Mitochondrial analysis in autosomal dominant hereditary spastic paraplegia.
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Chromosomes, Human, Pair 14↗
Biomedical subjects
E Bonilla
Publications and source records attributed to E Bonilla.
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↗
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↗
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↗
Analysis of mtDNA deletions in muscle by in situ hybridization.
We compared the distribution of deleted mitochondrial DNA (Delta-mtDNA) in skeletal muscle of a patient with autosomal recessive (AR) and another with autosomal dominant (AD) progressive external ophthalmoplegia (PEO) by in situ hybridization (ISH). The patients studied had similar numbers of fibers deficient in cytochrome c oxidase (COX) activity (13.6% and 12.8%) and fibers with mitochondrial proliferation (5.5% and 5.3%). ISH suggested that each COX-deficient fiber contained a single species of Delta-mtDNA. Most deletions ablated the region between the genes encoding adenosine triphosphate (ATP) synthase subunit 8 and cytochrome b. Fibers that appeared to be depleted of mtDNA were also present. We conclude that muscle from patients with autosomally inherited PEO contains not only Delta-mtDNA but also focal depletion of mtDNA and that the distribution of these mtDNA defects appears to be similar. These changes most likely represent the common consequence of whatever genetic factors are responsible for the generation of Delta-mtDNA.
Adult↗
Neuropathologic aspects of cytochrome C oxidase deficiency.
Cytochrome c oxidase (COX) deficiency is an important cause of myopathy or encephalomyopathy. Considering the structural complexity of COX, its dual genetic control, and the several nuclear genes needed for its proper assembly, the phenotypic heterogeneity is not surprising. From a morphologic view point, the application of histochemistry and immunohistochemistry to the study of COX deficiency in muscle has revealed specific patterns that -we believe- are helpful both for diagnosis and for directing sequencing studies of either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes. Similar studies in brain have shown that patients with mutations in mtDNA appear to have different patterns of COX deficiency from patients with mutations in nDNA genes. The recent discovery of mutations in COX assembly genes coupled with the potential to generate knock-out mice with these mutations holds the promise of providing the neuropathologist with the animal models needed to study the pathogenesis of COX deficiency in brain and muscle.
Animals↗
Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2.
We screened 41 patients with undiagnosed encephalomyopathies and cytochrome c oxidase (COX) deficiency for mutations in two COX assembly genes, SURF-1 and SCO2; 6 patients had mutations in SURF-1 and 3 had mutations in SCO2. All of the mutations in SURF-1 were small-scale rearrangements (deletions/insertions); 3 patients were homozygotes and the other 3 were compound heterozygotes. All patients with SCO2 mutations were compound heterozygotes for nonsense or missense mutations. All of the patients with mutations in SURF-1 had Leigh syndrome, whereas the 3 patients with SCO2 mutations had a combination of encephalopathy and hypertrophic cardiomyopathy, and the neuropathology did not show the typical features of Leigh syndrome. In patients with SCO2 mutations, onset was earlier and the clinical course and progression to death more rapid than in patients with SURF-1 mutations. In addition, biochemical and morphological studies showed that the COX deficiency was more severe in patients with SCO2 mutations. Immunohistochemical studies suggested that SURF-1 mutations result in similarly reduced levels of mitochondrial-encoded and nuclear-encoded COX subunits, whereas SCO2 mutations affected mitochondrial-encoded subunits to a greater degree. We conclude that patients with mutations in SURF-1 and SCO2 genes have distinct phenotypes despite the common biochemical defect of COX activity.
Adult↗
Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo-obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26-58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 +/- 0.021 micromol/hr/mg (mean +/- SD; n = 16), compared with controls, 0.67 +/- 0.21 micromol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both.
Adult↗
[Huntington disease. A review].
Huntington's disease (HD) is a hereditary autosomal dominant neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. It affects about 1 in 10,000 individuals. The onset of symptoms typically occurs in the third or fourth decade of life, though it may appear at any age. The molecular basis of the disease is the expansion of the trinucleotide CAG in the first exon of a gene on chromosome four (4p 16.3). This gene encodes the protein huntingtin of 3136 amino acids. The mutation of huntingtin produces an expanded stretch of glutamine (Gln) residues. This CAG/polyGln expansion has 6 to 39 units in normal individuals and 36 to 180 units in HD patients. The normal function of huntingtin and the pathogenic mechanisms caused by the expanded polyGln of mutant huntingtin remain incompletely characterized. Huntingtin appears to be associated with synaptic vesicles and/or microtubules and seems to have an important role in vesicular transport and/or the binding to the cytoskeleton. It is thought that this protein is important in embryogenesis and that its mutant form alters the function of the mitochondrial respiratory chain. The toxic gain of function caused by huntingtin could either be an overactivity of the normal function or the introduction of a novel function. Its interactions with other proteins could lead to an impairment of the cellular function or to its own polymerization to form insoluble aggregates. The intraneuronal aggregates could affect gene transcription, protein interactions, protein transport inside the nucleus and cytoplasm, and the vesicular transport. However, since a dissociation between the aggregation of huntingtin and the selective pattern of striatal neuronal loss has been demonstrated, it is believed that other properties of the mutant huntingtin, like proteolysis and the interactions with other proteins that affect vesicular trafficking and nuclear transport, could be responsible for the neurodegeneration. On gross examination, 80% of HD brains show atrophy of the frontal lobes. A bilateral, symmetric atrophy of the striatum is observed in 95% of the HD brains. The mean brain weight in HD patients is approximately 30% lower than in normal individuals. Striatal degeneration has an ordered and topographic distribution. The tail of the caudate nucleus shows more degeneration than the head. The caudate atrophy is associated to a gradual atrophy and neuronal loss in other brain regions as the disease progresses. The striatal and cerebral cortex projection neurons are much more susceptible to the disease than interneurons. In the neostriatum, the levels of GABA, dynorphin and substance P are decreased, but the concentrations of somatostatin and neuropeptide Y increase. An impairment of energy metabolism in HD and a sensitivity to oxidative stress and to the cytotoxic effects of glutamate seem to contribute to the neuronal death in HD. It is proposed that melatonin should be assayed in cell cultures and in transgenic animals due to its potent antioxidant and free radical scavenger properties.
Basal Ganglia↗
Computerized brain tomography in patients with Schizophrenia.
We carried out brain tomography of 27 patients with schizophrenia and 17 normal control subjects. DSM-IV criteria were used for diagnosis. The parameters studied were: brain volume, lateral and third ventricles, brain surface and brain indexes. Previously the patients were evaluated with the following clinical scales: Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Global Assessment of Functioning Scale (GAF) and the GRAFFAR scale to evaluate cultural and socioeconomical levels. We detected an increase in the right and left lateral ventricles: brain ratios, an increase in the width of Sylvian fissures and in the third ventricle index. We did not find differences that could be related to sex or to a familial history of mental disease. No differences were observed in the group receiving medication when compared with the group of untreated patients.
Adult↗
Melatonin acts on the nucleus accumbens to increase acetylcholine release and modify the motor activity pattern of rats.
Brain microdialysis coupled to high performance liquid chromatography with electrochemical detection (HPLC-ED) was used to evaluate the influence of melatonin on extracellular concentration of acetylcholine (ACh) in the nucleus accumbens (NAc) of rats. Motor activity was simultaneously monitored during the dialysis sessions with an activity meter. Melatonin and prazosin were administered locally through the dialysis probe. It was found that melatonin dose-dependently increased accumbens ACh. Melatonin (3 microM) decreased horizontal activity and increased vertical activity, while another dose (100 microM) enhanced both horizontal and vertical activity. Prazosin, a putative melatonin antagonist, blocked the effects of melatonin on both motor activity and ACh release when given 20 min before melatonin. Overall, these results suggest that melatonin modulates the release of ACh in the NAc and the pattern of motor activity in the rat.
Acetylcholine↗
Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA.
BACKGROUND: The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy. METHODS: We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene. RESULTS: We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (from nucleotide 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All the point mutations involved the substitution of adenine for guanine, but all were in different locations. CONCLUSIONS: The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance.
Adult↗
Increased number of caveolae and caveolin-3 overexpression in Duchenne muscular dystrophy.
Caveolae are small pockets or invaginations localized at the plasma membrane. Caveolins are the principal protein components of caveolae and play an important structural role in the formation of caveolae membranes. Here, we studied by freeze fracture and immunological techniques the spatial organization of caveolae at the muscle cell plasma membrane and the expression of caveolin-3 in Duchenne muscular dystrophy (DMD) muscle fibers. In DMD muscle, we found an increased number of caveolae at the sarcolemma that corresponds to an overexpression of caveolin-3 by immunohistochemistry and by Western blot analysis. These findings suggest a possible role for caveolae and caveolin-3 in the pathogenesis of DMD.
Adolescent↗
Phenotypic analysis of autosomal dominant hereditary spastic paraplegia linked to chromosome 8q.
OBJECTIVE: To describe clinical, electrophysiologic, neuroimaging, and muscle biopsy features in a hereditary spastic paraplegia (HSP) kindred linked to a new HSP locus on chromosome 8q. BACKGROUND: HSP is a genetically diverse group of disorders characterized by insidiously progressive spastic weakness in the legs. We recently analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage to a novel HSP locus on chromosome 8q23-24. METHODS: Clinical analysis, nerve conduction studies, electromyography, somatosensory evoked potentials, MRI of brain and spinal cord, and muscle biopsy for mitochondrial analysis were performed in members of the first HSP kindred linked to chromosome 8q. RESULTS: Fifteen individuals showed insidiously progressive spastic paraparesis beginning between ages 22 and 60 years (average, 37.2 years). Spinal cord MRI in 1 moderately affected subject showed significant atrophy of the thoracic spinal cord as determined by cross-sectional area measurements. Somatosensory evoked potential recording, electromyography, nerve conduction studies, and muscle biopsy, including histochemical and biochemical analysis of mitochondrial function, were normal. CONCLUSIONS: The phenotype in this family is that of typical, but severe, uncomplicated HSP. Other than apparently increased severity, there were no clinical features that distinguished this family from autosomal dominant HSP linked to loci on chromosomes 2p, 14q, and 15q. This clinical similarity between different genetic types of autosomal dominant HSP raises the possibility that genes responsible for these clinically indistinguishable disorders may participate in a common biochemical cascade. Normal results of muscle histochemical and biochemical analysis suggest that mitochondrial disturbance, a feature of chromosome 16-linked autosomal recessive HSP due to paraplegin gene mutations, is not a feature of chromosome 8q-linked autosomal dominant HSP and may not be a common factor of HSP in general.
Adult↗
Disconnection of cerebellar Purkinje cells in Kearns-Sayre syndrome.
Kearns-Sayre syndrome (KSS) is a sporadic multisystem disorder due to rearrangements in mitochondrial DNA (mtDNA). To gain further insight into the pathogenesis of cerebellar dysfunction in KSS, antibodies against synaptophysin (SY) were used to identify presynaptic terminals and antibodies to calbindin D (CB) to identify Purkinje cells in the cerebellar cortex and in the dentate nucleus from two autopsied cases of KSS. By conventional neuropathology we found marked spongiform degeneration and by immunohistochemistry a disruption of presynaptic terminals and of the terminal arborizations of Purkinje cell axons on multipolar neurons of the dentate nucleus in the KSS patients. We suggest that a disconnection of Purkinje cells at the dentate nucleus may play a role in the pathogenesis of cerebellar ataxia in KSS.
Adolescent↗
Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN)) gene.
Thirty-six of 43 maternally related members of a large African American family experienced hearing loss. A muscle biopsy specimen from the proband showed cytochrome c oxidase (COX)-deficient fibers but no ragged-red fibers; biochemical analysis showed marked reduction of COX activity. A novel T7511C point mutation in the tRNA(Ser(UCN)) gene was present in almost homoplasmic levels (>95%) in the blood of 18 of 20 family members, and was also found in lower abundance in the other two. Single-fiber PCR showed that the mutational load was greater in COX-deficient muscle fibers. The tRNA(ser(UCN)) gene may be a "hot spot" for mutations associated with maternally transmitted hearing loss.
Adult↗
A new mitochondrial DNA mutation (A3288G) in the tRNA(Leu(UUR)) gene associated with familial myopathy.
We describe a family with a maternally inherited mitochondrial myopathy and an A3288G mutation in the tRNA(Leu(UUR)) gene. The proband had muscle cramping and mild weakness while her brother had long-standing limb and respiratory muscle weakness and her daughter had elevated serum CK. The mutation, which was nearly homoplasmic in muscle and heteroplasmic in blood, affects the TpsiC loop at a conserved site and was not found in 107 controls. This report confirms the frequent association of tRNA(Leu(UUR)) mutations with respiratory muscle involvement and bolsters the concept that tRNA(Leu(UUR)) is a hotspot for mtDNA mutations.
Adult↗
Mitochondrial involvement in Alzheimer's disease.
The causes of most neurodegenerative diseases, including sporadic Alzheimer's disease (AD), remain enigmatic. There is, however, increasing evidence implicating mitochondrial dysfunction resulting from deafferentiation of disconnected neural circuits in the pathogenesis of energy deficit in AD. The patterns of reduced expression of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoded genes is consistent with a physiological down-regulation of the mitochondrial respiratory chain in response to reduced neuronal activity. On the other hand, the role(s) of somatic cell or maternally inherited mtDNA mutations in the pathogenesis of mitochondrial dysfunction in AD are still controversial.
Alzheimer Disease↗