Leigh Disease
Encephalomalacia
Brain Diseases, Metabolic
Cytochrome-c Oxidase Deficiency
Uncommon morphologic characteristics in Leigh's disease. (1/128)
We describe a 4-month-old male patient with severe developmental delay and elevated lactate in blood and CSF. The MR images showed abnormalities differing from the typical pattern found in association with Leigh's disease. The examination of fibroblast cultures showed diminished activity of mitochondrial complexes I and III. The patient died at the age of 9 months. (+info)Characterization of SURF-1 expression and Surf-1p function in normal and disease conditions. (2/128)
Loss-of-function mutations of the SURF-1 gene have been associated with Leigh syndrome with cytochrome c oxidase (COX) deficiency. Mature Surf-1 protein (Surf-1p) is a 30 kDa hydrophobic polypeptide whose function is still unknown. Using antibodies against a recombinant, hemagglutinin-tagged Surf-1p, we have demonstrated that this protein is imported into mitochondria as a larger precursor, which is then processed into the mature product by cleaving off an N-terminal leader polypeptide of approximately 40 amino acids. By using western blot analysis with specific antibodies, we showed that Surf-1p is localized in and tightly bound to the mitochondrial inner membrane. The same analysis revealed that no protein is present in cell lines harboring loss-of-function mutations of SURF-1, regardless of their type and position. Northern blot analysis showed the virtual absence of specific SURF-1 transcripts in different mutant cell lines. This result suggests that several mutations of SURF-1 are associated with severe mRNA instability. To understand better whether and which domains of the protein are essential for function, we generated several constructs with truncated or partially deleted SURF-1 cDNAs. None of these constructs, expressed into Surf-1p null mutant cells, were able to rescue the COX phenotype, suggesting that different regions of the protein are all essential for function. Finally, experiments based on blue native two-dimensional gel electrophoresis indicated that assembly of COX in Surf-1p null mutants is blocked at an early step, most likely before the incorporation of subunit II in the nascent intermediates composed of subunit I alone or subunit I plus subunit IV. However, detection of residual amounts of fully assembled complex suggests a certain degree of redundancy of this system. (+info)Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency. (3/128)
Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency is an autosomal recessive neurodegenerative disorder caused by mutations in SURF1. Although SURF1 is ubiquitously expressed, its expression is lower in brain than in other highly aerobic tissues. All reported SURF1 mutations are loss of function, predicting a truncated protein (hSurf1) product. Western blot analysis with anti-hSurf1 antibodies demonstrated a specific 30 kDa protein in control fibroblasts, but no protein in LS patient cells. Steady-state levels of both nuclear- and mitochondrial-encoded COX subunits were also markedly reduced in patient cells, consistent with a failure to assemble or maintain a normal amount of the enzyme complex. An epitope (FLAG)-tagged hSurf1 was targeted to mitochondria in COS7 cells and a mitochondrial import assay showed that the hSurf1 precursor protein (35 kDa) was imported and processed to its mature form (30 kDa) in a membrane potential-dependent fashion. The protein was resistant to alkaline carbonate extraction and susceptible to proteinase K digestion in mitoplasts. Mutant proteins in which the N-terminal transmembrane domain or central loop were deleted, or the C-terminal transmembrane domain disrupted, did not accumulate and could not rescue COX activity in patient cells. Co-expression of the N- and C-terminal transmembrane domains as independent entities also failed to rescue the enzyme deficiency. These data demonstrate that hSurf1 is an integral inner membrane protein with an essential role in the assembly or maintenance of the COX complex and that insertion of both transmembrane domains in the intact protein is necessary for function. (+info)Sequence conservation from human to prokaryotes of Surf1, a protein involved in cytochrome c oxidase assembly, deficient in Leigh syndrome. (4/128)
The human SURF1 gene encoding a protein involved in cytochrome c oxidase (COX) assembly, is mutated in most patients presenting Leigh syndrome associated with COX deficiency. Proteins homologous to the human Surf1 have been identified in nine eukaryotes and six prokaryotes using database alignment tools, structure prediction and/or cDNA sequencing. Their sequence comparison revealed a remarkable Surf1 conservation during evolution and put forward at least four highly conserved domains that should be essential for Surf1 function. In Paracoccus denitrificans, the Surf1 homologue is found in the quinol oxidase operon, suggesting that Surf1 is associated with a primitive quinol oxidase which belongs to the same superfamily as cytochrome oxidase. (+info)Leigh syndrome in a 3-year-old boy with unusual brain MR imaging and pathologic findings. (5/128)
We report unusual MR serial imaging and electron microscopy findings in a 3-year-old boy who had Leigh syndrome with cytochrome-c oxidase (cox) deficiency. The MR imaging findings included periventricular white matter involvement, posteroanterior progression, and extension through the corpus callosum and internal capsule; however, no basal ganglia or brain stem abnormality was found, which was suggestive of leukodystrophy. The most noteworthy findings were the cystic foci with contrast enhancement in the affected white matter. (+info)Heterogeneous presentation in A3243G mutation in the mitochondrial tRNA(Leu(UUR)) gene. (6/128)
AIMS: To clarify the phenotype-genotype relation associated with the A3243G mitochondrial DNA mutation. METHODS: Five unrelated probands harbouring the A3243G mutation but presenting different clinical phenotype were analysed. Probands include Leigh syndrome (LS(3243)), mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS(3243)), progressive external ophthalmoplegia (PEO(3243)), and mitochondrial diabetes mellitus (MDM(3243)). Extensive clinical, histological, biochemical, and molecular genetic studies were performed on five families. RESULTS: All patients showed ragged red fibres (RRF), and focal cytochrome c oxidase (COX) deficiency except for the patient with MDM(3243). The mutation load was highest in the proband with LS(3243) (>90%), who also presented the highest proportion of RRF (68%) and COX negative fibres (10%), and severe complex I plus IV deficiency. These proportions were lower in the probands with PEO(3243) and with MDM(3243). CONCLUSION: The most severe clinical phenotype, LS(3243), was associated with the highest proportion of the A3243G mutation as well as the most prominent histological and biochemical abnormalities. (+info)Leigh syndrome: serial MR imaging and clinical follow-up. (7/128)
BACKGROUND AND PURPOSE: Subacute necrotizing encephalomyelopathy, or Leigh syndrome (LS), is a progressive neurodegenerative disorder characterized by symmetrical spongiform lesions in the brain with onset usually in infancy or early childhood. Little is known of the developing process of the brain lesions in LS that are particularly relevant to the occurrence of fatal respiratory failure. Our purpose was to determine whether fatal respiratory failure can be predicted before death on the basis of clinical characteristics or findings on longitudinal MR images of the brain. METHODS: Clinical records and serial MR studies of eight patients with LS aged 3 months to 12 years who met the diagnostic criteria for LS were reviewed retrospectively, with special reference to a correlation between loss of respiratory control and MR abnormalities. Both T1- and T2-weighted images were obtained at the onset of disease or when clinical symptoms worsened. RESULTS: Serial MR images were divided into three groups on the basis of the following findings: 1) symmetrical basal ganglia lesions before brain stem involvement (n = 4); 2) initial involvement of the brain stem (n = 2); and 3) cerebral white matter lesions followed by brain stem lesions (n = 2). Lesions of the lower brain stem were always present when patients had near fatal respiratory failure. However, upper brain stem lesions were transient and were found in parallel to reversible respiratory disorder. Fatal respiratory failure was unpredictable from clinical or neuroradiologic findings. CONCLUSION: Brain stem lesions are associated with the loss of respiratory control in patients with LS, but the time at which fatal respiratory failure will occur is unpredictable. (+info)Application of the obligate aerobic yeast Yarrowia lipolytica as a eucaryotic model to analyse Leigh syndrome mutations in the complex I core subunits PSST and TYKY. (8/128)
We have used the obligate aerobic yeast Yarrowia lipolytica to reconstruct and analyse three missense mutations in the nuclear coded subunits homologous to bovine TYKY and PSST of mitochondrial complex I (proton translocating NADH:ubiquinone oxidoreductase) that have been shown to cause Leigh syndrome (MIM 25600), a severe progressive neurodegenerative disorder. While homozygosity for a V122M substitution in NDUFS7 (PSST) has been found in two siblings with neuropathologically proven Leigh syndrome (R. Triepels et al., Ann. Neurol. 45 (1999) 787), heterozygosity for a P79L and a R102H substitution in NDUFS8 (TYKY) has been found in another patient (J. Loeffen et al., Am. J. Hum. Genet. 63 (1998) 1598). Mitochondrial membranes from Y. lipolytica strains carrying any of the three point mutations exhibited similar complex I defects, with V(max) being reduced by about 50%. This suggests that complex I mutations that clinically present as Leigh syndrome may share common characteristics. In addition changes in the K(m) for n-decyl-ubiquinone and I(50) for hydrophobic complex I inhibitors were observed, which provides further evidence that not only the hydrophobic, mitochondrially coded subunits, but also some of the nuclear coded subunits of complex I are involved in its reaction with ubiquinone. (+info)Leigh Disease, also known as Subacute Necrotizing Encephalomyelopathy (SNE), is a rare inherited neurometabolic disorder that affects the central nervous system. It is characterized by progressive degeneration of the brain and spinal cord. The condition typically appears in infancy or early childhood, although it can develop in adolescence or adulthood.
Leigh Disease is caused by mutations in mitochondrial DNA or nuclear genes that disrupt the function of the oxidative phosphorylation system, a part of the cellular energy production process. This results in decreased ATP (adenosine triphosphate) production and an accumulation of lactic acid in the body.
The symptoms of Leigh Disease can vary widely but often include vomiting, seizures, developmental delays, muscle weakness, loss of muscle tone, and difficulty swallowing and breathing. The condition can also cause lesions to form on the brainstem and basal ganglia, which can lead to further neurological problems.
There is no cure for Leigh Disease, and treatment is focused on managing symptoms and supporting affected individuals as they cope with the progression of the disease.
Encephalomalacia is a medical term that refers to the softening and degeneration of brain tissue. It is typically caused by an injury, infection, or lack of oxygen supply to the brain. This condition can lead to various neurological symptoms depending on the location and extent of the damage in the brain. Encephalomalacia may result in cognitive impairments, motor function loss, speech difficulties, and other long-term disabilities. Treatment options vary based on the underlying cause and severity of the condition but often include rehabilitation therapies to help manage symptoms and improve quality of life.
Metabolic brain diseases refer to a group of conditions that are caused by disruptions in the body's metabolic processes, which affect the brain. These disorders can be inherited or acquired and can result from problems with the way the body produces, breaks down, or uses energy and nutrients.
Examples of metabolic brain diseases include:
1. Mitochondrial encephalomyopathies: These are a group of genetic disorders that affect the mitochondria, which are the energy-producing structures in cells. When the mitochondria don't function properly, it can lead to muscle weakness, neurological problems, and developmental delays.
2. Leukodystrophies: These are a group of genetic disorders that affect the white matter of the brain, which is made up of nerve fibers covered in myelin, a fatty substance that insulates the fibers and helps them transmit signals. When the myelin breaks down or is not produced properly, it can lead to cognitive decline, motor problems, and other neurological symptoms.
3. Lysosomal storage disorders: These are genetic disorders that affect the lysosomes, which are structures in cells that break down waste products and recycle cellular materials. When the lysosomes don't function properly, it can lead to the accumulation of waste products in cells, including brain cells, causing damage and neurological symptoms.
4. Maple syrup urine disease: This is a genetic disorder that affects the way the body breaks down certain amino acids, leading to a buildup of toxic levels of these substances in the blood and urine. If left untreated, it can cause brain damage, developmental delays, and other neurological problems.
5. Homocystinuria: This is a genetic disorder that affects the way the body processes an amino acid called methionine, leading to a buildup of homocysteine in the blood. High levels of homocysteine can cause damage to the blood vessels and lead to neurological problems, including seizures, developmental delays, and cognitive decline.
Treatment for metabolic brain diseases may involve dietary changes, supplements, medications, or other therapies aimed at managing symptoms and preventing further damage to the brain. In some cases, a stem cell transplant may be recommended as a treatment option.
Cytochrome-c oxidase deficiency is a genetic disorder that affects the function of the mitochondria, which are the energy-producing structures in cells. Specifically, it is a deficiency in cytochrome-c oxidase (COX), also known as complex IV, which is an enzyme located in the inner membrane of the mitochondria that plays a critical role in the electron transport chain and oxidative phosphorylation.
Cytochrome-c oxidase deficiency can be caused by mutations in any of the genes that encode the subunits or assembly factors of COX. The severity of the disorder and the specific symptoms can vary widely, depending on the extent of the enzyme deficiency and the particular tissues and organs that are affected.
Symptoms of cytochrome-c oxidase deficiency may include muscle weakness, developmental delay, hypotonia (low muscle tone), seizures, lactic acidosis, and cardiac and neurological problems. In some cases, the disorder can be life-threatening in infancy or early childhood.
There is no cure for cytochrome-c oxidase deficiency, and treatment is generally supportive and aimed at addressing specific symptoms. Antioxidant therapy, such as vitamin C and E supplements, may help to reduce oxidative stress and improve mitochondrial function in some cases. In severe cases, a heart or liver transplant may be considered.