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Dmt Informative Speech



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It was unclear whether the segregation distortion was a direct consequence of the CTG repeat number or whether the preferential transmission of the larger allele was due to linkage to segregation distorting loci on the same chromosome. A trimodal distribution of CTG repeat lengths in the normal population was observed: 5 repeats, repeats, and repeats. Five-repeat alleles and 9- to repeat alleles were stably inherited. The third mode, repeats, was skewed toward increasing allele length with frequent de novo expansions. The authors also analyzed alleles with repeat lengths of repeats, or 'premutation' alleles. Individuals with premutation alleles were asymptomatic.

Premutation alleles were found to be very unstable and liable to frequent large expansions in the male germline, with expansion observed in 25 of 25 transmissions. Sperm from a premutation carrier demonstrated a range of diverse alleles positively skewed toward expansion. Leeflang et al. They studied samples of single sperm from 3 individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than the 19 CTG repeats.

To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelated to the allele size of the DM locus: D19S in 2 donors and D19S in the third. Using statistical models specifically designed to study single-sperm segregation data, they found no evidence of meiotic segregation distortion. This suggested to Leeflang et al. Magee and Hughes studied 44 sibships with myotonic dystrophy. When the transmitting parent was male, Magee and Hughes concluded that DM expansion tends to be transmitted preferentially.

Nakagawa et al. The sisters had symptoms from birth. The age of onset of DM in the father was 39 years. Analysis of the CTG trinucleotide expansion in this family showed increase in the repeat length with increasing severity, with the smallest expansion in the grandfather and the largest expansion in the younger of the 2 affected sisters. The observation refutes the hypothesis that congenital DM is exclusively of maternal origin. Bergoffen et al. This family illustrated that the congenital form can occur without intrauterine or other maternal factors operating. De Die-Smulders et al. The patient was a year-old, mentally retarded male suffering from severe muscular weakness who presented with respiratory and feeding difficulties at birth. His 2 sibs suffered from childhood-onset DM, whereas their father had adult onset of DM at around 30 years of age.

The authors concluded that paternal transmission of congenital DM preferentially occurs with onset of DM past 30 years of age in the father. Zunz et al. They cited several reports e. However, these studies were based on data from the analysis of pedigrees with ascertainment bias. Eighty-three fetuses were examined. Thirty of 62 mothers Unlike previous studies, the study of Zunz et al. Zeesman et al. In a study of mitochondrial DNA from 35 patients with congenital myotonic dystrophy, Poulton et al. Associated mitochondrial mutations might help account for the maternal inheritance pattern and the early onset of the congenital form. The linkage of secretor Se; and myotonic dystrophy was suspected by Mohr when he was doing the studies that demonstrated the first autosomal linkage in humans, that between secretor and Lutheran blood group Lu; Mohr failed to establish fully the DM linkage because of the relative insensitivity of the sib-pair method of linkage analysis he was using Smith, Renwick et al.

From study of a single large kindred, Larsen et al. Eiberg et al. Since fibroblast C3 had been assigned to chromosome 19, the finding indicated that myotonic dystrophy is on chromosome 19, providing serum C3 polymorphism of which was used in the above linkage studies is under the same genetic control or at least syntenic genetic control as fibroblast C3. Cook had found positive lod scores for serum C3 and peptidase D , a chromosome 19 locus.

Linkage of peptidase D to myotonic dystrophy O'Brien et al. Laberge et al. Meredith et al. Brook et al. Friedrich et al. The hereditary motor and sensory neuropathy in the family described by Jamal et al. Spaans et al. Shaw et al. Suppression of recombination near the centromere and the large male-female differences in recombination are 'complications' of linkage mapping of the DM locus and use of linkage markers in genetic counseling. Roses et al. Bartlett et al. In 3 large kindreds, Friedrich et al. Three-point linkage analysis excluded DM from the 19cen-C3 segment and strongly supported its assignment to the proximal long arm of chromosome Bird et al. Smeets et al. A maximum lod score of 7. The maximum lod score was Bender et al.

Johnson et al. Yamaoka et al. Walsh et al. A maximum lod score of 9. In a study of 65 myotonic dystrophy families from Canada and the Netherlands, Brunner et al. MacKenzie et al. Bailly et al. Harley et al. All affected individuals had inherited a unique APOC2 haplotype that was not found in their clinically and electrophysiologically normal sibs. In this family, a moderately severe neuropathy appeared to be the only clinical sign of myotonic dystrophy for many years. The results were consistent with either an unusual neuropathic mutation in the DM gene or involvement of 2 closely linked genes. Linkage studies by Cobo et al.

A 2-allele EcoRI polymorphism was seen in normal persons, but in most affected individuals one of the normal alleles was replaced by a larger fragment, which varied in length both between unrelated affected individuals and within families. The unstable nature of this region was thought to explain the characteristic variation in severity and age at onset of the disease. Aslanidis et al. The central part of the contig bridged an area of about kb between 2 flanking crossover borders.

This segment, which presumably contained the DM gene, was extensively characterized. Two genomic probes and 2 homologous cDNA probes were situated within approximately 10 kb of genomic DNA and detected an unstable genomic segment in myotonic dystrophy patients. The length variation in this segment showed similarities to the instability seen in the fragile X locus The authors proposed that the length variation was compatible with a direct role in the pathogenesis of myotonic dystrophy.

Using positional cloning strategies, Brook et al. This sequence is highly variable in the normal population. Unaffected individuals have between 5 and 27 copies. Myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat-containing segment up to several kilobase pairs. Tsilfidis et al. Shelbourne et al. In 3 families for whom the clinical and genetic data obtained with linked probes were ambiguous, the specific probe identified persons at risk and demonstrated that a possible sporadic case of myotonic dystrophy was, in fact, familial.

In 1 family, the size of the unstable myotonic dystrophy-specific fragment decreased on transmission to offspring who remained asymptomatic, which was an example of the reverse of anticipation. Thornton et al. The diagnosis of DM was based on involvement of the lens, cardiac conduction system, skin, and testes, in association with muscle weakness and myotonia. The diagnosis was supported by an autosomal dominant pedigree pattern and by features of muscle histopathology consistent with DM. This may be a situation like that of the fragile X syndrome in which rare affected individuals lack a trinucleotide repeat expansion and instead have deletions or point mutations.

They confirmed the findings of previous studies that there was no strong correlation between repeat length and clinical symptoms but found that the repeat length in peripheral blood cells of patients increased over a 5-year period, indicating continuing mitotic instability of the repeat throughout life. Junghans et al. One of the features discussed in detail was hypercatabolism of immunoglobulin G in myotonic dystrophy and the possible significance of the FCGRT gene to the DM locus. None of normal Czech alleles tested carried interruptions.

The expanded alleles contained either regular runs of a CCGCTG n hexamer or showed a much higher complexity; they were always located at the 3-prime end of the repeat. The number and location of the interruptions were very unstable within families and subject to substantial change during transmission. However, 4 of 5 transmissions of the interrupted expanded allele in 1 family were accompanied by repeat contraction, suggesting that the interruptions render the DMPK CTG repeat more stable or could even predispose it to contractions. Overall, the contribution of the interrupted alleles to the phenotype was uncertain. Musova et al. Buxton et al.

They reported a family in which persons in the first 2 generations had mild symptoms and a CTG repeat unit of approximately 60 repeats, whereas persons in the third and fourth generations had severe symptoms and a dramatic expansion in allele size--a demonstration of the physical basis of anticipation in myotonic dystrophy. Mahadevan et al. They likewise observed that an increase in the severity of the disease in successive generations was accompanied by an increase in the number of trinucleotide repeats. Thus, 'anticipation' progressively earlier onset and greater severity of symptoms , long a puzzling feature of DM, has an explanation and physical documentation in the progressive 'worsening' of the mutation.

The average increase in the pairs with congenital DM was not statistically greater than that shown by noncongenital DM pairs. In another analysis, they found that the intergenerational CTG repeat length increase was the same whether the father or the mother contributed the DM allele to the offspring. Fu et al. They suggested that the mutational mechanism leading to DM is triplet repeat amplification, similar to that occurring in the fragile X syndrome. The genomic repeat is p AGC n. They pointed out that this is the same repeat sequence found in the androgen receptor gene and amplified in Kennedy disease , although transcription in the latter disorder is from the opposite strand of DNA.

Richards and Sutherland indicated that the instability of the DM element extends beyond meiotic instability in affected pedigrees to mitotic instability, manifest as somatic variation--a smear of bands evident in some affected persons. Progression of somatic CTG repeat length heterogeneity in the blood cells of myotonic dystrophy patients was documented by Martorell et al. They studied repeat length changes over time intervals of 1 to 7 years in myotonic dystrophy patients with varying clinical severity and CTG repeat sizes.

There was a correlation between the progression of size heterogeneity over time and the initial CTG repeat size. The expansion of a CTG trinucleotide repeat, which represents the myotonic dystrophy mutation, is in complete linkage disequilibrium in both Caucasian Harley et al. This finding was unexpected for a dominant disease that in its severe form diminishes or abolishes reproductive fitness. Such diseases are usually characterized by a high level of new mutations that compensate for the loss of abnormal alleles due to the decreased fitness. It was therefore suggested that DM could be due to recurrent mutations occurring on the background of a predisposing allelic form of the normal gene. Imbert et al. The results strongly suggested that the initial predisposing event s consisted of a transition from a CTG -5 allele to an allele with 19 to 30 repeats.

Krahe et al. A single haplotype composed of 9 alleles within and flanking the DM locus over a physical distance of 30 kb had been shown to be in complete linkage disequilibrium with DM. However, unlike all other DM populations studied to that time, disassociation of the CTG n repeat expansion from other alleles of the putative predisposing haplotype was found. This weakens the hypothesis that a single ancestral haplotype predisposes to repeat expansion. Yamagata et al. All of the affected chromosomes were in complete linkage disequilibrium with the Alu insertion allele. A strikingly similar pattern of linkage disequilibrium observed in European populations suggested a common origin of the DM mutation in the Japanese and European populations.

The authors speculated that this mutation arose in a common Eurasian ancestor after the first separation of the African and the non-African populations, in light of the fact that the family reported by Krahe et al. Presumably, the mutation in that family represented a less-ancient event than the Eurasian mutation, accounting for the fact that DM is extremely rare in African populations. The largest repeat sizes, 1. Only 4 of parent-child pairs showed a definite decrease in repeat size in the offspring; almost all showed that the offspring had an earlier age of onset and a larger repeat size than their parents. Increase in repeat size from parent to child was similar for both paternal and maternal transmissions when the increase was expressed as a proportion of the parental repeat size.

Analysis of congenitally affected cases showed not only that they had on the average the largest repeat sizes, but also that their mothers had larger mean repeat sizes, supporting previous suggestions that a maternal effect is involved. Repeat lengths greater than were more common in offspring of male transmitters than in offspring of female transmitters. They suggested that selection against sperm with extreme amplifications may be required to explain maternal inheritance of congenital myotonic dystrophy.

Sutherland and Richards editorialized on the legitimization of anticipation. According to Harper et al. They observed 2 families in which an affected father transmitted a normal allele to an offspring; in each case, an expanded CTG trinucleotide repeat decreased in size to the normal range. This was the first report of spontaneous correction of a deleterious mutation upon transmission to unaffected offspring in humans. Abeliovich et al. See review by Brook Ashizawa et al. Approximately one-half of these cases showed clinical anticipation despite the reduced CTG repeat size in the offspring.

The most striking examples were 2 cases in which anticipation resulted in congenital DM in the offspring with contractions of the CTG repeat. They did not observe a single case in which the age at onset of DM in the symptomatic offspring was later than the age at onset in the parent, although Harley et al. Lavedan et al. With CTG sequences of more than 0. For CTG sequences under 0. Anvret et al. Dubel et al. A family with myotonic dystrophy described by de Jong was restudied by de Die-Smulders et al. They defined clinical anticipation as the cascade of mild, adult, childhood, or congenital disease in successive generations.

Such clinical anticipation appeared to be a relentless process occurring in all affected branches of the 5-generation family studied. The transition from the mild to the adult type was associated with transmission through a male parent. Gene loss in the patients in this family was complete, owing to infertility of the male patients with adult-onset disease and the fact that mentally retarded patients did not procreate. Of the 46 at-risk subjects in the 2 youngest generations, only 1 was found to have a full mutation. This is the only subject who may transmit the gene to the sixth generation. No protomutation carriers were found in the fourth and fifth generations.

Therefore, it seemed highly probable that the DM gene would be eliminated from this pedigree within 1 generation. Simmons et al. Barcelo et al. Their findings suggested that while a high number of repeats seem to be a necessary condition for congenital DM, this alone is not sufficient to explain its exclusive maternal inheritance. This was most clearly reflected in the fact that in their study group, approximately one-quarter of DM cases inherited from affected fathers had repeat numbers equal to or greater than those found in the congenital DM cases with the lowest number of repeats approximately repeats.

Novelli et al. Two affected mothers with similar numbers of repeats gave birth to offspring with discordant phenotypes. Childhood and congenital myotonic dystrophy affected the son and the daughter of one sister, with CTG triplet repeats in lymphocytes of and 1,, respectively. In contrast, the affected son of the other sister had onset mild myotonic dystrophy at age 14 years, despite having 1, CTG triplets detected in lymphocytes. Hamshere et al. Regression analysis predicted that the absolute size of the CTG repeat may not be a good indicator of the expected age of onset of symptoms when the size of the repeat is 0.

Khajavi et al. In all DM1 cell lines, the expanded CTG repeat alleles gradually shifted toward further expansion by 'step-wise' mutations. Of 29 cell lines, 8 yielded a rapidly proliferating mutant with a gain of large repeat size that became the major allele population, eventually replacing the progenitor allele population. By mixing cell lines with different repeat expansions, the authors found that cells with larger CTG repeat expansion had a growth advantage over those with smaller expansions in culture. This growth advantage was attributable to increased cell proliferation mediated by Erk1 and Erk2 activation, which is negatively regulated by p21 WAF1 The authors designated this phenomenon 'mitotic drive,' which they suggested is a novel mechanism that can explain the expansion bias of DM1 CTG repeat instability at the tissue level, on a basis independent of the DNA-based expansion models.

Since the life spans of the DM1 cells were significantly shorter than normal cell lines, the authors hypothesized that DM1 cells drive themselves to extinction through a process related to increased proliferation. Puymirat et al. In 1 family, 2 affected brothers with and repeats, respectively, transmitted the alleles to their 4 offspring, who had between and repeats. Three of the 4 young adult offspring were asymptomatic. In the second family, the transmitting father had repeats and his 4 asymptomatic young adult children all had repeats.

Arsenault et al. Most patients with 50 to 99 repeats were asymptomatic except for cataracts. Patients with to repeats were significantly more likely to have myotonia, weakness, excessive daytime sleepiness, and myotonic discharges on EMG. Barbe et al. The repeat size in congenital DM1 ranged from 1, to 4, Most non-CDM1 individuals were devoid of methylation, although a few showed downstream methylation. Only 2 non-CDM1 individuals showed upstream methylation; both had maternally-derived childhood-onset. In contrast, paternally-derived samples never showed upstream methylation.

The mechanism by which the expanded trinucleotide repeat in the 3-prime untranslated region of the DMPK gene leads to the clinical features is unclear. The DM region of chromosome 19 is gene rich, and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity, perhaps as a consequence of chromatin disruption. Boucher et al. Sequencing of the region showed that the island extends over 3. Comparison of genomic sequences downstream centromeric of the repeat in human and mouse identified regions of significant homology.

This led to the identification of the gene which Boucher et al. They found that this protein is expressed in a number of human tissues, including skeletal muscle, heart, and brain. Harris et al. They noted that published results on the effect of the trinucleotide repeat in the 3-prime end of DMPK on the gene's transcription have been contradictory. There were reports that DMPK expression is increased at the transcriptional level and reports that transcription is decreased. They noted also that the complexity of clinical manifestations in myotonic dystrophy and the results of animal studies suggest that other genes may be involved in this disease.

Roberts et al. Otten and Tapscott demonstrated that a nuclease-hypersensitive site is positioned adjacent to the CTG repeat at the wildtype DM locus and that large expansions of the repeat eliminated the hypersensitive site, converting the region surrounding the repeats to a more condensed chromatin structure. As nuclease-hypersensitive sites often coincide with gene regulatory regions, the decreased accessibility of transcription factors to this region in the expanded allele might affect local gene expression. Therefore Klesert et al. They found that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. Along the same line, Thornton et al. Sarkar et al.

Incremental expansions predominated in CTG tracts smaller than Okazaki fragment size, while saltatory expansions increased in repeat tracts larger than or equal to Okazaki fragment size. These results suggested to Sarkar et al. Saveliev et al. Silencing was correlated with a decrease in promoter accessibility and was enhanced by the classic position effect variegation PEV modifier heterochromatin protein-1 HP1; Notably, triplet repeat-associated variegation was not restricted to classic heterochromatic regions but occurred irrespective of chromosomal location. Because the phenomenon described shares important features with PEV, Saveliev et al.

Using methylation-sensitive restriction enzymes, Steinbach et al. The gene segment analyzed corresponded to the restriction fragment carrying exons 11 to There was constitutive methylation in intron 12 at restriction sites that were localized 1, to 1,bp upstream of the CTG repeat, whereas most, if not all, of the other restriction sites in this region were unmethylated, in normal individuals and most of the patients. In a number of young and severely affected patients, however, complete methylation of these restriction sites was found in the mutated allele. In most of these patients, the onset of the disease was congenital. Preliminary in vivo footprinting data gave evidence for protein-DNA contact in normal genes at an Sp1 consensus binding site upstream of the CTG repeat and for a significant reduction of this interaction in cells with a hypermethylated DMPK gene.

The findings suggested that hypermethylation may be another genetic factor causally related to earlier onset and more severe manifestations of myotonic dystrophy. Filippova et al. In contrast to the findings of Steinbach et al. The HhaI and HpaII sites were found to be constitutively unmethylated in all samples, including wildtype, whereas the SacII site showed differential methylation, but it did not correlate with expanded repeat or disease severity. Timchenko et al. Since myotonic dystrophy is caused by a CTG expansion in the 3-prime untranslated region of the DM gene, one model of DM pathogenesis suggests that RNAs from the expanded allele create a gain-of-function mutation by the inappropriate binding of proteins to the CUG repeats.

Philips et al. Splicing of cardiac troponin T was disrupted in DM striated muscle and in normal cells expressing transcripts that contain CUG repeats. To study the effects of the DM mutation in a controlled environment, Amack et al. By expressing chimeric reporter constructs containing a reporter gene fused to a human DMPK 3-prime-untranslated region 3-prime-UTR , they identified both cis and trans effects that were mediated by the DM mutation. They found that a mutant DMPK 3-prime-UTR, with as few as 57 CTGs, had a negative cis effect on protein expression and resulted in the aggregation of reporter transcripts into discrete nuclear foci. They determined by deletion analysis that an expanded CTG n tract alone was sufficient to mediate these cis effects.

These results provided evidence that the DM mutation acts in cis to reduce protein production consistent with DMPK haploinsufficiency and in trans as a 'riboregulator' to inhibit myogenesis. Savkur et al. IR-A predominates in DM1 skeletal muscle cultures, which exhibit a decreased metabolic response to insulin relative to cultures from normal controls. The CUGBP protein mediates this switch through an intronic element located upstream of the alternatively spliced exon 11, and specifically binds with this element in vitro. These results supported a model in which increased expression of a splicing regulator contributes to insulin resistance in DM1 by affecting alternative splicing of INSR pre-mRNA.

This implies that RNA foci formation and perturbation of any RNA binding factors involved in this process are not sufficient to block myoblast differentiation. Reduced expression of tau isoforms containing exon 2 was observed at both the mRNA and protein levels. Large expanded CTG repeats were detected and showed marked somatic heterogeneity between DM1 cases and in cortical brain regions analyzed. The authors suggested a relationship between the CTG repeat expansion and the alteration of tau expression. Mankodi et al. However, hybridization of muscle sections with fluorescence-labeled CAG-repeat oligonucleotides showed nuclear foci in DM2 similar to those seen in DM1. Muscleblind proteins see , which interact with expanded CUG repeats in vitro, localized to the nuclear foci in both DM1 and DM2.

The authors proposed that nuclear accumulation of mutant RNA is pathogenic in DM1, a similar disease process may occur in DM2, and muscleblind may play a role in the pathogenesis of both disorders. Using skeletal muscle from a transgenic mouse model of DM, Mankodi et al. Charlet-B et al. Ebralidze et al. Diverse genes are consequently reduced in expression, including the ion transporter CLC1, which has been implicated in myotonia.

The authors concluded that transcription factor leaching from chromatin by mutant RNA provides a potentially unifying pathomechanistic explanation for this disease. The myotubularin-related 1 gene MTMR1; belongs to a highly conserved family of eukaryotic phosphatases. Buj-Bello et al. One of the transcripts is muscle specific, is induced during myogenesis, and represents the major isoform in adult skeletal muscle. The authors found a striking reduction in the level of the muscle-specific isoform and the appearance of an abnormal MTMR1 transcript in differentiated congenital DM1 muscle cells in culture as well as in skeletal muscle from congenital DM1 patients.

The authors hypothesized that MTMR1 may play a role in muscle formation, and may represent another target for abnormal mRNA splicing in myotonic dystrophy. Jiang et al. The mutant transcripts accumulated in discrete foci within neuronal nuclei. In parallel, a subset of neuronal pre-mRNAs showed abnormal regulation of alternative splicing. Kimura et al. However, heterologous expression of ASI - in cultured cells showed decreased affinity for ryanodine but similar calcium dependency, and decreased channel activity in single-channel recording when compared with wildtype RYR1.

In support of this, RYR1-knockout myotubes expressing ASI - exhibited a decreased incidence of calcium oscillations during caffeine exposure compared with that observed for myotubes expressing wildtype RYR1. Hino et al. The expression of this aberrantly spliced SERCA1 could affect the regulation of calcium concentration of sarcoplasmic reticulum in DM1 patients. In mice, the effects on Nkx2. Furthermore, haploinsufficiency of Nkx2. Yadava et al.

Protein analysis showed that 1 of the abnormally spliced DTNA isoforms localized to the sarcolemma of DM1 muscle and caused enhanced recruitment of alpha-syntrophin SNTA1; to the sarcolemma. Nakamori et al. Botta et al. There was also a correlation between increased expansion size and the number of ribonuclear foci, which represented nuclear retention of untranslated DMPK transcripts. There was no relationship between expression levels of the DMPK transcript and repeat expansion size. Fugier et al. Expression of BIN1 without exon 11 resulted in little or no T tubule formation in cultured muscle cells, since this splice variant lacks a phosphatidylinositol 5-phosphate-binding site necessary for membrane-tubulating activities.

Skeletal muscle biopsies from patients with DM1 showed disorganized BIN1 localization and irregular T tubule networks. Promotion of the skipping of Bin1 exon 11 in mouse skeletal muscle resulted in abnormal T tubules and decreased muscle strength, although muscle integrity was maintained. There was also decreased expression of Cacna1s , which plays a role in the excitation-contraction coupling process.

The findings suggested a link between abnormal BIN1 expression and muscle weakness in myotonic dystrophy. Tang et al. A significant fraction of CAV1. Forced exclusion of exon 29 in normal mouse skeletal muscle altered channel gating properties and increased current density and peak electrically evoked calcium transient magnitude. Downregulation of Mbnl1 in mouse cardiac muscle or overexpression of Cugbp1 in mouse tibialis anterior muscle enhanced skipping of exon 29, suggesting that these splicing factors may be involved in the CAV1.

Rinaldi et al. However, MYH14 retained normal subcellular localization in DM1 patient muscle, albeit at lower amounts than in controls. Jain and Vale showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease , spinocerebellar ataxia e. Jain and Vale concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease. Furling et al. Satellite cells are quiescent muscle cells which retain the ability to become myogenic precursor cells myoblasts.

Human satellite cells were isolated from the quadriceps muscles of 3 CDM fetuses with different clinical severity. By Southern blot analysis, all 3 cultures were found to have approximately 2, CTG repeats. This CTG expansion was found to progressively increase during the proliferative life span, confirming instability of this triplet in skeletal muscle cells. The proliferative capacity of the CDM myoblasts was reduced and a delay in fusion, differentiation, and maturation was observed in the CDM cultures compared with unaffected myoblast cultures.

The clinical severity and delayed maturation observed in the CDM fetuses were closely reflected by the phenotypic modifications observed in vitro. The authors concluded that satellite cells are defective in CDM and may be implicated in the delay in maturation and muscle atrophy that has been described in CDM fetuses. In classic adult-onset cases, clinical diagnosis is straightforward with demonstration of progressive distal and bulbar dystrophy in the presence of myotonia, with frontal balding, and cataracts.

Clinical diagnosis can be difficult in mild cases, where cataracts may be the only manifestation Bundey et al. In studies of an extensively affected Labrador kindred, Webb et al. Many younger affected persons, including one in his 20s, did not have lens opacities despite clear muscular involvement. On the other hand, Ashizawa et al. The sensitivity of these 2 features was found to be Normal individuals have 5 to 37 CTG repeats, whereas patients have from more than 50 to several thousand CTG repeats in peripheral leukocytes see review by Pizzuti et al.

Reardon et al. Only 10 analyses out of proved uninformative, but a further 5 requests 1. Seven of 81 8. Lightweight ankle-foot orthoses are useful for foot drop, as are specially designed utensils for hand weakness. Weakness of respiratory muscles may require postural drainage and nocturnal respiratory support in advanced ages. Heart failure and aspiration pneumonia secondary to impaired esophageal motility should be considered. Nocturnal hypoventilation may contribute to a hypersomnia distinct from narcolepsy , and should be evaluated with sleep studies.

Prolongation of the PR interval can progress to heart block, requiring placement of a pacemaker. Periodic EKGs and avoidance of drugs such as procainamide and quinine Griggs et al. Myotonia is rarely a major clinical concern. Those patients with significant stiffness benefit most from avoiding cold and by doing warm-up exercises. In selected patients, dilantin, quinidine, procainamide, myxilitene, diamox, and other drugs reduce myotonia modestly.

Periodic ophthalmoscopy is needed to assess posterior capsular cataracts, which may require extraction if vision is impaired significantly--rarely before the third or fourth decade. If tarsorrhaphy is undertaken for repair of ptosis, care must be taken not to overcorrect lest failure of eyelid closure lead to corneal abrasion. Dysfunction of sex hormones does not cause infertility. Obstetric difficulties are common. Hypomotility of the intestinal tract is not infrequent but usually does not require treatment. Dysphagia is usually manageable with conservative dietary measures. Keller et al. They reported 2 premature infants with congenital myotonic dystrophy requiring prolonged ventilatory support who were successfully weaned using nasal continuous positive airway pressure.

In 15 patients with genetically confirmed DM1, Logigian et al. The delay in relaxation was much greater in tetanic than single-twitch recordings, and both were positively correlated with leukocyte DMPK CTG repeat length, suggesting a triplet repeat toxic dosage effect. Logigian et al. Orngreen et al. There was an increase in muscle fiber diameter without an increase in serum creatine kinase.

The authors concluded that aerobic training is safe and effective for improving fitness in myotonic dystrophy patients. It had been suggested that therapy aimed at eliminating the toxin would be beneficial. Timchenko commented on the study of Mahadevan et al. Developing an approach to reduce CUG repeats might be a viable therapeutic strategy. The results of Mahadevan et al. Wheeler et al. As MBNL1 is released from sequestration, the defect of alternative splicing regulation is corrected, thereby restoring ion channel function.

Mulders et al. Direct administration of this oligonucleotide in muscle of DM1 mice in vivo caused a significant reduction in the level of toxic CUG n RNA and showed a normalizing effect on aberrant pre-mRNA splicing. The data demonstrated proof of principle for therapeutic use of simple sequence antisense oligonucleotides in DM1 and potentially other unstable microsatellite diseases. The study involved 2 parts, each with 20 patients taking or mg 3 times daily, respectively, over 7 weeks. Mexiletine is a lidocaine analog that acts as a sodium-channel blocker in skeletal and cardiac muscle.

The overall prevalence of DM1 is estimated to be 1 in 8, Musova et al. In the Saguenay region of the province of Quebec, the prevalence of myotonic dystrophy is about 1 in ; about cases are known in a population of , Mathieu et al. They identified patients still alive distributed in 88 families in this region, and traced all patients to a couple who settled in New France in Dao et al. Bouchard et al. They were unable to demonstrate the selective disadvantage of the DM gene.

Ashizawa and Epstein claimed that DM among ethnic Africans, especially in central and southern Africa, as well as in Cantonese, Thai, and probably Oceanians, has a low prevalence. In their survey they used Duchenne muscular dystrophy as a control and found that it had an incidence similar to that in western nations. They suggested that the findings are consistent with the evolution and migration of the human species from Africa. They interpreted the findings as consistent with the low frequency reported by Ashizawa and Epstein and provided a molecular basis supporting a north Eurasian origin of the DM mutation.

The result was considered entirely consistent with previous population studies which indicated a very low mutation rate in DM Harper, Goldman et al. Thus it seemed likely that only a small number of these 'African' chromosomes were present in the progenitors of all non-African peoples. The data provided support for the 'out of Africa' model for the origin of modern humans and suggested that the rare ancestral DM mutation event may have occurred after the migration from Africa, thus accounting for the absence of DM in sub-Saharan Negroid peoples. Lotz and van der Meyden found no single case of DM in an indigenous Negroid or Khoisan person from southern Africa, despite a survey representing a population of more than 30 million Ashizawa and Epstein, Cobo et al.

They studied 33 Spanish families from 5 different geographic regions. Passos-Bueno et al. The authors thought that bias in ascertainment could not be the explanation. In 72 French families, Lavedan et al. They also detected significant linkage disequilibrium between the DM locus and D19S63 for which allelic frequencies were different from other European populations. The results were consistent with the hypothesis that the CTG expansion occurred on one or a few ancestral chromosomes carrying the large 1-kb insertion allele. The size and distribution of the CTG repeat were determined and showed that the alleles ranged in length from 5 to 22 repeats.

The South African Bantu-speaking Negroids and San thus had significantly larger repeat length alleles than do Caucasoid and Japanese populations. Again, Goldman et al. Deka et al. They found that the CTG repeat length is variable in human populations. Alleles with 19 or more CTG repeats were the most frequent in Europeans, followed by the populations of Asian origin, and are absent or rare in Africans. To understand the evolution of CTG repeats, Deka et al. However, these associations are not exclusive in non-Caucasian populations.

Most significantly, Deka et al. Tishkoff et al. They found that non-African populations had a subset of haplotype diversity present in Africa, as well as a shared pattern of allelic association. CTG alleles large normal were observed only in northeastern African and non-African populations and exhibited strong linkage disequilibrium with 3 markers flanking the CTG n repeat. The pattern of haplotype diversity and linkage disequilibrium observed supported a recent African-origin model of modern human evolution and suggested that the original mutational event that gave rise to DM-causing alleles arose in a population ancestral to non-Africans before migration of modern humans out of Africa.

Neville et al. With the exception of the case reported from Africa by Krahe et al. A similar multistep model has been suggested for Friedreich ataxia Pan et al. As in Caucasian and Japanese populations, all of the Taiwanese DM1 chromosomes examined were exclusively associated with the Alu insertion and 7 additional single base polymorphic markers haplotype A. The findings suggested that the Taiwanese, and maybe all non-African, DM1 chromosomes may have originated from a pool of large-sized normal alleles with haplotype A, which was generated after the migration out of Africa. Siciliano et al. A minimum prevalence rate of 9.

The results underlined the importance of direct genetic diagnosis of DM, especially in detecting mildly affected patients. In a comprehensive epidemiologic survey among Jews living in Israel, Segel et al. The rate of unrelated DM sibships per million persons of each community was used as an estimate of the transition rate from stable to unstable DMPK- CTG n alleles assuming that each transition is a beginning of a new DM sibship.

This study indicated that the difference in the incidence of DM is a result of higher mutation rate in the non-Ashkenazi Jews as compared to the rate in the Ashkenazi Jews. The intragenic haplotype of the DM alleles was the same as that in DM patients in many populations worldwide; however, 2 markers closely linked to DM, D19S and D19S, were in linkage disequilibrium with the DM mutation in patients of Yemeni and Moroccan the largest subgroup of the Sephardi Jews extractions but not in the Ashkenazi patients. This observation indicated a common ancestral origin for the DM premutation in patients of the same ethnic origin. Segel et al. Yotova et al. The results suggested the existence of 3 basic haplotype families, A, B, and C, with A being the most common.

By analyzing proportions of recombinant haplotypes, Yotova et al. The minor haplotypes B and C were likely introduced independently. Medica et al. The authors hypothesized that these patients with protomutations represented a source of full expansion mutation, which could be responsible for maintaining DM1 mutations in a population. Stable transmission to an unaffected offspring was observed in 1 individual with a protomutation. Three of the patients were from the Croatian region of Istria, which has a high prevalence of DM1.

Acton et al. Other unaffected family members had CTG repeats of 5 to A comparison with other ethnic groups showed that the African American individuals from Alabama had more CTG repeats than some African black populations, but fewer than European white or Japanese populations. These data suggested that the risk for DM1 in American blacks is intermediate between that of African blacks and whites of European descent. Suominen et al. One of the expanded DM1 mutations had 80 repeats, but the size of the other expansion could not be determined.

Overall, the DM1 mutation frequency was estimated to be 1 in 2, in the general population. In the same study, the frequency of DM2 was estimated to be 1 in 1, They carried out an analysis of Dmpk gene expression by performing RNA in situ hybridization on whole-mount embryos and body sections of embryos to identify cell lineages that could potentially be affected by abnormal expression of DMPK. The only histologic abnormality shown in the over-expressor model was transgene copy number-dependent cardiomyopathy. In these models other prominent features of myotonic dystrophy were lacking. They concluded that simple loss or gain of expression of DMPK was probably not the only crucial requirement for development of myotonic dystrophy.

Benders et al. Myotubes of knockout mice exhibited a higher resting intracellular calcium concentration than did myotubes of wildtype mice because of an altered open probability of voltage-dependent L-type calcium and sodium channels. Calcium flux was partially mediated by influx of extracellular calcium through the L-type calcium channel. These changes occurred in mice between 3 and 7 months of age. Reddy et al. Gourdon et al. Monckton et al. This cosmid clone not only housed the entire DM gene, but also contained sequences corresponding to the 2 genes immediately flanking the DM kinase gene. Both studies clearly documented intergenerational and somatic cell instability of the trinucleotide repeat in the transgenic mice.

Lia et al. These mice had been shown to reproduce the intergenerational and somatic instability of the 55 CTG repeat, suggesting that surrounding sequences and the chromatin environment are involved in instability mechanisms. As observed in some of the tissues of DM patients, there was a tendency for repeat length and somatic mosaicism to increase with the age of the mouse. Furthermore, Lia et al. Somatic mutation rates in different tissues were also not correlated to the relative intertissue differences in transcriptional levels of the 3 genes that surround the repeat: DMAHP , DMPK, and Similar studies by Seznec et al.

Klesert et al. Both animal models developed cataracts, leading Klesert et al. They hypothesized that the reduced SIX5 levels may contribute to the male reproductive defects in DM1. Dmpk knockout mice show only mild muscle weakness and abnormal cardiac conduction; Six5 knockout mice develop cataracts only; neither mouse model develops myotonia. They developed transgenic mice that express human skeletal actin ACTA1; with either a nonexpanded 5-CTG or an expanded approximately CTG repeat in the final exon of the ACTA1 gene, midway between the termination codon and the polyadenylation site. Mice that expressed the expanded repeat developed myotonia and myopathy, whereas mice expressing the nonexpanded repeat did not.

Mounsey et al. Single channel recordings revealed sodium channel reopenings, similar to the gating abnormality of human myotonic muscular dystrophy, which resulted in a plateau of sodium current. The gating abnormality deteriorated with increasing age. In tissues cultured from Dmt mice, Gomes-Pereira et al. The authors also observed the selection of cells carrying longer repeats during the first few passages of the cultures and frequent additional selective sweeps at later stages. The highest levels of instability were observed in cultured kidney cells, whereas the transgene remained relatively stable in eye cells and very stable in lung cells, paralleling the previous in vivo observations. No correlation between repeat instability and the cell proliferation rate was found, rejecting a simple association between length change mutations and cell division, and suggesting a role for additional cell-type specific factors.

Kanadia et al. In addition to muscle abnormalities, the mice also developed ocular cataracts similar to DM1. These mice showed decreased expression and abnormal splicing of Clcn1, Tnnt2, and Tnnt3 In Mbnl1-deficient Drosophila embryos, Machuca-Tzili et al. Wang et al. The mice also showed misregulation of developmental alternative splicing transitions, including the Tnnt2 and Fxr1 genes. All died of heart failure within 2 weeks. A time-course study showed that increased CUGBP1 cooccurred within hours of induced expression of the CUG repeat and coincided with reversion to embryonic splicing patterns.

By repressing the inclusion of this exon, the treatment restored the full-length reading frame of Clc1 mRNA, upregulated Clc1 expression, normalized Clc1 current density, and eliminated myotonic discharges. The findings supported the hypothesis that myotonia and chloride channelopathy observed in DM results from abnormal alternative splicing of CLC1. Osborne et al. The majority of changes induced by CUG exp RNA in skeletal muscle could be explained by reduced activity of Mbnl1, including many changes that are secondary to myotonia. The pathway most affected comprised genes involved in calcium signaling and homeostasis. However, several of the most highly dysregulated genes showed altered transcription, as indicated by parallel changes of the corresponding pre-mRNAs.

Koshelev et al. Within weeks of induction of CUGBP1 expression, transgenic mice exhibited impaired movement, reduced muscle function, abnormal gait, and reduced total body weight compared with uninduced controls. Histologic analysis of transgenic muscle overexpressing CUGBP1 revealed centrally located nuclei, myofiber degeneration with inflammatory infiltrate, and pyknotic nuclear clumps. Ward et al. In a transgenic mouse model of DM1, systemic administration of antisense oligonucleotides caused a rapid knockdown of CUG expansion RNA in skeletal muscle, correcting the physiologic, histopathologic, and transcriptomic features of the disease.

The effect was sustained for up to 1 year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat1 , a long noncoding RNA that is retained in the nucleus. Anticipation--earlier onset and more severe manifestations in more recent generations--was described in myotonic dystrophy as a rather striking feature. Penrose concluded that it is probably an artifact of ascertainment. However, elucidation of the molecular defect see above indicates that the mutation can worsen progressively in successive generations. Julia Bell, in her extensive compilation of myotonic dystrophy families, noted the phenomenon, which she referred to as 'antedating.

Both Bell and Penrose were aware of a low parent-child correlation. Penrose's conclusion was that anticipation was apparent rather than real and did not require a novel biologic explanation. He failed to consider the possibility that low parent-child correlation might itself be the result of anticipation. In the days long before the gene was identified, it was feasible to perform amniocentesis in selected families to determine secretor status of the fetus and thereby predict inheritance of the allele for myotonic dystrophy based upon the DM-Se linkage. The affected spouse had to be heterozygous at the secretor locus and the linkage phase between DM and Se must be established; the unaffected spouse must not be homozygous secretor-positive.

It is best if that spouse is secretor-negative, but useful information for counseling could be obtained if he is heterozygous for secretor. In some cases the secretor phenotype of the fetus could establish the genotype in the parents. Finally, recombination between DM and Se introduced a degree of uncertainty into the counseling Schrott et al. Caughey and Myrianthopoulos provided a monograph covering all aspects of myotonic dystrophy. Caughey and Myrianthopoulos privately published a second edition. The frontispiece is a Greek stamp commemorating Prince Ypsilante, a hero of Greek liberation who, along with his brother, was thought on good evidence to have had myotonic dystrophy. Cattaino and Vicario suggested that Amenhotep IV, better known as Akhenaten, the heretical pharaoh, a king of the New Kingdom of Ancient Egypt, had myotonic dystrophy.

Statues and reliefs of him showed abnormal features. He died at the age of about 36 years, without a male heir, although he had had 6 daughters by his principal wife. Perhaps because of religious reform, figurative art abandoned the classic style that had been almost immutable over the centuries and had imposed an idealized representation of the pharaoh, always vigorous and physically fit, with regular facial features showing an attitude of seraphic superiority. Surviving images from the time of Akhenaten are very different and have a realism never before seen in Ancient Egypt.

Statues of Akhenaten show a long face, with thin and hollow cheeks, a half-open mouth, and lowered eyelids. Others had commented that the extremely long and thin neck reminded them of 'a swan's neck. Several reliefs demonstrate distal hypotrophy of the lower limbs with features of an upside-down bottle, or, as defined by Aldred , of knickerbockers. Tramonte and Burns reviewed early descriptions of myotonic dystrophy. Abeliovich, D. Negative expansion of the myotonic dystrophy unstable sequence.

Acton, R. Akiguchi, I. Brain proton magnetic resonance spectroscopy and brain atrophy in myotonic dystrophy. Aldred, C. Akhenaten, King of Egypt. Amack, J. The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Cis and trans effects of the myotonic dystrophy DM mutation in a cell culture model. Note: Erratum: Hum. Antonini, G. Natural history of cardiac involvement in myotonic dystrophy: correlation with CTG repeats. Neurology , Anvret, M. Larger expansions of the CTG repeat in muscle compared to lymphocytes from patients with myotonic dystrophy. Arsenault, M.

Clinical characteristics of myotonic dystrophy type 1 patients with small CTG expansions. Patients should be tested during treatment for elevated blood sugars. Additionally, those with family histories diabetes should have their fasting levels of blood sugar tested before starting treatment and periodically throughout treatment to detect the onset of diabetes. Any patient developing symptoms that suggest diabetes during treatment should be tested for diabetes.

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death when taking Seroquel. There are no systematically collected data to specifically address switching patients from other antipsychotics to Seroquel. While immediately quitting the previous? In all cases, the period of overlapping the meds should be minimized. Many people have experienced troublesome effects with regard to weight management after starting Seroquel. Exactly how this drug and other atypical antipsychotics like it effect weight is unknown. Through most of these beliefs are based on anecdotal evidence if you know any studies, let us know in the comments below. This is because Seroquel likely affects the Hypothalamus gland which is the control center for hunger in the body.

What it does is mainly negate our satiety center meaning no matter how much you eat, you still feel hungry because that mechanism is not working normally as it should. Many people discover their triglyceride levels go through the roof and can develop a decent amount of extra weight.? Adverse effects on your metabolism are a very real concern. And that sucks. Basically, it comes down to having to take another medication to counteract the vicious consequences of Seroquel. With the two most popular being Orlistat Xenical and sibutramine Meridia. There are also drugs such as Phentermine, better known as Adipex P, which is a stimulant drug amphetamine that will cause appetite suppression and weight loss. Problem is it can be addicting and most doctors will not put people on these upper style weight meds unless all else fails.

It is usually a last resort type of thing. Diet and exercise, of course, are the best, but with Seroquel for many people, this does not seem to matter. In some instances, weight gain can happen after stopping Seroquel. But in most cases, you will slowly begin to lose any weight that you gained. Basically, everyone either gains or stays the same weight. Occasionally people will experience weight loss while they are on Seroquel but it is likely due to interactions with other drugs or other events going on in their life that are affecting their brain chemistry.

Many people have noticed a relationship between Seroquel potentially causing or? A large number of individuals who started the meds had a very thin athletic body before going on it, with very good health, low cholesterol, and blood pressure. After a short while on the medication, pre-diabetes sets in. Later, full of diabetes. This happens far too often. The answer is, truly, nobody knows for sure how this is happening. But there are a few theories.

Research is suggesting that Seroquel affects the functioning of the pancreas , which is responsible for insulin regulation. Insulin disruptions can lead to many things, including food cravings, diabetes, and weight gain. One thing is for sure, Seroquel often makes people want to eat more , which causes weight gain, and overweight people are more likely to have diabetes. Especially troubling is that the type of foods one craves on Seroquel tend to be sugary high carb snacks. Patients who have schizophrenia have higher rates of diabetes regardless of their course of treatment in general, so it may be that the disease, not the drug, is correlated wi e diabetes. However, Seroquel patients who are not schizophrenic have also been found in some studies to have increased risk.

Moreover, some studies have shown increased risk even when weight or weight gain are controlled for. And as well, the direct evidence that eating too much or eating too much sugar causes diabetes is suspect. Seroquel has some effect on blood sugar levels directly. Patients who take the drug tend to have higher blood sugar levels generally. It sends in the immune system to kill off some cells, and your pancreas can no longer produce as much insulin as before, making the insulin crises more manageable. This is called medication-induced diabetes. It is not the same reason other Type II diabetes develops. This medication, along with various others, causes a change in blood sugar.

In order to stay healthy and not get the damage from diabetes one must be treated. Often when the medication ends, diabetes will also. However, if you have a predisposition for diabetes, it runs in family or you are prone to obesity, then the medication may increase the blood sugar levels. A study of U. Additional studies have confirmed that patients receiving atypical antipsychotics i. While there are no adequate studies of quetiapine in pregnant women only animal studies have been done , quetiapine should be used in pregnancy only if the physician feels that it is necessary and that the potential benefits justify the unknown risks.

The periods that have the most potential for the drug to cause harm to the fetus are the first and last trimester. But there is inherent risk throughout the whole pregnancy. For nursing mothers: quetiapine is excreted in the milk of animals during lactation. Breastfeeding is important though for a babies health, so strongly consider coming off the drug to provide your child with healthy breast milk over potentially destructive formulas. This might be so, but we need to consider long-term effects.?

Seroquel effects the neurochemistry of the mother profoundly, and this altering of brain chemicals is no doubt also affecting the brain of the child from conception through infancy. We have absolutely no idea how profound the impacts could be over a whole lifetime for the child. Please fix the typos or atleast start proofreading when done. I see all these typos and wounder if I should believe any of it. Maybe you are experiencing the side efect of irritability as I think Iam as well.

Getting all upset about typo errors is really not a big deal and calling her a dumb bitch clearly indicates your unprofessional manner…did this start as a side effect or have you always been a jerk…you owe her an apology and talk to your Dr my aggetation is more physical not knowing if Iam hot or cold…Iam a very patient woman usually but have found myself swearing at video games and am finding it difficult to figure out why certain clothes make me irritable I dont like being this way but refuse to only live on 4 hours of sleep….

I have spent decades of going to work at night and coming home and just sleeping, doing nothing else and not going outside during the day. I have tried all the meds and seen shrinks been hypnotised and nothing worked. After a week on Seroquel my life has completely changed, i am a new person and am living a full and happy life. I have been diagnosed with bi polar and major depression, i take mg before i go to sleep and have a great sleep. I I owe my life to this drug, for me it is amazing. Do you still feel the same way you did about seroquel?

Are you still taking it? I have taken Seroquel for 10 years. It was perfect at first for sleep, then I had to keep upping the dose. I weaned off over a years time. And I? I get maybe 3 hours of sleep, mostly broken. During the night while trying to sleep, I have attacks of panic and thinking I? It has damaged my brain. I had an MRI and I now have spots on my brain that weren? I have MS symptoms, but they say I don? I doubt I? Please do not take this for sleep only and expect to just stop, you are forever altered.

I only used it because I had horrible sleep and now it? Serequel is the Devils drug. I took it for 15 years,the last 5 really wanting off but it was impossible to sleep without it. I sleep about 3 hours on a good night. I also had a TBI about 15 years ago so maybe this is contributing to my Insomnia however the human body grows dependent on the drug to sleep. My guess is do just about anything,even Benzos are effective and much easier to come off of,in my opinion. The addiction to sleep is stronger than any opiate. Try marijuana,eat it if you cant smoke. No sleep can turn into so much. Good luck. You will be able to sleep and obsessive thoughts abate quite a lot.

In my experience, this has been around mgs at night. If you regularly take this medication, you WILL gain weight. Hope everyone is doing ok! Richard So far the damage by Seroquel is Pre-Diabetes. I had no choice in taking it for war trauma insomnia. I made a big mistake in not checking the side effects in functional medicine. One is a known whistleblower, Mike Adams of Natural News! I am now going through withdrawals, down from mg to 50mg. Will share more later on that journey!

I started taking seroquel more than 10 years ago as a sleep aid. I was told it worked like an anti-depressent and was non addictive. It worked great at first but the dosage had to be increased because like most things it became less effective over time. I went from mg to mg then mg. What a mistake!!! The first thing that happened was I stopped menstruating which is not that big of a deal except the reason was an increase of prolactin which has now given me osteoporosis. I gained weight…at least 50lbs over a 7 year period. I began exercising daily almost three years ago and have only been able to drop 20 lbs.

Anotherwards I eat healthy. I decided to start decreasing the dosage when last spring I became tachycardic high heart rate. I saw a cardiologist in October who said I developed atrial fibrillation and in December I was hospitalized where they performed a procedure to shock my heart. I was told to stop taking Seroquel. I forgot to write the whole reason I came on this site!! Three months since I lowered my dose from to 75mg and I feel like I am losing my mind.

I am either angry or crying and the rest of the time I feel numb. I started this to help me sleep and today my Dr gave me an antidepressant to counteract the side effects from coming off this drug! Has anybody else had such severe withdrawal symptoms? The rest of my comment is above. I have taken serequel for 4 yrs and I felt great but blood sugar went up a little. Hopefully I can get back. I totally agree with Donna, I saw no errors because I was focused on my issue at hand as well. I take mg in the am and mg at pm. This drug helps me, better than any other out there. A little dose of irony never hurt anyone, huh?

Anyhows next time you decide to criticize a persons typos at least try to spell things correctly yourself. Also, to judge an individuals whole credibility on a few typos is pretty retarded indeed. Who gives a shit of the typos or misspelling I clicked on this website to help me learn about the drug I was put on not to see a bunch of rude people insult each other. Never checked my heart or blood preasure once during my time on sequel. But put a paper in front of me to sign giving gaurdianship of my son if i became uncapable of raising him. I had depression only. I completly agree!!! But ur comment was very funny though.

Thanks for laugh! Really informational. Everyone makes mistakes. There mom made one with them. Thanks you! Thank you Jono. You said what I was thinking oh, so very well. Not to read rude and totally immature comments.. Dumb people calling others? So much perplexing irony. Instead it? I am trying to get off this horrible medication the longer you take it the more side affects you get. I now have nightmares every night along with stacks of other wicked side affects. You tell him sweetie! And I agree with it being a side effect irritability. I have good days and bad days good out ways bad. Oh and by the way when I get irritable I remove myself from the situation and try to lay down and relax. Why does everyone have 2 be so mean?? People please! Why all the anger?

Listen to yourselves I think we all need to try to respect each other and realize we are all on this site because NONE OF US are perfect and we are looking for answers! John what a sick sad person you must be…to spout such a vile comment…. Greatly appreciate your time. What is the big deal about typos as long as you understand the meaning of what the person is saying. Some people just have to pick on other people, because that is the only thing that will make them happy. I thought the article was very informative, and well put together. Has anyone had success taking it just for insomnia without complications? I appreciate any feedback. The prescribed amount is 50 mg. I have, at 25 mg, at it worked fine with no side effects. BUT I can tell you that in my experience the low dosage 25 mg is fine and works wonders for sleeping.

It would knock me out almost 12 hours. My migraine doctor prescribed it so that I would sleep through migraines while my other meds kicked in. Heather, I started Seroquel 16 days ago 25 mg and am concerned about the side-effects. I am greatly concerned and frightened after reading many articles about it. He prescribed this medication for me to help the insomnia. Of course, every situation is different but the lawsuits freak me out. The Pharma company never admitted to wrongdoing…. July I took MG seroquel. Within 10 min I was out. Was in coma for 4 days. When I woke up I had a tube down my throat, tubing was every where, and I was restrained to my bed.

Later I was told I should consider myself lucky to be alive. My O2 saturation level was My intention was to end my life. My mental illness is schizophrenic affective disorder, I was also in active addiction. So this is my reply to this page, and I will end saying this, there is nobody nor nothing worth taking your own life. When I o. I had attempted suicide several occasions before this. Prescription drugs can and will take your life!!!! I went into this site to find out how much of this medication i would have to take to end my life i have bipolar had many different meds over the last 45yrs including ECT on several in ward stays. If been sectioned in many occasions and take mg a day i get to this point as I can see nothing better or ahead.

Please do not end your life, Susan. He Loves you, Susan; you truly do matter to Him, to me, and to so many others. Please do not listen to lies!!! Dear Jesus, Please show Susan that her life is worth living. Please show her Yourself and save her from the hopelessness she feels. Hi annalee, your right. Nice prayer. God bless all those in this state of mind. Please Lord Jesus be Our Guiding light. My last episode only lasted a few days but was so intense that I took safe medications to keep me sleeping until I felt better. After trying many treatments, I eventually got better but I was moderately depressed for 2 years after a very serious bout of several depression following a manic episode.

I take Lamictal, Seroquel, and paxil. Every single night, about 1 hour after taking Seroquel I go from not hungry at all to starving. Try to keep alive even if you have to sleep a lot or go to the hospital to get through it. On average I killed roughly 17 people a year the guilt was horrendous but after taking these meds I can kill 17 a month and my conscience is clear. Thanks magic drug. You all have mental health issues. So the arguments may just be side effects. Realize that. Fucking idiots. Seroquel is a serious drug overall.

Ask your doc for other options. Good idea for anyone to consider. I have been on it for two years. Best of luck! If I had known at the beginning how serious this drug is I would have considered other options. I think this post was very helpful. I will be much more cautious before I take any medication. I have been out of seroquel for 10 days and feel like crap. I went to my doctor today and he just says if you had diabetes you would take your insulin. It was Prescribed to me for insomnia. I wish I had never started to take it! Can I ask I am on mg daily I have read the side effects but learning more about this medication is also good but I have a question why do your breasts swell.

Right around the age of Sex drive is completely gone i feel like im just going thru the motions. I used to enjoy relating and joking with friends, now i just keep to myself. All of a sudden i had a hard time retaining information, like everything became dull like background noise. I know 60 year olds shaper than i am. I had that problem too and have felt better tapering off of it.

Thanks for sharing. I felt so guilty since I thought exercise would help but I feel too blah to do it. Not terribly sad anymore but still not interested in things I used to do and I get the brain fog you mentioned. Saved my life and never had a problem other than weight gain. I say that unfortunately. I have store glee with mental health issues for over have of my life… I started on lexapro at 19 and then was fully diagnosed at 21 and now in on 6 , yes 6 different medications. I have to agree with that comment. War with my mind. So I appreciate the sobering facts of the article. It really makes me feel not alone… Even though whoever commented or read this page maybe different from me, at least I know that other people are fighting their batles too.

It gives me hope in fighting mine. I just wanted to say think you. I also wanted to say maybe someday there will be a better way. First sentence correction. Sorry guys. I dont sleep well and have major depression my provider added this to my nighttime meds which is ambien hope it helps. Any comments welcome. Ash I hope you are doing better! You are not alone,my 2 sisters and I suffer mental illnesses, it runs in my family, 5 members committed suicide, with medicine we are trying to live better and to open doors for our kids so they find a way to deal with our lives instead of killing ourselves. Keep up honey,while there is life there is HOPE! Ash, no offense but after dealing with several SO with those issues, my advise is to instead of looking for meds to treat the symptoms, go to a therapist and address the issues that are causing them.

Obviously you have had a tragic, traumatic event s in your life and you need to learn to let go of that them and take control of your life and realize that life is what YOU make it. We all have to deal with that on a daily basis. You need to empower yourself with armor, like everyone else and confront the bad positive energy captures and subdues negative. We all have freedom of choice to choose which of those we walk in. We all walk in one or the other light altho most are walking right on the line, in both lights. Btw, the Red light is negative energy and the Blue is Positive energy.

I beg to differ. We can actually change our own brain and body functions and chemistries by our own shear will, in a good or bad way. YES Ash, you can actually heal yourself. You have that power. Imo, no one has shown you that. This drug is no joke. Sorry to say, alprazolam has very serious effects too, if taken in high doses. I never knew this drug was such a high risk. Seroquel increases these effects. But at least, for me, tapering alprazolam is not making me too uncomfortable.

But some patients are in pure hell for a year or more, even if they do taper off very slowly. Thank you, I found your article interesting. I used Quetiapine during second and third trimester of pregnancy. My eight year old son displays ridiculous behaviour after eating sugars, luckily I have the will to help him manage this and he is indeed a happy, healthy child.

There is history of mental illness in my family and I would imagine medication was used in the past. My Grandad died whilst having ECT in a psychiatric hospital. I hope I see the day when psychiatry is given the research opportunities it more than deserves and the mystery behind it, is unveiled. In the mean time I am the best person in the world to look after my son and I will do everything I possible can to help him to have a happy and healthy life. I believe in human adaptation and believe that his brain accepted Quetiapine and has adapted to function appropriately within the real world. Seriously effects thyroid function. In rare causes actually causes insomnia and auditory hallucinations.

Suicidal ideation is another possible side effect, especially at the beginning. This drug is not for everyone. When starting and during increases, doctors should monitor patients closely. In FOUR months I gained 15 pounds, became severely depressed suicidal thoughts and all and felt like I walking around like an emotionless zombie. After shooting me up with ketamine and severely overdrugging me for 2 weeks at a psych ward my doctors decided to convince herself that I had schizo affective disorder and put me on this shit drug. After 7 months being pumped full of random antipsychotics, benzos, antidepressants. Ketamine, ativan, zyprexa, cogentin, risperdol, seroquel, invega, zoloft, benadryl I have gained 50 pounds, probably have diabetes, probably have heart damage, brain damage, nerve damage and every other ailment under the sun because of my imaginary mental disorder.

So why were you in the psych ward in the first place? Try this one. My boy was grieving over an online friend he had and both kids could talk about anything with each other. Turned into a very good friendship. Unfortunately his friend was a victim in the parkland Florida school shooting and did not survive. My son was already in counseling for being a victim of molestation and asked his counselor for help with the grief. He is weaning himself off the drug. Does anyone know if this tremor could be permanent?

And one last thing. And I was also in the room with my son while he was talking to his counselor. So I know what he said. This counselor just finished her internships, and the ink was barely dry on her license to practice. Absolutely gross negligence on her part. And if I had known she had absolutely no experience I would have brought him to a different counselor. His first counselor moved out of state and she was his replacement. Seriously ill…on an off of seroquel.

Only been on it for about 2months off an on …. While on it an serious upper right stomach pain an head pain an back pain an groin pain a very badly sick off of this …an this is not the only drug that has severe side effects. I have severe sensitivites to most all drugs.. I stepped up to 50mg briefly but was so wiped out in the morning I had to drop back down. No way would I risk having this drug in my system whilst a fetus was developing. How the HELL would you know. Imo what you did was potentially dangerous and completely irresponsible. My son was born with a tight muscle in his neck and had to have physical therapy for the first 2 years of his life.

I do blame the doctor for not telling me. He had me on mg twice daily and after I had my son he raised it to mg three times a day. I quite it 3 months later and stayed off it for 3 years and I went back to see my Dr and he put me back on mg twice a day last week. You made your choice and fortunately there were no problems as this may not hold true for every case and others should be free to do the same without criticism. I am the spouse of a long term user of Seroquel. My wife had been diagnosed with Arthritis and Fybro. After the first pain management doctor overdosed her into renal failure we became extremely watchful of medications. She was prescribed Seroquel XR 50 at first then after 2 months it was increased to As anyone who has dealt with long term Fybro will know there are good days and bad ones.

Last week she developed Tardive Dyskinesia. They tell us it is a known long term very common side effect with most psychopathic medications. Have been informed that TD may last for a life time. He side effects manifested in less than 2 weeks. Primary physician the prescriber told us to seek a Neuro doctor. They take 30 days to set up 1st visit. Primary did not tell us to stop meds. Now we have possibly a life time to wonder… What if we never took Seroquel? I was on Seroquel for about a year for anxiety and insomnia. Went off it about two months ago. Had the itching, some nausea, vivid dreams and exhaustion after sleeping ten hours.

Most of the withdrawal symptoms have gone except for the exhaustion. My daily dose was mg. Can anyone relate? Yes, I related to your story. I just use it as sleeping aid. Recently I did blood work and I was told that I am pre diabetes. That news really concerned me because I am very active and eat healthy. I decided to do some search about this medication. I am scared. No matter what it takes, I am stopping this medication. I hope this help to anyone who is using this medication for sleeping aid. But — Seroquel is a rather potent Serotonin blocker — beginning at doses around mg. Taking seroquil takes some dedication and is completely relevant.

Mania is so god damn shitty especially if your mania is a side affect of you being awake. So go ahead take the seroquil. Give up you fucking pussy. I am glad I found this drug through an excellent doctor. I suffered from mania, insomnia with no feeling of being tired for days, which is very dangerous, and spontaneous and uncontrollable anger. I know I could not have lived with my sickness. Quietiapine works for me. I take 75 mg and have for over a year now. Did u never learn that if u dont have anything nice or positive to say, say nothing at all? I have been taking 25 milligram seroquel at night for 2 weeks now for bipolar hypomania.

It has greatly reduced my hypomania and I feel great and like my normal self again. I am on the lowest dose because my body is very sensitive to any medication action and side effects. I am worried about the weight gain and have been exercising regularly and eating healthy so hopefully that will not happen or I will have to try something else. I have been sleeping great which I think was a big problem before as I have restless leg syndrome also. Hearing these stories from others scares me but I am going to stay positive. All antipsychotics have bad effects on some people, just depends on the person.

Good luck everybody. I stopped all meds for 4 years, after waking up 2 weeks later to a pill induced coma suicide attempt. If you have high blood pressure or cholesterol you manage it with meds. The same goes for metal disorders, you NEED your medication. After a short while, they realise how incredibly aware I am and how in tune with my body I am, therefore they start taking me a little more seriously. Aside from posts like this, I find articles written outside the US far more accurate and candid.

The doctors here are not trained to seek the truth, to observe patients objectively , or listen to the patient when they say bizarre things are happening to them. I started taking seroquel 25mg not even a week ago for my anger problems. I am bipolar and nothing ever calms my anger or anxiety. I have Xanax and Ambien but I cannot take either every week or I get very sad, depressed, and violent, so nobody knows how to treat my sleep issues and anxiety problems.

I wonder if I will ever be able to feel like a normal person…whatever that means. I digress. Not good. For example, right before I started Seroquel, I got under for the first time in 3 years but my cholesterol is still a whopping Thanks so much for this info and also to all of you who have forewarned against ever beginning Seroquel. Good luck fellow nut jobs. We are the most misunderstood population on the planet. What is wrong with you man? Why are you even on this site?

You have absolutely no empathy or compassion and more importantly not a shred of advice. You are so pathetically abusive. Get over yourself. I think you are looking at things in the wrong way. Instead of Quetiapine, have you tried relaxation methods or even herbal teas. The problem with weight gain is all in the head, the drug slows thinking and you have no full switch, plus you crave sugar. Its easy to stay healthy, only buy healthy stuff!!! There are no scientific studies -anywhere- to substantiate your claim that Seroquel and Dextromethorphan DXM are dangerous in combination.

Thank you for adding this comment. I decided to double check the combinations safety tonight I always check before taking two diff drugs. Finally, I landed on a news article linked below. The article made no mention of any negative interactions and explicitly said volunteers took varying doses of Seroquel, all of whom were frequent cocaine abusers the studies also documented how much coke each individual used per week and money spent on it CLEARLY, seroquel and coke are safe when used together.

How can you even make a statement like that. Mixing drugs is always dangerous. Good Luck. I have just found this article and while it has been very useful I do feel that some people are mixing too much emotion in their replies. I am 35 I have a history of Bi-polar and ADHA behavior and have spent a lot of my life on and off perscription drugs, special diets and behavior therapy. My personal side effects have been similar to other peoples, drowsiness, weight gain, larthargic attitude and the worst is the constipation and hemorrhoids caused by it, but there have been so very positive effects as well.

I am able to communicate a lot better with people and I am now able to breath and think before my emotions get the better of me and I have been able to be more productive in my personal development, call it an active action plan if you will. BUT what I have discovered is sometimes this is just a mask for being tardy and once I have taken the initial step to get off my arse I enjoy the activities like I always have.

I have found that alcohol is not the best thing for me but I do like to have a spliff and a cup of tea to relax again I have taught myself not to abuse that drug as well, but again this is my personal preference and might not work for everyone. Depression is a tide that some people will always have to fight but I have met a lot of people who use it as an excuse for being lazy and non productive, my only piece of advice is to not let depression be your life but a part of it that you are proud to be a warrior against.

This was intresting. When I stop I cold turkey it and never withdrawl. Been on 25mg seroq for 5months now. Got a job but lost it in this time period.. Seroq helps me sleep but does not help me wake up.. I need 12hours of sleep before I stand up and show up for work and still am tired and need to take a nap a few hours later. I have not gained weight but i have less balance as my reflexes are slower and my eyesight is foggy. I have no power for excersize and if i do i get very tired and exchausted after a short time. I sometimes feel the hemorige and i usually have constipation. But I havent had the bursting rage mood tantrums as i used to have in the time ive been on seroquel but I feel scared of being on seroquel..

All those side affects are making me more like a slow motion zombie and i feel life is not as frisky and fun. I feel down and let down by seroquel so i think im going off the medication. Im scared of the long term side effects and reading all those stories just makes me terrified. The thought of seroquel having effect on my body for the rest of my life even after stopping using it is horrible. I found the article very interesting and knowledgeable I certainly did not focus on typos! My son has bi-polar disorder and is taking mg 2x daily.

Unfortunately it is not agreeing with him at all and he is begging to get off this medication! His doctor insists he take it, and told him to just try and deal with the side effects….. He is angry, irritable, nasty, yelling all the time. Needless to say living with him is a nightmare. My son is bi-polar on Lithium mg twice a day and has been experiencing insomnia and agitation. Was taking risperidone 1 mg but experienced too many side effects weight gain, etc. This drug sounds very scary. I am diagnosed bipolar and squitzoed effective dosorder. I took this medication at mg at night and woke up feeling extremely hung over and had slurred speech. I discontinued the drug after a year without consulting my psychiatris.

Fortunately there were no detox issues. I would not reccomend taking this drug for the sole purpose of treating insomnia. I have a brain tumor. Even though this tumor is causing horrible and increasing pain, my pain management doctors have cut back my dosage of pain meds, almost every month since January , because? Because the pain is so extreme and now, uncontrolled, I have trouble falling asleep and staying asleep. My GP just prescribed Seroquel. After reading these posts, I am really scared to take it!

I have no psychosis, I am just in pain. I really need some advice! Dr increased Seroquel from 75MG reg release To mg. Then, increases again to mg. So, my body reacts strongly I auger walk into walls feet itch legs and feet release and contract I can,t sit still,heart races blood pressure rises. I tell him of my reaction and he wants to prescribe a higher dose. I feel this drug will kill me, and am going to taper Any one else have these reactions? Hi, Thank you discoveryrehab. I was diagnosed with schizoprenia yes a typo at 28 years of age in after a? I have been on many drugs since, have had 2 relapses and many years are a blurrrrr.

In time, I finally accepted my psychosis and realised much of it was self-induced, and set about changing my mind and thinking. I accepted my doctors recommendation to go on Seroquel I think this was about 12 years ago. At first I was paranoid about what I was taking: Seroquel or quetiapine same thing , and being a pawn in another multi-national drug scam. In fact, my sleep improved and Seroquel has helped make me a more stable person. In time, I began to address the psychological aspects of my character. I went to university and studied.

I read a lot. One of the most helpful books I found was? I was and still am obsessive about some things, but I am more in control. I now take more time and care to deal with my emotional stress, so as to avoid thinking errors. Over time I have reduced my dosage of Seroquel to the minimum 25 Mg and now my aim is to be drug free and free of the mental care heath system.

I believe this is a realistic goal but only if I can deal with my sleeplessness. My experience with psychiatrists is they are unlikely to recommend me going off the drug, but may suggest another one. With my doctor? The withdrawal, which is characterised by tension, volatility and distraction, is manifested by sleeplessness, which is part of the vicious circle of my condition. I remain hopeful someone will have tried another medication herbal or otherwise to successfully get off Seroquel and to eventually have a good nights sleep, drug free.

Thanks, Tim. I was diagnosed with bi-polar II at age

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