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Judy Savige

Publications and source records attributed to Judy Savige.

At least 19 recordsLinked to original sources
PubMed2007

Do mutations in COL4A1 or COL4A2 cause thin basement membrane nephropathy (TBMN)?

Thin basement membrane nephropathy (TBMN) is the commonest cause of persistent glomerular haematuria and often presents in childhood. Only 40% of affected individuals have mutations identified in the COL4A3 and COL4A4 genes, but mutations in the genes for other COL4A isoforms also result in thinned membranes in humans (COL4A5) and mice (COL4A1). This study examined whether COL4A1/COL4A2 represented a further genetic locus for TBMN. Nine families with TBMN in whom haematuria did not segregate with COL4A3/COL4A4, were examined for linkage to COL4A1/COL4A2 using five micro-satellite markers. In addition, index cases from these families plus a further 14 unrelated individuals with TBMN that was not due to COL4A3 or COL4A4 mutations (n=23) were screened for mutations in each of the 52 exons of COL4A1 and the 47 exons of COL4A2 using single stranded conformational analysis (SSCA). DNA samples that demonstrated bandshifts were sequenced. Haplotype analysis demonstrated that haematuria segregated with the COL4A1/COL4A2 locus in only two small families (2/9, 22%). No definite COL4A1 or COL4A2 mutations were identified in the 23 unrelated individuals with TBMN although novel polymorphisms were demonstrated. This study indicates that COL4A1/COL4A2 does not represent a further major genetic locus for TBMN.

Child↗
PubMed2007

Nine novel COL4A3 and COL4A4 mutations and polymorphisms identified in inherited membrane diseases.

Both thin basement membrane nephropathy (TBMN) and autosomal recessive Alport syndrome result from mutations in the COL4A3 and COL4A4 genes, and this study documents further mutations and polymorphisms in these genes. Thirteen unrelated children with TBMN and five individuals with autosomal recessive Alport syndrome were examined for mutations in the 52 exons of COL4A3 and the 47 coding exons of COL4A4 using single-stranded conformation polymorphism (SSCP) analysis. Amplicons producing different electrophoretic patterns were sequenced, and mutations were defined as variants that changed an amino acid but were not present in 50 non-hematuric normals. Three further novel mutations were identified. These were IVS 22-5 T>A in the COL4A3 gene in a consanguineous family with autosomal recessive Alport syndrome, and R1677C and R1682Q in the COL4A4 gene. In addition, six novel polymorphisms (G455G, I462I, G736G and IVS 38-8 G>A in COL4A3, and L658L and A1577A in COL4A4) were demonstrated.Many different COL4A3 and COL4A4 mutations cause TBMN and autosomal recessive Alport syndrome. The identification of polymorphisms in these genes is particularly important to enable diagnostic laboratories to distinguish mutations from uncommon normal variants.

Adolescent↗
PubMed2006

Characterization of the peripheral retinopathy in X-linked and autosomal recessive Alport syndrome.

BACKGROUND: Alport syndrome is an inherited disease resulting in kidney failure, hearing loss and ocular abnormalities. Alport syndrome is however often unrecognized, and the aim of this study was to characterize the associated but rarely described peripheral retinopathy and determine whether its demonstration was diagnostically helpful. METHODS: Index cases were diagnosed with Alport syndrome on renal biopsy in themselves or a family member. Inheritance and affected status were determined using microsatellite markers at the COL4A5 and COL4A3/COL4A4 loci, respectively. Participants' eyes were dilated, and examined with direct and indirect ophthalmoscopy, and slit lamp biomicroscopy by an expert ophthalmologist who was unaware of the patients' disease status. RESULTS: Ten males and nine females with X-linked Alport syndrome and seven with autosomal recessive disease were studied. Of the 26 patients, 16 had central retinopathy (62%), and 19 patients had peripheral retinopathy (74%). The peripheral changes occurred in both males and females with X-linked and autosomal recessive Alport syndrome, and were more common when renal failure, hearing loss, lenticonus and the central changes were present, but were also noted in 3 X-linked carriers with normal renal function. CONCLUSIONS: The peripheral retinopathy occurs in X-linked and autosomal recessive Alport syndrome even when the central retinopathy is absent. Careful retinal examination and photography that includes the periphery is a safe and inexpensive method that may help in the diagnosis of Alport syndrome especially in carriers of X-linked disease.

Adolescent↗
PubMed2005

Persistent familial hematuria in children and the locus for thin basement membrane nephropathy.

This study examined how often children with persistent familial hematuria were from families where hematuria segregated with the known genetic locus for the condition known as benign familial hematuria or thin basement membrane nephropathy (TBMN) at COL4A3/COL4A4. Twenty-one unrelated children with persistent familial hematuria as well as their families were studied for segregation of hematuria with haplotypes at the COL4A3/COL4A4 locus for benign familial hematuria and at the COL4A5 locus for X-linked Alport syndrome. Eight families (38%) had hematuria that segregated with COL4A3/COL4A4, and four (19%) had hematuria that segregated with COL4A5. At most, eight of the other nine families could be explained by disease at the COL4A3/COL4A4 locus if de novo mutations, non-penetrant hematuria or coincidental hematuria in unaffected family members was present individually or in combination. This study confirms that persistent familial hematuria is not always linked to COL4A3/COL4A4 (or COL4A5) and suggests the possibility of a further genetic locus for benign familial hematuria. This study also highlights the risk of excluding X-linked Alport syndrome on the basis of the absence of a family history or of kidney failure.

Adolescent↗
PubMed2005

What do antineutrophil cytoplasmic antibodies (ANCA) tell us?

Antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against antigens found in the cytoplasmic granules of neutrophils and monocytes. ANCA testing is usually performed to help diagnose or exclude Wegener's granulomatosis and microscopic polyangiitis. The three most commonly used assays are indirect immunofluorescence (IIF) and the direct and 'capture' enzyme-linked immunosorbent assays (ELISAs) for ANCA directed against proteinase 3 (PR3) and myeloperoxidase (MPO). Although the International Consensus Statement for Testing and Reporting ANCA recommends that all sera are screened for ANCA by IIF and that IIF-positivity is confirmed by direct ELISAs, some laboratories test by direct ELISA alone, others screen with direct ELISA and confirm positive sera by IIF, and a few use capture ELISAs. This chapter discusses the various forms of vasculitis associated with ANCA, the usefulness of each of the ANCA assays and how ANCA testing can be used in the management of patients with small-vessel vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2005

The epidemiology of thin basement membrane nephropathy.

The prevalence of this basement membrane nephropathy (TBMN) may be approximated from the known frequencies of glomerular hematuria in the population, and from the prevalence of autosomal-recessive Alport syndrome and its known relationship to TBMN. These approaches confirm that TBMN affects more than 1% (but < 10%) of the population, making it the commonest inherited renal disease, and one of the commonest conditions affecting the kidney after infections, hypertension, and stones. TBMN is the most frequent cause of persistent glomerular hematuria. Although we do not advocate mass screening for hematuria to detect TBMN, we strongly support investigating hematuria that is discovered incidentally. Individuals with TBMN and isolated hematuria should be evaluated initially by a nephrologist and subsequently reviewed by their family doctor. Those with proteinuria, hypertension, or renal impairment are at risk for progressive renal impairment and should by examined carefully for features of Alport syndrome or an additional glomerular or tubulointerstitial lesion, undergo a renal biopsy examination, be treated symptomatically, and be monitored by a renal physician.

China↗
PubMed2005

Hematuria in thin basement membrane nephropathy.

Thin basement membrane nephropathy (TBMN) often is diagnosed clinically when there is persistent dysmorphic or glomerular hematuria, but minimal proteinuria, normal kidney function, and no other obvious cause. This study investigated hematuria in patients with TBMN. A total of 112 patients with biopsy examination-proven TBMN were studied. All had hematuria at the time of presentation, with a mean urinary red blood cell (RBC) count of 256 +/- 250 x 10 3 /mL. Seventy-five (67%) patients attended for review over a median of 48 months (range, 3-120 mo) and provided a total of 485 urine specimens. Twenty-one patients (28%) had no hematuria by phase-contrast microscopy on at least 1 occasion. These corresponded to 32 urine specimens (7% of total). Of the 21 patients, the most recent urinary RBC counts were within the normal range in 11 (52%), but hematuria had recurred in the other 10 (48%). Hematuria is persistent in most patients with TBMN, but occasionally it resolves or is intermittent.

Diagnosis, Differential↗
PubMed2005

The genetics of thin basement membrane nephropathy.

The diagnosis of thin basement membrane nephropathy (TBMN) usually is made on the basis of the clinical features or the glomerular membrane ultrastructural appearance. Only now are we beginning to understand the genetics of TBMN and the role of diagnostic genetic testing. The similarity of clinical and glomerular membrane features first suggested TBMN might represent the carrier state for autosomal-recessive Alport syndrome. This was confirmed subsequently by the demonstration that 40% of families with TBMN have hematuria that segregates with the corresponding locus ( COL4A3/COL4A4 ), and identical mutations occur in both conditions. To date, about 20 COL4A3 and COL4A4 mutations have been shown in TBMN, and these mainly are single nucleotide substitutions that are different in each family. The families in whom hematuria does not appear to segregate with the COL4A3/COL4A4 locus cannot all be explained by de novo mutations, and nonpenetrant or coincidental hematuria. This suggests a further TBMN locus. In patients with persistent hematuria, testing for COL4A3 and COL4A4 mutations to diagnose TBMN is problematic because of the huge size of these genes, their frequent polymorphisms, and the likelihood of a further gene locus. It is far more practicable to perform genetic testing to exclude or confirm X-linked Alport syndrome because this condition is the major differential diagnosis of TBMN and has a very different prognosis.

Autoantigens↗
PubMed2005

The risks of thin basement membrane nephropathy.

Most individuals with thin basement membrane nephropathy (TBMN) have an excellent prognosis. For these patients, the only hazards are the anxiety related to misconceptions about the diagnosis and the inconvenience, expense, and wastefulness of unnecessary investigations. However, there also are specific genetic implications for individuals with TBMN because, on average, half their offspring inherit the causative mutations and most of these have hematuria. In addition, despite the generally excellent outcome, some individuals with TBMN develop hypertension, proteinuria, or renal impairment. In some cases, renal failure is caused by apparently progressive but otherwise uncomplicated TBMN, and in others it results from a secondary or coincidental glomerular or tubulointerstitial renal lesion. In particular, TBMN appears to predispose to immunoglobulin (Ig)A glomerulonephritis, and the outcome for these patients is worse than for those with TBMN alone. The risks for patients with TBMN in relation to pregnancy and transplantation have not been well-studied but are described elsewhere in this issue.

Diagnostic Errors↗
PubMed2004

COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN).

BACKGROUND: Thin basement membrane nephropathy (TBMN) is often caused by mutations in the COL4A3 and COL4A4 genes. METHODS: We examined 62 unrelated individuals diagnosed with TBMN by renal biopsy (N= 49, 79%) or a positive family history of hematuria but without a biopsy (N= 13, 21%) for mutations in the COL4A3 gene and the COL4A3/COL4A4 promoter. All 52 exons of COL4A3 as well as the COL4A3/COL4A4 promoter were screened with single-stranded conformational polymorphism (SSCP) analysis at 4 degrees C and at room temperature. Amplicons that demonstrated electrophoretic abnormalities were sequenced. RESULTS: Seven mutations were demonstrated in seven patients: G532C and G584C in exon 25, G596R in exon 26, G695R in exon 28, and IVS 2224 - 11C>T, IVS 2980 + 1G>A and IVS 3518 - 7C>G. No mutations were found in the COL4A3/COL4A4 promoter. Four novel polymorphisms or variants (P116T in exon 6, P690P in exon 27, and G895G and A899A in exon 33) were also demonstrated. In addition, P1109S and Q1495R, which had been described previously but whose status was unclear, were shown to be polymorphisms. All seven mutations described here were associated with hematuria. While one mutation (2980 + 1G>A) was found in an individual who also had proteinuria, none of her family members with the same mutation had increased urinary protein. None of the patients with these seven mutations had renal impairment. Hematuria was completely penetrant in families with the G532C, G584C, G596R, and IVS 2980 + 1G>A mutations but not with the G695R and IVS 3518 - 7C>G mutations. CONCLUSION: COL4A3 mutations are common in TBMN.

Autoantigens↗
PubMed2003

Clinical, histopathologic, and genetic studies in nine families with focal segmental glomerulosclerosis.

BACKGROUND: Familial forms of focal segmental glomerulosclerosis (FSGS) are caused by mutations in genes at 1q25-31 (gene for steroid-resistant nephrotic syndrome 2 [NPHS2]), 11q21-22, 19q13 (gene for alpha-actinin 4 and NPHS1), and at additional unidentified chromosomal loci. METHODS: We describe clinical and histopathologic features and results of linkage analysis in nine consecutive index cases with familial FSGS who, together with their families, were referred for genetic studies. RESULTS: Two of the index cases presented in childhood (22%) and seven cases presented in adolescence or adulthood (78%). Six of their families (67%), including the two cases with childhood-onset disease, showed probable autosomal recessive inheritance. FSGS segregated at the 1q25-31 locus in two of these families and at the 11q21-22 locus in four families. None had disease caused by mutations in genes at the 19q13 locus, and no locus was identified in the three remaining families. Clinical features of proteinuria, minimal hematuria, hypertension, preeclampsia, and progressive renal impairment were usually present with autosomal recessive or dominant inheritance and with disease that segregated at the different loci. Eighteen renal biopsies from affected members of eight families showed a strong correlation between tubulointerstitial damage and percentage of obsolescent glomeruli (rho = +0.76; P < 0.01). None of the 13 patients from eight families who underwent transplantation developed recurrent FSGS in their grafts. In general, carriers of autosomal recessive disease had no distinctive clinical features apart from the development of preeclampsia in successive pregnancies. CONCLUSION: Familial forms of FSGS are not uncommon, and presentation frequently is in adolescence or adulthood, even when inheritance is autosomal recessive. Furthermore, carriers of autosomal recessive FSGS often have no distinctive phenotype.

Adolescent↗
PubMed2003

Visual impairment caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis type II ("dense deposit disease").

Patients with mesangiocapillary glomerulonephritis (MCGN) type II usually present by early adulthood with hematuria, proteinuria, and renal impairment, and these features often are accompanied by a partial lipodystrophy and an autoantibody for the alternative complement pathway convertase (C3NeF). The diagnosis of MCGN type II depends on the demonstration of "dense deposits" in the glomerular basement membrane (GBM). Most patients also have multiple subretinal white spots or drusen that are histopathologically identical with the GBM deposits and evident ophthalmoscopically by the time renal failure develops. Initially visual acuity and visual fields are preserved, but fluorescein angiography and specialized tests of retinal function, such as dark adaptation, electroretinography, and electrooculography, may be abnormal and will worsen progressively. Over the next 20 years, vision often deteriorates because of retinal atrophy, and sometimes because of subretinal neovascular membranes, macular detachment, and central serous retinopathy. The authors describe a patient with MCGN type II who presented with renal failure and impaired vision at the age of 59. He already had widespread retinal atrophy, and subsequently a subretinal membrane developed. The drusen seen in MCGN type II, like the partial lipodystrophy, are a helpful clinical pointer to the diagnosis of this condition. All patients with MCGN type II should be warned of the risk of retinal complications and reviewed by an ophthalmologist at presentation and regularly after about 10 years to minimize the loss of visual acuity from complications of the retinopathy.

Atrophy↗
PubMed2003

Thin basement membrane nephropathy.

Thin basement membrane nephropathy. Thin basement membrane nephropathy (TBMN) is the most common cause of persistent glomerular bleeding in children and adults, and occurs in at least 1% of the population. Most affected individuals have, in addition to the hematuria, minimal proteinuria, normal renal function, a uniformly thinned glomerular basement membrane (GBM) and a family history of hematuria. Their clinical course is usually benign. However, some adults with TBMN have proteinuria >500 mg/day or renal impairment. This is more likely in hospital-based series of biopsied patients than in the uninvestigated, but affected, family members. The cause of renal impairment in TBMN is usually not known, but may be due to secondary focal segmental glomerulosclerosis (FSGS) or immunoglobulin A (IgA) glomerulonephritis, to misdiagnosed IgA disease or X-linked Alport syndrome, or because of coincidental disease. About 40% families with TBMN have hematuria that segregates with the COL4A3/COL4A4 locus, and many COL4A3 and COL4A4 mutations have now been described. These genes are also affected in autosomal-recessive Alport syndrome, and at least some cases of TBMN represent the carrier state for this condition. Families with TBMN in whom hematuria does not segregate with the COL4A3/COL4A4 locus can be explained by de novo mutations, incomplete penetrance of hematuria, coincidental hematuria in family members without COL4A3 or COL4A4 mutations, and by a novel gene locus for TBMN. A renal biopsy is warranted in TBMN only if there are atypical features, or if IgA disease or X-linked Alport syndrome cannot be excluded clinically. In IgA disease, there is usually no family history of hematuria. X-linked Alport syndrome is much less common than TBMN and can often be identified in family members by its typical clinical features (including retinopathy), a lamellated GBM without the collagen alpha3(IV), alpha4(IV), and alpha5(IV) chains, and by gene linkage studies or the demonstration of a COL4A5 mutation. Technical difficulties in the demonstration and interpretation of COL4A3 and COL4A4 mutations mean that mutation detection is not used routinely in the diagnosis of TBMN.

Basement Membrane↗
PubMed2003

Mutations in the COL4A4 gene in thin basement membrane disease.

BACKGROUND: Patients with thin basement membrane disease (TBMD) are often from families where hematuria segregates with the COL4A3 and COL4A4 genes. These genes also are affected in autosomal recessive Alport syndrome. The aim of this study was to demonstrate COL4A4 mutations in TBMD. METHODS: Forty-eight unrelated individuals with TBMD who had no family members with autosomal recessive Alport syndrome were examined for COL4A4 mutations. The diagnosis of TBMD had been confirmed by renal biopsy (43/48, 90%) or by a family history of hematuria but without a renal biopsy (5/48, 10%). The 47 coding exons of COL4A4 were screened for mutations with the methods of enzyme mismatch cleavage or single stranded conformational polymorphism (SSCP) analysis, and exons that demonstrated electrophoretic abnormalities were sequenced. RESULTS: Nine variants that altered the coding sequences were identified. These were nonsense and frameshift mutations that resulted in stop codons (N = 3), and glycine (N = 3) and non-glycine missense variants (N = 3). Four intronic variants and three neutral polymorphisms were also detected. In total, four variants were considered 'pathogenic' principally because they resulted in stop codons or were not present in non-hematuric normal subjects. Three variants were considered 'possibly pathogenic' but two of these were each present in one of 46 non-hematuric normal subjects. CONCLUSIONS: Pathogenic COL4A4 mutations were demonstrated in three of the nine (33%) families in whom hematuria segregated with the COL4A3/COL4A4 locus. Two stop codons (R1377X and 2788/91delG) and a glycine substitution (G960R) resulted in hematuria in all 16 members who were tested from these three families. The S969X mutation described here in TBMD for the first time, as well as the R1377X mutation, also occur in autosomal recessive Alport syndrome.

Adolescent↗
PubMed2003

Addendum to the International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies. Quality control guidelines, comments, and recommendations for testing in other autoimmune diseases.

Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in Wegener granulomatosis, microscopic polyangiitis and its renal-limited variant (pauci-immune crescentic glomerulonephritis), and Churg-Strauss syndrome. The International Consensus Statement on testing and reporting of ANCA states that ANCA are demonstrated most readily in these conditions by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 or myeloperoxidase. The group that produced the International Consensus Statement has developed guidelines for the corresponding quality control activities, examples of comments for various IIF patterns and ELISA results, and recommendations for ANCA testing when inflammatory bowel disease and other nonvasculitic ANCA-associated autoimmune diseases are suspected.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2002

Three novel COL4A4 mutations resulting in stop codons and their clinical effects in autosomal recessive Alport syndrome.

Autosomal recessive Alport syndrome is caused by mutations in the COL4A3 and COL4A4 genes which code for the alpha3 and alpha4 chains of type IV collagen. These mutations result in haematuria, progressive renal impairment and often hearing loss, lenticonus and retinopathy. We describe here the mutations demonstrated by screening the 47 coding exons of the COL4A4 gene in six families with autosomal recessive Alport syndrome using PCR-single stranded conformational polymorphism (SSCP) analysis. Six sequence variants were identified. These included three novel mutations (2846delG, 2952delG and S969X) in exons 30 - 32 that all resulted in premature stop codons. These mutations were demonstrated in the heterozygous form in 3 families, and the S969X mutation was also present in the homozygous form in one of the two consanguinous families. These three mutations accounted for 40% (4/10) of the total mutant alleles in the six families studied. Six of the seven (86%) individuals with autosomal recessive Alport syndrome who had these mutations in the compound heterozygous or homozygous forms developed renal failure in adulthood, as well as hearing loss and ocular abnormalities. Haematuria was present in 15 of the 17 (88%) heterozygous mutation carriers. The other non-pathogenic sequence variants noted in COL4A4 included a nonglycine missense variant (L1004P), an intronic variant (4731-8 T>C) and a neutral polymorphism (V1516V).

Adult↗