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BACKGROUND AND PURPOSE: Doxorubicin causes a chronic cardiomyopathy in which reactive oxygen species (ROS) accumulate over time and are associated with genetic and functional lesions of mitochondria. Dexrazoxane is a cardioprotective iron chelator that interferes with ROS production. We aim to analyze the effects of dexrazoxane on mitochondria in the prevention of doxorubicin-induced chronic myocardial lesions. EXPERIMENTAL APPROACH: Wistar rats (11 weeks of age) were injected with intravenous doxorubicin (0.8 mg kg(-1) weekly for 7 weeks) with or without simultaneous dexrazoxane (8 mg kg(-1)). Animals were killed at 48 weeks. Cardiomyopathy was scored clinically and histologically and cardiac mitochondria were analyzed. KEY RESULTS: Compared to control rats receiving saline, rats treated with doxorubicin alone developed a clinical, macroscopic, histological and ultrastructural cardiomyopathy with low cytochrome c-oxidase (COX) activity (26% of controls). The expression of the mtDNA-encoded COX II subunit was reduced (64% of controls). Myocardia exhibited a high production of ROS (malondialdehyde 338% and superoxide 787% of controls). Mitochondria were depleted of mitochondrial DNA (mtDNA copy number 46% of controls) and contained elevated levels of mtDNA deletions. Dexrazoxane co-administration prevented all these effects of doxorubicin on mitochondria, except that hearts co-exposed to doxorubicin and dexrazoxane had a slightly lower mtDNA content (81% of controls) and mtDNA deletions at low frequency. CONCLUSIONS AND IMPLICATIONS: Dexrazoxane prevented doxorubicin induced late-onset cardiomyopathy and also protected the cardiac mitochondria from acquired ultrastructural, genetic and functional damage.

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We report a novel type of congenital myopathy, which is characterized by an early arrest of muscle formation prior to formation of myotubes. A female infant born prematurely at 32 weeks of gestational age died after six weeks of continuous ventilatory support. Various muscle specimens including quadriceps, deltoid, pectoral, neck, psoas, tongue, and diaphragm musculature were studied. Light and electron microscopy revealed well-demarcated fascicular structures interspersed with undifferentiated, mononuclear myogenic cells. Multinucleated myotubes and muscle fibres were not detectable, pointing towards a defect prior to the generation of myotubes during myogenesis. Immunohistochemistry identified the absence of dystrophin, N-CAM, MyoD and myogenin expression in these myogenic cells, compatible with a block of the complex transcriptional network necessary for correct embryonic muscle formation at an early stage of muscle development. These myopathological findings were absent in cardiac muscle, indicating that the defect exclusively affects skeletal muscle formation.

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We describe 6 unrelated patients affected by infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) with prolonged survival upon mechanical ventilation (4.5-11 years), which has not been reported before. Biallelic mutations in the IGHMBP2 gene proved the diagnosis of SMARD1 in all patients. Disease onset was in the first 2 months in the described patients, starting with generalised hypotonia, failure to thrive, and early breathing difficulties. Diaphragmatic palsy was diagnosed and permanent ventilation was initiated 2-8 months after onset. Within months a more distal muscular atrophy became evident associated with joint contractures (talipes), hand drops, and fatty finger pads. Motor development remained minimal, loss of function was observed within the first year after which no further progression was recorded. Voiding dysfunction with reflux nephropathy was observed in 3 patients and has not been reported before. Further evidence of autonomic nerve dysfunction resulting in cardiac arrhythmia, hypertension, and excessive sweating was given in 2 patients. Investigative results were largely compatible with those obtained in classic SMA. However, neurogenic atrophy muscle was more pronounced in distal muscles, if examined, and there was evidence of peripheral nerve involvement at least in some patients.

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Danon disease (DD) is a rare lysosomal glycogen storage disease with normal acid maltase activity, which is characterised clinically by cardiomyopathy and myopathy, and a variable degree of mental retardation. The causative gene, LAMP2, has been mapped to chromosome Xq24-q25. LAMP2 encodes a lysosome-associated membrane glycoprotein. We identified a novel LAMP2 mutation of the exon 8 splice acceptor site (IVS7-1G --> A) in an affected male and female, which predicts abnormal splicing. Both affected individuals presented solely with hypertrophic cardiomyopathy. Muscle weakness and mental impairment were absent. Diagnosis of Danon disease was established by muscle biopsy, when the male index patient developed transient severe muscle weakness following heart transplantation. Typical biopsy findings were also found in a heart muscle specimen. Demonstration of the LAMP2 mutation in affected male and female siblings is compatible with X-linked dominant inheritance. Danon disease should be actively looked for in cardiomyopathy patients.

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A 47-year-old man suffering from a bipolar disorder and intermittent myoglobinuria presented with acute rhabdomyolysis with renal failure after starting therapy with valproic acid. On morphological examination, skeletal muscle revealed increased lipid storage. Biochemically, decreased enzyme activity of carnitine palmitoyltransferase (CPT) type II with carnitine levels in the lower limit was found. Genetic analysis detected the common Ser113Leu substitution on one allele of the CPT2 gene. We conclude that valproic acid should be avoided in patients with CPT type II deficiency.

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Reduced mucociliary clearance in primary ciliary dyskinesia (PCD) causes recurrent infections of the upper and lower respiratory tract. The disease is usually inherited as an autosomal recessive trait. To identify a gene locus for PCD, we studied a large consanguineous family of Arabic origin. Direct examination of the respiratory cilia revealed ciliary akinesia. Electron microscopic examination of cilia showed absence of the outer dynein arms. Two of four affected individuals exhibited a situs inversus, typical for Kartagener syndrome, due to randomization of the left/right body axis. A total genome scan with 340 highly polymorphic microsatellites was performed. We localized a new gene locus for PCD to a region of homozygosity by descent on chromosome 5p15-p14 with a parametric multipoint logarithm of odds ratio (LOD) score of Zmax = 3.51 flanked by markers D5S2095 and D5S502 within an interval of 20 centimorgans sex-averaged genetic distance. Applying a polymerase chain reaction-based approach, we identified a 1.5-kb partial complementary DNA of DNAH5 encoding a Chlamydomonas-related axonemal heavy dynein chain within the critical disease interval of this new PCD locus. On the basis of the Chlamydomonas model for PCD, this gene represents an excellent candidate for PCD.

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Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.

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Our objective was to study the value of 99mtechnetium-pyrophosphate (99mTc-PYP) muscle scintigraphy and magnetic resonance imaging (MRI) in detecting areas of likely muscle inflammation and in increasing the rate of positive muscle biopsies in patients with suspected myositis. The results showed that in 13 out of 13 patients with clinical and/or signs of inflammatory muscle disease, increased 99mTc-PYP uptake was demonstrated at different muscle sites 3 h after isotope injection. Subsequent MRI of symmetric muscle areas with enhanced 99mTc-PYP uptake revealed signal patterns suggesting inflammation in all cases. Biopsy of these targeted muscles demonstrated characteristic histopathologic signs of muscle inflammation in 9 out of 13 patients. Four of these 9 patients had clinically atypical disease or did not show elevated creatine phosphokinase levels. Seven of these 9 patients had not been pretreated with corticosteroids. In 4 patients only muscle fiber atrophy and/or necrosis without cellular infiltrations was seen. These 4 patients had received either high doses of corticosteroids or low doses over longer periods of time before muscle biopsy. In conclusion, the combination of 99mTc-PYP muscle scintigraphy and MRI demonstrated muscle areas with maximum inflammatory signal patterns. Targeting of muscles by MRI only will probably yield reliable results of muscle biopsy in cases of clinically and serologically characteristic myositis. 99mTc-PYP muscle scintigraphy may provide useful initial information about localization of inflamed muscle tissue, especially in atypical disease. Treatment with corticosteroids prior to histologic diagnosis may abolish inflammatory infiltrations in affected muscle tissue.

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Centronuclear myopathy (CNM) is a congenital myopathy which manifests itself as a severe neonatal (also termed myotubular myopathy), early-onset, or adult form. The histological pattern of each is marked by a considerable number of nuclei of muscle fibers being internally placed. Owing to their remote resemblance to myotubes, and their expression of developmentally regulated proteins, most authors now favor the concept that myogenesis is arrested or delayed in this disease. We here present two muscle biopsy specimens of a patient with early-onset CNM, taken at the age of 5 months and 14 years, respectively. The first biopsy sample contained internally placed nuclei in 7% of the muscle fibers, abundant minute myotubes, and hypertrophic muscle fibers. The second biopsy sample showed internally placed nuclei in 40% of the muscle fibers, and hypotrophic fibers. We suggest that the histological findings in early-onset CNM are the result of a complex dynamic process, which includes a delay in maturation.

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Three newborn siblings presented with generalized weakness, asphyxia, facial diplegia, and external ophthalmoplegia. Electrophysiological testing showed inexcitability of motor and sensory nerves and myographic signs of denervation. Nerve biopsies and postmortem examination showed loss of myelinated fibers and axonal damage in sensory and mixed nerves. Many spinal motor neurons were chromatolytic although their number was normal. Molecular genetic investigations revealed a homozygous deletion of the survival motor neuron (SMN) gene and a loss of markers Ag1-CA and C212 in the paternal haplotype. These findings are consistent with the diagnosis of an unusually severe type of spinal muscular atrophy. Given the large extent of the deletion, it must be considered that the unusual severe phenotype with involvement of brainstem nuclei and afferent nerves might also be due to changes of yet unknown genes neighboring the SMN gene.

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Becker muscular dystrophy (BMD) was diagnosed in a male patient with Klinefelter's syndrome (47, XXY karyotype). The BMD was confirmed by (i) immunohistological methods and Western blotting, showing decreased quantity of dystrophin in muscle biopsy specimen and (ii) molecular genetic analysis which demonstrated a homozygous deletion of exons 45-47 within the dystrophin gene on both X-chromosomes. The same deletion was found on one of the X-chromosomes in the patient's mother. It can be deduced therefore that Klinefelter's syndrome in this patient is most likely due to a non-disjunctional error which occurred either during the second maternal meiotic division or during early postzygotic mitotic divisions.

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Mitochondrial DNA (mtDNA) deletions have been found in the majority of patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. A large number of different mtDNA deletions have been identified. They generally spare the two origins of replication and are frequently flanked by direct or indirect repeats. We have found a 3.1-kb deletion of mtDNA in a patient with Kearns-Sayre syndrome that has some unusual features. First, it encompasses nucleotides 11259 to 14368, a localization that was not described before. Second, the deletion is not flanked by direct or indirect repeats, supporting the view that homologous recombination and slip-replication do not account for all mtDNA deletions.

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A family with myoclonus epilepsy has been described previously as suffering from an X-linked disorder, because at least four males were affected, and only mild and variable symptoms were seen in some female carriers. In this family, we have now identified a mitochondrial A-->G (8344) heteroplasmic point mutation. This point mutation has been described in families with maternally inherited myoclonus epilepsy and ragged red fibers. The degree of severity of the disorder in the different family members was reflected in the relative quantity of mutated mitochondrial DNA. It is concluded that the mode of inheritance in this family is not X-linked but maternal.

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The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness, and primary asphyxia, has recently been mapped to Xq28. This report presents the first four prenatal diagnoses of XLR-CNM using DNA markers of the Xq28 region. The analyses of one female and three male fetuses revealed maternal transmission of the XLR-CNM-associated alleles in all four cases. Two of the male fetuses have been aborted, and the pregnancies of the third male and the female fetuses have been continued. The diagnosis of XLR-CNM at the birth of the third boy, as well as the pathologic findings in the muscle of one of the aborted fetuses, confirmed the linkage results of the prenatal analyses. Our findings prove the DNA markers St14, cpX67, DX13, and pSt35-691 to be useful in prenatal diagnosis of XLR-CNM and present the possibility to confirm the diagnosis by histologic examination of the first-trimester abortus. This permits an indirect prenatal diagnosis of XLR-CNM in chorionic villus biopsies at 9 to 12 wk gestation, using DNA-based linkage analyses allowing early termination of an affected pregnancy.

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30-day-old polymyopathic hamsters (strain BIO 82.62) were orally treated with either magnesium pyridoxal 5-phosphate glutamate 100 mg/kg, equimolar amounts of magnesium alone (MgCl2 55 mg/kg), or water b.i.d. for 30 days, or sacrificed before treatment. 60-day-old healthy hamsters (strain CLAC) served as controls. Magnesium pyridoxal 5-phosphate glutamate lowered the myocardial calcium content (42.8 +/- 13.1 mmol/kg dry weight) as compared to MgCl2 (70.3 +/- 11.9 mmol/kg dry weight) and water (72.7 +/- 13.6 mmol/kg dry weight). The serum and tissue lipid pattern did not differ between BIO 82.62 and normal hamsters except high serum cholesterol and triglyceride levels in 30-day-old BIO 82.62 hamsters. Myocardial necroses were influenced by neither magnesium pyridoxal 5-phosphate glutamate nor MgCl2. Cytochemical investigation of the ultrastructural calcium localization in the aorta revealed less calcium precipitates with magenesium pyridoxal 5-phosphate glutamate in media myocytes. It is concluded that magnesium pyridoxal 5-phosphate glutamate exerts a calcium antagonistic effect in the cardiomyopathy of the Syrian hamster which is related neither to the magnesium content of magnesium pyridoxal 5-phosphate glutamate nor to its lipid lowering activity.

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A female infant was seen at the age of 2 months because of hypotonia, delayed motor development, and lactic acidosis, and she died at age 13 months due to respiratory failure. In a muscle specimen taken at 11 months and in a liver specimen obtained 1.5 hours postmortem, we found decreased activities of cytochrome c oxidase and long-chain acyl coenzyme A dehydrogenase. Neuropathological changes were typical for Leigh's subacute necrotizing encephalomyelopathy. To our knowledge, this is the first report of a combined defect of complex IV of the respiratory chain and of the long-chain specific acyl coenzyme A dehydrogenase of beta-oxidation in muscle and liver.

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Kearns-Sayre syndrome has been associated with large heteroplasmic mitochondrial DNA deletions and morphological alterations at the cytological level. We have measured the activities of different respiratory chain complexes in 3 patients presenting mitochondrial DNA deletions and found no close correlation between gene deletions and enzymatic activities. These data, therefore, point out the importance of analyses at the mitochondrial DNA level in such mitochondrial disorders because gross biochemistry may miss any defect.

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