奥尔波特综合征Alportsyndrome
奥尔波特综合征(Alport syndrome)
奥尔波特综合征(Alport syndrome)奥尔波特综合征(Alport syndrome)，又名奥尔波特氏综合征(Alport’s syndrome),也被称作遗传性肾炎（hereditary nephritis）。
可在罕见疾病网上查询：Q87.801，奥尔波特氏综合征（遗传性肾炎和耳聋）。
Alport syndrome or hereditary nephritis is a genetic disorder characterized by glomerulonephritis, endstage kidney disease, and hearing loss. Alport syndrome can also affect the eyes (lenticonus). The presence of blood in the urine (hematuria) is almost always found in this condition.It was first identified in a British family by Dr. Cecil A. Alport in 1927, though William Howship Dickinson is considered by some to have made contributions to the characterization.病因：Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney, inner ear, andeye. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein into the urine.The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.遗传方式：Alport syndrome can have different inheritance patterns that are dependent on the genetic mutation.In most people with Alport syndrome, the condition is inheritedin an X-linked pattern, due to mutations in the COL4A5 gene.A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.Alport syndrome can be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.Past descriptions of an autosomal dominant form are now usually categorized as other conditions, though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published.临床诊断：Gregory et al., 1996, gave the following 10 criteria for the diagnosis of Alport syndrome; Four of the 10 criteria must bemet:1. Family history of nephritis of unexplained haematuria in a first degree relative of the index case or in a male relative linked through any numbers of females.2. Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney disease or IgA nephropathy.3. Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30 years.4. A mutation in COL4An (where n = 3, 4 or 5).5. Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.6. Widespread GBM ultrastructural abnormalities, in particular thickening, thinning and splitting.7. Ocular lesions including anterior lenticonus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.8. Gradual progression to ESRD in the index case of at least two family members.9. Macrothrombocytopenia or granulocytic inclusions, similar to the May-Hegglin anomaly.10. Diffuse leiomyomatosis of esophagus or female genitalia, or both.(The use of eye examinations for screening has been proposed.)免疫组织化学：Immunohistochemical (IHC) evidence of the X-linked form Alport syndrome may be obtained from biopsies of either the skin or the renal glomerulus. In this processes, antibodies are used to detect the presence or absence of the alpha3, alpha4, and alpha5 chains of collagen type 4.All three of these alpha chains are present in the glomerular basement membrane of normal individuals. In individuals expressing the X-linked form of Alport's syndrome, however, the presence of the dysfunctional alpha5 chain causes the assembly of the entire collagen 4 complex to fail, and none of these three chains will be detectable in either the glomerular or the renal tubular basement membrane.Of these three alpha chains, only alpha5 is normally expressed in the skin,[citation needed] so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.治疗：As there is no known cure for the condition, treatments are symptomatic. Patients are advised on how to manage the complications of kidney failure and the proteinuria that develops is often treated with ACE inhibitors, although they are not always used simply for the elevated blood pressure.Once kidney failure has developed, patients are given dialysis or can benefit from a kidney transplant, although this can cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.Gene therapy as a possible treatment option has been discussed.另附一篇关于本病的介绍：Diseases of the Kidney: Alport SyndromeVersion of Aug 31, 1999These citations, from the three most recent editions of the large three-volume monograph "Diseases of the Kidney," refer to comprehensive clinical descriptions of Alport syndrome by our University of Utah group.CL Atkin, MC Gregory, WA Border. Alport syndrome. Pp 617-641 (Chapter 19) in RW Schrier, CW Gottschalk (Eds), Diseases of the Kidney, 4th ed, Little, Brown & Co., Boston, 1988.MC Gregory, CL Atkin. Alport syndrome. Pp 571-591 (Chapter 19) in RW Schrier, CW Gottschalk (Eds), Diseases of the Kidney, 5th ed, Little, Brown & Co., Boston, 1993.MC Gregory, CL Atkin. Alport's Syndrome, Fabry's Disease, and Nail-Patella Syndrome, chapter 19 in RW Schrier, CW Gottschalk (Eds), Diseases of the Kidney, 6th ed, Little, Brown & Co.,Boston, pp. 561-590, 1997. NLM Call No.WJ 300 D611 1996, ISBN 0-316-77456-1."Diseases of the Kidney" may be purchased from the publisher, but is readily found in medical school libraries. I, Curtis L. Atkin, have as yet been unable to obtain the publisher's permission to completely reprint here this copyrighted material. The following essay was adapted and condensed from these Chapters by Dr Martin C. Gregory for the HNF Newsletter No. 27, September 1995. My notes and emendations to Dr Gregory's piece are [bracketed].---------------------------------------------------------------------INTRODUCTIONHereditary nephritis is a disparate group of often ill-defined conditions that are similar only in that they run in families and present many diagnostic difficulties. Because the incidence and diversity of such diseases are not generally recognized, opportunities for timely diagnoses and genetic counseling are lost. The most common and best known hereditary nephritis is Alport syndrome. In this chapter, Alport syndrome will be defined as progressive hereditary hematuric nonimmuneglomerulonephritis characterized ultrastructurally by irregular thickening, thinning, and lamellation of the glomerular basement membrane (GBM). In some kindreds nonrenal features occur. These include hearing loss, various ocular defects, abnormalities of platelet number and function, granulocyte inclusions, and esophageal and genital leiomyomatosis (tumors). We regard nonrenal features as helpful diagnostic pointers in some kindreds, although they are not essential to the diagnosis.---------------------------------------------------------------------DISEASE DEFINITIONSTerminology and diagnostic criteria in many reports vary, and it is difficult to define exactly what Alport syndrome or progressive hereditary nephritis should include. Alport did not perform renal histological studies and as his kindred "has rid itself of Alport's disease," no means exist for defining the syndrome he described in modern terms. This kindred had dominantly inherited kidney disease that was characterized in both sexes by hematuria and urinary erythrocyte casts, variable proteinuria, and especially in males by progressive hearingloss and renal failure. Affected males had hearing loss, died in adolescence, and had no offspring. Progressive azotemia (excesses of urea and creatinine in the blood) and ESRD (end stage renal disease) especially in males, complex ultrastructural anomalies of GBM (glomerular basement membrane), and negative glomerular immunofluorescence studies are characteristics of all types of Alport syndrome. Eventual ESRD of nearly all affected males is a central feature. [Now that Type IV disease (below) is better understood, it has become clear that hearing loss essentially always accompanies renal failure in Alport syndrome]. Many reports have expanded the classic dyad of aural and renal symptoms to include other associated nonrenal anomalies and traits [such as] thrombocytopathia (bleeding disorder characterized by defective platelets), ocular abnormalities, or leiomyomatosis. [Anti-basement membrane collagen antisera that bind] normal GBM and epidermal basement membrane (EBM) fail to bind these membranes in many but not all Alport kindreds].---------------------------------------------------------------------AFFECTED INDIVIDUALSChronic hematuria (blood in the urine) is the cardinal sign of Alport syndrome. Persons with hematuria and a gene for Alport syndrome are affected. Clinically normal gene carriers (preponderantly females) should be identified for genetic studies, counseling, and selection of kidney donors; it is, however, misleading to characterize them as affected persons. Our minimal criterion for affectedness is greater than or equal to 3 red cells per high-power field of the centrifuged fresh urine sediment (with rigorous exclusion of menstrual blood) but choice of [either 1 or more, or of 10 or more] erythrocytes per field would change few diagnoses. Urinary erythrocyte casts and proteinuria support the diagnosis of Alport syndrome, but are not necessary for it, whereas other urinary findings (pyuria, positive urine cultures, or proteinuria in the absence of hematuria) are not signs of Alport syndrome. The prime criterion for ascertainment of Alport syndrome in kindreds is the demonstration of a family history of chronic glomerulonephritis in multiple closely related persons.---------------------------------------------------------------------CLASSIFICATIONClinical features regularly displayed by affected persons in a kindred define the characteristic phenotype of Alport syndrome in that kindred. The severity [and timing] of symptoms may vary [amongst relatives] according to age and gender, [yet many kindreds show statistically distinct averages]. Kindreds clearly differ in [rates of progression of renal failure,] typical ages of ESRD, [rates of progression] of hearing loss, [and presence of] ocular abnormalities. Different phenotypes and different modes of inheritance [demonstrate genetic heterogeneity and phenotypic heterogeneity] of Alport syndrome.Juvenile versus Adult Types of Alport Syndrome. Schneider first recognized that males in some kindreds with Alport syndrome experienced ESRD in childhood or adolescence, while in other kindreds, males that had ESRD were middle-aged. Bimodality of age of ESRD has been shown repeatedly; juvenile kindreds are those in which males develop ESRD at a mean age below 31 years; in adult types of Alport syndrome ESRD occurs in males at a mean age greater than 31 years.Major Types of Alport Syndrome. Our analysis of 65 kindredsindubitably suffers from nonuniformity of diagnostic criteria in the original reports, but most fit the following classification well. [The scheme, however, grows ever more obsolete; in particular it does not include autosomal recessive inheritance. Nascent, improved classifications are based on DNA analyses and difficult but gradually improving discrimination of clinical features (phenotype).]Type I Alport Syndrome is dominantly inherited juvenile type nephritis with hearing loss, where affected males have no offspring. Pedigree analyses are uninformative for X-linked vs. autosomal dominant inheritance. Type I is an interim category subject to reclassification because ESRD treatment may now allow the affected males to reproduce, or newer genetic methods may allow chromosomal localization of the nephritis genes. Ocular abnormalities are restricted to the juvenile types (I, II, VI) of Alport syndrome, but may not be present in all kindreds with juvenile disease.Type II Alport Syndrome is X-linked dominant, juvenile type nephritis with hearing loss [caused by mutations of the COL4A5 gene for alpha-5 chain of basement membrane (Type IV) collagen].Types II and VI Alport syndrome may be difficult to distinguish because most of the kindreds have few offspring of affected males.Type III Alport Syndrome is X-linked dominant, adult type nephritis with hearing loss [caused by mutations of the COL4A5 gene].Type IV Alport Syndrome is X-linked dominant, adult type nephritis [caused by mutations of the COL4A5 gene. Until the advent of dialysis and transplantation, families had no marked hearing loss, but now it is clear that hearing loss follows a decade or so after ESRD; see reference 38 in our Bibliography].Type V Alport Syndrome is autosomal dominant nephritis with hearing loss and thrombocytopathia. Type V corresponds to McKusick's category No. 15365, (Epstein Syndrome). This disease has been reported in 12 families and 4 sporadic cases; there were clear instances of male to male transmission. Because ESRD data were limited, the distinction of juvenile- vs. adult-type Alport syndrome could not be made in these kindreds. Prevalence of ESRD of females with type V disease mayapproach that of males, but data are scanty. [See additional article by Dr. Gregory, "Macrothrombocytopathy, Nephritis, and Deafness (Epstein syndrome; Alport syndrome with Macrothrombocytopenia) in the HNF Newsletter No. 27, September 1995. The responsible genes are unknown as of 5/99]Type VI Alport Syndrome is autosomal dominant, juvenile type nephritis with hearing loss [caused in at least some cases by mutations in COL4A3 and COL4A4 genes for alpha-3 and -4 chains of basement membrane (Type IV) collagen. Other autosomal genes are sought].Indeterminate types of Alport Syndrome are unclassifiable as types I-VI in the above scheme. Nineteen of the 65 kindreds in our retrospective study were unclassifiable. Alport syndrome associated with leiomyomatosis is another distinct entity [caused by large deletions spanning the adjacent X-linked COL4A5 and COL4A6 genes and perhaps other genes, making it a "contiguous gene syndrome"].---------------------------------------------------------------------GENE FREQUENCYThe estimated gene frequency [for X-linked Alport syndrome] is 1:5000 in the Intermountain West of the United States. Shaw and Kallen estimated Alport syndrome gene frequency 1:10,000 elsewhere in the United States. We could not estimate worldwide incidence of Alport syndrome. It has been reported in many races and is probably not associated with race or geography. We believe that the observed incidence of Alport syndrome in Utah is about twice that elsewhere, not because of the "founder principle", but because of the unusual extent of our studies. The origins and large founding size of the Utah population, and high rates of gene flow have resulted in gene frequencies that are similar to those in northern Europe.[Dr David Barker tentatively estimates the frequency of autosomal recessive (COL4A3 and COL4A4) mutations at 1:250.]---------------------------------------------------------------------MODES OF INHERITANCEPenetrance and Dominance. Hematuria and ESRD are both manifestations of Alport syndrome, with penetrances thateventually coincide in males, but may be widely disparate in females. Penetrance of hematuria and ESRD is 100% in males with types II, III, and IV disease. For types I, V, and VI hematuria and ESRD likely also approach 100%. For females with types III or IV disease prevalence of hematuria is 90% and eventual prevalence of ESRD in females approximates 15%. ESRD may supervene in close to 100% of females with type V disease. In both males and females the penetrance of hematuria remains constant with age.[X-linked recessive inheritance has in past been implicated from observations of ESRD in most males and much less ESRD in females. In truly X-linked recessive traits such as hemophilia and colorblindness, males are affected and females are clinically normal. In Alport syndrome, however,] hematuria indicates nephritis in most gene-carriers of either [gender. Thus X-linked recessive Alport syndrome is a specious category].X-linked Dominant Inheritance. Starting with the original studies of Utah Kindred P, forms of X-linked, sex-linked, or gender-influenced inheritance have been proposed in a minorityof reports on Alport syndrome. In the large Utah kindreds there were numerous offspring of affected males but no male to male transmission when stringent diagnostic criteria were applied. Classical genetic analysis and likelihood analysis established X-linkage in several kindreds. X-linkage was proven for various kindreds with types II, III, and IV Alport syndrome by findings of close genetic linkage of the Alport locus ATS to restriction fragment length polymorphic markers in or near the Xq22 chromosomal region. Genetic linkage of nephritis with mutations in the COL4A5 gene proves X-linkage in some of the same and other kindreds. Similar linkage to highly polymorphic microsatellite markers within the COL4A5 proves X-linkage in still other families. [X-linkage characterizes roughly 85% of Alport families.][Autosomal Recessive Inheritance characterizes about 15% of Alport families. Regardless of gender, the full array of symptoms are suffered not only by homozygotes of COL4A3 or -4 mutations, but also by double heterozygotes of the COL4A3 and -4 genes. It is becoming clear that heterozygotes of either COL4A3 or COL4A5 may show some but decreased symptoms.]Autosomal Dominant Inheritance. Male to male transmission established autosomal dominant inheritance of Alport syndrome in kindreds which may be categorized as having types V or VI Alport syndrome. [Autosomal dominance characterizes roughly 1% of Alport families. Some but not all of them have mutations of COL4A3 or COL4A4 genes.]---------------------------------------------------------------------GENETIC COUNSELINGDominant inheritance of Alport syndrome may be assumed even with minimal pedigree information. As a group, males with Alport syndrome have about 30% fewer children than normal; many males with juvenile type disease will have no offspring.Incomplete penetrance of Alport syndrome in females must always be kept in mind. In kindreds with X-linkage, daughters of affected males will all be gene carriers regardless of their urinalysis results. Unless there is information from genetic markers or from urinalyses of the next generation, each clinically normal daughter of the three other sorts of gene carrier parents (mothers in kindreds with X-linkage, andparents of either sex in kindreds with autosomal dominance) stands a real probability of having an undetected nephritis gene.---------------------------------------------------------------------CLINICAL FEATURES, TYPES I-VIRenal Symptoms. Hematuria is the cardinal feature, persistent and present from birth in males and in 80-90% of females who have a nephritis gene. The child's mother may note occasionally or persistently red diapers, but hematuria is usually inconspicuous in adult-type disease. Episodes of gross hematuria may follow sore throats or other infections in children and may be the presenting symptom. Macroscopic hematuria is not common in adults and perhaps a feature of juvenile types of disease. Red cell excretion rate is increased by acute infections and by pregnancy.In adult types of Alport syndrome, renal function is typically normal for years and then wanes inexorably to renal failure. The reciprocal of serum creatinine falls linearly with time during this phase (roughly six years from early to end-staterenal failure in adult-type Alport syndrome); hypertension appears, and worsens as renal function deteriorates. Crescentic glomerulonephritis may occur, especially in juvenile types of Alport syndrome, and be accompanied by rapidly progressive renal failure.With either juvenile or adult type Alport syndrome, renal failure is inevitable for affected males, but few females become uremic, and then generally when elderly. ESRD of females in kindreds with type V Alport syndrome may be as frequent as for the males.Sensorineural Hearing Loss. Kindreds with type IV Alport syndrome and some with indeterminate type Alport syndrome have socially normal hearing, whereas progressive and ultimately profound, bilateral, sensorineural hearing loss distinguishes kindreds with all other types. Patients can be unaware of a high frequency loss that is readily shown by audiometry (hearing test). Hearing loss generally occurs later, less severely, and less frequently in females, although some women and girls may have a profound loss. In some families with Alport syndrome and hearing loss, affected members may have apparently normalhearing even after ESRD, but as a rule those family members without hearing loss have less severe renal disease. In Utah Kindred P with type III Alport syndrome, noticeable hearing loss generally coincides with the onset of renal failure.Ocular Features. Eye defects appear limited to kindreds with juvenile type nephritis with hearing loss. In start contrast to hearing loss, which is common in hereditary nephritis, but not specific for it, anterior lenticonus [protrusion of the substance of the crystalline lens] is uncommon though nearly pathognomonic. All cases of anterior lentinconus reported between 1964 and 1982 have been associated with nephritis and/or hearing loss. Lenticonus is more common in males and is usually, but not invariably, bilateral.---------------------------------------------------------------------DIAGNOSISThe path to the correct diagnosis lies through a carefully extended family history and personal examination of the urinary sediment, specifically for hematuria. The proband will commonly be a child with unexplained hematuria or an adolescentto middle-aged male with ESRD, with a vague history of kidney disease in brothers or relatives on the maternal side. Systematic urinalyses may reveal several relatives with hematuria.Of great interest are the forthcoming genetic methods of diagnosis. It appears that probing with cDNAs from COL4A5 will reveal mutations in equal to or less than 10% of kindreds. Emerging techniques with microsatellite markers within COL4A5, exon scanning, single stranded DNA fragment conformational analyses, etc., should soon provide specific genetic tests for gene-carrier status in most families.---------------------------------------------------------------------TREATMENTNo specific treatment is known to affect the underlying pathological process or to alter the clinical course. Antibiotics, anticoagulants, steroids, and immunosuppressives have wrought no benefit. Control of hypertension is mandated on general grounds and protein restriction may prove to be of value once nephron loss gives rise to hyperfiltration.Management of advancing renal failure is along conventional lines. When terminal uremia occurs, dialysis and transplantation pose no particular problems, although the lack of certain GBM antigens invites a slender risk of de novo anti-GBM nephritis after transplantation. Except for one unconvincing example, the glomerular defect of Alport syndrome has not recurred after transplantation. Particular care must be taken in selection of living donors: meticulous and repeated urinalysis for hematuria is the most important step.Great care should be taken to avoid adding insults from drug ototoxicity to the advancing aural injury. Improvement or stabilization of hearing loss has occasionally been noted after transplantation of Alport patients; others have noted no benefit nor have we. Interpretation of these findings is difficult because dialysis or the uremic state have been held culpable for reversible hearing loss. When hearing loss worsens the patient will become more dependent on lip-reading and other visual cues. We have observed poor to fair success with hearing aids. Visual acuity should be monitored at intervals in those with or at risk of lenticonus and consideration given to early lens extraction and intra-ocular lens implantation. Keepsteroid doses low after transplantation and monitor regularly for cataracts; poor vision is a disproportionate handicap to the deaf.关于奥尔波特综合征患者肾移植后排斥的报告奥尔波特综合征患者移植肾失功的主要原因是慢性同种异体移植物肾病(69%)和急性排斥反应(22%)。
家族性出血性肾炎(Alport综合征)有哪
家族性出血性肾炎（Alport综合征）有哪*导读：本文向您详细介绍家族性出血性肾炎（Alport综合征）症状，尤其是家族性出血性肾炎（Alport综合征）的早期症状，家族性出血性肾炎（Alport综合征）有什么表现？得了家族性出血性肾炎（Alport综合征）会怎样？以及家族性出血性肾炎（Alport综合征）有哪些并发病症，家族性出血性肾炎（Alport综合征）还会引起哪些疾病等方面内容。
……*家族性出血性肾炎（Alport综合征）常见症状：尿素廓清障碍、出血倾向、阴蒂肥大、血小板减少*一、症状1.肾脏表现Alport综合征最主要的临床表现是血尿，受影响的男性患者表现为持续性镜下血尿。
在20岁以内，许多患者在上呼吸道感染后常突然出现发作性肉眼血尿。
受影响的女性实际上往往是杂合子，可能会表现出间断性血尿，10%～15%杂合子女性从未发生血尿。
受影响的男孩在1岁之内就可发生血尿，并很可能一出生就发生。
10岁之内仍未发生血尿的男孩就不再可能发生了。
本病男性患者常会最终发生蛋白尿。
开始时只是微量蛋白尿，尿蛋白随着年龄的增长逐渐增加，常发展至肾病综合征。
高血压发生率和严重程度也随着年龄的增长而增长。
尽管该综合征在10岁前可发展至肾功能衰竭，但多数患者在20～50岁发展至终末期肾脏病。
男性患者预后差，所有男性患者都会发展到终末期肾脏病，发展的速度表现出显著的家族间的变异。
一些学者观察到在同一家族内发展至肾功能衰竭的速率相当固定。
这种表型的异质性过去被认为是反映了与特别基因的相关性或受到环境因素的影响，现在多数认为是继发于X染色体上单一位点上突变的等位基因的异质性。
同一家族内男性患者发展至肾功能衰竭的速度变异偶有报道。
家族中的女性患者预后良好，多数生存年纪较大，且仅有较轻肾脏病表现。
Grunfeld等发现儿童期肉眼血尿、肾病综合征和电子显微镜下弥漫性肾小球基底膜增厚是提示女性患者肾炎进展的特征，感觉神经性耳聋和晶体受损也提示预后不良。
家族性出血性肾炎(Alport综合征)应该1
家族性出血性肾炎（Alport综合征）应该*导读：本文向您详细介家族性出血性肾炎（Alport综合征）应该做哪些检查，常用的家族性出血性肾炎（Alport综合征）检查项目有哪些。
以及家族性出血性肾炎（Alport综合征）如何诊断鉴别，家族性出血性肾炎（Alport综合征）易混淆疾病等方面内容。
*家族性出血性肾炎（Alport综合征）常见检查：常见检查：血清化学检查、尿液细胞学检查、肾脏切片、尿蛋白质、肾脏叩诊*一、检查血尿和蛋白尿，男性患者表现为持续性镜下血尿。
开始时只是微量蛋白尿，尿蛋白随着年龄的增长逐渐增加，常发展至肾病综合征蛋白尿。
可有血小板缺陷及明显出血倾向。
发生肾功能衰竭时可有尿素氮、肌酐增高等改变。
1.光镜光学显微镜下肾脏病变无特异性。
疾病早期肾小球病变大致正常，仅有轻度局灶节段性系膜组织增生，随病变进展，肾小球渐发展至肾小球硬化，晚期肾小球出现纤维化及球性硬化，肾间质可从炎症细胞浸润发展到纤维化，并伴肾小管萎缩。
本病在肾脏皮、髓质交界处常见间质泡沫细胞。
此泡沫细胞胞质含有中性脂肪、黏多糖、胆固醇及磷脂。
该病变非本病特异，但在本病出现率高，对提示本综合征仍有重要意义。
另外，有10%～25%的Alport综合征病人具有胎儿型肾小球。
胎儿型肾小球也能见于非Alport综合征儿童，尤其是先天性肾病综合征婴儿，但5岁后，非Alport综合征就很难再看到这一病变。
此胎儿型肾小球主要见于10岁前患儿，尤其是5岁前的婴幼儿。
成人Alport综合征患者少见。
2.电镜肾小球基底膜(GBM)的超微结构改变对本病有诊断意义，而且早于光学显微镜改变。
其主要病变有3种：GBM增厚、变薄及两者相间。
变薄的GBM常仅达正常厚度的1/4，多见于儿童及女性;增厚的GBM的可达正常厚度的2～5倍，其上皮侧缘常呈不规则波浪形，增厚的致密带纵向劈裂分层，相互交错成网，网眼中含有类脂颗粒，多见于成人及男性。
如果增厚的GBM广泛存在，并与变薄的GBM相间出现，对本病诊断极有意义。
遗传性慢性进行性肾炎疾病详解
疾病名：遗传性慢性进行性肾炎英文名：hereditary progressive chronic nephritis缩写：别名：遗传性肾炎；奥尔波特综合征；Alport 综合征；Alport's syndrome；AS；hereditary nephritis ；Alport syndrome ；家族性出血性肾炎；familial hemorrhagic nephritis疾病代码：ICD：N07.8概述：遗传性肾炎又称Alport's syndrome(AS)，属一种家族性慢性进行性肾炎，临床特征以血尿为主，部分病例可表现为蛋白尿或肾病综合征。
常伴有神经性听力障碍及进行性肾功能减退。
现今在其遗传方式、临床表现、病理特点方面的认识已比较清楚，且近 10 年来随着分子生物学的迅猛发展，对于AS 的研究已进入分子水平和基因水平。
流行病学：1875 年Dickinson 报道一家三代的血尿患者，1902 年Guthrie 描述了其遗传方式的传递，1927 年Alport 通过对该家系的研究，提出其特点为肾炎性尿沉渣改变、听力下降和进行性肾功能减退，后被称为Alport 综合征。
遗传性慢性进行性肾炎在临床上并不罕见。
世界各地均有报道。
据欧洲透析移植协会(EDTA)报告，1975～1982 年在该会登记的14.1 万病人中，有遗传性慢性进行性肾炎 803 例。
在美国，儿童终末期肾脏病中 2.5%为遗传性慢性进行性肾炎所致，成人中为0.3%。
遗传性慢性进行性肾炎占肾移植患者的 2.3%，截至1997 年我国曾报道88 个家系，遗传性慢性进行性肾炎患者470 人。
病因：病变的根本原因为基底膜的重要组分Ⅳ型胶原不同α链(α1-αa6)的突变，其编码基因称为COL4A1-COL4A6，分别位于不同的染色体上。
约85%AS 病人为性连锁显性遗传(X-Linked AS，XLAS)，致病基因定位于X 染色体长臂中段Xq 22，为编码Ⅳ型胶原α5链(COL4A5)基因突变所致；其余病人为常染色体隐性遗传(autosomal recessive AS，ARAS)和常染色体显性遗传AS(autosomal dominant AS，ADAS)，前者致病基因为COL4A3 或COL4A4 基因，而后者具有遗传多源性。
alport综合征诊断标准
alport综合征诊断标准
Alport综合征的诊断标准主要包括以下几项：
血尿或慢性肾功能衰竭家族史。
肾活检电镜检查有典型改变。
进行性感音神经性耳聋。
眼部异常。
在满足以上4项中的3项时，即可诊断为Alport综合征。
然而，研究表明仅有45%～55%的Alport综合征患者表现有耳聋，眼部异常的发生率仅为30%～40%，因此上述标准过于严格，会有不少患者漏诊。
对于Alport综合征家系患者诊断，在直系家庭成员中应符合标准中的4条，对于旁系成员及仅表现为不明原因血尿、终末期肾病或听力障碍的个体诊断应十分慎重。
若该个体符合相应遗传型，再符合标准2～10中的一条，可拟诊，符合两条便可确诊。
以上信息仅供参考，建议咨询专业医生获取更准确的信息。
Alport综合征【108页】
XLAS Male
正常 1 (IV)
正常 5 (IV)
AS女性 1 (IV)
AS女性 5 (IV)
IF Staining of renal biopsy
1（IV）
3（IV）
4（IV）
5（IV）
Normal
XLAS male
ARAS
IF Staining of renal biopsy
3
5
正常
AS 女性
光学染色
10/24例：IgM阳性
22/24例：GBM弥漫性增厚及厚薄 电 不均，部分致密层出现撕裂、分层 镜
2/24例：GBM大部分均匀变薄、 无分层、撕裂及电子致密物沉积
Alport综合征的病理
近年开展 组织基底膜IV型胶原链 免疫荧光学染色
特异的单克隆抗体： 皮肤：抗1和5链的单抗 肾脏：抗1、 3、 4和5链单抗
Jamshid Khoshnoodi and Karl Tryggvason, Current Opinion in Genetics & Development. 2001, 11:322–327
Glomerular Capillary Loop
Endothelia Basement Membrane Podocyte
spouse consanguineous carriers
Male pt female pt died pt
death index
临床表现——肾脏表现，肾功能
XLAS
男性：开始至“终末肾”：5-10年;各家系不同：
31岁，青少年型；31岁，成年型
女性：40岁约12%; >60岁约30-40% JASN, 2000
Alport综合征
Alport综合征，，即遗传性肾炎，是一种的遗传性肾小球基底膜疾病，是由于编码肾小球基底膜的主要胶原成分-IV胶原基因突变而产生的疾病，临床上表现为血尿及进行性肾功能不全，同时伴有耳病变（高频感音神经性耳聋）和眼部病变（圆锥形角膜、前球形晶状体、黄斑中心凹微颗粒等）肾外表现。
根据遗传方式可分为①X连锁显性遗传（X-linked dominant，XL，约占80%），致病基因在X染色体上，遗传与性别有关。
②常染色体隐性遗传（autosomal recessive，AR；约占15%），致病基因在常染色体上。
③常染色体显性遗传（autosomal dominant，AD；极少数）。
电镜下可观察到Alport综合征特征性的病理改变，GBM广泛增厚、或变薄以及致密层分裂为其典型病变。
GBM致密层可增厚至1200nm （正常为100-350nm），并有不规则的内、外轮廓线； GBM弥漫性变薄（可薄至100nm以下）多见于年幼患儿、女性患者或疾病早期，偶见于成年男性患者。
在肾活检以及简单易行的皮肤活检组织进行免疫荧光检查，可用于诊断X连锁遗传型Alport综合征患者、筛选基因携带者以及判断遗传型，迄今，没有药物可以改善Alport综合征患者组织基膜中IV型胶原的损伤。
对于Alport综合征出现终末期肾病患者，有效治疗措施之一是实施肾移植手术。
Alport综合征
Alport综合征Alport综合征又称眼-耳-肾综合征，为遗传性肾炎中最常见一种。
临床表现似慢性肾小球肾炎。
1875年由DicRinson首先在一个三代血尿家族中报道。
1902年Guthri e报道在一个家族中多人出现血尿，1927年Alport描述除血尿外，患者尚见有听力障碍，男性较女性易进入肾功能衰竭，从而确立本病诊断。
病理变化本病光镜下肾组织改变甚为多样，可表现为肾小球肾炎、间质性肾炎或肾盂肾炎等。
肾小球可有系膜增生、程度不等的基膜增厚或节段性或全小球硬化等改变。
肾小管间质病变与小球病变相平行。
在间质中可见多量泡沫细胞。
免疫荧光检查常无免疫球蛋白沉积。
肾小球基底膜缺乏肾炎源性抗原，与抗肾小球基底膜抗体不起反应，此是诊断价值。
电镜下可见肾小球基膜不规则增厚、断裂，可呈分层状、网状、碎片状或花篮状；肾小管或肾小球囊基膜也有相似病变，但程度较轻。
由于病变累及区域较广，且不伴其它肾小球肾炎之特征性变化，上述电镜下变化有重要诊断意义。
鉴于本征早期肾形态学改变轻微甚至缺如，阴性肾活检结果不能摒除本征。
该病50％为性连锁显性遗传，病变基因位于X染色体长臂中部（X921．3）也有少部分为常染色体显性或隐性遗传。
最近获知，该症的原发缺陷是C0L4A5 基因异常，该基因对应Ⅳ型胶原的α5-多肽。
此外，尚发现有其他基因的异常：如患者血清淀粉样P物质缺乏。
正常情形下，位于2号染色体的基因所决定的Ⅳ型胶原α1、α2-多肽链不应在肾小球基底膜区出现，而在Alport病时则广泛分布在该区。
总之，由于基因的缺陷或异常导致的肾小球基底膜生物合成异常，包括组成、空间结构、理化特性等改变，可能是本症的重要发病机理。
病理临床联系血尿为最主要的临床症状，男性病情较女性重，前者血尿常呈持续性，后者呈间断性甚至无血尿。
常在运动、劳累及呼吸道感染后加重。
早期一般无蛋白尿，随病程进展可渐出现，但达肾病综合征程度者少见。
高血压随年龄及病程而渐出现。
罕见病：奥尔波特综合征的诊疗
罕见病：奥尔波特综合征的诊疗别名：家族性出血性肾炎就诊科室：眼底科耳鼻咽喉科肾病内科概述常见血尿、蛋白尿、听力减退、视力下降等症状；常引发肾性贫血、电解质紊乱、肾衰竭等并发症；为遗传性疾病，无法根治，优生优育是预防关键。
简介奥尔波特综合征是一种罕见的由基因突变引起的遗传性胶原病，具有以下特点的疾病：不明原因的发热、不痒的皮疹、关节肌肉疼、关节肿胀、红细胞在一定条件下的沉降速度升高。
主要病因是编码Ⅳ型胶原蛋白的基因发生突变。
本病可于儿童早期发病，主要临床表现为肾脏病变（血尿、蛋白尿、肾功能进行性恶化）、眼部改变（近视、白内障等）及听力受损（听力下降）等。
目前无法根治，主要通过药物进行干预、手术或透析进行治疗，部分患者预后较好。
若不及时规范有效治疗，可能会导致失明、肾衰竭、甚至死亡。
症状表现：典型症状是肾脏病变（血尿、蛋白尿、肾功能进行性恶化）、眼部改变（近视、白内障等）及听力受损（听力下降）等。
诊断依据：医生通过询问患者的病史（如慢性肾炎综合征、慢性肾功能不全）或家族史，结合临床表现（血尿、蛋白尿、近视、白内障、听力障碍等）、借助实验室检查（血尿、蛋白尿、肾功能不全）、电测听（高频范围听力下降）、眼科检查（前圆锥形晶状体、或后多形性角膜萎缩、或视网膜斑）、组织病理检查（肾脏肾小球基底膜出现大范围的增厚、变薄以及中层纵裂分层的特征性改变等）、基因检查（COL4A3、COL4A4或COL4A5基因缺陷）以确诊。
奥尔波特综合征有哪些类型？1.根据遗传方式的不同，可分为：（1）X连锁遗传；（2）常染色体隐性遗传；（3）常染色体显性遗传；2.根据患病家系发生肾功能衰竭的年龄分为：（1）青少年型；（2）成人型；是否具有传染性？无是否常见？本病罕见。
目前缺乏大样本流行病学数据，发病率尚不清楚。
X连锁遗传者男女均可发病，男性发病率和病情严重程度都高于女性。
是否可以治愈？部分患者可治愈。
主要通过药物进行干预、手术或透析进行治疗。
1Alport综合征
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临床表现
AS临床表现多样，XLAS男性、ARAS病人发病多较早、病情较重，而XLAS女性和ADAS病人 则较晚和较轻 肾脏表现 ➢ 血尿、蛋白尿、肾功能受损，其中血尿是最常见的临床表现，几乎所有XLAS男性和ARAS病
人可见镜下血尿，且多呈持续性，90%以上的XLAS女性和约50%~80% ARAS病人的杂合子 家属可见镜下血尿，约30~70%病人可伴反复肉眼血尿，往往与感染或劳累有关。蛋白尿在发 病初可无或少量，随病程进展可加重，肾病综合征少见。几乎所有XLAS男性和ARAS病人不 可避免进入终末期肾功能衰竭（ESRD），仅部分XLAS女性和ADAS病人可出现肾功能受累 听力改变 ➢ 主要表现为感音神经性耳聋，常累及2~8kHz，病变以双侧为主
➢ 免疫荧光（IF）：多为阴性，少数标本系膜区、毛细血管壁可有IgA、IgG、IgM、C3、C4等局 灶节段或弥漫沉积，有报道及我科资料均显示极少数病人可有IgA在系膜区弥漫沉积，甚至被误 诊为IgA肾病
➢ 电镜：电镜改变多种多样，典型呈弥漫肾小球基底膜（GBM）厚薄不均、分层、网篮样改变， 极少数可见GBM断裂，多数XLAS男性、ARAS病人及少数XLAS女性、ADAS病人表现典型改 变，部分儿童、XLAS女性和ADAS病人表现为弥漫GBM变薄
实验室检查
➢ 皮肤及肾组织IV型胶原不同α链间接免疫荧光检测 正常情况下，IV型胶原α3、 α4 链在GBM、远端肾小管基底膜（dTBM）沉积，而IV型胶原α5链在 GBM、包氏囊（BC）、dTBM、表皮基底膜（EBM）沉积，采用针对α3、α4和α5链的特异性抗体 进行免疫荧光检测，在肾组织及皮肤组织相应部位可见连续线样沉积。在XLAS、ARAS病人肾组 织和皮肤，IV型胶原α3-5链沉积出现异常，见于约75%XLAS男性和50%XLAS女性及部分ARAS 病人。IV型胶原不同α链间接免疫荧光检测具有重要诊断意义，且有助于AS遗传方式的确定
Alport综合征（奥尔波特综合征）
奥尔波特综合征Alport综合征(Alport syndrome,AS又称眼-耳-肾综合征)是以进行性血尿，肾功能不全为主，伴有耳聋和/或眼病变的一种遗传性疾病。
男性比女性发病早且严重，可因肾功能衰竭而死亡。
1927年Alport首次对该病进行详细描述，认为耳聋与肾炎相伴并非巧合，而是一种临床综合征，1954年Sohar报道本病还可出现眼病变。
1961年Wi lliamson将本病正式命名为Alport综合征。
AS并不罕见，在家族性肾炎中约占50%，在欧洲肾脏替代治疗患者中占0.6%。
AS 系单基因遗传病，Ⅳ型胶原基因突变为其病因。
临床表现1.1 肾脏损害：进行性肾脏损害是本病最主要特点和首发症状。
反复发作的肉眼/镜下血尿，在非特异感染、劳累、妊娠后加重，继而出蛋白尿，有时可见红细胞管型尿。
随着病情发展出现肾功能不全、高血压、贫血、高氨基酸血症。
大多数男性患者比女性肾损害发生早且严重。
男患者5岁前全部出现血尿，继而全部出现蛋白尿。
20岁前肾功能恶化，进入慢性肾衰终末期的平均年龄为21岁，甚至有9岁前出现肾功能衰竭者。
30岁以后极少有肾功能正常者。
男患者开始出现高血压的平均年龄为15岁。
女患者除个别与男患者发病时间、程度相近外，绝大多数女患者终生不出现症状。
女性患者出现肾衰晚或不出现肾衰。
女性9岁时76%出现血尿(肉眼血尿36%，镜下血尿40%)，20岁前全部出现镜下血尿，中年时高血压发生率约为1/3，肾功能不全发生率为15%。
1.2 听力障碍：通常为双侧感音神经性聋，也有单侧耳聋者。
早期听力轻度下降，要作纯音测听才能发现。
儿童期听力呈进行性下降，中年后听力损害基本稳定。
即使听力损害较严重的患者也有残余听力。
高频听力损害为主，还有低频下降型和谷型听力减退型。
听力损害程度与肾损害程度有一定的相关性，故可以耳聋程度粗略评估肾脏损害程度。
肾移植后听力有所提高，可能与尿毒症的缓解有关。
听力损害男性也比女性严重：男性患者11岁时已有83%出现听力损害，语言频率范围内听力平均值为66 dB，而女性在中年时只有57%出现明显听力下降，语言频率范围内听力损失平均值50 dB。
alport肾病确诊标准
alport肾病确诊标准Alport肾病（Alport Syndrome，AS）是一种常染色体隐性遗传性肾脏疾病，可导致有重要影响的肾小球滤过功能及以上皮尿管障碍呈典型的血尿的三大特征：肾小球性质病变（慢性肾小球硬化、尿蛋白尿、肾小球衰竭及末转换）、慢性伴有严重的肾小球萎缩性肾病和以上皮尿管障碍性肾病。
此外，Alport肾病发病和表型也有其遗传特征，以某种方式进行的遗传扩散。
它的遗传形式可以是常染色体隐性遗传形式或X遗传形式，其患者表型也会随着家系提前。
Alport肾病诊断是基于患者生物化学及尿蛋白分析，影像检查，血液分析，家族史，临床表型等。
1. 临床表型：一般患者伴有血尿及前列腺炎症状。
2. 尿蛋白分析：24小时尿蛋白测定结果出现无节制的尿蛋白尿，其值一般在3.5g/24h以上，可达到20g/24h或更多，可以增加确诊的可信度。
3. 生物化学检查：血清尿酸升高可影响肾小球萎缩性肾病进程，也可见到肌酐值增加等。
4. 肾脏影像检查：CT或MRI扫描可提示肾脏萎缩，尿管平衡受损和肾小球缺损等。
5. 家族史：Alport肾病有显著的家族史，查询患者家族史可以提供进一步的证据，确认投诉的诊断。
6. 基因分型：血清或细胞因子分析也可作为Alport肾病的工具，可以有效地筛选疾病发病方式，鉴别家族性疾病阴性的潜在的携带者，以及家族结构。
以上是Alport肾病确诊的相关标准，综合诊断结果，结合临床和家族史，在确诊Alport肾病之前，一定要查看患者全面及全面的家族史，而且需要结合家族史，以及检测尿蛋白，血清生化指标，影像学检查结果，将拟诊患者检测Alport肾病相关基因影像等，以达到准确的辅助诊断目的。
奥尔波特综合征的健康宣教
03
家庭成员应帮助患者建立规 律的生活习惯，保持良好的 作息时间。
04
家庭成员应关注患者的情绪 变化，及时提供心理支持和 安慰。
社会支持
01
家庭支持：家庭成员的理
解和支持对康复至关重要
02
朋友支持：朋友提供情感
支持和鼓励，帮助患者度
过难关
03
社区支持：社区提供康复 资源和服务，帮助患者融 入社会
04
腺功能异常
奥尔波特综合 征的预防措施
健康生活方式
保持良好的作息习惯，保证充 足的睡眠
保持适量的运动，每周至少进 行三次有氧运动
保持健康的饮食习惯，多吃蔬 菜水果，少吃油腻食物
保持良好的心理状态，学会释 放压力，保持乐观积极的心态
定期体检
及时发现疾病， 及早治疗
保持良好的心理 状态，避免过度
焦虑和紧张
保持良好的作息习惯，保证 充足的睡眠
保持健康的饮食习惯，多吃 蔬菜水果，少吃油腻食物
保持适量的运动，提高身体 素质
学会释放压力，保持良好的 心态
避免过度劳累，注意休息和 放松
定期进行身体检查，及时发 现并治疗疾病
奥尔波特综合征 的康复与支持
康复计划制定
01
制定个性化的康复计划， 根据患者的具体情况和 需求进行定制
专业支持：康复机构和专
业人员提供康复指导和治
疗，帮助患者恢复健康
谢谢
汇报人：x
奥尔波特综合征的 健康宣教
汇报人：x
目录
01 奥尔波特综合征的基本知识 03 奥尔波特综合征的治疗方法
02 奥尔波特综合征的预防措施 04 奥尔波特综合征的康复与支持
奥尔波特综合 征的基本知识
Alport综合征：从基础到临床
5’
3’
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
COL4A5 基因
基因组DNA分析: PCR-SSCP: 检测率 50~79%
Hum Mutat 1999; Am J Kidney Dis 2001
PCR-直接测序: 检测率85%
J Am Soc Nephrol 1998
COL4A5 基因大小: ~250kb
基因结构: 51外显子 无 “热点突变” 花费高 (51外显子) 已报道的检测率不高(不超过1例: 常染色体隐性
Chin J Pediatr 1999
血尿2年
无家族史 父母非近亲婚配
199例AS中2例为ARAS
Alport综合征:从基础到临床
通过皮肤穿刺进行临床诊断 通过mRNA分析进行基因诊断
COL4A5基因突变后mRNA的表达量
IV型胶原5链甘氨酸替代的影响
新技术-- 5(IV)链mRNA分析
皮肤穿刺 方便 创伤小 3×1mm
2/3 免疫荧光
1/3
皮肤成纤维
细胞培养
RNA提取
RT-PCR
5个相互重叠 的片段
新技术: 5(IV)链mRNA分析
▪ RT-PCR
电泳: 大的缺失/插入
直接测序: 小的/点突变
▪ 通过基因组DNA证实
基因诊断
检测率: 90.3% 3/28 (10.7%) 小的插入或缺失 12/28 (42.8%) 错义突变 2/28 (7.1%) 无义突变 4/28 (14.4%) 单体型 7/28 (25.0%) 剪切突变 4/28 (14.3%) 典型的剪切位点 3/28 (10.7%) 不典型或隐藏的剪切位点
家族性出血性肾炎(Alport综合征)是怎
家族性出血性肾炎（Alport综合征）是怎*导读：本文向您详细介绍家族性出血性肾炎（Alport综合征）的病理病因，家族性出血性肾炎（Alport综合征）主要是由什么原因引起的。
*一、家族性出血性肾炎（Alport综合征）病因*一、发病原因Alport综合征是单基因遗传病，患者是杂合子。
现代认为本病遗传存在异质性，共有3种遗传方式，即性连锁显性遗传、常染色体显性遗传及常染色体隐性遗传。
1.性连锁显性遗传(sex-linked dominant inheritance)为本病主要遗传方式。
由于致病基因在X染色体上，故遗传与性别有关。
母病传子也传女，子女得病机会均等，为50%。
父病不传子，却传全部女儿。
如此，家系中女性患者多于男性患者。
但病情男重于女，因为女性还有一条正常的同源染色体(杂合子)，而男性却无(半合子)。
20世纪80年代中后期一些学者开始该致病基因定位探索，一致发现定位于X染色体长臂中段(Xq22)。
但是，这是什么基因突变当时并不清楚，直至1990年Myers等才证实这突变基因是胶原Ⅳα链亚单位α5(Ⅳ)的基因，即COL4A5。
但是，1993年Zhou等又在此Xq22部位上发现了胶原Ⅳα链亚单位α6(Ⅳ)的基因CoL4A6，并证实COL4A6突变亦可导致本病。
2.常染色体显性遗传(autosomal dominantinheritance)1/7～1/3家系按此方式遗传。
由于致病基因在常染色体上，故遗传与性别无关。
患病父或母亲的儿女得病机会相同，均约一半，父病能传子。
患者病情轻重与性别无关，男、女病情严重度相似。
在发现本病性连锁显性遗传患者的致病基因定位后，人们一直在探索该遗传方式患者的致病基因定位。
已知胶原Ⅳα链其他4个亚单位的基因均在常染色体上：α1(Ⅳ)及α2(Ⅳ)的基因COL4A1及COL4A2定位于染色体13;α3(Ⅳ)及α4(Ⅳ)的基因COL4A3及COL4A4定位于染色体2。
奥尔波特综合征(Alport--syndrome)
奥尔波特综合征(Alport--syndrome)奥尔波特综合征(Alport syndrome)奥尔波特综合征(Alport syndrome)，又名奥尔波特氏综合征(Alport’s syndrome),也被称作遗传性肾炎（hereditary nephritis）。
可在罕见疾病网上查询：Q87.801，奥尔波特氏综合征（遗传性肾炎和耳聋）。
Alport syndrome or hereditary nephritis is a genetic disorder characterized by glomerulonephritis, endstage kidney disease, and hearing loss. Alport syndrome can also affect the eyes (lenticonus). The presence of blood in the urine (hematuria) is almost always found in this condition.It was first identified in a British family by Dr. Cecil A. Alport in 1927, though William Howship Dickinson is considered by some to have made contributions to the characterization.病因：Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structuralcomponent of basement membranes in the kidney, inner ear, and eye. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein into the urine.The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.遗传方式：Alport syndrome can have different inheritance patterns that are dependent on the genetic mutation.In most people with Alport syndrome, the condition is inherited in an X-linked pattern, due to mutations in the COL4A5 gene.A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.Alport syndrome can be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. Past descriptions of an autosomal dominant form are now usually categorized as other conditions, though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published.临床诊断：Gregory et al., 1996, gave the following 10 criteria for thediagnosis of Alport syndrome; Four of the 10 criteria must be met:1. Family history of nephritis of unexplained haematuria ina first degree relative of the index case or in a male relative linked through any numbers of females.2. Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney disease or IgA nephropathy.3. Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30 years.4. A mutation in COL4An (where n = 3, 4 or 5).5. Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.6. Widespread GBM ultrastructural abnormalities, in particular thickening, thinning and splitting.7. Ocular lesions including anterior lenticonus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.8. Gradual progression to ESRD in the index case of at least two family members.9. Macrothrombocytopenia or granulocytic inclusions, similar to the May-Hegglin anomaly.10. Diffuse leiomyomatosis of esophagus or female genitalia, or both.(The use of eye examinations for screening has been proposed.)免疫组织化学：Immunohistochemical (IHC) evidence of the X-linked form Alport syndrome may be obtained from biopsies of either the skin or the renal glomerulus. In this processes, antibodies are used to detect the presence or absence of the alpha3, alpha4, and alpha5 chains of collagen type 4.All three of these alpha chains are present in the glomerular basement membrane of normal individuals. In individuals expressing the X-linked form of Alport's syndrome, however, the presence of the dysfunctional alpha5 chain causes the assembly of the entire collagen 4 complex to fail, and none of these three chains will be detectable in either theglomerular or the renal tubular basement membrane.Of these three alpha chains, only alpha5 is normally expressed in the skin,[citation needed] so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.治疗：As there is no known cure for the condition, treatments are symptomatic. Patients are advised on how to manage the complications of kidney failure and the proteinuria that develops is often treated with ACE inhibitors, although they are not always used simply for the elevated blood pressure.Once kidney failure has developed, patients are given dialysis or can benefit from a kidney transplant, although this can cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.Gene therapy as a possible treatment option has been discussed.另附一篇关于本病的介绍：Diseases of the Kidney: Alport SyndromeVersion of Aug 31, 1999These citations, from the three most recent editions of the large three-volume monograph "Diseases of the Kidney," refer to comprehensive clinical descriptions of Alport syndrome by our University of Utah group.CL Atkin, MC Gregory, WA Border. Alport syndrome. Pp 617-641 (Chapter 19) in RW Schrier, CW Gottschalk (Eds), Diseases of the Kidney, 4th ed, Little, Brown & Co., Boston, 1988.MC Gregory, CL Atkin. Alport syndrome. Pp 571-591 (Chapter 19) in RW Schrier, CW Gottschalk (Eds), Diseases of the Kidney, 5th ed, Little, Brown & Co., Boston, 1993.MC Gregory, CL Atkin. Alport's Syndrome, Fabry's Disease, andNail-Patella Syndrome, chapter 19 in RW Schrier, CW Gottschalk (Eds), Diseases of the Kidney, 6th ed, Little, Brown & Co., Boston, pp. 561-590, 1997. NLM Call No.WJ 300 D611 1996, ISBN 0-316-77456-1."Diseases of the Kidney" may be purchased from the publisher, but is readily found in medical school libraries. I, Curtis L. Atkin, have as yet been unable to obtain the publisher's permission to completely reprint here this copyrighted material. The following essay was adapted and condensed from these Chapters by Dr Martin C. Gregory for the HNF Newsletter No. 27, September 1995. My notes and emendations to Dr Gregory's piece are [bracketed].---------------------------------------------------------------------INTRODUCTIONHereditary nephritis is a disparate group of often ill-defined conditions that are similar only in that they run in families and present many diagnostic difficulties. Because the incidence and diversity of such diseases are not generally recognized, opportunities for timely diagnoses and genetic counseling are lost. The most common and best known hereditarynephritis is Alport syndrome. In this chapter, Alport syndrome will be defined as progressive hereditary hematuric nonimmune glomerulonephritis characterized ultrastructurally by irregular thickening, thinning, and lamellation of the glomerular basement membrane (GBM). In some kindreds nonrenal features occur. These include hearing loss, various ocular defects, abnormalities of platelet number and function, granulocyte inclusions, and esophageal and genital leiomyomatosis (tumors). We regard nonrenal features as helpful diagnostic pointers in some kindreds, although they are not essential to the diagnosis.---------------------------------------------------------------------DISEASE DEFINITIONSTerminology and diagnostic criteria in many reports vary, and it is difficult to define exactly what Alport syndrome or progressive hereditary nephritis should include. Alport did not perform renal histological studies and as his kindred "has rid itself of Alport's disease," no means exist for defining the syndrome he described in modern terms. This kindred had dominantly inherited kidney disease that was characterized inboth sexes by hematuria and urinary erythrocyte casts, variable proteinuria, and especially in males by progressive hearing loss and renal failure. Affected males had hearing loss, died in adolescence, and had no offspring. Progressive azotemia (excesses of urea and creatinine in the blood) and ESRD (end stage renal disease) especially in males, complex ultrastructural anomalies of GBM (glomerular basement membrane), and negative glomerular immunofluorescence studies are characteristics of all types of Alport syndrome. Eventual ESRD of nearly all affected males is a central feature. [Now that Type IV disease (below) is better understood, it has become clear that hearing loss essentially always accompanies renal failure in Alport syndrome]. Many reports have expanded the classic dyad of aural and renal symptoms to include other associated nonrenal anomalies and traits [such as] thrombocytopathia (bleeding disorder characterized by defective platelets), ocular abnormalities, or leiomyomatosis. [Anti-basement membrane collagen antisera that bind] normal GBM and epidermal basement membrane (EBM) fail to bind these membranes in many but not all Alport kindreds].----------------------------------------------------------AFFECTED INDIVIDUALSChronic hematuria (blood in the urine) is the cardinal sign of Alport syndrome. Persons with hematuria and a gene for Alport syndrome are affected. Clinically normal gene carriers (preponderantly females) should be identified for genetic studies, counseling, and selection of kidney donors; it is, however, misleading to characterize them as affected persons. Our minimal criterion for affectedness is greater than or equal to 3 red cells per high-power field of the centrifuged fresh urine sediment (with rigorous exclusion of menstrual blood) but choice of [either 1 or more, or of 10 or more] erythrocytes per field would change few diagnoses. Urinary erythrocyte casts and proteinuria support the diagnosis of Alport syndrome, but are not necessary for it, whereas other urinary findings (pyuria, positive urine cultures, or proteinuria in the absence of hematuria) are not signs of Alport syndrome. The prime criterion for ascertainment of Alport syndrome in kindreds is the demonstration of a family history of chronic glomerulonephritis in multiple closely related persons.----------------------------------------------------------CLASSIFICATIONClinical features regularly displayed by affected persons in a kindred define the characteristic phenotype of Alport syndrome in that kindred. The severity [and timing] of symptoms may vary [amongst relatives] according to age and gender, [yet many kindreds show statistically distinct averages]. Kindreds clearly differ in [rates of progression of renal failure,] typical ages of ESRD, [rates of progression] of hearing loss, [and presence of] ocular abnormalities. Different phenotypes and different modes of inheritance [demonstrate genetic heterogeneity and phenotypic heterogeneity] of Alport syndrome.Juvenile versus Adult Types of Alport Syndrome. Schneider first recognized that males in some kindreds with Alport syndrome experienced ESRD in childhood or adolescence, while in other kindreds, males that had ESRD were middle-aged. Bimodality of age of ESRD has been shown repeatedly; juvenile kindreds are those in which males develop ESRD at a mean age below 31 years; in adult types of Alport syndrome ESRD occurs in males at a mean age greater than 31 years.Major Types of Alport Syndrome. Our analysis of 65 kindreds indubitably suffers from nonuniformity of diagnostic criteria in the original reports, but most fit the following classification well. [The scheme, however, grows ever more obsolete; in particular it does not include autosomal recessive inheritance. Nascent, improved classifications are based on DNA analyses and difficult but gradually improving discrimination of clinical features (phenotype).]Type I Alport Syndrome is dominantly inherited juvenile type nephritis with hearing loss, where affected males have no offspring. Pedigree analyses are uninformative for X-linked vs. autosomal dominant inheritance. Type I is an interim category subject to reclassification because ESRD treatment may now allow the affected males to reproduce, or newer genetic methods may allow chromosomal localization of the nephritis genes. Ocular abnormalities are restricted to the juvenile types (I, II, VI) of Alport syndrome, but may not be present in all kindreds with juvenile disease.Type II Alport Syndrome is X-linked dominant, juvenile typenephritis with hearing loss [caused by mutations of the COL4A5 gene for alpha-5 chain of basement membrane (Type IV) collagen]. Types II and VI Alport syndrome may be difficult to distinguish because most of the kindreds have few offspring of affected males.Type III Alport Syndrome is X-linked dominant, adult type nephritis with hearing loss [caused by mutations of the COL4A5 gene].Type IV Alport Syndrome is X-linked dominant, adult type nephritis [caused by mutations of the COL4A5 gene. Until the advent of dialysis and transplantation, families had no marked hearing loss, but now it is clear that hearing loss follows a decade or so after ESRD; see reference 38 in our Bibliography].Type V Alport Syndrome is autosomal dominant nephritis with hearing loss and thrombocytopathia. Type V corresponds to McKusick's category No. 15365, (Epstein Syndrome). This disease has been reported in 12 families and 4 sporadic cases; there were clear instances of male to male transmission.Because ESRD data were limited, the distinction of juvenile- vs. adult-type Alport syndrome could not be made in these kindreds. Prevalence of ESRD of females with type V disease may approach that of males, but data are scanty. [See additional article by Dr. Gregory, "Macrothrombocytopathy, Nephritis, and Deafness (Epstein syndrome; Alport syndrome with Macrothrombocytopenia) in the HNF Newsletter No. 27, September 1995. The responsible genes are unknown as of 5/99]Type VI Alport Syndrome is autosomal dominant, juvenile type nephritis with hearing loss [caused in at least some cases by mutations in COL4A3 and COL4A4 genes for alpha-3 and -4 chains of basement membrane (Type IV) collagen. Other autosomal genes are sought].Indeterminate types of Alport Syndrome are unclassifiable as types I-VI in the above scheme. Nineteen of the 65 kindreds in our retrospective study were unclassifiable. Alport syndrome associated with leiomyomatosis is another distinct entity [caused by large deletions spanning the adjacent X-linked COL4A5 and COL4A6 genes and perhaps other genes, making it a "contiguous gene syndrome"].---------------------------------------------------------------------GENE FREQUENCYThe estimated gene frequency [for X-linked Alport syndrome] is 1:5000 in the Intermountain West of the United States. Shaw and Kallen estimated Alport syndrome gene frequency 1:10,000 elsewhere in the United States. We could not estimate worldwide incidence of Alport syndrome. It has been reported in many races and is probably not associated with race or geography. We believe that the observed incidence of Alport syndrome in Utah is about twice that elsewhere, not because of the "founder principle", but because of the unusual extent of our studies. The origins and large founding size of the Utah population, and high rates of gene flow have resulted in gene frequencies that are similar to those in northern Europe.[Dr David Barker tentatively estimates the frequency of autosomal recessive (COL4A3 and COL4A4) mutations at 1:250.]---------------------------------------------------------------------MODES OF INHERITANCEPenetrance and Dominance. Hematuria and ESRD are both manifestations of Alport syndrome, with penetrances that eventually coincide in males, but may be widely disparate in females. Penetrance of hematuria and ESRD is 100% in males with types II, III, and IV disease. For types I, V, and VI hematuria and ESRD likely also approach 100%. For females with types III or IV disease prevalence of hematuria is 90% and eventual prevalence of ESRD in females approximates 15%. ESRD may supervene in close to 100% of females with type V disease. In both males and females the penetrance of hematuria remains constant with age.[X-linked recessive inheritance has in past been implicated from observations of ESRD in most males and much less ESRD in females. In truly X-linked recessive traits such as hemophilia and colorblindness, males are affected and females are clinically normal. In Alport syndrome, however,] hematuria indicates nephritis in most gene-carriers of either [gender. Thus X-linked recessive Alport syndrome is a specious category].X-linked Dominant Inheritance. Starting with the original studies of Utah Kindred P, forms of X-linked, sex-linked, or gender-influenced inheritance have been proposed in a minority of reports on Alport syndrome. In the large Utah kindreds there were numerous offspring of affected males but no male to male transmission when stringent diagnostic criteria were applied. Classical genetic analysis and likelihood analysis established X-linkage in several kindreds. X-linkage was proven for various kindreds with types II, III, and IV Alport syndrome by findings of close genetic linkage of the Alport locus ATS to restriction fragment length polymorphic markers in or near the Xq22 chromosomal region. Genetic linkage of nephritis with mutations in the COL4A5 gene proves X-linkage in some of the same and other kindreds. Similar linkage to highly polymorphic microsatellite markers within the COL4A5 proves X-linkage in still other families. [X-linkage characterizes roughly 85% of Alport families.][Autosomal Recessive Inheritance characterizes about 15% of Alport families. Regardless of gender, the full array of symptoms are suffered not only by homozygotes of COL4A3 or -4 mutations, but also by double heterozygotes of the COL4A3 and-4 genes. It is becoming clear that heterozygotes of either COL4A3 or COL4A5 may show some but decreased symptoms.]Autosomal Dominant Inheritance. Male to male transmission established autosomal dominant inheritance of Alport syndrome in kindreds which may be categorized as having types V or VI Alport syndrome. [Autosomal dominance characterizes roughly 1% of Alport families. Some but not all of them have mutations of COL4A3 or COL4A4 genes.]---------------------------------------------------------------------GENETIC COUNSELINGDominant inheritance of Alport syndrome may be assumed even with minimal pedigree information. As a group, males with Alport syndrome have about 30% fewer children than normal; many males with juvenile type disease will have no offspring.Incomplete penetrance of Alport syndrome in females must always be kept in mind. In kindreds with X-linkage, daughters of affected males will all be gene carriers regardless of their urinalysis results. Unless there is information from geneticmarkers or from urinalyses of the next generation, each clinically normal daughter of the three other sorts of gene carrier parents (mothers in kindreds with X-linkage, and parents of either sex in kindreds with autosomal dominance) stands a real probability of having an undetected nephritis gene.---------------------------------------------------------------------CLINICAL FEATURES, TYPES I-VIRenal Symptoms. Hematuria is the cardinal feature, persistent and present from birth in males and in 80-90% of females who have a nephritis gene. The child's mother may note occasionally or persistently red diapers, but hematuria is usually inconspicuous in adult-type disease. Episodes of gross hematuria may follow sore throats or other infections in children and may be the presenting symptom. Macroscopic hematuria is not common in adults and perhaps a feature of juvenile types of disease. Red cell excretion rate is increased by acute infections and by pregnancy.In adult types of Alport syndrome, renal function is typicallynormal for years and then wanes inexorably to renal failure. The reciprocal of serum creatinine falls linearly with time during this phase (roughly six years from early to end-state renal failure in adult-type Alport syndrome); hypertension appears, and worsens as renal function deteriorates. Crescentic glomerulonephritis may occur, especially in juvenile types of Alport syndrome, and be accompanied by rapidly progressive renal failure.With either juvenile or adult type Alport syndrome, renal failure is inevitable for affected males, but few females become uremic, and then generally when elderly. ESRD of females in kindreds with type V Alport syndrome may be as frequent as for the males.Sensorineural Hearing Loss. Kindreds with type IV Alport syndrome and some with indeterminate type Alport syndrome have socially normal hearing, whereas progressive and ultimately profound, bilateral, sensorineural hearing loss distinguishes kindreds with all other types. Patients can be unaware of a high frequency loss that is readily shown by audiometry (hearing test). Hearing loss generally occurs later, lessseverely, and less frequently in females, although some women and girls may have a profound loss. In some families with Alport syndrome and hearing loss, affected members may have apparently normal hearing even after ESRD, but as a rule those family members without hearing loss have less severe renal disease. In Utah Kindred P with type III Alport syndrome, noticeable hearing loss generally coincides with the onset of renal failure.Ocular Features. Eye defects appear limited to kindreds with juvenile type nephritis with hearing loss. In start contrast to hearing loss, which is common in hereditary nephritis, but not specific for it, anterior lenticonus [protrusion of the substance of the crystalline lens] is uncommon though nearly pathognomonic. All cases of anterior lentinconus reported between 1964 and 1982 have been associated with nephritis and/or hearing loss. Lenticonus is more common in males and is usually, but not invariably, bilateral.---------------------------------------------------------------------DIAGNOSISThe path to the correct diagnosis lies through a carefully extended family history and personal examination of the urinary sediment, specifically for hematuria. The proband will commonly be a child with unexplained hematuria or an adolescent to middle-aged male with ESRD, with a vague history of kidney disease in brothers or relatives on the maternal side. Systematic urinalyses may reveal several relatives with hematuria.Of great interest are the forthcoming genetic methods of diagnosis. It appears that probing with cDNAs from COL4A5 will reveal mutations in equal to or less than 10% of kindreds. Emerging techniques with microsatellite markers within COL4A5, exon scanning, single stranded DNA fragment conformational analyses, etc., should soon provide specific genetic tests for gene-carrier status in most families.---------------------------------------------------------------------TREATMENTNo specific treatment is known to affect the underlying pathological process or to alter the clinical course.Antibiotics, anticoagulants, steroids, and immunosuppressives have wrought no benefit. Control of hypertension is mandated on general grounds and protein restriction may prove to be of value once nephron loss gives rise to hyperfiltration. Management of advancing renal failure is along conventional lines. When terminal uremia occurs, dialysis and transplantation pose no particular problems, although the lack of certain GBM antigens invites a slender risk of de novo anti-GBM nephritis after transplantation. Except for one unconvincing example, the glomerular defect of Alport syndrome has not recurred after transplantation. Particular care must be taken in selection of living donors: meticulous and repeated urinalysis for hematuria is the most important step.Great care should be taken to avoid adding insults from drug ototoxicity to the advancing aural injury. Improvement or stabilization of hearing loss has occasionally been noted after transplantation of Alport patients; others have noted no benefit nor have we. Interpretation of these findings is difficult because dialysis or the uremic state have been held culpable for reversible hearing loss. When hearing lossworsens the patient will become more dependent on lip-reading and other visual cues. We have observed poor to fair success with hearing aids. Visual acuity should be monitored at intervals in those with or at risk of lenticonus and consideration given to early lens extraction and intra-ocular lens implantation. Keep steroid doses low after transplantation and monitor regularly for cataracts; poor vision is a disproportionate handicap to the deaf.关于奥尔波特综合征患者肾移植后排斥的报告奥尔波特综合征患者移植肾失功的主要原因是慢性同种异体移植物肾病(69%)和急性排斥反应(22%)。
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奥尔波特综合征Alportsyndrome
概述
奥尔波特综合征 Alport syndrome（本文后称 Alport 综合征）是一种遗传性胶原病，为编码Ⅳ型胶原蛋白α-3 链、α-4 链和α-5 链的基因COL4An（n=3、4、5）突变导致的基底膜病变。
最常累及肾脏，其次累及眼和耳。
由于上述突变导致器官胶原结构异常，进而表现为遗传性肾小球疾病，包括血尿、蛋白尿及肾功能进行性下降，常伴有感音神经性听力损失和眼部异常。
病因和流行病学
由于缺乏大样本流行病学数据，发病率尚不清楚。
美国报告的Alport 综合征的基因频率为1/10 000～1/5000。
男性和女性的发病率及病情轻重与突变基因类型有关。
X 连锁遗传者男女均可发病，但男性发病率高于女性，且病情较女性重。
Alport综合征病理机制的分子基础是编码Ⅳ型胶原蛋白的基因发生突变，使其α-3链、α-4链或α-5链结构和功能异常，进而导致肾小球、眼及内耳基底膜的Ⅳ型胶原结构和功能损害而致病。
常见的遗传方式依次为X连锁遗传（80％～85％）、常染色体隐性（15％）遗传和常染色体显性遗传（5％）。
表现为X连锁遗传者几乎均为COL4A5基因突变。
该基因位于X染色体q22片段，编码Ⅳ型胶原蛋白α5链（α5【Ⅳ】）。
常染色体隐性遗传及显性遗传者为COL4A3或COL4A4基因突变，该基因位于2号染色体，编码Ⅳ型胶原蛋白α3及α4链。
突变基因和突变类型的不同决定其临床表现的差异。
COL4A5基因缺失及严重的剪接错误会导致严重的肾脏损伤和早期听力损失；错义突变可能会造成青少年型听力损失、成人型伴或不伴有听力损失。
COL4A5基因5’末端及邻近COL4A6基因5’末端缺失则可能出现食管和生殖器平滑肌瘤。
COL4A3或COL4A4基因（染色体2）突变的纯合子或杂合子会表现为常染色体隐性的Alport综合征，杂合子突变则表现为良性家族性血尿的疾病（如家族性薄基底膜病TBMD）。
临床表现
Alport 综合征可于儿童期早期起病。
典型的临床表现包括肾脏、眼部改变及听力受损。
肾脏表现为血尿、蛋白尿和肾功能进行性恶化，其中血尿常为持续性镜下血尿，可在运动后或发热时出现肉眼血尿，更常见于青少年型。
听力改变为感音神经性听力损失，并随病程逐渐加重，但需注意进展为ESRD的X染色体连锁遗传患者不一定会出现明显听力下降，因此不能将听力下降视为Alport综合征固有特征，否则容易造成漏诊。
眼部异常表现为近视、青年环和白内障，但缺乏特异性。
三种具有诊断意义的眼部改变包括：前圆锥形晶状体、后多形性角膜萎缩和视网膜斑（视网膜中心凹区域周围的白色或黄色颗粒）。
我国男性患者听力受损发生率高于国外报道（68％比 55％），女性则低于国外报道（7％比 45％），眼异常发生率与国外报道相近。
少数患者还可出现平滑肌瘤，可累及呼吸道、胃肠道及女性生殖道；偶有动脉瘤病变、面中部发育异常和精神发育迟滞的报道。
患者常有家族史。
常染色体隐性遗传患者或X 连锁遗传的男性患者病情进展较快，常于16～35 岁进入终末期肾病；而常染色体显性遗传和X 连锁遗传的女性患者多病程较为缓慢，肾功能衰竭出现较晚。
在同一个患病家系中，所有男性成员发生肾功能衰竭的年龄相似，但不同家系中的男性成员发生肾功能衰竭的年龄可以不同。
因此，可根据患病家系发生肾功能衰竭的年龄分为：青少年型（肾衰竭发生在青少年时期）与成人型（肾衰竭发生在成年以后）。
其中青少年型肾外表现更为突出，男孩通常在繁衍后代前即死亡，致病基因常为新发突变；而成人型家系中的患者较年长，较少新发突变。
辅助检查
1. 实验室检查尿常规检查显示镜下血尿和蛋白尿。
肾功能检查提示血肌酐逐渐升高最终达到终末期肾病水平。
随肾功能恶化，还会伴
发其他化验异常。
如血常规检查提示正细胞正色素性贫血，代谢性酸中毒及电解质异常，低血钙、高血磷、血甲状旁腺素水平升高等。
2.电测听早期表现为高频范围听力下降。
随病程进展，听力下降范围逐渐扩大，甚至发展为全音域。
双侧耳聋程度可不完全对称。
3.眼科检查可发现视力下降、白内障，但具有诊断性的三类病变为：前圆锥形晶状体、后多形性角膜萎缩和视网膜斑。
4.组织病理改变
①肾脏活检：特征性改变需电子显微镜下观察到肾小球基底膜（GBM）广泛增厚、变薄以及致密层网篮状纵裂分层。
光镜下无特征性的病理变化，但常可见到GBM染色不良、婴儿样肾小球和肾间质泡沫细胞，肾小球可出现局灶节段系膜损伤和毛细血管壁增厚，约30％肾小球可见球囊粘连。
免疫荧光学检查也无特异性，有时可见系膜区及沿GBM节段或弥漫性颗粒状C3和IgM沉积，有时为全阴性。
②皮肤活检：光镜没有特异性改变。
但皮肤和肾脏组织的Ⅳ型胶原免疫染色可发现Ⅳ型胶原α-3链、α-4链和（或）α-5链缺失或异常分布。
5.基因检查是诊断本病的金标准。
可表现为COL4A3、COL4A4或COL4A5基因缺陷。
诊断Alport 综合征诊断依靠临床表现、组织病理、家系分析及基因诊断。
慢性肾炎综合征合并慢性肾功能不全的患者，如果有家族史，同时存在高频范围听力下降、前圆锥形晶状体、或后多形性角膜萎缩、或视网膜斑；病理检查发现肾脏GBM 出现广泛的增厚、变薄以及致密层纵裂分层的特征性改变，肾脏或皮肤组织Ⅳ型胶原免疫染色发现Ⅳ型胶原α-3 链、α-4 链和（或）α-5 链缺失或异常分布，则高度提示本病，确诊需要检测COL4A3、COL4A4 或COL4A5 基因缺陷。
鉴别诊断
1. 需要与表现为血尿、蛋白尿及肾功能损害的慢性肾小球肾炎，尤其是IgA肾病和薄基底膜肾病鉴别。
可通过家族史、听力检测、眼科检查、皮肤或肾脏活检进行鉴别。
2. 如同时存在肾炎、感音性耳聋病史及家族史者，还需与
Epstein 综合征/Fechtner 综合征进行鉴别，这两类疾病为 22 号染色体编码非肌肉肌球蛋白重链9（MYH9）的基因突变所致，可通过基因诊断鉴别。
3. 药物如氨基糖苷类抗生素可同时造成听力下降及肾功能异常，需仔细询问病史、用药史帮助鉴别。
治疗
Alport 综合征暂无根治疗法。
目前治疗以支持和肾脏替代治疗为主。
1. 非特异性药物干预肾素-血管紧张素系统（RAAS）抑制剂，包括血管紧张素转化酶抑制剂、血管紧张素Ⅱ受体拮抗剂和醛固酮受体拮抗剂等可以通过抑制RAAS 活化、调整球管反馈，降低肾小球高滤过而减少蛋白尿，延缓肾小球硬化和疾病进展。
但需要监测血钾和肾功能，警惕高钾血症和肾功能快速进展的副作用。
此外，需对症处理肾功能不全所带来的并发症，如肾性高血压、钙磷代谢异常、肾性贫血和电解质、酸碱平衡紊乱。
2. 肾脏替代治疗对于进展到终末期肾病的患者需进行肾脏替代治疗，可选择血液透析、腹膜透析和肾脏移植。
肾移植术后需警惕发生抗肾小球基底膜病，尤其是 COL4A5 基因突变患者更需关注。
3. 耳鼻喉科处理助听器有助于改善下降的听力，但不能完全纠正听力异常；耳鸣通常对任何治疗无效，助听器可通过扩大外周声音而减小耳鸣干扰。
4. 眼科处理视网膜病变通常不会影响视力，不需要治疗；圆锥晶状体或白内障造成的严重视力损害不能通过眼镜或隐形眼镜矫正；晶状体摘除及眼内晶体植入是行之有效的标准治疗。
5. 患者管理包括疾病多学科综合管理。
建议在肾脏内科、耳鼻喉科及眼科规律随诊，定期评价患者慢性肾病并发症、听力及视力改变。
避免肾毒性药物、耳毒性药物，避免长期暴露于高噪音环境。
遗传咨询患者及基因携带者需要进行遗传咨询，必要时需要进行产前诊断。