Biomedical subjects

Birgit Lorenz

Publications and source records attributed to Birgit Lorenz.

At least 37 records · Page 2Linked to original sources

PubMed2004

Unilateral adult malignant optic nerve glioma.

INTRODUCTION: Adult malignant optic nerve gliomas are rare and rapidly fatal visual pathway tumours. They represent a clinical entity different from the more common childhood benign optic nerve gliomas, which are frequently associated with neurofibromatosis I. CASE REPORT: A 61-year-old woman presented with rapidly progressing right vision loss, lower altitudinal visual field defect and papilloedema. MRI showed intraorbital and intracranial swelling of the right optic nerve. Resection of the intracranial part of the right optic nerve up to the chiasm revealed anaplastic astrocytoma grade III. Within 1 year, the patient died of leptomeningeal metastasis despite radiotherapy. Clinical and MRI evaluation of the left eye and optic nerve were normal at all times. DISCUSSION: Unilateral adult malignant glioma of the optic nerve is exceptional. The final diagnosis was only confirmed by optic nerve biopsy. In the literature, only one patient has been reported with a unilateral tumour manifestation; he was lost to follow-up 3 months later. All other cases were bilateral. To date, 44 case reports of adult malignant optic nerve glioma have been published, either malignant astrocytoma or glioblastoma. These tumours can mimic optic neuritis in their initial presentation. The diagnosis is seldom made before craniotomy. On MRI images, malignant glioma cannot be distinguished from optic nerve enlargement due to other causes. Although radiotherapy appears to prolong life expectancy, all presently available treatment options (radiation, surgery, radio-chemotherapy) are of limited value. Most patients go blind and die within 1 or 2 years.

Fatal Outcome↗

PubMed2004

Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65.

PURPOSE: Fundus autofluorescence is due to accumulation of lipofuscin in the retinal pigment epithelium (RPE) resulting from incomplete digestion of N-retinylidene-phosphatidyl-ethanolamine from shed photoreceptor outer segment discs. Alteration in autofluorescence reflects changes in lipofuscin content of the RPE. Mutations on both alleles of RPE65 result in absent or largely decreased formation of rhodopsin, due to a defect in all-trans retinol isomerization in the RPE. Autofluorescence could therefore be altered. This study was conducted to evaluate fundus autofluorescence in patients with early-onset severe retinal dystrophy (EOSRD, or early-onset rod-cone dystrophy) associated with mutations on both alleles of RPE65. DESIGN: Case series. PARTICIPANTS AND CONTROLS: Ten 10- to 55-year-old patients with EOSRD and compound heterozygous or homozygous mutations in RPE65. For comparison, 6 heterozygous parents and 2 patients with other forms of EOSRD were examined. METHODS: Participants underwent, in addition to standard clinical and electrophysiological examination, autofluorescence imaging using a confocal scanning laser ophthalmoscope. Three of the patients were also examined by optical coherence tomography (OCT) to evaluate the status of retinal degeneration. Mutations in 7 patients have been reported previously; the other patients were investigated by polymerase chain reaction-single-strand conformation polymorphism and direct sequencing for mutations in RPE65 and lecithin retinol acyltransferase (LRAT). MAIN OUTCOME MEASURES: Fundus autofluorescence and OCT. RESULTS: Absent or minimal autofluorescence was found in all patients with compound heterozygous or homozygous RPE65 mutations. Autofluorescence was normal in the heterozygous parents. Autofluorescence was present in 2 children with EOSRD not associated with mutations in RPE65 or LRAT, another gene involved in retinol recycling. Optical coherence tomography in younger patients revealed an intraretinal appearance similar to that of their healthy, heterozygous parents. CONCLUSIONS: Lack of autofluorescence in patients with EOSRD associated with mutations in RPE65 is in accordance with the biochemical defect and can be used as a clinical marker of this genotype. Optical coherence tomography results in younger patients would indicate still viable photoreceptors despite the absence of autofluorescence.

Adolescent↗

PubMed2003

FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.

Blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in FOXL2, a putative forkhead transcription factor gene. We previously reported 22 FOXL2 mutations and suggested a preliminary genotype-phenotype correlation. Here, we describe 21 new FOXL2 mutations (16 novel ones) through sequencing of open reading frame, 5' untranslated region, putative core promoter, and fluorescence in situ hybridization analysis. Our study shows the existence of two mutational hotspots: 30% of FOXL2 mutations lead to polyalanine (poly-Ala) expansions, and 13% are a novel out-of-frame duplication. In addition, this is the first study to demonstrate intra- and interfamilial phenotypic variability (both BPES types caused by the same mutation). Furthermore, the present study allows a revision of the current genotype-phenotype correlation, since we found exceptions to it. We assume that for predicted proteins with a truncation before the poly-Ala tract, the risk for development of POF is high. For mutations leading to a truncated or extended protein containing an intact forkhead and poly-Ala tract, no predictions are possible, since some of these mutations lead to both types of BPES, even within the same family. Poly-Ala expansions may lead to BPES type II. For missense mutations, no correlations can be made yet. Microdeletions are associated with mental retardation. We conclude that molecular testing may be carefully used as a predictor for POF risk in a limited number of mutations.

5' Untranslated Regions↗

PubMed2003

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy.

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.

Alternative Splicing↗

PubMed2003

Analysis of three genes in Leber congenital amaurosis in Indonesian patients.

PURPOSE: To assess the frequency, the pattern of disease causing mutations, and phenotypic variations in patients with Leber congenital amaurosis (LCA) from Indonesia. PATIENTS AND METHODS: Twenty-one unrelated index cases with a clinical diagnosis of LCA were screened for mutations in the coding sequence of RetGC1, RPE65 and AIPL1 gene with single strand conformation polymorphism analysis followed by direct sequencing and restriction enzyme digestion. RESULTS: Four novel disease causing mutations were identified: Three in the RPE65 gene (106del9bp, G32V and Y435C) in two of 21 index cases and one in the AIPL1 (K14E). Two of them were homozygous and one was compound-heterozygous. No disease causing mutation was identified in RetGC1. CONCLUSIONS: The four novel disease causing mutations identified in this study confirmed the diagnosis of LCA which has not been recognized before in Indonesia. The frequency of RPE65 mutations was 9.5%; and of AIPL1 mutations 4.8%. This was in general accordance with previous studies reported from other countries. Unlike in those studies, no disease causing RetGC1 mutations could be identified in our patients. Phenotypically, the RPE65 and AIPL1 mutations identified in this study caused nearly total blindness by the second decade of life, but had a different onset of symptoms. The patients with the RPE65 mutations retained some useful visual function until the end of the first decade, which progressed to total blindness during the second decade of life, whereas the (homozygous) AIPL1 mutation was associated with nearly total blindness from infancy on. Therefore, RPE65 mutations have to be considered to cause early onset severe retinal degeneration (EOSRD), and AIPL1 mutations a form of LCA.

Adaptor Proteins, Signal Transducing↗

PubMed2003

[On the effect of mutations of the fibroblast growth factor receptors as exemplified by three cases of craniosynostoses].

PURPOSE: Craniosynostoses are premature ossifications of cranial sutures. They occur isolated and syndromic. Syndromic craniosynostoses are mainly associated with mutations of the Fibroblast Growth Factor Receptors (FGFR) 1 - 3. This paper gives an overview of the etiology and pathophysiology of isolated and syndromic craniosynostoses and discusses the molecular genetic results in 21 index cases (19 seemingly isolated craniosynostoses, 2 cases with a clinical diagnosis of Crouzon's syndrome). METHOD: Mutation analysis in exons of the FGFR 1 - 3 known to be preferentially affected in craniosynostoses was performed on DNA samples from peripheral blood and bone specimen excised at the time of surgery to correct the craniosynostosis. RESULTS: In a girl with seemingly isolated plagiocephaly we identified a P250L (749C-->T) mutation in FGFR3. Her mother showed minor signs of craniosynostosis when the family was re-evaluated. She was shown to carry the same mutation. In two patients with suspected Crouzon's syndrome 2 different mutations were detected at the same nucleotide (1025G-->A or C) and confirmed the clinical diagnosis. No mutation was found in 18/19 seemingly isolated craniosynostosis cases. CONCLUSION: In contrast to syndromic forms isolated craniosynostoses are rarely associated with mutations in FGFR. The affection of further family members is a strong indication of involvement of FGFR mutations. Because of variable expressivity, parents should be examined carefully in isolated craniosynostoses to identify minor signs.

Adult↗

PubMed2003

Phenotype in two families with RP3 associated with RPGR mutations.

OBJECTIVE: To describe the phenotype of three patients and two carriers from two families with mutations in the RPGR gene. The genotypes (a 75-kb deletion on the X chromosome spanning the RPGR gene and the first exon of the SRPX gene, and a stop mutation (G52X) in the RPGR gene) have been reported previously. METHODS: A clinical examination including Goldmann perimetry, full-field electroretinography (ERG), dark adaptometry, and dark- and light-adapted two-color threshold (500-nm cut-off, 600-nm cut-on filter) perimetry was performed in all patients and one carrier. The second carrier was only examined clinically. RESULTS: All affected males presented with a marked decrease in visual acuity of 0.3 to 0.5 at the age of 17-22.5 years, and a typical fundus appearance. The stop mutation (G52X) appeared to be associated with a more pronounced bone spicule formation compared to the deletion of the entire RPR gene and the first exon of the SRPX gene. The kinetic visual fields were constricted to < 20 degrees eccentricity, in part with a residual island in the temporal field. Using two-color dark-adapted threshold perimetry, rod function was more reduced than cone function. The ERG was extinguished. The carrier with the stop mutation showed sectorial peripheral bone spicules and ERG changes typical of carriers of XLRP. The carrier with the deletion had no visual complaints, full visual acuity, and only minimal peripheral retinal changes. Goldmann perimetry showed minor peripheral defects with small targets. ERG amplitudes were reduced below the 10th percentile of normals, without selective loss in rods or cones. The scotopic (rod) sensitivity loss at 500 nm was more pronounced than the photopic (cone) sensitivity loss at 600 nm. Neither of the two carriers showed a tapetal reflex. CONCLUSION: The affected males of the two families with RPGR mutations already exhibited retinitis pigmentosa with severe impairment of the rod and cone system during their second decade of life. The degree of bone spicules differed between the two families. Psychophysics detected a slightly more pronounced affection of the rod system compared to the cone system in both the hemizygous males and the carrier with the deletion of the RPGR gene and the first exon of the SRPX gene. Psychophysics disclosed mild progression of the disease in the carrier underlining the potential of the method in monitoring the disease course. As in most other reported phenotypes of RPGR mutations, no tapetal reflex was found in the carriers.

Adolescent↗

PubMed2003

Phenotypic variability in three carriers from a family with choroideremia and a frameshift mutation 1388delCCinsG in the REP-1 gene.

PURPOSE: To perform genotype-phenotype correlations in a family with choroideremia. METHODS: A three-generation family with two affected males and five carriers was the subject of the study. Molecular genetic analysis using single-strand conformation polymorphism analysis (SSCP) was conducted in all subjects, while electroretinography (ERG), multifocal ERG (mfERG), scanning laser ophthalmoscope microperimetry (SLO perimetry), fluorescein angiography, and Arden contrast color testing were performed in one male and three carriers. RESULTS: The findings in the affected male were typical for advanced choroideremia. The three carriers demonstrated a variable clinical phenotype including reduction of visual acuity and ERG and angiographic changes in one. Molecular genetic analysis revealed a functional null mutation (1388delCCinsG) in the REP-1 gene. CONCLUSIONS: A severe retinal pathology was found in the affected male, indicating that the 1388delCCinsG is a severe mutation. Varying phenotypes were present in the three carriers examined. The phenotype in carriers has been explained by random X-inactivation with varying expression of the inactivated and activated gene copy inside the same cell of both the retinal pigment epithelium and the rods. This thesis is in agreement with the clinical data obtained here.

Adaptor Proteins, Signal Transducing↗

PubMed2003

X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15.

PURPOSE: A comprehensive screening was conducted for RP2 and retinitis pigmentosa GTPase regulator (RPGR) gene mutations including RPGR exon ORF15 in 58 index patients. The frequency of RPGR mutations was assessed in families with definite X-linked recessive disease (xlRP), and a strategy for analyzing the highly repetitive mutational hot spot in exon ORF15 is provided. METHODS: Fifty-eight apparently unrelated index-patients were screened for mutations in all coding exons of the RP2 and the RPGR genes, including splice-sites, by single-strand conformation polymorphism (SSCP) analysis, except for RPGR exon ORF15. A strategy for directly sequencing the large repetitive stretch of exon ORF15 from a 1.6-kb PCR-product was developed. According to pedigree size and evidence for X linkage, families were subdivided into three categories. RESULTS: Screening of 58 xlRP families revealed RP2 mutations in 8% and RPGR mutations in 71% of families with definite X-linked inheritance. Mutations clustered within a approximately 500-bp stretch in exon ORF15. In-frame sequence alterations in exon ORF15 ranged from the deletion of 36 bp to the insertion of 75 bp. CONCLUSIONS: Mutations in the RPGR gene are estimated to cause 15% to 20% of all cases of RP, higher than any other single RP locus. This report provides a detailed strategy to analyze the mutational hot spot in RPGR exon ORF15, which cannot be screened by standard procedures. The discrepancy of the proportion of families linked to the RP3 locus and those having RPGR mutations is resolved in a subset of families with definite X linkage.

Carrier Proteins↗

PubMed2002

Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation.

PURPOSE: To determine the phenotypic variability in patients with compound heterozygous or homozygous ABCA4 mutations, and to correlate the phenotypes with the functional properties of the altered protein. METHODS: Sixteen patients from 13 families with signs of Stargardt macular dystrophy/fundus flavimaculatus and known mutations on both alleles of the ABCA4 gene (15 compound heterozygous, one homozygous) were characterized by clinical examination, fundus autofluorescence, psychophysics (color vision, kinetic and two-color dark- and light-adapted static threshold perimetry), and electrophysiology (Ganzfeld, multifocal ERG, EOG). RESULTS: The homozygous 5917delG mutation resulted in the earliest disease manifestation (at 5 years) and a general cone-rod dysfunction, whereas the compound heterozygous mother (5917delG, G1961E) exhibited a very mild phenotype. Compound heterozygotes for the IVS40+5G-->A and the C1488Y or Y362X mutation showed also an early age of onset but only a central dysfunction. The effect of the 2588G-->C mutation, the G1961E mutation, and the complex mutation L541P-A1038V depended on the mutation in the second allele. Genotype-phenotype correlation appeared possible in most instances. Psychophysics revealed a simultaneous yet not necessarily congruent cone and rod dysfunction. CONCLUSIONS: The type and combination of ABCA4 mutations in compound heterozygous patients determined were compatible with the severity of the phenotype as to age of onset and the functional consequences in the majority of patients. Unexplained phenotypic differences indicate the influence of other factors. ABCA4 mutations result in cone and rod dysfunction. Different disease durations limit the power of presently available genotype-phenotype correlations.

ATP-Binding Cassette Transporters↗

PubMed2002

Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia.

Achromatopsia is an autosomal recessively inherited visual disorder that is present from birth and that features the absence of color discrimination. We here report the identification of five independent families with achromatopsia that segregate protein-truncation mutations in the GNAT2 gene, located on chromosome 1p13. GNAT2 encodes the cone photoreceptor-specific alpha-subunit of transducin, a G-protein of the phototransduction cascade, which couples to the visual pigment(s). Our results demonstrate that GNAT2 is the third gene implicated in achromatopsia.

Color Vision Defects↗

PubMed2002

First evidence of an endogenous Spiroplasma sp. infection in humans manifesting as unilateral cataract associated with anterior uveitis in a premature baby.

PURPOSE: To elucidate a previously unknown aetiology of rapidly progressive unilateral cataract in a premature baby associated with severe anterior uveitis. METHODS: The lens and vitreous material were saved as part of a special protocol in a 4-month-old premature baby at the time of pars plana lensectomy with anterior vitrectomy. We performed (1) microbiological cultures to detect viable bacterial and fungal organisms; (2) PCR reaction to viral, bacterial and fungal agents; (3) transmission electron microscopy (TEM). In addition, serological examinations were performed for HSV-1 and -2, CMV, VZV and Mycoplasmainfection. RESULTS: PCR detected Spiroplasma sp.; TEM confirmed the presence of Spiroplasma within the lens fibres. Serological testing and microbiological cultures of the vitreous and lens were negative. CONCLUSION: Endogenous Spiroplasma infection in a premature baby may manifest as rapidly progressive acquired unilateral cataract with anterior uveitis. Beyond this, Spiroplasma infection has never been reported to occur naturally in vertebrates, although experimentally Spiroplasma mirum produces panophthalmitis associated with cataract in a wide range of rodents and in chicks. In acquired infantile cataract with inflammatory signs, PCR and TEM should be performed in the lensectomy/vitrectomy material to detect infectious agents not evident on routine laboratory and microbiological examinations.

Base Sequence↗

PubMed2002

Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D.

Usher syndrome (USH) is a group of autosomal recessive sensory disorders characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment. Usher syndrome type 1 (USH1), with additional vestibular dysfunction, represents the most severe form and shows extensive allelic and non-allelic heterogeneity. At least six USH1 loci exist (USH1A-F), and four of the underlying genes have been identified. Recently, a novel gene, cadherin 23 (CDH23), was shown to be mutated in USH1D. We performed mutation screening by single strand conformation polymorphism (SSCP) analysis and direct sequencing on 33 USH1 patients previously excluded for USH1B and USH1C. On eight disease alleles of four patients, four different mutations were identified, three of them novel (c.6933delT, c.5712G-->A, and IVS45-9G-->A). Exon trapping experiments were performed with two mutations. In the case of a c.5712G-->A transition of the last base of exon 42, that is an apparently synonymous mutation, skipping of exon 42 was observed. By the mutation IVS45-9G-->A, a novel splice acceptor site was created and the insertion of 7 intronic bp was observed. Two mutations, IVS45-9G-->A and the previously described IVS51+5G-->A, were each found in more than one patient. Haplotype analysis by SNPs within CDH23 suggests common ancestors for each of the mutations. Among the total of 52 USH1 cases studied by us, CDH23 mutations account for about 10% of all disease alleles. Our results further suggest that in patients with a typical USH1D phenotype, a significant portion of CDH23 mutations leads to premature termination of translation or loss of numerous amino acid residues, with a high frequency of changes causing aberrant splicing of CDH23 mRNA.

Adolescent↗

PubMed2002

Evidence of intrafamilial variability of CBFA1/RUNX2 expression in cleidocranial dysplasia--a family study.

AIM: To investigate the phenotypical expression of an identical mutation of the CBFA1/RUNX2 gene within a family with cleidocranial dysplasia. PATIENTS AND METHOD: A five-member family underwent clinical examination. Two members, father and son, showed dissimilar symptoms of cleidocranial dysplasia. The two affected patients were examined for syndrome-typical symptoms, and the genotype was determined by molecular-genetic analysis. RESULTS: In both patients an identical missense mutation (G146R) in exon 2 of the CBFA1/RUNX2 gene was identified. In father and son the dental disturbances were similarly clearly expressed. However, the craniofacial skeleton of the son exhibited fewer dysostotic ossification features than that of the father. In the three clinically healthy family-members no mutation of the CBFA1/RUNX2 gene was found. CONCLUSION: In two patients with cleidocranial dysplasia an identical missense mutation in the CBFA1/RUNX2 gene leading to a divergent craniofacial phenotype was determined. The results indicate marked variability in the phenotypical expression of CBFA1/RUNX2 mutations.

Adult↗

PubMed2002

Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina.

X-linked CSNB patients may exhibit myopia, nystagmus, strabismus and ERG abnormalities of the Schubert-Bornschein type. We recently identified the retina-specific L-type calcium channel alpha1 subunit gene CACNA1F localised to the Xp11.23 region, which is mutated in families showing the incomplete type (CSNB2). Here, we report comprehensive mutation analyses in the 48 CACNA1F exons in 36 families, most of them from Germany. All families were initially diagnosed as having the incomplete type of CSNB, except for two which have been designated as Aland Island eye disease (AIED)-like. Out of 33 families, a total of 30 different mutations were identified, of which 24 appear to be unique for the German population. The mutations, 20 of which are published here for the first time, were found to be equally distributed over the entire gene sequence. No mutation could be found in a classic AIED family previously shown to map to the CSNB2 interval. Cacna1f expression in photoreceptor-negative mice strains indicate that the gene is expressed in the outer nuclear, the inner nuclear, and the ganglion cell layer. Such a distribution points to the central role of calcium regulation in the interaction of retinal cells that mediate signal transmission.

Amino Acid Sequence↗

PubMed2002

Genetics of isolated and syndromic strabismus: facts and perspectives.

Family studies have demonstrated the genetic etiology of concomitant strabismus (prevalence in different populations 1-5%, positive family history in 37% on average), as have twin studies (mean concordance in monozygous twins 73% compared to 35% in dizygous twins). In Duane's syndrome, three chromosomal loci have been identified to date: 2q31, 8q13, and 22q11; loci have also been identified in Moebius syndrome (various inheritance patterns): 13q12.2-q13, 3q21-q22, and 10q21.3-q22, as well as in congenital fibrosis of the extraocular muscles (CFEOM; 3 loci, 1 gene).(1) Already identified are the genes for a number of rarer muscular dystrophy syndromes with ocular involvement, various forms of congenital myasthenia, and mitochondrial diseases (with the primary defect located either in the mtDNA, resulting in a mitochondrial inheritance pattern, or in the nuclear DNA with Mendelian inheritance). A number of hereditary retinal diseases (Mendelian inheritance) may also be associated with strabismus. More than one gene is likely to be involved in the frequently occurring concomitant strabismus, making the analysis more difficult. Patients with chromosomal rearrangements, large families and isolated populations (see also the contributions by Preising and Zitzlsperger et al. in this issue)(2,3) will be instrumental in gene identification. In view of the high prevalence of concomitant strabismus, the disclosure of its etiology will have considerable medical, psychosocial and health-cost impact.

Child↗

PubMed2002

In search for increased prevalence rates of strabismus and microstrabismus in two Bavarian districts, Oberpfalz and Niederbayern, to spot populations for gene identification.

PURPOSE: This study was intended to identify communities with an increased prevalence rate of inherited eye diseases (different forms of strabismus, juvenile maculopathy, AMD, myopia magna, etc.) in the districts Oberpfalz (Opf.) and Niederbayern (Ndb.). The data obtained in this study will serve to identify larger families and inbred populations for genetic testing to identify the cause of eye diseases with autosomal recessive and multifactorial inheritance. DESIGN: In cooperation with the local ophthalmologists in two Bavarian districts anonymized lists were compiled correlating diagnosis, postal code, and municipality of strabismus patients. The office software used in the participating practices was a limiting factor as well as the hand-written records used in most of these. The collected data were correlated with the published prevalence rates in the general population. RESULTS: Of the 104 local ophthalmologists who were invited to participate, only 17 provided information. The results indicate an increased prevalence rate of strabismus and microstrabismus patients from Neumarkt (Opf.) / Postbauer-Heng, Amberg, Hauzenberg and Pocking. CONCLUSION: Documentation as it is currently done - local ophthalmologist generally have written records and computer systems that are unsuitable for detailed surveys - restricts the possibility of completing the survey in the whole area. Nevertheless, regional accumulations of strabismus/microstrabismus could be described, providing populations for further investigations to uncover the genetic causes.

Chromosome Mapping↗

PubMed2002

BIGH3 mutation spectrum in corneal dystrophies.

PURPOSE: To investigate the molecular pathology underlying BIGH3-related corneal dystrophies (CDs) and to further delineate genotype-phenotype specificity. METHODS: Sixty-one index patients with CDs were subjected to phenotypic and genotypic characterization. The corneal phenotypes of all patients were assessed by biomicroscopy and documented by slit lamp photography. The BIGH3 gene was amplified exon by exon from constitutional DNA to perform single-strand conformation polymorphism (SSCP) analysis, followed by direct bidirectional sequencing of abnormal conformers. RESULTS: The phenotypes of CDs were classified as lattice CD in 30 patients, Groenouw type I in 12 (CDGGI), Avellino in 7 (CDA), Reis-Bückler in 8 (CDRB), and Thiel-Behnke in 4 (CDTB). Fifty occurrences of 16 distinct mutations were identified, including 8 novel mutations responsible for lattice type IIIA in three patients (CDLIIA), intermediate type I/IIIA (CDLI/IIIA) in four patients, and atypical CDL with deep deposits in one patient (CDL-deep). CONCLUSIONS: Disease-causing mutations were identified in 80% of the patients (50/61). All mutations localize in two regions of kerato-epithelin: the amino acid R124 and BIGH3 fasc domain 4. This study also confirms the mutation hot spot at positions R124 and R555 with nearly 50% of the mutations targeting these two amino acids (24/50). In addition the corneal phenotypes induced by changes at R124 and R555 are amino acid specific: R124C in CDLI, R555W and R124S in CDGGI, R124H in CDA, R124L in CRRB, and R555Q in CDTB. In CDLIIIA, CDLI/IIIA, and CDL-deep the genotype-phenotype correlation is domain specific, with all changes occurring at the boundary or within the fasc4 domain.

Amino Acid Sequence↗