Paula und Bobby
Eltern von Lillie
Was ist Bardet-Biedl syndrome?
Bardet-Biedl ist eine seltene genetische Störung, die bei ungefähr 1 bei jeder 250,000 Lebendgeburt auftritt.
Die Symptome können zwischen Individuen erheblich variieren und mehrere Körperteile betreffen. Charakteristische Merkmale dieser seltenen Krankheit sind Fettleibigkeit, geistige Behinderung und Probleme in Bezug auf Augen, Nieren und Genitalien.
Obwohl selten, hat die Störung eine höhere Inzidenzrate in Neufundland, Kanada und im Nahen Osten unter Beduinenpopulationen.
Was Genveränderungen verursachen Bardet-Biedl syndrome?
Der Zustand ist das Ergebnis von Fehlfunktionen der primären Zilien. Zilien sind für die Kommunikation zwischen den Zellen verantwortlich. Bisher wurden 24 Gene mit diesem Syndrom in Verbindung gebracht.
Es wird autosomal-rezessiv vererbt. Autosomal-rezessive Vererbung bedeutet, dass eine betroffene Person von jedem ihrer Elternteile eine Kopie eines mutierten Gens erhält, wodurch sie zwei Kopien eines mutierten Gens erhält. Eltern, die nur eine Kopie der Genmutation tragen, zeigen im Allgemeinen keine Symptome, haben jedoch eine 25% ige Chance, die Kopien der Genmutationen an jedes ihrer Kinder weiterzugeben.
Was sind die wichtigsten symptome von Bardet-Biedl syndrome?
Die Hauptsymptome des Syndroms können in ihrer Schwere zwischen Individuen variieren. Einige der weithin anerkannten Symptome sind Degeneration der Netzhaut, verminderte Nierenfunktion und Fettleibigkeit.
Zu den körperlichen Merkmalen des Syndroms gehören Zahnanomalien, Kleinwuchs, träge Augen- und Zehen- oder Fingeranomalien.
Andere sekundäre Symptome sind Lernschwierigkeiten, Entwicklungsverzögerungen, Verhaltens- und neurologische Probleme, Bluthochdruck und mögliche Sprachstörungen. Ein Mangel an Geruchssinn und Schilddrüsenprobleme sind ebenfalls potenzielle Syndromes.
Wie wird jemand getestet? Bardet-Biedl syndrome?
Die ersten Tests für Bardet-Biedl syndrome kann mit einem Gesichtsanalyse-Screening beginnen, durch die FDNA Telehealth Telegenetik-Plattform, die die Schlüsselmarker der syndrom und skizzieren Sie die Notwendigkeit weiterer Tests. Es folgt ein Beratungsgespräch mit einem genetischen Berater und dann einem Genetiker.
Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.
Medizinische Informationen zu Bardet-Biedl syndrome
Strictly speaking Bardet-Biedl is separate from Laurence-Moon syndrome (qv). The difference is that patients with Laurence-Moon syndrome are spastic, thin and do not have polydactyly. Both conditions present with retinal dystrophy, mental handicap and hypogenitalism. Bardet-Biedl syndrome, the commoner of the two, is variable in its manifestations. 70% of cases have post-axial polydactyly which, when present, might only affect one limb. Beales et al., (1999) provide diagnostic criteria. Manouvrier-Hanu et al., (1999) reported a rare case with features of the condition who had preaxial polydactyly, and Deffert et al., (2007) reported a family with insertional polydactyly and situs inversus. Syndactyly and brachydactyly are very common (Green et al., 1989). A characteristic face has been claimed (Beales et al., 1999; Lord-Sanchez et al., 2001), however this is difficult to see in the photographs produced in the latter reference. Characteristic features are said to be a wide forehead, mild downward slanting palpebral fissures, a large nose, a small mouth with a thin upper lip and a slightly everted lower lip, and a prominent mandible on front view but retrognathia on lateral view. Rudling et al., (1996) studied the radiological features in 43 cases and noted that a short middle phalanx of the 5th digit was common and that either a long or short styloid of the ulna with the appearance of Madelung deformity in some cases was present in 5-10%. Beales et al., (1999) present evidence suggesting that heterozygotes are predisposed to renal malformation and renal cell carcinoma. Croft et al., (1995) found that 27% of fathers of affected children were significantly overweight compared to only 9% of the general US population. This suggested a heterozygote effect of the gene in males.
Renal problems are common and might be present in 90% of cases when looked for (Harnett et al., 1988). Abnormalities include calyceal clubbing, cysts or diverticulae, fetal lobulations, renal cortical loss and a reduced ability to concentrate urine - renal failure can occur. There may also be renal dysplasia. The picture can be that of juvenile nephronophthisis. Gupta et al., (2005) reported a case with multiple fractures due to a renal osteodystrophy. O'Dea et al., (1996) studied 38 patients and found that 25% developed renal impairment by the age of 48 years but abnormalities on renal imaging were present in 96% of patients. Urogenital abnormalities are also common in females. These include vaginal atresia, septate vaginas, ectopic urethras, and hypoplasia or duplication of the uterus and fallopian tubes (Stoler et al., 1995; Mehrotra et al., 1997). David et al., (1999) reported nine female infants presenting with vaginal atresia and post-axial polydactyly who were initially diagnosed as having Kaufman-McKusick syndrome, but who later developed obesity and retinal dystrophy indicating a diagnosis of Bardet-Biedl syndrome. A sib of a patient with Bardet-Biedl (no description given) had post-axial polydactyly, and hydrometrocolpos, hydronephrosis and renal failure (Cherian et al., 2008). Hirschsprung disease and anal atresia are rare associations (Islek et al., 1996; Lord-Sanchez et al., 2000, Cherian et al., 2008). Situs inversus has also occasionally been reported (Lorda-Sanchez et al., 1999, 2000). Yamada et al., (2000) reported a case with a brainstem glioma. Merks et al., (2005) reported a case who developed in childhood acute lymphoblaatic leukaemia.
Note that some patients with a mutation might be non-dysmorphic, have a slim build, be of normal intelligence and just have polydactyly and the retinal dystrophy (Cannon et al., 2008, Pawlik et al., 2010). In single families the phenotype can vary from nephronophthisis to Joubert to Bardet-Biedl (Zaki et al., 2011).
Elbedour et al., (1994) studied 22 cases from three inbred Bedouin families with echocardiography. They found abnormalities in seven of these cases. One case had a dilated cardiomyopathy, two cases thickening of the interventricular septum, one case a bicuspid aortic valve and one case each of mild pulmonary valve stenosis and moderate tricuspid regurgitation. The sibs reported by McLoughlin et al., (1964) with heart defects most likely had Carpenter syndrome. Dextrocardia has been reported with situs inversus (Sudharkar et al., 1987, Lorda-Sanchez et al., 2000)
Johnson et al., (2003) groups this condition as a 'hepatocystic renal syndrome' and provides an excellent review of these conditions. Karmous-Benailly et al., (2005) note the confusion that can arise prenatally with Meckel syndrome.
Mental retardation might not always be present. Green et al., (1989) found this in 41% of cases. Other abnormalities include obesity (90%), diabetes mellitus (50%), hypogonadism in males (88%) and menstrual problems in females (100%) (Green et al., 1989). Two patients in the report by Green et al., (1989) had vaginal atresia. In general four of the five major manifestations are necessary for a positive diagnosis. Barnett et al., (2002) studied the behavioural phenotype in children with Bardet-Biedl syndrome. 21 children were studied. There seemed to be a tendency towards feeling withdrawn, anxious or depressed. There were also attention problems and 'a significant minority scored in the clinical range on a measure of autistic symptoms'.
Visual abnormalities characteristically consist of an atypical pigmentary retinopathy with early macular involvement. Electrophysiological studies reveal a cone-rod dystrophy. Onset of visual impairment is in the second and third decade and in one study 63.6% of patients were legally blind by the age of 20 years (reviewed by Campo and Aaberg, (1982) and Fulton et al., (1993) - see also Green et al., (1989)). Other ophthalmological abnormalities include myopia, astigmatism, nystagmus, glaucoma (Ventura et al., 2006), cataracts (Green et al., 1989) and Duane retraction syndrome (Jethani et al., 2007).
Riise (1996) studied the cause of death in 14 patients. Average age at death was 43 years in males and 46.4 years in females. The cause was mainly renal disease or myocardial infarction.
Diaz et al., (1991) reported a possibly affected 9-year-old boy with a hypothalamic hamartoma, suggesting overlap with the Pallister-Hall syndrome.
Kwitek-Black et al., (1993) found linkage to markers at 16q13-q22 in a large inbred Bedouin family. However in a second family linkage was excluded, suggesting genetic heterogeneity. Leppert et al., (1994) showed linkage to markers at 11q13 in some families. Katsanis et al., (1999) and Young et al., (1999) refined this linkage. Sheffield et al., (1994) demonstrated linkage to markers at 3p11-p13 in a further large inbred Bedouin kindred. Yet another locus was identified in a highly inbred Bedouin kindred, mapping to 15q22 (Carmi et al., 1995). Carmi et al., (1995) presented evidence suggesting that alleles at the different loci may cause slightly different phenotypic effects. They suggested that chromosome 3 associated cases have polydactyly of all four limbs, whilst in chromosome 15 associated cases this is mostly confined to the hands. Chromosome 16 associated cases are least inclined to obesity whereas chromosome 15 cases have early onset morbid obesity. Beales et al., (1997) studied 18 families both clinically and genetically. They found that 44% linked to 11q13 (BBS1) and 17% linked to 16q21 (BBS2). One family linked to 15q22 (BBS4) and none to 3p12(BBS3). BBS1 patients tended to be taller than their parents. BBS1 patients required less special help at school than BBS4 patients. Myopia occurs in BBS3 and BBS4 but not in BBS2 (Heon et al., 2005). A fifth locus (BBS5) was mapped to 2q31 by Young et al., (1999). A further type 3 family mapping to 3p12-p13 was reported by Ghadami et al., (2000).
Slavotinek et al., (2000) and Katsanis et al., (2000) reported mutations in the MKKS gene mapping to 20p12, which is responsible for Kaufman-McKusick syndrome. Missense, nonsense, and frameshift mutations were found. It was hypothesised that homozygosity for null mutation caused the Bardet-Biedl phenotype (BBS6), but hypomorphic alleles cause the Kaufman-McKusick phenotype. Slavotinek and Biesecker (2000) provide a literature review of cases with overlapping features between the two conditions. However, Beales et al., (2001) presented data suggesting that only 4% of North Americans/European families with BBS have mutations in the MKKS gene. The most common loci in this population are BBS1 and BBS2. BBS4 is most prevalent amongst the Turkish and Pakistani populations. There was evidence of further unlinked loci in these populations.
Nishumura et al., (2001) cloned a novel gene and demonstrated mutations in BBS2 mapping to 16q. The gene coded for a novel protein.
Mykytyn et al., (2001) demonstrated mutations in a novel gene in BBS4 families by positional cloning. This may code for a glucosamine transferase. Katsanis et al., (2002) showed that BBS4 mutations were not a major cause of Bardet-Biedl syndrome but may participate in triallelic inheritance (see below). Mutations in the gene contributed to less than 3% of affected families from a multi ethnic cohort of 177 families. There was evidence that BBS4 participated in triallelic inheritance with BBS2 and BBS1 but not other known loci.
Karsanis et al., (2001) presented evidence that in some families alleles at least 2 loci are involved in the degree of penetrance. A 163 BBS families were screened for mutations in both BBS2 and BBS6 genes. In four pedigrees 3 mutant alleles were detected in affected individuals. In addition, in two pedigrees unaffected individuals were detected who had two BBS2 mutations but not a BBS6 mutation. The authors suggest that three mutant alleles are needed to manifest the phenotype and term this triallelic inheritance, although in a commentary by Burghes et al., (2001) suggests that ""recessive inheritance with a modifier of penetrance"" is alternative description. Katsanis et al., (2001) provide a good review of the molecular basis of the condition upto the middle of 2001.
Mykytyn et al., (2002) demonstrated mutations in a gene of unknown function in BBS1 families mapping to 11q13. There was a common mutation (Met390Arg). 60 unrelated North American probands with BBS were studied and 22 individuals had at least one copy of the Met390Arg mutation. 16 were homozygous for this mutation. There was no evidence of triallelic inheritance in BBS families with the Met390Arg mutation and no evidence for this mutation in BBS2, BBS4 or BBS6 families. Slavotinek et al., (2002) studied patients with atypical Bardet-Biedl and Kaufman-McKusick syndrome and also patients where linkage to the MKKS gene could not be ruled out. Only one mutant allele in the MKKS gene was found in nearly half of all patients (combining data with the literature) suggesting further evidence of 'tri-allelic' inheritance. Mykytyn et al., (2003) studied 129 probands and found BBS1 mutations in 30%. The M390R mutation accounted for 80% of all BBS1 mutations. There was little evidence of complex (triallelic) inheritance. In another study (Hichri et al., 2005), looking for triallelic inheritance, no evidence was found, but in 7 of the 14 families with mutations, only a single heterozygous mutation could be identified, suggesting the involvement of other, unidentified genes.
Beales et al., (2003) presented data suggesting that BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. They identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. The data indicated that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other. Badano et al., (2003) reported three families with two mutations in either BBS1 or BBS2, in which some but not all patients carried a third mutation in BBS1, BBS2 or the putative chaperonin BBS6. The presence of three mutant alleles correlated with a more severe phenotype. Fauser et al., (2003) presented further evidence for digenic inheritance.
Badano et al., (2003) demonstrated mutations in a gene BBS2L1 in Bardet-Biedl syndrome type VII (BBS7)
Ansley et al., (2003) cloned BBS8, which encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility in ciliated cells. In one family, a homozygous null BBS8 mutation resulted in randomization of left-right body axis symmetry. Stoetzel et al., (2006) found only 3 BBS8 mutations in a cohort of 128 families. BBS3 (3p12) is caused by a mutation in a member (ARL6) of the Ras superfamily of small GTP-binding proteins (Fan et al., 2004).
There have been a number of reports (Ansley et al., 2003, Chiang et al., 2004, Kaluga et al., 2004) that ciliary dysfunction underlies the pathogenesis of Bardet-Biedl. Iannaccone et al., (2005) reported 2 patients with clinical evidence of dysfunction. BBS9 has now been uncovered (Nishimura et al., 2005). It is at 7p14 and the gene is B1. BBS10 is located at 12q21.1, the gene is C12ORF58 (or as stated by White et al., 2007, FLJ23560), and it is assumed that 20% of all BBS patients show mutations in this gene (Stoetzel et al., 2006). BBS11 has mutations in TRIM32 on 9q33.1
BBS12 is situated on chromosome 4q27 with mutations in FLJ35630 (C4ORF24) - Pawlik et al., 2010.The clinical phenotype was mild, there only beong polydactyly and late-onset RP.
Patients with SDCCAG8/NPHP10 mutations (that cause Senior-Loken syndrome - see elsewhere) can have a phenotype that would meet the Bardet-Biedl criteria, but without polydactyly (Schaefer et al., 2010).. Mutations in IFT172 are also causative (Bujakowska et al., (2015).
Lindstrand et al. (2016) identified exon-disruptive CNVs in 18.5% (17/92) individuals with Bardet-Biedl syndrome, including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively).
Heon et al. (2016) reported a female with progressive myopia, retinal atrophy, progressive rod-cone dystrophy, overweight, post-axial polydactyly, horseshoe kidney, mild learning disability, and elevated hepatic enzymes. Molecular studies revealed a homozygous nonsense mutation in C8ORF37, a gene that has been previously linked to retinal atrophy and rod-cone dystrophy, but not to Bardet-Biedl syndrome.
Braun et al. (2016) compared the volume of olfactory bulb in 20 patients with Bardet-Biedl versus 12 control subjects. They found a correlation between loss of olfactory bulb volume and dysosmia and the presence of the diagnosis of Bardet-Biedl syndrome.
* This information is courtesy of the L M D.
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