Familial nephropathic systemic amyloidosis caused by apolipoprotein Al variant Arg26

A point mutation in the apolipoprotein Al (apoAl) gene causingautosomal dominant non-neuropathic systemic amyloidosis is describedin a previously unreported Canadian family of British originwith five affected individuals in three generations. Amyloiddeposits in the renal biopsy from the prob-and, a 31-year-oldfemale presenting with hypertension and renal failure, stainedimmunospecifically with antiserum to apoAl. The plasma of allfamily members with amyloidosis contained both wild-type apoAland a variant bearing one additional positive charge. Sequencingof the apoAl gene demonstrated that the proband was a heterozygotefor a single base substitution in exon 3, changing codon 26from GGC(Gly) to CGC(Arg). Concordance of the mutant allelewith the presence of variant plasma apoAl and clinical featuresof amyloidosis was demonstrated. This is the third family inwhich this amyloidotic mutation has been described, but thedistribution of amyloid deposits and their clinical effectsare clearly determined by other genetic and/or environmentalfactors.     

Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.

We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.     

RhD variant caused by an in‐frame triplet duplication in the RHD gene

BACKGROUND: The RHD gene is highly polymorphic and a large number of D variants have already been detected. Several mechanisms are involved in the origin of D variants. In‐frame deletions, resulting in a single‐amino‐acid deletion, have been described associated with RhD and RhCE variants. No in‐frame duplications and/or insertions have been reported in the RH genes to date. STUDY DESIGN AND METHODS: Blood samples from a Brazilian blood donor and his sister were serologically tested with routine anti‐D reagents and anti‐D panels (ALBAclone advanced partial D typing kit, Alba Bioscience Limited; and D‐Screen, Diagast), followed by molecular biology techniques, RHD polymerase chain reaction with sequence‐specific priming and sequencing. RESULTS: Samples tested negative with routine immunoglobulin M (IgM) anti‐D reagents and positive with IgG anti‐D, which detect weak D cells. The pattern of results with anti‐D panels did not correspond to any described before. A 3‐bp in‐frame duplication within Exon 1 (c.75_77dupTCT), resulting in the duplication of leucine 26 (p.Leu26dup), was identified in the two samples. CONCLUSION: We report the first RhD variant associated with a 3‐bp in‐frame duplication in the RHD gene, predicted to be located within the RhD protein transmembrane domain that might be expected to result in a weak‐D–like phenotype, concordant with serologic findings.     

Submucosal hematoma producing mechanical obstruction in the sigmoid colon, complicated by systemic amyloidosis

A case of systemic amyloidosis involving the gastrointestinal tract is presented. The initial manifestation of this case was mechanical obstruction. On laparotomy, a submucosal hematoma of the sigmoid colon which completely obliterated the lumen, was found. With intense medical treatment, the obstructed lumen became patent, but segmental ischemic colitis ensued. The terminal course of this case was complicated by chronic renal failure, upper gastrointestinal bleeding and coagulopathy. Pathological examination of the stomal specimen revealed massive amyloid deposits in the wall of the large intestine as well as other vital organs.     

Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score

OBJECTIVE: To examine whether the outcome of patients with primary systemic amyloidosis (AL) has improved over time and to identify predictors of early mortality in patients with AL.PATIENTS AND METHODS: We studied 2 separate cohorts of patients. The first cohort, consisting of 1998 patients with AL seen at Mayo Clinic between January 1977 and August 2006, was used to examine the trends in overall survival (OS) from diagnosis during this 30-year period. The second cohort, consisting of 313 patients seen between September 2006 and August 2009, was used to validate a model for predicting early mortality.RESULTS: The 4-year OS from diagnosis improved during each decade of follow-up: 21%, 24%, and 33%, respectively, for the periods 1977-1986, 1987-1996, and 1997-2006 (P<.001). Within the last group (1997-2006), 4-year OS during 1997-1999, 2000-2002, and 2003-2006 was 28%, 30%, and 42%, respectively (P=.02). However, the 1-year mortality remained high during the 30-year period. A risk stratification score using cardiac troponin T, N-terminal probrain natriuretic peptide, and uric acid identified patients at risk of early mortality. The 1-year mortality with 0, 1, 2, or 3 risk factors was 19%, 37%, 61%, and 80%, respectively, in this training cohort of 459 patients. This was confirmed in a validation cohort of 313 patients.CONCLUSION: Survival in AL has improved over time, with maximum improvement occurring in the past decade. However, early mortality remains high, and prospective identification of patients at risk of early mortality may allow development of risk-adapted strategies.AL = primary systemic amyloidosis; CI = confidence interval; cTnT = cardiac troponin T; NT-proBNP = N-terminal pro-brain natriuretic peptide; OS = overall survival; SCT = stem cell transplantPrimary systemic, or light-chain, amyloidosis (AL) is a clonal plasma cell disorder characterized by a relatively low plasma cell burden and multiorgan deposition of immunoglobulin light-chain–derived amyloid fibrils.^1-5 Although amyloid fibrils can originate from more than 25 different proteins, AL is the most common form of amyloidosis. The survival of patients with amyloidosis is quite variable, with median survival ranging from 12 to 18 months in different series, and largely depends on the number of organs involved and the severity of their involvement.^1,2,6 High-dose therapy and stem cell transplant (SCT) have been increasingly used for treatment of this disease, and case-control studies suggest an improved outcome, although this modality is an option only for a minority of patients.^6-11 Treatment of amyloidosis has typically followed developments in therapy for multiple myeloma, in which a marked shift in treatment approaches has occurred because of the availability of several effective new drugs in the past 10 years.¹² These changes have improved survival in patients with myeloma during the past decade.¹³ In addition to new drugs, the combination of melphalan and dexamethasone is an effective regimen for AL, and risk-adapted approaches to SCT have decreased treatment-related mortality.^14-24 Whether recent progress in risk stratification and treatment approaches has translated into improved survival for these patients is unclear. Therefore, we undertook this study to examine trends in survival of patients with AL over time, with an emphasis on identifying patient characteristics predicting outcome.     

Hypofibrinogenemia caused by a nonsense mutation in the fibrinogen Bβ chain gene

Summary.  Congenital hypofibrinogenemia, fibrinogen Tottori II, caused by a nonsense mutation in the fibrinogen Bβ chain gene, was found in a 68-year-old Japanese female. The plasma fibrinogen level was 99.2 mg dL⁻¹ as determined by the thrombin time method. No overt molecular abnormalities were observed in purified patient fibrinogen by SDS–PAGE analysis. After sequencing all exons and exon–intron boundaries of three fibrinogen genes, we found a heterozygous single point mutation of T→G at position 3356 of the patient fibrinogen Bβ chain gene. This nucleotide mutation results in a nonsense mutation (TAT sequence for Bβ 41Tyr to TAG sequence for a translation termination signal). The mutation was confirmed by polymerase chain reaction-restriction fragment length polymorphism analysis, since this nucleotide mutation results in a new NheI recognition sequence at this position. These data indicated that the nonsense mutation of the fibrinogen Bβ chain gene caused a truncated fibrinogen Bβ chain, which may not be assembled in the fibrinogen molecule.     

Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation.

During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIa(WT)). When compared with FXIa(WT), FXIa-Glu555 activates factor IX at a greatly reduced rate ( approximately 400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIa(WT) and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable k(cat)s. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2' site and the P2' residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.     

Variant of type B blood in an El Salvador family. Expression of a variant B gene enhanced by the presence of an A2 gene

A variant of type B blood was found in three members of a family from El Salvador. In two members, both genotype BO, the blood and saliva had the characteristics of the phenotype Be1 . In the third member, genotype A2B, the red cell B antigen was stronger than in his BO genotype relatives. Thus, in this family, the presence of the A2 gene appeared to enhance the expression of the B gene.     

The multiple cases of Fabry disease in a Russian family caused by an E341K amino acid substitution in the alpha-galactosidase A

A large Russian family with multiple cases of Fabry disease in several generations is presented. Fourteen family members were clinico-biochemically examined. Among 12 adult children (19-32 years old) of one couple, five sons manifested angiokeratotic skin lesions and other Fabry symptoms. Biochemical studies including an enzyme assay, the analysis of glycosphingolipid excretion and isoelectric focusing of a patient leukocyte extract allowed us to identify Fabry disease in four affected brothers and to establish the heterozygous status of their mother. The analysis of genomic DNA of four patients and their mother revealed a novel E341K missense mutation caused by a G to A transition (codon 341 GAA-AAA) in the alpha-galactosidase A gene.     

Hemorrhage in the upper digestive tract caused by an aorto-esophageal fistula

The case of a 75-year-old patient admitted to our Center with hematemesis is presented. At oral endoscopy a pulsating vegetative mass was found in the distal third of the esophagus, which aroused suspicion of an aortic aneurysm fistulized to the esophagus; this was confirmed by arteriography. He underwent two surgical procedures, the aneurysm being resected and replaced by an aortic prosthesis, and esophagectomy performed. The patient died of postoperative complications. The endoscopic appearance is shown.     

Serial echocardiographic observations in patients with primary systemic amyloidosis: an introduction to the concept of early (asymptomatic) amyloid infiltration of the heart

Echocardiography was used for the serial assessment of 27 patients with primary systemic amyloidosis. Thirteen patients had no clinical cardiac deterioration between the two echocardiographic studies (group 1), whereas in 14 patients (group 2), congestive heart failure or arrhythmias (or both) appeared or worsened during a mean observation period of 19 months. The only echocardiographic changes in group 1 were a mild increase in left ventricular mass and a mild decrease in left ventricular wall systolic thickening. Patients in group 2 had significant changes in left ventricular wall thickness (mean increase, 34%), in left ventricular mass (mean increase, 42%), in right ventricular wall thickness (mean increase, 78%), in left atrial size (mean increase, 19%), in left ventricular mass/voltage ratio (mean increase, 68%), in left ventricular radius/thickness ratio (mean decrease, 29%), and in left ventricular fractional shortening (mean decrease, 13%). Significant correlations were found in group 2 between changes in systolic and diastolic blood pressure and changes in ventricular wall thickness and mass. Changes in left ventricular systolic function did not correlate significantly with changes in other clinical, electrocardiographic, or echocardiographic measurements. In six cases (two in group 1), in which amyloid infiltration of the heart was proved by myocardial biopsy or autopsy, the only echocardiographic abnormality when the patients were asymptomatic was a moderate increase in left or right ventricular wall thickness. We found that M-mode and two-dimensional echocardiographic examinations can substantiate progressive amyloid infiltration of the heart and are useful tools for the noninvasive serial assessment of patients with primary systemic amyloidosis.     

Efficacy of daptomycin versus vancomycin in an experimental model of foreign-body and systemic infection caused by biofilm producers and methicillin-resistant Staphylococcus epidermidis

Staphylococcus epidermidis is a frequent cause of device-associated infections. In this study, we compared the efficacy of daptomycin versus vancomycin against biofilm-producing methicillin-resistant S. epidermidis (MRSE) strains in a murine model of foreign-body and systemic infection. Two bacteremic biofilm-producing MRSE strains were used (SE284 and SE385). The MIC of daptomycin was 1 mg/liter for both strains, and the MICs of vancomycin were 4 and 2 mg/liter for SE284 and for SE385, respectively. The in vitro bactericidal activities of daptomycin and vancomycin were evaluated by using time-kill curves. The model of foreign-body and systemic infection of neutropenic female C57BL/6 mice was used to ascertain in vivo efficacy. Animals were randomly allocated into three groups (n = 15): without treatment (controls) or treated with daptomycin at 50 mg/kg/day or vancomycin at 440 mg/kg/day. In vitro, daptomycin showed concentration-dependent bactericidal activity, while vancomycin presented time-dependent activity. In the experimental in vivo model, daptomycin and vancomycin decreased liver and catheter bacterial concentrations (P < 0.05) and increased the survival and the number of sterile blood cultures (P < 0.05) using both strains. Daptomycin produced a reduction in the bacterial liver concentration higher than 2.5 log(10) CFU/g compared to vancomycin using both strains, with this difference being significant (P < 0.05) for infection with SE385. For the catheter bacterial concentrations, daptomycin reduced the concentration of SE284 3.0 log(10) CFU/ml more than did vancomycin (P < 0.05). Daptomycin is more effective than vancomycin for the treatment of experimental foreign-body and systemic infections by biofilm-producing methicillin-resistant S. epidermidis.     

Artefactual increase in serum thyrotropin concentration caused by heterophilic antibodies with specificity for IgG of the family Bovidea

A 19-year-old white woman presented with symptoms compatible with mild hyperthyroidism and biochemical evidence suggestive of autonomous thyrotropin (TSH) secretion. Intensive investigation of the pituitary-thyroid axis suggested that the basal concentrations of TSH were artefactually increased owing to heterophilic antibodies in the patient's serum with a broad specificity for immunoglobulin class G of the family Bovidea. These heterophilic antibodies complexed with the ovine antisera to human thyrotropin that are used in the RIA system, in particular blocking the binding of TSH but also partly blocking interaction with the second antibody. When TSH was measured immunometrically or by an RIA with TSH-specific antisera of rabbit origin, the concentrations measured were within the appropriate reference intervals. The blocking effect can be overcome by including large quantities of non-TSH-specific ovine IgG in assay incubation mixtures. Interference of this type is generally not appreciated and its incidence is poorly characterized, but it may have implications for any method in which antibodies are used as reagents.     

Release of mediators of systemic inflammatory response syndrome in the course of a severe delayed hemolytic transfusion reaction caused by anti-D

BACKGROUND: In vitro studies suggest that mediators of systemic inflammatory response syndrome are generated in the course of hemolytic transfusion reactions. Evidence for the in vivo significance of these findings is given by the present clinical and laboratory analysis of a severe delayed hemolytic transfusion reaction (DHTR). CASE REPORT: A 67- year-old patient (blood group O, D-negative) with a negative pretransfusion antibody screen received a massive transfusion because of arterial bleeding (Day 1). The transfusion of group O, D-positive red cell concentrates was unavoidable because of limited supplies. At Day 10, the patient developed a DHTR with symptoms of septic-toxic syndrome and signs of hemolysis; he received an exchange transfusion. Serologic markers, as well as proinflammatory and anti-inflammatory mediators, were monitored at the onset of the DHTR and during the exchange transfusion. RESULTS: At Day 10, the direct antiglobulin test was positive; anti-D was present, most likely as the result of an anamnestic immune response. Interleukin (IL)-1 was not detectable; all other mediators monitored were elevated: IL-1 receptor antagonist, tumor necrosis factor, IL-6, IL-8, IL-10, neopterin, elastase, C3a- desArg, C-reactive protein, and fibrinogen. Most of the values declined during the exchange transfusion, which was followed by an improvement of the clinical presentation. CONCLUSIONS: Mediators of systemic inflammatory response syndrome were released in the course of a DHTR caused by anti-D. Severe clinical symptoms could be treated successfully by exchange transfusion.     

Obturator nerve impingement caused by an osteophyte in the sacroiliac joint: A case report

BACKGROUNDCases of obturator nerve impingement (ONI) caused by osteophytes resulting from bone hyperplasia on the sacroiliac articular surface have never been reported. This paper presents such a case in a patient in whom severe lower limb pain was caused by osteophyte compression of the sacroiliac joint on the obturator nerve.CASE SUMMARYA 65-year-old Asian man presented with severe pain and numbness in his left lower limb, which became aggravated during walking and showed intermittent claudication. The physical examination revealed that the muscle strength of the left lower limb had decreased and that the passive knee flexion test result was positive. Computed tomography (CT) and 3D reconstruction showed a large osteophyte located in the anterior lower part of the left sacroiliac joint. The results of electrophysiological examination showed peripheral neuropathy. A CT-guided obturator nerve block significantly reduced the severity of pain in this patient. According to the above findings, ONI caused by the osteophyte in the sacroiliac joint was diagnosed. This patient underwent an operation to remove the bone spur and symptomatic treatment. After therapy, the patient''s pain and numbness were significantly relieved. The last follow-up was performed 6 mo after the operation, and the patient recovered well without other complications, returned to work, and resumed his normal lifestyle.CONCLUSIONOsteophytes of the sacroiliac joint can cause ONI, which leads to symptoms including severe radiative pain in the lower limb in patients. The diagnosis and differentiation of this disease should attract the attention of clinicians. Surgical excision of osteophytes should be considered when conservative treatment is not effective.     

Clinical outcomes of COVID-19 caused by the Alpha variant compared with one by wild type in Kobe,Japan. A multi-center nested case-control study

ObjectivesThe emergence of the Alpha variant of novel coronavirus 2019 (SARS-CoV-2) is a concerning issue but their clinical implications have not been investigated fully.MethodsWe conducted a nested case-control study to compare severity and mortality caused by the Alpha variant (B.1.1.7) with the one caused by the wild type as a control from December 2020 to March 2021, using whole-genome sequencing. 28-day mortality and other clinically important outcomes were evaluated.ResultsInfections caused by the Alpha variant were associated with an increase in the use of oxygen (43.4% vs 26.3%. p = 0.017), high flow nasal cannula (21.2% vs 4.0%, p = 0.0007), mechanical ventilation (16.2% vs 6.1%, p = 0.049), ICU care (30.3% vs 14.1%, p = 0.01) and the length of hospital stay (17 vs 10 days, p = 0.031). More patients with the Alpha variant received medications such as dexamethasone. However, the duration of each modality did not differ between the 2 groups. Likewise, there was no difference in 28-day mortality between the 2 groups (12% vs 8%, p = 0.48), even after multiple sensitivity analyses, including propensity score analysis.ConclusionThe Alpha variant was associated with a severe form of COVID-19, compared with the non-Alpha wild type, but might not be associated with higher mortality.