Effectiveness and waning of protection with the BNT162b2 vaccine against the SARS-CoV-2 Delta variant in immunocompromised individuals.

Introduction: In Hungary, the HUN-VE 3 study determined the comparative effectiveness of various primary and booster vaccination strategies during the Delta COVID-19 wave. That study included more than 8 million 18-100-year-old individuals from the beginning of the pandemic. Immunocompromised (IC) individuals have increased risk for COVID-19 and disease course might be more severe in them. In this study, we wished to estimate the risk of SARS-CoV-2 infection and COVID-19 related death in IC individuals compared to healthy ones and the effectiveness of the BNT162b2 vaccine by reassessing HUN-VE 3 data. Patients and methods: Among the 8,087,988 individuals undergoing follow-up from the onset of the pandemic in the HUN-VE 3 cohort, we selected all the 263,116 patients with a diagnosis corresponding with IC and 6,128,518 controls from the second wave, before vaccinations started. The IC state was defined as two occurrences of corresponding ICD-10 codes in outpatient or inpatient claims data since 1 January, 2013. The control group included patients without chronic diseases. The data about vaccination, SARS-CoV-2 infection and COVID-19 related death were obtained from the National Public Health Center (NPHC) during the Delta wave. Cases of SARS-CoV-2 infection were reported on a daily basis using a centralized system via the National Public Health Center (NPHC). Results: Out of the 263,116 IC patients 12,055 patients (4.58%) and out of the 6,128,518 healthy controls 202,163 (3.30%) acquired SARS-CoV-2 infection. Altogether 436 IC patients and 2141 healthy controls died in relation to COVID-19. The crude incidence rate ratio (IRR) of SARS-CoV-2 infection was 1.40 (95%CI: 1.37-1.42) comparing IC patients to healthy controls. The crude mortality rate ratio was 4.75 (95%CI: 4.28-5.27). With respect to SARS-CoV-2 infection, interestingly, the BNT162b2 vaccine was more effective in IC patients compared to controls. Primary vaccine effectiveness (VE) was higher in IC patients compared to controls and the booster restored VE after waning. VE regarding COVID-19 related death was less in IC patients compared to healthy individuals. Booster vaccination increased VE against COVID-19-related death in both IC patients and healthy controls. Conclusion: There is increased risk of SARS-CoV-2 infection and COVID-19 related mortality in IC patient. Moreover, booster vaccination using BNT162b2 might restore impaired VE in these individuals.

Evaluation of the Efficacy of BBIBP-CorV Inactivated Vaccine Combined with BNT62b2 mRNA Booster Vaccine.

OBJECTIVES: In this prospective study, SARS-CoV-2 spike protein specific total immunoglobulin (Ig) levels were analyzed before and after BNT162 b2 mRNA booster vaccination in individuals previously administered with two doses of BBIBP-CorV vaccine in comparison to immunized participants with three doses of BNT162 b2 vaccination. METHODS: Sixty-one Caucasian volunteers (39 females, 22 males) vaccinated by BBIBP-CorV were included (mean age: 63.9 years). Sixty-one patients (41 females, 20 males) as controls were vaccinated with BNT162b2 (mean age: 59.9 years). Both groups received the third booster BNT162b2 vaccine. Total anti-SARS-CoV-2 S1-RBD Ig levels were measured by an immunoassay (Roche Diagnostics) and their calculated ratios after/before booster dose were compared between the two groups. RESULTS: At baseline, significantly lower anti-SARS-CoV-2 S1-RBD total antibody levels were determined after initial immunization by two doses of inactivated BBIBP-CorV compared to BNT62b2 mRNA vaccine (p < 0.001). After BNT162b2 boosters, similarly high total Ig levels were detected in both the heterologous (27,195 [15,604-42,754] BAU/mL, p < 0.001) and the homologous booster cohort (24,492 [13,779-42,671] BAU/mL, p < 0.001) compared to baseline. Hence, the ratio of after/before total Ig levels was significantly higher with heterologous vs homologous immunization (p < 0.001). CONCLUSION: To address the concept that basic BBIBP-CorV vaccination is not as effective as BNT162b, we analyzed the effect of heterologous vaccination with BNT162b2. Our results suggest that BNT162b2 can successfully boost the effects of two-dose BBIBP-CorV vaccination.

Adaptive Immunity to Viruses: What Did We Learn from SARS-CoV-2 Infection?

The SARS-CoV-2 virus causes various conditions, from asymptomatic infection to the fatal coronavirus disease 2019 (COVID-19). An intact immune system can overcome SARS-CoV-2 and other viral infections. Defective natural, mainly interferon I- and III-dependent, responses may lead to the spread of the virus to multiple organs. Adaptive B- and T-cell responses, including memory, highly influence the severity and outcome of COVID-19. With respect to B-cell immunity, germinal centre formation is delayed or even absent in the most severe cases. Extrafollicular low-affinity anti-SARS-CoV-2 antibody production will occur instead of specific, high-affinity antibodies. Helper and CD8+ cytotoxic T-cells become hyperactivated and then exhausted, leading to ineffective viral clearance from the body. The dysregulation of neutrophils and monocytes/macrophages, as well as lymphocyte hyperreactivity, might lead to the robust production of inflammatory mediators, also known as cytokine storm. Eventually, the disruption of this complex network of immune cells and mediators leads to severe, sometimes fatal COVID-19 or another viral disease.

COVID-19: autoimmunity, multisystemic inflammation and autoimmune rheumatic patients.

Coronavirus disease 2019 (COVID-19) is associated with autoimmunity and systemic inflammation. Patients with autoimmune rheumatic and musculoskeletal disease (RMD) may be at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, based on evidence from the literature, as well as international scientific recommendations, we review the relationships between COVID-19, autoimmunity and patients with autoimmune RMDs, as well as the basics of a multisystemic inflammatory syndrome associated with COVID-19. We discuss the repurposing of pharmaceutics used to treat RMDs, the principles for the treatment of patients with autoimmune RMDs during the pandemic and the main aspects of vaccination against SARS-CoV-2 in autoimmune RMD patients.

Antiviral and anti-inflammatory therapies in COVID-19 / Antivirális és gyulladásellenes kezelési lehetoségek COVID-19-ben.

Összefoglaló. Az új típusú koronavírus-fertozés (COVID-19) nagy terhet ró az egészségügyi ellátórendszerre és a társadalomra. A betegségnek három nagy szakasza van, melyek alapvetoen meghatározzák a kezelést. Az I-IIA fázisban az antivirális, míg a IIB-III. fázisban a gyulladásgátló kezelés áll elotérben, melyhez intenzív terápiás, szupportív kezelés csatlakozik. A jelen ajánlás kizárólag a gyógyszeres kezelésre vonatkozik, és a rendelkezésre álló bizonyítékok alapján foglalja össze a terápiás lehetoségeket. Emellett egy javasolt kezelési algoritmust is tartalmaz. Orv Hetil. 2021; 162(17): 643-651. Summary. The novel coronavirus infection (COVID-19) places a heavy burden on the health care system and our society. There are three major stages in the disease that fundamentally determine treatment approaches. Phases I-IIA require primarily antiviral treatment. In phases IIB-III, anti-inflammatory treatment is needed accompanied by intensive and supportive care. This recommendation applies only to pharmacotherapy and summarizes the therapeutic options based on the available evidence. It also includes a proposed treatment algorithm. Orv Hetil. 2021; 162(17): 643-651.

Reconsidering the technical aspects and quality management background of faecal microbiota transplantation due to the novel coronavirus pandemic / A székletmikrobiota-transzplantáció technológiájának és minoségirányítási hátterének újragondolása a SARS-CoV-2 víruspandémia kapcsán.

Összefoglaló. A székletmikrobiota-transzplantáció (faecalismikrobiota-transzplantáció - FMT) a Clostridioides difficile fertozés (CDI) kezelésében nemzetközileg széles körben elfogadott, megfelelo szakmai háttér mellett végezve biztonságos, potenciálisan életmento, költséghatékony, valamint a hospitalizációs ido és az orvos-beteg találkozások jelentos redukálására képes eljárás. Az FMT elvégzésére egyes országokban magas szintu minoségirányítási háttérrel muködo, célfeladatra szervezodött donor- és székletbankok rendezkedtek be. Máshol, így például hazánkban, az eljáráshoz az egyértelmu jogi szabályozási környezet, a standardizált technológiai háttér és a finanszírozás hiánya miatt nem egységes a hozzáférés. Régóta idoszeru továbbá, hogy a heterogén, nemegyszer háztartási eszközökkel elokészített beavatkozások helyett a nemzetközi és legújabban már a hazai ajánlásokban is megfogalmazott, a betegbiztonságot legjobban garantáló elvárások mellett történjen a széklettranszplantáció. Az új koronavírus (SARS-CoV-2) okozta pandémia megjelenése eroteljes szakmai érv országos szinten az FMT minoségirányítási környezetének és technológiai hátterének újragondolására, mert a SARS-CoV-2 egyszerre jelent kockázatot a CDI miatt kórházban kezelt sérülékeny betegpopulációnak, és egyben veszélyezteti az FMT biztonságosságát mind a recipiens, mind pedig az eljárást végzo egészségügyi személyzet tekintetében. Ezekre a szakmai és társadalmi kihívásokra reagálva, a széles köru beteghozzáférés és a legmagasabb szintu betegbiztonság garantálására, a Debreceni Egyetemen új eljárásrendet dolgoztunk ki az FMT végzésére. Ezen eljárásrendnek a COVID-19-pandémia miatt módosított, a fagyasztottgraftbank üzemeltetése és a rendszerszemlélet tekintetében releváns elemeit ismertetjük. Javasolt, hogy országos szinten hasonló, megfelelo minoségirányítási és technológiai környezettel, a SARS-CoV-2-fertozés kizárását is integráló donorszurési rendszerrel, továbbá fagyasztottgraft-banki háttérrel muködo laboratóriumok vegyenek részt a széklettranszplantációk végzésében. Felmerül továbbá, hogy az eljárást a számos analógia és a donor-recipiens koncepció alapján a sejt- és szövettranszplantációkra vonatkozó szabályozórendszer keretei közé ajánlott beágyazni. Orv Hetil. 2020; 161(44): 1858-1871. Summary. Stool transplantation (faecal microbiota transplantation - FMT) is a widely accepted, potentially life-saving, cost-effective medical intervention for the treatment of Clostridioides difficile infection (CDI), which has an acceptable safety profile if performed with an appropriate professional background. FMT can significantly reduce hospitalization time and the number of patient visits. National donor and stool banks with high-standard quality management systems were established in certain countries for supporting the procedures. In other regions, including Hungary, patient access is not uniform due to the lack of clear legal regulations, standardized technology or financial reimbursement. It has been expected for a long time to replace the heterogenous techniques, occasionally utilizing household equipment with a technology providing improved patient safety and fulfilling international and recently published local FMT guidelines. The emergence of the novel coronavirus (SARS-CoV-2) pandemic is a very powerful argument in favour of urgently reconsidering the quality management and technological background of FMT procedures. SARS-CoV-2 is a major threat to the vulnerable patients suffering from CDI and also impose risks for the recipient and healthcare personnel involved in carrying out the transplantation. New FMT guidelines were implemented at the University of Debrecen to address these professional and public challenges, to provide wide patient access and to guarantee the highest achievable patient safety. Relevant elements of this new protocol are presented, focusing on a systemic quality management approach, on the operation of a frozen stool bank and on a modified donor screening algorithm taking the risks of COVID-19 into consideration. We suggest that laboratories with proper quality assurance and technological conditions, implementing SARS-CoV-2 donor screening and operating a frozen graft bank should participate in faecal microbiota transplantations. It is also recommended that, based on the analogies and the similar donor-recipient concept, FMT should be embedded under the organ tissue and cell transplantation polices in Hungary. Orv Hetil. 2020; 161(44): 1858-1871.

Pneumococcal vaccination in autoimmune rheumatic diseases.

Streptococcus pneumoniae is the leading cause of the community-acquired pneumonia. The mortality rate of invasive pneumococcal infections is high. Immunocompromised patients suffering from autoimmune inflammatory rheumatic diseases (AIRD) have a high risk for acquiring these infections. Protection against infection can be improved with vaccination. After using polysaccharide vaccines (PPV-23), in July 2013, a 13-valent conjugate vaccine (PCV-13) was approved for adults. Due to its conjugate form, this vaccine is the recommended choice in pneumococcal vaccine-naive patients. PCV-13 is also recommended in patients previously receiving PPV-23. Vaccination in AIRD is very important and needs deliberate scheduling to coordinate with the immunosuppressive therapy. Here, based on international and national vaccine guidelines, we provide a current review of PPV-23 and PCV-13 vaccines for specialists following patients with AIRD.

Evaluation of the immunogenicity of the 13-valent conjugated pneumococcal vaccine in rheumatoid arthritis patients treated with etanercept.

OBJECTIVES: To prospectively evaluate the immunogenicity of a 13-valent conjugated pneumococcal vaccine (PCV13) in rheumatoid arthritis (RA) patients undergoing etanercept therapy. METHODS: Twenty-two RA patients treated with etanercept (ETA) in combination with methotrexate (MTX) (n=15) or monotherapy (n=7) for at least one year were included. Altogether 24 osteoarthritis patients not receiving biological or MTX therapy, treating only NSAIDs or analgesics served as controls. All subjects were vaccinated with a single dose (0.5ml) of the PCV13. Pneumococcal antibody levels at baseline, 4 and 8weeks were assessed by a VaccZyme™ Anti-PCP IgG Enzyme Immunoassay Kit. Based on recommendations of the American Academy of Allergy, Asthma & Immunology, an at least two-fold increase in antibody level, as the protective antibody response (pAR) was an indicator of responsiveness (i.e., ratio of postvaccination and prevaccination antibody levels). The antibody levels and their ratios were analysed in a variety of different ways, vaccine safety parameters (fever, infections, changes in regular antirheumatic treatments) were assessed at baseline, 4 and 8weeks after vaccination. RESULTS: Four weeks after vaccination, the anti-pneumococcal antibody levels significantly increased in both groups. At week 8, antibody levels somewhat decreased in both groups, however, still remained significantly higher compared to baseline. Compared with postvaccination levels at 4 and 8weeks between two groups, the mean protective antibody levels were higher in control group (1st month P=0.016; 2nd month: P=0.039). Possible predictors of pAR were analysed by logistic regression model. In RA, increases of antibody levels at week 8 compared to baseline exerted a negative correlation with age, (Spearman's R=-0,431; P=0.045). There were no clinically significant side effects or reaction after administration of vaccine observed in any of these patients after the 2-month follow-up period, all patients medical condition were stable. CONCLUSIONS: In RA patients treated with ETA, vaccination with PCV13 is effective and safe, resulting in pAR one and two months after vaccination. Higher age at vaccination was identified as predictors of impaired pAR. The efficacy of vaccination may be more pronounced in younger RA patients. The vaccine is safe in RA patients on ETA.

Association of ANCA-associated vasculitis-rheumatoid arthritis overlap syndrome in four patients: rituximab may be the right choice?

OBJECTIVES: There have been few reports on the association of rheumatoid arthritis (RA) with anti-neutrophil cytoplasmic antigen (ANCA)-associated systemic vasculitides. METHODS: Here we present four cases of RA overlapping with Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). All these cases had both the diagnosis of RA and that of ANCA-associated vasculitis. RESULTS: After we tried corticosteroids, multiple immunosuppressive drugs, sometimes plasmapheresis, rituximab was introduced to 3 out of 4 cases. Rituximab therapy was found to be effective in these three overlap cases. In the fourth case, rituximab was and will be considered; however, the patient has not given consent. CONCLUSION: To our knowledge, this is the first report on RA+CSS association. Common pathogenic background, such as genetic predisposition and ANCA may account for the development of RA+vasculitis overlaps. In DMARD-refractory cases, such as the ones presented here, biologics, especially rituximab may be highly effective.

Malignancy or inflammation? A case report of a young man with fever of unknown origin.

A case of a young man with fever of unknown origin is presented. This diagnosis can be frustrating for both patients and physicians because the diagnostic workup often involves numerous noninvasive and invasive procedures that sometimes fail to explain the fever. In the presented case some of the imaging diagnostic findings suggested malignant hematological disorder. However, histopathological and microbiological investigation proved vertebral osteomyelitis caused by Staphylococcus haemolyticus. Diagnosis was established by positron emission tomography, magnetic resonance imaging, and culture and histopathological analysis of a spinal biopsy. 3 months of antibiotic therapy was curative. Biopsy and microbiological investigation may be necessary in patients with fever, back pain and evidence of a spinal lesion on imaging, even if neoplastic disease is suspected.

[Management of Fabry disease]. / Fabry-betegség - terápiás útmutató

Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive and the first symptoms usually present in childhood. Consequences of the disease are disability and premature death. The disease in females could be as severe as in males although women may be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline has been summarized by a Hungarian multi-disciplinary working group consisting of physicians who are involved in diagnosis and care of Fabry patients. Previous clinical studies, published articles, and recently established international treatment guidelines were reviewed by the group.

[Fabry disease--diagnostic guideline]. / Fabry-betegség. Diagnosztikai útmutató.

Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive, first symptoms usually present in childhood. Consequencies of the diseases are disability and premature death. The disease in females could be as severe as in males although women may also be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline was established by a Hungarian multi-disciplinary working group, consisting of physicians who are involved in health care of Fabry patients. Previous clinical studies, published materials, and recently established international treatment guidelines were reviewed by the group.

Association of renal ectopia with Fabry's disease in 3 patients.

PURPOSE: Fabry's disease is a rare, inherited lysosomal storage disorder characterized by decreased activity of the lysosomal hydrolase alpha-galactosidase A and impaired degradation of globotriaosylceramide, which accumulates in the lysosomes of virtually every cell in the body. Kidney damage is a prominent feature of the disease but to our knowledge renal ectopia as a comorbidity has not been previously reported. We present clinical and genetic features in 2 female and 1 male patient with Fabry's disease and renal ectopia. MATERIALS AND METHODS: The diagnosis of Fabry's disease was made by measuring alpha-galactosidase A activity in blood leukocytes and by mutational analysis of the alpha-galactosidase A gene. The anatomical location of the kidneys was defined by native and single bolus 3-phase coronal computerized tomography angiography. To determine the possible genetic association of Fabry's disease and renal ectopia we performed a genetic analysis of informative, closely linked microsatellite markers surrounding the gene. RESULTS: All patients carried the c.469C>T mutation in the alpha-galactosidase A gene, causing premature stop codon (Glu157X). In all 3 patients downward dislocation of the right kidney (pelvic kidney) was found in association with double renal arteries. We noted that a haplotype telomeric to the alpha-galactosidase A gene cosegregated with renal ectopia in 3 family members, suggesting the existence of a gene for X-linked renal ectopia in the region of DXS1001-DXS1073. CONCLUSIONS: To our knowledge this is the first report of an association of renal ectopia with Fabry's disease.

Novel sequence variants of the alpha-galactosidase A gene in patients with Fabry disease.

We carried out molecular studies of 15 unrelated Hungarian families diagnosed with Fabry disease (FD). Genetic analysis of the alpha-galactosidase A gene was performed in 22 hemizygous males and 34 females. One of the female patients with severe disease phenotype showed homozygosity for the recurrent c.644A>G mutation due to parental consanguinity. The c.644A>G mutation that has previously been found mostly in patients with the cardiac variant of FD, was associated with renal but not cardiac involvement in this female and in two other family members. In nine families, eight novel sequence variants such as small deletions (c.363delT, c.477delT, c.746delAC) and single nucleotide changes (c.107T>C, c.493G>C, c.796G>T, c.866T>G, c.871G>A) were found in addition to six previously described private mutations. This report contributes to the identification of novel disease-causing mutations in FD, and increases our knowledge on demographics and molecular characteristics of this rare lysosomal storage disorder. This is the first comprehensive overview of molecular genetic features of Hungarian patients with FD.

Neuroendocrine carcinoma associated with X-linked hyper-immunoglobulin M syndrome: report of four cases and review of the literature.

X-linked hyper-immunoglobulin M syndrome (XHIGM) is a primary immunodeficiency disorder characterized by severe defects of both cellular and humoral immunity due to impaired expression of CD40 ligand on activated T lymphocytes. Patients with XHIGM usually present with a wide variety of infections caused by common and opportunistic pathogens including Pneumocystis jirovecii. In addition, subjects with XHIGM have an increased risk for hepatocellular and bile duct carcinomas, which are rarely observed in other primary immunodeficiencies. We present here clinical, immunological, and molecular findings of four patients with CD40 ligand deficiency associated with neuroendocrine carcinoma (NEC). NEC developed as a rapidly disseminated solid cancer leading to death in three patients. Data presented here and published previously suggest that CD40 ligand deficiency may predispose patients for the development of NEC. Histochemical findings suggested that CD56, in addition to cytokeratin and chromogranin A, may be a useful marker for early detection of NEC. We conclude that patients with XHIGM should be carefully followed to diagnose and treat NEC, a formidable neuroendocrine cancer.

Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups.

We performed clinical, immunological and genetic studies of 12 hyper-IgE syndrome (HIES) patients from 4 Hungarian, 2 Lebanese, one Russian, one Polish, and one Swedish families with autosomal dominant (AD) or sporadic forms of the disease to reveal cross-ethnicity of recurrent and novel mutations in the signal transducer and activator of transcription-3 gene (STAT3). Four patients from 3 Hungarian families, and one Russian, and one Swedish patient carried the heterozygous R382W germline mutation at the DNA-binding site of STAT3. The recurrent V637M mutation affecting the SRC homology 2 (SH2) domain was detected in one Lebanese and one Polish family, and the V463del deletion located in the DNA-binding domain was unveiled in another Lebanese family. A novel H332Y mutation affecting the DNA-binding site of STAT3 in three Hungarian patients from a Gypsy family was also found. The segregation of this mutation with HIES, restriction fragment length polymorphism analysis of STAT3 from patients and controls and the negligible production upon IL-6 stimulation of monocyte chemotactic protein-1 by the patient's blood mononuclear cells suggested that the H332Y mutation was disease-causing. These data suggest, that dominant negative mutations of the DNA-binding and SH2 domains of STAT3 cause AD and sporadic cases of HIES in different ethnic groups with R382W as the predominant mutation found in 5 of the 9 families. Functional and genetic data support that the novel H332Y mutation may result in the loss of function of STAT3 and leads to the HIES phenotype.

Hospital antibiotic management in Hungary--results of the ABS maturity survey of the ABS International group.

BACKGROUND: The prudent use of antibiotics is considered a very important issue in hospitals throughout Europe. The project ABS International developed a questionnaire to survey antibiotic-related structures and services in the hospitals of participating countries. This article describes the situation in Hungary. METHODS: Questionnaires were sent to all the hospitals in Hungary, which numbered 182 at the time of the survey. A total of 68 hospitals, accounting for 37.4% of all hospitals, returned the answered questionnaires. These 68 hospitals accounted for 52.4% of the hospital beds available in Hungary at the time of the survey. The answers were stratified according to the function and position of the hospitals and analyzed by calculating means, medians and standard deviations of various parameters. MAIN FINDINGS: The cumulative maturity figure for Hungary was 3.42+/-0.55. The lowest cumulative figures were found in chronic-care hospitals and the highest in the university hospitals. Significant differences were found in the availability of diagnostic services. The level of control of antibiotic consumption was similar between hospitals. The availability of bedside microbiological tests, such as legionella antigen detection, was rated as poor. Resources dedicated for antibiotic officers were very minor. CONCLUSION: Antibiotic stewardship cannot be conducted without appropriate resources (time, financing) provided by hospital management or the authorities. The technical background (microbiology, organizations, etc.) on which to build is already available in Hungarian hospitals.

[Molecular pathology and clinical manifestations of Fabry disease]. / A Fabry-kór molekuláris patológiája és klinikai megjelenési formái.

Fabry disease is a rare, progressive lysosomal storage disorder caused by mutation in the GAL gene and an impaired function of the alpha-galactosidase A enzyme. The enzymatic defect results in the progressive accumulation of glycosphingolipids in endothelial cells, smooth muscle cells, leucocytes and fibroblasts leading to organ damage in the skin, eye, nervous system, kidney and heart. Major clinical manifestations include acroparesthesis, angiokeratoma, corneal opacities, vascular diseases of the heart, kidney, and the central nervous system. Enzyme replacement therapy has recently become available for the treatment of Fabry patients. In this review the authors describe clinical features of Fabry disease in 31 Hungarian patients. At the time of this analysis the database consisted of 31 cases (15 males, 16 females) of whom 5 have died (4 males, 1 female). The most common disease-specific manifestation was angiokeratoma in males, and eye symptoms in females. 25% of female subjects were symptom free. Genotyping was performed in all cases and disease-causing mutations were found in all families. Three new mutations were identified. Twelve patients (8 males and 4 females) are currently receiving enzyme replacement therapy.

Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene.

OBJECTIVE: A 5-month-old male infant presenting with recurrent respiratory tract infections, chronic diarrhea, and failure to thrive was found to be pancytopenic. Bone marrow and x-ray examinations were consistent with Shwachman-Diamond syndrome (SDS). Genomic DNA sequencing, restriction fragment analysis, and studies of the mutant proteins were performed to gain further knowledge on the molecular pathology of SDS. MATERIALS AND METHODS: Exons 1 to 5 of the SBDS gene were amplified and sequenced. COS-7 cells were transfected with expression vectors containing wild-type cDNA or mutant cDNAs generated by site-directed mutagenesis. Protein expression of SBDS variants were examined by Western blotting. Pulse-chase assay and densitometry were used to study protein stability. RESULTS: Two novel missense mutations (c.362A > C in exon 3, and c.523C > T in exon 4) of the SBDS gene were identified in the patient. These mutations result in p.N121T and p.R175W amino acid replacements and correspond to amino acid residues that are highly conserved in SBDS proteins. In vitro expression studies revealed a markedly decreased half-life of the p.R175W protein, whereas stability of the p.N121T mutant was not significantly reduced compared to that of the wild type. CONCLUSION: This is the first report of compound heterozygous missense mutations occurring in patients with SDS. These mutations may not eliminate SBDS expression but may result in impaired protein stability and protein function leading to severe disease.

Characterization of a new disease-causing mutation of SH2D1A in a family with X-linked lymphoproliferative disease.

Males with an expressed mutation in the SH2D1A gene that encodes an SH2 domain protein named SH2D1A or SAP (NP_002342; signaling lymphocyte activating molecule [SLAM]-associated protein), have an X-linked syndrome characterized by an increased vulnerability to infection with Epstein-Barr virus (EBV). We evaluated two related male patients with fatal infectious mononucleosis (FIM) and mutation in the SH2D1A gene. Sequence analysis revealed a hemizygous c.47G>A mutation in one of the patients, and heterozygosity for this mutation in the genomic DNA from his mother and maternal grandmother. This mutation resulted in p.G16D amino acid change in the sequence of the SAP protein. To analyze the effect of this missense mutation on protein function cDNA was generated by site-directed mutagenesis and expressed in COS cells. We found that half-life of the p.G16D protein was comparable to that of wild type SAP. However, the mutant protein was defective in binding to its physiological ligands SLAM and 2B4. These results suggest that a defect in ligand binding contributes to the loss of function of the SAP protein in patients carrying p.G16D mutation.