ATYPICAL FOVEAL AND PARAFOVEAL ABNORMALITIES IN SICKLE CELL DISEASE.

PURPOSE: The primary aim was to describe the patterns of paramacular involvement, not yet reported but that optical coherence tomography angiography can now detect in patients with sickle cell disease. The secondary aim was to search arguments concerning the physiopathogeny of paramacular involvement. METHODS: This institutional cohort retrospective study was conducted in a Referral Center for Ophthalmological Rare Diseases. Follow-up included an ophthalmologic examination with optical coherent tomography and optical coherent tomography angiography. RESULTS: One hundred and thirty-two patients with SCD were included. Typical sickle cell maculopathy was observed in temporal area in 84 eyes (40.0%) of SS patients and eight eyes (14.8%) of SC patients ( P < 0.001). Enlargement of the foveal avascular zone was observed in 10 eyes of eight SS patients. Two atypical parafoveal abnormalities were found in SS patients only. The first one consisted of macular thinning with normal vascularization in 15 eyes of 11 patients. The second atypical maculopathy was large areas of loss of vascularization without retinal thinning 10 eyes of six patients. Multivariate analysis did not show a statistically significant relation between the peripheral sickle retinopathy stage and the different type of sickle cell maculopathy ( P = 0.21). CONCLUSION: Those atypical sickle cell maculopathy may correspond to early forms preceding a typical sickle cell disease maculopathy (SCDM). This would point toward several physiopathogenic mechanisms. The first one included the existence of ischemia that can be related to anemia. Presence of retinal thinning without vascular involvement point out to a neurogenic mechanism.

A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies.

Leber's hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e-05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.

Cardiac Disorders in Patients With Leber Hereditary Optic Neuropathy.

BACKGROUND: Cardiac abnormalities have been described in patients with Leber hereditary optic neuropathy (LHON). Some are life-threatening because of the risk of ventricular fibrillation and sudden death. The purpose of our study was to better characterize the cardiac abnormalities in a large patient cohort with LHON. METHODS: A retrospective study of the electrocardiogram (EKG) results performed on all patients with LHON evaluated at The Reference Center for Rare Diseases in Ophthalmology, Paris, France, from January 2015 to June 2017. RESULTS: Our series included 73 patients with LHON (9 women/64 men) with a mean age of 30.29 ± 14.48 years. Although only 1 patient had cardiac complaints, cardiac abnormalities were detected in 17 patients (23.2%): 9 patients had an excitation syndrome, 6 had atrioventricular block, and 2 had repolarization abnormalities. All patients harbored mtDNA point mutations 11778 or 3460. CONCLUSIONS: Cardiac abnormalities occur frequently enough in patients with LHON that a baseline EKG is warranted. However, further studies are needed to determine the true cardiac risk associated with specific LHON mtDNA mutations.

International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.

Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations.

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.

The Optic Nerve at Stake: Update on Environmental Factors Modulating Expression of Leber's Hereditary Optic Neuropathy.

Optic neuropathies are characterized by the degeneration of the optic nerves and represent a considerable individual and societal burden. Notably, Leber's hereditary optic neuropathy (LHON) is a devastating vision disease caused by mitochondrial gene mutations that hinder oxidative phosphorylation and increase oxidative stress, leading to the loss of retinal ganglion neurons and axons. Loss of vision is rapid and severe, predominantly in young adults. Penetrance is incomplete, and the time of onset is unpredictable. Recent findings revealed that the incidence of genetic LHON susceptibility is around 1 in 1000, much higher than believed till now. Environmental factors are critical in LHON triggering or severity. Families at risk have a very strong demand for how to prevent the onset or limit the severity of the disease. Here, we review recent knowledge of the extrinsic determinants of LHON expression, including lifestyle, dietary supplements, common chemicals, and drugs.

Relationship between paramacular thinning, cerebral vasculopathy, and hematological risk factors in sickle cell disease.

Purpose: To identify risk factors for sickle cell maculopathy due to hematological parameters (especially anemia and hemolysis) or cerebral vasculopathy. Methods: This retrospective study was conducted at a Referral Center. The follow-up included optical coherent tomography/optical coherent tomography angiography, neuro-radiological imaging, and a hematological assessment (hemoglobin, hemoglobin S level, reticulocytes, mean corpuscular volume, bilirubin, and lactate dehydrogenase). Results: Hundred and thirty-two sickle cell patients were included. Maculopathy was observed in 127 eyes of SS patients and 10 eyes of SC patients (p < 0.001), unrelated to peripheral retinopathy. Cerebral vasculopathy was more frequent in SS patients (p < 0.001) and was also associated with the presence of maculopathy (p = 0.049), and it was related to peripheral retinopathy (p < 0.001). All biological parameters significantly differed according to the genotype (p < 0.001) but not according to the presence of cerebral vasculopathy or maculopathy. In the multivariate analysis, reticulocytes and bilirubin were associated with the presence of cerebral vasculopathy and maculopathy. Conclusion: The data obtained were consistent with the role of anemia or hemolysis markers in cerebral vasculopathy and macular involvement. As a trend of hemolysis appears to be a risk factor for these complications, this validates the use of preventive plasmapheresis in these patients.

[Decrease in visual acuity: retinal or optic nerve?]. / Baisse de l'acuité visuelle: rétine ou nerf optique?

Identify the role of the retina or of the optic nerve as an etiology of visual decease is sometimes difficult and requires eliminating obvious causes, including toxic or inherited ones. These two last causes are responsible for bilateral forms, though sometimes asymmetrical. The existence of an abnormality of the retinal examination and pupillary movement is an important diagnostic argument that must be systematically looked for, as well as the existence of an afferent pupillary defect in unilateral visual deficit. It is often required perform complementary examinations and to compare their results. However, in some cases, only the disease progression and the repetition of examinations allow to settle between these two etiologies.

Case Report: Abnormalities of sperm motility and morphology in a patient with Leber hereditary optic neuropathy: Improvement after idebenone therapy.

Case: We report the sperm characteristics of a male patient who developed, when he was 18 years old, a Leber hereditary optic neuropathy, a hereditary optic neuropathy due to mtDNA mutation as well as variants in the nuclear DNA. At the age of 30 years-old, he complained of infertility lasting for 2 years. Semen analyses showed low motility spermatozoa and a high percentage of morphological or ultrastructural abnormalities. Levels of epididymal markers were strongly atypical. Idebenone was prescribed as treatment of his Leber hereditary optic neuropathy in order to improve his visual acuity. After 5 months of this treatment, motility of spermatozoa increased, and their vitality improved. A natural conception occurred. Outcome: This case is the first description of an anomaly of spermatozoas and of the epididymis epithelium in a patient with Leber hereditary optic neuropathy. It draws attention to sperm pathologies in patients with mitochondrial disorders. The role of the mtDNA mutations must be suspected since it plays an important role in the development and motility of spermatozoa. In addition, idebenone can by-pass the complex I and transfer electrons to complex III. It has been suspected to have a favorable effect on spermatogenesis. Conclusion: This case confirms the possibility of sperm dysfunction in Leber hereditary optic neuropathy and the interest of idebenone as a treatment for infertility due to mtDNA mutations in human.

MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy.

Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the first decade of life. After analysing 51 families with negative molecular diagnostic tests, from a cohort of 200 families with hereditary optic neuropathy (HON), we identified two novel MCAT mutations in a female patient who presented with acute, sudden, bilateral, yet asymmetric, central visual loss at the age of 20. This presentation is consistent with a Leber hereditary optic neuropathy (LHON)-like phenotype, whose existence and association with NDUFS2 and DNAJC30 has only recently been described. Our findings reveal a wider phenotypic presentation of MCAT mutations, and a greater genetic heterogeneity of nuclear LHON-like phenotypes. Although MCAT pathological variants are very uncommon, this gene should be investigated in HON patients, irrespective of disease presentation.

Carotid artery dissection revealed by an oculosympathetic spasm.

Internal carotid dissection can be responsible for stroke and lead to severe neurological and functional complications. Thus, it must be diagnosed and treated with heparin as soon as possible. Horner syndrome is one of the most usual manifestations of internal carotid dissection. We report the case of a patient who presented with a unilateral non-reactive enlargement of the right pupil that did not last longer than 30 s. As a carotid dissection was not recognized from this atypical symptomatology, magnetic resonance angiography was performed only a few days later when Horner syndrome occurred. It disclosed a dissection of the internal carotid artery ipsilateral from its origin. The evolution and the duration of the pupil involvement suggest that the initial episode of mydriasis was caused by an oculosympathetic spasm, a rare form of sympathetic dysfunction that can be observed when the sympathetic nerve or the pericarotid plexus is irritated. It is important to recognize this oculosympathetic spasm because it has equal value as Horner syndrome for the diagnosis of internal carotid dissection.

[Preservation of automatic ocular saccades in healthy elderly: alteration in patients with dementia with Lewy body]. / Longévité et robustesse de la saccade oculaire automatique chez le sujet âgé sain : atteinte dans des cas de démence à corps de Lewy.

We studied, in healthy elderly subjects (aged from 63 to 83 years) and adults (aged from 20 to 32 years), ocular saccades in two conditions: one the one hand, the gap condition, where the central target disappears; then follows a period of 200 ms during which the fixation and attention were disengaged; finally, a visual target appears in the periphery. On the other hand, the overlap condition, in which the peripheral target appears when the central target is still present, the subject should voluntarily disengage his attention and fixation to orient them toward the peripheral target. These paradigms stimulate automatic versus controlled triggering of saccades. The average saccade latency (measured by video-oculography) was longer in the elderly, and irrespectively of the condition. However, the elderly as the young subjects produced shorter latencies in the gap condition than in the overlap condition. Moreover, in the gap condition, we observed the emergence of a considerable number of reflex saccades with very short latency (between 80 and 120 ms, minimal conduction time) called "express saccades". The occurrence rate of such saccades was similar in the young and the elderly subjects. These results suggest the existence of separate circuits, one non-being sensitive to age (express saccades), the other suffering the effects of aging (controlled saccades). In another ongoing study, this methodology has been applied to patients with Lewy body dementia. The preliminary results from three patients showed an abnormal slowness of latencies, even in the gap condition expected to promote automatic and reflex saccades. Furthermore, we observed a total absence of saccades with express latency. These promising results suggest a deficit even for automatic and express saccades in these patients.

How the brain obeys Hering's law: a TMS study of the posterior parietal cortex.

PURPOSE: Human ocular saccades are not perfectly yoked; the origin of this disconjugacy (muscular versus central) remains controversial. The purpose of this study was to test a cortical influence on the binocular coordination of saccades. METHODS: The authors used a gap paradigm to elicit vertical or horizontal saccades of 10 degrees , randomly interleaved; transcranial magnetic stimulation (TMS) was applied on the posterior parietal cortex (PPC) 100 ms after the target onset. RESULTS: TMS of the left or right PPC increased (i) the misalignment of the eyes during the presaccadic fixation period; (ii) the size difference between the saccades of the eyes, called disconjugacy; the increase of disconjugacy was significant for rightward and downward saccades after TMS of the right PPC and for downward saccades after TMS of the left PPC. CONCLUSIONS: The authors conclude that the PPC is actively involved in maintaining eye alignment during fixation and in the control of binocular coordination of saccades.

Cyclosporine A does not prevent second-eye involvement in Leber's hereditary optic neuropathy.

BACKRGROUND: Evaluation of the efficacy of oral cyclosporine A as a prophylactic agent in preventing second-eye involvement in Leber's hereditary optic neuropathy (LHON) in a prospective, open-label, non-randomized, multicenter pilot study. Only LHON patients aged 18 years or more, with confirmed primary mitochondrial DNA mutations and strictly unilateral optic neuropathy occurring within 6 months prior to enrolment, were included in the study. All these patients, receiving treatment with oral cyclosporine (Neoral®, Novartis) at 2.5 mg/kg/day, were examined at three-month intervals for a year. The primary endpoint was the best corrected visual acuity in the unaffected eye; the secondary endpoints were the best corrected visual acuity in the first eye affected, the mean visual field defect on automated perimetry, the thickness of the perifoveal retinal ganglion cell inner plexiform layer, and the thickness of the peripapillary retinal nerve fiber layer in both eyes. RESULTS: Among the 24 patients referred to our institution with genetically confirmed LHON, between July 2011 and April 2014, only five patients, four males and one female, fulfilled the inclusion criteria. Age at enrolment ranged from 19 to 42 years (mean: 27.2 years; median: 26 years), four patients harbored the m.11778G > A pathogenic variant, and one the m.14484 T > C pathogenic variant. The time-interval between the onset of symptoms and inclusion in the study ranged from 7 to 17 weeks (mean: 11.8 weeks; median: 9 weeks). Despite treatment with oral cyclosporine A, all patients eventually experienced bilateral eye involvement, occurring within 11-65 weeks after the initiation of treatment. Over the study time period, the average best corrected visual acuity worsened in the first eye affected; by the end of the study, both eyes were equally affected. CONCLUSIONS: Oral cyclosporine, at 2.5 mg/kg/day, did not prevent second-eye involvement in patients with strictly unilateral Leber's hereditary optic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02176733 . Registrated June 25, 2014.

Nonpenetrating external trabeculectomy for congenital glaucoma: a retrospective study.

OBJECTIVE: To evaluate the results of nonpenetrating external trabeculectomy (NPET) for primary congenital glaucoma (CG). DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Forty-three eyes of 27 consecutive patients with primary CG. METHODS: Initial intent of NPET with intraoperative conversion to trabeculectomy in cases where aqueous humor outflow was deemed insufficient or where Schlemm's canal appeared to be absent. MAIN OUTCOME MEASURES: Intraocular pressure (IOP). Success was defined as an IOP less than 12.5 mmHg at 1 year after the procedure or later, using adjunctive pressure-lowering topical medications whenever needed. RESULTS: Mean initial measures of IOP were 18.8 mmHg. Of the 43 eyes, a total of 13 required conversion to trabeculectomy: 9 because of insufficient filtration, 3 because of an apparent absence of Schlemm's canal, and 1 because of accidental perforation. Of these 13 eyes that ultimately underwent trabeculectomy, 11 achieved successful IOP control, 3 in association with topical therapy. In 1 eye, a retinal detachment developed, and in 7 eyes, other complications were observed. Among the 30 remaining eyes that underwent NPET, 2 underwent the procedure twice, and 1 eye underwent the procedure 3 times. Postoperative complications were not noted in this NPET-only group. Mean postoperative IOP was 10.8 mmHg, with final IOP controlled in 28 of the 30 eyes (93%; P<0.0001), occasionally after repeat surgeries and in combination with topical therapy. CONCLUSIONS: Nonpenetrating external trabeculectomy may be considered as an initial procedure for some cases of primary CG. It appears to be an alternative to trabeculectomy with fewer risks of postoperative complications.

Identification of four new PITX2 gene mutations in patients with Axenfeld-Rieger syndrome.

PURPOSE: Axenfeld Rieger syndrome (ARS) is an autosomal dominant inherited disorder affecting development of the ocular anterior chamber, abdomen, teeth and facial structures. The PITX2 gene is a major gene encoding a major transcription factor associated with ARS. METHODS: ARS patients were collected from six unrelated families. Patients and their families were ophthalmologically phenotyped and their blood was collected for DNA extraction. We screened the coding region of human PITX2 gene by direct sequencing. The consequences of the mutations described were investigated by generating crystallographic representations of the amino acid changes. In order to better understand the occurrence of glaucoma in ARS patients, we studied the PITX2 gene expression in human embryonic and fetal ocular tissue sections. RESULTS: We identified four novel PITX2 genetic alterations in four unrelated families with ARS. These mutations included two nonsense mutations (E55X and Y121X), an eight nucleotides insertion (1251 ins CGACTCCT) and a substitution (F58L), in familial and sporadic cases of ARS. We also showed for the first time that PITX2 is expressed at early stages of the human embryonic and fetal periocular mesenchyme, as well as at later stages of human development in the fetal ciliary body, ciliary processes, irido corneal angle and corneal endothelium. The human fetal eye PITX2 gene expression pattern reported here for the first time provides a strong basis for explaining the frequent occurrence of glaucoma in patients affected by PITX2 gene mutations. CONCLUSIONS: Two mutations identified affect the homeodomain (E55X and F58L). The E55X nonsense mutation is likely to alter dramatically the DNA-binding capabilities of the PITX2 homeodomain. Furthermore, there is a complete loss of the carboxy-terminal part of the PITX2 protein beyond the site of the mutation. The phenylalanine F58 is known to contribute to the hydrophobic network of the homeodomain. The crystallographic representations of the mutation F58L show that this mutation may change the conformation of the helical core. The F58L mutation is very likely to modify the homeodomain conformation and probably alters the DNA binding properties of PITX2. The other mutations (Y121X and the eight-nucleotide insertion (1251 ins CGA CTC CT) CGA CTC CT, at position 224 in PITX2A) result in partial loss of the C-terminal domain of PITX2. Pitx2 synergistically transactivates the prolactin promoter in the presence of the POU homeodomain protein Pit-1. Pitx2 activity is regulated by its own C-terminal tail. This region contains a highly conserved 14-amino-acid element involved in protein-protein interactions. The C-terminal 39-amino-acid tail represses DNA binding activity and is required for Pitx2 interactions with other transcription factors, for Pitx2-Pit-1 interaction and Pit-1synergism. Pit-1 interaction with the Pitx2 C terminus masks the inhibitory effect and promotes increased DNA binding activity. Thus, the partial or complete loss of the C terminus tail can lead to decreased or absent DNA binding activity and trigger severe ARS phenotypes. Our in situ hybridization results obtained on human embryonic and fetal ocular tissue sections constitute the first molecular histological data providing an explanation for the occurrence of precocious glaucoma in human patients affected by ARS caused by PITX2 mutations. Further structural and biochemical studies are needed for understanding the wide spectrum of clinical phenotypes caused by the increasing number of new PITX2 mutations found in ARS affected patients.

Relevance of Identifying JAG1 Mutations in Patients With Isolated Posterior Embryotoxon.

PURPOSE: Although posterior embryotoxon (PE) has a high incidence in the general population, clinicians should exclude any sign of glaucoma in its presence. This anatomic abnormality is often referred to as "isolated" when the intraocular pressure is normal. Nevertheless, it may be the only sign of Alagille syndrome (AS) that can be clinically heterogenous, as presented here. This possibility must be known, to look for involvement of other organs, and in case of suspicion, mutation of the JAG1 gene must be considered. METHODS: In this case series, we present the observation of a family with 3 individuals from 3 generations, in whom PE was a marker of AS. RESULTS: PE were observed in these 3 patients and considered as "isolated" as the intraocular pressure was normal. The 2 elder patients were also followed for atypical retinal dystrophy with speckling of the retinal pigment and optic disc drusen. AS syndrome was suspected when mild liver dysfunction was detected in the youngest girl. The detection of JAG1 mutation confirmed this diagnosis. CONCLUSIONS: As AS can be clinically heterogenous, it must be considered in case of isolated PE. Involvement of other organs must be looked for to search for mutation of the JAG1 gene in relevant cases.