M P Clarke

Northern Institute For Cancer Research, Newcastle-on-Tyne, England, United Kingdom

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Publications (7)20.71 Total impact

  • Source
    Journal of Medical Genetics 04/2002; 39(3):221-3. · 5.70 Impact Factor
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    ABSTRACT: To describe the phenotype in three family members affected by a novel mutation in the gene coding for the enzyme tissue inhibitor of metalloproteinase-3 (TIMP-3). Three members of the same family were seen with a history of nyctalopia and visual loss due to maculopathy. Clinical features were consistent with Sorsby's fundus dystrophy. Exon 5 of the gene coding for TIMP-3 was amplified by the polymerase chain reaction, single strand conformation polymorphism analysis undertaken and exon 5 amplicons were directly sequenced. Onset of symptoms was in the third to fourth decade. Five of six eyes had geographic macular atrophy rather than neovascularisation as a cause for central visual loss. Peripheral retinal pigmentary disturbances were present. Scotopic ERGs were abnormal in all three. Mutation analysis showed a G-->T transversion in all three resulting in a premature termination codon, E139X, deleting most of the carboxy terminal domain of TIMP-3. The patients described had a form of Sorsby's fundus dystrophy which fell at the severe end of the spectrum of this disease. Postulated disease mechanisms include deposition of dimerised TIMP-3 protein.
    British Journal of Ophthalmology 12/2001; 85(12):1429-31. · 2.73 Impact Factor
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    ABSTRACT: Sorsby's fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age. It has been shown to be caused by mutations in the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). Five different mutations have previously been identified, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP-3 molecule; however, the significance of these mutations to the disease phenotype was unknown. In this report, we describe the expression of several of these mutated genes, together with a previously unreported novel TIMP-3 mutation from a family with SFD that results in truncation of most of the C-terminal domain of the molecule. Despite these differences, all of these molecules are expressed and exhibit characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wild-type TIMP-3, they all form dimers. These observations, together with the recent finding that expression of TIMP-3 is increased, rather than decreased, in eyes from patients with SFD, provides compelling evidence that dimerized TIMP-3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration, the most common cause of blindness in the elderly in developed countries. We hypothesize that overexpression of TIMP-3 may prove to be a critical step in the progression of a variety of degenerative retinopathies.
    Journal of Biological Chemistry 10/2000; 275(35):27027-31. · 4.65 Impact Factor
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    M P Clarke, K W Mitchell
    British Journal of Ophthalmology 07/1999; 83(6):759. · 2.73 Impact Factor
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    ABSTRACT: Thirty patients on long-term benzodiazepine medication were subjected to full ophthalmoscopic examination. Of these 19 (63.3%) complained of symptoms of irritation, blurred vision or difficulty in reading. None, however, had reduced visual acuities apart from two where the cause was longstanding amblyopia. Thirteen patients had some form of retinal finding, 9 macular and 4 non-macular. Of the 14 who presented for flash and pattern electroretinography (ERG), none showed any abnormality which could be ascribed to the medication, its total dose, or duration. We conclude, on the basis of the evidence from this small cohort, that long-term benzodiazepine medication has little effect upon retinal function as signalled by the ERG.
    Documenta Ophthalmologica 02/1999; 99(1):55-68. · 1.54 Impact Factor
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    M P Clarke, K W Mitchell, M Gibson
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    ABSTRACT: The results of flash visual evoked potentials (VEPs) in 44 infants blind or severely visually impaired from non-ocular causes are presented, and related to the subsequent visual outcome. Ocular causes of visual impairment were excluded by clinical examination and electroretinography. Using a 2 x 2 contingency table, a significant association between VEP and outcome was demonstrated (chi 2 = 3.51, 1 d.f., p = 0.05). Of 13 infants with normal VEPs, 11 demonstrated substantial visual improvement (negative predictive value = 84.6%). However, of the 31 with abnormal VEPs, only 14 remained severely impaired/blind; the other 17 demonstrating visual improvement (positive predictive value = 45.1%). The sensitivity of the method was high in that 14 of 16 (87.5%) infants who remained impaired/blind had abnormal VEPs, but specificity was low as only 11 of 28 (39.3%) who showed visual improvement had normal VEPs. The accuracy of the technique was therefore low, 25 of 44 (56.8%) being true positive/ negative. With regard to visual outcome when faced with an apparently blind infant, it is important not to be too pessimistic for, as is shown in this study, 28 of 44 demonstrated substantial improvement. There are no absolute indicators of prognosis, but the presence of structural cerebral lesions and a history of either neonatal meningitis or encephalopathy are relatively bad prognostic signs. The flash VEP, despite its limitations, is a useful prognostic tool, particularly in those apparently blind infants whose normal ocular examination/electroretinogram is accompanied by normal VEPs. Those with abnormal VEPs, however, do not necessarily have a poor prognosis, but should be followed-up as maturational changes and/or improvements in function of the sensory pathway will be reflected in the evoked potentials.
    Eye 02/1997; 11 ( Pt 3):398-402. · 1.82 Impact Factor
  • M P Clarke, K W Mitchell, S McDonnell
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    ABSTRACT: The flash and pattern electroretinogram were investigated in a group of families with rare forms of inherited macular dystrophy, which included Sorsby's fundus dystrophy, X-linked retinoschisis and macular dystrophy of uncertain classification and variable expression. Flash electroretinograms, under both photopic and scotopic conditions, were attenuated in both Sorsby's fundus dystrophy and X-linked retinoschisis--with some effect on implicit time being noted in the latter condition--but in the unknown group the effect was less demonstrable, only 50% having attenuated flash electroretinograms. Pattern electroretinograms were reduced in all three conditions and in almost all cases. The study demonstrates that some so-called macular dystrophies also have widespread abnormalities affecting the peripheral retina. These findings may contribute to a better understanding of the underlying pathophysiologic mechanisms in these rare forms of retinal dysfunction.
    Documenta Ophthalmologica 11/1996; 92(4):325-39. · 1.54 Impact Factor

Publication Stats

68 Citations
20.71 Total Impact Points

Institutions

  • 2001
    • Northern Institute For Cancer Research
      Newcastle-on-Tyne, England, United Kingdom
  • 2000
    • The University of Sheffield
      • Medical School
      Sheffield, ENG, United Kingdom
  • 1996
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom