Genetic Diseases: Alport Syndrome and Thin Basement Membrane
Does this patient have Alport syndrome?
This question arises when a boy from a family with Alport syndrome is found to have hematuria, either microscopic - detected on a routine urinalysis or an episode of macroscopic hematuria. Alport syndrome is a hereditary disease that in its most typical form is characterized by several males in a family having end-stage renal disease (ESRD) before the age of 30 years accompanied by worsening hearing loss and ocular abnormalities. In 80-85% of families Alport syndrome is transmitted in an X-linked manner, in 10-15% as an autosomal recessive disease, and in approximately 5% as an autosomal dominant disorder. Family history is negative in the index case of autosomal recessive disease, because both parents are usually asymptomatic carriers, although they may have microscopic hematuria on further investigation. Family history is also negative when X-linked Alport syndrome results from a new mutation, which is estimated to occur in 10-15% of Alport cases.
In X-linked Alport syndrome, men are more severely affected than women. If a male is affected, his mother is the carrier except in cases of de novo mutations. Most carriers also have signs of the disease, usually microscopic hematuria (95% of females), and some of them develop proteinuria and progressive kidney disease leading to ESRD.
The variable but usually milder course in carriers is due to random X chromosome inactivation. On average 50% of a woman's cells express the normal X chromosome and 50% the disease bearing X chromosome; however, these proportions can be significantly skewed, and females can be severely affected if 90% of their renal cells express the mutant X chromosome. It is estimated that 15 to 30% of female carriers eventually develop ESRD, usually after the age of 40 years.
In autosomal recessive disease both males and females are equally affected. Typically, affected men and women develop ESRD before the age of 30 years. Hearing loss and eye findings are common. Diagnosing autosomal recessive Alport syndrome in the index case of a family requires a high index of suspicion, and often it is an unexpected diagnosis revealed by kidney biopsy or genetic testing (see below).
Autosomal dominant Alport syndrome may be more common than previously thought, owing to misdiagnosis because of its milder course. It affects family members in successive generations, equally distributed between men and women. The course is highly variable between and within families, with ESRD occurring as early as age 19 years but more commonly after age 40-60 years. Hearing difficulties and ocular manifestations are less common in dominant disease, with older age at onset and high interindividual variability.
Alport syndrome is a disorder of the glomerular basement membrane resulting in glomerular hematuria. Microscopic hematuria is usually present from birth, and episodes of macroscopic hematuria may develop in children after respiratory infections.
Varying degrees of proteinuria develop in, male children and adolescents with X-linked disease and in patients with autosomal recessive disease, often beginning in childhood, The proteinuria can progress to nephrotic syndrome, which implies a worse prognosis. Nephrotic syndrome occurring in siblings may be the first presentation of autosomal recessive Alport syndrome in a family and may be misdiagnosed as familial FSGS (focal segmental glomerulosclerosis). Females with X-linked Alport syndrome and individuals with the autosomal dominant form may also develop proteinuria but typically at a later age, and progression is much slower.
Hypertension is usually associated with progressive renal function decline, which in severely affected patients starts in adolescence, and results in ESRD before age 30 years. ESRD develops in all affected males with X-linked disease, but may be delayed until after age 50 years in some families with mild (usually missense) mutations. ESRD also occurs in all patients with autosomal recessive disease, often before 30 years of age, in 15-30% of female carriers of X-linked disease, usually after age 40 years, and in up to 80% of subjects with autosomal dominant disease over age 60 years.
Sensorineural hearing loss often becomes detectable in adolescence; it is never present from birth. It may progress to deafness in parallel to the course of the renal disease, or sometimes many years later. Hearing loss is not universal, and the absence of hearing abnormalities does not rule out the diagnosis of Alport syndrome in a patient or family.
In several studies, only 50-80% of males with X-linked disease and 20-30% of heterozygous females reported hearing loss. In autosomal dominant Alport syndrome hearing loss is highly variable, occurring in 68% of patients in different reports, often after age 40 years. but occasionally in children. Hearing loss is not specific for Alport syndrome.
A wide range of eye abnormalities have been reported, but the most frequent and distinctive are anterior lenticonus and "dot and fleck" retinopathy. Eye abnormalities are usually not present in children but develop in adolescents and young adults. The retinopathy consists of yellow or white spots around the macula, as well as more peripheral pigmentary changes, white or dark. They do not affect visual acuity.
The retinopathy is found in 50-90% of men and about 15% of women with X-linked Alport syndrome, in up to 90% of patients with autosomal recessive disease, and rarely in the autosomal dominant form. "Dot and fleck" retinopathy and anterior lenticonus, when present, are considered pathognomonic for Alport syndrome
Anterior lenticonus is a conical protrusion of the anterior aspect of the lens due to weakening of the lens capsule, and can lead to severe visual impairment requiring lens replacement. Anterior lenticonus develops in 20-40% of men with X-linked disease and in up to 80% of subjects with autosomal recessive disease, but is rare in heterozygous women with the X-linked form; it has only recently (in 2015) been reported in a patient with autosomal dominant Alport syndrome.
Aortic disease may be a feature of severe Alport syndrome. In 2010 Kashtan et al. reported a series of five males with X-linked disease and ESRD by age 20 years who had aortic complications at an early age: Two suffered thoracic aortic dissection at ages 25 and 32 years, one ruptured an ascending aortic aneurysm at age 32, one required replacement of the aortic root and valve because of severe aortic insufficiency at age 23, and one had asymptomatic dilatation of the ascending and descending aorta at age 21 years. There are also case reports of ruptured abdominal aortic aneurysm at age 36 and ruptured intracranial aneurysm at age 14 years in two males with X-linked Alport syndrome.
Several families have been reported who have X-linked Alport syndrome associated with muscular hypertrophy and leiomyomas of the esophagus. Females in these families may also have hypertrophy of the clitoris and vulva. Hearing loss and early onset cataracts are common in this disorder, called Alport-leiomyomatosis syndrome. It is caused by contiguous deletion of adjacent 5' ends of collagen -4 alpha-5 and alpha-6 genes (see below).
The main differential diagnoses in a child with glomerular hematuria (dysmorphic red blood cells in the urine) are thin basement membrane nephropathy (formerly called benign familial hematuria), postinfectious glomerulonephritis, and IgA-nephropathy. Postinfectious glomerulonephritis typically presents as an acute illness, occurring 1 to 3 weeks after a streptococcal (also after staphylococcal and viral) infection, and is characterized by hematuria, proteinuria, marked hypertension, and rapid development of varying degrees of renal failure. This course is clearly different from the protracted course of Alport syndrome.
IgA-nephropathy may present in children or adolescents with recurrent episodes of macrohematuria 1-3 days after an upper respiratory infection or as asymptomatic microscopic hematuria with or without proteinuria, all of which can also be manifestations of Alport syndrome. Family history is usually negative with IgA-nephropathy (a few familial cases) have been reported) but often positive with Alport syndrome. As stated above, approximately 10-30% of patients with Alport syndrome have no affected family members and, either because they are the index case of autosomal recessive disease or because they have a new mutation.
The most common disorder in the differential diagnosis is thin basement membrane nephropathy (TBMN), which is characterized clinically by persistent microscopic hematuria, minimal or no proteinuria, stable renal function and absence of extrarenal signs or symptoms. TBMN is estimated to affect 1% of the general population and is transmitted as an autosomal dominant trait. Therefore asymptomatic microscopic hematuria is found in about 50% of family members in successive generations, but typically there is no family history of ESRD. However, a few families have been reported who developed proteinuria, hypertension and ESRD late in life.
What tests to perform?
The first step in the diagnosis is examination of the urine sediment by the physician. Reliance on urine dipstick results is inadequate because dipstick heme can be false-positive or false-negative. If there are five or more red blood cells on repeated examination, further workup depends on whether there is a family history of confirmed Alport syndrome and the proband fits into an X-linked or autosomal recessive transmission pattern. For instance, if the proband is a boy with persistent glomerular hematuria and male relatives with confirmed Alport syndrome on his mother's side, further testing to establish the diagnosis is usually not necessary.
If the family history is vague or negative and the proband is a child with asymptomatic hematuria, non-glomerular causes of hematuria should be ruled out by ultrasound imaging and 24-hour urine collection (or urine calcium to creatinine ratio) to look for hypercalciuria. A calcium to creatinine ratio of > 0.2 (mg/mg) in a spot urine sample indicates hypercalciuria, which can cause hematuria in the absence of stones. Other causes of non-glomerular hematuria are polycystic kidney disease (autosomal dominant or recessive) and sickle-cell disease or trait.
If the proband is a male adolescent or young adult with hematuria, proteinuria and decreased renal function but no or a vague family history of ESRD, an ophthalmologic examination may reveal "dot-and-fleck" retinopathy and/or anterior lenticonus, which are considered specific for Alport syndrome. However, a normal eye exam does not rule out the diagnosis. Hearing loss is suggestive, but can occur with other hereditary renal diseases, and therefore is not diagnostic. Absence of hearing loss in the family does not rule out the diagnosis.
New guidelines recommend genetic testing for collagen type 4 mutations for all patients in whom the diagnosis of Alport syndrome is a possibility, to facilitate early identification of affected children and adolescents and their family members, with the goal of early treatment to delay progression to renal failure. This requires a high index of suspicion, as disease presentation can be atypical, with negative family history (see above), absence of extrarenal manifestations, and initial manifestation with nephrotic syndrome.
Molecular diagnosis by DNA analysis is offered by clinical and research laboratories and detects 80-90% of mutations, but it is costly. Failure to identify a mutation does not rule out the diagnosis. Gene panels are being developed for analyzing many genes simultaneously using the technique of “next generation sequencing”, which will greatly reduce the time and costs of genetic testing. Once a mutation has been identified in a family, testing of carriers and prenatal diagnosis are relatively easy. DNA testing can also give information on prognosis, because missense mutations often result in a less severe phenotype than large deletions or truncating mutations.
If genetic testing is not available and X-linked Alport syndrome is suspected in a boy, a skin biopsy with immunofluorescence staining for the alpha-5 chain of type 4 collagen can be performed. The alpha-5 chain is absent from the epidermal basement membrane in approximately 80% of males with X-linked Alport syndrome. About 20% of male Alport patients, usually those with missense or point mutations, do stain positive for the alpha-5 chain. Therefore, positive staining does not rule out Alport syndrome, but absence of staining is diagnostic.
Skin biopsy with immunofluorescence is often nondiagnostic in female carriers and therefore of little value in women. Skin biopsy is always normal in autosomal recessive Alport syndrome, because the collagen chains that bear mutations in recessive Alport syndrome (i.e. the alpha-3 and alpha-4 chains) are not expressed in the epidermis.
If the above tests are inconclusive, a kidney biopsy that combines light microscopy with immunofluorescence and electron microscopy will allow a definitive diagnosis in most many cases. Light microscopy findings are usually normal in children, but may show nonspecific focal glomerulosclerosis and tubular atrophy, in adolescents and young adults. However, electron microscopy typically shows alternating areas of thinning and thickening of the glomerular basement membrane (GBM), with longitudinal splitting and lamellation of the lamina densa and an irregular outer contour of the GBM.
Longitudinal splitting of the lamina densa is considered diagnostic of Alport syndrome, but it may be absent in children with early disease. Children may show only diffuse thinning of the GBM, with the typical findings developing as the GBM deteriorates with age.
If diffuse thinning of the GBM is the only abnormal finding in a kidney biopsy specimen, the differential diagnosis is between early Alport syndrome and thin basement membrane nephropathy (TBMN), two disorders with very different prognosis. TBMN is usually a benign condition. Immunofluorescence staining with monoclonal antibodies for the alpha-3 and alpha-5 chains of type 4 collagen, will often allow the correct diagnosis: The alpha-3 and alpha-5 chains are normally expressed in TBMN but are absent from the GBM in most patients with X-linked and autosomal recessive Alport syndrome.
The ultrastructural renal biopsy findings are variable in female carriers of X-linked disease and range from normal to diffuse thinning of the GBM, to alternating thin and thick segments, or to the full phenotype of longitudinal splitting and lamellation. Diffuse splitting portends a poor prognosis.
Patients with an established diagnosis of Alport syndrome and isolated microhematuria should be monitored at least annually for the development of proteinuria as this predicts renal disease progression. A urine protein over creatinine ratio > 0.3 indicates overt proteinuria. Once overt proteinuria has developed, regular monitoring of blood pressure and serum creatinine become necessary. These recommendations also apply to female carriers of X-linked disease. Hearing and ophthalmologic evaluation should be performed at the earliest sign of symptoms.
How should patients with AS be managed?
Until recently there were no guidelines or specific recommendations for the management of patients with Alport syndrome. That changed with the publication in 2012 of a report from the European Alport Registry, which collected data on 283 patients with confirmed Alport syndrome (either males with X-linked disease or homozygous subjects with recessive disease) over more than two decades. Pediatric nephrologists in Europe had been treating patients with Alport syndrome with angiotensin-converting enzyme inhibitors (ACEI) as soon as proteinuria was detected and sometimes even in the isolated hematuria stage, although the children were usually normotensive. Data were submitted to the Alport Registry and their analysis revealed a rather dramatic effect: 109 patients were not treated because of a delayed diagnosis; their median age at the start of dialysis was 22 years, which is consistent with other reports in the literature. If treatment with ACEI was started for overt proteinuria while renal function was still normal (n = 115), ESRD was delayed to a median age of 40 years, and life expectancy was also significantly improved. No treated patient with isolated hematuria or microalbuminuria (n = 33) has developed ESRD so far, after 1-14 years of treatment. There were very few side effects, although most subjects did not have hypertension at baseline. The results of this observational study, are strengthened by the fact that the birth year of the untreated patients was not significantly different from that of the treated patients, and analysis of sibling pairs with the same mutation confirmed the overall results.
Based on this large study (310 centers) with long follow-up (> 20 years), the Alport Syndrome Research Collaborative issued the recommendation to treat children and adolescents with Alport syndrome and overt proteinuria (> 300 mg/day) with ACEI (or angiotensin receptor blockers in case of ACEI intolerance) to reduce proteinuria as much as possible. Treatment should also be considered for children with microalbuminuria if they have severe mutations or a family history of early onset ESRD. A randomized placebo-controlled trial is being conducted in multiple centers in Germany to assess the effects of ACEIramipril therapy, initiated in the isolated hematuria or microalbuminuria stage, on progression to overt proteinuria, as well as any adverse effects (ClinicalTrials.gov NCT 01485978). This trial is expected to be completed in August 2019.
Female carriers of X-linked disease and individuals who are carriers of autosomal recessive disease should also be treated with ACEI or angiotensin receptor blockers if they have proteinuria, hypertension or decreased renal function, based on observations from the European Alport Registry that this treatment can delay progression to ESRD.
Isolated case reports showed a benefit of cyclosporine that could not be confirmed by other studies. Because of the risk of nephrotoxicity the use of cyclosporine is not recommended for the treatment of Alport syndrome.
Hearing aids are useful for patients with hearing loss. Ototoxic medications should be avoided in all patients with Alport syndrome.
Lenticonus and "dot and fleck" retinopathy are frequently asymptomatic, but severe lenticonus leads to visual impairment and lens replacement may be necessary.
For patients with ESRD renal transplantation is the treatment of choice. Patient and graft survival are similar or better than for patients with ESRD due to other causes. Alport syndrome does not recur in the allograft, however a small proportion (3-5%) of allograft recipients will develop anti-GBM glomerulonephritis due to antibodies against the donor alpha-3 or alpha-5 chain of type 4 collagen. This anti-GBM glomerulonephritis is often resistant to treatment, leading to graft loss in 80-90% of cases. The recurrence risk in subsequent transplants is very high (93% in a summary report). It is not known why only a few patients develop this complication, nor is it possible to predict who will be affected.
What happens to patients with AS?
Alport syndrome is a rare disease, occurring world-wide. Prevalence estimates range from 1 in 5,000 to 1 in 50,000 live births. It is a disease of the glomerular basement membrane (GBM) caused by a recessive mutation in one of 3 genes which encode different alpha chains of type 4 collagen. These 3 genes are COL4A3, COL4A4 and COL4A5.
In contrast, TBMN is a common disorder with an estimated prevalence of 1% of the general population. It is inherited as an autosomal dominant trait and caused by a heterozygous mutation in COL4A3 or COL4A4.
Type 4 collagen is a major constituent of basement membranes and is composed of 6 different protein chains, alpha-1 to 6. The respective genes are COL4A1 to COL4A6. The alpha chains self assemble into 3 kinds of triple helical molecules, called the collagen protomers: α1,α1,α2; α3,α4,α5; and α5,α5,α6. Several protomers become cross-linked to form the collagen network. The α1,α1,α2 protomers are found in all basement membranes, including the GBM during fetal development. The α3,α4,α5 protomers are restricted to the mature GBM and some basement membranes of the inner ear, lung, retina and lens of the eye.
Podocytes of the glomerulus produce the alpha 3-5 chains for incorporation into the GBM. α5,α5,α6 protomers are found in the basement membranes of the epidermis, Bowman's capsule, distal renal tubules, and smooth muscle cells of the esophagus.
In patients with Alport syndrome a mutation in any one of the 3 COL4A3-5 genes prevents the assembly of the α3,α4,α5 network. Therefore the fetal α1,α1,α2 network persists in the basement membranes of the glomerulus, inner ear, lens and retina. The mature α3,α4,α5 collagen network is more heavily cross-linked than the α1,α1,α2 network and therefore more resistant to degradation by proteases and/or mechanical and oxidative stress. This may explain why the GBM, cochlea and lens deteriorate with age in Alport syndrome. Some mutations result in the accumulation of defective or misfolded alpha chains within podocytes leading directly to podocyte dysfunction and damage.
COL4A5 is located on the X-chromosome and, when mutated, causes X-linked Alport syndrome. It lies head-to-head with the COL4A6 gene, and therefore large deletions which involve both the COL4A5 and the COL4A6 genes account for Alport-leiomyomatosis syndrome. COL4A3 and COL4A4lie head-to-head on chromosome 2. Recessive Alport syndrome results from mutations involving both alleles of either gene; these mutations can be homozygous or compound heterozygous. Several patients have been reported who have mutations or variants in more than one of the 3 collagen-4 genes.
Single heterozygous mutations in COL4A3 or COL4A4 have been found in many families with thin basement membrane nephropathy (TBMN) but also in families with autosomal dominant Alport syndrome. It is not entirely clear what distinguishes these mutations.
Individual genetic background and/or modifier genes may be responsible for different phenotypes associated with heterozygous COL4A3 and COL4A4 mutations. TBMN is usually a benign condition and confined to the kidney; however, a few families have been reported who developed proteinuria, hypertension and ESRD at older ages (>50 years). Autosomal dominant Alport syndrome is distinguished from TBMN by lamellation of the GBM and common development of ESRD and hearing problems, although often at an older age than in the X-linked and recessive forms. It is important to recognize that TBMN due to COL4A3 and COL4A4 mutations represents the carrier state for autosomal recessive Alport syndrome. Whether all cases of TBMN are caused by these collagen gene mutations is not entirely clear.
ESRD is inevitable for males with X-linked Alport syndrome and for all patients with autosomal recessive disease. The age at which ESRD develops is variable but usually involves young adults. About 70% of these patients reach ESRD before age 30 years and 90-95% before age 40 years (data from various natural history studies, in the absence of early treatment with ACEI). Occasionally ESRD occurs in children or is delayed until after age 50 years. Late-onset ESRD occurs in families with non-truncating missense mutations, which result in residual protein expression (their kidney biopsies may show positive, although reduced staining for the α3, α4, and α5 chains).
Hearing impairment, when present, first becomes evident in late childhood and often progresses in parallel with the renal disease, but sometimes deafness does not develop until many years after onset of ESRD.
The prognosis is very variable for female carriers of X-linked Alport syndrome and for patients with autosomal dominant disease. Most female carriers have microscopic hematuria, and while many remain asymptomatic through their lives, up to 30% develop proteinuria and ESRD, usually after age 40 years. The prognosis of young female carriers is not predictable and not related to disease severity in affected male relatives. Therefore these patients need monitoring for the development of proteinuria, hypertension and decreased renal function, best by a nephrologist, throughout their lives. This recommendation also applies to patients with autosomal dominant Alport syndrome. and to individuals with TBMN who are older than 40-50 years.
How to utilize team care?
The necessity for specialty consultations is dictated by disease manifestations. All patients need the care of a nephrologist, usually from the time of diagnosis. Patients with hearing problems need referral to an ENT specialist and those with visual symptoms referral to an ophthalmologist.
Patients with a family history of Alport syndrome should be referred for genetic counseling before considering pregnancy so that they are fully informed about the risks of having affected children, and about the possibility of pre-implantation diagnosis, particularly if the specific mutation in the family is known.
In X-linked disease there is no father-to-son transmission, but every daughter of an affected male will be a carrier. Each offspring of a female carrier has a 50% chance of inheriting the disease causing X chromosome. Therefore every son of a female carrier has a 50% chance of having the disease, whereas every daughter has a 50% chance of being a carrier.
In autosomal recessive Alport syndrome the disease is present in siblings, and both parents are heterozygous carriers with TBMN. Each child in the family has a 25% chance of having the disease, a 50% chance of being a carrier and a 25% chance of having 2 normal alleles.
All family members of patients with a diagnosis of Alport syndrome should be encouraged to undergo evaluation in order to identify additional affected subjects and female carriers, with the goal of instituting early treatment and counseling.
Dietary counseling is indicated for patients with heavy proteinuria or with decreasing renal function, similar to patients with renal disease in general. Vocational counseling and training are important for all adolescents and young adults with progressive disease. Timely referral to a kidney transplant center for preemptive renal transplantation and appropriate donor selection is mandatory to achieve optimal outcomes.
Are there clinical practice guidelines to inform decision making?
Clinical practice recommendations were issued online in March 2012 by the Alport Syndrome Research Collaborative (published in Pediatric Nephrology 28:5-11, 2013; DOI 10.1007/s00467-012-2138-4). The authors recommend treating patients with overt proteinuria with angiotensin-converting-enzyme inhibitors (ACEI) regardless of blood pressure level, and considering treatment for individuals with severe mutations even earlier. They also encourage practitioners to report de-identified data on treatments and outcomes to the Alport Syndrome Registry.
More comprehensive guidelines on diagnostic testing, genetic counseling, monitoring patients and family members, treatment with ACEI or angiotensin receptor blockers (ARB), renal transplantation and kidney donation (from carriers) were published by an international expert panel in the Journal of the American Society of Nephrology in 2013. In this special article the authors discuss 18 specific recommendations, including the use of genetic testing whenever possible as the gold standard, for diagnosing the disease, evaluation and nephrologist monitoring of all patients and carriers from the time of diagnosis, treatment of males with X-linked disease and all patients with autosomal recessive disease with ACEI as soon as overt proteinuria is detected and possibly in the microalbuminuria stage, and treatment of female carriers of X-linked disease with ACEI if they have proteinuria or hypertension. The authors also caution against kidney donation by carriers because of their own risk for renal function loss. If a carrier donates a kidney, both donor and recipient should be treated with ACEI or ARB from the time of surgery.
Clinical studies and trials
The University of Minnesota maintains an Alport Syndrome Treatments and Outcomes Registry (ASTOR), which is currently recruiting up to 1000 participants, age less than 30 years, with normal renal function and a family or individual history of confirmed Alport syndrome (ClinicalTrials.gov identifier: NCT00481130). The goal of this registry is to conduct natural history studies and therapeutic trials in children and adolescents with Alport syndrome. Contact Theresa F Cassidy, MPH, 612-626-7632, email firstname.lastname@example.org, or Katherine Tabaka, 612-624-6135, email email@example.com. Principal Investigator is Dr. Clifford Kashtan at the University of Minnesota, Department of Pediatrics.
Another observational study, sponsored by Regulus Therapeutics Inc,, is currently recruiting at multiple centers in the US, Canada, Australia, France, Germany and the UK (ClinicalTrials.gov. NCT02136862). Goal is to characterize the rate of renal function decline in patients with confirmed Alport syndrome age 16 years or older with baseline GFR 30-75 ml/min. Contact email is ATHENA_alportstudy@agility-clinical.com.
Other clinical studies can be found at ClinicalTrials.gov, a publicly accessible database provided by the US National Institutes of Health.
The ICD-10 Diagnosis code for Alport syndrome is. Q87.81. The codes for chronic kidney disease stages1 through 5 are N18.1 through N18.5. The code for end-stage renal disease is N18.6.
VII. What's the evidence?
Kashtan, CE. "Alport syndrome and thin glomerular basement membrane disease". J Am Soc Nephrol. vol. 9. 1998. pp. 1736-1750.(Review article (Disease of the month), describing type 4 collagen genes and proteins, diagnostic issues, and management of Alport syndrome and TBMN.)
Hudson, BG, Tryggvason, K, Sundaramoorthy, M, Neilson, EG. "Alport's syndrome, Goodpasture's syndrome, and type IV collagen". N Engl J Med. vol. 348. 2003. pp. 2543-2556.(Review article, describing structure and distribution of type 4 collagen, genetics and clinical features of Alport and Goodpasture syndrome, and their treatment.)
Jais, JP, Knebelmann, B, Giatras, I. "X-linked Alport syndrome: Natural history in 195 families and genotype-phenotype correlations in males". J Am Soc Nephrol. vol. 11. 2000. pp. 649-657.(Report from a large, multi-center observational study and genetic database in Europe.)
Jais, JP, Knebelmann, B, Giatras, I. "X-linked Alport syndrome: Natural history in 195 families and genotype-phenotype correlations in girls and women belonging to 195 families: A "European Community Alport Syndrome Concerted Action" study". J Am Soc Nephrol. vol. 14. 2003. pp. 2603-2610.(Report from a large, multi-center observational study and genetic database in Europe.)
Heidet, L, Gubler, MC. "The renal lesions of Alport syndrome". J Am Soc Nephrol. vol. 20. 2009. pp. 1210-1215.(Case report and discussion of Alport syndrome.)
Marcocci, E, Uliana, V, Bruttini, M. "Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome". Neprhol Dial Transplant. vol. 24. 2009. pp. 1464-1471.(Clinical and molecular characterization of 38 patients from eight families with autosomal dominant Alport syndrome, and comparison with previously reported cases.)
Dagher, H, Buzza, M, Colville, D. "A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome". Am J Kidney Dis. vol. 38. 2001. pp. 1217-1228.(Description of clinical and histopathological findings in affected patients and carriers of X-linked Alport syndrome, and comparison with clinical and histopathological findings in affected patients and carriers of autosomal recessive Alport syndrome.)
Fawzi, AA, Lee, NG, Eliott, D. "Retinal findings in patients with Alport syndrome: expanding the clinical spectrum". Br J Ophthalmol. vol. 93. 2009. pp. 1606-1611.(Original report of new retinal findings in patients with Alport syndrome, and review of the range of ophthalmic manifestations.)
Kashtan, CE, Segal, Y, Flinter, F. "Aortic abnormalities in males with Alport syndrome". Nephrol Dial Transplant. vol. 25. 2010. pp. 3554-3560.(Original report of severe aortic disease in five young males with X-linked Alport syndrome.)
Garcia-Torres, R, Orozco, L. "Alport-Leiomyomatosis syndrome: An update". Am J Kidney Dis. vol. 22. 1993. pp. 641-648.(Clinical and pathologic description of 38 cases and identification as a contiguous gene deletion syndrome.)
Proesmans, W, Van Dyck, M. "Enalapril in children with Alport syndrome". Pediatr Nephrol. vol. 19. 2004. pp. 271-275.(Ten pediatric patients treated with enalapril for 5 years had a decrease in proteinuria and preservation of renal function; no control group.)
Massella, L, Muda, AO, Legato, A. "Cyclosporine A treatment in patients with Alport syndrome: a single-center experience". Pediatr Nephrol. vol. 25. 2010. pp. 1269-1275.(Fifteen adolescents treated with cyclosporine A for a mean of 3.5 years, with no clear benefit.)
Gross, O, Kashtan, CE. "Treatment of Alport syndrome: beyond animal models". Kidney Int. vol. 76. 2009. pp. 599-603.(Review article of current and possible future therapies.)
Kashtan, CE. "Renal transplantation in patients with Alport syndrome". Pediatr Transplantation. vol. 10. 2006. pp. 651-657.(Review article discussing living donor selection, outcomes of transplantation and anti-GBM nephritis after transplantation.)
Badenas, C, Praga, M, Tazon, B. "Mutations in the COL4A4 and COL4A3 genes cause familial benign hematuria". J Am Soc Nephrol. vol. 13. 2002. pp. 1248-1254.(Original article, identifying mutations in the COL4A3 and COL4A4 genes in 11 families with biopsy-proven thin basement membrane nephropathy.)
Savige, J, Rana, K, Tonna, S. "Thin basement membrane nephropathy". Kidney Int. vol. 64. 2003. pp. 1169-1178.(Review article discussing epidemiology, clinical features, genetics, prognosis, and differentiation from Alport syndrome.)
Tryggvason, K, Patrakka, J. "Thin basement membrane nephropathy". J Am Soc Nephrol. vol. 17. 2006. pp. 813-822.(Review article, focussing on the molecular pathogenesis, pathological features, and genetics of thin basement membrane nephropathy.)
Voskarides, K, Damianou, L, Neocleous, V. "COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy". J Am Soc Nephrol. vol. 18. 2007. pp. 3004-3016.(Original article, describing 10 families with COL4A3/COL4A4 mutations and a significant proportion of patients developing ESRD at an older age.)
Kashtan, CE, Segal, Y. "Genetic disorders of glomerular basement membranes". Nephron Clin Pract. vol. 118. 2011. pp. c9-c18.(Review article, which includes other rare diseases of the GBM due to mutations in other, noncollagen genes.)
Gross, O, Licht, C, Anders, HJ. "Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy". Kidney Int. vol. 81. 2012. pp. 494-501.(Original article, describing the results of early treatment with angiotensin-converting enzyme inhibitors compared to no treatment in 283 patients with Alport syndrome from the European Alport Registry; observational study.)
Temme, J, Peters, F, Lange, K. "Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations". Kidney Int. vol. 81. 2012. pp. 779-783.(Original article from the European Alport Registry reporting a 17% incidence of ESRD in heterozygous carriers of mostly X-linked disease, and a significant delay of ESRD with early RAAS blocking treatment; observational study.)
Kashtan, CE, Ding, J, Gregory, M. "Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative". Pediatr Nephrol. vol. 28. 2013. pp. 5-11.(Review article, recommends monitoring for microalbuminuria and proteinuria as soon as the diagnosis of Alport syndrome is established, and initiating ACE-inhibitor therapy for proteinuria reduction even in normotensive children.)
Savige, J, Gregory, M, Gross, O. "Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy". J Am Soc Nephrol. vol. 24. 2013. pp. 364-375.(Review article, discusses 18 recommendations about diagnosis, including genetic testing, of patients and family members with suspected Alport syndrome or thin basement membrane nephropathy; treatment with ACE-inhibitors at an early stage of Alport syndrome and for patients with thin basement membrane nephropathy and hypertension; renal transplantation and kidney donation by carriers; genetic counseling.)
Gross, O, Friede, T, Hilgers, R. "Safety and efficacy of the ACE-inhibitor ramipril in Alport Syndrome: The double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients". ISRN Pediatrics. 2012. pp. 436046.(Original article describing the rationale and organization of the ramipril trial in children with early-stage Alport syndrome.)
Savige, J, Sheth, S, Leys, A. "Ocular features in Alport syndrome: Pathogenesis and clinical significance". Clin J Am Soc Nephrol. vol. 10. 2015. pp. 703-709.(Review article, in-depth description of ocular manifestations and discussion of their usefulness for the diagnosis and prognosis of Alport syndrome.)
Moriniere, V, Dahan, K, Hilbert, P. "Improving mutation screening in familial hematuric nephropathies through next generation sequencing". J Am Soc Nephrol. vol. 25. 2014. pp. 2740-2751.(Original article, describing the advantages of simultaneous next generation sequencing of COL4A3, COL4A4 and COL4A5; in this study of 101 patients the proportion of autosomal dominant forms of Alport syndrome appeared to be higher than previously reported.)
Rosado, C, Bueno, E, Felipe, C. "Study of the true clinical progression of autosomal dominant Alport syndrome in a European population". Kidney Blood Press Res. vol. 40. 2015. pp. 435-442.(Original article, descriptive study of 19 patients from 5 families with autosomal dominant Alport syndrome, documenting the high inter- and intrafamilial variability of renal and extrarenal manifestations in patients with heterozygous COL4A3 or COL4A4 mutations.)
Malone, AF, Phelan, PJ, Hall, G. "Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis". Kidney Int. vol. 86. 2014. pp. 1253-1259.(Original article; whole-exome sequencing was performed in 70 families with clinical familial FSGS, and in 7 of them a mutation in COL4A3 or in COL4A4 was found, showing that autosomal recessive or dominant Alport syndrome can present as phenocopy of FSGS.)
Xie, J, Wu, X, Ren, H. "COL4A3 mutations cause focal segmental glomerulosclerosis". J Mol Cell Biol. vol. 6. 2014. pp. 498-505.(Original article, revealing heterozygous COL4A3 mutations in a Chinese cohort of patients with familial (12%) or sporadic (2%) FSGS.)
Gast, C, Pengelly, RJ, Lyon, M. "Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis". Nephrol Dial Transplant. 2015.(Original article, finding mutations in COL4A3-5 in 6 of 76 families with FSGS, using a next generation sequencing panel of 39 genes implicated in FSGS.)
Weber, S, Strasser, K, Rath, S. "Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy". Pediatr Nephrol. vol. 31. 2016. pp. 941-955.(Original article describing the genotypic spectrum of COL4A3-5 mutations and associated phenotypes in 216 patients.)
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