[The Phenotypic Spectrum of Ophthalmic Changes in CEP290 Mutations]. / Das phänotypische Spektrum der Augenveränderungen bei CEP290-Sequenzvariationen.

PURPOSE: Inherited retinal diseases (IRDs) may be caused by variations in genes affecting the connecting cilium of photoreceptor cells and intraflagellar transport, manifested as ciliopathies. CEP290 is frequently mutated in non-syndromic, but also syndromic IRDs. In preparation for clinical treatment trials, detailed phenotypic work-up including longitudinal follow-up is mandatory. METHODS: We performed genotype-phenotype correlations in 30 patients with biallelic mutations in CEP290. The study was approved by the IRB of the medical faculty of the Justus-Liebig University Giessen. The patients received a comprehensive clinical examination, including spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) recording, and electrophysiology whenever possible. RESULTS: Thirty patients aged 1 month to 84 years (median at first visit 0.6 y) were followed between 5 months and 25.7 years (median 4.8 y). Twenty-three of these patients carried the c.2991+1655A>G mutation (30/60 allele 2, 7 homozygous). The second most frequent mutation was p.K1575* (9/60 alleles). The full-field electroretinogram showed residual response in a few patients only. After progression, electrophysiological responses were below threshold in all patients. Severely reduced visual acuity persisted from birth. Eight patients had quantifiable best corrected visual acuity (BCVA, logMAR 2 - 0.3), in one case up to the age of 84 y. Absent fixation of targets was noted in 15 patients during the first months of life. Ten of these patients did not improve during follow-up past the second year of life. The other patients developed at least light perception (LP, n = 7) or hand movement (HM, n = 3). Better BCVA was not restricted to the c.2991+1655A>G mutation. Fundus photography documented degenerative changes throughout the retina with macular degeneration and circular increased fundus autofluorescence signals (9/30 patients) in the perimacular ring and in the rod ring, and spotty changes in the periphery. SD-OCT (6/30 patients) disclosed reduced photoreceptor layer (OPL to OS) thickness and preserved inner retinal thickness (RNFL to INL). Better BCVA did not correlate to genotype or central photoreceptor layer thickness. CONCLUSION: As reported earlier, CEP290 variations are one of the most frequent causes of IRDs with infancy onset. In our patient cohort of 30 patients, only 33% had no LP, 67% at least LP, and among these 26% logMAR 2 to 0.3. Together with preserved ganglion cell and nerve fibre cell layers, success with gene therapeutic approaches appears possible.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

Set-shifting and its relation to clinical and personality variables in full recovery of anorexia nervosa.

OBJECTIVE: First, this study aimed to explore whether set-shifting is inefficient after full recovery of anorexia nervosa (recAN). Second, this study wanted to explore the relation of set-shifting to clinical and personality variables. METHOD: A total of 100 recAN women were compared with 100 healthy women. Set-shifting was assessed with Berg's Card Sorting Test. Expert interviews yielded assessments for the inclusion/exclusion criteria, self-ratings for clinical and personality variables. RESULTS: Compared with the healthy control group, the recAN participants achieved fewer categories, showed more perseverations and spent less time for shifting set. Perfectionism is correlated with set-shifting but in converse directions in the two groups. DISCUSSION: Our study supports the findings of inefficiencies in set-shifting after full recovery from AN. Higher perfectionism in the recAN group is associated with better set-shifting ability, whereas higher perfectionism in the healthy control group is related to worse set-shifting ability.

Central coherence in full recovery of anorexia nervosa.

OBJECTIVE: This study examined central coherence as a possible endophenotype in a large sample of women recovered from anorexia nervosa (rec AN). Recovery was defined by considering physiological, behavioural and psychological variables. METHOD: A total of 100 rec AN women and 100 healthy women completed the Rey Complex Figure Test, a measure for visual-spatial central coherence. The participants were matched 1:1 for age and educational level. RESULTS: Compared with the healthy control group, the rec AN group showed better accuracy in the copy condition. There was a trend for a local strategy in the rec AN group compared with a global strategy in the healthy control group. CONCLUSIONS: This sample of rec AN women showed no inefficiencies in global processing but a superior local processing after full recovery from AN.

The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Decision-making and planning in full recovery of anorexia nervosa.

OBJECTIVE: Based on findings of persisting neuropsychological impairments in women recovered from anorexia nervosa (rec AN), this study examined decision-making and planning, for achieving a desired goal, as central executive functions in a large sample of rec AN. The definition of recovery included physiological, behavioral, and psychological variables. METHOD: A total of 100 rec AN women were compared to 100 healthy women, 1:1 matched for age and educational level. Decision-making was assessed with the Iowa Gambling Task and planning with the Tower of London. Expert interviews and self-ratings were used for assessing the inclusion/exclusion criteria and control variables. RESULTS: Compared to healthy controls, rec AN women were better in decision-making and worse in planning even after considering control variables. DISCUSSION: This study does not support results from other studies showing that rec AN participants perform better in decision-making. Results from this study show that planning is impaired even after full recovery from AN.

Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7.

Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

C3-Glomerulopathy Autoantibodies Mediate Distinct Effects on Complement C3- and C5-Convertases.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

[An interdisciplinary concept to optimize patient safety--a pilot study]. / Ein interdisziplinäres Konzept zur Optimierung der Patientensicherheit - Eine Pilotstudie.

OBJECTIVE: Which effects has the interdisciplinary collaboration including pharmacists and psychologists in depressive patients? METHODS: In a 3-arm (each N = 10) randomized pilot study, we compared SC (standard care by specialized physicians in a tertiary care center) with SC + pharmaceutical medication management and SC + psychological counselling in respect to the number of drug-drug interactions, guideline conformity, patient knowledge, and medication adherence (according to MARS). RESULTS: The number of drug-drug interactions decreased by the MM up to 67 % (p < 0.05). Guideline conformity was fulfilled in all groups before and after intervention. Patient knowledge and medication adherence were not influenced by additional medication management or psychological counselling. CONCLUSION: In a greater patient group, these explorative results should now be verified.

Standardisation of the factor H autoantibody assay.

The screening of all atypical haemolytic uraemic syndrome (aHUS) patients for factor H autoantibodies is best practice. However, there is no consensus assay for the reporting of factor H autoantibody titres. In this study, three European complement laboratories with expertise in the field of autoantibody testing address this by systematically evaluating several ELISA methods used for the detection of factor H autoantibodies. All methods tested adequately detect high titre samples. However, this study recommends the Paris method for the detection and reporting of factor H autoantibodies to be used when setting up a factor H autoantibody screen. The importance of individual sample background subtraction in these ELISA tests was established. The use of a relative or arbitrary unit index with a common positive and negative serum allowed for consistent comparison of findings from different test centres. Therefore, it is recommended that a standard arbitrary unit scale based on a titration curve from a common positive anti-serum be adopted to allow future establishment of the relative importance of particular titres of factor H autoantibodies in aHUS. Systematic assay for the presence of factor H autoantibodies in patients using the Paris method will provide the longitudinal analysis needed to fully establish the importance of factor H autoantibodies in disease. This will feed into additional research to clarify whether additional factors have a bearing on the phenotype/outcome of autoimmune aHUS.

Internet-based relapse prevention for anorexia nervosa: nine- month follow-up.

BACKGROUND: To study the longer term effects of an internet-based CBT intervention for relapse prevention (RP) in anorexia nervosa. METHODS: 210 women randomized to the RP intervention group (full and partial completers) or the control group were assessed for eating and general psychopathology. Multiple regression analysis identified predictors of favorable course concerning Body Mass Index (BMI). Logistic regression analysis identified predictors of adherence to the RP program. RESULTS: Most variables assessed showed more improvement for the RP than for the control group. However, only some scales reached statistical significance (bulimic behavior and menstrual function, assessed by expert interviewers blind to treatment condition). Very good results (BMI) were seen for the subgroup of "full completers" who participated in all nine monthly RP internet-based intervention sessions. "Partial completers" and controls (the latter non-significantly) underwent more weeks of inpatient treatment during the study period than "full completers", indicating better health and less need for additional treatment among the "full completers". Main long-term predictors for favorable course were adherence to RP, more spontaneity, and more ineffectiveness. Main predictors of good adherence to RP were remission from lifetime mood and lifetime anxiety disorder, a shorter duration of eating disorder, and additional inpatient treatment during RP. CONCLUSIONS: Considering the high chronicity of AN, internet-based relapse prevention following intensive treatment appears to be promising.

Does internet-based prevention reduce the risk of relapse for anorexia nervosa?

Technological advancements allow new approaches to psychotherapy via electronic media. The eating disorder literature currently contains no studies on internet intervention in anorexia nervosa (AN). This study presents a RCT on an internet-based relapse prevention program (RP) over nine months after inpatient treatment for AN. The sample comprised 258 women, randomized to the RP or treatment as usual (TAU). Expert- and self-ratings were evaluated by intent-to-treat analyses. Concerning age, age at onset and comorbidity, both groups were comparable at randomization. During the RP, the intervention group gained weight while the TAU group had minimal weight loss. RP completers gained significantly more body weight than patients in the TAU condition. Group-by-time comparisons for eating-related cognitions and behaviors and general psychopathology showed a significantly more favorable course in the RP program for "sexual anxieties" and "bulimic symptoms" (interview), and "maturity fears" and "social insecurity" (EDI-2). General psychopathology showed no significant group-by-time interaction. Important factors for successful relapse prevention were adherence to the intervention protocol and increased spontaneity. Considering the unfavorable course and chronicity of anorexia nervosa (AN), internet-based relapse prevention in AN following inpatient treatment appears a promising approach. Future internet-based programs may be further improved and enhanced.

Polytetrafluoroethylene (Goretex) for muscle elongation in the surgical treatment of strabismus with restricted motility.

PURPOSE: Repeated strabismus surgery as well as eye muscle fibrosis in various forms of strabismus, can be followed by restriction of the motility of the eye. Tendon elongation may be necessary if further improvement of the deviation and duction of the eye muscle is to be achieved. We used polytetrafluoroethylene (Goretex) and looked at its user comfort, compatibility and dose-rate relationship. METHOD: Three patients with consecutive exotropia after repeated operations for congenital esotropia, two patients with VI nerve palsy and residual head turn after combined convergence operation and one child with congenital fibrosis syndrome underwent muscle tendon elongation with Goretex (7-15 mm) of either the medial or the lateral rectus muscle, which had already been resected and/or recessed in former surgeries. Forced duction under general anaesthesia was restricted in all patients. RESULTS: The correction of the deviation in primary position (deviation at distance + 3 degrees to - 4 degrees and at near - 1 degrees to - 8 degrees ) and in side gaze was satisfactory and motility was clearly improved. There were no postoperative complications (infection, shrinkage, scarring) and the postoperative results in terms of the angle of deviation and the improvement in motility remained stable for 1-6 years. CONCLUSION: Polytetrafluoroethylene (Goretex) is a good material with which to resolve complicated cases of strabismus in which muscle tendon elongation for bulbus restriction is necessary.

[Ocular myasthenia: a diagnostic and management challenge--a review]. / Okuläre Myasthenie: eine diagnostische und therapeutische Herausforderung--eine Ubersicht.

BACKGROUND: Ocular myasthenia is a localised form of myasthenia clinically involving the extraocular muscles, the m. levator palpebrae superioris and the m. orbicularis oculi. Various symptoms can masquerade peripheral and supranuclear eye muscle palsies and ptosis. MATERIALS AND METHOD: This literature review of recent years focuses on the diagnostic tests that may be helpful to confirm myasthenia especially in patients without acetylcholine receptor antibodies. CONCLUSIONS: Ocular dysfunction accounts for 50-80% of the initial manifestation of myasthenia gravis. Clinical manifestations, diagnostic tests and treatment assessment are reviewed. Early recognition of the disease is important for better prognosis.

[Diagnosis and therapy of Graves' ophthalmopathy--consensus guidelines]. / Diagnostik und Therapie der endokrinen Orbitopathie--Konsensusrichtlinien.

On 22-09-2001 the VIth Grazer Hormonsymposion took place. Diagnosis and therapy of Graves' Ophthalmopathy was discussed in an interdisciplinary way by endocrinologists, surgeons and ophthalmologists. The results of the round-table discussion and the consensus talk are presented.