Yoshihiko Nishida

Lupus Erythematosus-like Syndrome with Selective Complete Deficiency of C1q

A 37-year-old Japanese man in previously good health was hospitalized because of swelling of the auricles had discoid erythema of the face. Clinical and laboratory findings satisfied the diagnostic criteria for systemic lupus erythematosus proposed by the American Rheumatism Association. However, serologic studies showed weakly positive antinuclear factor and absence of anti-DNA antibody and lupus erythematosus cells. A striking abnormality was the total absence of serum hemolytic complement activity (CH50). Further studies showed selective complete deficiency of C1q, a subunit of the first component of complement (C1). This is the first reported case of lupus erythematosus-like syndrome with selective complete deficiency of C1q.

Missense and Nonsense Mutations in the Lysosomal α-Mannosidase Gene (MANB) in Severe and Mild Forms of α-Mannosidosis

Summary α-Mannosidosis is an autosomal recessive lysosomal-storage disorder caused by a deficiency of lysosomal α-mannosidase activity. This disease shows a wide range of clinical phenotypes, from a severe, infantile form (type I), which is fatal at

Clinical, pathological, and genetic features of limb‐girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families

We report on the clinical, pathological, and genetic features of 7 patients with limb‐girdle muscular dystrophy type 2A (LGMD2A) from three Japanese families. The mean age of onset was 9.7 ± 3.1 years (mean ± SD), and loss of ambulance occurred at 38.5 ± 2.1 years. Muscle atrophy was predominant in the pelvic and shoulder girdles, and proximal limb muscles. Muscle pathology revealed dystrophic changes. In two families, an identical G to C mutation at position 1080 the in calpain 3 gene was identified, and a frameshift mutation (1796insA) was found in the third family. The former mutation results in a W360R substitution in the proteolytic site of calpain 3, and the latter in a deletion of the Ca2+‐binding domain.

Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation.

We performed clinicopathological analyses of two amyotrophic lateral sclerosis (ALS) patients with homozygous Q398X optineurin (OPTN) mutation. Clinically, both patients presented signs of upper and lower motor neuron degeneration, but only Patient 1 showed gradual frontal dysfunction and extrapyramidal signs, and temporal lobe and motor cortex atrophy. Neuropathological examination of Patient 1 revealed extensive cortical and spinal motor neuron degeneration and widespread degeneration of the basal ganglia. Bilateral corticospinal tracts exhibited degeneration. Loss of spinal anterior horn cells (AHCs) and gliosis were observed, whereas posterior columns, Clarkes columns, intermediate lateral columns, and the Onufs nucleus were spared. In the brainstem, moderate neuronal loss and gliosis were noted in the hypoglossal and facial motor nuclei. No Bunina bodies were found in the surviving spinal and brainstem motor neurons. Transactivation response (TAR) DNA‐binding protein 43 (TDP‐43)‐positive neuronal and glial cytoplasmic inclusions were observed throughout the central nervous system. The Golgi apparatus in motor neurons of the brainstem and spinal cord was often fragmented. Immunoreactivity for OPTN was not observed in the brain and spinal cord, consistent with nonsense‐mediated mRNA decay of OPTN. The TDP‐43 pathology of Q398X was similar to that of an autosomal dominant E478G mutation. This result suggests that the loss‐of‐function, but not the proteinopathy itself, of OPTN results in TDP‐43 deposits in neuronal and glial cytoplasm and Golgi apparatus fragmentation, leading to multisystem neurodegeneration.

Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism.

OBJECTIVES Mutational analysis of the sterol 27-hydroxylase (CYP27) gene was performed on three patients from two Japanese families who had cerebrotendinous xanthomatosis (CTX) associated with parkinsonism. METHODS Clinical evaluations, brain MRI studies, and laboratory analyses were completed on the three patients. The CYP27 gene was analysed for mutations by PCR amplification of gene segments followed by direct sequencing. RESULTS Two different, homozygous mutations were identified in these families. One is a novel transition, substituting T for G at Glu162 (GAG) resulting in a stop codon (TAG). The other is also a transition, substituting T for C at Arg441 (CGG) resulting in Trp (TGG). The second is located in two amino acids ahead of the heme ligand binding site (Cys443) of the protein likely rendering it non-functional. It is the most common CTX mutation in Japanese patients. CONCLUSIONS CTX with parkinsonism is caused by mutations with a severe impact on enzyme function. The two mutations described here are likely to cause loss of function because they are chain terminating or affect an essential site in the protein.

Decrease in urinary excretion of 3-methylhistidine by patients with Duchenne muscular dystrophy during glucocorticoid treatment.

Seven patients, aged 10–17 years, with Duchenne muscular dystrophy were treated orally with prednisolone (PSL) at a dose of 0.8–1.0 mg/kg per day for 8 weeks. During the treatment their muscle strength, serum creatine kinase (CK) activity, serum levels of myoglobin (Mb), and urinary excretion of 3-methyl-histidine (3-MeH) and glycine (Gly) were measured serially. In all the patients, the motor function or muscle strength improved, and the serum CK activity and Mb level decreased during PSL treatment. Urinary excretion of 3-MeH, a unique constituent of muscle contractile proteins, decreased to 51–63% of the baseline value in weeks 6–9 after the start of PSL administration, and returned to the baseline level in week 12. The ratios of 3-MeH to creatinine and to Gly also decreased during the treatment. Urinary excretion of Gly, which is ubiquitous in all tissues including muscle, did not decrease during the treatment. These findings suggest that PSL inhibits proteolysis of muscle contractile protein.

HTLV‐I‐associated myelopathy with adult T‐cell leukemia

We report a 42-year-old Japanese woman with HTLV-I-associated myelopathy (HAM) combined with adult T-cell leukemia (ATL). Combination of the 2 diseases has been extremely rare. The infrequency is explained by HLA types unique to each disease. Our patient suggests that the HAM-associated HLA haplotype does not prevent the development of ATL.

Acute neurotoxicity ofl-glutamate induced by impairment of the glutamate uptake system

We examined the effect of the glutamate uptake inhibitorl-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) on the neurotoxicity ofl-glutamate in organotypic cultures of rat spinal cord. Eighteen-day-old cultures were incubated with 500 μMl-glutamate, 1 mM PDC, or both. After 72 hours, the tissues were stained for acetylcholinesterase (AChE), and the ventral horn AChE-positive neurons (VHANs) analyzed using morphometry. Neitherl-glutamate nor PDC affected AChE staining, but in combination they produced markedly reduced AChE staining in the dorsal horn and a significant decrease in the number of VHANs (especially the smaller VHANs) as compared with the control. Moreover, treatment with 200 μM PDC for 2 weeks preferentially affected the smaller VHANs. The neurotoxicity ofl-glutamate plus PDC was blocked by the N-methyl-d-aspartate (NMDA) antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP).Results suggest that glutamate uptake system has an important protective function in the aggravation of acute neuronal damage.

Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles

Among the pathological findings in Alzheimers disease (AD), the temporal and spatial profiles of granulovacuolar degeneration (GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles (NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin‐1, a marker of lipid rafts, accumulates in lysosomes of tangle‐bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol‐4,5‐bisphosphate [PtdIns(4,5)P2], in AD and other neurodegenerative disorders.

Skeletal muscle pathology of mannosidosis in two siblings with spastic paraplegia

SummaryDeficiency of α-d-mannosidase was found in two siblings with muscle weakness and spastic paraplegia. A biopsy of the vastus lateralis muscle was studied by light and electron microscopy. Cryostat sections showed mild fiber size variation but no necrosis. Semithin Epon sections revealed many vacuoles in the muscle cells and fibroblasts. Electron microscopy showed that the vacuoles, presumably lysosomal, had a single limiting membrane and contained finely granular or granulo-reticular material, membranous structures, and electron-dense ovoids. The vacuoles were identical with those in lymphocytes and other cells of patients with mannosidosis. Disorganization of sarcomere alignment and widening of intermyofibrillar spaces were also observed. Deficiency of α-d-mannosidase is considered to cause slowly progressing degeneration of muscle fibers.