Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome




Purpose


To describe a series of patients with Bardet-Biedl syndrome (BBS) and predominantly retinal cone dysfunction, a previously only rarely reported association.


Design


Retrospective observational case series.


Methods


Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular phenotyping, which included fundus examination, Goldmann visual fields, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Mutational screening in the BBS genes was performed either by direct Sanger sequencing or targeted next-generation sequencing.


Results


All 7 patients had proven BBS mutations; 1 had a cone dystrophy phenotype on ERG and 6 had a cone-rod pattern of dysfunction. Macular atrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. OCT confirmed loss of outer retinal structure within the atrophic areas. No clear genotype-phenotype relationship was evident.


Conclusions


Patients with Bardet-Biedl syndrome usually develop early-onset retinitis pigmentosa. In contrast, the patients described herein, with molecularly confirmed Bardet-Biedl syndrome, developed early cone dysfunction, including the first reported case of a cone dystrophy phenotype associated with the disorder. The findings significantly expand the phenotype associated with Bardet-Biedl syndrome.


Bardet-Biedl syndrome is an emblematic ciliopathy associated with severe and early-onset retinal dystrophy, postaxial polydactyly, early obesity, renal dysfunction, hypogonadism, and learning difficulties. It is genetically heterogeneous, with 20 BBS genes identified ( BBS1 to BBS20 ) to date, all of which encode proteins involved in the development and the maintenance of the primary cilium.


The retinal dystrophy associated with Bardet-Biedl syndrome is usually severe but expression can be variable. Electroretinography (ERG) is an important diagnostic investigation and can be abnormal prior to the development of fundus abnormalities. A rod-cone dystrophy is usually present, with initial symptoms of night blindness and constricted peripheral fields with later central retinal involvement. Cone-rod dystrophy has also been reported but is very uncommon.


The present report describes 7 patients with molecularly confirmed Bardet-Biedl syndrome who have predominantly cone dysfunction, contrasting with previous series and expanding the phenotype that can be associated with the disorder.


Methods


This is a retrospective, observational case series.


Seven patients with Bardet-Biedl syndrome from 6 unrelated families were identified as having cone or cone-rod dystrophy on ERG. Patients in Cases 1 and 2 were examined in the Center for Rare Genetic Ophthalmologic Diseases (CARGO) in the Strasbourg University Hospital (Strasbourg, France); in Cases 3 and 4 at Moorfields Eye Hospital (London, UK); and in Cases 5–7 in the University Hospital of Lille (Lille, France). Ethical approval was obtained from the local ethics committee of Strasbourg University Hospital and Lille Hospital and The Research Management Committee of Moorfields Eye Hospital.


All patients had a standard ophthalmic examination, including best-corrected visual acuity, slit-lamp examination, dilated fundus examination, and ERG. Visual fields were assessed with a Goldmann perimeter in Cases 1, 2, and 5–7. Full-field ERG was recorded according to the guidelines of the International Society for Clinical Electrophysiology of Vision (ISCEV) in all centers. Full-field ERG was performed in Cases 1, 3, and 4 with the Espion system (Diagnosys LLC, Lowell, MA, USA), and in Cases 2 and 5–7 with a Metrovision system (Pérenchies, France). The diagnosis of cone dystrophy was based on progressive decline of visual acuity, severe central retinal dysfunction, and reduced and delayed cone responses on full-field ERG with normal rod-mediated responses at the time of diagnosis. Cone-rod dystrophy has both abnormal cone and rod responses on full-field ERG, with cone function being more severely affected. Spectral-domain optical coherence tomography (OCT) and fundus autofluorescence imaging (FAF) were performed for Cases 1–4 with a spectral-domain OCT device (Spectralis OCT; Heidelberg Engineering, Germany) and for Cases 5–7 with Cirrus HD-OCT (Carl Zeiss Meditec, Oberkochen, Germany). FAF in Cases 5–7 was performed by means of a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph; Heidelberg Engineering, Dossenheim, Germany).


The study protocol adhered to the tenets of the Declaration of Helsinki and received approval from the local ethics committee. Written informed consent was obtained from each subject prior to genetic investigation.


Genetic Analysis


DNA of the patients was extracted from peripheral blood lymphocytes. The analysis was performed in either the research setting of the Medical Genetics Laboratory (Institut de Génétique Médicale d’Alsace, University of Strasbourg, INSERM U1112) or the Genetic Diagnostic Laboratory of the Strasbourg University Hospital. The mutational screening of the BBS genes was different between the patients depending on the strategy used at the time of the analysis, as the duration of the study was more than 8 years. The patient in Case 1 initially underwent homozygosity mapping (GeneChip Human Mapping 250K Nsp Array) (Platform IGBMC) (HomoSNP in house software) identifying a putative locus in which a mutation was detected by Sanger sequencing. Targeted Sanger sequencing of the more frequently involved BBS genes ( BBS1 , BBS10 , and BBS12 ) allowed the molecular diagnosis for Cases 2 and 4. Cases 3, 5, and 6 were diagnosed by using targeted exome sequencing of the BBS genes. The screening of BBS1 BBS12 and of other ciliopathy genes ( AHI1 , NPHP2 NPHP8 , MKS1 , MKS3 , TTC21B , ALMS1 ) was undertaken for Case 7 by a program performed by the Centre National de Séquençage (Evry, France) in 2009–2010.




Results


The ophthalmologic and extraocular features of the 7 patients are detailed in Table 1 and the ERG findings in Table 2 . Fundus photographs and FAF and OCT images appear in Figures 1 and 2 , with ERG imaging appearing in Figure 3 .



Table 1

Key Clinical Features and Molecular Results of Bardet-Biedl Syndrome Patients With Predominantly Cone Dysfunction

























































































































































Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7
Sex Male Male Female Male Male Male Male
Age at last examination 37 years 45 years 25 years 27 years 54 years 36 years 36 years
Family history C (2nd degree) Simplex Simplex Simplex S (Case 6) S (Case 5) Simplex
Extraocular features
Hexadactyly + + + + + + +
Obesity + + + + + +
Learning difficulties + + +
Hypogonadism + + +
Renal failure +
Others Psychiatric disorders, diabetes, deafness, hyposmia Imperforate anus Polydipsia, diabetes, amenorrhea Hydronephrosis, interatrial communication
Features of onset (age) Decreased VA (6 y)
Photophobia
Diagnosis of retinal dystrophy (10 y)
Decreased VA Decreased VA (8 y)
Photophobia
Dyschromatopsia
Decreased VA (18 y)
Red-green dyschromatopsia
Decreased VA
Red-green dyschromatopsia
Red-green dyschromatopsia Decreased VA (10 y)
VA (Snellen) 20/100
20/100
20/200
20/200
Right eye 6/120 6/9.5 6/9 6/18 20/125
Left eye 6/120 6/38 6/9 6/12 20/250
Ocular phenotype Cone-rod dystrophy Cone-rod dystrophy Cone-rod dystrophy Cone-rod dystrophy Cone-rod dystrophy Cone-rod dystrophy Cone dystrophy
Molecular diagnosis BBS5 p.[M1L];[M1L] BBS12 p.[P159L];[I346T] BBS10 p.[R95S];[V707fs*] BBS1 p.[M390R(;)G318Vfs*61] BBS10 p.[R49W(;)Q139P] BBS10 p.[R49W(;)Q139P] BBS6 p.[M1I];[Y37C]

C = consanguinity; S = affected sibling; VA =visual acuity.


Table 2

Summary of Most Recent Electroretinogram Findings in Bardet-Biedl Patients With Predominantly Cone Dysfunction












































Case Dark-Adapted Responses Light-Adapted Responses Phenotype
1 Mildly reduced Severely reduced and delayed Severe CORD
2 Mildly reduced Severely reduced and delayed Severe CORD
3 Moderately reduced Very severely reduced and delayed Severe CORD
4 Mildly reduced Mildly reduced Mild CORD
5 Moderately reduced Undetectable Severe CORD
6 Moderately reduced Severely reduced and delayed Severe CORD
7 Normal Moderately reduced and delayed Moderately severe COD

COD = cone dystrophy; CORD = cone-rod dystrophy.

Grade of amplitude reduction for age: Mild, 70%–100%; Moderate, 40%–70%; Severe, 10%–40%; Very severe, <10%; Undetectable.



Figure 1


Fundus photographs and autofluorescence (FAF) showing macular involvement in Bardet-Biedl syndrome patients. (Left two columns) Fundus photographs (respectively, right eye, left eye) show macular atrophy. (Right two columns) FAF (respectively, right eye, left eye) contains variably sized regions of reduced autofluorescence at the central macula surrounded by a ring of increased autofluorescence for all cases and, for Cases 5, 6, and 7, an additional central foveal hyperautofluorescent spot.



Figure 2


Optical coherence tomography (right eye, left eye) showing disruption or loss of the foveal ellipsoid line in Bardet-Biedl syndrome patients.



Figure 3


International Society for Clinical Electrophysiology of Vision (ISCEV) Standard full-field and pattern electroretinograms (PERG) showing predominant cone dysfunction in Bardet-Biedl patients (from 1 eye each of patients in Cases 3 and 4). There is no significant interocular asymmetry in either patient. Case 3 shows undetectable PERG and full-field cone electroretinograms (ERGs) (light-adapted [LA 3.0 and LA 30 Hz]) with subnormal dark-adapted (DA 0.01 rod specific) and bright flash dark-adapted (DA 10.0) ERGs, which were stable over a 4-year follow-up period. Case 4 demonstrates severely abnormal PERG with normal ERG in 2008. There was deterioration in both cone and rod function when tested in 2012. Data from a representative normal control subject are shown for comparison.


The patient in Case 1 was born from related Syrian parents (second degree of consanguinity) and has a similarly affected older brother. The patient presented with reduced visual acuity at the age of 6 years. He later developed photophobia and macular atrophy was confirmed at age 10 years. Fundus examination at age 37 years showed central macular atrophy. OCT showed reduced macular thickness and absence of the foveal ellipsoid photoreceptor line. Central abnormal hypoautofluorescence surrounded by a ring of hyperautofluorescence was present in both eyes, whereas the periphery disclosed normal autofluorescence. Goldmann visual fields showed good preservation of peripheral isopters, but there was a failure to detect the I1e stimulus centrally in each eye. The ERG showed abnormal cone responses with mildly abnormal rod function. The patient had scars from surgical removal of hexadactyly, obesity (body mass index 38.6 kg/m 2 ), learning difficulties, hypogonadism, dyslipidemia, hepatic steatosis, and diabetes. He also suffered from depression and sleep apnea. SNP (single nucleotide polymorphism) analysis showed homozygosity in the BBS5 region and Sanger sequencing revealed a homozygous p.M1L mutation in BBS5 .


The patient in Case 2 was born to unrelated parents. He presented at age 45 years with reduced visual acuity. There was bilateral macular atrophy on fundus examination. FAF showed an area of central hypoautofluorescence corresponding to the atrophy, surrounded by a ring of hyperautofluorescence. Goldman visual fields showed good preservation of peripheral isopters. The ERG showed severe cone dysfunction with no detectable responses on flicker stimulation and mildly abnormal rod function. He had a history of imperforate anus, present from birth; hexadactyly; obesity; renal failure; and learning difficulties. Bardet-Biedl syndrome was confirmed by Sanger sequencing of BBS12 , revealing a compound heterozygote status with the p.P159L and p.I346T mutations.


The patient in Case 3 first developed central visual disturbance at age 8, with photophobia and progressive alteration of color vision. Fundus examination at 21 years of age showed macular atrophy. Central FAF showed an area of hypoautofluorescence surrounded by a ring of hyperautofluorescence with disruption of the foveal ellipsoid line on OCT corresponding to the area of reduced autofluorescence. ERG (at age 18 years) showed severely abnormal cone function with milder rod system involvement. There was hexadactyly, obesity (body mass index 48.8 kg/m 2 ), amenorrhea, polydipsia, and diabetes. Targeted exome sequencing of the BBS genes revealed 2 mutations in BBS10 , p.R95S and p.V707fs*.


The patient in Case 4 was noted at birth to have an extra digit on each hand and foot. At the age of 18 years, he noticed difficulty with distance vision. By 20 years of age visual acuity was 6/12 in each eye. He had poor color vision (he could only see 3 of the Ishihara color vision plates). Fundus examination showed mild macular atrophy. FAF demonstrated central hypoautofluorescence with a ring of increased autofluorescence in each eye, with OCT again demonstrating a disrupted foveal ellipsoid line corresponding to the reduced autofluorescence. Electrophysiological assessment at age 21 years showed bilateral abnormalities of the pattern ERG, indicating bilateral central macular dysfunction but a normal full-field ERG. A repeat ERG at age 25 years showed an abnormal full-field ERG with cone ERGs showing marked deterioration and the development of mild rod-system abnormalities. There was no subjective deterioration in vision. Bardet-Biedl syndrome was confirmed by Sanger sequencing of BBS1 , which revealed the recurrent mutation p.M390R and a deep intronic mutation c.951+58C>T in intron 10 creating a cryptic splice donor site, leading to the inclusion of a part of intron 10 and to a premature stop codon (p.G318Vfs*61) ( Supplemental Figure , available at AJO.com ).


The patients in Cases 5 and 6 were brothers, both of whom had had surgery for postaxial polydactyly. In Case 5, the patient (the older brother) had obesity and oligospermia; his brother, in Case 6, had only oligospermia. The brother in Case 5 was initially examined at the age of 31 years when he presented with reduced vision, photophobia, and color vision disturbance. He had a small central scotoma but peripheral isopter V was normal. The ERG showed abnormal cone responses with normal scotopic responses. After 25 years of evolution, he had developed macular changes on fundus examination. FAF imaging revealed a central hypoautofluorescence with a ring of increased autofluorescence. OCT showed a disrupted foveal ellipsoid line corresponding to the reduced autofluorescence. A repeat ERG showed undetectable cone system responses with moderately reduced rod system responses.


The brother in Case 6 was noted to have reduced visual acuity at the age of 12. He had slight photophobia. Fundus examination showed normal maculae, vessels, and periphery. FAF and OCT revealed changes that were similar to (although less extensive than) his brother. ERG performed at the age of 16 showed absent photopic responses with normal scotopic responses. Fundus examination was normal. At 36 years, the ERG showed severe cone dysfunction with abnormal rod responses. The visual field showed a 10 degree central scotoma. Targeted exome sequencing revealed 2 mutations in BBS10 , p.R49W and p.Q139P, in each brother.


The patient in Case 7 had a history of polydactyly, obesity, hydronephrosis, and interatrial communication. He presented with decreased visual acuity at age 7 years. The examination of the fundus was normal apart from an absence of the foveal reflex. Color vision testing was abnormal and Goldmann visual fields showed a central scotoma with normal peripheral isopters (III and V). When last examined (at age 36 years), he showed cone dystrophy with a mildly decreased visual acuity and photophobia. FAF demonstrated central macular abnormalities with increased foveal autofluorescence surrounded by hypoautofluorescence, with a further ring of increased autofluorescence surrounding this. OCT demonstrated a disrupted foveal ellipsoid line corresponding to the reduced autofluorescence. ERG showed abnormal cone function with no significant rod system involvement. Sequencing of BBS6 revealed 2 mutations, p.M1I and p.Y37C.

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Jan 7, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome
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