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Regular health checkups for mothers of patients with Duchenne muscular dystrophy have been performed at National Hospital Organization Tokushima Hospital since 1994. Among 43 mothers participated in this study, 28 dystrophinopathy carriers were identified. Skeletal and cardiac muscle functions of these subjects were examined. High serum creatine kinase was found in 23 subjects (82.1%). Obvious muscle weakness was present in 5 (17.8%) and had progressed from 1994 to 2015. Cardiomyopathy was observed in 15 subjects (60.0%), including dilated cardiomyopathy-like damage that was more common in the left ventricular (LV) posterior wall. Late gadolinium enhancement on cardiac MRI was found in 5 of 6 subjects, suggesting fibrotic cardiac muscle. In speckle tracking echocardiography performed seven years later, global longitudinal strain was decreased in these subjects, indicating LV myocardial contractile abnormality. These results suggest that female dystrophinopathy carriers should receive regular checkups for detection and treatment of cardiomyopathy, even if they have no cardiac symptoms.

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

The level of plasma brain natriuretic peptide (BNP) was elevated in 8 of 15 female gene carriers of Duchenne muscular dystrophy (DMD), and the level correlated with indices of cardiac function. In one of these carriers, whose clinical course was followed for one year, the plasma BNP level was elevated before the development of cardiac symptoms, further increased with the evolution of cardiac symptoms, and then decreased after treatment for cardiac failure. These results suggest that the plasma BNP level may be useful for the early detection of cardiac dysfunction and for evaluating the efficacy of cardiac treatment in female DMD carriers.

The intracellular localization of dystrophin and beta-dystroglycan mRNA in skeletal muscles of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) and normal subjects was examined by in situ hybridization using biotinylated oligonucleotide probes. These mRNAs were found preferentially in sarcolemma in the skeletal muscles of both normal subjects and affected patients. Quantitative analysis of mRNA signals demonstrated no prominent reduction of dystrophin or beta-dystroglycan mRNA in DMD/BMD muscles. These results suggest that even mRNAs with deletions contain specific information that affects their localization, and the characteristic defect of dystrophin in DMD/BMD muscles seems to be caused mainly by the instability of dystrophin protein, as a post-transcriptional event.

To investigate the relationship between human T-lymphotropic virus (HTLV) types I and II and the pathogenesis of autoimmune thyroid diseases, we examined serum anti-thyroid antibodies in 1019 blood donors with or without serum anti-HTLV-I antibody as well as proviral DNA for HTLV-II in leukocyte DNA by the polymerase chain reaction in 395 blood donors with or without anti-thyroid antibodies. The frequency of donors with anti-HTLV-I antibody who also showed anti-thyroid antibodies (7.9%) tended to be higher than that (6.3%) among donors who did not have the anti-HTLV-I antibody. The frequency of anti-thyroid antibodies in 125 young male donors aged 16–39 years with anti-HTLV-I antibody (4.8%) was significantly higher (P

Human T-lymphotropic virus type l (HTLV-I) protein and messenger RNA (mRNA) for HTLV-I were examined in thyroid tissues from two patients with Hashimoto's thyroiditis and serum anti-thyroid antibody. The virus envelope protein and signals for the mRNA were detected in many of the follicular epithelial cells of the thyroid tissue from one of the patients, respectively, by immunohistochemistry and in situ hybridization. PCR-Southern blotting revealed the presence of HTLV-I DNA in the thyroid tissue, in which the viral protein and mRNA were detected, although no virus particles were found in the epithelial cells by electron microscopy. HTLV-I virus was not present in the thyroid tissue from the second patient. The present findings suggest that infection of thyroid tissue with HTLV-I is associated with the pathogenesis of Hashimoto's thyroiditis in some patients.

症例は58歳,女性.主訴は吐血.上部消化管内視鏡検査で食道静脈瘤と胃前庭部にびまん性に小斑状の発赤を認め,胃前庭部毛細血管拡張症(GAVE)と診断した.口腔乾燥症状があり,顔面,背部に血管拡張像,手指に皮膚硬化を認め抗セントロメア抗体,抗ミトコンドリア抗体,抗SS-A, B抗体陽性で,腹腔鏡検査,肝生検,唾液腺造影等から強皮症,原発性胆汁性肝硬変(PBC), Sjogren症候群(SjS)に合併したGAVEと診断した.

Background: Chronic progressive external ophthalmoplegia (CPEO), which includes Kearns-Sayre syndrome, is a mitochondrial disorder with large deletions of mitochondrial DNA. Recently, mtDNA deletions in cardiac muscle cells were thought to be a cause of dilated cardiomyopathy. However, the cardiac involvement in patients with CPEO is generally considered to be limited to the cardiac conduction system. Hypothesis: The purpose of this study was to evaluate left ventricular function in patients with CPEO. Methods: We evaluated the cardiac function of five patients with CPEO by means of carotid pulse recording and Doppler echocardiography. Results: The ratio of the pre-ejection period to ejection time was increased to 0.67 in one patient and to 0.50 in another. Echocardiography showed left ventricular dilatation and diffuse hypokinetic wall motion in both cases. Left ventricular fractional shortening was decreased to 5 and 19%, respectively, and the mean rate of circumferential shortening was decreased to 0.12 and 0.63 circ/s, respectively. One of the two patients died of congestive heart failure 2 months after the study. The Doppler pattern of left ventricular filling in the three remaining patients showed a decrease in the ratio of peak flow velocity in early diastole to that in late diastole, with an increase in deceleration time. Conclusion: Although cardiac involvement in patients with CPEO is generally considered to be limited to the cardiac conduction system, left ventricular dysfunction may be present and should receive more attention in the management of patients with CPEO.

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.

Object: The aim of this study was to reveal variations in the patterns of expression of the cell surface proteins in regenerating fibers and those in the number of satellite cells to gain an understanding of the pathological processes involved in sarcoglycanopathy. Methods: We have reported that there is a reduction of the beta-1 subunit of laminin, heparan sulfate proteoglycan (HSPG), and HCAM (CD44) in Japanese patients with sarcoglycanopathy. Here, we investigated immunohistocheniically the expression of the neural cell adhesion molecule (NCAM), which is a marker for human regenerating muscle and satellite cell, and CD24, which appears to be expressed in the early stages of the regeneration process. Patients: We investigated six Japanese patients with sarcoglycanopathy, and compared to age-matched Becker muscular dystrophy. Results: We found that the incidences of muscle fibers with increased NCAM were not statistically different between the two groups. However, the incidences of muscle fibers with increased CD24 and those of NCAM positive satellite cells were very low in sarcoglycanopathy and were statistically different between sarcoglycanopathy and age-matched Becker muscular dystrophies. Conclusion: The poor expression of CD24 and the fewer satellite cells in sarcoglycanopathy without significant difference in the number of total regenerating fibers suggest that a different regeneration process is involved in sarcoglycanopathy compared to that in other types of muscular dystrophy.(Interal Medicine 38: 412-415, 1999)

Genomic clones of human MANB gene encoding the lysosomal enzyme, alpha-mannosidase, have been isolated, sequenced and analyzed. The human MANB gene spans approximately 22 kb and consists of 24 exons. The 5' flanking region of the gene shows a high G+C content and has two Sp1 and three AP-2 sites. Promoter analysis using deletion constructs of the 5' flanking region fused to the bacterial CAT gene showed that 150 bp of 5' sequence could drive the expression of MANB in COS 7 cells. Determination of the sequence of the 5' end of the alpha-mannosidase mRNA by 5' RACE protocol showed that transcription is initiated from a cluster of sites centered -28 and -20 bp from the first in-frame ATG. These data demonstrate that, like other lysosomal enzyme genes such as those for beta-glucuronidase or beta-hexosaminidase, the human MANB gene is controlled by a short 5' flanking sequence located near the initiation codon.

The precise localization and semiquantitative correlation of dystrophin, utrophin and {beta}-dystroglycan expression on the sarcolemma of skeletal muscle cells obtained from patients with Becker muscular dystrophy (BMD) was studied using three types of double immunofluorescence. Staining intensity was measured using a confocal laser microscope. Each of these proteins was identified at the same locus on the sarcolemma. The staining intensities of dystrophin and utrophin were approximately reciprocal at sarcolemmal sites where dystrophin expression was obviously observed. The staining intensity of {beta}-dystroglycan was strong in areas where dystrophin staining was also strong and utrophin expression was weak. Quantitative analysis revealed that the staining intensity of {beta}-dystroglycan minus that of dystrophin approximated the staining intensity of utrophin, indicating that the sum of dystrophin and utrophin expression corresponds to that of {beta}-dystroglycan. These results suggest that utrophin may compensate for dystrophin deficiency found in BMD by binding to {beta}-dystroglycan. 35 refs., 3 figs., 1 tab.

Effects of calcitonin gene-related peptide (CGRP) and interleukin 6 (IL-6) on muscle cell differentiation were studied using cultured rat myoblasts (L6 cells). Cell morphology and the amounts of the messenger RNAs (mRNAs) of myogenin and Myf-5, DNA content, creatine kinase (CK) activity, and myoglobin (Mb) content in the cultured cells were examined serially over 10 days of culture. In the presence of CGRP or IL-6, the mRNAs of myogenin and Myf-5 were expressed earlier and at a higher concentration in the treated cells than in the control cells. The ratios of CK activity to DNA content (CK/DNA) and of Mb content to DNA content (Mb/DNA) on day 10 of culture also were greater than in the control cells. Furthermore, the mRNAs of myogenin and Myf-5 in cultured cells incubated with both CGRP and IL-6 increased more rapidly than in cells cultured with CGRP or IL-6 alone, and the ratios of CK/DNA and Mb/DNA on day 10 were more than twice those in the presence of CGRP or IL-6. These findings indicate that both CGRP and IL-6 facilitate the differentiation of myoblasts and may have an additive effect.

Homozygous adhalin gene mutations were found in three patients from two consanguineous families with autosomal recessive childhood onset muscular dystrophy. Muscle biopsies from patients in each family showed complete absence of adhalin. Sequencing of adhalin cDNA prepared from skeletal muscle by reverse transcription PCR demonstrated a cytosine to thymidine substitution at nt 229 in the patient in family 1 and an adenine to guanine substitution at nt 410 and a 15-base insertion between nt 408 and 409 in the two patients in family 2. Sequencing of genomic DNA prepared from peripheral blood leukocytes by PCR confirmed these mutations. The parents in each family were found to be heterozygous for the respective mutations. These adhalin gene mutations are presumed to be responsible for the absence of adhalin in the skeletal muscle. Adhalin deficiency likely causes disruption of the muscle cell membrane, resulting in dystrophic changes in the skeletal muscle similar to dystrophin deficiency in Duchenne muscular dystrophy.

Three carriers of human T-lymphotropic virus type I (HTLV-I) with Graves' disease are reported. All three cases were complicated with uveitis, and one also showed chronic arthropathy. Anti-HLTV-I antibody was found in the serum by the particle agglutination method and western blotting, and HTLV-I proviral DNA was detected in peripheral lymphocytes by the polymerase chain reaction and Southern blotting. HTLV-I is a causal agent of adult T-cell leukemia and HTLV-I associated myelopathy/tropical spastic paraparesis, and is believed to be related to the pathogenesis of diseases such as chronic arthropathy, uveitis, chronic bronchoalveolitis, and Sjogren's syndrome. On the other hand, retrovirus infection is considered to cause autoimmune diseases. Thus, the pathogenesis of Graves' disease in the present patients might be associated with HTLV-I infection.

We describe two HTLV-I virus carriers who have biopsy-proven Hashimoto's thyroiditis. The first patient, a 64-year-old female, has had goiter and hypothyroidism since the age of 56. The second patient, a 66-year-old male, developed hyperthyroidism and goiter at the age of 44, but at present he is hypothyroid. Both patients are positive for anti-thyroid antibodies and anti-HTLV-I virus antibody. Findings of the thyroid biopsy specimens were consistent with Hashimoto's thyroiditis. These data suggest that Hashimoto's thyroiditis develops in HTLV-I carriers who have no clinical evidence of HAM/TSP.

The isozyme patterns of leukocyte α-d-mannosidase in two sisters with mannosidosis, their parents and a patient with trisomy 19 were studied. The isozyme pattern of liver mannosidase of a normal subject was also studied. In the patients with mannosidosis the neutral isozyme (isozyme C or fraction C) was present, but the acidic isozymes (isozyme A and B or fraction A and B) were not detectable. In their parents the activity of the acidic isozymes was one-third of the normal activity. These findings suggest that the patients are homozygous and their parents are heterozygous in terms of deficiency of acidic isozymes. In the patients with trisomy 19, the activity of α-d-mannosidase was 4.9 times the upper limit of the normal value, while the levels of other lysozomal enzymes were normal. This increase was mainly due to increases of the A and B isozymes of mannosidase. This finding suggests that the gene encoding acidic isozymes, but not that encoding the neutral isozyme, is located on chromosome 19. The isozyme pattern of α-d-mannosidase differed in different tissues of normal subjects, and the difference in severity of lesions in different organs of the patients with mannosidosis could be explained by differences in the isozyme patterns of the enzyme in these organs.

Fetal hemoglobin (HbF) levels determined in healthy Japanese adults ranged from 0.3% to 16.0% as F cells and 0.17% to 2.28% as HbF content, which were the same as those obtained in other countries. The frequency distribution of 300 healthy adults with various numbers of F cells consisted statistically of two different groups, low and high F-cell groups. Individuals with greater than or equal to 4.4% of F cells (HbF about 0.7%) were defined as the high F-cell trait, which accounted for 11.3% of males and 20.7% of females. Family studies of 21 probands with this trait and sex-different frequency analyses in the population and probands revealed X-linked dominant inheritance. Two other families of the trait associated with color blindness were described, although no definitive evidence for linkage was obtained between the two. A review of population and family studies reported in the literature indicated that persons with Swiss-type hereditary persistence of fetal hemoglobin (HPFH) are of the same kind as this trait in their incidence and inheritance form, but represent a portion of the trait with higher levels of HbF or F cells. The existence of X chromosome-localized regulatory gene(s) for the developmental switch of human Hb production is discussed.

常染色体優性の遺伝性を示す家族性特発性大脳基底核石灰化症(FIBGC)の1家系3症例を報告した.発端者16才,女性で, 12才時に拍動性の頭痛を訴えるようになり, 16才で軽度の小脳性運動失調を認めた.そして,頭部X線像および頭部CT像で両側の大脳基底核部と視床に石灰化像を認めた.不随意運動や筋緊張の異常はなく,副甲状腺機能も正常であった.母と母方祖父にも大脳基底核の石灰化像がみられたが,神経症状はみられなかった.本家系では石灰化像の軽い若年の発端者にのみ神経症状が出現しているのが特徴であり,従来のFIBGCの報告例と異なっている.また,錐体外路症状はなく,基底核部石灰化による神経障害は少ないと考えられた.

Human metmyoglobin was separated electrophoretically into four subfractions: Mb(1), Mb(2), Mb(3), and Mb(4), which divide into at least two biochemically independent groups: Mb(1) and Mb(2), and Mb(3), and Mb(4). In normal subjects, Mb(1) constituted the predominant component; Mb(2), Mb(3), and Mb(4) were the minor components in this descending order. In the Duchenne type of progressive muscular dystrophy, on the contrary, a remarkable decrease in Mb(1) and a concomitant increase in Mb(3) were observed. This unique abnormality in the relative distribution of myoglobin subfractions was recognized only in the Duchenne type and not in other types of progressive muscular dystrophy or in other myopathies.