Adriano Magli

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.

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Epithelium-off corneal collagen cross-linking versus transepithelial cross-linking for pediatric keratoconus.

Purpose: To compare efficiency and safety of epithelium-off corneal cross-linking (CXL) and transepithelial cross-linking (TE-CXL) in pediatric patients with progressive keratoconus. Methods: Uncorrected and corrected visual acuity, corneal topography and pachymetry (Pentacam; Oculus Pentacam), and in vivo confocal microscopy (HRT II, Rostock Cornea Module, Heidelberg Engineering, Heidelberg, Germany) were evaluated at baseline and at 3, 6, and 12 months. Results: In the epithelium-off CXL group (19 patients, 23 eyes; mean age, 14.75 ± 2.1 years), a significant improvement at month 12 was present for Kmax [−1.11 diopters (D), P = 0.01], Kmin (−3.2 D, P = 0.001), mean K (−1.47 D, P = 0.01), surface asymmetry index (−0.64 D, P = 0.001), inferior–superior symmetry index (−0.54 D, P = 0.01), index of height asymmetry (−2.97, P = 0.03), and anterior elevation at the thinnest location (−2.82 D, P = 0.01) and at the apex (−2.27 D, P = 0.01). Postoperative corneal edema lasted 3 months in 16 eyes (69.5%) and more than 6 months in 2 eyes (8.7%). In the TE-CXL group (10 patients, 14 eyes; mean age, 15 ± 4.2 years), a significant improvement at month 12 was present for Kmax (−1.14 D, P = 0.02), Kmin (−2.04 D, P = 0.01), mean K (−1.63 D, P = 0.01), surface asymmetry index (−0.86 D, P = 0.001), inferior–superior symmetry index (−0.55 D, P = 0.001), index of height asymmetry (−2.95, P = 0.01), and anterior elevation at the thinnest location (−2.96 D, P = 0.01) and at the apex (−2.19 D, P = 0.01). No postoperative corneal edema after TE-CXL was observed. Changes at month 12 from baseline were not significantly different between the 2 groups (P > 0.05). TE-CXE was significantly less painful than epithelium-off CXL. Conclusions: In pediatric patients with progressive keratoconus, TE-CXL was less painful, provided similar effectiveness and fewer complications than epithelium-off CXL at 12-month follow-up.

Treatment of blepharospasm with botulinum neurotoxin type A: long-term results.

Purpose To describe the long-term efficacy and side effects of treatment of blepharospasm with botulinum neurotoxin type A (Botox). Methods A total of 178 patients with blepharospasm were treated by injections of botulinum toxin in the Eye Clinic of the University of Naples from 1980 to 2001. The severity of spasm for each patient was graded on a four-point scale. Duration of improvement was assessed and reported in months. Results Of 178 cases, 10 were lost to follow-up; of the remaining patients, 93% reported improvement after treatments. The mean duration of improvement was 3.6 months. Twelve patients (76%) who underwent more than 14 treatments maintained stable relief. Three patients (1.7%) had a total remission of spasms. Side-effects were local; none of the 168 patients experienced any systemic or toxic reaction. Conclusions Botulinum toxin therapy for blepharospasm can provide long-lasting relief and reduction of spasms in the majority of patients. This therapy has the advantages of being safe, simple, and repeatable.

Incidence of ocular pathologies in Italian children with Down syndrome

Purpose This study identifies the incidence of primary ocular pathologies in a population of Italian children with Down syndrome. Methods A total of 157 Italian children with Down syndrome, age between 1 month and 18 years, were screened between February 2005 and October 2006. The ophthalmologic evaluation included a global inspection of orbit and bulbus oculi, evaluation of ocular motility and visual acuity, slit lamp biomicroscopy, cycloplegic skiascopy, tonometry, and indirect ophthalmoscopy. Results The overall incidence of ocular abnormalities was epicanthal fold (132 patients, 84%), hyperopia (93 patients, 59%), astigmatism (44 patients, 28%), myopia (14 patients, 9%), strabismus (56 patients, 36%, 45 cases of esotropia and 11 cases of exotropia), congenital nasolacrimal duct obstruction (35 patients, 22%), cataract (18 patients, 11%), nystagmus (9 patients, 6%), blepharitis and conjunctivitis (6 patients, 4%), and retinal anomalies (10 patients, 6%). Unlike previous reports in patients with Down syndrome, no congenital glaucoma, keratoconus, or Brushfield spots were observed. Conclusions Compared to other studies in patients with Down syndrome, we observed a higher incidence of hyperopia and a lower incidence of myopia. The incidence of nystagmus, blepharitis, and conjunctivitis was less than that reported in other studies, while strabismus, especially exotropia (20%), had a high incidence in our cohort. We also frequently observed obstruction of the nasolacrimal duct (22%), but no keratoconus or glaucoma.

Molecular and Clinical Characterization of Albinism in a Large Cohort of Italian Patients

PURPOSE The purpose of this study was to identify the molecular basis of albinism in a large cohort of Italian patients showing typical ocular landmarks of the disease and to provide a full characterization of the clinical ophthalmic manifestations. METHODS DNA samples from 45 patients with ocular manifestations of albinism were analyzed by direct sequencing analysis of five genes responsible for albinism: TYR, P, TYRP1, SLC45A2 (MATP), and OA1. All patients studied showed a variable degree of skin and hair hypopigmentation. Eighteen patients with distinct mutations in each gene associated with OCA were evaluated by detailed ophthalmic analysis, optical coherence tomography (OCT), and fundus autofluorescence. RESULTS Disease-causing mutations were identified in more than 95% of analyzed patients with OCA (28/45 [62.2%] cases with two or more mutations; 15/45 [33.3%] cases with one mutation). Thirty-five different mutant alleles were identified of which 15 were novel. Mutations in TYR were the most frequent (73.3%), whereas mutations in P occurred more rarely (13.3%) than previously reported. Novel mutations were also identified in rare loci such as TYRP1 and MATP. Mutations in the OA1 gene were not detected. Clinical assessment revealed that patients with iris and macular pigmentation had significantly higher visual acuity than did severe hypopigmented phenotypes. CONCLUSIONS TYR gene mutations represent a relevant cause of oculocutaneous albinism in Italy, whereas mutations in P present a lower frequency than that found in other populations. Clinical analysis revealed that the severity of the ocular manifestations depends on the degree of retinal pigmentation.

The Gorlin-Goltz syndrome: case report.

Focal dermal hypoplasia is a syndrome characterized by anomalies of cutaneous, osseous, dental and ocular structures. Because of the ocular anomalies, this syndrome should be regarded as a fifth type of phakomatosis. The differences between the fibroblasts obtained from skin lesions and fibroblasts obtained from normal skin and controls could be the demonstration of mosaicism and the consequence of lyonization. The authors present the case of a baby with typical anomalies of the Gorlin-Goltz syndrome and abnormal growth characteristics of skin fibroblasts.

Treatment of Infantile Capillary Hemangioma of the Eyelid with Systemic Propranolol.

PURPOSE To assess the efficacy and safety of systemic propranolol for infantile capillary hemangiomas of the eyelid. DESIGN Prospective, interventional cases series. METHODS All patients with eyelid infantile capillary hemangiomas at risk of developing amblyopia seen between January 2009 and January 2012 at the University Federico II, Naples, Italy, were treated with systemic propranolol (2 mg/kg body weight per day). Maximum length of treatment was 4 months, and propranolol was suspended when complete regression of lesions was obtained or in case of collateral effects. Minimum follow-up was 6 months. RESULTS Of 17 patients with eyelid infantile capillary hemangiomas, 3 were excluded for asthma and 14 (7 males, 7 females; mean age, 20.85 ± 29.7 months; range, 1 to 72 months) underwent treatment with systemic propranolol. Capillary hemangiomas involved the upper eyelid in 10 cases and the lower eyelid in 4 cases. Propranolol was stopped in 1 case for hypotension and in 1 case for allergy. Treatment was administered over a mean of 2.5 ± 1.3 months (range, 1 to 4 months); the mean follow-up was 10.64 ± 8.7 months (range, 6 to 39 months). Ten patients were younger than 1 year and demonstrated complete regression. Two patients older than 5 years also benefited from treatment. In 4 cases, amblyogenic astigmatism was present and decreased from 1.25 ± 0.5 diopters before treatment to 0.25 ± 0.2 diopters after treatment. No regrowth was observed. CONCLUSIONS Four months of treatment with oral propranolol for eyelid infantile capillary hemangiomas led to complete regression of the lesion in patients younger than 1 year. No major collateral effects were observed. Treatment also may be considered in patients older than 5 years to reduce astigmatism and for aesthetic purposes.

LASIK and PRK in refractive accommodative esotropia: a retrospective study on 20 adolescent and adult patients

Purpose To evaluate the clinical results obtained with excimer laser treatment of fully refractive accommodative esotropia. Methods Fully refractive accommodative esotropia was corrected in 17 patients with laser in situ keratomileusis (LASIK) and in 3 patients with photorefractive keratectomy (PRK). The mean age of the patients at time of refractive surgery was 18.8 years (range 14 to 24 years). All surgical procedures were performed under local anesthesia. The preoperative and postoperative data were retrospectively analyzed with regards to visual acuity, ocular alignment, and stereopsis. Results The mean preoperative deviation without correction was 18.1Δ for near vision and 13.7Δ for distance vision. After refractive surgery the mean postoperative deviation was 4Δ esophoria at near, and 2.5Δ of esophoria at distance: 10 patients (50%) showed esophoria for both distance and near vision, 2 patients (10%) esophoria only for near vision, and 8 patients (40%) orthophoria for both distance and near vision. Emmetropia (±1.00 D) was obtained in 97.5% of eyes (39 of 40). The mean correction obtained with excimer laser was +4.62 D (range +2.25 to +7.75, SD 4.52). The preoperative BSCVA was in all eyes greater than or equal to 20/30. There were no significant differences observed between the preoperative and postoperative mean best-corrected visual acuity (p=0.32). There were no complications. The follow-up period lasted a mean of 30.2 months. Conclusions The treatment of fully refractive accommodative esotropia with excimer laser was found effective and safe, even in young or adolescent patients. More studies are needed to increase the patient experience and extend the follow-up period in order to evaluate the stability of these results over time.

Prenatal screening for congenital toxoplasmosis in Campania: preliminary report on activities and results

By 1997, an open cohort of 1,652 live newborn of 1,637 mothers with gestational toxoplasmosis had been recruited in the Campania region to monitor the burden of congenital toxoplasmosis (CT). Of the 1,556 mother-child pairs that completed the follow up, 92 definite cases were detected, yielding a 5.9% (4.8-7.1 95% CI) transmission rate. The onset was patent for 43% of patients and sensorineural complications were shown for a further 15% of subclinical onset patients later than two years of age. The overall prevalence of toxoplasmosis during gestation was 2.46 of 1,000 deliveries, while the prevalence of definite CT was 1.38 of 10,000 live newborns. However, there is still room for intervention, as only 23% of the maternal diagnoses were proven through seroconversion, 63 of the late-gestation seroconverters remained untreated, and six probable CT diagnoses were made following referrals due to patent sequelae and born during the study period. There was a positive secular trend on the rates of infant referral and definite CT diagnosis, according to the live birth rate (Chi2 for trend < 0.001). Extension of this surveillance system across the country could help to define a future strategy for prevention.