-
John L Berk,
Ole B Suhr,
Yoshiki Sekijima,
Taro Yamashita,
Michael Heneghan,
Steven R Zeldenrust,
Yukio Ando,
Shu-ichi Ikeda,
Peter Gorevic,
Giampaolo Merlini,
Jeffrey W Kelly,
Martha Skinner,
Alice B Bisbee,
Peter J Dyck, Laura Obici
[show abstract]
[hide abstract]
ABSTRACT: Familial amyloidotic polyneuropathy (FAP) is a protein folding disorder that induces neuropathy and cardiomyopathy, leading to death within 7-15 years after onset of clinical disease. In vitro, small ligands binding the thyroid hormone docking site stabilize tetrameric transthyretin, inhibiting amyloid fibril formation. We undertook a randomized, placebo-controlled clinical trial to determine whether diflunisal, a well-known non-steroidal anti-inflammatory drug (NSAID) alters neurologic disease progression in FAP. We enrolled 130 subjects with wide age and FAP mutation representation. To date, few recognized complications of NSAIDs have occurred in the study cohort. Data collection will be completed by November 2012.
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 05/2012; 19 Suppl 1:37-8. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We designed a phase II, open-label study to evaluate the efficacy, tolerability, safety, and pharmacokinetics of orally doxycycline (100 mg BID) and tauroursodeoxycholic acid (TUDCA) (250 mg three times/day) administered continuously for 12 months. Primary endpoint is response rate defined as nonprogression of the neuropathy and of the cardiomyopathy. Since July 2010, we enrolled 20 patients. Seventeen patients have hereditary ATTR, two patients have senile systemic amyloidosis, and one is a domino recipient. Seven patients completed 12-month treatment, 10 completed 6-month treatment, two discontinued because of poor tolerability, and one is lost at follow-up. No serious adverse events were registered. No clinical progression of cardiac involvement was observed. The neuropathy (Neuropathy Impairment Score in the Lower Limbs [NIS-LL] and Kumamoto score) remained substantially stable over 1 year. These preliminary data indicate that the combination of Doxy-TUDCA stabilizes the disease for at least 1 year in the majority of patients with an acceptable toxicity profile.
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 05/2012; 19 Suppl 1:34-6. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis, autoinflammatory syndromes, Crohn's disease, malignancies and conditions predisposing to recurrent infections. Organ damage results from the extracellular deposition of proteolytic fragments of the acute-phase reactant serum amyloid A (SAA) as amyloid fibrils. A sustained high concentration of SAA is the prerequisite for developing AA amyloidosis. However, only a minority of patients with long-standing inflammation actually presents with this complication, pointing to the existence of disease-modifying factors, the best characterised of which being SAA1 genotype. The kidneys, liver and spleen are the main target organs of AA amyloid deposits. In more than 90% of patients proteinuria, nephrotic syndrome and/or renal dysfunction dominate the clinical picture at onset. If not effectively treated, this disease invariably leads to end stage kidney disease and renal replacement therapy, that are still associated with a poor outcome. Although the incidence of AA in rheumatoid arthritis and other chronic arthritides has continuously decreased over the past ten years, thanks to the increasing availability of more effective anti-inflammatory and immunosuppressive therapies, AA remains a life-threatening disease with several areas of uncertainty and unmet needs, deserving continuous efforts at prevention and effective treatment. The deeper understanding of the molecular mechanisms of amyloid formation and regression is now driving the development of novel treatments targeting different steps in the amyloidogenic cascade. These therapies will hopefully improve the quality of life and outcome of these patients in a near future.
Schweizerische medizinische Wochenschrift 01/2012; 142:w13580. · 1.68 Impact Factor
-
A Foli,
G Palladini,
R Caporali,
L Verga,
P Morbini, L Obici,
P Russo,
G Sarais,
S Donadei,
C Montecucco,
G Merlini
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:75-7. · 2.12 Impact Factor
-
F Lavatelli,
V Valentini,
G Palladini,
L Verga,
P Russo,
A Foli, L Obici,
G Sarais,
V Perfetti,
S Casarini,
G Merlini
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:59-61. · 2.12 Impact Factor
-
P Russo,
G Palladini,
A Foli,
L Zenone Bragotti,
P Milani,
M Nuvolone, L Obici,
V Perfetti,
S Brugnatelli,
R Invernizzi,
G Merlini
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:87-8. · 2.12 Impact Factor
-
S Perlini,
F Musca,
F Salinaro,
I Fracchioni,
G Palladini, L Obici,
R Albertini,
R Moratti,
F Lavatelli,
C Rapezzi,
G Merlini
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:91-2. · 2.12 Impact Factor
-
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:56-8. · 2.12 Impact Factor
-
J L Berk,
P J Dyck, L Obici,
S R Zeldenrust,
Y Sekijima,
T Yamashita,
Y Ando,
S-I Ikeda,
P Gorevic,
G Merlini,
J W Kelly,
M Skinner,
A B Bisbee,
O B Suhr
Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 06/2011; 18 Suppl 1:191-2. · 2.12 Impact Factor
-
M Gattorno,
M P Sormani,
A D'Osualdo,
M A Pelagatti,
F Caroli,
S Federici,
M Cecconi,
N Solari,
A Meini,
F Zulian, [......],
A Tommasini,
G Bossi,
A Govers,
I Touitou,
P Woo,
J Frenkel,
I Koné-Paut,
M Baldi,
I Ceccherini,
A Martini
[show abstract]
[hide abstract]
ABSTRACT: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes.
A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set).
Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened.
The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.
Arthritis & Rheumatism 07/2008; 58(6):1823-32. · 7.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the efficacy and safety of treatment with the interleukin-1 receptor antagonist anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) requiring high cumulative doses of steroids.
Four children (mean age 9.1 years [range 4-13 years]) and 1 adult (age 33 years) with TRAPS were enrolled in the study. The 3 children with cysteine mutations (C52Y, C55Y, C43R) had prolonged and frequent attacks of fever. One child with the R92Q mutation and the adult patient with the C43R mutation displayed a more chronic disease course, with fluctuating, nearly continuous symptoms and persistent elevation of acute-phase reactant levels (including serum amyloid A [SAA]). All patients were treated with anakinra (1.5 mg/kg/day).
All of the patients had a prompt response to anakinra, with disappearance of symptoms and normalization of acute-phase reactant levels, including SAA. In all pediatric patients, anakinra was withdrawn after 15 days of treatment. After a few days (mean 5.6 days [range 3-8]) a disease relapse occurred, which dramatically responded to reintroduction of anakinra. During the following period of observation (mean 11.4 months [range 4-20 months]), the patients did not experience episodes of fever or other disease-related clinical manifestations. Levels of acute-phase reactants remained in the normal range. No major adverse reactions or severe infections were observed.
Continuous treatment with anakinra effectively controlled both the clinical and laboratory manifestations in patients with TRAPS and prevented disease relapses.
Arthritis & Rheumatism 06/2008; 58(5):1516-20. · 7.87 Impact Factor
-
F Salvi,
C Scaglione,
R Michelucci,
R P Linke, L Obici,
A Ravani,
P Rimessi,
A Ferlini,
S Meletti,
T Cavallaro,
C A Tassinari,
P Martinelli
[show abstract]
[hide abstract]
ABSTRACT: Two sisters from an Italian family shared progressive motor symptoms, preceding the onset of sensory and autonomic disturbances. The familial occurrence of axonal and slowly progressive polyneuropathy led us to consider these patients as candidates for TTR molecular analysis. We found a missense mutation causing Ile68Leu TTR substitution in both. The aims of this work are to report the possibility of a motor onset of amyloid polyneuropathy and to suggest the search for TTR mutations in familial cases of axonal polyneuropathy. Second, to stress the possible occurrence of amyloid within the spinal canal as the potential pathogenesis and responsible for motor presentation.
Amyloid 10/2003; 10(3):185-9. · 2.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Protein aggregation occurs in vivo as a result of improper folding or misfolding. Diverse diseases arise from protein misfolding and are now grouped under the term "protein conformational diseases", including most of the neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, the prion encephalopathies and Huntington's disease, as well as cystic fibrosis, sickle cell anemia and other less common conditions. The hallmark event in these diseases is a change in the secondary and/or tertiary structure of a normal, functional protein, leading to the formation of protein aggregates with various supramolecular organizations. In most cases the aggregates are organized in structurally well-defined fibrils forming amyloid deposits. The crucial feature of the amyloidogenic proteins is their structural instability induced either by mutations, post-translational modifications, or local conditions, such as pH, temperature, and co-solutes. The conformational change may promote the disease either by gain of a toxic activity or by the lack of biological function of the natively folded protein. As different molecular mechanisms are involved in the formation of the various forms of protein aggregates, the laboratory diagnostic approach remains frequently elusive.
Clinical Chemistry and Laboratory Medicine 12/2001; 39(11):1065-75. · 2.15 Impact Factor
-
The American Journal of Medicine 09/2001; 111(3):243-4. · 5.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High-dose dexamethasone (HD-Dex) has been reported to benefit AL amyloidosis patients with varying response rates. Our preliminary experience with the usual HD-Dex schedule indicated that the induction phase was rather toxic in AL patients. We therefore adopted a milder schedule consisting of dexamethasone 40 mg on d 1-4 q21 d for up to eight cycles. Overall 8 out of 23 (35%) treated patients responded to treatment in a median time of 4 months (range 2-6 months) without significant toxicity. This regimen may be considered front-line therapy when autologous stem cell transplantation is not feasible and when a rapid response is particularly important.
British Journal of Haematology 07/2001; 113(4):1044-6. · 4.94 Impact Factor
-
P Mangione,
M Sunde,
S Giorgetti,
M Stoppini,
G Esposito,
L Gianelli, L Obici,
L Asti,
A Andreola,
P Viglino,
G Merlini,
V Bellotti
[show abstract]
[hide abstract]
ABSTRACT: We recently described a new apolipoprotein A1 variant presenting a Leu174Ser replacement mutation that is associated with a familial form of systemic amyloidosis displaying predominant heart involvement. We have now identified a second unrelated patient with very similar clinical presentation and carrying the identical apolipoprotein A1 mutation. In this new patient the main protein constituent of the amyloid fibrils is the polypeptide derived from the first 93 residues of the protein, the identical fragment to that found in the patient previously described to carry this mutation. The X-ray fiber diffraction pattern obtained from preparations of partially aligned fibrils displays the cross-beta reflections characteristic of all amyloid fibrils. In addition to these cross-beta reflections, other reflections suggest the presence of well-defined coiled-coil helical structure arranged with a defined orientation within the fibrils. In both cases the fibrils contain a trace amount of full-length apolipoprotein A1 with an apparent prevalence of the wild-type species over the variant protein. We have found a ratio of full-length wild-type to mutant protein in plasma HDL of three to one. The polypeptide 1--93 purified from natural fibrils can be solubilized in aqueous solutions containing denaturants, and after removal of denaturants it acquires a monomeric state that, based on CD and NMR studies, has a predominantly random coil structure. The addition of phospholipids to the monomeric form induces the formation of some helical structure, thought most likely to occur at the C-terminal end of the polypeptide.
Protein Science 02/2001; 10(1):187-99. · 2.80 Impact Factor
-
A Ferlini, L Obici,
E Manzati,
O Biadi,
E Tarantino,
P Conigli,
G Merlini,
M D'Alessandro,
V Mazzaferro,
C A Tassinari,
F Salvi
[show abstract]
[hide abstract]
ABSTRACT: Transthyretin gene mutations are associated with autosomal dominant familial amyloidosis. The commonest phenotype in the patients is peripheral neuropathy, but restrictive cardiomyopathy is also a frequent sign. More than 70 different mutations in the gene have been described. Although these mutations are randomly distributed, some hot spots have also been reported notably at position 6, 30, 33, 58, 109, 119 and 122. A few of these codons contain a CpG dinucleotide. We describe an additional 'hot spot' occurring at codon 47, in which we report one novel and two previously described mutations. This codon, however, does not contain a CpG dinucleotide, suggesting that other mechanisms might be responsible for the allelic heterogeneity. All the reported mutations in codon 47 are located in the exon 2 consensus sequence and are potentially involved in splicing. We performed transcription analysis on two livers obtained from transplanted patients carrying the Ala47 mutation. These livers showed a normally spliced message, indicating that this mutation does not affect splicing.
Clinical Genetics 05/2000; 57(4):284-90. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We characterised the expression, localisation and developmental regulation of the three major dystrophin isoforms in human foetal skeletal and cardiac muscles and in the corresponding cultures. Gene expression studies in foetal cardiac muscle-tissue and cultures showed that the Muscle- and the Brain- but not the Purkinje-transcripts were always co-expressed. In skeletal muscle the Muscle-isoform was already present at 11.8 weeks while the Brain-isoform was detected only after 13 weeks. Myoblast cultures showed a similar sequence of isoform transcription. The Purkinje-isoform was never detected. Localisation studies showed that in cardiac muscle dystrophin was seen discontinuously at the sarcolemma from 8.5 weeks, and evenly expressed by 15 weeks. Cardiomyocyte cultures expressed desmin but not dystrophin after 7 days. Protein studies in foetal skeletal muscle suggested that dystrophin is expressed in the cytoplasm from 8.5 weeks and at the sarcolemma only after 10.5 weeks. Similar results were obtained in cultured myoblasts. This study shows that in cardiac muscle both the Muscle- and Brain-isoforms are transcribed in parallel from the very early stages of development, while in skeletal muscle transcription of the Muscle-isoform occurs first, followed by the Brain-isoform.
Neuromuscular Disorders 01/2000; 9(8):541-51. · 2.80 Impact Factor
-
L Obici,
V Bellotti,
P Mangione,
M Stoppini,
E Arbustini,
L Verga,
I Zorzoli,
E Anesi,
G Zanotti,
C Campana,
M Viganò,
G Merlini
[show abstract]
[hide abstract]
ABSTRACT: We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu(174) --> Ser, in a patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly affected the heart of the proband, who underwent transplantation for end-stage congestive heart failure. Amyloid fibrils of myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spectrometry analysis, by an amino-terminal polypeptide ending at Val(93) of apolipoprotein A-I (apoA-I); no other significant fragments were detected. The mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings. The plasma levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polypeptide fragment deposited as fibrils. Visualization of the mutation in the three-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located near position 93 of an adjacent chain and suggests that the amino acid replacement in position 174 is permissive for a proteolytic split at the C-terminal of Val(93).
American Journal Of Pathology 10/1999; 155(3):695-702. · 4.89 Impact Factor
-
Blood 03/1999; 93(3):1112-3. · 9.90 Impact Factor
