish mutation (ATTR Gly53Glu
    GENETICS

) is a

    woman
    GENDER

 who sought medical attention at the

    age of 57
    AGE

 because of

    increasing dyspnea
    SYMPTOMS

.

    Echocardiographic examination
    PARACLINICAL

 disclosed a

    hypertrophic cardiomyopathy
    SYMPTOMS

 with

    diastolic impairment
    SYMPTOMS

. The diagnosis of

    systemic amyloidosis
    DIAGNOSIS

 was made by

    fat aspiration biopsy
    PARACLINICAL

 and

    histopathology
    PARACLINICAL

. The patient developed

    severe intractable heart failure
    SYMPTOMS

, with

    pulmonary effusion
    SYMPTOMS

 and

    ascites
    SYMPTOMS

.

    She
    GENDER

    died
    SYMPTOMS

 four years after the onset of her disease of

    intractable heart and kidney failure
    SYMPTOMS

.

    Post mortem examination of biopsy specimens and blood
    PARACLINICAL

 revealed

    TTR amyloid deposits
    MICROSCOPIC

 and the

    ATTR Gly53Glu mutation
    GENETICS

 was detected.

late-onset cardiac amyloidosis
TTR amyloidosis
systemic amyloidosis

heart failure
increasing dyspnea
restrictive cardiomyopathy
moderate symptoms
increasing dyspnea
hypertrophic cardiomyopathy
diastolic impairment
severe intractable heart failure
pulmonary effusion
ascites
died
intractable heart and kidney failure


Amyloid heart disease mimicking hypertrophic cardiomyopathy.

To investigate the importance of transthyretin (TTR) gene mutations in explaining the phenotypic expression in patients diagnosed with hypertrophic cardiomyopathy (HCM) in northern Sweden.

Hypertrophic cardiomyopathy is relatively common and often caused by mutations in sarcomeric protein genes. Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. These circumstances were highlighted by the finding of an index case with amyloidosis, presenting itself as HCM. Initial rectal and fat biopsies did not show amyloid deposits. Later on, the patient was shown to carry a TTR gene mutation, and cardiac amyloidosis was confirmed by myocardial biopsy. Only then was a repeated fat biopsy positive for amyloid deposits.

Cross-sectional study.

Cardiology tertiary referral centre.

Forty-six unrelated individuals with HCM and the index case were included. Common diagnostic criteria for HCM were used. The 46 patients with HCM were previously analysed for mutations in eight sarcomeric protein genes and the TTR gene was now analysed by denaturing high-performance liquid chromatography and direct sequencing.

One mutation in the TTR gene (Val30Met) was found in three individuals and the index case.

Three of the 46 cases with HCM carried the Val30Met mutation, and were considered likely to have cardiac amyloidosis, like the index case. As a correct diagnosis of cardiac amyloidosis is mandatory for a potentially life-saving treatment, TTR mutation analysis should be considered in cases of HCM not explained by mutations in sarcomeric protein genes.

To investigate the importance of

    transthyretin (TTR) gene mutations
    GENETICS

 in explaining the phenotypic expression in patients diagnosed with

    hypertrophic cardiomyopathy (HCM)
    DIAGNOSIS

 in

    northern Sweden
    ETHNICITY

.

    Hypertrophic cardiomyopathy
    DIAGNOSIS

 is relatively common and often caused by

    mutations in sarcomeric protein genes
    GENETICS

.

    Mutations in the TTR gene
    GENETICS

 are also common, one of which causes

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

, with

    peripheral polyneuropathy
    SYMPTOMS

 and frequently,

    cardiac hypertrophy
    SYMPTOMS

. These circumstances were highlighted by the finding of an index case with

    amyloidosis
    DIAGNOSIS

, presenting itself as

    HCM
    DIAGNOSIS

.

    Initial rectal and fat biopsies did not show amyloid deposits
    NEG_FINDINGS

. Later on, the patient was shown to carry a

    TTR gene mutation
    GENETICS

, and

    cardiac amyloidosis
    DIAGNOSIS

 was confirmed by

    myocardial biopsy
    PARACLINICAL

. Only then was a

    repeated fat biopsy
    PARACLINICAL

    positive for amyloid deposits
    MICROSCOPIC

.

    Cross-sectional study
    PARACLINICAL

.

Cardiology

    tertiary referral centre
    MEDICATION

.

Forty-six unrelated individuals with

    HCM
    DIAGNOSIS

 and the index case were included. Common diagnostic criteria for

    HCM
    DIAGNOSIS

 were used. The 46 patients with

    HCM
    DIAGNOSIS

 were previously analysed for

    mutations in eight sarcomeric protein genes
    GENETICS

 and the

    TTR gene
    PARACLINICAL

 was now analysed by

    denaturing high-performance liquid chromatography and direct sequencing
    PARACLINICAL

.

    One mutation in the TTR gene (Val30Met)
    GENETICS

 was found in three individuals and the index case.

Three of the 46 cases with

    HCM
    DIAGNOSIS

 carried the

    Val30Met mutation
    GENETICS

, and were considered likely to have

    cardiac amyloidosis
    DIAGNOSIS

, like the index case. As a correct diagnosis of

    cardiac amyloidosis
    DIAGNOSIS

 is mandatory for a potentially life-saving treatment,

    TTR mutation analysis
    PARACLINICAL

 should be considered in cases of

    HCM
    DIAGNOSIS

    not explained by mutations in sarcomeric protein genes
    NEG_FINDINGS

.

hypertrophic cardiomyopathy (HCM)
Hypertrophic cardiomyopathy
familial amyloid polyneuropathy (FAP)
amyloidosis
HCM
cardiac amyloidosis
HCM
HCM
HCM
HCM
cardiac amyloidosis
cardiac amyloidosis
HCM

peripheral polyneuropathy
cardiac hypertrophy


Chronic traumatic encephalopathy in a National Football League player.

We present the results of the autopsy of a retired professional football player that revealed neuropathological changes consistent with long-term repetitive concussive brain injury. This case draws attention to the need for further studies in the cohort of retired National Football League players to elucidate the neuropathological sequelae of repeated mild traumatic brain injury in professional football.

The patient's premortem medical history included symptoms of cognitive impairment, a mood disorder, and parkinsonian symptoms. There was no family history of Alzheimer's disease or any other head trauma outside football. A complete autopsy with a comprehensive neuropathological examination was performed on the retired National Football League player approximately 12 years after retirement. He died suddenly as a result of coronary atherosclerotic disease. Studies included determination of apolipoprotein E genotype.

Autopsy confirmed the presence of coronary atherosclerotic disease with dilated cardiomyopathy. The brain demonstrated no cortical atrophy, cortical contusion, hemorrhage, or infarcts. The substantia nigra revealed mild pallor with mild dropout of pigmented neurons. There was mild neuronal dropout in the frontal, parietal, and temporal neocortex. Chronic traumatic encephalopathy was evident with many diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas. There were no neurofibrillary tangles or neuropil threads in the hippocampus or entorhinal cortex. Lewy bodies were absent. The apolipoprotein E genotype was E3/E3.

This case highlights potential long-term neurodegenerative outcomes in retired professional National Football League players subjected to repeated mild traumatic brain injury. The prevalence and pathoetiological mechanisms of these possible adverse long-term outcomes and their relation to duration of years of playing football have not been sufficiently studied. We recommend comprehensive clinical and forensic approaches to understand and further elucidate this emergent professional sport hazard.

We present the results of the

    autopsy
    PARACLINICAL

 of a retired

    professional football player
    AGE

 that revealed

    neuropathological changes consistent with long-term repetitive concussive brain injury
    SYMPTOMS

. This case draws attention to the need for further studies in the cohort of retired National Football League players to elucidate the neuropathological sequelae of

    repeated mild traumatic brain injury
    SYMPTOMS

 in

    professional football
    AGE

.

The patient's premortem medical history included

    symptoms of cognitive impairment
    SYMPTOMS

, a

    mood disorder
    DIAGNOSIS

, and

    parkinsonian symptoms
    SYMPTOMS

. There was

    no family history of Alzheimer's disease
    NEG_FINDINGS

    or any other head trauma outside football
    NEG_FINDINGS

. A

    complete autopsy
    PARACLINICAL

 with a

    comprehensive neuropathological examination
    PARACLINICAL

 was performed on the retired National Football League player approximately 12 years after retirement.

    He
    GENDER

    died
    SYMPTOMS

 suddenly as a result of

    coronary atherosclerotic disease
    DIAGNOSIS

. Studies included

    determination of apolipoprotein E genotype
    PARACLINICAL

.

    Autopsy
    PARACLINICAL

 confirmed the presence of

    coronary atherosclerotic disease
    DIAGNOSIS

 with

    dilated cardiomyopathy
    DIAGNOSIS

. The brain demonstrated

    no cortical atrophy
    NEG_FINDINGS

,

    cortical contusion, hemorrhage, or infarcts
    NEG_FINDINGS

. The

    substantia nigra
    SYMPTOMS

 revealed

    mild pallor with mild dropout of pigmented neurons
    SYMPTOMS

. There was

    mild neuronal dropout in the frontal, parietal, and temporal neocortex
    SYMPTOMS

.

    Chronic traumatic encephalopathy
    DIAGNOSIS

 was evident with

    many diffuse amyloid plaques
    MICROSCOPIC

 as well as

    sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas
    MICROSCOPIC

. There were

    no neurofibrillary tangles or neuropil threads in the hippocampus or entorhinal cortex
    NEG_FINDINGS

.

    Lewy bodies were absent
    NEG_FINDINGS

. The

    apolipoprotein E genotype was E3/E3.
    GENETICS

This case highlights potential

    long-term neurodegenerative outcomes
    SYMPTOMS

 in retired professional National Football League

    players
    GENDER

 subjected to

    repeated mild traumatic brain injury
    SYMPTOMS

. The prevalence and pathoetiological mechanisms of these possible

    adverse long-term outcomes
    SYMPTOMS

 and their relation to duration of

    years of playing football
    MEDICATION

 have not been sufficiently studied. We recommend comprehensive clinical and forensic approaches to understand and further elucidate this emergent professional sport hazard.

mood disorder
coronary atherosclerotic disease
coronary atherosclerotic disease
dilated cardiomyopathy
Chronic traumatic encephalopathy


Pleural effusions in systemic amyloidosis.

Large, recurrent pleural effusions in systemic amyloidoses are rare but clinically challenging events predominantly affecting patients with primary systemic amyloidosis. Examining the mechanisms by which these effusions form and persist offers perspective on the pathophysiology and basis for therapeutic interventions.

Between 1977 and 2003, the literature consisted of approximately 21-25 case reports on pleural effusions in systemic amyloidosis. In 2003, Boston University published a retrospective single-center analysis of 35 primary systemic amyloidosis patients with large, refractory pleural effusions. To define the role of cardiomyopathy in large, refractory pleural effusions, the Boston University Amyloid Program compared demographics, pleural fluid chemistries, echocardiographic indices, and renal function measures of the pleural effusion group with data from 120 primary systemic amyloidosis cardiomyopathy patients with no pleural effusions. Neither cardiomyopathy nor nephrotic syndrome explained pleural effusions in primary systemic amyloidosis patients. The large number of exudative effusions supported primary disruption of the pleural surface and its function by amyloid. Disease mechanisms, natural history, and management options are discussed here.

Large pleural effusions in systemic amyloidosis occur most often in primary systemic amyloidosis, predominantly resulting from direct infiltration of the parietal pleural surface. Left atrial hypertension from primary systemic amyloidosis cardiomyopathy contributes to but is not sufficient to form and sustain these effusions. Untreated patients have a median survival of 1.6 months. Secondary, familial, and senile systemic amyloidosis do not infiltrate the pleural surfaces or induce pleural effusions in a clinically significant fashion.

    Large, recurrent pleural effusions
    SYMPTOMS

 in

    systemic amyloidoses
    DIAGNOSIS

 are rare but clinically challenging events predominantly affecting patients with

    primary systemic amyloidosis
    DIAGNOSIS

. Examining the mechanisms by which these

    effusions
    SYMPTOMS

 form and persist offers perspective on the pathophysiology and basis for therapeutic interventions.

Between 1977 and 2003, the literature consisted of approximately 21-25 case reports on

    pleural effusions
    SYMPTOMS

 in

    systemic amyloidosis
    DIAGNOSIS

. In 2003, Boston University published a retrospective single-center analysis of 35

    primary systemic amyloidosis
    DIAGNOSIS

 patients with

    large, refractory pleural effusions
    SYMPTOMS

. To define the role of

    cardiomyopathy
    DIAGNOSIS

 in

    large, refractory pleural effusions
    SYMPTOMS

, the Boston University Amyloid Program compared demographics,

    pleural fluid chemistries
    PARACLINICAL

,

    echocardiographic indices
    PARACLINICAL

, and

    renal function measures
    PARACLINICAL

 of the

    pleural effusion
    DIAGNOSIS

 group with data from 120

    primary systemic amyloidosis cardiomyopathy
    DIAGNOSIS

 patients with

    no pleural effusions
    NEG_FINDINGS

.

    Neither cardiomyopathy nor nephrotic syndrome
    NEG_FINDINGS

 explained

    pleural effusions
    NEG_FINDINGS

 in

    primary systemic amyloidosis
    DIAGNOSIS

 patients. The large number of

    exudative effusions
    SYMPTOMS

 supported

    primary disruption of the pleural surface and its function
    SYMPTOMS

 by

    amyloid
    SYMPTOMS

. Disease mechanisms, natural history, and management options are discussed here.

    Large pleural effusions
    SYMPTOMS

 in

    systemic amyloidosis
    DIAGNOSIS

 occur most often in

    primary systemic amyloidosis
    DIAGNOSIS

, predominantly resulting from

    direct infiltration of the parietal pleural surface
    MICROSCOPIC

.

    Left atrial hypertension
    SYMPTOMS

 from

    primary systemic amyloidosis cardiomyopathy
    DIAGNOSIS

 contributes to but is not sufficient to form and sustain these

    effusions
    SYMPTOMS

. Untreated patients have a median survival of 1.6 months.

    Secondary, familial
    DIAGNOSIS

, and

    senile systemic amyloidosis
    DIAGNOSIS

 do

    not infiltrate the pleural surfaces or induce pleural effusions in a clinically significant fashion
    NEG_FINDINGS

.


A novel transthyretin mutation V32A in a Chinese man with late-onset amyloid polyneuropathy.

We report a Chinese patient with amyloidotic polyneuropathy associated with a novel transthyretin mutation (V32A). He presented with slowly progressive sensorimotor polyneuropathy accompanied by autonomic dysfunction and cardiomyopathy by echocardiography. This mutation is likely to be associated with late onset and low-penetrance phenotype.

We report a

    Chinese
    ETHNICITY

 patient with

    amyloidotic polyneuropathy
    DIAGNOSIS

 associated with a

    novel transthyretin mutation (V32A)
    GENETICS

.

    He
    GENDER

 presented with

    slowly progressive sensorimotor polyneuropathy
    SYMPTOMS

 accompanied by

    autonomic dysfunction
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

 by

    echocardiography
    PARACLINICAL

. This mutation is likely to be associated with late onset and

    low-penetrance phenotype
    GENETICS

.

novel transthyretin mutation (V32A)
low-penetrance phenotype


An unusual transthyretin gene missense mutation (TTR Phe33Val) linked to familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy is a rare autosomal dominant disease, with clinical symptoms beginning in most kindreds within the third to seventh decades of life. The primary defect results from one of a number of mutations in the transthyretin (TTR) gene. Over 80 mutations in the TTR gene have been described. Most mutations give rise to adult onset progressive peripheral and autonomic neuropathy, due to amyloid deposition within the nerves, and often subclinical cardiac amyloid and vitreous deposits. We report here the clinical and molecular characterization of a rare TTR missense mutation discovered in a young woman from Macedonia, showing severe axonal sensory-motor polyneuropathy, restrictive cardiomyopathy and bilateral vitreous deposits. The transthyretin gene, analyzed by direct nucleotide sequencing, demonstrated a T to G transversion at nucleotide 183 in the exon 2 which is predicted to cause a heterozygous valine for phenylalanine substitution at codon 33 (TTR Phe33Val). This mutation has been previously reported only twice, without complete clinical descriptions.

    Familial amyloidotic polyneuropathy
    DIAGNOSIS

 is a

    rare autosomal dominant disease
    GENETICS

, with clinical symptoms beginning in most kindreds

    within the third to seventh decades of life
    AGE

. The primary defect results from one of a number of

    mutations in the transthyretin (TTR) gene
    GENETICS

. Over 80

    mutations in the TTR gene
    GENETICS

 have been described. Most mutations give rise to

    adult onset progressive peripheral and autonomic neuropathy
    SYMPTOMS

, due to

    amyloid deposition within the nerves
    MICROSCOPIC

, and often

    subclinical cardiac amyloid and vitreous deposits
    SYMPTOMS

. We report here the clinical and molecular characterization of a

    rare TTR missense mutation
    GENETICS

 discovered in a

    young
    AGE

    woman
    GENDER

 from

    Macedonia
    ETHNICITY

, showing

    severe axonal sensory-motor polyneuropathy
    SYMPTOMS

,

    restrictive cardiomyopathy
    SYMPTOMS

 and

    bilateral vitreous deposits
    SYMPTOMS

.

    The transthyretin gene, analyzed by direct nucleotide sequencing
    PARACLINICAL

, demonstrated a

    T to G transversion at nucleotide 183 in the exon 2 which is predicted to cause a heterozygous valine for phenylalanine substitution at codon 33 (TTR Phe33Val)
    GENETICS

. This mutation has been previously reported only twice, without complete clinical descriptions.


A rare transthyretin mutation (Asp18Glu) associated with cardiomyopathy.

The identification of a rare transthyretin (TTR) gene mutation (Asp18Glu) in a middle-aged male with biopsy proven amyloid disease featuring cardiomyopathy is described. The more commonly occurring light chain amyloidosis (AL) was initially considered, but negative hematologic testing prompted screening for a pathologic TTR mutation. A differential diagnosis of familial transthyretin type amyloidosis (ATTR) was established using a combination of molecular genetic and biochemical techniques. Single-strand conformation polymorphism (SSCP) screening of exons 2, 3 and 4 of the TTR gene indicated the presence of atypical DNA. SSCP testing was performed using a new non-radioactive, silver stained minigel technique. The genetic abnormality was identified by direct DNA sequence analysis as a T to A transversion at the third base position in codon 18. This result was confirmed by restriction fragment length polymorphism (RFLP) testing. The presence of the variant protein, TTR Asp18Glu, in serum from the proband was confirmed by mass spectrometric analysis.

The identification of a

    rare transthyretin (TTR) gene mutation (Asp18Glu)
    GENETICS

 in a

    middle-aged
    AGE

    male
    GENDER

 with

    biopsy
    PARACLINICAL

 proven

    amyloid disease
    DIAGNOSIS

 featuring

    cardiomyopathy
    SYMPTOMS

 is described. The more commonly occurring

    light chain amyloidosis (AL)
    DIAGNOSIS

 was initially considered, but

    negative hematologic testing
    NEG_FINDINGS

 prompted screening for a

    pathologic TTR mutation
    GENETICS

. A differential diagnosis of

    familial transthyretin type amyloidosis (ATTR)
    DIAGNOSIS

 was established using a combination of

    molecular genetic and biochemical techniques
    PARACLINICAL

.

    Single-strand conformation polymorphism (SSCP) screening of exons 2, 3 and 4 of the TTR gene
    PARACLINICAL

 indicated the presence of

    atypical DNA
    GENETICS

.

    SSCP testing
    PARACLINICAL

 was performed using a new

    non-radioactive, silver stained minigel technique
    PARACLINICAL

. The

    genetic abnormality
    GENETICS

 was identified by

    direct DNA sequence analysis
    PARACLINICAL

 as a

    T to A transversion at the third base position in codon 18
    GENETICS

. This result was confirmed by

    restriction fragment length polymorphism (RFLP) testing
    PARACLINICAL

. The presence of the

    variant protein, TTR Asp18Glu, in serum
    BIOCHEMICAL

 from the proband was confirmed by

    mass spectrometric analysis
    PARACLINICAL

.


Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American-Finnish families.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder associated with more than 80 different transthyretin (TTR) mutations. The clinical features of FAP are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timming of treatment by orthotopic liver transplantation. FAP in association with TTR Gly47Glu has been described previously in an Italian kindred, and we report here its phenotype in 7 additional patients from Dutch, British, and American (Finnish) families. Characteristic clinical features included amyloid cardiomyopathy and autonomic failure but, unusually, moderate to severe renal failure was present in more than half of the cases. Only four patients were deemed to be sufficiently fit to undergo orthotopic liver transplantation, and clinical deterioration was generally rapid. These observations support early intervention with orthotopic liver transplantation in patients with FAP associated with TTR Gly47Glu.

    Familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 is an

    autosomal dominant disorder
    GENETICS

 associated with more than 80 different

    transthyretin (TTR) mutations
    GENETICS

. The clinical features of

    FAP
    DIAGNOSIS

 are broad and variable, but knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timming of treatment by

    orthotopic liver transplantation
    MEDICATION

.

    FAP
    DIAGNOSIS

 in association with

    TTR Gly47Glu
    GENETICS

 has been described previously in an

    Italian
    ETHNICITY

 kindred, and we report here its phenotype in 7 additional patients from

    Dutch
    ETHNICITY

,

    British
    ETHNICITY

, and

    American (Finnish)
    ETHNICITY

 families. Characteristic clinical features included

    amyloid cardiomyopathy
    SYMPTOMS

 and

    autonomic failure
    SYMPTOMS

 but, unusually,

    moderate to severe renal failure
    SYMPTOMS

 was present in more than half of the cases. Only four patients were deemed to be sufficiently fit to undergo

    orthotopic liver transplantation
    MEDICATION

, and

    clinical deterioration was generally rapid
    SYMPTOMS

. These observations support

    early intervention with orthotopic liver transplantation
    MEDICATION

 in patients with

    FAP
    DIAGNOSIS

 associated with

    TTR Gly47Glu
    GENETICS

.

autosomal dominant disorder
transthyretin (TTR) mutations
TTR Gly47Glu
TTR Gly47Glu

Italian
Dutch
British
American (Finnish)


Combined heart and liver transplantation for familial amyloidotic neuropathy: considerations from the hepatic point of view.

Few cases of combined heart and liver transplantation (CHLT) for familial amyloidotic polyneuropathy have been reported, and the technique for the operation is far from being consolidated. Three patients with amyloidogenic transthyretin (ATTR)-related (variant Glu89Gln to ATTR Glu89Gln) cardiomyopathy underwent CHLT at our institution. Patient 1 had no serious involvement of other organs, whereas patients 2 and 3 had evident peripheral neuropathy and gastrointestinal motility alterations. Patient 3 also had high-grade orthostatic hypotension. All three patients underwent cardiac and sequential hepatic transplantation using the piggyback technique with organs procured from the same donor. Venovenous bypass (VVB) was used only in patient 1, with an uncomplicated procedure. After CHLT, his cardiac performance remained normal, and no progression of amyloidosis was observed. Patient 2 had no intraoperative complications, but experienced postoperative bleeding, renal failure, sepsis, and heart failure and eventually died of multiorgan failure 2 months after transplantation. In patient 3, right hemicolectomy was required intraoperatively because of intestinal ischemia without significant hemodynamic perturbations, whereas extracardiac symptoms of amyloidosis gradually worsened postoperatively. Two patients (no. 1 and 3) currently are alive after 38 and 18 months, respectively. CHLT for ATTR Glu89Gln can be performed successfully, even in patients with advanced disease. However, the most compromised patients are more exposed to intraoperative risks, postoperative complications, and worsening of extracardiac and extrahepatic symptoms. The need for VVB remains to be evaluated.

Few cases of

    combined heart and liver transplantation (CHLT)
    MEDICATION

 for

    familial amyloidotic polyneuropathy
    DIAGNOSIS

 have been reported, and the technique for the operation is far from being consolidated. Three patients with

    amyloidogenic transthyretin (ATTR)-related (variant Glu89Gln to ATTR Glu89Gln) cardiomyopathy
    DIAGNOSIS

 underwent

    CHLT
    MEDICATION

 at our institution. Patient 1 had

    no serious involvement of other organs
    NEG_FINDINGS

, whereas patients 2 and 3 had evident

    peripheral neuropathy
    SYMPTOMS

 and

    gastrointestinal motility alterations
    SYMPTOMS

. Patient 3 also had

    high-grade orthostatic hypotension
    SYMPTOMS

. All three patients underwent

    cardiac and sequential hepatic transplantation using the piggyback technique with organs procured from the same donor
    MEDICATION

.

    Venovenous bypass (VVB)
    MEDICATION

 was used only in patient 1, with an uncomplicated procedure. After

    CHLT
    MEDICATION

, his

    cardiac performance remained normal
    NEG_FINDINGS

, and

    no progression of amyloidosis
    NEG_FINDINGS

 was observed. Patient 2 had

    no intraoperative complications
    NEG_FINDINGS

, but experienced

    postoperative bleeding
    SYMPTOMS

,

    renal failure
    SYMPTOMS

,

    sepsis
    SYMPTOMS

, and

    heart failure
    SYMPTOMS

 and eventually

    died
    SYMPTOMS

 of

    multiorgan failure
    SYMPTOMS

 2 months after

    transplantation
    MEDICATION

. In patient 3,

    right hemicolectomy
    MEDICATION

 was required intraoperatively because of

    intestinal ischemia
    SYMPTOMS

    without significant hemodynamic perturbations
    NEG_FINDINGS

, whereas

    extracardiac symptoms of amyloidosis gradually worsened
    SYMPTOMS

 postoperatively. Two patients (no. 1 and 3) currently are alive after 38 and 18 months, respectively.

    CHLT
    MEDICATION

 for

    ATTR Glu89Gln
    DIAGNOSIS

 can be performed successfully, even in patients with advanced disease. However, the most compromised patients are more exposed to intraoperative risks,

    postoperative complications
    SYMPTOMS

, and

    worsening of extracardiac and extrahepatic symptoms
    SYMPTOMS

. The need for

    VVB
    MEDICATION

 remains to be evaluated.


Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg.

Mutations in the gene for apolipoprotein AII (apoAII) have recently been found to cause hereditary renal amyloidosis. In each case amyloid deposition has been associated with a peptide extension at the carboxyl-terminus of apoAII, the result of mutations in the normal stop codon.

A Caucasian man who has had progressive renal dysfunction since age of 34 was found to have amyloidosis on renal biopsy at age 56. Echocardiogram showed mild intraventricular septal thickness and technetium-99m (99mTc)-pyrophosphate scintigraphy demonstrated uptake by cardiac muscle consistent with amyloid deposition in the myocardium. His father died of renal failure and his paternal half brother has renal dysfunction.

DNA sequencing of the apoAII gene in the proband showed a T to C transition at the first position of the stop codon indicating replacement of the stop codon by l-arginine (Arg) at residue 78. Western analysis of the proband's plasma under reducing conditions using anti-apoAII revealed an extra band at approximately 10 kD in addition to the normal apoAII band at 8 kD. Western analysis of solubilized amyloid fibrils isolated from rectal biopsy tissue contained only the variant apoAII.

These results indicate that the proband's amyloid fibrils are derived from apoAII and the amyloidogenesis is linked to the peptide extension at the carboxyl-terminus of variant apoAII. Of particular interest is that this novel apoAII variant may cause amyloid cardiomyopathy in addition to renal amyloid.

    Hereditary systemic amyloidosis
    DIAGNOSIS

    associated with a new apolipoprotein AII stop codon mutation Stop78Arg.
    GENETICS

    Mutations in the gene for apolipoprotein AII (apoAII)
    GENETICS

 have recently been found to cause

    hereditary renal amyloidosis
    DIAGNOSIS

. In each case

    amyloid deposition
    MICROSCOPIC

 has been associated with a

    peptide extension at the carboxyl-terminus of apoAII
    MICROSCOPIC

, the result of

    mutations in the normal stop codon
    GENETICS

.

A

    Caucasian
    ETHNICITY

    man
    GENDER

 who has had

    progressive renal dysfunction
    SYMPTOMS

 since

    age of 34
    AGE

 was found to have

    amyloidosis
    DIAGNOSIS

 on

    renal biopsy
    PARACLINICAL

 at

    age 56
    AGE

.

    Echocardiogram
    PARACLINICAL

 showed

    mild intraventricular septal thickness
    SYMPTOMS

 and

    technetium-99m (99mTc)-pyrophosphate scintigraphy
    PARACLINICAL

 demonstrated

    uptake by cardiac muscle consistent with amyloid deposition in the myocardium
    MICROSCOPIC

.

    His
    GENDER

    father died of renal failure
    FAMILY

 and

    his paternal half brother has renal dysfunction
    FAMILY

.

    DNA sequencing of the apoAII gene in the proband
    PARACLINICAL

 showed a

    T to C transition at the first position of the stop codon indicating replacement of the stop codon by l-arginine (Arg) at residue 78
    GENETICS

.

    Western analysis of the proband's plasma under reducing conditions
    PARACLINICAL

 using

    anti-apoAII
    BIOCHEMICAL

 revealed an extra band at approximately 10 kD in addition to the normal apoAII band at 8 kD.

    Western analysis of solubilized amyloid fibrils isolated from rectal biopsy tissue
    PARACLINICAL

 contained only the

    variant apoAII
    BIOCHEMICAL

.

These results indicate that the

    proband's amyloid fibrils are derived from apoAII
    MICROSCOPIC

 and the

    amyloidogenesis
    MICROSCOPIC

 is linked to the

    peptide extension at the carboxyl-terminus of variant apoAII
    GENETICS

. Of particular interest is that this

    novel apoAII variant
    GENETICS

 may cause

    amyloid cardiomyopathy
    DIAGNOSIS

 in addition to

    renal amyloid
    DIAGNOSIS

.

Hereditary systemic amyloidosis
hereditary renal amyloidosis
amyloidosis
amyloid cardiomyopathy
renal amyloid

progressive renal dysfunction
mild intraventricular septal thickness


First Spanish family with familial amyloidotic polyneuropathy associated to TTR Thr49Ile mutation.

We present a Spanish patient with familial amyloidotic polyneuropathy associated with the TTR Thr49Ile mutation previously described in a Japanese patient. This is the first report in a Caucasian patient and the second in the literature. Age of onset at 66 and the clinical picture were similar to the Japanese patient: sensorimotor polyneuropathy, digestive autonomic disturbances, cardiomyopathy and loss of weight. The mutation was diagnosed by DNA sequencing and induced mutation restriction analysis.

We present a

    Spanish
    ETHNICITY

 patient with

    familial amyloidotic polyneuropathy
    DIAGNOSIS

 associated with the

    TTR Thr49Ile mutation
    GENETICS

 previously described in a

    Japanese
    ETHNICITY

 patient. This is the first report in a

    Caucasian
    ETHNICITY

 patient and the second in the literature.

    Age of onset at 66
    AGE

 and the clinical picture were similar to the

    Japanese
    ETHNICITY

 patient:

    sensorimotor polyneuropathy
    SYMPTOMS

,

    digestive autonomic disturbances
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

 and

    loss of weight
    SYMPTOMS

. The mutation was diagnosed by

    DNA sequencing
    PARACLINICAL

 and

    induced mutation restriction analysis
    PARACLINICAL

.

sensorimotor polyneuropathy
digestive autonomic disturbances
cardiomyopathy
loss of weight


Transthyretin Tyr69-to-Ile mutation (double-nucleotide substitution in codon 69) in a Japanese familial amyloidosis patient with cardiomyopathy and carpal tunnel syndrome.

A 61-year-old Japanese woman with transthyretin amyloid (ATTR) Tyr69Ile, which was caused by the mutation of TTR gene TAC to ATC at codon 69, is described. The patient had no family history and developed carpal tunnel syndrome followed by congestive heart failure due to cardiac amyloidosis. Various phenotypes of familial transthyretin amyloidosis including FAP are caused by TTR variants with single amino-acid substitutions, the latter being caused by one-point mutations in the coding region of the TTR gene. This is the first report showing a novel double-nucleotide substitution in the causative TTR gene abnormality.

A

    61-year-old
    AGE

    Japanese
    ETHNICITY

    woman
    GENDER

 with

    transthyretin amyloid (ATTR) Tyr69Ile
    DIAGNOSIS

, which was caused by the

    mutation of TTR gene TAC to ATC at codon 69
    GENETICS

, is described. The patient had

    no family history
    NEG_FINDINGS

 and developed

    carpal tunnel syndrome
    SYMPTOMS

 followed by

    congestive heart failure
    SYMPTOMS

 due to

    cardiac amyloidosis
    DIAGNOSIS

. Various phenotypes of

    familial transthyretin amyloidosis
    DIAGNOSIS

 including

    FAP
    DIAGNOSIS

 are caused by

    TTR variants with single amino-acid substitutions
    GENETICS

, the latter being caused by

    one-point mutations in the coding region of the TTR gene
    GENETICS

. This is the first report showing a

    novel double-nucleotide substitution in the causative TTR gene abnormality
    GENETICS

.

transthyretin amyloid (ATTR) Tyr69Ile
cardiac amyloidosis
familial transthyretin amyloidosis
FAP

carpal tunnel syndrome
congestive heart failure


Transthyretin mutation (TTRGly47Ala) associated with familial amyloid polyneuropathy in a French family.

A French family in which three individuals had familial amyloid polyneuropathy (FAP) was investigated. The proband presented cardiomyopathy with atrial arrhythmia and then developed axonal polyneuropathy, carpal tunnel syndrome, and sclerodactyly. Nucleotide sequencing of exons 2, 3 and 4 of the transthyretin (TTR) gene revealed heterozygosity for a single base change in the second position of codon 47. This G to C transversion predicts replacement of a glycine by an alanine at position 47 in the mature protein. This mutation (G47A) was previously identified in two different families of Italian origin both of which had FAP and cardiomyopathy. Here we report the first identification of this mutation in a non-Italian family.

A

    French family in which three individuals had familial amyloid polyneuropathy (FAP)
    ETHNICITY

 was investigated. The

    proband
    GENDER

 presented

    cardiomyopathy with atrial arrhythmia
    SYMPTOMS

 and then developed

    axonal polyneuropathy
    DIAGNOSIS

,

    carpal tunnel syndrome
    SYMPTOMS

, and

    sclerodactyly
    SYMPTOMS

.

    Nucleotide sequencing of exons 2, 3 and 4 of the transthyretin (TTR) gene
    PARACLINICAL

 revealed

    heterozygosity for a single base change in the second position of codon 47
    GENETICS

. This

    G to C transversion predicts replacement of a glycine by an alanine at position 47 in the mature protein
    GENETICS

. This

    mutation (G47A)
    GENETICS

 was previously identified in two different families of

    Italian
    ETHNICITY

 origin

    both of which had FAP and cardiomyopathy
    FAMILY

. Here we report the first identification of this mutation in a

    non-Italian family
    ETHNICITY

.

cardiomyopathy with atrial arrhythmia
carpal tunnel syndrome
sclerodactyly


Transthyretin Val 107 in a Japanese patient with familial amyloid polyneuropathy.

A 70-year-old Japanese man with amyloid polyneuropathy associated with a Val 107 transthyretin (TTR) mutation is reported. The patient presented with carpal tunnel syndrome, cardiomyopathy, bulbar palsy, dysphonia and polyneuropathy. DNA analysis of the TTR gene revealed a point mutation responsible for substitution of valine for isoleucine at position 107 of the TTR molecule. Taken together with reports of patients with the same TTR variant, Val 107 TTR mutation is probably associated with a clinical phenotype characterized by carpal tunnel syndrome, cardiomyopathy, bulbar palsy and dysphonia. This case implies a worldwide distribution of the Val 107 TTR mutation with a common clinical phenotype, despite different ethnic background.

A

    70-year-old
    AGE

    Japanese
    ETHNICITY

    man
    GENDER

 with

    amyloid polyneuropathy
    DIAGNOSIS

 associated with a

    Val 107 transthyretin (TTR) mutation
    GENETICS

 is reported. The patient presented with

    carpal tunnel syndrome
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

,

    bulbar palsy
    SYMPTOMS

,

    dysphonia
    SYMPTOMS

 and

    polyneuropathy
    SYMPTOMS

.

    DNA analysis of the TTR gene
    PARACLINICAL

 revealed a

    point mutation responsible for substitution of valine for isoleucine at position 107 of the TTR molecule
    GENETICS

. Taken together with reports of patients with the same TTR variant,

    Val 107 TTR mutation
    GENETICS

 is probably associated with a clinical phenotype characterized by

    carpal tunnel syndrome
    SYMPTOMS

,

    cardiomyopathy
    SYMPTOMS

,

    bulbar palsy
    SYMPTOMS

 and

    dysphonia
    SYMPTOMS

. This case implies a worldwide distribution of the

    Val 107 TTR mutation
    GENETICS

 with a common clinical phenotype, despite different ethnic background.

carpal tunnel syndrome
cardiomyopathy
bulbar palsy
dysphonia
polyneuropathy
carpal tunnel syndrome
cardiomyopathy
bulbar palsy
dysphonia


Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred.

The most frequent localization of amyloid in transthyretin (TTR) mutations is in the peripheral nerve, causing familial amyloidpolyneuropathy (FAP). It is generally accompanied by involvement of other organs such as the myocardium and kidney. To date, over 70 TTR point mutations have been reported in literature, with different phenotypes depending on the location of the mutation in the TTR gene. This paper deals with a point mutation in exon 2 position 47 of the TTR gene, encoding the substitution of glycine with glutamate. The mutation was found in an Italian family with 5 patients over 3 generations. The phenotype was characterised by peripheral neuropathy and autonomic dysfunction, associated in some patients with cardiomyopathy and renal involvement. The symptoms were very severe and the patients did not survive long, thus suggesting the aggressive nature of the pathological process. Moreover, in the succeeding generations of this family, there was genetic anticipation in the age of onset of the disease.

The most frequent localization of amyloid in

    transthyretin (TTR) mutations
    DIAGNOSIS

 is in the peripheral nerve, causing

    familial amyloidpolyneuropathy (FAP)
    DIAGNOSIS

. It is generally accompanied by

    involvement of other organs such as the myocardium and kidney
    SYMPTOMS

. To date, over 70

    TTR point mutations
    GENETICS

 have been reported in literature, with different phenotypes depending on the location of the

    mutation in the TTR gene
    GENETICS

. This paper deals with a

    point mutation in exon 2 position 47 of the TTR gene, encoding the substitution of glycine with glutamate
    GENETICS

. The mutation was found in an

    Italian
    ETHNICITY

    family with 5 patients over 3 generations
    FAMILY

. The phenotype was characterised by

    peripheral neuropathy
    SYMPTOMS

 and

    autonomic dysfunction
    SYMPTOMS

, associated in some patients with

    cardiomyopathy
    SYMPTOMS

 and

    renal involvement
    SYMPTOMS

. The

    symptoms were very severe
    SYMPTOMS

 and the patients

    did not survive long
    NEG_FINDINGS

, thus suggesting the aggressive nature of the pathological process. Moreover, in the succeeding generations of this family, there was

    genetic anticipation in
    FAMILY

 the age of onset of the disease.

transthyretin (TTR) mutations
familial amyloidpolyneuropathy (FAP)


Transthyretin Thr60Ala Appalachian-type mutation in a Japanese family with familial amyloidotic polyneuropathy.

A Japanese case with familial amyloidotic polyneuropathy (FAP) associated with the transthyretin mutation Thr60Ala (Appalachian-type mutation) is described This is the first reported case of a non-Caucasian harboring this type of TTR mutation. The patient developed severe late-onset restrictive cardiomyopathy as well as sensorimotor and autonomic polyneuropathy, which were essentially similar to the previously reported clinical pictures of Appalachian-type FAP.

A

    Japanese
    ETHNICITY

 case with

    familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 associated with the

    transthyretin mutation Thr60Ala (Appalachian-type mutation)
    GENETICS

 is described This is the first reported case of a

    non-Caucasian
    ETHNICITY

 harboring this

    type of TTR mutation
    GENETICS

. The patient developed

    severe late-onset restrictive cardiomyopathy
    SYMPTOMS

 as well as

    sensorimotor and autonomic polyneuropathy
    SYMPTOMS

, which were essentially similar to the previously reported clinical pictures of

    Appalachian-type FAP
    DIAGNOSIS

.


Cardiac amyloidosis associated with the transthyretin Ile122 mutation in a Caucasian family.

The Ile122 transthyretin variant associated with restrictive cardiomyopathy has been described in African-Americans and estimated to be present in approximately 4% of the Black population. We report the first American-Caucasian family with cardiomyopathy due to the TTR Ile122 mutation. The high prevalence of this mutation in the Black population and the discovery that it may cause disease in other ethnic populations highlights the importance of considering this autosomal dominant systemic amyloidosis in all individuals with restrictive cardiomyopathy. Inadequate diagnosis combined with inappropriate treatment may have a significant impact on morbidity and mortality.

The

    Ile122 transthyretin variant
    GENETICS

 associated with

    restrictive cardiomyopathy
    DIAGNOSIS

 has been described in

    African-Americans
    ETHNICITY

 and estimated to be present in approximately 4% of the Black population. We report the first

    American-Caucasian
    ETHNICITY

    family with cardiomyopathy
    FAMILY

 due to the

    TTR Ile122 mutation
    GENETICS

. The high prevalence of this mutation in the Black population and the discovery that it may cause disease in other ethnic populations highlights the importance of considering this

    autosomal dominant systemic amyloidosis
    DIAGNOSIS

 in all individuals with

    restrictive cardiomyopathy
    DIAGNOSIS

. Inadequate diagnosis combined with

    inappropriate treatment
    NEG_FINDINGS

 may have a significant impact on morbidity and mortality.

Ile122 transthyretin variant
TTR Ile122 mutation

restrictive cardiomyopathy
autosomal dominant systemic amyloidosis
restrictive cardiomyopathy


Recurrent cerebral embolism in a familial amyloid polyneuropathy patient who received partial liver transplantation from a living donor.

Cerebral embolism in relation to cardiac amyloidosis has not been widely noted. A 47-year-old woman who had been suffering from familial amyloid polyneuropathy (FAP) for 7 years was treated with partial liver transplantation from a living donor and her early postoperative course was uneventful. During the 391st to 613th postoperative day she experienced recurrent cerebral infarctions, but clinical examinations revealed no disorders capable of producing cerebral embolism. At autopsy splenic infarction and intracardiac thrombi adhering to the mitral valve and left atrium were found, and these areas showed severe amyloid deposition. Amyloid heart is considered to be one possible cause of systemic embolism.

    Cerebral embolism
    SYMPTOMS

 in relation to

    cardiac amyloidosis
    DIAGNOSIS

 has not been widely noted. A

    47-year-old
    AGE

    woman
    GENDER

 who had been suffering from

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

    for 7 years
    MEDICATION

 was treated with

    partial liver transplantation from a living donor
    MEDICATION

 and

    her
    GENDER

 early postoperative course was

    uneventful
    SYMPTOMS

. During the 391st to 613th postoperative day

    she
    GENDER

 experienced

    recurrent cerebral infarctions
    SYMPTOMS

, but

    clinical examinations
    PARACLINICAL

 revealed

    no disorders capable of producing cerebral embolism
    NEG_FINDINGS

. At

    autopsy
    PARACLINICAL

    splenic infarction
    SYMPTOMS

 and

    intracardiac thrombi adhering to the mitral valve and left atrium
    SYMPTOMS

 were found, and these areas showed

    severe amyloid deposition
    MICROSCOPIC

.

    Amyloid heart
    DIAGNOSIS

 is considered to be one possible cause of

    systemic embolism
    SYMPTOMS

.

cardiac amyloidosis
familial amyloid polyneuropathy (FAP)
Amyloid heart


A case of late onset cardiac amyloidosis with a new transthyretin variant (lysine 92).

A new transthyretin (TTR) variant (lysine 92), which causes late onset cardiac amyloidosis, is described in a 71-year-old man. The patient at first had syncope due to ventricular tachycardia and was admitted our hospital. Typical findings of cardiac amyloidosis were observed by echocardiography, and a diagnosis of systemic amyloidosis was made by rectal biopsy. The man died approximately 3 years and 6 months after first admission, with gradually worsening congestive heart failure. Pathological examination showed prominent amyloid deposits in the heart and the vascular wall of many organs including the liver, pancreas, kidney, lung, and gastrointestinal tracts. Amyloid protein of transthyretin type was indicated by immunohistochemical study, and DNA sequencing identified a novel mutation in the transthyretin gene encoding 92 glutamine --> lysine. A polymerase chain reaction-induced mutation restriction analysis with a mismatched antisense primer showed that the patient was heterozygous for the TTR Lys92 allele.

A

    new transthyretin (TTR) variant (lysine 92)
    GENETICS

, which causes

    late onset cardiac amyloidosis
    DIAGNOSIS

, is described in a

    71-year-old
    AGE

    man
    GENDER

. The patient at first had

    syncope
    SYMPTOMS

 due to

    ventricular tachycardia
    SYMPTOMS

 and was admitted our hospital. Typical findings of

    cardiac amyloidosis
    SYMPTOMS

 were observed by

    echocardiography
    PARACLINICAL

, and a diagnosis of

    systemic amyloidosis
    DIAGNOSIS

 was made by

    rectal biopsy
    PARACLINICAL

. The

    man
    GENDER

    died
    SYMPTOMS

 approximately 3

    years and 6 months
    AGE

 after first admission, with

    gradually worsening congestive heart failure
    SYMPTOMS

.

    Pathological examination
    PARACLINICAL

 showed

    prominent amyloid deposits in the heart and the vascular wall of many organs including the liver, pancreas, kidney, lung, and gastrointestinal tracts
    MICROSCOPIC

.

    Amyloid protein of transthyretin type
    MICROSCOPIC

 was indicated by

    immunohistochemical study
    PARACLINICAL

, and

    DNA sequencing
    PARACLINICAL

 identified a

    novel mutation in the transthyretin gene encoding 92 glutamine --> lysine
    GENETICS

. A

    polymerase chain reaction-induced mutation restriction analysis with a mismatched antisense primer
    PARACLINICAL

 showed that the patient was

    heterozygous for the TTR Lys92 allele
    GENETICS

.

late onset cardiac amyloidosis
systemic amyloidosis


Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene: ATTR Ala45Ser.

Cardiac failure in transthyretin (TTR) amyloidosis patients has been shown to be caused by different mutations in the TTR gene. In the present case, a 73-year-old man from Northern Sweden was evaluated for heart failure. Amyloid deposits were found in subcutaneous fat and in intestinal biopsies. The presence of a variant form of TTR was detected in the plasma by electrospray ionisation mass spectrometry (ESI-MS). The mutation was located by single-strand conformation polymorphism (SSCP) analysis of the TTR gene where a band shift was seen in exon 2. Direct sequencing of exon 2 revealed a single base-pair substitution (G1724T). This transversion results in an amino acid substitution at codon 45, alanine to serine (ATTR Ala45Ser). Mass spectrometry analysis excluded that the variant is a polymorphism, since no similar shift in molecular weight has been present in more than 200 control samples. Congo red and immunostaining of duodenum biopsy specimens confirmed the presence of systemic ATTR amyloidosis, and clinical examination, including echocardiography, found evidence of a restrictive cardiomyopathy. He had 10 years previously been operated for a bilateral carpal tunnel syndrome, but otherwise no symptoms were present that could be attributed to his systemic amyloidosis. No axonal polyneuropathy was noted at nerve conduction studies. This novel mutation is the second amyloidogenic TTR mutation found in the Swedish population.

    Cardiac failure
    SYMPTOMS

 in

    transthyretin (TTR) amyloidosis
    DIAGNOSIS

 patients has been shown to be caused by different

    mutations in the TTR gene
    GENETICS

. In the present case, a

    73-year-old
    AGE

    man
    GENDER

 from

    Northern Sweden
    ETHNICITY

 was evaluated for

    heart failure
    SYMPTOMS

.

    Amyloid deposits were found in subcutaneous fat and in intestinal biopsies
    MICROSCOPIC

. The

    presence of a variant form of TTR
    BIOCHEMICAL

 was detected

    in the plasma
    BIOCHEMICAL

 by

    electrospray ionisation mass spectrometry (ESI-MS)
    PARACLINICAL

. The mutation was located by

    single-strand conformation polymorphism (SSCP) analysis of the TTR gene
    PARACLINICAL

 where a

    band shift was seen in exon 2
    GENETICS

.

    Direct sequencing of exon 2
    PARACLINICAL

 revealed a

    single base-pair substitution (G1724T)
    GENETICS

. This

    transversion results in an amino acid substitution at codon 45, alanine to serine (ATTR Ala45Ser)
    GENETICS

.

    Mass spectrometry analysis
    PARACLINICAL

 excluded that the variant is a polymorphism, since no similar shift in molecular weight has been present in more than 200 control samples.

    Congo red and immunostaining of duodenum biopsy specimens
    PARACLINICAL

 confirmed the presence of

    systemic ATTR amyloidosis
    DIAGNOSIS

, and

    clinical examination
    PARACLINICAL

, including

    echocardiography
    PARACLINICAL

, found

    evidence of a restrictive cardiomyopathy
    SYMPTOMS

.

    He
    GENDER

 had

    10 years previously been operated for a bilateral carpal tunnel syndrome
    MEDICATION

, but

    otherwise no symptoms were present that could be attributed to his systemic amyloidosis
    NEG_FINDINGS

.

    No axonal polyneuropathy was noted at nerve conduction studies
    NEG_FINDINGS

. This

    novel mutation
    GENETICS

 is the second

    amyloidogenic TTR mutation
    GENETICS

 found in the

    Swedish
    ETHNICITY

 population.

transthyretin (TTR) amyloidosis
systemic ATTR amyloidosis

presence of a variant form of TTR
in the plasma


A novel variant of transthyretin (Glu89Lys) associated with familial amyloidotic polyneuropathy.

We detected a point mutation in the transthyretin (TTR) gene associated with familial amyloidotic polyneuropathy (FAP) in a 57-year old male presenting with sensorimotor polyneuropathy, severe autonomic dysfunction and cardiomyopathy using a non-isotopic RNase cleavage assay (NIRCA). NIRCA suggested that the mutation site was near either amino acid position 58 of mature TTR or the 3' end of exon 3. Direct DNA sequencing showed both a normal GAG (Glu) and a variant AAG (Lys) codon at amino acid position 89 of mature TTR, which has not been previously reported. The site of this mutation is near the 3' end of exon 3, consistent with the result of NIRCA. This mutation was also confirmed by polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA).

We detected a

    point mutation in the transthyretin (TTR) gene
    GENETICS

 associated with

    familial amyloidotic polyneuropathy (FAP)
    DIAGNOSIS

 in a

    57-year old
    AGE

    male
    GENDER

 presenting with

    sensorimotor polyneuropathy
    SYMPTOMS

,

    severe autonomic dysfunction
    SYMPTOMS

 and

    cardiomyopathy
    SYMPTOMS

 using a

    non-isotopic RNase cleavage assay (NIRCA)
    PARACLINICAL

.

    NIRCA
    PARACLINICAL

 suggested that the

    mutation site was near either amino acid position 58 of mature TTR or the 3' end of exon 3
    GENETICS

.

    Direct DNA sequencing
    PARACLINICAL

 showed

    both a normal GAG (Glu) and a variant AAG (Lys) codon at amino acid position 89 of mature TTR
    GENETICS

, which has not been previously reported. The site

    of this mutation is near the 3' end of exon 3
    GENETICS

, consistent with the result of

    NIRCA
    PARACLINICAL

. This mutation was also confirmed by

    polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA)
    PARACLINICAL

.

sensorimotor polyneuropathy
severe autonomic dysfunction
cardiomyopathy


Sequential (domino) transplantation of the liver in a transthyretin-50 familial amyloid polyneuropathy. Special reference to cardiological diagnosis and complications.

General shortage of cadaveric organs has led to a search for alternative methods to expand the donor pool. Sequential (domino) transplantation is yet another attempt to compensate for the declining consent to organ donation.

To qualify for a domino liver transplantation, the following preconditions must be fulfilled: (1) extrahepatic disease must exist, (2) liver must be fully functional, and (3) the genetic defect in the host should recur within a sufficient latency period. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease which involves a genetic defect for transthyretin (TTR), which is predominantly produced in the liver.

In this report, we describe a rare case of a FAP TTR-50 variant undergoing domino liver transplantation. Since myocardial symptoms precede peripheral polyneuropathy, special emphasis should be placed on arrhythmias and the restrictive cardiomyopathy necessitating a veno-venous bypass or a cardiac pacemaker in order to improve cardiac contractility. The type of anastomosis of the suprahepatic inferior vena cava and possible alternatives are discussed.

Despite ethical problems, the advantages of the domino procedure are obvious: (1) expansion of the donor pool, (2) ability to use living donors, and (3) presence of very short ischemic time and thus excellent liver function. Due to the kinetics of TTR production and deposition, donors and recipients of FAP livers should be followed up using an extensive neurological and cardiological protocol.

General shortage of cadaveric organs has led to a search for alternative methods to expand the donor pool.

    Sequential (domino) transplantation
    MEDICATION

 is yet another attempt to compensate for the

    declining consent to organ donation
    NEG_FINDINGS

.

To qualify for a

    domino liver transplantation
    MEDICATION

, the following preconditions must be fulfilled: (1)

    extrahepatic disease
    SYMPTOMS

 must exist, (2)

    liver must be fully functional
    SYMPTOMS

, and (3) the

    genetic defect in the host
    GENETICS

 should recur within a sufficient latency period.

    Familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 is an

    autosomal dominant disease
    GENETICS

 which involves a

    genetic defect for transthyretin (TTR)
    GENETICS

, which is predominantly produced in the liver.

In this report, we describe a rare case of a

    FAP TTR-50 variant
    DIAGNOSIS

 undergoing

    domino liver transplantation
    MEDICATION

. Since

    myocardial symptoms
    SYMPTOMS

 precede

    peripheral polyneuropathy
    SYMPTOMS

, special emphasis should be placed on

    arrhythmias
    SYMPTOMS

 and the

    restrictive cardiomyopathy
    SYMPTOMS

 necessitating a

    veno-venous bypass or a cardiac pacemaker
    MEDICATION

 in order to

    improve cardiac contractility
    SYMPTOMS

. The

    type of anastomosis of the suprahepatic inferior vena cava
    MEDICATION

 and possible alternatives are discussed.

Despite ethical problems, the advantages of the

    domino procedure
    MEDICATION

 are obvious: (1) expansion of the donor pool, (2) ability to use

    living donors
    MEDICATION

, and (3) presence of

    very short ischemic time
    SYMPTOMS

 and thus

    excellent liver function
    SYMPTOMS

. Due to the kinetics of

    TTR production and deposition
    BIOCHEMICAL

, donors and

    recipients
    MEDICATION

 of

    FAP livers
    MEDICATION

 should be followed up using an

    extensive neurological and cardiological protocol
    PARACLINICAL

.

extrahepatic disease
liver must be fully functional
myocardial symptoms
peripheral polyneuropathy
arrhythmias
restrictive cardiomyopathy
improve cardiac contractility
very short ischemic time
excellent liver function

genetic defect in the host
autosomal dominant disease
genetic defect for transthyretin (TTR)

Familial amyloid polyneuropathy (FAP)
FAP TTR-50 variant


A case of hereditary amyloidosis transthyretin variant Met 30 with amyloid cardiomyopathy, less polyneuropathy, and the presence of giant cells.

Transthyretin-Met 30 (TTR-Met 30) is a variant of transthyretin and is usually associated with familial amyloid polyneuropathy. It is rare that patients with TTR-Met 30 will primarily develop amyloid cardiomyopathy. This report presents a patient with late-onset TTR-Met 30 who primarily developed amyloid cardiomyopathy, with less amyloid polyneuropathy in the peripheral nervous system than is usually seen. An autopsy was performed, and histological examination revealed many foreign-body giant cells and macrophages in the area of amyloid deposition that was found in nearly all of the organs.

    Transthyretin-Met 30 (TTR-Met 30)
    GENETICS

 is a

    variant of transthyretin
    GENETICS

 and is usually associated with

    familial amyloid polyneuropathy
    DIAGNOSIS

. It is rare that patients with

    TTR-Met 30
    GENETICS

 will primarily develop

    amyloid cardiomyopathy
    DIAGNOSIS

. This report presents a patient with

    late-onset
    DIAGNOSIS

    TTR-Met 30
    GENETICS

 who primarily developed

    amyloid cardiomyopathy
    DIAGNOSIS

, with

    less amyloid polyneuropathy in the peripheral nervous system
    SYMPTOMS

 than is usually seen. An

    autopsy
    PARACLINICAL

 was performed, and

    histological examination
    PARACLINICAL

 revealed

    many foreign-body giant cells and macrophages in the area of amyloid deposition that was found in nearly all of the organs
    MICROSCOPIC

.

Transthyretin-Met 30 (TTR-Met 30)
variant of transthyretin
TTR-Met 30
TTR-Met 30

familial amyloid polyneuropathy
amyloid cardiomyopathy
late-onset
amyloid cardiomyopathy


Hereditary cardiac amyloidosis associated with the transthyretin Ile122 mutation in a white man.

An 83 year old white man with atrial fibrillation was admitted to hospital after a cerebral infarct. Echocardiography was characteristic of cardiac amyloid deposition and subsequent tests confirmed amyloidosis of transthyretin (TTR) type, in association with the Ile122 mutation of the TTR gene; this has only been reported previously in African Americans in whom it occurs with an allele frequency of 2%. Haplotype analysis did not suggest a different founder than for the African Ile122 mutation. Cardiac amyloidosis should be considered among elderly patients presenting with cardiac failure and/or arrhythmia, particularly if they are resistant to conventional treatment; if confirmed, it should be followed by precise characterisation of amyloid fibril type. The prevalence of autosomal dominant cardiac TTR amyloidosis in elderly white people is unknown but early diagnosis and supportive treatment may prevent complications among affected family members.

An

    83 year old
    AGE

    white
    ETHNICITY

    man
    GENDER

 with

    atrial fibrillation
    SYMPTOMS

 was admitted to hospital after a

    cerebral infarct
    SYMPTOMS

.

    Echocardiography
    PARACLINICAL

 was characteristic of

    cardiac amyloid deposition
    SYMPTOMS

 and subsequent tests confirmed

    amyloidosis of transthyretin (TTR) type,
    DIAGNOSIS

 in association with the

    Ile122 mutation of the TTR gene
    GENETICS

; this has only been reported previously in

    African Americans
    ETHNICITY

 in whom it occurs with an allele frequency of 2%.

    Haplotype analysis did not suggest a different founder than for the African Ile122 mutation
    NEG_FINDINGS

.

    Cardiac amyloidosis
    DIAGNOSIS

 should be considered among

    elderly
    AGE

 patients presenting with

    cardiac failure
    SYMPTOMS

 and/or

    arrhythmia
    SYMPTOMS

, particularly if they are

    resistant to conventional treatment
    NEG_FINDINGS

; if confirmed, it should be followed by

    precise characterisation of amyloid fibril type
    PARACLINICAL

. The prevalence of

    autosomal dominant cardiac TTR amyloidosis
    DIAGNOSIS

 in

    elderly
    AGE

 white people is unknown but early diagnosis and

    supportive treatment
    MEDICATION

 may

    prevent complications among affected family members
    SYMPTOMS

.


A new transthyretin variant (Ser23Asn) associated with familial amyloidosis in a Portuguese patient.

The detection and characterization of a new transthyretin (ATTR) variant, Ser23Asn, associated with cardiomyopathy in a Portuguese patient with familial amyloidosis is described. Isoelectric focusing (IEF) of serum from the propositus demonstrated heterozygosity for the presence of wild type and variant ATTR. A combination of mass spectrometric (MS) analyses, including electrospray ionization mass spectrometry (ESI MS), high performance liquid chromatography (HPLC)/ESI MS and matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) performed on the serum-derived TTR were used to identify and locate the amino acid replacement in the variant protein. Genetic mutation analysis by DNA sequencing and allele-specific PCR confirmed this finding.

The detection and characterization of a

    new transthyretin (ATTR) variant, Ser23Asn
    GENETICS

, associated with

    cardiomyopathy
    DIAGNOSIS

 in a

    Portuguese
    ETHNICITY

 patient with

    familial amyloidosis
    DIAGNOSIS

 is described.

    Isoelectric focusing (IEF) of serum from the propositus
    PARACLINICAL

 demonstrated

    heterozygosity for the presence of wild type and variant ATTR
    GENETICS

. A combination of

    mass spectrometric (MS) analyses
    PARACLINICAL

, including

    electrospray ionization mass spectrometry (ESI MS)
    PARACLINICAL

,

    high performance liquid chromatography (HPLC)/ESI MS
    PARACLINICAL

 and

    matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS)
    PARACLINICAL

 performed

    on the serum-derived TTR
    PARACLINICAL

 were used to identify and locate the

    amino acid replacement in the variant protein
    GENETICS

.

    Genetic mutation analysis by DNA sequencing and allele-specific PCR
    PARACLINICAL

 confirmed this finding.


Progression of cardiomyopathy and neuropathy after liver transplantation in a patient with familial amyloidotic polyneuropathy caused by tyrosine-77 transthyretin variant.

Familial amyloidotic polyneuropathy is an inherited form of amyloidosis associated with a mutant form of a protein called transthyretin. The Methionine-30 variant is the most frequent mutation observed. This disorder is caused by deposition of this protein as amyloid in several organs, such as the heart, kidneys, and peripheral nervous system. The disease is always progressive and fatal, and patients die 7 to 10 years after the onset of symptoms. Liver transplantation is at present the only choice for these patients because it provides improvement of symptoms and/or stops progression of the disease in most patients. We report the case of a patient who showed clear progression of cardiomyopathy and neuropathy after liver transplantation.

    Familial amyloidotic polyneuropathy
    DIAGNOSIS

 is an

    inherited form of amyloidosis
    GENETICS

 associated with a

    mutant form of a protein called transthyretin
    GENETICS

. The

    Methionine-30 variant
    GENETICS

 is the most frequent mutation observed. This disorder is caused by

    deposition of this protein as amyloid in several organs, such as the heart, kidneys, and peripheral nervous system
    MICROSCOPIC

. The disease is always progressive and

    fatal
    SYMPTOMS

, and patients

    die
    SYMPTOMS

 7 to 10 years after the onset of symptoms.

    Liver transplantation
    MEDICATION

 is at present the only choice for these patients because it provides

    improvement of symptoms
    SYMPTOMS

 and/or

    stops progression of the disease
    SYMPTOMS

 in most patients. We report the case of a patient who showed

    clear progression of cardiomyopathy and neuropathy
    SYMPTOMS

 after

    liver transplantation
    MEDICATION

.

Liver transplantation
liver transplantation


A new amyloidogenic transthyretin variant (Val122Ala) found in a compound heterozygous patient.

A new TTR variant, Val122Ala, was characterized in an individual who carried the Gly6Ser polymorphism on the opposite allele. The main clinical feature of this familial transthyretin amyloidosis (ATTR) variant is extensive cardiomyopathy. The detection and characterization of the variant were performed using a combination of isoelectric focusing (IEF), restriction fragment length polymorphism (RFLP), immunoprecipitation, electrospray ionization mass spectrometry (ESIMS), HPLC (high performance liquid chromatography)/ESIMS, and matrix-assisted laser desorption/ionization mass spectrometry (MALDIMS). The results were confirmed by DNA analysis. The propositus has a brother who carries the new variant but not the polymorphism.

A

    new TTR variant, Val122Ala
    GENETICS

, was characterized in an individual who

    carried the Gly6Ser polymorphism on the opposite allele
    GENETICS

. The main clinical feature of this

    familial transthyretin amyloidosis (ATTR) variant
    DIAGNOSIS

 is

    extensive cardiomyopathy
    SYMPTOMS

. The detection and characterization of the variant were performed using a combination of

    isoelectric focusing (IEF)
    PARACLINICAL

,

    restriction fragment length polymorphism (RFLP)
    PARACLINICAL

,

    immunoprecipitation
    PARACLINICAL

,

    electrospray ionization mass spectrometry (ESIMS)
    PARACLINICAL

,

    HPLC (high performance liquid chromatography)/ESIMS
    PARACLINICAL

, and

    matrix-assisted laser desorption/ionization mass spectrometry (MALDIMS)
    PARACLINICAL

. The results were confirmed by

    DNA analysis
    PARACLINICAL

. The

    propositus has a brother who carries the new variant but not the polymorphism
    FAMILY

.


A novel variant of transthyretin (Glu42Asp) associated with sporadic late-onset cardiac amyloidosis.

A sixty-three year old French man presented with isolated late-onset amyloid cardiomyopathy proven by endomyocardial biopsy. There was no known family history of amyloidosis. Immunohistochemistry of cardiac deposits suggested that amyloi fibrils were derived from transthyretin. DNA sequencing revealed a point mutation in exon 2 of the transthyretin gene responsible for a novel amyloidogenic variant Asp42.

A

    sixty-three year old
    AGE

    French
    ETHNICITY

    man
    GENDER

 presented with

    isolated late-onset amyloid cardiomyopathy
    SYMPTOMS

 proven by

    endomyocardial biopsy
    PARACLINICAL

. There was

    no known family history of amyloidosis
    NEG_FINDINGS

.

    Immunohistochemistry of cardiac deposits
    PARACLINICAL

 suggested that

    amyloi fibrils were derived from transthyretin
    MICROSCOPIC

.

    DNA sequencing
    PARACLINICAL

 revealed a

    point mutation in exon 2 of the transthyretin gene responsible for a novel amyloidogenic variant Asp42.
    GENETICS


Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1.

Autosomal dominant hereditary amyloidosis with a unique cutaneous and cardiac presentation and death from heart failure by the sixth or seventh decade was found to be associated with a previously unreported point mutation (thymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene. The predicted substitution of proline for leucine at amino acid position 90 was confirmed by structural analysis of amyloid protein isolated from cardiac deposits of amyloid. The subunit protein is composed exclusively of NH2-terminal fragments of the variant apoA1 with the longest ending at residue 94 in the wild-type sequence. Amyloid fibrils derived from four previously described apoA1 variants are composed of similar fragments with carboxyl-terminal heterogeneity, but contrary to those variants, which all carry one extra positive charge, the substitution Leu90Pro does not result in any charge modification. It is unlikely, therefore, that amyloid fibril formation is related to change of charge for a specific residue of the precursor protein. This is in agreement with studies on transthyretin amyloidosis in which no unifying factor such as change of charge for amino acid residues has been noted.

    Autosomal dominant hereditary amyloidosis
    DIAGNOSIS

 with a

    unique cutaneous and cardiac presentation
    SYMPTOMS

 and

    death from heart failure
    SYMPTOMS

    by the sixth or seventh decade
    AGE

 was found to be associated with a

    previously unreported point mutation (thymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene
    GENETICS

. The predicted

    substitution of proline for leucine at amino acid position 90
    GENETICS

 was confirmed by

    structural analysis of amyloid protein isolated from cardiac deposits of amyloid
    PARACLINICAL

. The subunit protein is composed

    exclusively of NH2-terminal fragments of the variant apoA1 with the longest ending at residue 94 in the wild-type sequence
    MICROSCOPIC

.

    Amyloid fibrils derived
    MICROSCOPIC

 from four previously described

    apoA1
    MICROSCOPIC

 variants

    are composed of similar fragments with carboxyl-terminal heterogeneity
    MICROSCOPIC

, but contrary to those variants, which all carry one

    extra positive charge
    GENETICS

, the

    substitution Leu90Pro does not result in any charge modification
    GENETICS

. It is unlikely, therefore, that

    amyloid fibril
    MICROSCOPIC

 formation is related to change of charge for a specific residue of the precursor protein. This is in agreement with studies on

    transthyretin amyloidosis
    DIAGNOSIS

 in which no unifying factor such as change of charge for

    amino acid residues
    NEG_FINDINGS

 has been noted.


Transthyretin Tyr77 familial amyloid polyneuropathy: a clinicopathological study of a large kindred.

More than 40 point mutations (producing different clinical manifestations) have been described in diverse points of the plasma protein transthyretin (TTR). The Met30 is considered the most common mutation, the Tyr77 mutation being the second most prevalent. However, data from patients with this late mutation are scarce, and usually come from isolated case reports or tables. The Tyr77 mutation is not as well characterized as the Met30 mutation, especially with respect to such aspects as prognosis or possible treatment by liver transplantation. We therefore present the clinical and pathological features of an extensive family with the Tyr77 TTR mutation, comprising 12 affected individuals over four generations. Six living individuals were followed over a 10-year period. Retrospective data were obtained with regard to the deceased family members. We found that an initial and sometimes prolonged carpal tunnel syndrome, beginning between the 6th and 7th decades, characterizes the Tyr77 mutation. In most cases this evolved to generalized peripheral nerve involvement, restrictive cardiomyopathy, and intestinal malabsortion. Although survival is usually high, there are progressive cases that should be candidates for liver transplant, before severe impairment has developed.

More than 40

    point mutations
    GENETICS

 (producing different clinical manifestations) have been described

    in diverse points of the plasma protein transthyretin (TTR)
    GENETICS

. The

    Met30
    GENETICS

 is considered the most common mutation, the

    Tyr77 mutation
    GENETICS

 being the second most prevalent. However, data from patients with this late mutation are scarce, and usually come from isolated case reports or tables. The

    Tyr77 mutation
    GENETICS

 is not as well characterized as the

    Met30 mutation
    GENETICS

, especially with respect to such aspects as prognosis or possible treatment by

    liver transplantation
    MEDICATION

. We therefore present the clinical and pathological features of an extensive family with the

    Tyr77 TTR mutation
    GENETICS

, comprising 12 affected individuals over four generations. Six living individuals were followed over a 10-year period. Retrospective data were obtained with regard to the deceased family members. We found that an

    initial and sometimes prolonged carpal tunnel syndrome
    SYMPTOMS

, beginning

    between the 6th and 7th decades
    AGE

, characterizes the

    Tyr77 mutation
    GENETICS

. In most cases this evolved to

    generalized peripheral nerve involvement
    SYMPTOMS

,

    restrictive cardiomyopathy
    SYMPTOMS

, and

    intestinal malabsortion
    SYMPTOMS

. Although survival is usually high, there are progressive cases that should be candidates for

    liver transplant
    MEDICATION

, before

    severe impairment
    SYMPTOMS

 has developed.


Transthyretin mutation (serine 84) associated with familial amyloid polyneuropathy in a Hungarian family.

A Hungarian family with familial amyloid polyneuropathy (FAP) was studied. The disease presented in two individuals with carpal tunnel syndrome in the fourth and fifth decades of life. The proband subsequently developed vitreous opacities requiring vitrectomy and now has evidence of cardiomyopathy. Single strand conformation polymorphism analysis and direct DNA sequencing revealed a variant AGC (serine) codon at amino acid position 84 of the amyloid precursor protein, transthyretin (TTR). The same single amino acid substitution in TTR was detected in an Indiana kindred with Swiss/German origin. Six individuals of the 11 tested being at risk for FAP proved to have the mutation in the present Hungarian kindred. This is the first description of this TTR gene mutation in Europe. Despite TTR gene haplotype analysis which suggests that the Hungarian and Indiana kindreds may have a common origin, no genealogical link has been identified between the families living in Indiana and Hungary.

A

    Hungarian
    ETHNICITY

 family with

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 was studied. The disease presented in two individuals with

    carpal tunnel syndrome
    SYMPTOMS

 in the

    fourth and fifth decades of life
    AGE

. The proband subsequently developed

    vitreous opacities
    SYMPTOMS

 requiring

    vitrectomy
    MEDICATION

 and now has evidence of

    cardiomyopathy
    SYMPTOMS

.

    Single strand conformation polymorphism analysis
    PARACLINICAL

 and

    direct DNA sequencing
    PARACLINICAL

 revealed a

    variant AGC (serine) codon at amino acid position 84 of the amyloid precursor protein, transthyretin (TTR)
    GENETICS

. The same

    single amino acid substitution in TTR
    GENETICS

 was detected in an

    Indiana kindred with Swiss/German origin
    ETHNICITY

. Six individuals of the 11 tested being at risk for

    FAP
    DIAGNOSIS

    proved to have the mutation in the present Hungarian kindred
    FAMILY

. This is the first description of this

    TTR gene mutation
    GENETICS

 in

    Europe
    ETHNICITY

. Despite

    TTR gene haplotype analysis
    GENETICS

 which suggests that the

    Hungarian
    ETHNICITY

 and

    Indiana kindreds may have a common origin
    ETHNICITY

,

    no genealogical link has been identified between the families living in Indiana
    FAMILY

 and

    Hungary
    ETHNICITY

.

familial amyloid polyneuropathy (FAP)
FAP

carpal tunnel syndrome
vitreous opacities
cardiomyopathy


[Myocardial scintigraphic studies with 123I-MIBG, 201Tl and 99mTc-PYP in patients with cardiac amyloidosis].

Myocardial scintigraphic studies, using 123I-metaiodobenzylguanidine (MIBG), 99mTc-pyrophosphate (PYP) and 201Tl were performed in 4 patients with cardiac amyloidosis. In MIBG myocardial images, 2 patients with familial amyloid polyneuropathy (FAP) showed complete or partial defect and the other 2 with primary amyloidosis had normal myocardial uptake of MIBG. In PYP myocardial images, diffuse myocardial uptake of PYP was mild in 2 patients with FAP and moderate in the other 2. 201Tl myocardial images revealed normal myocardial uptake of 201Tl in 2 patients with FAP and 1 with primary amyloidosis, and intense myocardial uptake in the other one with primary amyloidosis. These results suggest that myocardial scintigraphies with PYP and 201Tl may be useful for the detection of cardiac amyloidosis and estimation of its pathophysiology. And MIBG myocardial scintigraphy may provide useful information about sympathetic nerve abnormalities which vary with type of the fibril protein, clinical syndromes and disease process of cardiac amyloidosis.

    Myocardial scintigraphic studies, using 123I-metaiodobenzylguanidine (MIBG), 99mTc-pyrophosphate (PYP) and 201Tl
    PARACLINICAL

 were performed in 4 patients with

    cardiac amyloidosis
    DIAGNOSIS

. In

    MIBG myocardial images
    PARACLINICAL

, 2 patients with

    familial amyloid polyneuropathy (FAP)
    DIAGNOSIS

 showed

    complete or partial defect
    SYMPTOMS

 and the other 2 with

    primary amyloidosis
    DIAGNOSIS

 had

    normal myocardial uptake of MIBG
    NEG_FINDINGS

. In

    PYP myocardial images
    PARACLINICAL

,

    diffuse myocardial uptake of PYP was mild
    SYMPTOMS

 in 2 patients with

    FAP
    DIAGNOSIS

 and moderate in the other 2.

    201Tl myocardial images
    PARACLINICAL

 revealed

    normal myocardial uptake of 201Tl
    NEG_FINDINGS

 in 2 patients with

    FAP
    DIAGNOSIS

 and 1 with

    primary amyloidosis
    DIAGNOSIS

, and

    intense myocardial uptake
    SYMPTOMS

 in the other one with

    primary amyloidosis
    DIAGNOSIS

. These results suggest that

    myocardial scintigraphies with PYP and 201Tl
    PARACLINICAL

 may be useful for the detection of

    cardiac amyloidosis
    DIAGNOSIS

 and estimation of its pathophysiology. And

    MIBG myocardial scintigraphy
    PARACLINICAL

 may provide useful information about

    sympathetic nerve abnormalities
    SYMPTOMS

 which vary with type of the fibril protein, clinical syndromes and disease process of

    cardiac amyloidosis
    DIAGNOSIS

.

cardiac amyloidosis
familial amyloid polyneuropathy (FAP)
primary amyloidosis
FAP
FAP
primary amyloidosis
primary amyloidosis
cardiac amyloidosis
cardiac amyloidosis

normal myocardial uptake of MIBG
normal myocardial uptake of 201Tl