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1.
Rhinology ; 57(4): 242-251, 2019 Aug 01.
Article in English | MEDLINE | ID: mdl-30907391

ABSTRACT

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder, with a wide variety of clinical manifestations due to the presence of multiple arteriovenous manifestations. Severe bleeding from the gastrointestinal (GI) tract and/or epistaxis presents a significant problem in a subgroup of patients and systemic bevacizumab, an angiogenesis inhibitor, has been suggested to benefit these patients. OBJECTIVE: To perform a review of the literature concerning the efficacy of systemic bevacizumab in treatment of bleeding from the nose or GI tract in patients with HHT, including patients from our own HHT-center. METHODS: A literature review was performed using the guideline "Preferred Reporting Items for systematic Reviews and MetaAnalysis statement" (PRISMA). RESULTS: After careful selection, we finally analysed the results of eight case series and 33 case reports. Among 195 patients 171 (88%) had reduced bleeding after bevacizumab. CONCLUSIONS: Based on the literature review and data from our own case series, systemic bevacizumab is very promising as treatment for HHT patients with severe epistaxis and/or GI-bleeding. However, care should be taken using bevacizumab, a potent angiogenesis inhibitor; long-term side effects have not been studied in this population. A randomized controlled study is warranted to support the results in HHT patients.


Subject(s)
Angiogenesis Inhibitors , Bevacizumab , Epistaxis , Gastrointestinal Hemorrhage , Telangiectasia, Hereditary Hemorrhagic , Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Epistaxis/drug therapy , Epistaxis/etiology , Gastrointestinal Hemorrhage/drug therapy , Gastrointestinal Hemorrhage/etiology , Humans , Research Design , Telangiectasia, Hereditary Hemorrhagic/complications , Telangiectasia, Hereditary Hemorrhagic/drug therapy
2.
Sleep Med ; 46: 107-113, 2018 06.
Article in English | MEDLINE | ID: mdl-29773203

ABSTRACT

OBJECTIVE/BACKGROUND: To evaluate REM sleep without atonia (RSWA) in REM sleep behavior disorder (RBD) several automatic algorithms have been developed. We aimed to validate our algorithm (Mayer et al., 2008) in order to assess the following: (1). capability of the algorithm to differentiate between RBD, night terror (NT), somnambulism (SW), Restless legs syndrome (RLS), and obstructive sleep apnea (OSA), (2). the cut-off values for short (SMI) and long muscle activity (LMI), (3). which muscles qualify best for differential diagnosis, and (4). the comparability of RSWA and registered movements between automatic and visual analysis of videometry. PATIENTS/METHODS: RSWA was automatically scored according to Mayer et al., 2008 in polysomnographies of 20 RBD, 10 SW/NT, 10 RLS and 10 OSA patients. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of SMI and LMI. Independent samples were calculated with t-tests. Boxplots were used for group comparison. The comparison between motor events by manual scoring and automatic analysis were performed with "Visual Basic for Applications" (VBA) for every hundredth second. RESULTS: Our method discriminates RBD from SW/NT, OSA and RLS with a sensitivity of 72.5% and a specificity of 86.7%. Automatic scoring identifies more movements than visual video scoring. Mentalis muscle discriminates the sleep disorders best, followed by FDS, which was only recorded in SW/NT. Cut-off values for RSWA are comparable to those found by other groups. CONCLUSION: The semi-automatic RSWA scoring method is capable to confirm RBD and to discriminate it with moderate sensitivity from other sleep disorders.


Subject(s)
Algorithms , REM Sleep Behavior Disorder/physiopathology , Restless Legs Syndrome/physiopathology , Sleep, REM/physiology , Aged , Case-Control Studies , Facial Muscles/physiology , Female , Humans , Male , Middle Aged , Night Terrors/physiopathology , Polysomnography/methods , Sensitivity and Specificity , Sleep Apnea, Obstructive/physiopathology
3.
J Immigr Minor Health ; 18(1): 274-6, 2016 Feb.
Article in English | MEDLINE | ID: mdl-25784139

ABSTRACT

Prayer marks (PMs) are commonly occurring dermatologic changes in muslims who pray and develop over a long period of time as a consequence of repeated and extended pressure. PMs need careful examination especially for patients with diabetes, who are more vulnerable due to predisposing factors such as venous insufficiency and peripheral neuropathy. A total of 166 patients with diabetes (150 males, 16 females) and 65 normal subjects from Bangladesh were examined for the appearance of PMs. Twenty-eight patients (16.9 %) and one normal subject (1.5 %) had PMs. The marks were not itchy or painful and they were observed on the dorsal aspect of the left foot, which was attributed to a more typical prayer position that placed pressure on the left foot. PMs are not a rare clinical entity among muslim patients with diabetes and most clinicians should be aware of it as it can be the predominant cause of an ulcer.


Subject(s)
Diabetes Mellitus/ethnology , Emigrants and Immigrants , Islam , Pressure Ulcer/ethnology , Adult , Bangladesh/ethnology , Female , Greece/epidemiology , Humans , Male , Middle Aged
4.
CNS Oncol ; 4(1): 25-35, 2015.
Article in English | MEDLINE | ID: mdl-25586423

ABSTRACT

AIM: Tumor hypoxia and presence of tumor stem cells are related to therapeutic resistance and tumorigenicity in glioblastomas. The aim of the present study was therefore to identify microRNAs deregulated in acute hypoxia and to identify possible associated changes in stem cell markers. MATERIALS & METHODS: Glioblastoma spheroid cultures were grown in either 2 or 21% oxygen. Subsequently, miRNA profiling was performed and expression of ten stem cell markers was examined. RESULTS: MiRNA-210 was significantly upregulated in hypoxia in patient-derived spheroids. The stem cell markers displayed a complex regulatory pattern. CONCLUSION: MiRNA-210 appears to be upregulated in hypoxia in immature glioblastoma cells. This miRNA may represent a therapeutic target although it is not clear from the results whether this miRNA may be related to specific cancer stem cell functions.


Subject(s)
MicroRNAs/metabolism , Neoplastic Stem Cells/metabolism , Up-Regulation/physiology , Cell Hypoxia , Cell Line, Tumor , Gene Expression Profiling , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , MicroRNAs/genetics , Oligonucleotide Array Sequence Analysis , Spheroids, Cellular , Time Factors
5.
Mol Vis ; 17: 2118-28, 2011.
Article in English | MEDLINE | ID: mdl-21850187

ABSTRACT

PURPOSE: To describe an Australian pedigree of European descent with a variable autosomal dominant phenotype of: pediatric cortical cataract (CC), asymmetric myopia with astigmatism, familial exudative vitreoretinopathy (FEVR), and primary open-angle glaucoma (POAG). METHODS: Probands with CC, FEVR, and POAG were enrolled in three independent genetic eye studies in Tasmania. Genealogy confirmed these individuals were closely related and subsequent examination revealed 11 other family members with some or all of the associated disorders. RESULTS: Twelve individuals had CC thought to be of childhood onset, with one child demonstrating progressive lenticular opacification. One individual had severe retinal detachment while five others had dragged retinal vessels. Seven individuals had POAG. Seven individuals had myopia in at least one eye ≤-3 Diopters. DNA testing excluded mutations in myocilin, trabecular meshwork inducible glucocorticoid response (MYOC) and tetraspanin 12 (TSPAN12). Haplotype analysis excluded frizzled family receptor 4 (FZD4) and low density lipoprotein receptor-related protein 5 (LRP5), but only partly excluded EVR3. Multipoint linkage analysis revealed multiple chromosomal single-nucleotide polymorphisms (SNPs) of interest, but no statistically significant focal localization. CONCLUSIONS: This unusual clustering of ophthalmic diseases suggests a possible single genetic cause for an apparently new cataract syndrome. This family's clinical ocular features may reflect the interplay between retinal disease with lenticular changes and axial length in the development of myopia and glaucoma.


Subject(s)
Astigmatism/genetics , Cataract/genetics , Eye/physiopathology , Glaucoma, Open-Angle/genetics , Myopia/genetics , Osteoporosis/genetics , Polymorphism, Single Nucleotide , Vitreoretinopathy, Proliferative/genetics , White People/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Astigmatism/complications , Cataract/complications , Child , Child, Preschool , DNA Mutational Analysis , Eye/pathology , Familial Exudative Vitreoretinopathies , Female , Genetic Linkage , Glaucoma, Open-Angle/complications , Haplotypes , Humans , Male , Middle Aged , Mutation , Myopia/complications , Osteoporosis/complications , Pedigree , Tasmania , Vitreoretinopathy, Proliferative/complications
6.
Resuscitation ; 82(9): 1130-7, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21555177

ABSTRACT

BACKGROUND: The scientific evidence of a beneficial effect of ALS in pre-hospital treatment in trauma patients or patients with any acute illness is scarce. The objective of this systematic review of controlled studies was to examine whether ALS, as opposed to BLS, increases patient survival in pre-hospital treatment and if so, to identify the patient groups that gain benefit. METHODS: A systematic review of studies published in the databases Medline (PubMed), EMBASE, Cochrane Library and Scopus up to July 31st, 2010. Controlled studies comparing survival after the pre-hospital ALS treatment versus BLS treatment in trauma patients or patients with cardiac arrest were included. RESULTS: We identified 1081 studies of which 18 met our inclusion criteria. In nine of 18 studies including 16,857 trauma patients in the intervention group, ALS care did not increase survival compared to BLS treatment (pooled OR 0.892, 95% CI, 0.775-1.026). In nine of 18 studies including 7659 patients with cardiac arrest in the intervention group, ALS care increased survival compared to BLS treatment (OR 1.468, 95% CI, 1.257-1.715). Most subgroup analyses revealed no significant interactions, but data from six trials, where ALS was provided by physicians, increases the probability of survival at hospital discharge even more (OR 2.047, 95% CI 1.593-2.631). CONCLUSION: Implementation of ALS care to non-traumatic cardiac arrest patients can increase survival and further research is unlikely to change our confidence in the estimate of the effect. On the contrary, in trauma patients our meta-analysis revealed that ALS care is not associated with increased survival. However, only few controlled studies of sufficient quality and strength examining survival with pre-hospital ALS treatment exist.


Subject(s)
Advanced Cardiac Life Support , Emergency Medical Services/methods , Heart Arrest/mortality , Heart Arrest/therapy , Cardiopulmonary Resuscitation/methods , Female , Greece , Humans , Male , Risk Assessment , Survival Analysis
7.
Chirurgia (Bucur) ; 106(1): 7-10, 2011.
Article in English | MEDLINE | ID: mdl-21520773

ABSTRACT

Dominique-Jean Larrey was a distinguished surgeon in chief of Napoleon's army and a faithful servant of the Empire. His surgical skills and inventions, his absolute attachment and devotion to his profession, his humanitarian spirit and courage entitled him as one of history's greatest military surgeons.


Subject(s)
Altruism , Ambulances/history , Amputation, Surgical/history , General Surgery/history , Military Medicine/history , Triage/history , Wounds and Injuries/history , Amputation, Surgical/methods , Character , France , History, 18th Century , History, 19th Century , Humans , Textbooks as Topic/history , Warfare , Wounds and Injuries/surgery
8.
J Med Genet ; 47(10): 665-9, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20805371

ABSTRACT

BACKGROUND: Cone-rod dystrophy is a retinal dystrophy with early loss of cone photoreceptors and a parallel or subsequent loss of rod photoreceptors. It may be syndromic, but most forms are non-syndromic with autosomal dominant, autosomal recessive or X-linked recessive inheritance. METHODS AND RESULTS: We identified a small consanguineous family with six patients with cone-rod dystrophy from the Faroe Islands. Homozygosity mapping revealed a single homozygous locus of 4.2 Mb on chromosome 10q23.1-q23.2, encompassing 11 genes. All patients were homozygous for a 1-bp duplication in PCDH21, c.524dupA, which results in a frameshift and a premature stop codon (p.Q175QfsX47). CONCLUSION: To our knowledge, this is the first report of mutations in PCDH21 as a cause of human disease. PCDH21 is highly expressed in the retinal photoreceptor cells. It encodes protocadherin 21, which belongs to the cadherin superfamily of large cell surface proteins characterised by a variable number of extracellular cadherin domains. A PCDH21 knockout mouse model has previously shown loss of photoreceptor cells and abnormal cone and rod function, similar to the findings in the patients.


Subject(s)
Cadherins/genetics , Genes, Recessive , Mutation , Nerve Tissue Proteins/genetics , Retinitis Pigmentosa/genetics , Adolescent , Adult , Animals , Cadherin Related Proteins , Child, Preschool , Consanguinity , Denmark , Electrophysiological Phenomena , Female , Frameshift Mutation , Humans , Infant , Male , Mice , Mice, Knockout , Pedigree , Photoreceptor Cells, Vertebrate/metabolism , Retinal Dystrophies/genetics
9.
Clin Genet ; 78(4): 388-97, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20236115

ABSTRACT

Usher syndrome (USH) is the most common genetic disease that causes both deafness and blindness. USH is divided into three types, USH1, USH2 and USH3, depending on the age of onset, the course of the disease, and on the degree of vestibular dysfunction. By homozygosity mapping of a consanguineous Danish family of Dutch descent, we have identified a novel locus for a rare USH3-like syndrome. The affected family members have a unique association of retinitis pigmentosa, progressive hearing impairment, vestibular dysfunction, and congenital cataract. The phenotype is similar, but not identical to that of USH3 patients, as congenital cataract has not been reported for USH3. By homozygosity mapping, we identified a 7.3 Mb locus on chromosome 15q22.2-23 with a maximum multipoint LOD score of 2.0. The locus partially overlaps with the USH1 locus, USH1H, a novel unnamed USH2 locus, and the non-syndromic deafness locus DFNB48.


Subject(s)
Cataract/congenital , Chromosomes, Human, Pair 15/genetics , Genetic Loci , Usher Syndromes/genetics , Base Sequence , Cataract/embryology , Cataract/genetics , Chromosome Mapping , Consanguinity , DNA Mutational Analysis , Denmark , Female , Genetic Linkage , Genotype , Humans , Lod Score , Male , Mutation , Netherlands , Pedigree , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Retinitis Pigmentosa/genetics , Sequence Analysis, DNA
10.
Br J Ophthalmol ; 93(3): 409-13, 2009 Mar.
Article in English | MEDLINE | ID: mdl-18669544

ABSTRACT

BACKGROUND/AIM: Bardet-Biedl syndrome is a multiorgan disease presenting with retinitis pigmentosa leading to blindness. The aim of the study was to investigate the genetic background of Bardet-Biedl syndrome in the Faroe Island. It was hypothesised that a common genetic background for the syndrome would be found. METHODS: Patients were identified from the files of the Retinitis Pigmentosa Register at the National Eye Clinic, Denmark. The diagnosis of Bardet-Biedl syndrome was verified from medical files. Mutational screening of BBS1, BBS2, BBS4, MKKS and BBS10 was done by denaturing high-performance liquid chromatography. RESULTS: Out of 13 prevalent cases in the Faroe Islands, 10 patients from nine families were included. A novel splice site mutation in BBS1, c.1091+3G>C, was identified, and this was predicted to affect protein function by skipping 16 amino acids. Nine patients were homozygous for this mutation, while one patient was compound heterozygous with a recurrent BBS1 mutation, p.Met390Arg. The patients presented with severe ophthalmic phenotypes, while the systemic manifestations of the disease were apparently milder. CONCLUSION: A novel BBS1 mutation was identified, most probably a founder mutation, further confirming the Faroe Islands as a genetic isolate. The phenotypic expression of the Faroese patients suggests that different mutations in BBS1 affect various organs differently.


Subject(s)
Bardet-Biedl Syndrome/epidemiology , Bardet-Biedl Syndrome/genetics , Founder Effect , Protein Isoforms , Proteins/genetics , Adult , Age of Onset , Aged , Bardet-Biedl Syndrome/pathology , Chromatography, High Pressure Liquid , DNA Mutational Analysis , Denmark/epidemiology , Female , Fundus Oculi , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Male , Microtubule-Associated Proteins , Middle Aged , Prevalence , Retina/pathology , Reverse Transcriptase Polymerase Chain Reaction
11.
Rev Sci Instrum ; 80(12): 124501, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20059157

ABSTRACT

Coupling of the solar wind to the Earth magnetosphere/ionosphere is primarily through the high latitude regions, and there are distinct advantages in making remote sensing observations of these regions with a network of ground-based observatories over other techniques. The Antarctic continent is ideally situated for such a network, especially for optical studies, because the larger offset between geographic and geomagnetic poles in the south enables optical observations at a larger range of magnetic latitudes during the winter darkness. The greatest challenge for such ground-based observations is the generation of power and heat for a sizable ground station that can accommodate an optical imaging instrument. Under the sponsorship of the National Science Foundation, we have developed suitable automatic observing platforms, the Automatic Geophysical Observatories (AGOs) for a network of six autonomous stations on the Antarctic plateau. Each station housed a suite of science instruments including a dual wavelength intensified all-sky camera that records the auroral activity, an imaging riometer, fluxgate and search-coil magnetometers, and ELF/VLF and LM/MF/HF receivers. Originally these stations were powered by propane fuelled thermoelectric generators with the fuel delivered to the site each Antarctic summer. A by-product of this power generation was a large amount of useful heat, which was applied to maintain the operating temperature of the electronics in the stations. Although a reasonable degree of reliability was achieved with these stations, the high cost of the fuel air lift and some remaining technical issues necessitated the development of a different type of power unit. In the second phase of the project we have developed a power generation system using renewable energy that can operate automatically in the Antarctic winter. The most reliable power system consists of a type of wind turbine using a simple permanent magnet rotor and a new type of power control system with variable resistor shunts to regulate the power and dissipate the excess energy and at the same time provide heat for a temperature controlled environment for the instrument electronics and data system. We deployed such systems and demonstrated a high degree of reliability in several years of operation in spite of the relative unpredictability of the Antarctic environment. Sample data are shown to demonstrate that the AGOs provide key measurements, which would be impossible without the special technology developed for this type of observing platform.

12.
J Med Genet ; 43(5): 435-40, 2006 May.
Article in English | MEDLINE | ID: mdl-16648378

ABSTRACT

Autosomal dominant optic atrophy (ADOA) is genetically heterogeneous, with OPA1 on 3q28 being the most prevalently mutated gene. Additional loci are OPA3, OPA4, and OPA5, located at 19q13.2, 18q12.2, and 22q12.1-q13.1, respectively. Mutations in the WFS1 gene, at 4p16.3, are associated with either optic atrophy (OA) as part of the autosomal recessive Wolfram syndrome or with autosomal dominant progressive low frequency sensorineural hearing loss (LFSNHL) without any ophthalmological abnormalities. Linkage and sequence mutation analyses of the ADOA candidate genes OPA1, OPA3, OPA4, and OPA5, including the genes WFS1, GJB2, and GJB6 associated with recessive inherited OA or dominant LFSNHL, were performed. We identified one novel WFS1 missense mutation E864K, c.2590G-->A in exon 8 that co-segregates with ADOA combined with hearing impairment and impaired glucose regulation. This is the first example of autosomal dominant optic atrophy and hearing loss associated with a WFS1 mutation, supporting the notion that mutations in WFS1 as well as in OPA1 may lead to ADOA combined with impaired hearing.


Subject(s)
Blood Glucose/analysis , Hearing Loss, Sensorineural/genetics , Membrane Proteins/genetics , Mutation, Missense , Optic Atrophy, Autosomal Dominant/genetics , Adult , Aged , Chromosome Mapping , Connexin 26 , Connexins , DNA Mutational Analysis , Female , Genetic Linkage , Hearing Loss, Sensorineural/complications , Humans , Male , Middle Aged , Optic Atrophy, Autosomal Dominant/complications , Optic Atrophy, Autosomal Dominant/diagnosis
13.
Noise Health ; 8(33): 139-46, 2006.
Article in English | MEDLINE | ID: mdl-17851218

ABSTRACT

In several laboratory animal studies, it has been documented that the hearing, vision, and brain can be injured due to exposure to organic solvents. This finding formed the background for a pilot study (n=16) aimed at identifying new ways of qualifying diagnostics, treatment, and rehabilitation of patients suffering from brain injury due to exposure to organic solvents, also referred to as toxic encephalopathy. Diagnosing toxic encephalopathy is complicated because the symptoms of this type of diffuse brain injury are non-specific. So, it was initially hypothesised that some of the difficulties involved in diagnosing toxic encephalopathy could be minimized by extending the diagnostic procedure. Apart from clinical interviewing and neuropsychological testing, the diagnosis should include the examination of hearing and vision. This will help in achieving new measures that could improve in diagnosing toxic encephalopathy with more certainty. On the basis of ranking, only one patient in the pilot study was considered to have a normal neuropsychological test profile, which was defined as a test profile without any marked deviations when compared with a normal population. A total of 10 patients were considered to have "discrete problems." These patients had a test profile showing either a few strikingly negative results or an array of results slightly below the expected level when compared with a normal population. A total of four patients were considered to suffer from "moderate problems" and one patient from "severe problems." The patients with "moderate problems" and "severe problems" showed consistent negative results and an unambiguous negative test profile. However, the overall results of all neuropsychological examinations performed revealed a dispersed picture. Quite remarkably, all the 13 patients who had their hearing examined showed a loss of hearing, 7 patients complained about tinnitus, and all patients had a history of exposure to both noise and organic solvents, which had not been observed at the initial examination, but seemed to have serious implications for their prognosis and future life.


Subject(s)
Hearing Loss, Noise-Induced/diagnosis , Neurotoxicity Syndromes/diagnosis , Adult , Aged , Audiology , Denmark/epidemiology , Female , Hearing Loss, Noise-Induced/epidemiology , Hearing Loss, Noise-Induced/physiopathology , Humans , Male , Middle Aged , Neuropsychological Tests , Neurotoxicity Syndromes/epidemiology , Neurotoxicity Syndromes/physiopathology , Noise, Occupational/adverse effects , Pilot Projects
14.
Aging Ment Health ; 9(4): 331-6, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16019289

ABSTRACT

Self-reported health and reactions to providing care to older adults with cognitive or physical impairments were examined. Health status was examined on a single occasion in 177 persons (aged 63-94 years) referred to programs within a comprehensive set of geriatric care services and the 133 family members involved in their care (ages 31-96 years). The five-scale Caregiver Reaction Assessment (CRA) was administered to the family members. Reliability analyses revealed that the CRA had good internal consistency. Being older was related to experiencing greater health problems in the caregiver role. Greater health problems from providing care were reported by caregivers in worse physical health and also when the care recipient had more physical pain. Caregivers who reported fewer health problems attributed to caregiving reported better mental health and less depressive symptomatology. Caregivers with health problems may be at increased risk of suffering from stress from caregiving.


Subject(s)
Caregivers/psychology , Health Status , Mental Health , Stress, Psychological , Adult , Age Factors , Aged , Aged, 80 and over , Cross-Sectional Studies , Depression , Family Relations , Female , Humans , Male , Middle Aged , Prognosis , Risk Factors
15.
J Med Genet ; 42(4): 292-8, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15805154

ABSTRACT

BACKGROUND: EEM syndrome is the rare association of ectodermal dysplasia, ectrodactyly, and macular dystrophy. METHODS: We here demonstrate through molecular analysis that EEM is caused by distinct homozygous CDH3 mutations in two previously published families. RESULTS: In family 1, a missense mutation (c.965A-->T) causes a change of amino acid 322 from asparagine to isoleucine; this amino acid is located in a highly conserved motif likely to affect Ca2+ binding affecting specificity of the cell-cell binding function. In family 2, a homozygous frameshift deletion (c.829delG) introduces a truncated fusion protein with a premature stop codon at amino acid residue 295, expected to cause a non-functional protein lacking both its intracellular and membrane spanning domains and its extracellular cadherin repeats 3-5. Our mouse in situ expression data demonstrate that Cdh3 is expressed in the apical ectodermal ridge from E10.5 to E12.5, and later in the interdigital mesenchyme, a pattern compatible with the EEM phenotype. Furthermore, we discuss possible explanations for the phenotypic differences between EEM and congenital hypotrichosis with juvenile macular dystrophy (HJMD), which is also caused by CDH3 mutations. CONCLUSIONS: In summary, we have ascertained a third gene associated with ectrodactyly and have demonstrated a hitherto unrecognised role of CDH3 in shaping the human hand.


Subject(s)
Cadherins/genetics , Corneal Dystrophies, Hereditary/genetics , Ectodermal Dysplasia/genetics , Mutation , Adult , Amino Acid Sequence , Animals , Base Sequence , Cadherins/metabolism , Child , Homozygote , Humans , Hypotrichosis/genetics , In Situ Hybridization , Mice , Models, Genetic , Molecular Sequence Data , Pedigree , Phenotype , Sequence Alignment , Syndrome
16.
Am J Med Genet A ; 132A(3): 324-8, 2005 Jan 30.
Article in English | MEDLINE | ID: mdl-15690381

ABSTRACT

Basal cell nevus syndrome (Gorlin syndrome) is an autosomal dominant disorder characterized by the presence of multiple basal cell carcinomas (BCC), odontogenic keratocysts, palmoplantar pits, and calcification in the falx cerebri caused by mutational inactivation of the PTCH gene. In few cases, the syndrome is due to a microdeletion at 9q22. Using high-resolution chromosome analysis we have identified a patient with the karyotype, 46,XY,del(9)(q21.3q31) de novo. He had typical clinical features consistent with basal cell nevus syndrome, but also additional features likely to be caused by loss of additional chromosomal material in this region. The deletion breakpoints were characterized with fluorescence in situ hybridization (FISH) analysis using BAC clones. The 15 Mb long deletion includes 87 RefSeq genes including PTCH. Hemizygosity of one or more genes might contribute to the additional symptoms observed in this patient.


Subject(s)
Basal Cell Nevus Syndrome/genetics , Chromosome Deletion , Chromosomes, Human, Pair 9/genetics , Adult , Basal Cell Nevus Syndrome/pathology , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male
18.
Br J Ophthalmol ; 87(8): 980-3, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12881340

ABSTRACT

AIMS: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1 mutation in a patient with Leber's congenital amaurosis (LCA). METHODS: A patient with LCA and no light perception from birth had both eyes enucleated at the age of 22 years because of excruciating pain. Mutation analysis was performed on known LCA genes. The eyes were processed for casts of the vascular tree, routine histopathology, and electron microscopy. RESULTS: A novel H82Y (244C-->T) mutation and a H90D (286G-->C) polymorphism were detected in exon 2 of the AIPL1 gene. Both the cast and the histopathological examination showed dilated retinal vessels, mainly venules, primarily localised in the posterior pole. In the mid-peripheral retina the density of capillaries on the arteriolar side of the microcirculatory units was significantly decreased. The vascular system was seen to gradually attenuate towards the retinal periphery, and to stop at a zone located approximately 4 mm from the ora serrata along the whole circumference. In this zone pigmented aggregates characteristic of retinitis pigmentosa were seen to ensheath the retinal vessels. The photoreceptors were almost totally absent and retinal gliosis was present. A decreased number of ganglion cells and an increased vacuolisation of the nerve fibre layer were observed. The retinal pigment cells and Bruch's membrane appeared normal in all regions. CONCLUSION: An unusual retinal vascular morphology in an LCA patient is presented and possible pathogenic mechanisms of the findings are discussed.


Subject(s)
Carrier Proteins/genetics , Mutation , Optic Atrophy, Hereditary, Leber/pathology , Retina/pathology , Adaptor Proteins, Signal Transducing , Adult , Eye Proteins , Humans , Male , Optic Atrophy, Hereditary, Leber/genetics
19.
Hum Genet ; 109(5): 498-502, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11735024

ABSTRACT

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.


Subject(s)
Exons , Frameshift Mutation , GTP Phosphohydrolases/genetics , Optic Atrophy, Autosomal Dominant/genetics , Alleles , Base Sequence , DNA , Denmark/epidemiology , Female , Haplotypes , Humans , Male , Optic Atrophy, Autosomal Dominant/epidemiology , Pedigree , Prevalence
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