[New treatment option for Leber hereditary optic neuropathy: early diagnosis is required]. / Nieuwe therapie voor hereditaire opticusneuropathie van Leber.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is an orphan disease which leads to painless subacute loss of central vision in both eyes. It develops mainly in young adults and is more common in males. It most often leads to lifelong blindness. Idebenone has shown to have a favourable effect in promoting vision recovery in LHON-patients with recent visual impairement. CASE DESCRIPTION: Two male LHON patients, aged 27 and 54 years of age were misdiagnosed during one year with optic neuritis and conversion disorder. The delay caused unnecessary emotional suffering and took away the opportunity of idebenone treatment. This can be prevented by greater awareness of disease characteristcs and OCT-scanning. CONCLUSION: Therapy for LHON requires a timely diagnosis.

Psychometric properties of the Dutch version Adult Strabismus-20 Questionnaire (AS-20).

PURPOSE: Strabismus often has an impact on a patient's quality of life (QoL). The Adult Strabismus-20 questionnaire (AS-20) is an instrument developed to assess the strabismus-specific QoL. The aim was to investigate several psychometric properties of the Dutch-AS-20 among adult patients with strabismus. METHODS: Patients with any type of strabismus completed the Dutch-AS-20, the EuroQol five-dimensional questionnaire (EQ-5D-5L) and the Amblyopia and Strabismus Questionnaire (A&SQ) (N = 286). Psychometric properties were evaluated with the use of item response theory (IRT) analysis (graded response model) and by determining the internal consistency, test-retest reliability after two weeks, targeting and measurement precision. Construct validity of the AS-20 was tested against the EQ-5D-5L and the A&SQ. RESULTS: Principal component analysis indicated a psychosocial and function subscale. After collapsing underutilised response options for 10 items, subsequent fit analysis showed that the function subscale benefitted from removal of two items. Differential item functioning (DIF) was detected on four items for age and gender subgroups, but with minimal impact on the total score. Internal consistency (Cronbach's alpha 0.93 psychosocial and 0.87 function subscale) and test-retest reliability (ICC 0.91 psychosocial and 0.88 function subscale) were sufficient. Targeting and measurement precision of both subscales was appropriate for patients with low to moderate levels of visual and psychosocial functioning but suboptimal for patients with high levels of visual and psychosocial functioning. Correlations were between 0.4 and 0.7 for (subscales of) the Dutch-AS-20 and the A&SQ or EQ-5D-5L, confirming expected construct validity. CONCLUSIONS: The 18-item Dutch-AS-20 has sound psychometric properties to assess the strabismus-specific QoL among Dutch adult patients with low to moderate levels of visual and psychosocial functioning. Care must be taken when interpreting the results due to lower measurement precision at the higher end of both subscales. In future longitudinal studies, properties to assess treatment effects should be evaluated.

LONGITUDINAL STUDY OF RPE65-ASSOCIATED INHERITED RETINAL DEGENERATIONS.

PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

PURPOSE: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. DESIGN: Case series. PARTICIPANTS: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. METHODS: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. MAIN OUTCOME MEASURES: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. RESULTS: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. CONCLUSIONS: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

Ectopia lentis et pupillae in four generations caused by novel mutations in the ADAMTSL4 gene.

OBJECTIVES: To identify the phenotype, genetic defect and inheritance pattern of ectopia lentis et pupillae (ELP) in a large Dutch family, previously diagnosed as presumed autosomal dominant ELP because of the occurrence of ELP in three generations. DESIGN: A clinical and genetic study of children and adults. PARTICIPANTS: Eight patients of the ELP family, including five new patients from the youngest generation. METHODS: Standard ophthalmological examinations were performed. For molecular genetic analysis, the coding region of ADAMTSL4 was sequenced. Main outcome measures were the ocular phenotype of the new ELP patients, the inheritance pattern and the identification of mutations in the ADAMTSL4 gene in the family. RESULTS: Of the eight patients with ectopia lentis, seven fulfilled the clinical diagnostic criteria of ELP. Molecular genetic analysis of these seven patients disclosed two novel mutations in the ADAMTSL4 gene: homozygous (p.Q752X/p.Q752X) in six patients and compound heterozygous (p.Q752X/p.Q758fs) in one patient. Heterozygosity in phenotypically normal parents proved autosomal recessive (AR) inheritance. The pseudodominant inheritance pattern can be explained by high carrier frequency in this small community and/or consanguinity. CONCLUSIONS: Patients from a family with ELP in four generations have AR ELP caused by novel mutations in ADAMTSL4. The clinical presentation of ELP can be variable, but all patients of our study with homozygous p.Q752X mutation have ectopia lentis and pupillary dysfunction in common.

Axial eye length growth and final refractive outcome after unilateral paediatric cataract surgery.

AIM To compare the axial eye length growth of the two fellow eyes within one patient after unilateral paediatric cataract surgery and to assess changes in refraction and keratometry. PATIENTS/METHODS A retrospective study in 90 eyes of 45 patients was performed. The 45 patients were divided into group 1 (patients younger than 18 months at the time of surgery, n=25) and group 2 (patients 18 months or older at the time of surgery, n=20). The axial eye length, spherical equivalent refraction and keratometry were measured during surgery and at follow-up. All outcome data in the operated eyes were compared with the outcome data of the fellow non-operated eyes. The Student t test was used for statistical analysis. Values of p<0.05 were considered statistically significant. RESULTS In group 1 the absolute growth (mm) of the operated eyes was borderline statistically significantly less than in the fellow non-operated eyes (p=0.049). No statistically significant difference in the rate of axial growth between the two eyes was found (p=0.25). A larger myopic shift (p=3.85x10(-5)) and a larger change in keratometry (p=0.02) were found in the operated eyes. In group 2 no statistically significant differences were found between the two eyes. CONCLUSION We did not find a statistically significant difference in axial length growth between the operated eyes and fellow non-operated eyes in our unilateral paediatric cataract patients.

Cyclotorsion: a possible cause of residual astigmatism in refractive surgery.

PURPOSE: To determine whether cyclotorsion occurs when a subject changes from binocular to monocular fixation and to assess positionally induced cyclotorsion. SETTING: Clinics of the Rotterdam Eye Hospital, Rotterdam, The Netherlands. METHODS: The axis of astigmatism was measured with the Nidek handheld keratometer in 15 normal subjects under monocular and binocular fixation and in seated and supine positions. The limits of agreement for the repeatability of measurements with the Nidek keratometer were used to identify subjects with statistically significant cyclotorsion. RESULTS: Two subjects (13%) showed statistically significant excyclotorsion when changing from binocular to monocular fixation in a seated position. In a supine position, 3 subjects (20%) showed excyclotorsion when the fixation changed. Body position itself had no influence on ocular torsion. CONCLUSIONS: Significant cyclotorsion may occur under monocular viewing conditions. If monocular photorefractive keratectomy procedures are based on binocular keratometry readings, an undercorrection of myopic astigmatism may result. Individuals at risk should be identified before refractive keratectomy is performed.