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At least 1,243 records · Page 69Linked to original sources
PubMed2001

The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes.

Duplication and deletion of the 1.4-Mb region in 17p12 that is delimited by two 24-kb low copy number repeats (CMT1A-REPs) represent frequent genomic rearrangements resulting in two common inherited peripheral neuropathies, Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP). CMT1A and HNPP exemplify a paradigm for genomic disorders wherein unique genome architectural features result in susceptibility to DNA rearrangements that cause disease. A gene within the 1.4-Mb region, PMP22, is responsible for these disorders through a gene-dosage effect in the heterozygous duplication or deletion. However, the genomic structure of the 1.4-Mb region, including other genes contained within the rearranged genomic segment, remains essentially uncharacterized. To delineate genomic structural features, investigate higher-order genomic architecture, and identify genes in this region, we constructed PAC and BAC contigs and determined the complete nucleotide sequence. This CMT1A/HNPP genomic segment contains 1,421,129 bp of DNA. A low copy number repeat (LCR) was identified, with one copy inside and two copies outside of the 1.4-Mb region. Comparison between physical and genetic maps revealed a striking difference in recombination rates between the sexes with a lower recombination frequency in males (0.67 cM/Mb) versus females (5.5 cM/Mb). Hypothetically, this low recombination frequency in males may enable a chromosomal misalignment at proximal and distal CMT1A-REPs and promote unequal crossing over, which occurs 10 times more frequently in male meiosis. In addition to three previously described genes, five new genes (TEKT3, HS3ST3B1, NPD008/CGI-148, CDRT1, and CDRT15) and 13 predicted genes were identified. Most of these predicted genes are expressed only in embryonic stages. Analyses of the genomic region adjacent to proximal CMT1A-REP indicated an evolutionary mechanism for the formation of proximal CMT1A-REP and the creation of novel genes by DNA rearrangement during primate speciation.

Animals↗
PubMed2001

Polymorphic short tandem repeats for diagnosis of the Charcot-Marie-Tooth 1A duplication.

BACKGROUND: A 1.5-Mb microduplication containing the gene for peripheral myelin protein 22 (PMP22) on chromosome 17p11.2-12 is responsible for 75% of cases of the demyelinating form of Charcot-Marie-Tooth disease (CMT1A). Methods for molecular diagnosis of CMT1A use Southern blot and/or amplification by PCR of polymorphic poly(AC) repeats (microsatellites) located within the duplicated region, or the detection of junction fragments specific for the duplication. Difficulties with both strategies have led us to develop a new diagnostic strategy with highly polymorphic short tandem repeats (STRs) located inside the CMT1A duplicated region. METHODS: We tested 10 STRs located within the duplication for polymorphic behavior. Three STRs were selected and used to test a set of 130 unrelated CMT1A patients and were compared with nonduplicated controls. The study was then extended to a larger population of patients. Alleles of interest were sequenced. A manual protocol using polyacrylamide electrophoresis and silver staining and an automated capillary electrophoresis protocol to separate fluorescently labeled alleles were validated. RESULTS: We identified three new STRs covering 0.55 Mb in the center of the CMT1A duplication. One marker, 4A, is located inside the PMP22 gene. The two others, 9A and 9B, more telomerically positioned, have the highest observed heterozygosity reported to date for CMT1A markers: 0.80 for 9A, and 0.79 for 9B. Tetra- and pentanucleotide repeats offered clear amplification, accurate sizing, and easy quantification of intensities. CONCLUSIONS: Combined use of the three STRs allows robust diagnosis with almost complete informativeness. In our routine diagnosis for CMT1A, they have replaced the use of other polymorphic markers, either in a manual adaptation or combined with fluorescence labeling and allele sizing on a DNA sequencer.

Charcot-Marie-Tooth Disease↗
PubMed2001

A somatic and germline mosaic mutation in MPZ/P(0) mimics recessive inheritance of CMT1B.

OBJECTIVE: To identify the molecular basis of a demyelinating Charcot-Marie-Tooth disease type 1 (CMT1) with presumed autosomal recessive inheritance. BACKGROUND: CMT1, an inherited motor and sensory neuropathy with low nerve conduction velocities, is caused by dominantly inherited mutations in the genes of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ/P(0)), and early growth response 2 transcription factor (EGR2/Krox-20). PATIENTS AND METHODS: Two young sisters born of clinically and electrophysiologically healthy parents had a severe CMT1 neuropathy of presumed autosomal recessive inheritance. The older sister underwent a nerve biopsy. The authors analyzed PMP22, MPZ/P(0), and EGR2/Krox-20 by automated direct nucleotide sequencing. For rapid mutation detection, they determined the restriction-fragment-length polymorphisms for TaqI in the fluorescein-labeled target DNA sequence amplified by PCR. RESULTS: Nerve biopsy disclosed a demyelinating and remyelinating neuropathy with onion bulb formations. Both sisters had a novel heterozygous G308-->A transition of MPZ/P(0) without any mutation of PMP22 or EGR2/Krox-20. The G308-->A transition was a nonconservative mutation that changed a glycine into a glutamate at the amino acid residue 74 in the extracellular domain of the mature MPZ/P(0). None of 50 healthy controls had the mutation. The healthy mother had a low amount of the mutation in blood (congruent with 20%) as well as in skin, buccal epithelium, and hairs (30%). Because the healthy mother carried clones of somatic mutant cells and had transmitted the G308-->A transition to the affected daughters, she also harbored germline mutant cells. CONCLUSION: In hereditary demyelinating neuropathies, somatic and germline mosaicism of dominant mutations in the myelin protein genes may mimic autosomal recessive inheritance.

Adolescent↗
PubMed2006

Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes.

BACKGROUND: Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction. OBJECTIVE: To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation. DESIGN AND PARTICIPANTS: Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy. MAIN OUTCOME MEASURES: Pathological changes in sural nerve. RESULTS: Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum). CONCLUSIONS: Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).

Aged, 80 and over↗
PubMed2003

Clinical and electrophysiologic features of HNPP patients with 17p11.2 deletion.

OBJECTIVES: Although the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is important for correct prognostic evaluation and genetic counseling, the diagnosis is frequently missed or delayed. Our main aim on undertaking this study was to characterize the electrodiagnostic features of HNPP. MATERIAL AND METHODS: Clinical, electrophysiologic and molecular studies were performed on Korean HNPP patients with 17p11.2 deletion. The results of electrophysiologic studies were compared with those of Charcot-Marie-Tooth disease type 1 A (CMT1A) patients carrying 17p11.2 duplication. RESULTS: Eight HNPP (50 motor, 39 sensory nerves) and six CMT1A (28 motor, 16 sensory nerves) patients were included. Sensory nerve conduction was slow in 97% of HNPP nerves. Motor nerve conduction at common entrapment sites was also abnormally slow in 87.5%, whereas at non-entrapment sites conduction slowing was infrequent. Distal motor latency (DML) was prolonged in 80% of HNPP nerves, and terminal latency index (TLI) was significantly lower in HNPP than in normal controls and in CMT1A patients (P < 0.01). In contrast to CMT1A, where severity of nerve conduction slowing was not different among nerve groups, HNPP sensory nerve conduction was more slowed in the median and ulnar nerves than in the sural nerve (P < 0.01), and DML was more prolonged in the median nerve than in the other motor nerves (P < 0.01). TLIs were significantly lower in HNPP than in the normal control and CMT1A patients for the median and ulnar nerves (P < 0.01), and were also significantly reduced for the peroneal nerve (P < 0.05) compared with those of the normal controls. CONCLUSION: HNPP is characterized electrophysiologically by a generalized neuropathy, superimposed by focal entrapment neuropathies. The slowing of sensory conduction in nearly all nerves and the distal accentuation of motor conduction abnormalities are the main features of background polyneuropathy in HNPP. The distribution and severity of the background electrophysiologic abnormalities are closely related to the topography of common entrapment or compression sites, which suggests the possible pathogenetic role of subclinical pressure injury at these sites in the development of the distinct background polyneuropathy in HNPP.

Adolescent↗
PubMed2001

Altered gene expression in Schwann cells of connexin32 knockout animals.

The discovery that the dominant X-linked form of Charcot-Marie-Tooth disease (CMTX), a genetic disease of the peripheral nervous system (PNS), is associated with mutations in connexin32 (Cx32) has brought attention to the importance of connexins in glial cell biology. To gain further insight into the consequences of Cx32 deficiency, we have undertaken a detailed characterization of the gene expression profile of Schwann cells isolated from the sciatic nerve of wild-type and Cx32-null mice. Schwann cells exhibit two distinct phenotypes, myelinating and nonmyelinating, which are defined by their different morphology with respect to axons and by their unique profile of gene expression. Our findings show that, regardless of the mouse genotype, cultured Schwann cells express similar levels of messages for a number of connexins and for genes characteristic of both the myelinating and the nonmyelinating phenotypes. Furthermore, we have identified Cx36, a member of the gamma subclass of connexins, which are preferentially expressed in neuronal cells of mouse brain and retina, as an additional connexin present in Schwann cells. Mice lacking Cx32, however, exhibited a marked up-regulation of glial fibrillary acidic protein (GFAP), a cytoskeletal protein usually synthesized only by nonmyelinating Schwann cells. This observation was extended to the PNS in vivo and did not reflect a general perturbation of the expression of other nonmyelinating Schwann cell genes. These findings demonstrate that the absence of Cx32 results in a distinct pattern of gene dysregulation in Schwann cells and that Schwann cell homeostasis is critically dependent on the correct expression of Cx32 and not just any connexin. Identifying the relationship between increased GFAP expression and the absence of Cx32 could lead to the definition of specific roles for Cx32 in the control of myelin homeostasis and in the development of CMTX.

Animals↗
PubMed2003

A new quantitative PCR multiplex assay for rapid analysis of chromosome 17p11.2-12 duplications and deletions leading to HMSN/HNPP.

A 1.4-Mb tandem duplication, including the gene for peripheral myelin protein 22 (PMP22) in chromosome 17p11.2-12 is responsible for 70% of the cases of the demyelinating type 1 of Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy I (CMT1A/HMSN I). A reciprocal deletion of this CMT1A region causes the hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A duplication increases the PMP22 gene dosage from two to three, the HNPP deletion reduces the gene dosage from two to one. Currently, routine diagnosis of HMSN/HNPP patients is mainly performed with polymorphic markers in-between the repetitive elements flanking the CMT1A region. These show quantitative and/or qualitative changes in case of a CMT1A duplication and a homozygous allele pattern in case of HNPP deletion. In HNPP patients the deletion is usually confirmed by fluorescence in situ hybridisation (FISH). We now developed a reliable, single tube real-time quantitative PCR assay for rapid determination of PMP22 gene dosage directly. This method involves a multiplex reaction using FAM labelled Taqman-probe with TAMRA quencher derived from PMP22 exon 3 and a VIC labelled probe with non-fluorescent quencher from exon 12 of the albumin gene as internal reference. Copy number of the PMP22 gene was determined by the comparative threshold cycle method (deltadeltaCt). Each sample was run in quadruplicate and analysed at two different threshold levels. The level giving the smallest standard deviation was scored. We evaluated this method through the retrospective analysis of 252 HMSN patients with known genotype and could confirm the previous findings in 99% of cases. Two patients were wrongly diagnosed with microsatellite analysis while quantitative real-time PCR identified the correct genotype, as confirmed by FISH. Thus, this method shows superior sensitivity to microsatellite analysis and has the additional advantage of being a fast and uniform assay for quantitative analysis of both CMT1A and HNPP.

Biological Assay↗
PubMed2006

[Molecular genetics of inherited neuropathies].

Inherited neuropathies are clinically and genetically heterogeneous. At least 28 genes and 12 loci have been associated with Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Most causes of inherited neuropathy have been discovered by positional cloning technique and in the past two years, the pace of CMT gene discovery has accelerated. Genetic studies have revealed the following gene mutations as the causes of inherited neuropathies; PMP22, MPZ, EGR2, SOX10, SIMPLE/LITAF, ARHGEF10 for CMT1 (autosomal dominant demyelinating form); GDAP1, MTMR2, SBF2/MTMR13, KIAA1985, NDRG1 PRX for CMT4 (autosomal recessive demyelinating form), MFN2, KIF1B, RAB7, GARS, NEFL, HSPB1, HSPB8 for CMT2 (autosomal dominant axonal form); LMNA, GAN1, KCC3, TDP1, APTX, SETX for AR-CMT2 (autosomal recessive axonal form); GIB1 for CMTX (X-linked CMT); DNM2 for CMT-DI (autosomal dominant CMT with intermediate nerve conduction velocities); and DHH for minifascicular neuropathy. These discovered CMT causing genes/proteins include those which show unpredictable correlations with the peripheral nervous system. However, these genes/proteins are definitely important for the peripheral nerve, and their discovery should pave the way for dramatic progress in the understanding of peripheral nerve biology. On the other hand, genotype-phenotype correlations of these genes are also important in order to understand the pathomechanisms of inherited neuropathy. Because, based on mutation studies, a large number of genes associated with both the CMT1/4 and CMT2 forms have been identified, it is usually difficult to predict the causative gene based on clinical information from patients without specific complications. To clarify the specific features and molecular mechanisms of five diseases that we previously reported, we reviewed recent progress in HMSN-P linked to chromosome 3, CMT4F caused by PRX, CMT4A caused by GDAP1, CMT4B2 caused by SBF2/MTMR13, and SCAN1 caused by TDP1. HMSN-P is characterized by late onset, proximal dominant severe muscle weakness, fasciculations, muscle cramp and sensory involvement. HMSN-P is a primary neuronopathy. Mutations in periaxin are associated with a broad spectrum of demyelinating neuropathies including DSS, a sensory dominant form and early onset slowly progressive CMT. Pathologically, loss of myelinated fibers, demyelination, small onion bulb formations, tomacula formation and myelin foldings were seen in sural nerves. Absence of septate like junction in the paranodal loop suggests that periaxin could be required for the adhesion complex. GDAP1 is a relatively common cause of CMT4. Half of reported patients showed the demyelinating form, while the rest showed the axonal form. The typical feature of CMT4A is paresis of the vocal cords and diaphragm. CMT4B2 is characterized by autosomal recessive, juvenile onset glaucoma and focally folded myelin in sural nerves. SBF2/MTMR13 mutations cause CMT4B2. Early onset glaucoma was seen in patients with nonsense mutations. SBF2/MTMR13 and MTMR2, which is the cause of CMT4B1, could be acting on the same 3-phosphoinositide signaling pathway. Clinical phenotypes of patients with TDP1, APTX, or SETX mutations share common clinical findings, namely cerebellar ataxia and axonal neuropathy. TDP1 and aprataxin both act on the single strand break repair pathway, with TDP1 working specifically on topoisomerase I related SSBR. Senataxin is a RNA helicase acting on RNA maturation and termination in yeast. Since these three proteins share a common pathway, disruption in any of them could induce a delay in the transcription process. The low rate of protein supply could lead to deaths of large neuronal cells.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Morphological changes in diseased cementum layers: a scanning electron microscopy study.

The aim of this study was to compare the morphological changes that occurred in root cementum layers due to periodontal disease by using scanning electron microscopy (SEM). Ninety-two periodontally hopeless teeth extracted from 29 patients were studied. Measurements of probing depth (PD) and clinical attachment loss (CAL) were taken prior to extractions. After the longitudinal fracturing process of root specimens, healthy and diseased cementum layers of roots were evaluated by SEM for the thickness of the cementum and the morphological changes in collagen fibers. The result of SEM evaluation revealed a significant ( P < 0.001) decrease in the thickness of cementum layer on the diseased root surfaces compared to the healthy surfaces. There were denser and conspicuous collagen fibers with their interfibrillar matrix in cementum layers on the healthy root surfaces compared to the diseased surfaces. Within the limits of this study, the thickness of cementum layers in diseased areas was found to be significantly less than that in the healthy areas of root surfaces. However, there exist variations in the density and visibility of cemental fibers between individuals and within the individual.

Adult↗
PubMedDate not supplied

Oral lesions caused by habits.

Oral lesions caused by habits can be of teeth only, of teeth and the soft tissues of the mouth or may be only of the soft tissues. Lesions of teeth are permanent and may remain even when there has been total destruction of soft tissues. Recognition of lesions due to habits such as betel chewing, snuff dipping, pipe smoking and certain sexual practices may help towards establishing the sex, the ethnic grouping or even the place of origin of a person or their remains. Certain dental and gingival changes may indicate a person's working circumstances and even the type of treatment received.

Areca↗
PubMed2005

Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis.

While 1 to 2% of amyotrophic lateral sclerosis (ALS) is caused by mutations in the SOD1 gene, the basis of the remaining instances of inherited disease is unknown. Neuropathology, mouse modeling, and human genetics have implicated neurofilaments in the pathogenesis of motor neuron diseases such as ALS and Charcot-Marie-Tooth disease (CMT). A systematic analysis of the coding region and intron-exon boundaries of all three neurofilament genes is now reported from DNA samples derived from more than 200 non-SOD1 linked familial and sporadic ALS patients, along with >400 non-disease control individuals. Rare variants within each of the three neurofilament subunits that are predicted to affect neurofilament assembly properties were identified at higher frequency in non-SOD1 mutant ALS samples. However, none could be unambiguously linked to dominantly inherited disease. Thus, mutations in neurofilaments are possible risk factors that may contribute to pathogenesis in ALS in conjunction with one or more additional genetic or environmental factors, but are not significant primary causes of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Dyskeratosis congenita: report of a case.

Dyskeratosis congenita is a rare multisystem condition involving mainly the ectoderm. It is characterized by a triad of reticular skin pigmentation, nail dystrophy and leukoplakia of mucous membranes. Oral and dental abnormalities may also be present. Complications are a predisposition to malignancy and bone marrow involvement with pancytopenia. The case of a 14-year-old girl is described who presented with several of the characteristic systemic features of this condition, together with the following oral features: hypodontia, diminutive maxillary lateral incisors, delayed dental eruption, crowding in the maxillary premolar region, short roots, poor oral hygiene, gingival inflammation and bleeding, alveolar bone loss, caries and a smooth atrophic tongue with leukoplakia. Although this condition is rare, dental surgeons should be aware of the dental abnormalities that exist and the risk of malignant transformation within the areas of leukoplakia.

Adolescent↗
PubMed1998

Oral health and dental treatment needs in Nigerian patients with epilepsy.

PURPOSE: We determined the prevalence of oral disorders and the dental treatment needs of outpatients with epilepsy. METHODS: A questionnaire was administered to 56 consecutive patients (35 males, 21 females) presenting to an outpatient clinic. All patients underwent dental examinations. The clinical and diagnostic features of each patient's epilepsy were also obtained. RESULTS: The mean age (+/-SD) of the patients was 25.1 +/- 12.1 years (range, 12-56 years). Of 9 patients receiving phenytoin (PHT) monotherapy, 3 (33.3%) had gingival hypertrophy; 15 of 18 (83.3%) patients receiving PHT in combination with phenobarbital (PB) manifested the disorder. Traumatized anterior teeth were found in 26 (46.4%) patients with the males significantly more affected than females (p = 0.02). When the dental treatment needs were considered, 24 (42.9%) patients required dental prophylaxis with oral hygiene instruction, and an equal number required various types of restorative treatments. Only 13 patients (23.2%) had previously visited a dental clinic; the 43 (76.8%) who had never sought dental treatment claimed they did not see any need for it. CONCLUSIONS: Our study showed an increased predilection to anterior dental injuries in patients with epilepsy as compared with the prevalence earlier reported for those without epilepsy in Nigeria (p = 0.00). There is a clear need for effective interaction between medical and dental practitioners in the management of epilepsy.

Adolescent↗
PubMed1986

Oral assessment of the dentulous elderly patient.

The percentage of elderly persons retaining natural teeth is increasing. Although many of these individuals cannot be convinced to see a dentist regularly, they are generally seen by a physician or nurse relatively frequently. The physician or nurse can provide a vital service for these patients by performing oral screening examinations. A technique is described for accomplishing this.

Aged↗