183 research outputs found
DMD Phenotype in Girls with a de novo Balanced X;3 Autosome Translocation: A Case Report
No full textLeishmania DNA quantification by real-time PCR in naturally infected dogs treated with miltefosine
No full textA new drug that has just become available in India for treatment of human visceral leishmaniasis (VL) is miltefosine, an alkyphospholipid that was originally developed as an oral antineoplastic agent. Miltefosine is not only directly toxic for Leishmania parasite, but it also enhances both T cell and macrophage activation and production of microbicidal reactive nitrogen and oxygen intermediates. It is highly effective in the treatment of Leishmania infection in mice and human beings. However, adverse effects in dogs treated with miltefosine have been reported, but there are no data on the efficacy of this drug for the treatment of canine visceral leishmaniasis (CVL). The aim of this study was to use a real-time PCR assay to monitor the Leishmania load in the blood samples and lymph node aspirates of 18 naturally infected dogs before and after treatment with miltefosine (2 mg/kg for 30 days). The results of our study showed that the therapy with miltefosine shows a drastic and progressive reduction of parasite load in lymph node aspirates, but does not suppress the parasite in lymph nodes. In all dogs the real-time PCR assay demonstrated an irregular presence of parasites in blood. Therefore, blood does not seem a suitable substrate for the purpose of quantifying Leishmania DNA
Comparison of X chromosome inactivation in Duchenne muscle/myocardium manifesting carriers, non manifesting carriers and related daughters
No full textFemale carriers of Duchenne muscular dystrophy are usually asymptomatic. However 2.5%-7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non-manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation-based assay. The results showed that DMD manifesting carriers had a preferential inactivation of the X chromosome carrying the normal allele, while non-manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/ asymptomatic mother-daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers is associated with non-random patterns of X inactivation
Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy.
No full textDuchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene that lead to absent or reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD female carriers are usually asymptomatic, although about 8 % may exhibit muscle or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have been hypothesized to explain the clinical manifestations and, in particular, the role of the skewed XCI is questioned. In this review, the mechanism of XCI and its involvement in the phenotype of BMD/DMD carriers with both a normal karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of the DMD gene) will be analyzed. We have previously observed that DMD carriers with moderate/severe muscle involvement, exhibit a moderate or extremely skewed XCI, in particular if presenting with an early onset of symptoms, while DMD carriers with mild muscle involvement present a random XCI. Moreover, we found that among 87.1 % of the carriers with X;autosome translocations involving the locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is involved in the onset of phenotype in DMD carriers, the X chromosome carrying the normal DMD gene being preferentially inactivated and leading to a moderate-severe muscle involvement
Leishmania DNA quantification by real-time PCR in naturally infected dogs treated with miltefosine
No full textA new drug that has just become available in India for treatment of human visceral leishmaniasis (VL) is miltefosine, an alkyphospholipid that was originally developed as an oral antineoplastic agent. Miltefosine is not only directly toxic for Leishmania parasite, but it also enhances both T cell and macrophage activation and production of microbicidal reactive nitrogen and oxygen intermediates. It is highly effective in the treatment of Leishmania infection in mice and human beings. However, adverse effects in dogs treated with miltefosine have been reported, but there are no data on the efficacy of this drug for the treatment of canine visceral leishmaniasis (CVL). The aim of this study was to use a real-time PCR assay to monitor the Leishmania load in the blood samples and lymph node aspirates of 18 naturally infected dogs before and after treatment with miltefosine (2 mg/kg for 30 days). The results of our study showed that the therapy with miltefosine shows a drastic and progressive reduction of parasite load in lymph node aspirates, but does not suppress the parasite in lymph nodes. In all dogs the real-time PCR assay demonstrated an irregular presence of parasites in blood. Therefore, blood does not seem a suitable substrate for the purpose of quantifying Leishmania DNA
Genetic counseling in Pompe disease.
No full textPompe disease is caused by glycogen accumulation due to a deficiency of the lysosomal acid alpha-glucosidase enzyme by which it is degraded. It is a rare disease, accounting for 1:40.000 births. It is inherited as an autosomal recessive trait so that a couple presents a recurrent risk of 25% to have a child affected, at each pregnancy. The diagnosis could be achieved by biochemical and/or molecular testing. Carrier detection and prenatal diagnosis are available when the molecular defect is know
Skewed X-chromosome inactivation plays a crucial role in the onset of symptoms in carriers of Becker muscular dystrophy.
No full textAbstract
BACKGROUND:
Becker muscular dystrophy (BMD) is an X-linked recessive disorder affecting approximately 1: 18.000 male births. Female carriers are usually asymptomatic, although 2.5-18% may present muscle or heart symptoms. In the present study, the role of the X chromosome inactivation (XCI) on the onset of symptoms in BMD carriers was analysed and compared with the pattern observed in Duchenne muscular dystrophy (DMD) carriers.
METHODS:
XCI was determined on the lymphocytes of 36 BMD carriers (both symptomatic and not symptomatic) from 11 families requiring genetic advice at the Cardiomyology and Medical Genetics of the Second University of Naples, using the AR methylation-based assay. Carriers were subdivided into two groups, according to age above or below 50 years. Seven females from the same families known as noncarriers were used as controls. A Student's t-test for nonpaired data was performed to evaluate the differences observed in the XCI values between asymptomatic and symptomatic carriers, and carriers aged above or below 50 years. A Pearson correlation test was used to evaluate the inheritance of the XCI pattern in 19 mother-daughter pairs.
RESULTS:
The results showed that symptomatic BMD carriers had a skewed XCI with a preferential inactivation of the X chromosome carrying the normal allele, whereas the asymptomatic carriers and controls showed a random XCI. No concordance concerning the XCI pattern was observed between mothers and related daughters.
CONCLUSIONS:
The data obtained in the present study suggest that the onset of symptoms in BMD carriers is related to a skewed XCI, as observed in DMD carriers. Furthermore, they showed no concordance in the XCI pattern inheritanc
A rare co-occurrence of phosphorylase kinase deficiency (GSD type IXd) and alpha-glycosidase deficiency (GSD Type II) in a 53-year-old man presenting with an atypical glycogen storage disease phenotype
No full textGlycogen Storage Disease (GSD) IXd, caused by PHKA1 gene mutations, is an X-linked rare disorder that can be asymptomatic or associated with exercise intolerance. GSD type II is an autosomal recessive disorder caused by mutations in the GAA gene that lead to severe cardiac and skeletal muscle myopathy. We report the first case of co-occurrence of type IXd and type II GSDs in a 53-year-old man with an atypical glycogen storage disease presentation consisting in myalgia in the lower limbs at both rest and after exercise and increased levels of transaminases from the age of 16. At the age of 43, the patient presented a steppage gait, inability to run and walk on his heels, hypotrophy of the pectoral and proximal muscles, reflexes not elicitable, and CK levels 3.6 times the upper reference limit. Next Generation Sequencing (NGS) identified one variant in the PHKA1 gene, c.1360A > G p.Ile454Val (exon 14) inherited by his mother, and two heterozygous variants in the GAA gene, c.784G > A (exon 4) and c.956-6T > C (exon 6). A review of GSD IXd cases reported to date in the literature is also provided
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