A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome

Dagher, Hayat; Buzza, Mark; Colville, Deb; Jones, Colin L.; Powell, Harley R.; Fassett, R. G.; Wilson, D.; Agar, John; Savige, Judy

doi:10.1053/ajkd.2001.29217

Cited by 54 publications

(46 citation statements)

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“…Alport syndrome was diagnosed on renal biopsy in 18 (90%) families, and X-linked inheritance was confirmed with linkage studies in 15 (75%) (8). All participants were older than 14 yr, which is when ocular abnormalities are often first evident in male individuals.…”

Section: Patientsmentioning

confidence: 86%

“…The retinopathy is nevertheless helpful diagnostically because it is specific for Alport syndrome and is usually obvious especially in retinal photographs. Affected female individuals with X-linked Alport syndrome typically have hematuria, and the likelihood of complications increases with increasing age, with approximately 30% eventually developing renal failure, hearing loss, or the ocular abnormalities (7,8). Clinical features in males are often consistent within families, reflecting the strong genetic influence (5).…”

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confidence: 99%

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Alport Retinopathy Results from “Severe” COL4A5 Mutations and Predicts Early Renal Failure

Tan

Colville²,

Wang³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Previous studies of X-linked Alport syndrome demonstrated that "severe" COL4A5 mutations (large deletions and rearrangements, nonsense and frame-shift mutations, and glycine substitutions in the carboxy-terminal residues) were associated with early-onset renal failure, hearing loss, and lenticonus in affected male patients. This study examined whether severe mutations also resulted in the typical perimacular dot-and-fleck retinopathy.Design, setting, participants, & measurements: Twenty unrelated families with X-linked Alport syndrome were studied for the causative mutation in the COL4A5 gene. Nineteen affected male and 22 affected female individuals aged at least 14 yr from these families were examined for clinical and, in particular, ophthalmologic features.Results: Nineteen pathogenic mutations were identified in the COL4A5 gene in the 20 families using a thermal melt analyzer (HRM RotorGene 6000; Corbett) or direct sequencing of hair root or skin fibroblast cDNA. Fifteen mutations were classified severe and four as moderate. Severe mutations were associated with the central dot-and-fleck Alport retinopathy in male individuals (P ‫؍‬ 0.0256) in addition to early-onset renal failure, hearing loss, and lenticonus (P ‫؍‬ 0.0009, 0.009, and 0.009, respectively). Severe mutations did not correlate with clinical features in female individuals.Conclusions: Severe mutations in male individuals with X-linked Alport syndrome are associated with the perimacular dot-and-fleck retinopathy. Furthermore, the retinopathy indicates that male individuals are at increased risk for renal failure before the age of 30 (P ‫؍‬ 0.0007).

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Section: Patientsmentioning

confidence: 86%

mentioning

confidence: 99%

Alport Retinopathy Results from “Severe” COL4A5 Mutations and Predicts Early Renal Failure

Tan

Colville²,

Wang³

et al. 2010

Clinical Journal of the American Society of Nephrology

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“…19,50 Lenticonus may not occur, and central retinopathy is rare. It is therefore debatable whether females should be considered affected or carriers.…”

Section: X-linked Alport Syndrome In Femalesmentioning

confidence: 99%

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

Savige

Gregory

Groß³

et al. 2013

Journal of the American Society of Nephrology

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Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

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“…Se han descrito tres formas de Síndrome de Alport (10,11,12,13). La forma más frecuente es la ligada al cromosoma X y afecta a los varones; las mujeres son portadoras y casi nunca hacen la enfermedad (11).…”

Section: Discusionunclassified

“…La forma de transmisión autonómica recesiva se sospecha cuando ocurre uno de los siguientes hallazgos: i) enfermedad renal temprana y severa en ambos, hombres y mujeres; ii) ausencia de síntomas severos en los padres (pueden ser completamente asintomáticos o tener hematuria microscópica); y iii) padres consanguíneos (4,13). Nuestra paciente cumple con las tres condiciones.…”

Section: Discusionunclassified

Síndrome de Alport autosómico recesivo. A propósito de un caso.

Zerpa

Arakaki²

2012

Rev Med Hered

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RESUMENMujer, de 14 años de edad procedente de San Martín (Perú), ingresó al hospital con historia de tres meses de disnea, palidez e hiporexia, y disminución del volumen urinario en el último mes. Dos semanas antes de su ingreso presentó cefalea global, diplopía y náuseas y vómitos. Acudió al hospital de su localidad donde le indicaron tratamiento con ampicilina y gentamicina, por sospecha de pielonefritis aguda; al no observar mejoría fue trasladada a nuestro hospital. No había antecedentes personales ni familiares de importancia, salvo que los padres eran consanguíneos. Al examen se encontró palidez, opacidades bilaterales en el cristalino, hipoacusia bilateral y flapping. Los exámenes de laboratorio mostraron anemia y retención nitrogenada (urea 233 mg/dL y creatinina 15 mg/dL). El examen de orina mostró alteraciones tubulares, proteinuria y hematuria. La ecografía renal mostró riñones pequeños. El examen ocular reveló catarata nuclear polar posterior en ojo derecho y catarata total en el ojo izquierdo y la audiometría, sordera neurosensorial bilateral. (Rev Med Hered 2008;19:25-28).PALABRAS CLAVE: Alport, hematuria, hipoacusia, insuficiencia renal. SUMMARYWoman, 14 year old from San Martin (Peru), was admitted to hospital with a history of three months of dyspnea, pallor and hyporexia, and decreased urine volume in the last month. Two weeks before his admission presented overall headache, nausea and vomiting. She went to his local hospital where indicated treatment with ampicillin and gentamicin, on suspicion of acute pyelonephritis; but not observe improvement was transferred to our hospital. There were no important personal or family history, except her parents were consanguineous. On physical examination we found pallor, bilateral opacities in the lens, bilateral hearing loss and flapping. Laboratory tests showed anemia and azotemia (creatinine 15 mg/dL and urea 233 mg/dL). Urianalysis revealed tubular abnormalities, proteinuria and hematuria. Renal ultrasonography showed small kidneys. Ocular examination revealed nuclear polar cataract in her right eye and total cataract in the left eye. Audiometry revealed bilateral sensorineural hearing loss. (Rev Med Hered 2008;19:25-28).

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A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome

Cited by 54 publications

References 21 publications

Alport Retinopathy Results from “Severe” COL4A5 Mutations and Predicts Early Renal Failure

Alport Retinopathy Results from “Severe” COL4A5 Mutations and Predicts Early Renal Failure

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

Síndrome de Alport autosómico recesivo. A propósito de un caso.

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