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1.
Children (Basel) ; 10(5)2023 Apr 24.
Article in English | MEDLINE | ID: mdl-37238317

ABSTRACT

Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous inherited disorder that is treatable. Although the disease usually develops at birth or during infancy, some patients develop the disease in the second to third decades of life. Collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ)-related CMS is CMS with mutations in the COLQ, which results in end-plate acetylcholinesterase deficiency. Diagnostic delay is common in patients with later-onset CMS due to slow progression and fluctuating symptoms. Understanding CMS with atypical and unusual presentations is important to treat this condition effectively. Here, we report a case of COLQ-related CMS. A 10-year-old girl presented with only marked fatigue, which was provoked by exercise but improved after 30-60 min of rest. While motor nerve conduction velocity was normal, a compound muscle action potential (CMAP) with four peaks was recorded. Repetitive stimulation of the accessory nerve exhibited a decrease in CMAP amplitude. Genetic tests revealed compound heterozygous mutations in COLQ (c.1196-1_1197delinsTG and c.1354C>T). Treatment with salbutamol improved fatigue but not the electrophysiological markers. Thus, significant fatigue is a hallmark of COLQ-related CMS; early diagnosis is essential for ensuring appropriate treatment.

2.
Microorganisms ; 10(10)2022 Oct 21.
Article in English | MEDLINE | ID: mdl-36296366

ABSTRACT

Previously, we developed a mathematical model via molecular simulation analysis to predict the infectivity of six SARS-CoV-2 variants. In this report, we aimed to predict the relative risk of the recent new variants of SARS-CoV-2 based on our previous research. We subjected Omicron BA.4/5 and BA.2.75 variants of SARS-CoV-2 to the analysis to determine the evolutionary distance of the spike protein gene (S gene) of the variants from the Wuhan variant so as to appreciate the changes in the spike protein. We performed molecular docking simulation analyses of the spike proteins with human angiotensin-converting enzyme 2 (ACE2) to understand the docking affinities of these variants. We then compared the evolutionary distances and the docking affinities of these variants with those of the variants that we had analyzed in our previous research. As a result, BA.2.75 has both the highest docking affinity (ratio per Wuhan variant) and the longest evolutionary distance of the S gene from the Wuhan variant. These results suggest that BA.2.75 infection can spread farther than can infections of preexisting variants.

3.
Microb Risk Anal ; 22: 100227, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35756961

ABSTRACT

Objectives: Variants of a coronavirus (SARS-CoV-2) have been spreading in a global pandemic. Improved understanding of the infectivity of future new variants is important so that effective countermeasures against them can be quickly undertaken. In our research reported here, we aimed to predict the infectivity of SARS-CoV-2 by using a mathematical model with molecular simulation analysis, and we used phylogenetic analysis to determine the evolutionary distance of the spike protein gene (S gene) of SARS-CoV-2. Methods: We subjected the six variants and the wild type of spike protein and human angiotensin-converting enzyme 2 (ACE2) to molecular docking simulation analyses to understand the binding affinity of spike protein and ACE2. We then utilized regression analysis of the correlation coefficient of the mathematical model and the infectivity of SARS-CoV-2 to predict infectivity. Results: The evolutionary distance of the S gene correlated with the infectivity of SARS-CoV-2 variants. The calculated biding affinity for the mathematical model obtained with results of molecular docking simulation also correlated with the infectivity of SARS-CoV-2 variants. These results suggest that the data from the docking simulation for the receptor binding domain of variant spike proteins and human ACE2 were valuable for prediction of SARS-CoV-2 infectivity. Conclusion: We developed a mathematical model for prediction of SARS-CoV-2 variant infectivity by using binding affinity obtained via molecular docking and the evolutionary distance of the S gene.

4.
Kobe J Med Sci ; 68(1): E23-E29, 2022 Dec 21.
Article in English | MEDLINE | ID: mdl-36647083

ABSTRACT

Sleep is important for the well-being of school-aged children. Almost all schools in Hyogo prefecture in Japan were closed from April 7 to May 31, 2020, owing to the coronavirus disease 2019 pandemic. The pandemic restrictions resulted in the disruption of the sleep routines of children. The number of children who experienced sleepiness in class after school closure increased. The number of children who visited our hospital 1 year before and after the closure was 208 (11.73 ± 3.24 years of age) and 155 (11.45 ± 3.30 years), respectively. The number of chief complaints of sleep-related symptoms at the first visits showed no significant difference between the two time periods. The percentage of patients who slept during class increased (but not significantly) after the school closure. However, the mean number and duration of sleep episodes during class significantly increased from 0.31 ± 0.76 to 1.04 ± 1.14 episodes/day and from 15.8 ± 38.6 to 45.7 ± 46.9 min/day (each P < 0.001) before and after school closure, respectively. The total number of patients in our hospital with the primary central disorders of hypersomnolence, i.e., narcolepsy, idiopathic hypersomnia, and Kleine-Levin syndrome, and the number of patients with insufficient sleep syndrome after the school closure significantly increased compared with those before closure (P = 0.034 and 0.048, respectively). School closure was associated with an increased incidence of sleeping during class; therefore, maintaining a stable daily routine for children with sleep disorders could have an alleviating effect.


Subject(s)
COVID-19 , Disorders of Excessive Somnolence , Kleine-Levin Syndrome , Narcolepsy , Child , Humans , COVID-19/epidemiology , Sleep , Disorders of Excessive Somnolence/diagnosis , Narcolepsy/diagnosis , Kleine-Levin Syndrome/diagnosis
5.
Sleep Med ; 87: 97-104, 2021 11.
Article in English | MEDLINE | ID: mdl-34547649

ABSTRACT

OBJECTIVE/BACKGROUND: Core body temperature (CBT) is considered a valuable marker for circadian rhythm. This study aimed to investigate the changes in CBT that are associated with the symptoms of circadian rhythm sleep-wake disorder (CRSWD) post-treatment in children. PATIENTS/METHODS: Twenty-eight school-age children [10 boys and 18 girls; mean age (±standard deviation), 13.68 ± 0.93 years] who were admitted to our hospital with CRSWD underwent treatment for 6-8 weeks according to the following protocol: lights-out for sleep at 21:00; phototherapy for waking at 6:00 or 7:00; light exercise everyday (eg, a 20- to 30-min walk). CBT was continuously measured for 24 h on the first day of admission and on the first day after treatment. RESULTS: The mean time of sleep onset/offset (±standard deviation; in hours:minutes) 1 week before admission and 1 week after treatment were 23:53 ± 2:26/9:58 ± 2:15 and 21:17 ± 0:19/6:46 ± 0:32, respectively. The mean times of sleep onset and offset measured post-treatment were significantly earlier than those measured pre-treatment (p < 0.001). The mean CBT and mean minimum CBT during sleep were significantly lower on the first day post-treatment than on the first day of admission (p = 0.011 and p < 0.001, respectively). CONCLUSIONS: Symptom improvements in patients with CRSWD were associated with a decrease in CBT during sleep, suggesting that CBT may be a biomarker for improvements in CRSWD. These results help elucidate the cause of this sleep disorder.


Subject(s)
Circadian Rhythm , Sleep Disorders, Circadian Rhythm , Body Temperature , Child , Female , Humans , Male , Schools , Sleep , Sleep Disorders, Circadian Rhythm/therapy
6.
J Clin Sleep Med ; 16(12): 2073-2078, 2020 12 15.
Article in English | MEDLINE | ID: mdl-32876042

ABSTRACT

STUDY OBJECTIVES: We aimed to investigate whether improvements in the symptoms of circadian rhythm sleep-wake disorder after treatment were associated with an increase in serum insulin-like growth factor-1 (IGF-1) concentration. METHODS: Eighty-seven school-aged children (32 males, 55 females), aged 14.31 ± 1.50 years (mean ± standard deviation), who were admitted to our hospital with circadian rhythm sleep-wake disorder received treatment for 6-8 weeks consisting of the following protocol: (1) lights-out for sleep occurred at 21:00, (2) phototherapy for waking started at 06:00 or 07:00, and (3) light exercise was required every day (eg, a 20- to 30-minute walk). Blood samples were collected at 08:00 am to measure the serum concentrations of IGF-1, pre- and posttreatment. RESULTS: The mean times of day of sleep onset and offset at the pre- and posttreatment timepoints were 23:32 ± 4.21 and 10:27 ± 2.98, and 21:26 ± 0.55 and 06:50 ± 0.70, respectively. The mean times of day of sleep onset and offset measured at the posttreatment timepoint were significantly earlier compared with the pretreatment baselines (P < .01). The mean serum levels of IGF-1 significantly increased from 315.59 ± 68.26 ng/mL at pretreatment to 335.09 ± 69.78 ng/mL at posttreatment (P < .01). CONCLUSIONS: Improvements in the symptoms of patients with circadian rhythm sleep-wake disorders were associated with increased serum concentrations of IGF-1, suggesting that serum IGF-1 may be a biomarker of improvements in school-aged children with circadian rhythm sleep-wake disorder.


Subject(s)
Insulin-Like Growth Factor I , Melatonin , Sleep Disorders, Circadian Rhythm , Adolescent , Biomarkers , Child , Circadian Rhythm , Female , Humans , Insulin-Like Growth Factor I/analysis , Male , Schools , Sleep , Sleep Disorders, Circadian Rhythm/diagnosis
7.
Sci Rep ; 7(1): 13473, 2017 10 18.
Article in English | MEDLINE | ID: mdl-29044175

ABSTRACT

Pompe disease is caused by an inborn defect of lysosomal acid α-glucosidase (GAA) and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD is still unclear. Here we generated induced pluripotent stem cells (iPSCs) from patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, which was dose-dependently rescued by rhGAA. We further demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in IOPD iPSC-derived myocytes. Comprehensive metabolomic and transcriptomic analyses suggested the disturbance of mTORC1-related signaling, including deteriorated energy status and suppressed mitochondrial oxidative function. In summary, we successfully established an in vitro skeletal muscle model of IOPD using patient-specific iPSCs. Disturbed mTORC1 signaling may contribute to the pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for Pompe disease.


Subject(s)
Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/metabolism , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Muscle, Skeletal/metabolism , Cell Differentiation , Cell Line , Energy Metabolism , Gene Expression , Glucose/metabolism , Glycogen/metabolism , Humans , Lysosomes/enzymology , Mechanistic Target of Rapamycin Complex 1/metabolism , Muscle Cells/metabolism , Muscle Development/genetics , Muscle, Skeletal/pathology , MyoD Protein/genetics , MyoD Protein/metabolism , Phenotype , Transduction, Genetic , alpha-Glucosidases/genetics
8.
No To Hattatsu ; 48(1): 45-7, 2016 Jan.
Article in Japanese | MEDLINE | ID: mdl-27012111

ABSTRACT

Hashimoto's encephalopathy is an anti-thyroid antibody-positive autoimmune encephalopathy. We herein report the case of a 13-year-old male patient with subacute vertigo, muscle weakness in the extremities and gait disturbance who was diagnosed with Hashimoto's encephalopathy. He showed no severe impairment of consciousness and no seizures, and there were no abnormalities on the brain MRI. However, epileptic spike and wave complexes were observed on an electroencephalogram, and a decline in blood flow was diffusely observed on brain SPECT (single photon emission computed tomography). His thyroid function was normal, but he was positive for anti-thyroid antibodies, such as anti-TPO (thyroid peroxidase) antibodies. He was also positive for serum anti-NAE (NH2-terminal alpha-enolase) antibodies. Systemic corticosteroid therapy and high-dose intravenous immunoglobulin therapy were effective, greatly improving his quality of life.


Subject(s)
Encephalitis/complications , Hashimoto Disease/complications , Muscle Weakness/etiology , Vertigo/etiology , Adolescent , Humans , Magnetic Resonance Imaging , Male , Tomography, Emission-Computed, Single-Photon , Ubiquitin-Activating Enzymes/analysis
9.
Mol Ther Methods Clin Dev ; 2: 15023, 2015.
Article in English | MEDLINE | ID: mdl-26199952

ABSTRACT

Pompe disease is an autosomal recessive inherited metabolic disease caused by deficiency of acid α-glucosidase (GAA). Glycogen accumulation is seen in the affected organ such as skeletal muscle, heart, and liver. Hypertrophic cardiomyopathy is frequently seen in the infantile onset Pompe disease. On the other hand, cardiovascular complication of the late-onset Pompe disease is considered as less frequent and severe than that of infantile onset. There are few investigations which show cardiovascular complication of late onset Pompe disease due to the shortage of appropriate disease model. We have generated late-onset Pompe disease-specific induced pluripotent stem cell (iPSC) and differentiated them into cardiomyocytes. Differentiated cardiomyocyte shows glycogen accumulation and lysosomal enlargement. Lentiviral GAA rescue improves GAA enzyme activity and glycogen accumulation in iPSC. The efficacy of gene therapy is maintained following the cardiomyocyte differentiation. Lentiviral GAA transfer ameliorates the disease-specific change in cardiomyocyote. It is suggested that Pompe disease iPSC-derived cardiomyocyte is replicating disease-specific changes in the context of disease modeling, drug screening, and cell therapy.

10.
PLoS One ; 9(12): e113052, 2014.
Article in English | MEDLINE | ID: mdl-25479600

ABSTRACT

Induced pluripotent stem cells (iPSCs) are potentially valuable cell sources for disease models and future therapeutic applications; however, inefficient generation and the presence of integrated transgenes remain as problems limiting their current use. Here, we developed a new Sendai virus vector, TS12KOS, which has improved efficiency, does not integrate into the cellular DNA, and can be easily eliminated. TS12KOS carries KLF4, OCT3/4, and SOX2 in a single vector and can easily generate iPSCs from human blood cells. Using TS12KOS, we established iPSC lines from chimpanzee blood, and used DNA array analysis to show that the global gene-expression pattern of chimpanzee iPSCs is similar to those of human embryonic stem cell and iPSC lines. These results demonstrated that our new vector is useful for generating iPSCs from the blood cells of both human and chimpanzee. In addition, the chimpanzee iPSCs are expected to facilitate unique studies into human physiology and disease.


Subject(s)
Cell Differentiation/genetics , Genetic Vectors , Sendai virus/genetics , Transduction, Genetic , Animals , Cell Line , Cellular Reprogramming/genetics , Gene Expression , Humans , Induced Pluripotent Stem Cells/cytology , Kruppel-Like Factor 4 , Pan troglodytes , Transgenes
11.
Sci Rep ; 4: 5066, 2014 Jun 11.
Article in English | MEDLINE | ID: mdl-24919035

ABSTRACT

The ZHTc6-MyoD embryonic stem cell line expresses the myogenic transcriptional factor MyoD under the control of a tetracycline-inducible promoter. Following induction, most of the ZHTc6-MyoD cells differentiate to myotubes. However, a small fraction does not differentiate, instead forming colonies that retain the potential for myocyte differentiation. In our current study, we found that parathyroid hormone type 1 receptor (PTH1R) expression in colony-forming cells at 13 days after differentiation was higher than that in the undifferentiated ZHTc6-MyoD cells. We also found that PTH1R expression was required for myocyte differentiation, and that parathyroid hormone accelerated the differentiation. Our analysis of human and mouse skeletal muscle tissues showed that most cells expressing PTH1R also expressed Pax7 and CD34, which are biomarkers of satellite cells. Furthermore, we found that parathyroid hormone treatment significantly improved muscle weakness in dystrophin-deficient mdx mice. This is the first report indicating that PTH1R and PTH accelerate myocyte differentiation.


Subject(s)
Cell Differentiation/physiology , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/physiology , Parathyroid Hormone/metabolism , Receptor, Parathyroid Hormone, Type 1/metabolism , Animals , Antigens, CD34/metabolism , Biomarkers/metabolism , Cell Differentiation/drug effects , Cell Line , Embryonic Stem Cells/drug effects , Embryonic Stem Cells/metabolism , Embryonic Stem Cells/physiology , Humans , Mice , Mice, Inbred mdx , Muscle Fibers, Skeletal/drug effects , MyoD Protein/metabolism , PAX7 Transcription Factor/metabolism , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/physiology , Satellite Cells, Skeletal Muscle/drug effects , Satellite Cells, Skeletal Muscle/metabolism , Satellite Cells, Skeletal Muscle/physiology , Tetracycline/pharmacology
12.
Pediatr Int ; 56(5): 748-52, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24689787

ABSTRACT

BACKGROUND: The purpose of this study was to evaluate the utility of a wrist actigraph for estimating muscle strength in Duchenne muscular dystrophy patients. METHODS: Twenty-two patients aged 4-19 years wore a wrist actigraph to monitor activities of daily living, and underwent a test of knee extension strength and the 6 min walk test. These measures were made at baseline and at 1 year later. The actigraph data were quantified using the zero crossing mode (ZCM), which indicates the frequency of movement, and the proportional integration mode (PIM), which indicates activity level or vigor of motion. RESULTS: The ZCM and PIM scores of ambulatory patients were higher than those of non-ambulatory patients (P < 0.001). The correlation coefficient between ZCM score and 6 min walk distance, ZCM score and knee extension strength, PIM score and 6 minute walk distance, and PIM score and knee extension strength was -0.44, 0.25, 0.58, and 0.63, respectively. This indicates that the PIM score had a moderate-good association with 6 min walk distance and knee extension strength. CONCLUSION: Muscle strength can be estimated using the PIM score calculated from actigraph data. The PIM score is a good tool for the estimation of muscle strength.


Subject(s)
Muscle Strength , Muscular Dystrophy, Duchenne/physiopathology , Actigraphy , Adolescent , Child , Child, Preschool , Humans , Young Adult
13.
Case Rep Pediatr ; 2013: 607678, 2013.
Article in English | MEDLINE | ID: mdl-23762716

ABSTRACT

Congenital fiber type disproportion (CFTD) is a form of congenital myopathy, which is defined by type 1 myofibers that are 12% smaller than type 2 myofibers, as well as a general predominance of type 1 myofibers. Conversely, myasthenia gravis (MG) is an acquired immune-mediated disease, in which the acetylcholine receptor (AChR) of the neuromuscular junction is blocked by antibodies. Thus, the anti-AChR antibody is nearly specific to MG. Herein, we report on a case of CFTD with increased anti-AChR antibody levels. A 23-month-old boy exhibited muscle hypotonia and weakness. Although he could walk by himself, he easily fell down and could not control his head for a long time. His blood test was positive for the anti-AChR antibody, while a muscle biopsy revealed characteristics of CFTD. We could not explain the relationship between MG and CFTD. However, we considered different diagnoses aside from MG, even when the patient's blood is positive for the anti-AChR antibody.

14.
Biol Pharm Bull ; 34(5): 712-6, 2011.
Article in English | MEDLINE | ID: mdl-21532162

ABSTRACT

It is known that gentamicin (GM) could be a possible treatment for Duchenne Muscular Dystrophy (DMD). However, GM therapy has been hindered by several problems such as severe side effects of GM. In order to resolve these problems, we developed the drug delivery system (DDS) of GM using hybrid liposomes (HL) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) lauryl ether (C12(EO)23). The hydrodynamic diameters of HL including GM (GM-HL) were 60-90 nm with a narrow range of the size distribution and the sizes were kept almost constant for over 4 weeks, suggesting that GM-HL could avoid the reticuloendothelial system in vivo. Furthermore, GM-HL accumulated more to the skeletal muscle cells of X chromosome-linked muscular distrophy (mdx) mice as compared to those of normal mice. Significantly, we succeeded in increasing dystrophin positive fibers in skeletal muscle cells of mdx mice using GM-HL along with the reduction of ototoxicity. It is suggested that GM should be carried more efficiently into the muscular cells of mdx mice by HL. These results indicate that HL could be an effective carrier in the DDS of GM therapy for DMD.


Subject(s)
Drug Delivery Systems , Gentamicins/therapeutic use , Liposomes , Muscular Dystrophy, Duchenne/drug therapy , Animals , Female , Gentamicins/administration & dosage , Gentamicins/adverse effects , Male , Mice , Microscopy, Confocal
15.
Pediatr Int ; 53(4): 524-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21342350

ABSTRACT

BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by abnormalities in the DMD gene. The majority of DMD patients have out-of-frame deletion(s), which disrupt the reading frame; while some cases of DMD are caused by duplication or nonsense mutation(s). Most patients with BMD have in-frame deletion(s), which preserve the reading frame. The phenotype of BMD is generally milder than that of DMD. Antisense morpholino-mediated exon skipping, which changes out-of-frame deletions to in-frame deletions, is a promising therapeutic approach for DMD. It is necessary, however, to confirm the exon-skipping event in cells of DMD patients before the clinical trial. METHODS: Fibroblasts isolated from four DMD patients were induced to differentiate into the myogenic lineage by infection with Ad.CAGMyoD. The cells were then transfected with two types of morpholino. The exon-skipping event was analyzed on reverse transcription-polymerase chain reaction. RESULTS: Morpholino B30, which is located at the splicing enhancer of exon 51 of the DMD gene, yielded the desired exon 51-skipping event in all deletion patterns of cells tested. Morpholino I25, which is located at the exon donor, induced two different exon-skipping patterns, which are total or partial exon 51-skipping events. According to the sequence analysis, the unexpected unskipped regions were the 95 bp section and the 188 bp section of exon 51, showing that the cryptic splicing donor was newly produced with I25. Unfortunately, these cryptic splicing donors gave rise to out-of-frame patterns. Based on these in vitro results, B30 would presumably be an effective therapy. Interestingly, the cocktail of B30 and I25 appeared to yield a more efficient exon 51-skipping event. CONCLUSION: An in vitro system was developed that could easily screen the effectiveness of antisense sequences and identify good candidates for therapy with morpholino.


Subject(s)
Exons , Genetic Therapy , Morpholinos/therapeutic use , Muscular Dystrophy, Duchenne/therapy , Oligonucleotides, Antisense/therapeutic use , Sequence Deletion , Clinical Trials as Topic , DNA/genetics , Fibroblasts , Humans , In Vitro Techniques , Muscular Dystrophy, Duchenne/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Thionucleotides/therapeutic use , Transfection
16.
Pediatr Neurol ; 41(1): 46-8, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19520275

ABSTRACT

Myoclonic epilepsy associated with ragged-red fibers is one of the mitochondrial encephalomyopathies. Pathogenic mitochondrial DNA mutations have been identified in the mitochondrial transfer RNA (tRNA)(Lys) at positions 8344 and 8356. Characteristics of myoclonic epilepsy associated with ragged-red fibers include myoclonic epilepsy, generalized epilepsy, hearing loss, exercise intolerance, lactic acidosis, and ragged-red fibers. The elevated lactate level is one of the most important symptoms needed to make a diagnosis of mitochondrial encephalomyopathy. In the present case, however, myoclonic epilepsy was associated with ragged-red fibers but without increased lactate levels. Therefore, myoclonic epilepsy associated with ragged-red fibers should be suspected in a patient who has myoclonic epilepsy that is difficult to control with antiepileptic medications and who has other symptoms of mitochondrial disease, such as mental retardation, even if the patient's lactate level is normal.


Subject(s)
Epilepsies, Myoclonic/blood , Epilepsies, Myoclonic/diagnosis , Lactic Acid/blood , Mitochondrial Encephalomyopathies/blood , Mitochondrial Encephalomyopathies/diagnosis , Adolescent , Anticonvulsants/therapeutic use , DNA Mutational Analysis , DNA, Mitochondrial , Diagnosis, Differential , Epilepsies, Myoclonic/complications , Epilepsies, Myoclonic/drug therapy , Humans , Male , Mitochondrial Encephalomyopathies/complications , Muscle, Skeletal/pathology , Mutation , Pedigree , RNA, Transfer, Lys/genetics
17.
Genet Med ; 11(3): 210-9, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19287243

ABSTRACT

PURPOSE: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease. METHODS: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort. RESULTS: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns. CONCLUSIONS: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.


Subject(s)
Glycogen Storage Disease Type II/drug therapy , alpha-Glucosidases/therapeutic use , Body Height , Body Weight , Child, Preschool , Cough/chemically induced , Echocardiography , Enzyme-Linked Immunosorbent Assay , Female , Glycogen/metabolism , Glycogen Storage Disease Type II/metabolism , Glycogen Storage Disease Type II/physiopathology , Humans , Immunoglobulin G/blood , Infant , Kaplan-Meier Estimate , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Skin Diseases/chemically induced , Time Factors , Treatment Outcome , alpha-Glucosidases/adverse effects , alpha-Glucosidases/immunology
18.
Brain Dev ; 31(2): 169-72, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18430534

ABSTRACT

Duchenne muscular dystrophy (DMD) is caused by mutation of the dystrophin gene. Cases of dystrophinopathy with a 2-bp deletion in the dystrophin gene commonly result in DMD. We report here a case of dystrophinopathy in a 9-years-old boy with a 2-bp deletion in exon 74 of the dystrophin gene; however, the boy had no clear clinical signs of muscle weakness. Immunohistochemical studies with N-terminal (DYS3) and rod-domain anti-dystrophin (DYS1) antibodies revealed that the dystrophin signals were weaker than in the control sample (non-dystrophinopathy) at the sarcolemma of myofibers, and the studies with C-terminus anti-dystrophin antibody (DYS2) were negative. Our patient's mutation is located between the binding sites of alpha-syntrophin and alpha-dystrobrevin. These results suggest that this mutation does not clearly induce muscle weakness at least through the age of 9 years.


Subject(s)
Dystrophin/genetics , Muscle Weakness/genetics , Sequence Deletion , Base Sequence , Binding Sites , Blotting, Western , Calcium-Binding Proteins/metabolism , Child , Dystrophin/metabolism , Dystrophin-Associated Proteins/metabolism , Exons , Genes , Humans , Immunohistochemistry , Male , Membrane Proteins/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle Proteins/metabolism , Muscle Weakness/physiopathology , Sarcolemma/metabolism
19.
J Child Neurol ; 22(7): 901-6, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17715288

ABSTRACT

One cause of X-linked dilated cardiomyopathies is mutation of the dystrophin gene. We report the case of a young boy who suffered from dilated cardiomyopathy caused only by dystrophin-deficient cardiac muscle, but who did not present with any clinical signs of skeletal myopathy. Sequence analysis of the patient's dystrophin gene revealed the presence of a novel single point mutation at the first exon-intron boundary, inactivating the 5' splice site consensus sequence of the first intron. The lack of muscle weakness observed clinically can be explained by expression of the brain and Purkinje dystrophin isoforms in skeletal muscle.


Subject(s)
Cardiomyopathy, Dilated/genetics , Consensus Sequence/genetics , Dystrophin/genetics , Point Mutation/genetics , RNA Splice Sites/genetics , Adolescent , Dystrophin/metabolism , Humans , Male , Muscle, Skeletal/metabolism , Myocardium/metabolism , Myocardium/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism
20.
Biochem Biophys Res Commun ; 357(4): 957-63, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17466266

ABSTRACT

We established genetically engineered ES (ZHTc6-MyoD) cells that harbor a tetracycline-regulated expression vector encoding myogenic transcriptional factor MyoD, for the therapy of muscle diseases, especially Duchenne muscular dystrophy (DMD). Almost all the ZHTc6-MyoD cells were induced into muscle lineage after removal of tetracycline. The undifferentiated ZHTc6-MyoD cells are Sca-1+ and c-kit+, but CD34-, all well-known markers for mouse hematopoietic stem cells. In addition, they are able to maintain themselves in the undifferentiated state, even after one month of culture. Therefore, it is possible to obtain a large quantity of ZHTc6-MyoD cells in the undifferentiated state that maintain the potential to differentiate only into muscle lineage. Additionally, at two weeks post-injection of these cells into muscle of mdx, a model mouse of DMD, clusters of dystrophin-positive myofibers were observed at the injection site. Therefore, ES cells have considerable therapeutic potential for treating muscle diseases.


Subject(s)
Cell Culture Techniques/methods , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Genetic Engineering/methods , Muscle Cells/cytology , Muscle Cells/metabolism , MyoD Protein/genetics , Animals , Cells, Cultured , Mice , Tissue Engineering/methods
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