Absence of ocular manifestations in autosomal dominant Alport syndrome associated with haematological abnormalties

Most patients with Alport syndrome have X-linked or autosomal recessive disease that is characterised by renal failure, hearing loss, and, in nearly 75% of the cases, a dot-and-fleck retinopathy and anterior lenticonus. There are only case reports of individuals with the rare autosomal dominant form, who can have haematuria or renal failure, deafness, and, in addition, low platelet counts and neutrophil inclusions. The ocular features of autosomal dominant inheritance have not been described. We have examined the eyes in the members of two families where Alport syndrome was diagnosed on the basis of the clinical features and family history, and where autosomal dominant inheritance was confirmed by father-to-son disease transmission, the associated haematological abnormalities, and haplotypes that segregated with the recently described locus at chromosome 22q. In Family A, the eyes of two individuals with haematuria, hearing loss, and haematological abnormalities and of nine unaffected family members were examined. In Family B, the eyes of two individuals with renal failure, normal hearing, and haematological abnormalities were examined. None of the affected or unaffected members in either family had a dot-and-fleck retinopathy, anterior lenticonus, a history suggesting recurrent corneal erosions, or corneal dystrophy. These results indicate that the protein abnormality in autosomal dominant Alport syndrome does not produce the retinopathy and lenticonus typical of X-linked and autosomal recessive disease. This may be because the abnormal protein is not present or is less important in the ocular basement membranes than elsewhere, or because the presence of a normal allele in autosomal dominant disease compensates for the defective allele.     

Albipunctatus retinopathy in inherited interstitial nephritis

We describe here a patient with familial interstitial nephritis and albipunctatus retinopathy. Albipunctatus is often seen in patients with Alport syndrome, which is an X-linked disorder characterised in affected males by renal failure by the age of 25, high-tone sensorineural deafness, anterior lenti-conus and albipunctatus. The diagnosis of Alport syndrome depends on the electron microscopic appearance of a trabeculated glomerular basement membrane (GBM); and mutations have been demonstrated in the gene for the alpha 5 chain of type IV collagen. In the familial interstitial nephritis described here, the inheritance was autosomal dominant, renal failure developed in middle age, and there was no associated hearing loss or anterior lenticonus.
The finding of albipunctatus retinopathy in this patient suggests that the genetic mutation responsible involves a protein common to both retinal and interstitial basement membranes. In addition, we conclude that the demonstration of albipunctatus in an individual with familial nephritis does not necessarily indicate that the underlying disease is Alport syndrome.     

Ocular abnormalities in thin basement membrane disease

AIM/BACKGROUND—Alport syndrome is an X linked disease that results in renal failure, deafness, and ocular abnormalities including a dot and fleck retinopathy and anterior lenticonus. The ultrastructural appearance of the glomerular basement membrane in thin basement membrane disease (TBMD) resembles that seen in some patients with Alport syndrome, and in some cases this disease is inherited too. The aim of this study was to determine whether patients with TBMD have any ocular abnormalities.
METHODS—The eyes of 17 unrelated individuals with TBMD were studied by slit-lamp, including biomicroscopic fundus examination with a 78 D lens, by direct ophthalmoscopy, and by fundal photographs. The findings were compared with those in patients with IgA glomerulonephritis or Alport syndrome, and in normals.
RESULTS—No patient with TBMD had a dot and fleck retinopathy or anterior lenticonus. A corneal dystrophy (n = 2) or pigmentation (n = 1), and retinal pigment epithelial clumping and maculopathy (n = 1) were noted. Corneal, lens, and retinal dots were found in five (29%), three (18%), and 16 (94%) patients, respectively, but these were also demonstrated in individuals with other renal diseases and in normal individuals.
CONCLUSIONS—The dot and fleck retinopathy and anterior lenticonus typical of Alport syndrome do not occur in TBMD. The protein abnormality and genetic defect in TBMD are not known, but the lack of ocular lesions suggests that the abnormal protein in this disease is more sparsely distributed or less important in the basement membranes of the eye than of the kidney. Alternatively, the protein may be less affected by the mutations responsible for TBMD.

     

Cone dystrophy associated with Alport syndrome

BACKGROUND: Alport's syndrome is a hereditary disease with renal, cochlear, and ocular involvement. We report a patient with Alport's syndrome who exhibited morphologic macular changes similar to cone dystrophy. HISTORY AND SIGNS: A 46-year-old man was evaluated for peculiar macular changes, which have caused a significant decrease in visual acuity over the last years. His general history was remarkable for the presence of sensorineural hearing impairment since infancy as well as end stage renal failure followed by renal transplantation. The ophthalmological findings in this patient included circumscribed macular lesions consisting of atrophy of the retinal pigment epithelium and bilateral anterior lenticonus. CONCLUSION: Alport's syndrome is a characteristic prototype of a genetic basement membrane disease with ocular, renal, and cochlear involvement. Common ocular findings are the dot-and-fleck retinopathy and the anterior lenticonus. In contrary to the anterior lenticonus retinal changes are rarely associated with visual impairment. An association with a macular lesion similar to the cone dystrophy has only infrequently been reported.     

Alport综合征眼部表现

目的 分析Alport综合征眼部病变的特征和发病情况,提高对此病的认识。方法 对14年来我院确诊的5名Alport综合征患者的资料进行回顾性分析,记录其一般情况、家族史、眼部、肾功能及耳科检查结果等。结果 患者均为男性。4人双眼具有典型Alport综合征眼部异常。3人接受肾活检明确诊断,3人有家族史。全部患者均有不同程度的血尿和感音神经性耳聋。结论 青年Alport综合征患者中眼部异常的发生率并不低,其表现有独特性;了解眼部病变特征燕结合全身病史可以提高疾病的确诊率。     

Ophthalmologic assessment of young patients with Alport syndrome.

BACKGROUND: Alport syndrome is an X-linked disease affecting basement membrane collagen. It is characterized by nephritis associated with high-tone sensorineural hearing impairment and ophthalmic signs. Although ocular changes have been described in adults, few data exist regarding the incidence of abnormal ocular features in adolescence and childhood. METHODS: Fifteen male and five female patients with Alport syndrome underwent ophthalmologic, audiologic, and nephrologic assessments. All patients studied had hematuria and a positive family history of Alport syndrome. Thirteen patients had a renal biopsy that showed characteristic electron microscopic changes of the disease. Eleven patients had high-tone sensorineural impairment. Electrophysiologic investigations performed included electroretinography, visual-evoked potentials, and electro-oculography. RESULTS: Two patients had early signs of anterior lenticonus, three had flecks in the retina, and two patients also had posterior subcapsular cataracts. None of the patients had significant electrophysiologic abnormalities. CONCLUSION: These findings indicate that ocular changes are uncommon and subtle in young patients with Alport syndrome, and suggest that the signs increase in frequency and severity with age.     

Rupture of the anterior lens capsule in Alport syndrome

Alport syndrome is an inherited disorder of type IV collagen, a major constituent of basement membranes. Eighty-five percent of cases are transmitted through X-linked dominant inheritance, although autosomal dominant and autosomal recessive inheritance has also been reported. Clinical manifestations of Alport syndrome include progressive glomerulopathy, sensorineural deafness, anterior lenticonus, posterior corneal dystrophy, and abnormal retinal pigmentation. Anterior lenticonus may lead to loss of vision because of progressive myopia or cataract formation. We report 2 cases of unusual cataract formation in adolescent boys who had a rupture of the anterior lens capsule. One rupture was spontaneous, and the other was traumatic.     

Alport综合征的临床表现

目的:分析Alport综合征患者的临床表现和眼部病变的特征。方法:对近21a来我院确诊的31例Alport综合征患者的资料进行回顾性分析,记录其一般情况、家族史、眼部、肾功能及耳科检查结果等。结果:患者中男21例(68%),女10例(32%)。确诊年龄19.8±9.7岁。患者中有17例满足3项以上诊断标准(55%),另外14例均进行了肾穿刺活检电镜检查支持诊断。12例有眼部异常(39%),4例同时有前锥形晶状体和黄斑周围视网膜斑点2项;1例仅有晶状体异常;7例仅有视网膜斑点。28例进行肾穿(90%),电镜检查符合诊断。20例有家族史(64%)。21例有听力障碍(68%)。结论:Alport综合征患者中眼部异常的表现有独特性;了解眼部病变特征并结合全身病史有助于疾病的诊断和随诊。     

Dot-and-fleck retinopathy in Alport syndrome caused by a novel mutation in the COL4A5 gene

PURPOSE: To describe an unusual form of dot-and-fleck retinopathy in a slower progressive form of X-linked Alport syndrome, caused by a novel missense mutation in the COL4A5 gene. METHOD: Ophthalmic examination, polymerase chain reaction, and single-strand conformational polymorphism analysis of genomic DNA were performed in the proband. RESULTS: Ophthalmoscopy revealed classic dot-and-fleck retinopathy but located in an unusual site. A novel COL4A5 gene mutation changing glycine to cysteine at 177 was identified. CONCLUSIONS: Although there is no correlation between mutation site and the resulting phenotype in Alport syndrome, our findings suggest that further novel mutations and different ocular manifestations may be associated with Alport syndrome.     

Bilaterale Visusminderung bei einem jungen Mann

We present the case of a 36-year-old male patient who presented with an increasing bilateral loss of vision which had existed for several years. Slit-lamp examination revealed a conical anterior protusion of the lens and funduscopy showed a discreet perimacular dot and fleck retinopathy. In consideration of all clinical findings the patient was diagnosed with anterior lenticonus as an ocular manifestation of an Alport's syndrome which is a rare X-linked disease. Besides renal failure and hearing loss which occur early, ocular changes usually manifest later on. Patients with a anterior lenticonus can be effectively treated with phacoemulsification and intraocular lens implantation. The visual outcome after surgery is excellent.     

Alport综合征6例临床分析

目的总结Alport综合征的临床特征,尤其是[部表现。方法对6例Alport综合征患者的[部、电听力及肾功能检查结果进行回顾性分析。结果有[部改变者4例,高频感音性神经性耳聋者2例,肾功能衰竭者3例,肾组织活检示Alport综合征改变者2例,阳性家族史5例。结论对于有前锥形晶体和/或视网膜黄斑周围微粒改变者应行肾活检以确诊Alport综合症。     

Alport综合征临床分析

目的总结Alport综合征的临床表现，尤其是眼部特征。方法回顾性分析32例被确诊为Alport综合征患者的内科、耳鼻喉科和眼科检查结果。结果所有患者均有不同程度的。肾脏病变：18例有。肾衰，4例肾功能不全，10例血尿。20例患者有感音神经性耳聋。13例患者有眼部异常表现，其中5例为典型性改变：前圆锥晶体3例，黄斑周围斑点2例。结论眼部异常不是Alport综合征诊断的必需条件，但因其典型的眼科表现应当引起眼科医师的注意。     

Increased microvascular disease in X-linked and autosomal recessive Alport syndrome: a case control cross sectional observational study

Background: Retinal microvascular disease reflects, in part, poor blood pressure control and systemic microvascular disease contributes to renal failure progression. This study examined the retinal microvasculature in Alport syndrome.

Materials and Methods: Retinal images from 28 males and 28 females with X-linked Alport syndrome, and 13 individuals with autosomal recessive disease were reviewed retrospectively for microvascular/ hypertensive retinopathy (Wong and Mitchell classification), and small vessel calibre (using a computerised semiautomated method and revised Knudtson formula). Data were compared with age and gender-matched individuals with normal blood pressure and renal function.

Results: Microvascular/hypertensive retinopathy was more common in males and females with X-linked Alport syndrome than age- and gender-matched controls (23, 82% and 10, 36%, p < 0.01; and 21, 75% and 13, 48%, p = 0.05, respectively), and in individuals with autosomal recessive disease compared with controls (12, 92% and 16, 43%, p < 0.01). Moderate microvascular/hypertensive changes were present in males and females with X-linked or autosomal recessive disease but not controls.

Arteriolar calibre was reduced in males with X-linked disease (142.5 ± 18.7 µm, and 150.7 ± 10.1 µm, p = 0.046) and in autosomal recessive disease (133.5 ± 11.10 µm and 149.1 ± 10.6 µm, p < 0.0001).

Microvascular/hypertensive retinopathy and arteriolar narrowing in males with X-linked disease were not different after renal transplantation and before (p NS).

Conclusions: Microvascular/hypertensive retinopathy was more common and more severe in Alport syndrome than normotensive controls. Improved BP levels may further slow the rate of renal functional decline in Alport syndrome.     

Bull’s eye and pigment maculopathy are further retinal manifestations of an abnormal Bruch’s membrane in Alport syndrome

Background and Objectives: The retinal features of Alport syndrome include a central and peripheral fleck retinopathy, temporal retinal thinning, and a macular hole. Here we describe further retinal abnormalities.

Methods: We identified a case of bull’s eye maculopathy 20 years previously in a 68-year-old female, and reviewed archived retinal images from our cohort of X-linked (28 males, 28 females) or autosomal recessive (n = 13) Alport syndrome. All individuals had Alport syndrome confirmed on genetic testing or renal biopsy, were examined by an ophthalmologist, and underwent retinal imaging (KOWA non-mydriatic camera, Japan).

Results: The index case had the p.Q379X variant in COL4A5 and currently had renal impairment, (eGFR = 45 ml/min/1.73 m²), bilateral hearing loss, and central and peripheral retinopathies. Her maculopathy had deteriorated, and she had a bilateral central visual field loss. Optical coherence tomography (Heidelberg Spectralis) demonstrated a disrupted retinal pigment epithelium and retinal atrophy. We identified a further early bull’s eye maculopathy (1/69, 1.4%) from a female with autosomal recessive disease and normal renal function. We also noted a subtle pigment maculopathy associated with an abnormal retinal pigment epithelium in 27 (27/69, 39%) subjects with Alport syndrome, in both males (8/28, 29%) and females (13/28, 46%) with X-linked disease, and in autosomal recessive disease (6/13, 38%).

Conclusions: The bull’s eye and pigment maculopathies in Alport syndrome result mainly from the damaged Bruch’s membrane and overlying retinal pigment epithelium. Bull’s eye maculopathy affects vision and patients should undergo regular monitoring for retinal complications.     

Posterior polymorphous dystrophy and Alport syndrome

Seventeen Thai patients from nine families with Alport syndrome underwent complete ocular examination and specular microscopy. Fourteen (82.3%) patients had ocular changes. Eleven (64.7%) had endothelial vesicles compatible with posterior polymorphous dystrophy. Four of these also had subepithelial opacities, a previously undescribed phenomenon. Other ocular changes included lenticonus and macular and midperipheral retinal flecks. A second group of 18 consecutive patients from 14 families with posterior polymorphous dystrophy detected during routine ocular examination underwent renal evaluation. Five had hematuria, four of whom had sensorineural hearing loss. Two of the four patients also had characteristic renal biopsy findings. Another had sensorineural hearing loss without hematuria, and renal biopsy showed a thin glomerular basement membrane. Posterior polymorphous dystrophy is a common but frequently overlooked finding in Alport syndrome. The frequent association of these two hereditary conditions suggests a common defect in basement membrane formation. Patients with posterior polymorphous dystrophy should be examined for renal abnormalities and hearing loss.     

Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy

Background and objectives: Alport syndrome is an inherited disease characterized by renal failure, hearing loss, and ocular abnormalities, including temporal retinal thinning. This study compared retinal thinning in Alport syndrome and other renal diseases.

Methods: Alport syndrome was diagnosed on renal biopsy and genetic testing. Subjects underwent optical coherence tomography (OCT) (Spectralis OCT, Heidelberg Instruments). Retinal thinning was determined from horizontal macular OCT scans through the foveal center using the formula: Temporal thickness index (TTI) = (nasal – temporal thickness) ÷ nasal thickness × 100%, and compared with the normal range for each age group. Statistical analysis was performed using Student’s t test, Mann–Whitney U test, and ROC analysis (SPPS, IBM).

Results: The mean temporal retinal thickness index was 12.4 ± 5.2% in men (n = 19) and 7.4 ± 1.4% in women (n = 28) with X-linked Alport syndrome; 13.1 ± 4.5% (n = 4) in recessive disease; 6.4 ± 2.2% (n = 5) in Thin basement membrane nephropathy; and 6.3 ± 3.3% (n = 14) in other renal diseases. Thinning was worse in men than women with X-linked disease (p < 0.01), and worse in men who developed early onset renal failure (R² = 0.75). Temporal retinal thinning was 84% sensitive for men with X-linked Alport syndrome and 67% specific (AUC = 0.83) compared with other renal diseases.

Conclusions: Retinal temporal thinning is diagnostic for X-linked Alport syndrome in men and distinguishes them this condition from Thin basement membrane nephropathy, but only in men (p = 0.002). Temporal retinal thinning may also identify men and women with the rarer autosomal recessive disease.     

Alport综合征眼部临床表现分析

目的:总结Alport综合征的临床表现,尤其是眼部特征。方法:回顾性分析32例被确诊为Alport综合征患者的内科、耳鼻喉科和眼科检查结果。结果:患者30例(93.7%)有疾病家族史。所有患者均有不同程度的肾脏病变:18例(56.3%)有肾功能衰竭,4例(12.5%)肾功能不全,10例(31.3%)血尿。患者20例(62.5%)有感音神经性耳聋。患者13例(40.6%)有眼部异常表现,其中5例(15.6%)为典型性改变:前圆锥晶体3例,黄斑周围斑点2例。结论:眼部异常不是Alport综合征诊断的必需条件,但因其典型的眼科表现应当引起眼科医师的注意,以便早期诊断治疗。     

超声乳化联合IOL植入治疗前圆锥晶状体伴有Alport综合征的视觉效果

目的:观察超声乳化联合IOL植入治疗7眼前圆锥晶状体伴有Alport综合征患者的手术效果。方法:Alport综合征患者4例,7眼因前圆锥晶状体行超声乳化联合IOL植入手术。结果:所有患者的术后视力均有明显提高。结论:我们认为对于前圆锥晶状体伴有Alport综合征患者采用超声乳化联合IOL植入手术治疗,是一种安全的疗法。     

Anterior lens capsule abnormalities in Alport syndrome

Alport syndrome is a hereditary, progressive disease characterized by progressive nephritis, sensorineural deafness, and ocular abnormalities, including anterior lenticonus. The ultrastructure of the lens capsule abnormalities in Alport syndrome is reported. Four anterior lens capsules from 31-year-old patient and 26-year-old patient with lenticonus who were affected by the Alport syndrome were obtained at capsulectomy. And all four anterior lens capsules were examined by transmission electron microscopy. The histopathologic findings showed that the thickness of the anterior lens capsules was decreased (4-13 microm) and that there were many vascular dehiscences localized at the inner part of the lens capsule. There were large numbers of capsular dehiscences containing fibrillar materials and vacuoles. The anterior capsules were clearly fragile in this disease, forming the basis for the progressive lenticonus and anterior polar cataract.     

Phacoemulsification and intraocular lens implantation in Alport syndrome with anterior lenticonus

Eleven eyes of 6 patients with Alport syndrome had phacoemulsification with implantation of a single-piece acrylic hydrophobic intraocular lens (IOL) (AcrySof SA6OAT, Alcon) because of anterior lenticonus. All patients had excellent visual acuity after surgery. We recommend phacoemulsification with IOL implantation as a safe and effective procedure in patients with anterior lenticonus secondary to Alport syndrome.