Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

Age-dependent retinal neuroaxonal degeneration in children and adolescents with Leber hereditary optic neuropathy under idebenone therapy.

BACKGROUND: The aim of this study was to investigate the neuroretinal structure of young patients with Leber hereditary optic neuropathy (LHON). METHODS: For this retrospective cross-sectional analysis, the peripapillary retinal nerve fiber layer (pRNFL) thickness and the macular retinal layer volumes were measured by optical coherence tomography. Patients aged 12 years or younger at disease onset were assigned to the childhood-onset (ChO) group and those aged 13-16 years to the early teenage-onset (eTO) group. All patients received treatment with idebenone. The same measurements were repeated in age-matched control groups with healthy subjects. RESULTS: The ChO group included 11 patients (21 eyes) and the eTO group 14 patients (27 eyes). Mean age at onset was 8.6 ± 2.7 years in the ChO group and 14.8 ± 1.0 years in the eTO group. Mean best-corrected visual acuity was 0.65 ± 0.52 logMAR in the ChO group and 1.60 ± 0. 51 logMAR in the eTO group (p < 0.001). Reduced pRNFL was evident in the eTO group compared to the ChO group (46.0 ± 12.7 µm vs. 56.0 ± 14.5 µm, p = 0.015). Additionally, a significantly lower combined ganglion cell and inner plexiform layer volume was found in the eTO compared to the ChO group (0.266 ± 0.0027 mm3 vs. 0.294 ± 0.033 mm3 , p = 0.003). No difference in these parameters was evident between the age-matched control groups. CONCLUSION: Less neuroaxonal tissue degeneration was observed in ChO LHON than in eTO LHON, a finding that may explain the better functional outcome of ChO LHON.

Gillespie's Syndrome with Minor Cerebellar Involvement and No Intellectual Disability Associated with a Novel ITPR1 Mutation: Report of a Case and Literature Review.

Variants in the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene have been recently identified as a cause of Gillespie's syndrome, a rare inherited condition characterized by bilateral iris hypoplasia, congenital muscle hypotonia, nonprogressive cerebellar ataxia, and intellectual disability. Here, we describe the clinical and genetic findings in a patient who presented with iris hypoplasia, mild gait ataxia, atrophy of the anterior cerebellar vermis but no cognitive deficits. Whole-exome sequencing (WES) uncovered a heterozygous ITPR1 p.Glu2094Lys missense variant, affecting a highly conserved glutamic acid residue for which other amino acid substitutions have already been reported in Gillespie's syndrome patients. Our data expand both the phenotypic and genetic spectrum associated with Gillespie's syndrome and suggest a mutation hotspot on Glu2094.

Effects of idebenone on color vision in patients with leber hereditary optic neuropathy.

BACKGROUND: The authors investigated the correlation of protan and tritan color vision with disease characteristics in Leber hereditary optic neuropathy (LHON). The authors also characterized the therapeutic potential of idebenone in protecting patients from developing dyschromatopsia in LHON. METHODS: Color contrast data of 39 LHON patients participating in a randomized, double-blind placebo-controlled intervention study were evaluated. Patients reported disease onset <5 years before enrolment and were genetically confirmed. Protan and tritan color contrast sensitivity was measured using a computer graphics method in patients receiving idebenone (Catena; 900 mg/d; N = 28) or placebo (N = 11) for 6 months. RESULTS: Mean age of patients was 28.1 years, 87.2% were men, 76.9% carried the m11778G>A mutation, and mean duration since onset was 2 years. Assessing protan and tritan color vision at baseline revealed a high degree of color confusion even in young patients (<25 years) and with a short history of disease (<1 year). Treatment with idebenone improved tritan color vision compared with placebo (P = 0.008 at week 24); a similar trend was seen for protan. The effect of idebenone was most prominent in patients with discordant visual acuity (interocular difference of logMAR >0.2). In this subgroup, the treatment effect at week 24 was 20.4% (P = 0.005) in favor of idebenone for the tritan color domain and 13.5% (P = 0.067) for the protan domain. CONCLUSION: This study confirms that protan and tritan color confusion is an early symptom in LHON. Treatment with idebenone can protect from loss of color vision, particularly in patients who are at imminent risk of further vision loss.

Childhood versus early-teenage onset Leber's hereditary optic neuropathy: visual prognosis and capacity for recovery.

OBJECTIVE: In Leber's hereditary optic neuropathy (LHON) in children and teenagers, the influence of age on visual prognosis has not yet been investigated. METHODS: Patients from the mitoNET registry with LHON onset at age 4-16 years with at least 4 years of follow-up without treatment were included. Visual acuity (VA) at baseline, lowest VA ever recorded (nadir) and VA at end of follow-up were compared between childhood onset (ChO, ≤12 years of age) and early-teenage onset (eTO; 13-16 years). RESULTS: Out of 231 patients with LHON, 19 met the inclusion criteria (8.2%). There were 11 patients in the ChO and 8 patients in the eTO group. Mean age at onset was 8.6 (SD 2.1) years (ChO) and 15.4 (SD 0.7) years (eTO) (p<0.00001). Follow-up was mean 184 (SD 129) months (ChO) and 119 (SD 78) months (eTO) (p=0.22). Baseline VA was similar between both groups in better (p=0.96) and worse eyes (p=0.54). In worse eyes, both groups deteriorated similarly (p=0.79) until nadir and showed similar recovery until end of follow-up (p=0.38). In better eyes, both groups deteriorated similarly (p=0.16) until nadir. From nadir until end of follow-up, better eyes in the ChO group showed a significantly better recovery (-0.35 (SD 0.36) vs -0.01 (SD 0.06) logMAR; p=0.02) than eTO eyes. CONCLUSION: Visual prognosis of LHON in children is much more favourable in cases of childhood onset (≤12 years of age) as compared with teenage onset (13-16 years), mostly due to better recovery from nadir in childhood onset.

KIF21A variant R954W in familial or sporadic cases of CFEOM1.

PURPOSE: To demonstrate the clinical characteristics and determine mutations in the KIF21A gene, encoding a kinesin motor protein in patients with congenital fibrosis of the extraocular muscles (CFEOM) type 1. METHODS: Patients of five families with congenital fibrosis syndrome and two simplex patients with CFEOM underwent ophthalmologic examination and mutation analysis in the KIF21A gene. RESULTS: Clinical examination and passive motility testing prior to surgery met criteria for CFEOM. All patients had congenital restrictive ophthalmoplegia primarily affecting muscles innervated by the oculomotor nerve. Complete mutation screening in the KIF21A gene revealed the presence of the known and most common recurrent variant R954W in three families and in two simplex cases. Two families demonstrated linkage to chromosome 16. CONCLUSIONS: The patients included in the study had marked restriction of movement bilaterally with nearly complete loss of vertical ocular motility, graded reduction of horizontal motility, ptosis, and compensatory chin elevation. The phenotype was variable in patients carrying the same mutation. In one family, all patients were diagnosed with mental retardation, indicating that this syndrome might not only affect the development of cranial nerves, but can also be responsible for general neurologic dysfunction. The screening data suggest frequent and exclusive appearance of the R454W variant in sporadic and familial cases of CFEOM1 in Germany.

A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD).

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined PADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (Pdiff = 0.0032) in that it was clearly confined to females with genome-wide significance [PADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: PADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMD pathogenesis.

Lens-induced astigmatism after perforating scleral injury.

Within 6 weeks of a penetrating scleral injury that included vitreous prolapse, a 6-year-old boy developed lenticular astigmatism with a regular component of 5.5 diopters (D). Visible indentational folds in the posterior lens capsule, caused by anterior vitreous fibers and anterior hyaloid, were presumed to be the origin of the astigmatism. Because of decreased visual acuity and the suspicion of early amblyopia, a pars plana vitrectomy with removal of the anterior hyaloid and the critical anterior vitreous fibers was performed. Dense fibrotic tissue between the lens equator and the site of the original scleral perforation limited reduction of the preoperative astigmatism to 4.0 D. However, the striae-like lenticular deformation disappeared completely, and full visual acuity was restored. During the 12-month follow-up, the lens remained clear

Hereditary retinal eye diseases in childhood and youth affecting the central retina.

Hereditary dystrophies affecting the central retina represent a heterogeneous group of diseases. Mutations in different genes may be responsible for changes of the choroid (choroideremia), of the retinal pigment epithelium [RPE] (Best's disease), of the photoreceptor outer segments (Stargardt's disease) and of the bipolar and Mueller cells (x-linked retinoschisis). The correct diagnosis of hereditary retinal dystrophies is important, even though therapeutic options are limited at the moment, as every patient should get a diagnosis and be informed about the expected prognosis. Furthermore, specific gene therapy of a number of diseases such as Leber congenital amaurosis, choroideremia, Stargardt's disease, Usher Syndrome and achromatopsia is being evaluated at present. Classic examinations for patients suffering from hereditary retinal dystrophies of the central retina are funduscopy - also using red-free light - visual-field tests, electrophysiologic tests as electro-retinogram [ERG] and multifocal ERG and tests evaluating color vision. Recently, new imaging modalities have been introduced into the clinical practice. The significance of these new methods such as high-resolution spectral-domain optic coherence tomography [SD-OCT] and fundus autofluorescence will be discussed as well as "next generation sequencing" as a new method for the analysis of genetic mutations in a larger number of patients.

Quantitative computerized color vision testing in diabetic retinopathy: A possible screening tool?

PURPOSE: To evaluate the efficacy of a computerized color vision testing (Arden color contrast test) as a screening test for detection of diabetic macular edema (DME). MATERIALS AND METHODS: A consecutive, prospective case series of 83 eyes of 42 diabetic patients with and without macular edema was enrolled. Macular edema was assessed clinically by stereoscopic grading and by central retinal thickness measurement with optical coherence tomography (OCT). Additionally, a computerized chromatest for the protan- and tritan-axis was performed. Analysis of test characteristics included receiver operating characteristic (ROC) curves and calculated sensitivity and specificity. RESULTS: Sixty-one eyes had clinically significant macular edema (CSME). OCT yielded an area under the ROC curve (AUC) of 0.92. Color vision testing yielded an AUC of 0.82 for the tritan- and 0.80 for the protan-axis. Using a cut off of 199 microns OCT resulted in a 100% sensitivity at 39% specificity. With a cut-off of 4.85, color testing yielded a sensitivity of 100% at a specificity of 8% on the tritan-axis, respectively. Considering OCT instead of clinical examination as a reference standard resulted in a comparable high sensitivity, but low specificity for color vision testing. Disturbance of the tritan axis was more pronounced than for the protan axis in present macular edema and also better correlated (r = 0.46) with retinal thickness measured with OCT. CONCLUSIONS: Computerized, quantitative color testing using the chromatest allows detection of diabetic maculopathy with high sensitivity. However, only a low specificity exists for retinal macular edema, as in diabetic retinopathy (DR) frequently abnormalities of the tritan axis exist before any retinal thickening occurs.

Muscle surgery in patients with Graves' disease using topical anesthesia.

PURPOSE: To report our experience in extraocular muscle surgery for Graves' disease using topical anesthesia. DESIGN: Retrospective, noncomparative, observational case series. PARTICIPANTS: In 135 patients with Graves' disease, a total of 200 ocular muscles were operated during the past 20 years at the Department of Ophthalmology, Ludwig-Maximilian-University, Munich, Germany. METHODS: Surgery was performed under topical anesthesia with tetracaine hydrochloride 1% eyedrops. Because of the restrictive nature of the motility impairment, recession of the muscles was used in all patients. The exact amount of recession was determined during the operation with active cooperation from the patient. MAIN OUTCOME MEASURES: Binocular single vision and the angle of deviation were evaluated preoperatively and postoperatively. RESULTS: Postoperative binocular single vision in the primary position was achieved by 78.7% of the patients on the first postoperative day. Subsequent evaluation demonstrated binocular single vision in 91.9% of all patients and in 96.4% of the group with only 1 muscle (inferior rectus) operated. CONCLUSIONS: The authors have demonstrated that topical anesthesia is a feasible and reliable method for performing extraocular muscle surgery in patients with Graves' disease. Intraoperative patient discomfort seemed insignificant, and the active cooperation of the patient in finding the appropriate extent of surgery was advantageous. The overall results showed that deviation surgery with the use of topical anesthesia is highly successful in restoring binocular single vision in patients with endocrine orbitopathy.