Clinical and immunohistochemical evidence for an X linked retinitis pigmentosa syndrome with recurrent infections and hearing loss in association with an RPGR mutation.
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Adolescent↗
Biomedical subjects
A Iannaccone
Publications and source records attributed to A Iannaccone.
Functionally rodless mice: transgenic models for the investigation of cone function in retinal disease and therapy.
Two genetically engineered strains of mice were used to characterize murine cone function electroretinographically, without interference of rod-driven responses: (1) mice with a deletion of the gene for the rod transducin alpha-subunit (transducin alpha-/-), and (2) mice with rod arrestin deleted (arrestin -/-). In the first three months of age, both strains have a normal complement of rods and normal rod structure, but transducin alpha-/- mice have no rod-driven responses to light, while rod-driven activity of arrestin -/- mice can be suppressed by a single intense flash for hours. In response to intense flashes the electroretinograms of these strains of mice showed a readily identifiable, pure-cone a-wave of approximately 10 microV saturating amplitude. A 530 nm background that saturates rod responses of wild type mice was found to desensitize the b-wave responses of mice of both transgenic lines, whether the b-waves were driven by photons captured by M- or UV-cone pigments. The desensitizing effect of the 530 nm background on UV-pigment driven responses provides new evidence in support of the hypothesis of functional co-expression of the M-pigment in cones expressing primarily the UV-pigment.
Animals↗
Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2).
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder with the primary clinical features of obesity, pigmented retinopathy, polydactyly, hypogenitalism, mental retardation and renal anomalies. Associated features of the disorder include diabetes mellitus, hypertension and congenital heart disease. There are six known BBS loci, mapping to chromosomes 2, 3, 11, 15, 16 and 20. The BBS2 locus was initially mapped to an 18 cM interval on chromosome 16q21 with a large inbred Bedouin kindred. Further analysis of the Bedouin population allowed for the fine mapping of this locus to a 2 cM region distal to marker D16S408. Physical mapping and sequence analysis of this region resulted in the identification of a number of known genes and expressed sequence tag clusters. Mutation screening of a novel gene (BBS2) with a wide pattern of tissue expression revealed homozygous mutations in two inbred pedigrees, including the large Bedouin kindred used to initially identify the BBS2 locus. In addition, mutations were found in three of 18 unrelated BBS probands from small nuclear families.
Amino Acid Sequence↗
Lactose supports Muller cell protein expression patterns in the absence of the retinal pigment epithelium.
PURPOSE: We have previously shown that lactose, but not mannose, promotes the assembly of nascent photoreceptor outer segments in the absence of the retinal pigment epithelium (RPE). The purpose of the present study was to determine if, in addition to the improved outer segment assembly observed in the presence of lactose, biosynthetic changes in Muller cells could also be detected. METHODS: The RPE was removed from intact isolated Xenopus embryonic eyes that were allowed to complete differentiation in Niu-Twitty medium, Niu-Twitty with mannose, or Niu-Twitty with lactose. Control retinas matured in vitro with an adherent RPE. Retinal morphology was evaluated for organized folding of outer segment membranes and cell loss. In addition, the expression of three Muller cell proteins, glial fibrillary acidic protein (GFAP), cellular retinaldehyde-binding protein (CRALBP), and glutamine synthetase, was examined. RESULTS: In control retinas, GFAP is undetectable, CRALBP heavily immunolabels Muller cells, and radial patterns of glutamine synthetase immunoreactivity are present. In the absence of the RPE, Muller cells upregulate GFAP expression, CRALBP labeling is present at a slightly reduced level, and glutamine synthetase immunolabeling is negligible. Neither mannose nor lactose modify significantly the expression of CRALBP. Similarly, both compounds completely prevent the upregulation of GFAP. However, normal glutamine synthetase expression was observed only in the presence of lactose, but not in the presence of mannose. Statistical analyses of slot blot-based protein quantification confirmed our immunochemical results. CONCLUSIONS: In RPE-deprived retinas supplemented with lactose, Muller cells were morphologically normal. The proper photoreceptor outer segment morphogenesis observed under these conditions was uniquely associated with normal levels of glutamine synthetase expression. The exact significance of this finding with respect to photoreceptor outer segment morphogenesis is unknown. We suggest that glutamine synthetase may be a marker of Muller cell metabolic or structural integrity that may reflect the enhanced ability of these cells, in the presence of lactose, to support photoreceptor outer segment morphogenesis.
Animals↗
Pigment epithelium-derived factor supports normal Müller cell development and glutamine synthetase expression after removal of the retinal pigment epithelium.
In conditions in which the retinal pigment epithelium (RPE) is dystrophic, carries a genetic mutation, or is removed physically, Müller cells undergo degenerative changes that contribute to the retinal pathology. We previously demonstrated that pigment epithelium-derived factor (PEDF), a glycoprotein secreted by the RPE cells with neuroprotective and differentiation properties, protects against photoreceptor degeneration induced by RPE removal. The purpose of the present study was to analyze the putative gliosupportive activity of PEDF on Müller cells of RPE-deprived retinas and assess whether protection of Müller cells was correlated with improved photoreceptor outer segment assembly. Eyes were dissected from Xenopus laevis tadpoles, and the RPE was removed before culturing in medium containing purified PEDF, PEDF plus anti-PEDF, or medium alone. Control eyes matured with an adherent RPE or in medium containing PEDF plus nonimmune serum. Müller cell ultrastructure was examined. Glial fibrillary acidic protein (GFAP) and glutamine synthetase were localized immunocytochemically, and the corresponding protein levels were quantified. In control retinas, Müller cells were structurally intact and formed adherens junctions with neighboring photoreceptors. In addition, they did not express GFAP, whereas glutamine synthetase expression was high. RPE removal dramatically altered the ultrastructure and biosynthetic activity of Müller cells; Müller cells failed to form adherens junctions with photoreceptors and glutamine synthetase expression was suppressed. PEDF prevented the degenerative glial response; Müller cells were ultrastructurally normal and formed junctional complexes with photoreceptors. PEDF also preserved the expression of glutamine synthetase at near-normal levels. The morphogenetic effects of PEDF were blocked by the anti-PEDF antibody. Our study documents the glioprotective effects of PEDF and suggests that maintenance of the proper Müller cell ultrastructure and expression of glutamine synthetase may be necessary to support the proper assembly of photoreceptor outer segments.
Animals↗
Reliability assessment of a rod photoreceptor outer segment grading system.
The purpose of this study was to assess the reliability of a rod photoreceptor outer segment (PR-OS) grading system based on the analysis of 1 microm thick retinal sections obtained from Xenopus laevis whole-eye organ cultures. Digitally captured images, representative of the entire spectrum of rod PR-OS organization levels, were selected and coded numerically. A total of 102 individual rod PR-OS profiles were graded according to a six-step classification scheme based on the percentage of rod PR-OS membrane organization. Unweighted (exact agreement) and weighted kappa (kappa) coefficients (for use with ordered categorical rating scales) were calculated. Differences between kappa coefficients were tested for by chi-square analysis. To investigate the intra- and inter-rater variability and the possible presence of an interaction of the measurements with time, a repeated-measures analysis of variance was performed. The overall unweighted and weighted intra-rater kappa coefficients were 0.78 and 0.92, respectively. The overall unweighted and weighted inter-rater kappa coefficients were 0.73 and 0.90, respectively. There was no significant difference between raters or between first and second reading, nor was interaction between raters and time of rating documented. Individual kappa coefficients were equivalent both between raters and between sessions. Intra- and inter-rater agreement was within one step in 100% of cases. The estimated values of the kappa coefficients are consistent with a good to excellent degree of reliability and reproducibility of this rod PR-OS grading system. This system will be useful in the assessment of rod PR-OS morphology in studies of photoreceptor physiology and pathology.
Analysis of Variance↗
Genotype-phenotype correlations and differential diagnosis in autosomal dominant macular disease.
In the past few years, great progress has been made in the understanding of macular diseases. A number of disease-causing genes have been cloned, and numerous loci for other conditions have been mapped. The purpose of this article is to provide an overview of the current understanding of the genotype-phenotype correlations in autosomal dominant macular diseases with an emphasis on differential diagnostic issues. Whenever possible, the molecular correlates have been reviewed and the implications for age-related macular degeneration have been discussed. The many similarities of these diseases to age-related macular degeneration of the atrophic or exudative type, which can be misleading in elderly subjects, have also been addressed. While some conditions yield disease truly confined to the macula, others show widespread retinal involvement on functional testing. Clear-cut genotype-phenotype correlations are possible only for some forms of macular diseases. To further complicate the diagnostic process, there is a considerable degree of clinical overlap between many of them, making the differential diagnostic process potentially challenging. Functional testing, careful assessment of family history and extensive family work-up are essential in differentiating at the clinical level most, but not all, of these disease entities. Awareness of all of these conditions is required to direct correctly diagnostic investigations, to formulate an accurate prognosis, and for proper genetic counseling.
Amino Acid Sequence↗
Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.
Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.
Bardet-Biedl Syndrome↗
Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal.
Dysfunction of the retinal pigment epithelium (RPE), its loss, or separation from the underlying neural retina results in severe photoreceptor degeneration. Pigment epithelium-derived factor (PEDF) is a glycoprotein with reported neuroprotective and differentiation properties that is secreted in abundance by RPE cells. The "pooling" of PEDF within the interphotoreceptor matrix places this molecule in a prime physical location to affect the underlying neural retina. The purpose of this study was to analyze the morphogenetic activity of PEDF in a model of photoreceptor dysmorphogenesis induced by removal of the RPE. Eyes were dissected from embryonic Xenopus laevis, and the RPE was removed before culturing in medium containing PEDF, PEDF plus anti-PEDF antibodies, or medium alone. Control retinas were maintained with an adherent RPE. Light and electron microscopic analysis was used to examine retinal ultrastructure. Opsin was localized immunocytochemically and quantified as an index of outer segment membranous material and photoreceptor protein expression. Removal of the RPE resulted in an aberrant assembly of photoreceptor outer segments, loss of fine subcellular ultrastructure in photoreceptors, and a reduction in opsin protein levels when compared with control retinas. The addition of PEDF prevented the dysmorphic photoreceptor changes induced by RPE removal. In particular, photoreceptor ultrastructure, outer segment membrane assembly, and steady-state levels of opsin were equivalent to control conditions. Anti-PEDF antibodies completely blocked the morphogenetic activity of PEDF. These results indicate that PEDF is able to mimic the supportive role of the RPE on photoreceptors during the final stages of retinal morphogenesis.
Animals↗
Targeted disruption of Müller cell metabolism induces photoreceptor dysmorphogenesis.
Within the retina, the Müller cells and photoreceptors are in close physical proximity and are metabolically coupled. It is unknown, however, whether Müller cells affect photoreceptor differentiation and outer segment membrane assembly. The objective of this study was to determine whether targeted disruption of Müller cell metabolism would induce photoreceptor dysmorphogenesis. Intact isolated Xenopus laevis embryonic eyes were cultured in medium with or without Müller cell-specific inhibitors (i.e., alpha-aminoadipic acid and fluorocitrate). To assess Müller cell injury, the gross retinal morphology was examined along with immunocytochemical assessment of Müller cell-specific protein expression patterns. The steady-state levels of opsin were quantified to determine whether the Müller cell inhibitors negatively affected photoreceptor protein synthesis. Müller and photoreceptor cell ultrastructure was scrutinized and the organization of the outer segment membranes was graded. In control retinas, there was no swelling of Müller cell cytoplasm. Glial fibrillary acidic protein (GFAP) was undetectable, whereas glutamine synthetase was abundant. The steady-state level of opsin was high and photoreceptors elaborated properly folded outer segments. Exposure to both Müller cell-specific inhibitors induced swelling of Müller cell endfeet, cytoplasmic paling and alterations of Müller cell-specific protein expression patterns. The steady-state level of opsin in retinas exposed to alpha-aminoadipic acid was unchanged compared with control eyes, whereas, in eyes exposed to fluorocitrate, opsin levels were slightly reduced. The most significant finding was that targeted disruption of Müller cell metabolism adversely affected photoreceptor outer segment membrane assembly, causing dysmorphogenesis of nascent outer segments. These results suggest that the termination signal(s) necessary for proper outer segment folding were disrupted by targeted inhibition of Müller cells and support the hypothesis that Müller cells interact with photoreceptors through mechanisms that may regulate, at least in part, the assembly of photoreceptor outer segment membranes.
2-Aminoadipic Acid↗
Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa.
PURPOSE: To determine the disease expression in heterozygotes for mutations in the RP1 gene, a newly identified cause of autosomal dominant retinitis pigmentosa (adRP). METHODS: Screening strategies were used to detect disease-causing mutations in the RP1 gene, and detailed studies of phenotype were performed in a subset of the detected RP1 heterozygotes using electroretinography (ERG), psychophysics, and optical coherence tomography (OCT). RESULTS: Seventeen adRP families had heterozygous RP1 changes. Thirteen families had the Arg677ter mutation, whereas four others had one of the following: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763 (5-bp del), and Tyr1053 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal variation in disease, with the far peripheral inferonasal retina being most vulnerable; central and superior temporal retinal regions were better preserved. The earliest manifestation of disease was rod dysfunction, detectable as reduced rod ERG photoresponse maximum amplitude, even in heterozygotes with otherwise normal clinical, functional, and OCT cross-sectional retinal imaging results. At disease stages when cone abnormalities were present, there was greater rod than cone dysfunction. Patients with the RP1 frameshift mutations showed similarities in phenotype to those with the Arg677ter mutation. CONCLUSIONS: Earliest disease expression of RP1 gene mutations causing adRP involves primarily rod photoreceptors, and there is a gradient of vulnerability of retinopathy with more pronounced effects in the inferonasal peripheral retina. At other disease stages, cone function is also affected, and severe retina-wide degeneration can occur. The nonpenetrance or minimal disease expression in some Arg677ter mutation-positive heterozygotes suggests important roles for modifier genes or environmental factors in RP1-related disease.
Adolescent↗
Clinical and functional features of patients with dominant optic atrophy.
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Humans↗
Effect of isosorbide mononitrate on the human optic nerve and choroidal circulations.
AIMS: To assess the effects of the nitric oxide donor 5-isosorbide mononitrate (ISMO) on blood flow in the optic nerve head (ON flow) and choroid (Ch flow). METHODS: Laser Doppler flowmetry was used to measure ON flow and Ch flow in 12 normal subjects by aiming the laser beam at the fovea and at the temporal rim, respectively. In a double masked, randomised, crossover design, each subject received orally on separate days either 20 mg of 5-isosorbide mononitrate (ISMO) or placebo. Ch flow and ON flow were determined monocularly at baseline and 1 hour after dosing. In the last six subjects, additional measurements were obtained at 3 hours. Mean arterial blood pressure (BPm), heart rate, and intraocular pressure (IOP) were monitored, and ocular perfusion pressure (PP) was estimated. RESULTS: No significant changes in ON flow, PP, IOP, or BPm were observed following placebo. Following ISMO, ON flow increased from baseline by 19.8% (SEM 9.3%) at 1 hour (paired t test, p = 0.058) and by 33.1% (7.5%) at 3 hours (p = 0.007). Compared with the changes following placebo, statistically significant increases in ON flow were observed both at 1 (p = 0.050) and 3 hours (p = 0.041) after ISMO treatment. Compared with placebo, PP decreased significantly 1 hour after ISMO dosing (p = 0.039), mainly as a function of reduced BPm. A significant inverse correlation (R = -0.618; p = 0.032) was observed between the percentage changes in PP and ON flow 1 hour following ISMO administration, but not after placebo. No significant change in foveal Ch flow was documented. CONCLUSIONS: These results suggest that, in normal subjects, ISMO increases significantly ON flow but not Ch flow. The inverse correlation observed between PP and ON flow suggests that the same mechanism(s) responsible for systemic vasodilatation and blood pressure decrease may also cause the ON flow increase.
Adult↗
Plasma endothelin-1 concentrations in patients with retinal vein occlusions.
AIMS: To investigate whether plasma levels of endothelin-1 (ET-1), a potent vasoconstricting peptide that is crucial in regulating retinal blood flow, were elevated in patients with retinal vein occlusion (RVO). METHODS: ET-1 plasma concentrations were determined by radioimmunoassays in a double blind fashion in a group of 18 selected patients with RVO, in 20 healthy age matched non-smoking, normoglycaemic, normotensive control subjects, and in 15 patients with uncomplicated essential hypertension in the same age range. RESULTS: Patients with RVO had significantly increased ET-1 plasma levels (14.22 (SD 4.6) pg/ml) compared with both normal subjects (7.90 (1.6) pg/ml; p < 0.05) and hypertensive patients (8.50 (2.9) pg/ml; p < 0.05). The highest concentrations of circulating ET-1 were found in patients with RVO of the ischaemic type (16.97 (3.5) pg/ml; p < 0.01; n = 7). Systemic hypertension alone did not account for the observed increase in plasma ET-1 concentrations. CONCLUSIONS: These findings raise the possibility that the increased circulating ET-1 levels in patients with RVO may be a marker of the occlusive event, thereby suggesting that ET-1 homeostasis may be relevant to RVO pathogenesis and retinal ischaemic manifestations.
Adult↗
Circulating endothelin-1 in non-insulin-dependent diabetic patients with retinopathy.
Endothelin-1 (ET-1), a novel 21-amino acid vasoconstrictive peptide secreted by endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with microvascular damage. To investigate whether ET-1 levels may be related to microangiopathy in diabetes mellitus, plasma ET-1 levels were measured in two groups of diabetic patients: A) 47 patients with non-insulin dependent diabetes mellitus (NIDDM) and retinopathy (28 M, 19 F; mean age 60.7+/-8.5 yrs) but without nephropathy (microalbuminuria < 30 mg/day) and hypertension (SBP < 140, DBP < 90 mmHg); group A was divided in three subgroups based on the severity of retinopathy: a) 16 with background retinopathy; b) 21 with pre-proliferative retinopathy; c) 10 with proliferative retinopathy. B) 8 patients with insulin-dependent diabetes mellitus (IDDM) recently diagnosed (6 M, 2 F; 16.4+/-3.8 yrs) without complications. C) 28 healthy subjects (HS) (16 M, 12 F; 47.8+/-11.8 yrs) as controls. In the NIDDM group the ET-1 concentration was significantly higher (17.3+/-2.4 pg/ml) than both in the HS (8+/-4.7 pg/ml) and IDDM patients (10.2+/-3.7 pg/ml) (p < 0.0001). In the subgroups with retinopathy the ET-1 levels were a) 15.1+/-4.3 pg/ml; b) 22.2+/-6.8 pg/ml and c) 16.6+/-5.1 pg/ml. These values were significantly elevated as compared to HS (p<0.001; p < 0.0001; p < 0.002, respectively), being the highest levels of ET-1 observed in the NIDDM patients with pre-proliferative retinopathy. In conclusion our study revealed that the ET-1 concentrations are elevated in NIDDM patients with retinopathy especially in those patients with pre-proliferative retinopathy.
Aged↗
The ocular phenotype of the Bardet-Biedl syndrome. Comparison to non-syndromic retinitis pigmentosa.
PURPOSE: To investigate 20 patients affected with Bardet-Biedl (BB) syndrome and compare them to an age-matched group of 70 non-syndromic patients with retinitis pigmentosa (RP) to identify hallmarks peculiar to the BB phenotype. METHODS: Patients were examined clinically and with functional tests (color vision, kinetic perimetry, electroretinography, ocular motility tests). Fundus findings were numerically graded for statistical purposes. RESULTS: Recurrent ocular features in BB patients were early and severe reduction of visual acuity, constantly altered color vision, high incidence of strabismus and nystagmus, mild-to-severe atrophic changes of the optic disc, and frequently absent or minimal pigmentary retinal changes. Visual acuity was more closely correlated to optic disc than to macular conditions. These findings were remarkably different from non-syndromic RP. CONCLUSIONS: This investigation further suggests that retinopathy in BB syndrome has features distinctive from those in non-syndromic RP. The early occurrence of optic disc atrophy in the BB syndrome, even in those patients with healthy maculas, suggests that optic atrophy could often be primary in nature and might play a major role in decreasing central vision in BB patients. Variability of some findings is in line with the documented heterogeneity of the BB syndrome.
Abnormalities, Multiple↗
Autosomal-dominant retinitis pigmentosa associated with an Arg-135-Trp point mutation of the rhodopsin gene. Clinical features and longitudinal observations.
PURPOSE: To report the clinical and functional characteristics of patients affected with autosomal-dominant transmitted retinitis pigmentosa (adRP) from a large Italian pedigree in which a point mutation predicting the Arg-135-Trp change of rhodopsin was identified by polymerase chain reaction-single-strand conformation polymorphism analysis. METHODS: Seven patients, ranging in age from 6 to 41 years, underwent a full clinical ophthalmologic evaluation, kinetic visual field testing, and electroretinographic testing. RESULTS: In agreement with previous reports, this rhodopsin mutation yielded a particularly severe phenotype, both clinically and functionally. The evaluation of patients from this pedigree in the first and second decade of life demonstrated that retinal function is still electroretinographically measurable at least until 18 years of age, although reduced to 2% to 4% of normal. Longitudinal measures showed that the rate of progression of the disease was unusually high, with an average 50% loss per year of electroretinographic amplitude and visual field area with respect to baseline. Later in the course of the disease, macular function is also severely compromised, leaving only residual central vision by the fourth decade of life. CONCLUSIONS: The phenotype associated with mutations in codon 135 of the rhodopsin molecule appears to have an unusually high progression rate and yields an extremely poor prognosis. These distinctive features make the Arg-135-Trp phenotype substantially different from the general RP population, and also from many of the other adRP pedigrees with known rhodopsin mutations reported to date.
Adolescent↗
Electroretinographic alterations in the Laurence-Moon-Bardet-Biedl phenotype.
Maximal 0.5-Hz and cone 30-Hz ERG responses were recorded from 19 patients showing a Laurence-Moon-Bardet-Biedl (LMDD) phenotype. Off-line averaging of 80 to 100 iterations was routinely performed. When needed, our previously described low-noise techniques and off-line fast Fourier transform procedures were used. The maximal ERG response was non-detectable in 52.6% of cases. About half of the recordable signals were below 5% of the lower normal amplitudes. Cone 30-Hz ERGs were measurable in 64.7% of cases. Of these, 63% of tracings were below 5% of the lower normal range. In most cases no dystrophic pattern was definable, due to severe reduction of both signals. Statistical analyses showed no correlation between ERG amplitudes and residual visual field areas. Clinical and electroretinographic observations suggest that retinopathy in most LMBB patients is a widespread form of degeneration, initially affecting rods but rapidly involving cones as well. However, there are also cases with a clear-cut cone-rod pattern, with fairly well preserved maximal ERG responses. The lack of correlation between maximal ERG responses and visual field residual areas, different from non-syndromic retinitis pigmentosa (RP) patients, could be related either to a low reliability of visual field testing in LMBB patients or to mechanisms accounting for the ongoing retinal degeneration in LMBB syndrome that are different from those of pure RP. Variable findings are in line with the documented genetic heterogeneity of the syndrome.
Adolescent↗