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Biomedical subjects

E Bonilla

Publications and source records attributed to E Bonilla.

At least 19 recordsLinked to original sources
PubMed2003

A novel autosomal dominant limb-girdle muscular dystrophy (LGMD 1F) maps to 7q32.1-32.2.

In 2001, the authors described the clinical features of a genetically distinct autosomal dominant limb-girdle muscular dystrophy (LGMD; LGMD 1F). Using a genome-wide screen with more than 400 microsatellite markers, the authors identified a novel LGMD disease locus at chromosome 7q32.1-32.2. Within this chromosomal region, filamin C, a gene encoding actin binding protein highly expressed in muscle, was an obvious candidate gene; however, the authors did not detect any defects in filamin C or its protein product.

Aged↗
PubMed2003

Reversion of mtDNA depletion in a patient with TK2 deficiency.

Mutations in the thymidine kinase 2 (TK2) gene cause a myopathic form of the mitochondrial DNA depletion syndrome (MDS). Here, the authors report the unusual clinical, biochemical, and molecular findings in a 14-year-old patient in whom pathogenic mutations were identified in the TK2 gene. This report extends the phenotypic expression of primary TK2 deficiency and suggests that factors other than TK2 may modify expression of the clinical phenotype in patients with MDS syndrome.

Adolescent↗
PubMed2002

Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.

BACKGROUND: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxy-guanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form. OBJECTIVES: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS. RESULTS: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls). CONCLUSIONS: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.

Child, Preschool↗
PubMed2001

Myopathy with tubulin-reactive crystalline inclusions.

A 61-year-old man with muscle aches and persistently elevated serum creatine kinase had aggregates of randomly oriented, rhomboidal or rectangular protein crystalline inclusions in the sarcoplasm of type II fibers. Immunochemical studies showed strong reactivity of the inclusions to tubulin antibodies, suggesting that these unique crystalline inclusions may be a consequence of altered synthesis, processing, or degradation of tubulin.

Crystallization↗
PubMed2001

Neuropathological features of mitochondrial disorders.

Genetic defects affecting the mitochondrial respiratory chain comprise an important cause of encephalomyopathies. Considering the structural complexity of the respiratory chain, its dual genetic control, and the numerous nuclear genes required for proper assembly of the enzyme complexes, the phenotypic heterogeneity is not surprising. From a neuropathological view point, application of in situ hybridization and immunohistochemistry to study the choroid plexus and brain-blood barrier in "prototypes" of mitochondrial encephalopathies have revealed alterations that we think are important in the pathogenesis of central nervous system dysfunction in these disorders. As the role of the blood-cerebrospinal fluid (CSF) and brain-blood barriers in mitochondrial encephalopathies is better understood, manipulation of their functions offers promises for therapeutic interventions.

Blood-Brain Barrier↗
PubMed2001

High intensity light increases olfactory bulb melatonin in Venezuelan equine encephalitis virus infection.

In mice infected with the Venezuelan equine encephalomyelitis (VEE) virus and exposed to high intensity light (2500 lux) with a 12 h light: 12 h dark photoperiod, a significant increase in the levels of melatonin in the olfactory bulb was observed. The significance of these findings deserves further studies to understand the mechanisms involved in this effect since the olfactory bulbs have been proposed as first portal for VEE virus entry into the CNS. The increase in melatonin content could represent one of the mechanisms of defense against the viral attack.

Animals↗
PubMed2001

Melatonin treatment enhances the efficiency of mice immunization with Venezuelan equine encephalomyelitis virus TC-83.

To determine whether treatment with melatonin (MLT) improves the efficiency of immunization against Venezuelan equine encephalomyelitis (VEE) virus, mice were vaccinated with TC-83 VEE virus and treated daily with MLT (1 or 5 mg/kg) starting 3 days before immunization, until 10 days after. IgM antibody titers were determined at days 7, 14, and 21 post-immunization. IL-10 levels were assayed at day 14 postvaccination. Treatment with MLT increased antibody titers 14 days after the immunization. IL-10 levels also increased with MLT treatment (1 and 5 mg/kg). Mice were challenged with live VEE virus at day 21 postimmunization, and viral titers were plaque assayed in chicken embryo fibroblasts 4 days after the infection. Following this challenge brain virus levels were significantly reduced. The results suggest that MLT treatment enhances the efficiency of mice immunization against VEE virus.

Adjuvants, Immunologic↗
PubMed2001

Effect of chronic manganese treatment on adenosine tissue levels and adenosine A2a receptor binding in diverse regions of mouse brain.

In the present study the effects of chronic manganese (Mn) treatment on adenosine A2a receptor binding in mouse brain have been assessed. Male albino mice were divided in two groups: In the Mn-treated group, the animals were injected intraperitoneally (i.p.) with MnCl2 (5 mg/kg/day) five days per week during 9 weeks; in the control group, they were injected likewise with a saline solution. A significant decrease of the Kd without alteration of Bmax in the cerebellum and, an increase of the Kd and Bmax in hippocampus of mice treated with Mn were found. Also, an increase of Kd in frontal cortex was observed. The binding parameters in caudate nucleus, olfactory bulb and hypothalamus were not altered by Mn. A significant decrease in the adenosine concentration in caudate nucleus, olfactory bulb and hypothalamus, without significant changes in hippocampus, frontal cortex and cerebellum was also detected. These findings suggest that chronic administration of Mn could affect adenosine receptor function and turnover, depending on the brain region analyzed.

Adenosine↗
PubMed2001

Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?

Navajo neurohepatopathy (NNH) is an autosomal recessive disease of full-blooded Navajo children living in the Navajo Reservation of southwestern United States. Clinical features of NNH include peripheral and central nervous system involvement, acral mutilation, corneal scarring or ulceration, liver failure, and metabolic and immunologic derangement. The cause of NNH is unknown, but the clinical features of NNH are similar to those of patients with mitochondrial DNA (mtDNA) depletion. Therefore, we studied mtDNA concentration in the liver from 2 patients with NNH. Using histochemical, biochemical, and molecular techniques, we found evidence of mtDNA depletion, and we propose that the primary defect in NNH is in the nuclear regulation of mtDNA copy number.

Citrate (si)-Synthase↗
PubMed2001

Diseases of oxidative phosphorylation due to mtDNA mutations.

Mitochondrial encephalomyopathies are disorders due to biochemical defects in the respiratory chain, which is under dual genetic control: 13 proteins are encoded by mitochondrial DNA (mtDNA), while all others are encoded by nuclear DNA. In the past 12 years, the small circle of mtDNA has proven to be a Pandora's box of pathogenic mutations, associated with a bewildering variety of multisystemic or tissue-specific disorders. After summarizing the principles of mitochondrial genetics, we attempt to provide general principles and practical clues to the diagnosis of mtDNA-related disorders by reviewing sequentially clinical presentation, family history, laboratory data, neuroradiology, exercise physiology, muscle morphology, muscle biochemistry, and molecular genetics.

DNA, Mitochondrial↗
PubMed2001

A5814G mutation in mitochondrial DNA can cause mitochondrial myopathy and cardiomyopathy.

We describe a 5-year-old child with hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis. Mitochondrial DNA analysis showed a heteroplasmic A5814G point mutation in the tRNA(Cys) gene. The mutational load was extremely high (>95%) in muscle, fibroblasts, and blood. This report expands the clinical heterogeneity of the A5814G mutation, which should be considered in the differential diagnosis of hypertrophic cardiomyopathy in childhood.

Acidosis, Lactic↗
PubMed2001

In mice the efficiency of immunization with Venezuelan Equine Encephalomyelitis virus TC-83 is transiently increased by dehydroepiandrosterone.

To determine whether treatment with dehydroepiandrosterone (DHEA) improves the efficiency of immunization against the Venezuelan Equine Encephalomyelitis (VEE) virus, mice were vaccinated with the TC-83 VEE virus. DHEA (10 mg/kg) was administered in a single dose, 4 hours before vaccination. IgM antibody titers were determined at days 7, 14 and 21 post-immunization. Treatment with DHEA increased antibody titers at day 14 after immunization. Mice were challenged with live VEE virus at day 21, and viral titers were plaque assayed in chicken embryo fibroblasts from days 2 to 5 post-infection. After the challenge, viremia decreased on day 2 and brain virus levels were reduced at day 4 in mice treated with DHEA. These results suggest that DHEA treatment could enhance the efficiency of immunization against VEE virus in mice.

Adjuvants, Immunologic↗
PubMed2000

Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.

OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle. BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria. METHODS: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR. RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. CONCLUSIONS: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.

Adult↗
PubMed2000

Kearns-sayre syndrome: oncocytic transformation of choroid plexus epithelium.

Kearns-Sayre syndrome (KSS) is a sporadic multisystem disorder due to a defect of oxidative phosphorylation and associated with clonally-expanded rearrangements of mitochondrial DNA (mtDNA) deletions (Delta-mtDNAs) and/or duplications (dup-mtDNAs). To gain further insight into the pathogenesis of CNS dysfunction in KSS, we studied the choroid plexus from two autoptic cases using in situ hybridization (ISH) of mtDNA, and immunohistochemistry to detect mtDNA and nuclear DNA-encoded subunits of the respiratory chain. Neuropathological examination of both cases showed oncocytic transformation of choroid plexus epithelial cells. In the same cells, ISH demonstrated that the predominant species of mtDNA were Delta-mtDNAs, and immunohistochemistry showed a decreased expression of mtDNA-encoded proteins. We suggest that mitochondrial abnormalities due to the presence of abundant Delta-mtDNAs in the choroid plexus play an important role in causing the increased cerebrospinal fluid (CSF) protein and reduced folic-acid levels that are characteristic of KSS.

Adolescent↗
PubMed2000

Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).

"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.

Antigens, CD↗