Takashi Ichiki

Mitochondrial leucine tRNA mutation in a mitochondrial encephalomyopathy.

We have identified another A-to-G transition in the dihydrouridine loop of the leucine tRNA (UUR) gene in mtDNa of two independent patients with mitochondrial myopathy, encephalopathy, lacticacidosis, and stroke-like syndrome (MELAS)

Molecular and Genetic Analyses of Two Patients with Pearson's Marrow-Pancreas Syndrome

ABSTRACT: Pearsons syndrome, a rare and fatal disorder characterized by refractory sideroblastic anemia and pancreatic insufficiency in infancy, is classified into mitochondrial cytopathies. To understand the molecular and genetic bases of this disorder, we have investigated the mitochondrial respiratory chain enzymes and the mitochondrial DNA (mtDNA) in two Japanese patients with Pearsons syndrome. Immunoblot analysis from various tissues showed the different grades of defects in the sub-units of respiratory enzyme complexes. The analyses of mtDNA showed that the deletion in patient 1 spanned 4977 bp from the ATPase 8 gene to the NADH dehydrogenase 5 gene between 13-bp direct repeats, whereas the deletion in patient 2 spanned 3151 bp from the transfer RNAHis gene to the cytochrome b gene unrelated to any repeated sequences. The deleted mtDNA was heteroplasmic in all the analyzed tissues, but the proportions of deleted mtDNA were quite different. We observed a tendency for the tissue with low percentages of normal-sized mtDNA to show low contents of complex I subunits. Analysis of the entire sequence of both patients mtDNA showed several nucleotide substitutions including alteration of the initiation codon of the NADH dehydrogenase 5 gene. Some of these nucleotide substitutions might contribute to the phenotypic expression of Pearsons syndrome synergistically with the deletion.

Disproportionate Deficiency of Iron-Sulfur Clusters and Subunits of Complex I in Mitochondrial Encephalomyopathy

ABSTRACT: To investigate the molecular abnormality in the mitochondria from various tissues of an autopsied patient exhibiting mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, we have examined the enzymatic activity, iron-sulfur cluster, and subunit composition of the NADH-ubiquinone oxidoreductase (complex I). Rotenone-sensitive NADH-cytochrome c reductase activity was found to be decreased in all the tissues examined. A detailed study of the liver mitochondria has shown that NADH-ubiquinone oxidoreductase activity was greatly diminished. Analysis of the electron paramagnetic resonance spectra of the liver submitochondrial particles revealed a disproportionate deficiency of iron-sulfur clusters in the complex I segment of the respiratory chain. Signals from the clusters N-2 and N-3 diminished more drastically than those from clusters N-1b and N-4. Immunoblotting analysis showed that the 75-kD, 51- kD, and several other subunits were markedly diminished among multiple subunit polypeptides of complex I. These findings suggest that the underlying bases for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are defects, at least, in the complex I subunits containing a flavin and/or iron-sulfur cluster(s), which resulted in deficiencies of some iron-sulfur clusters.

Diffuse central nervous system lupus involving white matter, basal ganglia, thalami and brainstem

We described an 11-year-old girl with acute central nervous system lupus showing diffuse lesions. She developed generalized convulsions followed by prolonged coma, and her psychomotor ability recovered fully after 3 months of steroid therapy. Cranial magnetic resonance imaging (MRI) showed high signal intensity in the cerebral deep white matter, bilateral basal ganglia, thalami, and brainstem on T2-weighted image. These lesions resolved over 1 month with residual atrophic change in the heads of the caudate nucleus on MRI. Acute SLE leukoencephalopathy may be recognized as a subtype of CNS lupus.

A Case of Febrile Ulceronecrotic Mucha-Habermann's Disease.

4歳男児。Febrile ulceronecrotic Mucha-Habermann’s disease(FUMHD)の1例を経験した。皮疹の形態は紅斑, 丘疹, 小水疱, 膿疱, および痂皮と多彩であった。その後の発熱·全身状態の悪化に伴い, 皮疹が急速に全身へ拡大し, 個診は大型化し多くは潰瘍化をみた。本症例は, Mucha-Habermann’s disease(MHD)の重症型であるFUMHDの範躊に属すると考えられた。ステロイド投与で解熱をみたが皮疹の新生は続いたので, DDS(4, 4’-diamino-diphenyl sulfone: レクチゾール®)を使用したところ皮疹の新生は止まった。DDS内服8週間で皮疹は瘢痕および脱色素斑を残し一旦治癒するも, 内服中止後3週間で再発した。現在, DDS内服で皮疹はほぼ消退している。

Fatal infantile mitochondrial encephalomyopathy with complex I and IV deficiencies

A 4-month-old male infant had a fatal infantile mitochondrial disease associated with cardiomyopathy. He had elevated lactate concentrations in blood and cerebrospinal fluid and an increased lactate/pyruvate ratio. Histochemical analysis of muscle biopsy revealed several ragged-red fibers on modified Gomori trichrome stain and mildly decreased cytochrome c oxidase (complex IV) activity. Complex I and IV activities of the respiratory chain in muscle were decreased to about 35% of normal values biochemically; subunits of the two complexes were decreased nonselectively on immunoblotting. Mitochondrial DNA analysis failed to detect any mutation. Complex I and IV deficiencies should be considered as one of the causes of fatal infantile mitochondrial disease.

Clinical and molecular heterogeneity in patients with mitochondrial encephalomyopathies due to complex I deficiency

The biogenesis of complex I (NADH-ubiquinone oxidoreductase, EC 1.6.99.3) is under dual control from mitochondrial and nuclear genomes. The polypeptides of complex I can be divided into three groups: the flavoprotein fraction (FP), the iron-sulphur protein fraction (IP) and the hydrophobic fraction (HP) (Hatefi, 1985). Seven of the polypeptides are encoded by the mitochondrial DNA and constitute a major part of the hydrophobic fraction (Chomyn et al., 1986). Clinical heterogeneity of complex I deficiency may be ascribable to this complexity. In this paper, we examine eleven patients with complex I deficiency and analyse biopsy samples of their skeletal muscles using immunochemical methods in order to elucidate the molecular defects in this disorder.

Multiple enzyme defects in mitochondria of a case with congenital lactic acidosis and hyperammonaemia.

M. KOBAYASHI 1, T. ICHIKI 1, N. SUGIYAMA 1, T. SANO 1, K. BAN 1, T. TSUBOI*, H. INAGAKI 1, K. OKAJIMA 1, H. SOBAJIMA 1, S. SUZUKI 1, H. TOGARI 1, Y. WADA 1, T. TADA 2, E. NAITO 3 and Y. KURODA 3 1Department of Pediatrics and 2Second Department of Pathology, Nagoya City University Medical School, Kawasumi-cho, Mizuho-ku, Nagoya 467, Japan; 3Department of Pediatrics, University of Tokushima School of Medicine, 3-Kuramoto-cho, Tokushima 770, Japan