X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.
Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.
Jais
Jean Philippe
JP
Biostatistique et Informatique Médicale, U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
Knebelmann
Bertrand
B
Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
Giatras
Iannis
I
Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
Marchi
Mario DE
M
The Italian Multicenter Study on Alport Syndrome, Italy.
Rizzoni
Gianfranco
G
The Italian Multicenter Study on Alport Syndrome, Italy.
Renieri
Alessandra
A
The Italian Multicenter Study on Alport Syndrome, Italy.
Weber
Manfred
M
Hospital Köln Merheim, Cologne, Germany.
Gross
Oliver
O
Hospital Köln Merheim, Cologne, Germany.
Netzer
Kai-Olaf
KO
Hospital Köln Merheim, Cologne, Germany.
Flinter
Frances
F
Guy's Hospital, University of London, United Kingdom.
Pirson
Yves
Y
Université Catholique de Louvain, Belgium.
Verellen
Christine
C
Université Catholique de Louvain, Belgium.
Wieslander
Jörgen
J
University Hospital, Lund, Sweden.
Persson
Ulf
U
University Hospital, Lund, Sweden.
Tryggvason
Karl
K
Karolinska Institute, Stockholm, Sweden.
Martin
Paula
P
Karolinska Institute, Stockholm, Sweden.
Hertz
Jens Michael
JM
Aarhus University Hospital, Denmark.
Schröder
Cornelis
C
University Hospital of Nijmegen, The Netherlands.
Sanak
Marek
M
Jagiellonian University Medical School, Krakow, Poland.
Krejcova
Sarka
S
Charles University, Prague, Czech Republic.
Carvalho
Maria Fernanda
MF
Curry Cabral Hospital, Lisbonne, Portugal.
Saus
Juan
J
Fundación Valenciana de Investigaciones Biomédicas, Instituto de Investigaciones Citológicas, Valencia, Spain.
Antignac
Corinne
C
Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
Smeets
Hubert
H
University of Maastricht, The Netherlands.
Gubler
Marie Claire
MC
Institut Nationale de la Santé et de la Recherche Médicale U423, Hôpital Necker Enfants Malades, Université René Descartes, Paris, France.
D000328:Adult; D001485:Basement Membrane / Q000378:metabolism / Q000648:ultrastructure; D003094:Collagen / Q000235:genetics; D003638:Deafness / Q000150:complications / Q000453:epidemiology; D018450:Disease Progression; D005128:Eye Diseases / Q000150:complications / Q000453:epidemiology; D015321:Gene Rearrangement; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic; D007678:Kidney Glomerulus / Q000378:metabolism / Q000648:ultrastructure; D016030:Kidney Transplantation; D008297:Male; D009154:Mutation / Q000235:genetics; D009394:Nephritis, Hereditary / Q000150:complications / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D010641:Phenotype; D014960:X Chromosome
D003094:Collagen