1/51. First prenatal diagnosis of defects in the HsPDX1 gene encoding protein X, an additional lipoyl-containing subunit of the human pyruvate dehydrogenase complex.We have previously reported a genetic study of a neonatal lactic acidosis linked to a pyruvate dehydrogenase complex deficiency due to the absence of the protein X subunit. This rare autosomal recessive disorder is associated with specific deletions in this polypeptide which is encoded by the HsPDX1 gene, located on chromosome 11p1.3. The pathology of the patient was considered to arise from a large homozygous deletion (78del85) found at the 5' end of the HsPDX1 coding sequence. Her heterozygous mother underwent prenatal diagnosis during a subsequent pregnancy. Chorionic villus samples were used for three independent studies: (1) normal levels of the protein X component of the PDH complex were detected by immunoblotting; (2) RT-PCR analysis showed no deletion at the 5' end of the cDNA but the presence of a distinct heterozygous deletion (965del59) at its 3' end inherited from the father; (3) haplotype analysis revealed the presence of the father's mutated allele and the mother's normal allele. It was concluded that the fetus was heterozygous for this separate 3' deletion, so, it was likely to be not affected. This study permitted us to characterize more precisely the genetic abnormalities of the HsPDX1 cDNA occurring in each family's member.- - - - - - - - - - ranking = 1keywords = family, member (Clic here for more details about this article) |
2/51. Two novel mutations of SURF1 in Leigh syndrome with cytochrome c oxidase deficiency.Cytochrome c oxidase (COX) deficiency is the most common cause of Leigh syndrome (LS). COX consists of ten nuclear-encoded and three mtDNA-encoded structural subunits. Although the nucleotide sequences of all 13 genes are known, no mutation was found in nuclear-encoded subunit genes of COX-deficiency patients. Zhu et al. (1998) and Tiranti et al. (1998) found nine mutations in the surfeit 1 (SURF1) gene in LS families with COX deficiency. The mouse surfeit gene cluster consists of six closely spaced housekeeping genes unrelated by sequence homology. Except for the Surf3 gene, the function is still not known. The juxtaposition of at least five of the surfeit genes is conserved between birds and mammals. We identified two novel mutations of SURF1 in a Japanese LS patient with COX deficiency using direct sequencing analysis. Firstly, a 2-bp deletion at nucleotide position 790 (790delAG) in exon 8 was found, which shifts the reading frame such that the mutant protein has a completely different amino acid sequence from codon 264 to the premature stop codon at 290. Secondly, we found a T-to-G transversion at nucleotide 820, resulting in the substitution of tyrosine by aspartic acid at codon 274 (Y274D). We also studied the parents' genes, and found that the Y274D mutation was in his father and the 790delAG mutation was in his mother heterozygously. Therefore, we concluded that the patient was a compound heterozygote with these mutations. These are the first pathogenetic SURF1 mutations identified in a Japanese family.- - - - - - - - - - ranking = 0.99505817795896keywords = family (Clic here for more details about this article) |
3/51. Unique astrocytic inclusion in a 2 month-old baby showing Leigh-like brain lesions with lactic acidosis.An unique cytoplasmic inclusion was found in astrocytes of a 2-month-old female baby who showed Leigh-like brain lesions with lactic acidosis, hypoglycemia and hepatomegaly. Although a defective enzyme was not determined, a metabolic disorder was suggested from clinicopathological observations. Symmetrically distributed lesions consisting of marked gliosis and proliferation of capillaries were observed in the basal ganglia, thalami and tegmentum. The astrocytic cytoplasmic inclusion was exclusively found in the cerebral and cerebellar white matter, where myelination was immature. The inclusion was round and eosinophilic, and positive for glial fibrillary acidic protein, vimentin, alphaB-crystallin, S-100 protein and microtubule associated protein 1B, immunohistochemically. An electron microscopic examination revealed an accumulation of intermediate filaments, ribosome and rough endoplasmic reticulum in the inclusion. The characteristic of this inclusion is different from that of other reported inclusions. The inclusion showed positive immunoreaction against CuZn superoxide dismutase, catalase, advanced glycation end-product and 4-hydroxy-2-nonenal antibodies, which suggest that oxidative stress is involved in the genesis of the inclusion.- - - - - - - - - - ranking = 0.0015578052517096keywords = life (Clic here for more details about this article) |
4/51. Autism associated with the mitochondrial dna G8363A transfer rna(Lys) mutation.We report a family with a heterogeneous group of neurologic disorders associated with the mitochondrial dna G8363A transfer ribonucleic acid (rna)Lys mutation. The phenotype of one child in the family was consistent with autism. During his second year of life, he lost previously acquired language skills and developed marked hyperactivity with toe-walking, abnormal reciprocal social interaction, stereotyped mannerisms, restricted interests, self-injurious behavior, and seizures. Brain magnetic resonance imaging (MRI) and repeated serum lactate studies were normal. His older sister developed signs of Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive regression. Her laboratory studies revealed increased MRI T2-weighted signal in the putamen and posterior medulla, elevated lactate in serum and cerebrospinal fluid, and absence of cytochrome c oxidase staining in muscle histochemistry. Molecular analysis in her revealed the G8363A mutation of the mitochondrial transfer rna(Lys) gene in blood (82% mutant mitochondrial dna) and muscle (86%). The proportions of mutant mitochondrial dna from her brother with autism were lower (blood 60%, muscle 61%). It is likely that the origin of his autism phenotype is the pathogenic G8363A mitochondrial dna mutation. This observation suggests that certain mitochondrial point mutations could be the basis for autism in some individuals.- - - - - - - - - - ranking = 1.9916741611696keywords = family, life (Clic here for more details about this article) |
5/51. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome.We report on a novel frameshift mutation in the mtDNA gene encoding cytochrome c oxidase (COX) subunit III. The proband is an 11-year-old girl with a negative family history and an apparently healthy younger brother. Since 4 years of age, she has developed a progressive spastic paraparesis associated with ophthalmoparesis and moderate mental retardation. The presence of severe lactic acidosis and Leigh-like lesions of putamina prompted us to perform muscle and skin biopsies. In both, a profound, isolated defect of COX was found by histochemical and biochemical assays. sequence analysis of muscle mtDNA resulted in the identification of a virtually homoplasmic frameshift mutation in the COIII gene, due to the insertion of an extra C at nucleotide position 9537 of mtDNA. Although the 9537C(ins) does not impair transcription of COIII, no full-length COX III protein was detected in mtDNA translation assays in vivo. Western blot analysis of two-dimensional blue-native electrophoresis showed a reduction of specific crossreacting material and the accumulation of early-assembly intermediates of COX, whereas the fully assembled complex was absent. One of these intermediates had an electrophoretic mobility different from those seen in controls, suggesting the presence of a qualitative abnormality of COX assembly. Immunostaining with specific antibodies failed to detect the presence of several smaller subunits in the complex lacking COX III, in spite of the demonstration that these subunits were present in the crude mitochondrial fraction of patient's cultured fibroblasts. Taken together, the data indicate a role for COX III in the incorporation and maintenance of smaller COX subunits within the complex.- - - - - - - - - - ranking = 0.99505817795896keywords = family (Clic here for more details about this article) |
6/51. The T9176G mtDNA mutation severely affects ATP production and results in Leigh syndrome.The authors identified a novel mtDNA mutation (T9176G) in the ATPase 6 gene in a family in which a 10-year-old girl had a severe neurodegenerative disorder, her elder sister had died of Leigh syndrome (LS), and a maternal uncle had a spinocerebellar disorder. Biochemical studies disclosed a reduced rate of ATP synthesis in skin fibroblast cultures from the proposita as the likely explanation of her severe illness. The findings expand the genetic variants associated with LS.- - - - - - - - - - ranking = 0.99505817795896keywords = family (Clic here for more details about this article) |
7/51. leigh disease: clinical, neuroradiologic, and biochemical study of three new cases with cytochrome c oxidase deficiency.Three cases of leigh disease are described. In all three, symptoms began in the first months of life, with muscle hypotonia, lactic acidosis, and psychomotor delay. The diagnosis was made on the basis of the clinical characteristics, biochemical abnormalities, and typical brain magnetic resonance imaging with symmetric lesions suggesting bilateral necrosis at the level of the basal ganglia and of the midbrain. Cytochrome c oxidase (complex IV of the mitochondrial respiratory chain) deficiency was demonstrated in muscle tissue in all patients and confirmed in skin fibroblasts in patient 3. A genetic heterogeneity was present in these patients since only one had a SURF-1 gene mutation. The clinical, biochemical, and neuroradiologic aspects are discussed. Finally, the finding of facial dysmorphisms in the cytochrome c oxidase deficiency observed in one of the described cases is of extreme interest; to our knowledge, this association has never been reported in the literature.- - - - - - - - - - ranking = 0.0015578052517096keywords = life (Clic here for more details about this article) |
8/51. Multiple neonatal deaths due to a homoplasmic mitochondrial dna mutation.Mutations of mitochondrial dna (mtDNA) are an important cause of genetic disease. We describe a family with an unusual homoplasmic mutation that resulted in six neonatal deaths and one surviving child with Leigh syndrome. The mother is clinically normal, but a severe biochemical and molecular genetic defect was present in both a fatally affected child and the mother. This family highlights the role of homoplasmic mt-tRNA mutations in genetic disease.- - - - - - - - - - ranking = 1.9901163559179keywords = family (Clic here for more details about this article) |
9/51. Leigh's disease in 3 sibs of a Kuwaiti family.OBJECTIVE AND IMPORTANCE: To describe Leigh's disease in 3 sibs of a Kuwaiti family. CASE PRESENTATION: Two brothers presented in early infancy with progressive neurological symptoms of hypotonia, delayed milestones and brisk reflexes. Investigations revealed metabolic acidosis, high serum and cerebrospinal fluid lactate. magnetic resonance imaging (MRI) showed characteristic changes of Leigh's disease. The 3rd brother, who was asymptomatic initially, was investigated because of his family history and was found to have similar changes. INTERVENTION: All children developed progressive neurological deterioration and persistent metabolic lactic acidosis, which was treated with sodium bicarbonate, and the 1st patient needed renal dialysis to control the acidosis. The 2nd child was placed on vitamins and carnitine. CONCLUSION: The neurological deterioration was progressive in all 3 sibs, and they eventually died of respiratory failure despite ventilatory support. Since MRI changes are characteristic, MRI should be done to confirm the diagnosis.- - - - - - - - - - ranking = 5.9703490677538keywords = family (Clic here for more details about this article) |
10/51. Neuropathologic and clinical features in eight Chinese patients with leigh disease.We present the neuropathologic and clinical features of eight Chinese patients with leigh disease. Five cases had onset before 1 year of age, the other three after 1 year of age. Cranial magnetic resonance imaging (MRI) demonstrated symmetric and bilateral long T1 and long T2 lesions mainly in the basal ganglia and brain stem. The putamen was most commonly and severely affected. Brain neuropathologic examinations showed multiple symmetric foci of degeneration and necrosis with capillary proliferation and dilation. In contrast to previous reports, these foci were mainly in the brain stem, not the basal ganglia. We examined mitochondrial dna from three patients and found the T8993G mitochondrial dna mutation in one of them. This patient inherited the mutation from his mother, who does not display any symptoms now. From this study, we found that the nuclei in the brain stem can be more frequently affected than those in the basal ganglia.- - - - - - - - - - ranking = 0.0015578052517096keywords = life (Clic here for more details about this article) |
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