Family History Of Amyloidosis Research Articles

Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting phenotypic heterogeneity. It is a clinically diagnosed disease supported by MEditerranean FeVer (MEFV) gene mutation analysis. However, the phenotype-genotype correlation is not yet established clearly. We aimed to determine the clinical findings, phenotype-genotype correlation, and treatment outcomes within a large pediatric FMF cohort. The medical charts of children with FMF who were diagnosed and followed up at the eight pediatric rheumatology units were reviewed retrospectively. All patients in the cohort were analyzed for sequence variants in exon 2,3,5 and 10 of the MEFV gene. Patients without any mutations or with polymorphisms including R202Q were excluded. A total of 3,454 children were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 12.1 ± 5.2, 5.1 ± 3.8, and 7.3 ± 4.0 years, respectively. Of 3,454 patients, 88.2% had abdominal pain, 86.7% had fever, 27.7% had arthritis, 20.2% had chest pain, 23% had myalgia, and 13.1% had erysipelas-like erythema. The most common MEFV mutation patterns were homozygous (32.5%) and heterozygous (29.9%) mutations of exon 10. Homozygous M694V was present in 969 patients (28.1%). Allele frequencies of common mutations were M694V (55.3%), M680I (11.3%), V726A (7.6%), and E148Q (7.2%). Children carrying homozygous or compound heterozygous exon 10 mutations had an earlier age of disease onset (4.6 vs. 5.6 years, p = 0.000) and a higher number of attacks per year (11.1 vs. 9.6, p = 0.001). Although 8% of the patients had a family history of amyloidosis, 0.3% (n = 11) had the presence of amyloidosis. M694V homozygosity was detected in nine patients who developed amyloidosis. Colchicine resistance was present in 4.2% of our patients. In this largest pediatric cohort reviewed and presented to date, patients with exon 10 mutations, particularly the M694V homozygous mutation, have been demonstrated earlier disease onset, annual attack count, and more frequent colchicine-resistant cases. Although E148Q is considered as a polymorphism in some populations, it was identified as a disease-causing mutation in our cohort. Secondary amyloidosis is still happening in adults however, it is extremely rare among children, presumably due to increased awareness, tight control, and the availability of anti-IL1 agents in colchicine-resistant cases.

ATTR-амилоидоз - системное заболевание с вовлечением почек

ATTR amyloidosis (transthyretin amyloidosis) is a progressive, fatal disease characterized by the accumulation of transthyretin amyloid mainly in the peripheral nervous system (somatic and autonomic) and heart, as well as in the kidneys, gastrointestinal tract, eyeballs, and ligaments, which impairs the normal function of organs and systems. The hereditary form of ATTR amyloidosis, or ATTRv amyloidosis, is found all over the world and is characterized by broad genetic and phenotypic heterogeneity, resulting in late diagnosis. The kidneys are a potential target organ in ATTRv amyloidosis. Clinically, nephropathy is manifested by albuminuria, proteinuria, nephrotic syndrome, or decreased renal function. A nephrologist may be involved in the diagnosis of amyloid nephropathy/ATTRv amyloidosis in a patient with symptoms of renal damage in an endemic region or with a family history of ATTRv amyloidosis, or, more difficult, in the diagnosis of a sporadic case of ATTRv amyloidosis when symptoms of nephropathy were detected in a patient in a non-endemic region without a known family history of amyloidosis. The diagnosis of amyloidosis, especially is sporadic cases, requires the nephrologist to know the specific symptoms, the so-called "red flags" of ATTR amyloidosis that allow suspecting amyloidosis, and methods to confirm the diagnosis. Kidney biopsy in the presence of nephropathy is the gold standard in the diagnosis of amyloidosis. Congo-red staining of biopsy specimens with subsequent visualization of the apple-green birefringence of congophilic masses with polarized light is crucial for histological confirmation of the diagnosis. Immunohistochemistry is used for amyloid typing. The less available method for typing is mass spectrometry of affected tissue. Detection of "red flags" of amyloidosis in a patient with nephropathy makes it possible to diagnose ATTR amyloidosis in some cases without a biopsy, by TTR gene sequencing or myocardial scintigraphy with 99mTc-pyrophosphate. After amyloidosis is diagnosed, it is necessary to conduct a detailed examination for assessing the damage to potential target organs, which requires an interdisciplinary approach. Early diagnosis and disease-modifying therapies can slow the progression of neuropathy and cardiomyopathy, and presumably nephropathy.

Adherence to best practice consensus guidelines for familial Mediterranean fever: a modified Delphi study among paediatric rheumatologists in Turkey.

BackgroundAlthough not validated fully, recommendations are present for diagnosis, screening and treatment modalities of patients with familial Mediterranean fever (FMF).ObjectiveTo review the current practices of clinicians regarding FMF and reveal their adherence to consensus guidelines.MethodsFifteen key points selected regarding the diagnosis and management of FMF were assessed by 14 paediatric rheumatologists with a three-round modified Delphi panel.ResultsConsensus was reached on the following aspects: genetic analysis should be ordered to all patients when clinical findings support FMF, but its result is not decisive alone. In the absence of clinical features, colchicine should be commenced when two pathogenic alleles and family history of amyloidosis are present. Serum amyloid A testing at each visit is recommended in patients resistant to colchicine, with subclinical inflammation and family history of amyloidosis. Consensus was reached on both the definition of colchicine resistance and starting biologic in resistant cases. Cost, efficiency, ease of use, treatment adherence, accessibility and emergence of adverse events are the factors affecting the choice of biologic agents. In patients without any attack and evidence of subclinical inflammation within the last 6 months following initiation of biologics, treatment dose intervals can be prolonged.ConclusionA consensus was achieved regarding the routine diagnosis and screening and treatment of FMF patients. The definition of colchicine resistance was made and a protocol was created for prolongation of treatment intervals of biologic agents. We anticipate that the results of the study reveal real-life data on the approach to patients in clinical practice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00296-020-04776-1.

Renal Amyloidosis Associated With 5 Novel Variants in the Fibrinogen A Alpha Chain Protein

IntroductionFibrinogen A alpha chain amyloidosis is an autosomal dominant disease associated with mutations in the fibrinogen A alpha chain (FGA) gene, and it is the most common cause of hereditary renal amyloidosis in the UK. Patients typically present with kidney impairment and progress to end-stage renal disease over a median time of 4.6 years.MethodsSix patients presented with proteinuria, hypertension, and/or lower limb edema and underwent detailed clinical and laboratory investigations.ResultsA novel FGA gene mutation was identified in each case: 2 frameshift mutations F521Sfs*27 and G519Efs*30 and 4 single base substitutions G555F, E526K, E524K, R554H. In 5 subjects, extensive amyloid deposits were found solely within the glomeruli, which stained specifically with antibodies to fibrinogen A alpha chain, and in one of these cases, we found coexistent fibrinogen A alpha chain amyloidosis and anti-glomerular basement membrane antibody disease. One patient was diagnosed with light-chain amyloidosis after a bone marrow examination revealed a small clonal plasma cell population, and laser microdissection of the amyloid deposits followed by liquid chromatography and tandem mass spectrometry identified kappa light chain as the fibril protein.DiscussionWe report 6 novel mutations in the FGA gene: 5 were associated with renal fibrinogen A alpha chain amyloidosis and 1 was found to be incidental to light-chain amyloid deposits discovered in a patient with a plasma cell dyscrasia. Clinical awareness and suspicion of hereditary amyloidosis corroborated by genetic analysis and adequate typing using combined immunohistochemistry and laser microdissection and mass spectrometry is valuable to avoid misdiagnosis, especially when a family history of amyloidosis is absent.

A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype

Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.

Amyloidosis and its related factors in Turkish patients with familial Mediterranean fever: a multicentre study

The primary aim of this study was to investigate the prevalence of amyloidosis and its related factors in a large number of FMF patients. Fifteen centres from the different geographical regions of Turkey were included in the study. Detailed demographic and medical data based on a structured questionnaire and medical records were collected. The diagnosis of amyloidosis was based on histological proof of congophilic fibrillar deposits in tissue biopsy specimens. There were 2246 FMF patients. The male/female ratio was 0.87 (1049/1197). The mean age of the patients was 34.5 years (S.D. 11.9). Peritonitis was the most frequent clinical finding and it was present in 94.6% of patients. Genetic testing was available in 1719 patients (76.5%). The most frequently observed genotype was homozygous M694V mutation, which was present in 413 (24%) patients. Amyloidosis was present in 193 patients (8.6%). Male sex, arthritis, delay in diagnosis, M694V genotype, patients with end-stage renal disease (ESRD) and family history of amyloidosis and ESRD were significantly more prevalent in patients with amyloidosis compared with the amyloidosis-negative subjects. Patients with homozygous M694V mutations had a 6-fold higher risk of amyloidosis compared with the other genotypes (95% CI 4.29, 8.7, P < 0.001). In this nationwide study we found that 8.6% of our FMF patients had amyloidosis and homozygosity for M694V was the most common mutation in these patients. The latter finding confirms the association of homozygous M694V mutation with amyloidosis in Turkish FMF patients.

83-Year-Old Man With Nausea, Constipation, and Peripheral Neuropathy

83-Year-Old Man With Nausea, Constipation, and Peripheral Neuropathy

Hereditary lysozyme amyloidosis – phenotypic heterogeneity and the role of solid organ transplantation

Lysozyme amyloidosis (ALys) is a form of hereditary systemic non-neuropathic amyloidosis, which is inherited in an autosomal dominant fashion. Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages. The aim of this study is to describe the phenotype and outcome of patients with ALys including the role of solid organ transplantation. Retrospective evaluation of patients with ALys. UK National Amyloidosis Centre. All 16 patients with ALys followed at the centre. A family history of amyloidosis was present in every affected individual. Although the phenotype was broadly similar amongst those from the same kindred, there were marked phenotypic differences between kindreds who possessed the same amyloidogenic mutation. Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy. All symptomatic ALys individuals had hepatic amyloid. Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively. All of the liver grafts were functioning at censor 1.7, 5.8, 9.0 and 11.0 years after OLT. Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx). There was no evidence of renal allograft dysfunction at censor 6.6, 1.8 and 0.8 years after RTx. Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history. There was a clear family history in all cases within this cohort, demonstrating a high clinical penetrance in the presence of an amyloidogenic lysozyme mutation. There is currently no amyloid-specific therapy for the condition which is managed symptomatically. OLT and RTx appear to be successful treatments for patients with liver rupture or end-stage renal disease, respectively, with excellent outcomes in terms of medium-term graft function and patient survival.

Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant

Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45-78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

Prevention of Amyloidosis in Familial Mediterranean Fever with Colchicine: A Case-Control Study in Armenia

Objective: To determine whether or not the use of colchicine decreases the risk of amyloidosis among Armenian patients with familial Mediterranean fever (FMF). Subjects and Methods: The study included 99 Armenian patients from the Center of Medical Genetics database with genetically ascertained FMF; 33 had renal amyloidosis and 66 were randomly selected control patients without renal amyloidosis. Self- reported colchicine use was assessed by interviewer-based questionnaire. Results: The patients with incident amyloidosis were more likely to be older men, but younger at the time of disease onset, and more likely to have had a family history of amyloidosis and M694F mutation in the MEFV gene compared to patients without amyloidosis. The risk of amyloidosis decreased with adequate colchicine use rather than nonadequate use (adjusted odds ratio, OR, 0.48, 95% confidence interval, CI, 0.16–1.43), continuous colchicine use rather than interrupted use (adjusted OR 0.15, 95% CI 0.04–0.53), earlier rather than later initiation age of colchicine treatment (adjusted OR 0.95, 95% CI 0.90–1.01), current colchicine rather than ever/never colchicine use (adjusted OR 0.20, 95% CI 0.05–0.89). Conclusion: The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2–1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF.

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.

The Abdominal Fat Pad Aspirate for Diagnosing Amyloidosis Is a Useful Tool.

Background: The diagnosis of amyloidosis is relevant in patients with monoclonal gammopathies (MG) and unexplained organ dysfunction, or in those with peripheral neuropathy or a family history of amyloidosis. Tissue diagnosis is essential to clinical evaluation but biopsy of involved viscera can be morbid and delay therapy. The abdominal fat pad aspirate (FPA) is a minimally invasive way to obtain a diagnostic specimen. The FPA is available for light microscopy (eg, Congo red staining, immunohistochemistry (IHC)) and electron microscopy (EM). At our center, we are referred 200 patients a year with MG as well as patients with neuropathy and family histories of amyloidosis. The FPA is performed by cytopathologists as part of the diagnostic evaluation on clinician request. All Congo red (CR) stained slides with controls are reviewed by a cytopathologist using polarized light and, on request, cases are also sent for transthyretin IHC or EM.Design: This study is a retrospective review of our experience with FPA in regards to sensitivity, specificity, and predictive values. A true positive FPA is when the FPA is CR+ and the diagnosis is confirmed by other biopsy or by non-invasive testing, while a false positive is CR+ but the diagnosis not confirmed. A true negative is when the FPA is CR- and the diagnosis not confirmed, while a false negative is CR- but the diagnosis confirmed. We reviewed 136 consecutive FPAs plus the clinical and pathologic reports for this study.Results: There were 133 patients (90M, 43W) with a median age of 61 years (range, 34–81); most were seen between 2000 and 2005. Of 109 CR+ FPA, 3 patients are still in evaluation and 106 have been evaluated. The diagnosis was confirmed in 85 including 63 with CR+ other biopsies and 22 with non-invasive testing and clinical confirmation (true positives), giving a positive predictive value of 80% (85/106). Of these, 75 had systemic AL, 7 had mutant transthyretin genes, 1 had secondary (AA) amyloid, 1 had a CR+ plasmacytoma associated with MG, and 1 (with CR+ kidney biopsy) could not be typed. In 21 patients the diagnosis was not confirmed (false positives): 12 not confirmed on non-invasive testing, 7 had CR- other biopsies, and 2 had negative EM. Of these 21, 19 had MG and 2 peripheral neuropathy without MG. There were 27 CR- FPA, all evaluable. Four had CR+ other biopsies (false negatives). Of the 23 true negatives, 2 had amyloid confined to soft-tissue plasmacytomas. The negative predictive value of FPA then is 85% (23/27). FPA were also analyzed by EM (n=8). Results were concordant with the CR stain (n=4 CR+, n=2 CR−), discordant with it (n=1 CR+ but EM negative) or were unsatisfactory (n=1).Conclusions: The sensitivity of FPA in this series is 95.5% (85/89) and the specificity 52.3% (23/44). The specificity is low because of the prevalence of amyloidosis in those suspected of it. Among those on whom FPA was performed, 80% had CR+ FPA, a rate much higher than at other centers. The utility of EM and organ biopsies as gold standards in equivocal cases is supported by our data; however, such approaches are not usually necessary given the sensitivity of the FPA. In sum, the FPA is a convenient and useful tool in the evaluation of patients suspected of amyloidosis.

Amyloses multisystémiques: Étude clinique de 39 patients au Liban

Clinical analysis of multisystem amyloidosis in Lebanon, by histological type.Retrospective study of 39 cases of multisystem amyloidosis diagnosed histologically in a university hospital center between 1991 and 2002. It analyzed the following clinical data: age, gender, type of presentation, time from symptom onset to diagnosis, clinical features, concomitant diseases, family history of amyloidosis, biopsy sites, presence of urinary or serum monoclonal gammopathy, immunohistochemical type, prognosis and treatment.Median age at diagnosis was 56+/-18 years. The overall ratio of men to woman was 1.4. AL amyloidosis (amyloid light chain) accounted for 54% (21/39) of the cases, AA (amyloid-associated) amyloidosis 36% (14/39), while 10% (4/39) were not typed. Among the 21 cases of AL amyloidosis, 12 were idiopathic (57%) and 9 (43%) were associated with multiple myeloma; among the 14 cases of AA amyloidosis, 7 were associated with familial Mediterranean fever and 5 with chronic disorders. Proteinuria was often the first symptom. The initial manifestations in AL amyloidosis patients with myeloma were more often related to amyloidosis than to myeloma. Renal involvement was seen in 95% (37/39) of all cases (95% of AL versus 93% of AA), proteinuria in 87% of cases and renal failure in 72%. Cardiac amyloidosis (57% of AL versus 7% of AA; p>0.05), infiltration of the tongue (19% of AL versus 0% of AA; p>0.05) and neurological manifestations (24% of AL versus 7% of AA; p>0.05) were more frequent in AL amyloidosis. The 7 patients who died (18%) had AL amyloidosis (5 of them had myeloma). Heart failure was the most frequent cause of death related to amyloid.Multisystem amyloidosis is frequent in Lebanon and familial Mediterranean fever is still frequently associated with the secondary type. Accurate diagnosis and classification are essential for the prognosis and treatment of the disease. Poor prognosis was associated with the AL type, especially when accompanied by myeloma, and with cardiac amyloidosis.

Secondary Glaucoma in Progressive Primary Orbital Amyloidosis

Orbital involvement in primary amyloidosis is uncommon. A 71-year old man with primary amyloidosis presented with painless proptosis, a palpable orbital mass, and restricted extraocular motility. Computed tomography, magnetic resonance imaging, and histopathologic analysis documented the mass. The patient had no clinical evidence of intraocular amyloid deposits, family history of amyloidosis, or systemic involvement. However, 7 years later intracranial involvement and secondary glaucoma became apparent.

Diagnostic tools for amyloidosis

Demonstration of amyloid deposits in biopsy specimens is the only means of confirming the diagnosis of amyloidosis. In experienced hands, nonsurgical biopsies of the rectal mucosa or, preferably, of the abdominal fat pad or labial salivary glands provide the diagnosis in 80 to 85% of cases. Immunolabeling studies help to determine the histological type of amyloidosis but are not performed routinely in everyday practice. In patients with a family history of amyloidosis, studies of the genome and amyloid protein can identify the protein variants capable of causing systemic amyloidosis. Once the diagnosis of amyloidosis is established, the extent of systemic involvement with amyloid should be evaluated by performing renal and hepatic function tests, a proteinuria assay, and an echocardiogram. Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific investigation that provides a map of the amyloid deposits. Deposits are usually seen in the liver and spleen. SAP component scintigraphy can provide support for the diagnosis of amyloidosis in patients with negative histological studies. Tissue retention of radioactivity predicts survival.

Familial Mediterranean fever and systemic amyloidosis in untreated Turkish patients.

We compared the frequencies of seven MEFV mutations (M694V, M680I, V726A, M694I, K695R, R761H, E148Q) and the clinical findings in 20 Turkish FMF patients who had not developed amyloidosis by the age of 40 years in the absence of colchicine therapy, with those in 27 Turkish amyloidosis patients. No mutation frequency, including that of M694V, was different between the two groups. Family history of amyloidosis and parental consanguinity were noted to be higher in the amyloidosis group. The seven mutations do not appear to be sufficient to explain the development of amyloidosis in Turkish FMF patients. Other genetic factors may be important for this association.

Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients.

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The gene responsible for the disease (MEFV/FMF) has been recently identified. Four common mutations in exon 10 of the MEFV gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a mixed population of Jewish and Arab children with FMF. Seventy patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the four mutations (M694V, M680I, V726A, M694I). We then correlated the presence of each mutation with ethnic origin, age of onset, clinical manifestations, disease severity, and occurrence of amyloidosis. The M694V mutation, which is predominant in non-Ashkenazi Jews, was found in 92% of our Jewish patients and in only 30% of the Arab patients. All four mutations were identified among 94% of the Arab patients, but with no particular prevalence for any one of them. The presence of a homozygous M694V mutation was significantly associated with a more severe form of the disease: the clinical onset of the disease manifested at an earlier age; the number of attacks per month was higher; the global assessment by the treating physician and the severity of pain scored higher; and arthritis was more frequent. Only patients with the M694V mutation had a family history of amyloidosis. No association was found between the type of mutation and the predominance of fever, abdominal pain, pleuritis, skin eruption, or response to colchicine in the clinical picture. Homozygosity for the M694V mutation, predominant among North African Jews, is associated with a severe course and prognosis for FMF. This mutation is less common among Arabs and, when present, occurs almost only in heterozygous form. In Arab patients, the disease tends to run a milder course and seems to bear a better prognosis. The phenotype/genotype patterns that are evident from our study of a mixed series of Jewish and Arab children with FMF might provide a rational basis for counseling about the natural history of the disease and for clinical treatment of FMF patients and their families.

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.

Transthyretin Ser 6 gene frequency in individuals without amyloidosis.

Transthyretin (TTR) Ser 6 was originally described in a Scottish kindred without amyloidosis. This variant, arising from a G-->A transition in codon 6 that destroys an MspI site and creates a BsrI site, was present in none of 50 controls, and was therefore thought to be rare. This variant has subsequently been found in a normal human cDNA liver library and in two unrelated patients with familial amyloidosis and other TTR variants, raising the question whether it is actually a common polymorphism. To address this question, we performed PCR and restriction digestion of 574 DNA samples from people without evidence of amyloidosis or a known family history of amyloidosis. The TTR Ser 6 allele frequency was 33/558 (.060) in Caucasians (including 8/192 (.04) in North American Ashkenazic Jews, 16/218 (.07) in North American non-Jews, and 9/148 (.06) in Portuguese), 3(242 (.01) in African Americans, 0/140 in Africans, and 0/208 in Asians. These data are most suggestive of a single Caucasian founder and the known 25% admixture of "Caucasian" genes in the African-American population. Alternatively, as this variant arose from a transition at a CG dinucleotide "hot spot," it may have arisen on multiple occasions. These data indicate that TTR Ser 6 is a common non-amyloidogenic population polymorphism in Caucasians.

Identification of a novel non-amyloidogenic transthyretin polymorphism (His 74) in the German population

We examined the transthyretin gene of a German individual by direct DNA sequencing and found a guanine to cytosine transversion at the first base ofcodon 74 which resulted in a replacement ofhistidinefor aspartic acid. This mutation was confirmed by restriction fragment length polymorphism analysis using the polymerase chain reaction and the variant protein was proven to exist in plasma by sequence analysis of purified transthyretin. This variant transthyretin which was found in 7 of 4000 individuals by isoelectric focusing gel analysis is considered to be a relatively common polymorphism in the German population. None of the 7 individuals has a family history of amyloidosis or thyroid disorder.