Search

PURPOSE. The purpose of this study was to compare the natural history of visual function change in cohorts of patients affected with retinal degeneration due to biallelic variants in Bardet-Biedl syndrome genes: BBS1 and BBS10. METHODS. Patients were recruited from nine academic centers from six countries (Belgium, Canada, France, New Zealand, Switzerland, and the United States). Inclusion criteria were: (1) female or male patients with a clinical diagnosis of retinal dystrophy, (2) biallelic disease-causing variants in BBS1 or BBS10, and (3) measures of visual function for at least one visit. Retrospective data collected included genotypes, age, onset of symptoms, and best corrected visual acuity (VA). When possible, data on refractive error, fundus images and autofluorescence (FAF), optical coherence tomography (OCT), Goldmann kinetic perimetry (VF), electroretinography (ERG), and the systemic phenotype were collected. RESULTS. Sixty-seven individuals had variants in BBS1 (n = 38; 20 female patients and 18 male patients); or BBS10 (n = 29; 14 female patients and 15 male patients). Missense variants were the most common type of variants for patients with BBS1, whereas frameshift variants were most common for BBS10. When ERGs were recordable, rod-cone dystrophy (RCD) was observed in 82% (23/28) of patients with BBS1 and 73% (8/11) of patients with BBS10; cone-rod dystrophy (CORD) was seen in 18% of patients with BBS1 only, and cone dystrophy (COD) was only seen in 3 patients with BBS10 (27%). ERGs were nondetectable earlier in patients with BBS10 than in patients with BBS1. Similarly, VA and VF declined more rapidly in patients with BBS10 compared to patients with BBS1. CONCLUSIONS. Retinal degeneration appears earlier and is more severe in BBS10 cases as compared to those with BBS1 variants. The course of change of visual function appears to relate to genetic subtypes of BBS.

International audience; Purpose: Bardet-Biedl syndrome (BBS) is a ciliopathy with a wide spectrum of symptoms due to primary cilia dysfunction, including genitourinary developmental anomalies as well as impaired reproduction, particularly in males. Primary cilia are known to be required at the following steps of reproduction function: (i) genitourinary organogenesis, (ii) in fetal firing of hypothalamo-pituitary axe, (iii) sperm flagellum structure, and (iv) first zygotic mitosis conducted by proximal sperm centriole. BBS phenotype is not fully understood.Methods: This study explored all steps of reproduction in 11 French male patients with identified BBS mutations.Results: BBS patients frequently presented with genitourinary malformations, such as cryptorchidism (5/11), short scrotum (5/8), and micropenis (5/8), but unexpectedly, with normal testis size (7/8). Ultrasonography highlighted epididymal cysts or agenesis of one seminal vesicle in some cases. Sexual hormones levels were normal in all patients except one. Sperm numeration was normal in 8 out of the 10 obtained samples. Five to 45% of sperm presented a progressive motility. Electron microscopy analysis of spermatozoa did not reveal any homogeneous abnormality. Moreover, a psychological approach pointed to a decreased self-confidence linked to blindness and obesity explaining why so few BBS patients express a child wish.Conclusions: Primary cilia dysfunction in BBS impacts the embryology of the male genital tract, especially epididymis, penis, and scrotum through an insufficient fetal androgen production. However, in adults, sperm structure does not seem to be impacted. These results should be confirmed in a greater BBS patient cohort, focusing on fertility.

Introduction/objectifs Le syndrome de Bardet–Biedl (BBS) est lie a une dysfonction de cils primitifs (CP) [1] . La litterature rapporte un hypogonadisme [1] mais la fertilite des hommes BBS n’a jamais vraiment ete etudiee alors meme que des structures ciliees sont impliquees dans l’organogenese genito-urinaire, le demarrage de l’axe hypothalamo-hypophysaire, la mobilite spermatique et que la premiere mitose embryonnaire implique le centriole spermatique proximal. Materiel/patients et methodes La reproduction est etudiee chez 11 patients BBS. Les donnees cliniques et biologiques reproductives sont confrontees au genotype. Enfin, la fecondation in vitro (FIV) est rapportee pour un des patients. Resultats Les malformations genito-urinaires frequemment observees sont : cryptorchidie (5 sur 11), scrotum court (4/8), micropenis (5/8). En revanche, le volume testiculaire est normal (7/8). Quand elle est realisee, l’echographie retrouve des kystes epididymaires ou une agenesie epididymaire. Une hypospermie severe leur semble associee (3/3). Les taux de gonadotrophines et testosterone sont normaux chez tous sauf un. La numeration spermatique est globalement normale (8/10). La mobilite progressive spermatique varie de 5 a 45 %. Quand elle est realisee, la microscopie electronique spermatique ne revele aucune anomalie specifique. Enfin, l’approche psychologique souligne un manque de confiance en soi. Aucune association avec le genotype n’a pu etre etablie. Pour le patient concerne, les differentes etapes de la FIV se deroulent normalement et menent a la naissance d’un enfant bien portant. Conclusions La ciliopathie du BBS altere l’organogenese genito-urinaire masculine, surtout le penis et le scrotum probablement par une production insuffisante d’androgenes fœtaux, mais aussi surtout l’epididyme par un autre mecanisme. La structure flagellaire ne semble pas atteinte. Enfin, le manque de confiance en soi probablement en lien avec la cecite et l’obesite, pourrait expliquer pourquoi si peu de patients BBS expriment un desir d’enfant. Ces resultats demandent confirmation dans une plus grande cohorte de patients BBS.