Surrendering control, or nothing to lose: Parents' preferences about participation in a randomised trial of childhood strabismus surgery.

BACKGROUND: Intermittent exotropia is the most common form of divergent strabismus (squint) in children. Evidence regarding its optimum management is limited. A pilot randomised controlled trial has recently been completed (Surgery versus Active Monitoring in Intermittent Exotropia trial) to determine the feasibility of a full randomised controlled trial. PURPOSE: To identify drivers for and barriers against parents' participation in Surgery versus Active Monitoring in Intermittent Exotropia and to seek their views on information received, the need for randomisation, and enhancing acceptability. METHODS: Multiple method qualitative study using semi-structured telephone interviews to explore parents' motivations and trial screening logs to provide an indication of common barriers. Exploratory thematic analysis identified key themes. RESULTS: A total of 48 interviews were conducted (14 participants; 34 non-participants). Barriers included no desire for surgery/preference to 'wait and see', wanting surgery immediately, feeling uncomfortable about 'surrendering control' over decision-making/being managed 'at random', lack of confidence in the effectiveness of surgery, believing the risks outweighed the benefits, and lack of trust. Drivers included desiring surgery, 'nothing to lose', benefits offsetting the risks, and being in a trial would result in better care. Some also mentioned 'doing their bit' for research. Suggestions for enhancing acceptability included allowing choice of treatment group, giving more time for decision-making, expanding on information given, and improving communication. Many felt the necessity of randomisation was adequately explained, but there was some indication that it was misunderstood. Information extracted from the screening logs of 80/89 eligible non-participants indicated the most prevalent barrier was not wanting surgery/preferring to observe (56%), followed by desiring surgery straightaway (15%). Opposition to randomisation/wanting to retain control was recorded in 9% of cases as was the belief that the child's squint was not severe enough to warrant surgery. LIMITATIONS: Interviews were not audio-recorded. Not all who consented to interview could be contacted, although the response/contact rate was good (48/62). A few parents did not provide reasons for refusing the trial. CONCLUSION: Opposition to surgery and concerns about surrendering control were common obstacles to participation, whereas parents keen for their child to undergo the operation but happy to defer tended to embrace a 'nothing to lose' attitude. Many non-participants would have consented if allowed to choose group, although most of these would have chosen observation. While most parents felt happy with information given and that randomisation was adequately explained, it is of concern that there may be some misunderstanding, which should be addressed in any trial. These findings will inform future trials in childhood exotropia, for example, consideration of preference arms and improving communication. Lessons learnt from the Surgery versus Active Monitoring in Intermittent Exotropia trial could prove valuable to paediatric and surgical trials generally.

Treating childhood intermittent distance exotropia: a qualitative study of decision making.

BACKGROUND: Engaging patients (parents/families) in treatment decisions is increasingly recognised as important and beneficial. Yet where the evidence base for treatment options is limited, as with intermittent distance exotropia (X(T)), this presents a challenge for families and clinicians. The purpose of this study was to explore how decisions are made in the management and treatment of X(T) and what can be done to support decision-making for clinicians, parents and children. METHODS: This was a qualitative study using face to face interviews with consultant ophthalmologists and orthoptists, and parents of children with X(T). Interview data were analysed using the constant comparative method. RESULTS: The drivers for clinicians in treatment decision-making for X(T) were the proportion of time the strabismus is manifest and parents' views. For parents, decisions were influenced by: fear of bullying and, to a lesser degree, concerns around the impact of the strabismus on their child's vision. Uncertainty around the effectiveness of treatment options caused difficulties for some clinicians when communicating with parents. Parental understanding of the nature of X(T) and rationale for treatment often differed from that of the clinicians, and this affected their involvement in decision-making. Though there were good examples of shared decision-making and parent and child engagement some parents said the process felt rushed and they felt excluded. Parents reported that clinicians provided sufficient information in consultations but they had difficulties in retaining verbal information to convey to other family members. CONCLUSIONS: Overall parents were happy with the care their child received but there is scope for better parent and (where appropriate) child engagement in decision-making. There was an expressed need for written information about X(T) to reinforce what was given verbally in consultations and to share with other family members. Access could be via the hospital website, along with videos or blogs from parents and children who have undergone the various management options. A method of assisting clinicians to explain the treatment options, together with the uncertainties, in a clear and concise way could be of particular benefit to orthoptists who have the most regular contact with parents and children, and are more likely to suggest conservative treatments such as occlusion and minus lenses.

Visual exploration in Parkinson's disease and Parkinson's disease dementia.

Parkinson's disease, typically thought of as a movement disorder, is increasingly recognized as causing cognitive impairment and dementia. Eye movement abnormalities are also described, including impairment of rapid eye movements (saccades) and the fixations interspersed between them. Such movements are under the influence of cortical and subcortical networks commonly targeted by the neurodegeneration seen in Parkinson's disease and, as such, may provide a marker for cognitive decline. This study examined the error rates and visual exploration strategies of subjects with Parkinson's disease, with and without cognitive impairment, whilst performing a battery of visuo-cognitive tasks. Error rates were significantly higher in those Parkinson's disease groups with either mild cognitive impairment (P = 0.001) or dementia (P < 0.001), than in cognitively normal subjects with Parkinson's disease. When compared with cognitively normal subjects with Parkinson's disease, exploration strategy, as measured by a number of eye tracking variables, was least efficient in the dementia group but was also affected in those subjects with Parkinson's disease with mild cognitive impairment. When compared with control subjects and cognitively normal subjects with Parkinson's disease, saccade amplitudes were significantly reduced in the groups with mild cognitive impairment or dementia. Fixation duration was longer in all Parkinson's disease groups compared with healthy control subjects but was longest for cognitively impaired Parkinson's disease groups. The strongest predictor of average fixation duration was disease severity. Analysing only data from the most complex task, with the highest error rates, both cognitive impairment and disease severity contributed to a predictive model for fixation duration [F(2,76) = 12.52, P ≤ 0.001], but medication dose did not (r = 0.18, n = 78, P = 0.098, not significant). This study highlights the potential use of exploration strategy measures as a marker of cognitive decline in Parkinson's disease and reveals the efficiency by which fixations and saccades are deployed in the build-up to a cognitive response, rather than merely focusing on the outcome itself. The prolongation of fixation duration, present to a small but significant degree even in cognitively normal subjects with Parkinson's disease, suggests a disease-specific impact on the networks directing visual exploration, although the study also highlights the multi-factorial nature of changes in exploration and the significant impact of cognitive decline on efficiency of visual search.

A randomized trial of increasing patching for amblyopia.

OBJECTIVE: After treatment with refractive correction and patching, some patients have residual amblyopia resulting from strabismus or anisometropia. We conducted a clinical trial to evaluate the effectiveness of increasing prescribed daily patching from 2 to 6 hours in children with stable residual amblyopia. DESIGN: Prospective, randomized, multicenter clinical trial. PARTICIPANTS: A total of 169 children aged 3 to <8 years (mean, 5.9 years) with stable residual amblyopia (20/32-20/160) after 2 hours of daily patching for at least 12 weeks. INTERVENTION: Random assignment to continue 2 hours of daily patching or increase patching time to an average of 6 hours/day. MAIN OUTCOME MEASURES: Best-corrected visual acuity (VA) in the amblyopic eye after 10 weeks. RESULTS: Baseline VA was 0.44 logarithm of the minimum angle of resolution (logMAR) (20/50(-2)). Ten weeks after randomization, amblyopic eye VA had improved an average of 1.2 lines in the 6-hour group and 0.5 line in the 2-hour group (difference in mean VA adjusted for acuity at randomization = 0.6 line; 95% confidence interval, 0.3-1.0; P = 0.002). Improvement of 2 or more lines occurred in 40% of participants patched for 6 hours versus 18% of those who continued to patch for 2 hours (P = 0.003). CONCLUSIONS: When amblyopic eye VA stops improving with 2 hours of daily patching, increasing the daily patching dosage to 6 hours results in more improvement in VA after 10 weeks compared with continuing 2 hours daily.

The impact of visual impairment on Mini-Mental State Examination Scores in the Newcastle 85+ study.

BACKGROUND: cognitive test scores and visual acuity are strongly associated in older people. This may be due to poor vision limiting performance on cognitive tasks specifically requiring vision, or an association between visual and neurodegenerative disorders. OBJECTIVE: to explore, using data from the Newcastle 85+ cohort study, the impact of sight impairment (SI) on Mini-Mental State Examination (MMSE) scores and whether reduced scores among SI participants are limited to tasks requiring vision. RESULTS: of 839 participants aged 85 years, 44 (5.2%) were registered SI. Median (inter-quartile range) sMMSE scores were 25 (22-29) for SI and 28 (25-29) for non-SI participants (P=0.006). SI participants had lower subscale scores on tasks requiring vision (P<0.001 for each) but also for some subscale scores not obviously requiring vision: orientation (P=0.018) and repetition (P=0.030). Excluding visual items, there was no significant difference in MMSE scores between those with/without SI. CONCLUSION: SI may be an obstacle to older people completing cognitive assessments including tasks requiring vision. People with SI also scored lower on some tasks not obviously requiring vision. An association between cognitive impairment and SI may exist beyond simply being unable to see the test material in cognitive tests.

Use of the PedsQL in childhood intermittent exotropia: estimates of feasibility, internal consistency reliability and parent-child agreement.

PURPOSE: To evaluate the PedsQLs performance in children with intermittent exotropia (X[T]) in terms of feasibility, internal consistency, floor-ceiling effects and levels of parent-child agreement. METHODS: Children with X(T) aged <12 years were recruited from 26 UK Hospital Eye Clinics/Orthoptic Departments. QOL was assessed using child (n = 166) and proxy (n = 392) versions of the PedsQLv4. Feasibility was assessed by percentage of missing responses; internal consistency by Cronbach's alpha and agreement by Bland-Altman plots and intraclass correlations. Analyses included age and gender comparisons. RESULTS: Missing response rates were no higher than 1.8%. Cronbach's alpha reached ≥ 0.70 on all but one parent-rated scale and on most child-rated Total, Psychosocial Summary and Social Functioning scales, but was <0.70 on most child-rated Physical, Emotional and School Functioning scales. On parent-rated scales, there were no floor effects; ceiling effects reached 27-56% in parents' Physical, Social and School Functioning. On child-rated scales, there were 0-1% floor effects and 0-28% ceiling effects. Parent-child agreement was fair to poor and varied by child's gender. CONCLUSIONS: Proxy-rated PedsQLs demonstrated good internal consistency/feasibility in parents of children with X(T); child-rated reports appeared acceptable, although caution is advised regarding Physical, Emotional and School Functioning scales in younger children. Low-fair agreement between proxy and self-ratings is common in paediatric QOL assessment, reiterating the importance of obtaining both perspectives. We encourage future studies to explore the influence of child's age and gender, and the relationship of the proxy respondent.

The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort.

BACKGROUND: The purpose of this study was to investigate current patterns of management and outcomes of intermittent distance exotropia [X(T)] in the UK. METHODS: This was an observational cohort study which recruited 460 children aged < 12 years with previously untreated X(T). Eligible subjects were enrolled from 26 UK hospital ophthalmology clinics between May 2005 and December 2006. Over a 2-year period of follow-up, clinical data were prospectively recorded at standard intervals from enrolment. Data collected included angle, near stereoacuity, visual acuity, control of X(T) measured with the Newcastle Control Score (NCS), and treatment. The main outcome measures were change in clinical outcomes (angle, stereoacuity, visual acuity and NCS) in treated and untreated X(T), 2 years from enrolment (or, where applicable, 6 months after surgery). Change over time was tested using the chi-square test for categorical, Wilcoxon test for non-parametric and paired-samples t-test for parametric data. RESULTS: At follow-up, data were available for 371 children (81% of the original cohort). Of these: 53% (195) had no treatment; 17% (63) had treatment for reduced visual acuity only (pure refractive error and amblyopia); 13% (50) had non surgical treatment for control (spectacle lenses, occlusion, prisms, exercises) and 17% (63) had surgery. Only 0.5% (2/371) children developed constant exotropia. The surgically treated group was the only group with clinically significant improvements in angle or NCS. However, 8% (5) of those treated surgically required second procedures for overcorrection within 6 months of the initial procedure and at 6-month follow-up 21% (13) were overcorrected. CONCLUSIONS: Many children in the UK with X(T) receive active monitoring only. Deterioration to constant exotropia, with or without treatment, is rare. Surgery appears effective in improving angle of X(T) and NCS, but rates of overcorrection are high.

Single vision during ocular deviation in intermittent exotropia.

Intermittent exotropia is a common oculomotor anomaly where one eye intermittently deviates outwards. Patients with this type of strabismus are often not aware of the exodeviation and do not usually experience diplopia. In this review, we discuss what is known about the cortical mechanisms which achieve single vision during exodeviation in this condition, and highlight some outstanding questions.

The prevalence and natural history of dominant optic atrophy due to OPA1 mutations.

PURPOSE: Autosomal dominant optic atrophy (DOA) is a major cause of visual impairment in young adults that is characterized by selective retinal ganglion cell loss. To define the prevalence and natural history of this optic nerve disorder, we performed a population-based epidemiologic and molecular study of presumed DOA cases in the north of England. DESIGN: Case series. PARTICIPANTS: Seventy-six affected probands with a clinical diagnosis of DOA were identified from our neuro-ophthalmology and neurogenetics database. METHODS: OPA1 genetic testing was performed using a polymerase chain reaction-based sequencing strategy. OPA1-negative cases were then screened for large-scale OPA1 rearrangements and OPA3 mutations. Additional affected family members identified through contact tracing were examined, and longitudinal visual data were analyzed. MAIN OUTCOME MEASURES: The prevalence and molecular characteristics of DOA in the north of England. Visual function and disease progression among patients with OPA1-positive mutations. RESULTS: The detection rate of OPA1 mutations was 57.6% among probands with a positive family history of optic atrophy (19/33) and 14.0% among singleton cases (6/43). Approximately two thirds of our families with DOA harbored OPA1 mutations (14/22, 63.6%), and 5 novel OPA1 mutations were identified. Only 1 family carried a large-scale OPA1 rearrangement, and no OPA3 mutations were found in our optic atrophy cohort. The minimum point prevalence of DOA in the north of England was 2.87 per 100,000 (95% confidence interval [CI], 2.54-3.20), or 2.09 per 100,000 (95% CI, 1.95-2.23) when only OPA1-positive cases were considered. Snellen visual acuity varied markedly between OPA1-positive cases with a mean of 20/173 (range 20/20 to hand movements), and visual function worsened in 67.4% of patients during follow-up. The mean rate of visual loss was 0.032 logarithm of the minimum angle of resolution per year, but some patients experienced faster visual decline (range = 0-0.171 logarithm of the minimum angle of resolution/year). OPA1 missense mutations were associated with a significantly worse visual outcome compared with other mutational subtypes (P=0.0001). CONCLUSIONS: Dominant optic atrophy causes significant visual morbidity and affects at least 1 in 35,000 of the general population.

The retina in Parkinson's disease.

As a more complete picture of the clinical phenotype of Parkinson's disease emerges, non-motor symptoms have become increasingly studied. Prominent among these non-motor phenomena are mood disturbance, cognitive decline and dementia, sleep disorders, hyposmia and autonomic failure. In addition, visual symptoms are common, ranging from complaints of dry eyes and reading difficulties, through to perceptual disturbances (feelings of presence and passage) and complex visual hallucinations. Such visual symptoms are a considerable cause of morbidity in Parkinson's disease and, with respect to visual hallucinations, are an important predictor of cognitive decline as well as institutional care and mortality. Evidence exists of visual dysfunction at several levels of the visual pathway in Parkinson's disease. This includes psychophysical, electrophysiological and morphological evidence of disruption of retinal structure and function, in addition to disorders of 'higher' (cortical) visual processing. In this review, we will draw together work from animal and human studies in an attempt to provide an insight into how Parkinson's disease affects the retina and how these changes might contribute to the visual symptoms experienced by patients.

Characterizing the Randot Preschool stereotest: Testability, norms, reliability, specificity and sensitivity in children aged 2-11 years.

PURPOSE: To comprehensively assess the Randot Preschool stereo test in young children, including testability, normative values, test/retest reliability and sensitivity and specificity for detecting binocular vision disorders. METHODS: We tested 1005 children aged 2-11 years with the Randot Preschool stereo test, plus a cover/uncover test to detect heterotropia. Monocular visual acuity was assessed in both eyes using Keeler Crowded LogMAR visual acuity test for children aged 4 and over. RESULTS: Testability was very high: 65% in two-year-olds, 92% in three-year-olds and ~100% in older children. Normative values: In 389 children aged 2-5 with apparently normal vision, 6% of children scored nil (stereoblind). In those who obtained a threshold, the mean log threshold was 2.06 log10 arcsec, corresponding to 114 arcsec, and the median threshold was 100 arcsec. Most older children score 40 arcsec, the best available score. We found a small sex difference, with girls scoring slightly but significantly better. Test/retest reliability: ~99% for obtaining any score vs nil. Agreement between stereo thresholds is poor in children aged 2-5; 95% limit of agreement = 0.7 log10 arcsec: five-fold change in stereo threshold may occur without any change in vision. In children over 5, the test essentially acts only as a binary classifier since almost all non-stereoblind children score 40 arcsec. Specificity (true negative rate): >95%. Sensitivity (true positive rate): poor, <50%, i.e. around half of children with a demonstrable binocular vision abnormality score well on the Randot Preschool. CONCLUSIONS: The Randot Preschool is extremely accessible for even very young children, and is very reliable at classifying children into those who have any stereo vision vs those who are stereoblind. However, its ability to quantify stereo vision is limited by poor repeatability in children aged 5 and under, and a very limited range of scores relevant to children aged over 5.

ASTEROID: A New Clinical Stereotest on an Autostereo 3D Tablet.

PURPOSE: To describe a new stereotest in the form of a game on an autostereoscopic tablet computer designed to be suitable for use in the eye clinic and present data on its reliability and the distribution of stereo thresholds in adults. METHODS: Test stimuli were four dynamic random-dot stereograms, one of which contained a disparate target. Feedback was given after each trial presentation. A Bayesian adaptive staircase adjusted target disparity. Threshold was estimated from the mean of the posterior distribution after 20 responses. Viewing distance was monitored via a forehead sticker viewed by the tablet's front camera, and screen parallax was adjusted dynamically so as to achieve the desired retinal disparity. RESULTS: The tablet must be viewed at a distance of greater than ∼35 cm to produce a good depth percept. Log thresholds were roughly normally distributed with a mean of 1.75 log10 arcsec = 56 arcsec and SD of 0.34 log10 arcsec = a factor of 2.2. The standard deviation agrees with previous studies, but ASTEROID thresholds are approximately 1.5 times higher than a similar stereotest on stereoscopic 3D TV or on Randot Preschool stereotests. Pearson correlation between successive tests in same observer was 0.80. Bland-Altman 95% limits of reliability were ±0.64 log10 arcsec = a factor of 4.3, corresponding to an SD of 0.32 log10 arcsec on individual threshold estimates. This is similar to other stereotests and close to the statistical limit for 20 responses. CONCLUSIONS: ASTEROID is reliable, easy, and portable and thus well-suited for clinical stereoacuity measurements. TRANSLATIONAL RELEVANCE: New 3D digital technology means that research-quality psychophysical measurement of stereoacuity is now feasible in the clinic.

Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia.

A girl with aniridia, microphthalmia, microcephaly and café au lait macules was found to have mutations in PAX6, NF1 and OTX2. A novel PAX6 missense mutation (p.R38W) was inherited from her mother whose iris phenotype had not been evident because of ocular neurofibromatosis. Analysis of the NF1 gene in the proband, prompted by the mother's diagnosis and the presence of café au lait spots, revealed a nonsense mutation (p.R192X). Subsequently an OTX2 nonsense mutation (p.Y179X) was identified and shown to be inherited from her father who was initially diagnosed with Leber's congenital amaurosis. Since individual mutations in PAX6, OTX2 or NF1 can cause a variety of severe developmental defects, the proband's phenotype is surprisingly mild. This case shows that patients with complex phenotypes should not be eliminated from subsequent mutation analysis after one or even two mutations are found.

Amblyopia.

Results from recent randomised clinical trials in amblyopia should change our approach to screening for and treatment of amblyopia. Based on the current evidence, if one screening session is used, screening at school entry could be the most reasonable time. Clinicians should preferably use age-appropriate LogMAR acuity tests, and treatment should only be considered for children who are clearly not in the typical range for their age. Any substantial refractive error should be corrected before further treatment is considered and the child should be followed in spectacles until no further improvement is recorded, which can take up to 6 months. Parents and carers should then be offered an informed choice between patching and atropine drops. Successful patching regimens can last as little as 1 h or 2 h a day, and successful atropine regimens as little as one drop twice a week. Intense and extended regimens might not be needed in initial therapy.

The use of the Newcastle Control Score in the management of intermittent exotropia.

AIM: To evaluate the use of the Newcastle Control Score (NCS) in the management of intermittent exotropia (X(T)). PARTICIPANTS AND METHODS: Children aged <11 years with X(T) had an assessment of NCS as part of routine management. Other data collected included visual acuity, near and distance alignment with alternating prism cover test and near (Frisby test) and distance stereoacuity (Frisby Davis Distance Stereotest (FD2TM)). Analysis involved correlation between baseline NCS, angle and stereoacuity, examination of change over time and logistic regression to determine predictors of surgery. RESULTS: Baseline data were obtained on 272 children and follow-up data on 157. Mean (SD) age was 4 (1.9) years. Complete NCSs were obtained for all except one child at baseline, and all children at follow-up. At baseline, total NCS and the home control component were correlated with near stereo (r = -0.22, p<0.01 and r = -0.19, p<0.02, respectively), near alignment (r = 0.34, p<0.001 and r = 0.19, p<0.02) and distance alignment (r = 0.30, p<0.001 and r = 0.26, p<0.001). The clinic near control component was correlated with near alignment (r = 0.39, p<0.001), but not near stereoacuity, and the clinic distance control with near alignment (r = 0.16, p<0.02), distance alignment (r = 0.27, p<0.001) and distance stereoacuity (r = -0.25, p<0.03). A high (poor) NCS (> or =4) at the latest follow-up predicted surgery (p<0.001, OR 29.3, 95% CI 6.2 to 138.7). CONCLUSION: The NCS is a useful measure of the clinical severity of X(T), can be used to serially assess improvement or deterioration and is a useful tool for the management of these patients.

Intermittent exotropia.

This article describes the clinical manifestations of and management options for intermittent exotropia. Control of the strabismus is one of the parameters that can be assessed for all children with the condition. A method of quantifying control, the Newcastle Control Score, is presented.

The treatment of amblyopia.

Recent studies suggest that children with amblyopia associated with anisometropia, strabismus, or both should be treated initially with best refractive correction until visual acuity is stable. This may take several months, and a proportion of children will achieve equal visual acuity with glasses alone. For residual anisometropic and strabismic amblyopia, the initial choice of patching or atropine should involve the parent and the child. The dose of prescribed patching or atropine may initially be quite modest, such as 2 hours of patching a day or twice weekly atropine. Treatment should be offered to children until at least 12 years of age and possibly to teenagers. Ongoing studies are addressing the role of undertaking near activities while patched and the role of atropine for severe amblyopia and for older amblyopic children. Future studies are needed to investigate the best treatment strategies for residual amblyopia, whether weaning treatment is needed at the end of a course, and how compliance can be enhanced.

Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby's fundus dystrophy patients.

Gingival fibroblast cell lines were derived from Sorsby's fundus dystrophy (SFD) patients carrying the S181C TIMP3 and the E139X TIMP3 mutations. These cell lines were grown in culture to study expression of the wild-type and mutant tissue inhibitor of metalloproteinase 3 (TIMP3) alleles from a normal diploid cell type. Firstly, patient cells were found to co-express the wild-type and mutant TIMP3 alleles, S181C TIMP3 or E139X TIMP3, at the mRNA level using restriction fragment length polymorphism (RFLP) analysis. A SpeI RFLP for E139X TIMP3 is described. Low levels of endogenous TIMP3 protein expression were elevated using the natural polysaccharide calcium pentosan polysulfate (CaPPs) in combination with the cytokine IL-1alpha. Immunoblotting detected protein expression from both wild-type and mutant alleles, S181C TIMP3 or E139X TIMP3. S181C TIMP3 from these cells was found to dimerise and retain MMP2 inhibitory activity. To facilitate studies of the E139X TIMP3 protein, the allele was expressed using HighFive insect cells. In this cell type, the E139X TIMP3 was synthesised as a mixture of monomer and dimer. Both monomeric and dimeric E139X TIMP3 protein retained MMP2 inhibitory activity in gelatin zymography. Expression of mutant E139X or S181C TIMP3 protein from a normal diploid patient-derived fibroblast cell had no effect on either MMP2 or MMP9 expression or activation whilst transcribed from their normal promoter context.