Severe IgA Research Articles

Celiac Disease.

Celiac Disease.

Atypical presentation of IgA-related immediate reaction with back pain and relative hypotension – anaphylaxis or not?

Anaphylactic transfusion reactions are rare occurring in approximately 1 in 50,000 red cell transfusions.1 One aetiology includes the development of antibodies against transfused IgA in patients with severe IgA deficiency. Diagnosis of IgA-related anaphylaxis involves the measurement of IgA levels and anti-IgA antibodies.2 Recently, the evidence underlying this entity and the causal relationship between laboratory tests and clinical manifestation has been questioned.3 We describe a case of a 50-year-old man with chronic anaemia with an infected enterocutaneous fistula.

Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy.

Glomerular complement 3 (C3) deposition is often observed in renal biopsies of patients with IgA nephropathy (IgAN); however, the relationship between the intensity of C3 deposition and the long-term prognosis of IgAN has rarely been reported. In this retrospective study, we aimed to evaluate the prognostic value of glomerular C3 deposition for IgAN progression. From June 2009 to June 2010, a total of 136 adult patients with IgAN were enrolled in the study. According to the intensity of glomerular C3 deposition, patients were divided into a glomerular C3high group (34 patients) and a glomerular C3low group (102 patients). The levels of clinical parameters, glomerular immune complexes, histopathological features, and serum cytokines of the two groups were compared. On the basis of an average of 105months of follow-up, the predictive value of glomerular C3 deposition for IgAN progression was also investigated. Patients in the C3high group had more severe glomerular IgA, IgG, IgM, and complement factor H deposition, a higher percentage of mesangial hypercellularity (M1), and higher levels of segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T2), and crescents (C2) than those in the C3low group. Renal biopsies in the C3high group showed higher densities of interstitial inflammatory cells and higher levels of serum interferon-γ than those in the C3low group. Multivariate Cox regression analysis revealed that a higher intensity of glomerular C3 deposition remained as an independent predictor of serum creatinine doubling and end-stage renal disease. A high intensity of glomerular C3 deposition is associated with the severity of renal lesions, and predicts long-term poor renal survival for IgAN patients.

P0448CHARACTERISTICS OF PRIMARY GLOMERULAR DISEASE PATIENTS WITH HEMATURIA IN TURKEY: THE DATA FROM TSN-GOLD WORKING GROUP

Abstract Background and Aims Hematuria is one of the most common laboratory findings in nephrology practice. In different regions of the world, the etiologic causes differ. To date, there is no enough data regarding the clinical and histopathologic characteristics of primary glomerular diseases (PGD) patients with hematuria in our country. Method Data were obtained from national multicenter (47 centers) data entered into the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) database between May 2009 and June 2019. The data of all PGD patients over the age of 16 years who were diagnosed with renal biopsy and had hematuria data were included in the study. The biopsy samples were processed using a light microscopy and immunofluorescence examination. Demographic characteristics such as age, sex, indications for biopsy, primary glomerular diseases, comorbidities, laboratory and biopsy findings of all patients were also recorded. Hematuria was defined as the presence of at least 5 red blood cells/hpf. Results Data of 3394 patients were included to the study after the exclusion of patients with secondary glomerulonephritis and patients with missing biopsy findings. While 1699 (50.1%) patients had hematuria, 1695 (49.9%) patients did not have hematuria. Demographic, laboratory, and histopathological characteristics of patients with and without hematuria are given in Table. Patients with hematuria had statistically higher systolic blood pressure (SBP), serum blood urea nitrogen, creatinine, albumin, levels and urine pyuria, however, these patients had statistically lower age, body mass index, presence of hypertension and diabetes, eGFR, 24-hour proteinuria, serum total, HDL and LDL-cholesterol and C3 levels when compared with patients without hematuria. Figure depicted the etiologic causes of patients with and without hematuria. According to histopathological findings, number of global sclerotic glomeruli, cellular and fibrocellular crescents, the levels of mesangial proliferation, endocapillary proliferation, exudative changes in glomeruli, severe tubular atrophy, interstitial inflammation, subendothelial deposition, moderate and severe IgA and C3 deposition were found to be significantly higher and the levels of basal membrane thickening, interstitial fibrosis, subepithelial deposition, severe IgG staining were found to be significantly lower in patients with hematuria. Conclusion This is the first multicenter national report regarding the demographic and histopathologic data of PGD patients with or without hematuria. Hematuria, a feature of nephritic syndrome, was found at a higher than expected in the PGDs presenting with nephrotic syndrome in our national database.

P0134PROTEINURIA IS NOT ALWAYS ASSOCIATED WITH PROGNOSIS IN IGA NEPHROPATHY

Abstract Background and Aims To date the most widely well studied risk factor for progression to ESRD in patients with IgA nephropathy is proteinuria. Recent report suggests proteinuria reduction as a surrogate end point in trial of IgA nephropathy(2019,CJASN). Sensitivity of most biomarkers such as blood and urine gd-IgA1 level, IgG/IgA autoantibody, sCD89, sCD71, NGAL, KIM-1, Cystatin-C etc were compared with the amount of proteinuria. Most nephrologists do not performing kidney biopsy in patients without proteinuria or proteinuria less than than 500mg/day even though IgA nephropathy is suspected. However we recently experienced severe IgA nephropathy (HSD Lee, grade IV) in patients with normal urinalysis, and more than half the patients showed stationary or aggravated renal pathology at the follow up renal biopsy although urinalysis findings were normalized after methylprednisolone pulse therapy. Method In our center we performed 892 renal biopsies during last 6 years, we experienced 253 IgA nephropathy, of which 152 cases were done follow up renal biopsies to see the pathologic changes who showed normalized urinalysis findings after methylprednisolone pulse therapy. Results Of the 253 patients 241 patients showed initial abnormal urinalysis like hematuria and or proteinuria. However eleven patients showed normal urinalysis at the time of renal biopsy, of which 5 cases were diagnosed as essential hypertension and 6 cases were normal urinalysis associated with lowered GFR. Of the 152 follow up renal biopsies we evaluated 99 cases who showed normalized urinalysis findings after therapy, of which 65 cases(65.7%) showed stationary or aggravated renal pathology. Conclusion In conclusion further long term studies are needed, proteinuria could not be a surrogate marker for prognosis of the IgA nephropathy, Regardless of proteinuria if associated with hypertension and or lowered GFR, renal biopsy should be done. Follow up renal biopsy might be needed to confirm the healing of IgA nephropathy regardless of urinary findings to see the disappearance of IgA deposition, decreasing mesangial and endocapillary hypercellularity, disappearance of crescent formation, decreasing sclerosis, etc.

A106 TTC7A MUTATION AND CHRONIC PRURITUS, A CASE REPORT

Abstract Background TTC7A mutation is a rare autosomal recessive disease that can present with various phenotypes including multiple intestinal atresia (MIA), very early onset inflammatory bowel disease (VEOIBD), and profound combined immunodeficiency with hypoplastic thymus, altered T- and B-cell maturation, lymphopenia, monocytosis and agammaglobulinemia. Although TTC7A mutation mostly affects immune and gut function, it is a multisystemic disease. Chronic pruritus has not been described yet. Aims To describe the case of a child with TTC7A mutation with chronic pruritus and the potential treatment options. Methods Case report and review of literature Results We report a child with TTC7A mutation who developed severe chronic pruritus. The child presented ileal atresia and pyloric stenosis and underwent ileo-caecal resection and pyloroplasty at birth. She required a latero-lateral anastomosis between the stomach and the duodenum because of recurring pyloric stenosis and several dilatations of her ileo-colic anastomosis. She remained dependant on parenteral nutrition for most of her caloric needs. Her immune deficiency manifested with a very low lymphocyte count and low immunoglobulins. She had pneumocystis Carinii infection at 3 months of age and was put on gammaglobulin injections and pentamidine prophylaxis. At 3 years of age, she developed severe pruritus that led to skin infection and recurrent Staphylococcus Aureus sepsis. A skin biopsy revealed eczematous dermatitis with eosinophilic infiltration. Various treatments were attempted. Replacing lipid fat emulsion by fish oil emulsion in her parenteral nutrition did not improve her symptoms. Amitryptiline, gabapentine, hydroxyzine hydrochloride and levofloxacine also failed. Corticosteroids seemed to have a mild effect. A trial of Mepolizumab (anti-IL 5) was unsuccessful. At age of 4, after a sepsis treated by vancomycin, she presented with severe bullous skin disease. Skin biopsy was compatible with linear IgA bullous dermatosis. She was put on dupilumab and systemic corticosteroids. Dupilumab inhibits signaling of both IL-4 and IL-13, two cytokines involved in inflammation that contribute to atopic dermatitis. With this combination of IV steroids and dupilumab, pruritus has improved significantly. Conclusions Our patient’s evolution suggests that some TTC7A mutation can be complicated with severe pruritus and IgA linear bullosis. Skin disease, combined with immunodeficiency and the presence of a central line can lead to life threatening sepsis. Pruritus did not respond to usual treatments but improved the combination of intravenous steroids and dupilumab suggesting a role of IL-4 and IL-13 in the pathophysiology of the pruritus associated with this disease. Hematopoietic stem cell transplantation, may be an alternative solution. Funding Agencies None

Atypical presentation of iga-related immediate reaction with back pain and relative hypotension – Anaphylaxis or not?

Anaphylactic transfusion reactions are rare, occurring in approximately 1 in 50,000 red cell transfusions.1 One aetiology includes the development of antibodies against transfused IgA in patients with severe IgA deficiency. Diagnosis of IgA-related anaphylaxis involves the measurement of IgA levels and anti-IgA antibodies.2 Recently, the evidence underlying this entity and the causal relationship between laboratory tests and clinical manifestation has been questioned.3 We describe a case of a 50-year-old man with chronic anaemia with an infected enterocutaneous fistula. He received six red cell transfusions where he developed severe back pain and relative hypotension within 15–30 minutes of transfusion, settling after transfusion was ceased. He was afebrile with no respiratory, dermatological or gastrointestinal manifestations typical of anaphylaxis. Direct antiglobulin test was negative, and blood cultures were sterile. Tryptase taken 2.6 hours after symptom onset was raised 16 μg/L (0.0–11.4 μg/L). IgA level was <0.10 g/L (0.80–4.40g/L). Anti-IgA titre was 400 U/mL (0–7 U/mL). IgA deficient components were prepared pre-operatively. He subsequently received three washed red cells uneventfully, one during a laparotomy for the enterocutaneous fistula. This case describes an atypical presentation of a rare but important complication of blood transfusion, as well as the diagnostic process and subsequent management.

Vascularite à IgA (purpura rhumatoïde) l’adulte

IgA vasculitis is a systemic vasculitis affecting small vessels. IgA vasculitis usually affect children whereas it is rare in adults (150 to 200 for 1) in which the disease is often more serious with more frequent and severe nephritis. Prevalence of adult IgA vasculitis is unknown and its annual incidence is 1 in 1 million. The dominant clinical features include cutaneous purpura, arthritis and gastrointestinal symptoms. Sometimes nephritis can add, typically as glomerulonephritis with IgA mesangial deposits. Pulmonary, cardiac, genital and neurological symptoms have also been observed. Although the cause is unknown, it is clear that IgA plays a pivotal role in the immunopathogenesis of IgA vasculitis. Only symptomatic treatment is advised in case of self-limited disease. Treatment of severe IgA vasculitis, nephritis or gastrointestinal manifestations, is not established but some studies, which need to be confirmed, reported the benefit of corticosteroids combined with immunosuppressive drugs. Short-term outcome depends of the severity of the gastro-intestinal manifestations. The long-term prognosis is heavily dependent on the presence and severity of nephritis. Studies with prolonged follow-up show up to one third of adult patients reaching end stage renal failure, as for IgA nephropathy. Some authors even suggest that IgA nephropathy and IgA vasculitis would be the same disease.

A case of posterior reversible encephalopathy syndrome after plasma exchange for severe IgA vasculitis

A case of posterior reversible encephalopathy syndrome after plasma exchange for severe IgA vasculitis

Favorable Renal Outcome of Japanese Children with Severe IgA Nephropathy With Nephrotic Syndrome

Nephrotic syndrome is a rare but severe feature of IgA nephropathy. Nine Japanese children with severe IgA nephropathy with nephrotic syndrome. All received low-dose intravenous methylprednisolone (IVMP) within five weeks after the disease onset. Eight out of nine patients achieved resolution of proteinuria without severe adverse events. Early low-dose intravenous methylprednisolone may be safe and effective for children with severe IgA nephropathy with nephrotic syndrome.

Severe Drug-Induced Linear IgA Bullous Dermatosis: Not Everything is Steven Johnsons Syndrome

Severe Drug-Induced Linear IgA Bullous Dermatosis: Not Everything is Steven Johnsons Syndrome

A Unique Infusion Reaction to Vedolizumab: A Case of Henoch-Schonlein Purpura: 2017 ACG Case Reports Journal Award; 2017 Presidential Poster Award

Vedolizumab is a novel monoclonal antibody against integrin α4β7 that was recently approved to treat moderate to severe inflammatory bowel disease (IBD). Side effects are thought to be similar to other biologics used to treat IBD and include infections and acute infusion reactions. However, given its relatively recent approval, few case reports on unique side effects have been published. We present the case of a 53 year old man with a history of Crohn's disease (CD) diagnosed 16 years prior and on vedolizumab as well as oral steroids with good control of his symptoms. The patient underwent his 14th vedolizumab infusion without incident. However, he noted an itchy rash on the dorsum of his feet and ankles roughly 5 hours after the infusion was completed. The rash spread cranially up to his buttocks and he concurrently developed bilateral ankle and knee pain. In addition, he noted significant fatigue. Given this, he presented to the emergency room and was found to have a purpuric rash on his lower extremities. Labs revealed an erythrocyte sedimentation rate of 67 mm/hr and a creatinine of 1.34mg/dL (baseline creatinine of 1.1). A skin biopsy was done, showing moderately severe IgA associated leukocytoclastic vasculitis without neutrophilia, consistent with a diagnosis of Henoch-Schonlein Purpura (HSP). Vedolizumab is a relatively novel agent being used to treat moderate to severe IBD and few side effects have been reported in the literature. HSP is an acute IgA mediated vasculitis of the small vessels that commonly causes symptoms in the skin, kidneys, lungs and central nervous system. Hallmark symptoms of HSP include a purpuric rash on the lower extremities with abdominal pain, bloody diarrhea, joint pain (often in the ankles and knees), and renal failure. While HSP often starts after an upper respiratory infection in young children, it can also be triggered by drugs such as Vancomycin, ACE inhibitors and ranitidine, likely through a type-three hypersensitivity reaction. However, this is the first case in the literature of a case of HSP secondary to a vedolizumab infusion. Clinicians who prescribe vedolizumab should be aware of this as a possible reaction, especially if patients develop a lower extremity rash in the immediate post infusion period.

Risk factors of progressive IgA nephropathy which progress to end stage renal disease within ten years: a case\u2013control study

BackgroundThere were few related studies aiming to severe IgA nephropathy (IgAN) which could progress rapidly to end stage renal disease (ESRD) within ten years. To find valuable clinical or pathological factors and promising precautions is essential.MethodsA single center case–control study was performed. Fifty ESRD patients with the primary cause of IgAN and a short renal survival time of less than ten years after diagnose were enrolled in the case group. One hundred IgAN patients with a renal survival time of more than ten years were enrolled in the control group. IgA Oxford classification scores, clinical data at baseline and during the follow-up were collected. Multivariate logistic regression was used to investigate factors associated with the development of ESRD.ResultsThere were significant differences in baseline clinical data between these two groups, as well as the constituent ratio of Oxford MEST-score. Distinct differences were observed in time-average uric acid(TA-UA), time-average hemoglobin(TA-Hb), time-average albumin(TA-Alb), time-average total cholesterol(TA-TC) and time-average urinary protein(TA-P) during the follow-up. In multivariate logistic models, IgA Oxford score M1(OR = 5.10, P = 0.018) and eGFR(OR = 0.97, P = 0.039) at biopsy, TA-UA (OR = 2.06, P = 0.026) and TA-Hb (OR = 0.53, P = 0.022) during the follow-up were identified independent factors for developing ESRD.ConclusionIgAN patients with pathological assessment of M1, low baseline eGFR, TA-Hb and high TA-UA were more likely to progress to ESRD, and should be paid more attention. Appropriate regulations of UA, Hb and urine protein after diagnose may be a promising treatment.

Predictors of outcome for severe IgA Nephropathy in a multi-ethnic U.S. cohort.

Although IgA nephropathy (IgAN) is the leading cause of glomerulonephritis worldwide, there are few large cohorts representative of U.S. Prognosis remains challenging, particularly as more patients are treated with RAAS blockade and immunosuppression. We analyzed a retrospective cohort of IgAN patients followed at Columbia University Medical Center from 1980 to 2010. We evaluated two outcomes - halving of eGFR and ESRD - using three proportional hazards models: 1) a model with only clinical parameters, 2) a model with only histopathologic parameters, and 3) a model combining clinical and histopathologic parameters. Of 154 patients with biopsy-proven IgAN, 126 had follow-up data available and 93 had biopsy slides re-read. Median follow-up was 47 months. The cohort was 64% male, 60% white, and the average age was 34 years at diagnosis. Median (IQR) eGFR and proteinuria at diagnosis were 64.1 (38.0 - 88.7) mL/min/1.73 m2 and 2.7 (1.3 - 4.5) g/day. Over 90% of subjects were treated with RAAS blockade, and over 66% received immunosuppression. In the clinical parameters-only model, baseline eGFR and African-American race predicted both halving of eGFR and ESRD. In the histopathologic parameters-only model, no parameter significantly predicted outcome. In the combined model, baseline eGFR remained the strongest predictor of both halving of eGFR (p = 0.03) and ESRD (p = 0.001), while the presence of IgG by immunofluorescence microscopy also predicted progression to ESRD. In this diverse U.S. IgAN cohort in which the majority of patients received RAAS blockade and immunosuppression, baseline eGFR, African-American race, and co-staining of IgG predicted poor outcome.

UMOD polymorphism rs12917707 is not associated with severe or stable IgA nephropathy in a large Caucasian cohort.

BackgroundGenetic factors are suspected in the pathogenesis of IgA nephropathy, as well as in the course of IgA nephropathy progression towards end stage renal failure. UMOD polymorphism rs12917707 is known to associate with end stage renal failure of mixed aetiologies.MethodsWe tested a large cohort of Caucasian patients for association of rs12917707 with IgA nephropathy showing a benign, stable course and with IgA nephropathy that progressed toward end stage renal failure.ResultsNo association was observed between either groups, and a non-significant trend was observed for more severe IgA nephropathy with the allele reported to protect against end stage renal failure of mixed aetiologies.ConclusionWe conclude that UMOD is unlikely to play a role in IgA nephropathy pathogenesis nor progression to end stage renal failure, and suggest that UMOD effects are restricted to some causes of renal disease, e.g. diabetes or hypertension.

Successful renal transplant in a patient with non-Herlitz junctional epidermolysis bullosa

Non-Herlitz junctional epidermolysis bullosa (NH-JEB) is a very rare inherited disorder, with an array of complications. We present the case of a 33-year-old patient of Chinese origin, diagnosed with NH-JEB in childhood, who developed severe IgA nephropathy. His renal impairment was initially treated by haemodialysis. He underwent successful renal transplantation, resulting in normalization of his renal function. To our knowledge, this is the first report of renal transplantation in a patient with epidermolysis bullosa, which should support use of this intervention in other similar cases.

Treatment of severe IgA nephropathy: mycophenolate mofetil/prednisone compared to cyclophosphamide/prednisone

To compare the efficacy of mycophenolate mofetil (MMF)/prednisone to cyclophosphamide (CYC)/prednisone in the treatment of severe IgA nephropathy. Patients (n = 84) with severe IgA nephropathy received either MMF/prednisone (MMF group) or CYC/prednisone (CYC group). The MMF induction dose was 1.5 g/d for 6 months and the maintenance dose was 0.75 - 1.0 g/day for 12 months. The CYC induction dose was 0.8 - 1.0 g/month for 6 months and the maintenance dose was 0.8 - 1.0 g/3 months for 12 months. Laboratory tests, clinical remission rate and side effects were investigated. After 18 months of treatment, the total effective rate in the MMF group was significantly higher than that of the CYC group. Patients' 24-hour urinary protein excretion in the MMF group was lower than the CYC group. Patients' plasma albumin and total protein in the MMF group was higher than the CYC group. MMF and prednisone reduced serum lipids, while in the CYC group serum lipids remained unchanged. There was also a lower incidence of adverse effects in the MMF group (4.76%) than in the CYC group (26.2%). Combination therapy with MMF and prednisone for severe IgA nephropathy achieved a higher remission rate compared to treatment with CYC and prednisone. This therapy also reduced the 24-hour urinary protein and serum lipids while increasing plasma albumin and improving renal function. The incidence of adverse effects was significantly lower in the MMF group compared to the CYC group. *These authors have contributed equally to this work.

Isotype Matched Paired Immunoglobulin Suppression Identifies High Risk Multiple Myeloma Patients and Is Independent Of Bone Marrow Infiltration Suggesting Significant Variability In The HLC Matched Pair Suppressive Activity Of Individual Myeloma Clones

IntroductionMultiple myeloma (MM) is characterised by the production of monoclonal immunoglobulins (MIg), both intact and a free light chain (FLC) component. The production of MIg can be associated with suppression of the non-involved isotypes which can easily be measured by conventional techniques while identification of a possible suppression of the HLC matched pair isotype was not possible before the introduction of the HLC assay. Here we assess the frequency and biologic relevance of the suppression of HLC pair matched isotypes and non-involved isotypes and correlate these findings and those of MIg measurements with bone marrow plasma cell (BMPC) infiltration. Patients and Methods113 previously untreated MM patients (72 IgG (46κ, 26λ) and 41 IgA (23κ, 18λ)) with a median age of 65 years (range 32-86 years) were enrolled and followed for up to 13 years (median: 4 range 0.25-13 years). Serum FLC (FLCκ/FLCλ) and HLC concentrations (IgGκ/IgGλ and IgAκ/IgAλ) measurements were made using polyclonal antisera assays (FreeliteTM, Binding Site, Birmingham, UK. and, HevyliteTM, Binding Site, Birmingham, UK) and results compared to standard serum assessments (SPE, IFE, β2M, Albumin, LDH and CRP) and bone marrow plasma cell (BMPC) infiltration. Severe non-involved isotype or HLC pair suppression was defined as >50% lower of than the published lower normal ranges for the relevant isotypes. Correlation and survival analysis was performed using the SPSS v 21 programme. ResultsMedian overall survival was 46 months (range 3-158). IgA MIg production correlated weakly to BMPC infiltration at presentation (Pearsons 0.327; p=0.026) but to no other marker. Uninvolved IgA HLC did not correlate to BMPC infiltration but had a weak correlation to LDH (Pearsons 0.436; p=0.002). By contrast, IgG MIg production showed significant correlation to ß2M (Pearsons 0.53; p<0.001), with uninvolved IgG HLC having no significant correlations. There was a greater degree of monoclonal production in IgG patients than in IgA patients (p=0.049). Severe IgG and IgM suppression was noted in 13/41 (31%) of IgA patients with 78% of patients having either isotype suppressed. In IgA MM patients IgM suppression was more commonly identified than IgG (32/41 v 13/41 patients respectively) and IgG suppression was always concomitant with IgM suppression. Severe IgA and IgM suppression was noted in 36/72 (50%) of IgG patients with 69% of patients having either isotype suppressed. In contrast to IgA patients there was no difference between the incidence of IgA or IgM suppression. Severe isotype matched pair suppression was more frequently noted in IgG compared to IgA patients (66% vs. 60%, p<0.01). Severe HLC pair suppression correlated with a decreased OS (46.6 vs. 84.4 months, p<0.044). By contrast neither non-involved isotype nor monoclonal Ig production was correlated with outcome. Discussion and ConclusionThe correlation between IgG MIg and BMPC infiltration indicates a greater uniformity in the inter-individual MIg production rate in patients with IgG compared to those with IgA MIg, which were only weakly correlated with BMPC infiltration. Part of this finding may also be due to greater variations in the catabolic rate of individual IgG MIgs. The absence of a correlation between the degree of HLC pair suppression and BMPC infiltration suggests significant variation in the ability of individual clones in suppressing the isotope matched pair. This uncoupling between the proportion of myeloma cells and isotype suppression was previously unknown. Myeloma clones with greater HLC matched isotype pair suppression reflect a more aggressive phenotype which correlates with short survival. Suppression of the non-involved isotype, in contradistinction, showed no prognostic relevance. Disclosures:Young:The Binding Site Group Ltd: Employment. Harding:The Binding Site Group Ltd: Employment.

Variant Ataxia Telangiectasia: Clinical and Molecular Findings and Evaluation of Radiosensitive Phenotypes in a Patient and Relatives

Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.

片側低形成腎に重症IgA腎症を合併した1症例

症例は11歳男児。生後から右腎低形成を指摘されていたが，11歳時，感冒を契機に肉眼的血尿が出現した後，蛋白尿，血尿が3か月間持続した。膀胱鏡で左右尿管から採尿し同程度の血尿，蛋白尿を認めたため両腎に同様の腎疾患が存在すると推定した。左健側腎を開放腎生検しIgA腎症重症例と診断した。ステロイドパルス療法後，多剤併用療法を行い3か月後に蛋白尿は消失した。残存ネフロン数が減少した先天性腎疾患に後天性腎炎が合併すると急速に末期腎不全へ進行することがある。自験例はステロイドパルス療法など強力な治療によって腎機能を保持することができた。また，片側低形成腎では長期的に対側腎が過濾過になり糸球体硬化が進行し蛋白尿などの尿異常を呈することがある。そのため後天性腎疾患の合併がないか判断に苦慮することがある。片側低形成腎の腎生検の適応を決めるにあたり左右尿管からの採尿は有用であると考えた。