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L Tranebjaerg

Publications and source records attributed to L Tranebjaerg.

At least 37 records · Page 2Linked to original sources
PubMed2000

[Genetic causes of hearing loss--status and perspectives].

Hearing impairment, defined as > or = 40 dB hearing loss, is the most prevalent sensory handicap, present in 1:750 children and in 4-36% of adults, depending on age. Genetic factors are of major importance in more than 50% of all hearing loss. An important distinction is made between syndromic deafness and isolated deafness depending on the presence or not of associated manifestations from other organs. The knowledge about genetic deafness has increased dramatically in the last few years. As of March 1999, at least 53 loci for isolated deafness of different types of monogenic inheritance have been identified. Suspected genetic heterogeneity has thus been confirmed. At least 15 genes for syndromic deafness have been cloned, leading to increased biological insight in shared developmental pathways in different species and leading to better diagnostic tools applicable to patients. The identification of a particularly frequent mutation in a gap junction gene, GJB2 (connexin 26), may turn out to be of particular diagnostic importance in the aetiological evaluation of childhood deafness even in isolated cases. Application of early screening tests, like otoacoustic emission (OAE), in combination with genetic tests will facilitate early and specific diagnosis of hearing impairment and thereby improve audiological rehabilitation. Syndromic deafness involves all organs, and care for and evaluation of affected individuals should be a multiprofessional task.

Abnormalities, Multiple↗
PubMed2000

Immunodeficiency in alpha-mannosidosis: a matched case-control study on immunoglobulins, complement factors, receptor density, phagocytosis and intracellular killing in leucocytes.

UNLABELLED: Patients with the autosomal recessive lysosomal storage disease alpha-mannosidosis suffer from recurrent infections. To study the mechanisms of this immunodeficiency, six patients were matched against six healthy controls and their humoral and cellular immunocompetence investigated. No differences in the number of circulating leucocytes including B-cells, levels of immunoglobulin main classes, nor IgG subclasses were observed. However, post-immunisation serum levels of specific antibodies against poliovirus, diphtheria toxin and tetanus toxin were significantly reduced. In patients, the density of the complement-binding receptor CD11b and the Fc-receptor CD16 was significantly enhanced on monocytes and polymorphonuclear neutrophils (PMN) and the number of phagocytosing PMN was significantly increased in the presence of pooled human serum. This was not observed in the presence of autologous serum, indicating altered opsonic properties. Also in normal PMN, phagocytosis was inhibited by a factor in the serum from the patients. Despite maintained oxidative burst, patient PMN demonstrated insufficient intracellular bacterial killing. CONCLUSION: Our data indicate that patients with alpha-mannosidosis have an immunodeficiency at both the humoral and cellular level.

Adolescent↗
PubMed2000

Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen.

Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive syndrome characterised by profound congenital sensorineural deafness and prolongation of the QT interval on the electrocardiogram, representing abnormal ventricular repolarisation. In a study of ten British and Norwegian families with JLNS, we have identified all of the mutations in the KCNQ1 gene, including two that are novel. Of the nine mutations identified in this group of 10 families, five are nonsense or frameshift mutations. Truncation of the protein proximal to the recently identified C-terminal assembly domain is expected to preclude assembly of KCNQ1 monomers into tetramers and explains the recessive inheritance of JLNS. However, study of a frameshift mutation, with a dominant effect phenotypically, suggests the presence of another assembly domain nearer to the N-terminus.

Amino Acid Substitution↗
PubMed2000

A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome.

We report the first de novo mutation in the DDP gene in a Dutch 11-year-old boy with deafness and dystonia. Previously reported mutations in the DDP gene have all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing the BTK gene. The clinical presentation was uniformly characterised by sensorineural hearing loss, dystonia, mental deterioration, paranoid psychotic features, and optic atrophy, indicating progressive neurodegeneration. Our report illustrates that de novo mutations occur and that a missense mutation, C66W, may cause an equally severe clinical picture. The diagnosis of sensorineural hearing impairment associated with neurologic and visual disability in a male, therefore, should encourage the search for mutations in the DDP gene, even in sporadic cases. The association of deafness-dystonia syndrome with a missense mutation provides valuable information for in vitro investigations of the functional properties of the deafness-dystonia peptide which was recently shown to be the human homolog of a yeast protein, Tim8p, belonging to a family of small Tim proteins involved in intermembrane protein transport in mitochondria.

Adult↗
PubMed2000

Identification of novel USH2A mutations: implications for the structure of USH2A protein.

Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigmentosa from the late teens. Mutations in the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have investigated the molecular pathology of Usher type II by screening the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway. Besides the frequent 2299delG mutation, which accounted for 44% of the disease alleles, a heterogeneous spectrum of mutations was identified. Sixteen new, putative disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-pathogenic polymorphisms were identified. All missense mutations resulted in major amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the laminin-type epidermal growth factor-like (LE) domain. The structural consequences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma1 chain.

Adolescent↗
PubMed2000

Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.

We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.

Alleles↗
PubMed2000

Health, life and disability insurance and hereditary risk for breast or colorectal cancer.

Fear of insurance discrimination affecting the insurance-seeker and family has been reported as the singlemost important reason why individuals choose not to undergo genetic testing. The eleven health insurers operating on the Norwegian market were mailed a questionnaire asking them to list their insurance products and evaluate two individuals' requests for insurance. The requests were constructed in order to illustrate a high genetic risk for (a) colorectal (HNPCC) and (b) breast cancer (BRCAI/BRCA2), respectively. Nine out of 11 insurers responded. While no restriction was documented concerning risk of BRCA1/BRCA2 and life insurance or disability pension, the premium paid by persons with susceptibility to HNPCC varied between the different insurers from standard to raised premiums. The product 'critical disease' insurance was refused or obtained at normal or raised premiums in both cases, depending on the insurer in question. On examining personal indemnity insurance, we found that the BRCA1/BRCA2-risk individual was offered insurance at the standard premium, whereas HNPCC-risk individuals were offered a standard or raised premium. Only the major Norwegian insurer is in fact diverging in its policies.

Breast Neoplasms↗
PubMed2000

DFNA7.

Explore the source record for details and available documents.

Adult↗
PubMed2000

Autosomal dominant cone-rod dystrophy due to a missense mutation (R838C) in the guanylate cyclase 2D gene (GUCY2D) with preserved rod function in one branch of the family.

We present the clinical and molecular genetic features of a large multi-generation Norwegian family with dominant cone-rod dystrophy. Ophthalmological evaluation including electroretinography showed cone dysfunction in younger patients, with rod dysfunction becoming apparent at more advanced stages of the disease. In one branch of the family, cone degeneration remained the only manifestation despite advancing age. Linkage analysis mapped the disease gene in this family to 17p12-p13, a chromosome region previously linked to cone-rod dystrophy in a Swedish family (CORD5). A maximum LOD score of 3.25 (straight theta = 0.00) for marker D17S1844 was obtained. Mutation analysis of the guanylate cyclase 2D gene (GUCY2D, MIM 600179, previously called RETGC1), located at 17p12-p13, showed a missense mutation (R838C) in exon 13, that co-segregated with the eye disease in the family. Our suspicion of the possibility of an interrelationship between the Swedish CORD5 family and the present family, both originating from Northern Scandinavia, initiated the linkage analysis in the Norwegian family. The R838C missense mutation was not, however, detected in the Swedish patients, strongly suggesting no relationship between these two families. The long-term ophthalmological evaluation in this large four-generation family, combined with the identification of the disease-causing mutation, provide critical information for refining the classification, prognosis, and genetic counselling of patients with cone-rod dystrophies.

Adult↗
PubMed1999

Jervell and Lange-Nielsen syndrome: a Norwegian perspective.

Jervell and Lange-Nielsen syndrome (MIM 220400; JLNS), is a rare form of profound congenital deafness combined with syncopal attacks and sudden death due to prolonged QTc; it is an autosomal recessive trait. After its first description in Norway in 1957, later reports from many other countries have confirmed its occurrence. Nowhere is the prevalence so high as in Norway, where we estimate a prevalence of at least 1:200,000. The KCNQ1 and KCNE1 proteins coassemble in a potassium channel, and mutations in either the KCNQ1 gene or the KCNE1 gene disrupt endolymph production in the stria vascularis in the cochlea, causing deafness. KCNQ1 seems to be the major gene in JLNS. Long QT syndrome (LQTS) is a separate disorder of either autosomal dominant or recessive inheritance caused by mutations in four different ion channel genes; KCNQ1 is the one most frequently involved. Some heterozygous carriers of JLNS mutations in either gene may suffer from prolonged QTc and be symptomatic LQTS patients with a need for appropriate medical treatment to prevent life-threatening cardiac arrhythmia. In general, frameshift/stop mutations cause JLNS, and missense/splice site mutations cause LQTS, but a precise genotype-phenotype correlation in LQTS and JLNS is not established, which complicates both genetic counseling and clinical risk evaluation in carriers. We review JLNS from a Norwegian perspective because of the unusually high prevalence, the genetic homogeneity associated with considerable mutational heterogeneity, and some evidence for recurrent mutational events as well as one founder mutation. We outline the clinical implications for investigation of deaf children and cases of sudden infant death syndrome as well as careful electrocardiographic monitoring of identified mutation carriers to prevent sudden death. Am. J. Med. Genet. (Semin. Med. Genet.) 89:137-146, 1999.

Female↗
PubMed1999

[Genetic causes of mental retardation--diagnostic possibilities].

Mental retardation is a life-long disability occurring in 2-3% of all children. Genetic causes are very heterogeneous and the clinical presentation most often non-specific. Current diagnostic tools can only identify a specific aetiology in 50-70%, and more importantly, often do not exclude a genetic cause in apparently sporadic cases of mental retardation. A proven genetic aetiology has many implications for the extended family. Fragile X syndrome is the most prevalent cause of inherited mental retardation and occurs in 2-6% of both females and males. Chromosomes and fragile X syndrome should be routinely investigated in patients with mental retardation of unknown aetiology. Molecular cytogenetics (FISH) provide specific diagnosis of several rare and clinically recognizable syndromes. Provision of extended clinical information is critical at referral, so that the most relevant investigations may be selected. Biochemical and molecular investigations can be performed for an increasing number of distinct but all very rare conditions associated with mental retardation. Efficient methods for simultaneous investigation of a panorama of rare biochemical and molecular abnormalities are now available and might improve the diagnostic yield considerably in the near future. We recommend a long-term diagnostic follow-up which allows us to apply modern methods and diagnose syndromes with phenotypes developing over several years.

Adult↗
PubMed1999

[Genetic causes of hearing loss--status and perspectives].

Hearing impairment, defined as > or = 40 dB hearing loss, is the most prevalent sensory handicap, present in 1:750 children and in 4-36% of adults, depending on age. Genetic factors are of major importance in more than 50% of all hearing loss. An important distinction is made between syndromic deafness and isolated deafness depending on the presence or not of associated manifestations from other organs. The knowledge about genetic deafness has increased dramatically in the last few years. As of March 1999, at least 53 loci for isolated deafness of different types of monogenic inheritance have been identified. Suspected genetic heterogeneity has thus been confirmed. At least 15 genes for syndromic deafness have been cloned, leading to increased biological insight in shared developmental pathways in different species and leading to better diagnostic tools applicable to patients. The identification of a particularly frequent mutation in a gap junction gene, GJB2 (connexin 26), may turn out to be of particular diagnostic importance in the aetiological evaluation of childhood deafness even in isolated cases. Application of early screening tests, like otoacoustic emission (OAE), in combination with genetic tests will facilitate early and specific diagnosis of hearing impairment and thereby improve audiological rehabilitation. Syndromic deafness involves all organs, and care for and evaluation of affected individuals should be a multiprofessional task.

Abnormalities, Multiple↗
PubMed1999

[X-linked recessive bulbospinal neuronopathy--Kennedy's syndrome].

Kennedy's syndrome is an inherited disease which was probably first described 100 years ago. Although rare, a recent report suggests that the prevalence may show considerable regional differences. A review of 30 different names of the disease is given. Originally, the disorder was regarded as a spinal and bulbar muscular atrophy but it is now obvious that there is severe axonal degeneration, also of the sensory fibres with the pattern of a central-peripheral distal axonal neuropathy. This was also present in the two recognized cases presented here. The sensory symptoms develop slowly and it is suggested that a peripheral sprouting compensates for the loss not only of motor, but also sensory fibres. It is important to distinguish the disease from motor neuron diseases since the progression is slow and the expected life span is normal. The clinical presentation with facial palsy and perioral contraction-fasciculations is pathognomonic. However, demonstration of increased (CAG)n repeat size in the androgen receptor gene is diagnostic. A normal (CAG)n repeat size excludes the diagnosis, since the abnormal expansion is the only mutation associated with the disease. Other types of mutations in the androgen receptor gene lead to a different clinical presentation, testicular feminization.

Adult↗