Publications by authors named "Keiko Ishigaki"

38 Publications

Urinary titin as a biomarker in Fukuyama congenital muscular dystrophy.

Neuromuscul Disord 2021 03 13;31(3):194-197. Epub 2021 Jan 13.

Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address:

Fukuyama congenital muscular dystrophy (FCMD) is the second most prevalent childhood-onset muscular dystrophy in Japan. It is an autosomal recessive disorder caused by the fukutin mutation (FKTN), characterized by muscle wasting and brain abnormalities. So far, serum creatine kinase (CK) is recognized as the only biomarker for FCMD. Recently, an ELISA assay to quantify the N-terminal fragment of titin in urine was developed. Urinary titin concentration is elevated in patients with Duchenne muscular dystrophy (DMD) compared to normal controls. Levels vary according to age with excellent sensitivity and specificity for detecting DMD, and they can be used as a diagnostic and disease progression marker. In this study, we measured the urinary titin concentration of 18 patients with FCMD. It was remarkably higher than normal controls and correlated with CK. Especially in homozygotes, the score for gross motor function measure, which is a quantitative motor scale for FCMD, was correlated with urinary titin concentration. Elevated urinary titin concentrations were thought to be reflective of a common pathophysiology with DMD. Urinary titin concentrations can assist with making the diagnosis of FCMD and to estimate the patient's motor function at that point.
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http://dx.doi.org/10.1016/j.nmd.2021.01.005DOI Listing
March 2021

Infection-associated decrease of serum creatine kinase levels in Fukuyama congenital muscular dystrophy.

Brain Dev 2021 Mar 2;43(3):440-447. Epub 2020 Dec 2.

Department of Pediatrics, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

Background: Marked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases.

Subjects And Methods: The influence of systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy.

Results: A total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions.

Conclusion: Apart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.
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http://dx.doi.org/10.1016/j.braindev.2020.11.009DOI Listing
March 2021

Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy.

J Hum Genet 2021 Apr 10;66(4):401-407. Epub 2020 Oct 10.

Department of Human Genetics, Graduate school of medicine, Yokohama City University, Yokohama, Japan.

Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.
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http://dx.doi.org/10.1038/s10038-020-00853-2DOI Listing
April 2021

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

Sleep Breath 2020 Aug 18. Epub 2020 Aug 18.

Department of Respiratory Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.

Background: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact.

Purpose: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes).

Methods: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed.

Result: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending).

Discussion: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection.

Clinical Trial Registration Number: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).
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http://dx.doi.org/10.1007/s11325-020-02170-6DOI Listing
August 2020

A short form of gross motor function measure for Fukuyama congenital muscular dystrophy.

Brain Dev 2020 May 4;42(5):383-388. Epub 2020 Mar 4.

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address:

Objectives: The objective of this study was to confirm the validity of a short form of gross motor function measure for Fukuyama congenital muscular dystrophy (GMFM for FCMD).

Methods: This study is a case series and was conducted at the Tokyo Women's Medical University. Fifteen patients with FCMD were assessed using both the GMFM for FCMD with 68 items, which was created as a motor function measure for patients with FCMD on the basis of Rasch analysis, and the original GMFM with 88 items. The correlation between the GMFM for FCMD and the Ueda classification was assessed. Time required for each assessment was also evaluated.

Results: We found significant correlation between the GMFM for FCMD and the Ueda classification (r = 0.935); furthermore, the mean assessment time tended to decrease when using the GMFM for FCMD.

Conclusions: GMFM for FCMD may be an appropriate motor function scale for patients with FCMD and might help decrease the assessment time.
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http://dx.doi.org/10.1016/j.braindev.2020.02.006DOI Listing
May 2020

Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy.

Ann Clin Transl Neurol 2020 02 20;7(2):181-190. Epub 2020 Jan 20.

National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D (PGD ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years.

Methods: Patients were randomized 1:1:1 to receive low-dose TAS-205 (6.67-13.33 mg/kg/dose), high-dose TAS-205 (13.33-26.67 mg/kg/dose), or placebo. The primary endpoint was the change from baseline in a 6-minute walk distance (6MWD) at Week 24.

Results: Thirty-six patients were enrolled, of whom 35 patients were analysed for safety. The mean (standard error) changes from baseline to Week 24 in 6MWD were -17.0 (17.6) m in the placebo group (n = 10), -3.5 (20.3) m in the TAS-205 low-dose group (n = 11), and -7.5 (11.2) m in the TAS-205 high-dose group (n = 11). The mean (95% confidence interval) difference from the placebo group was 13.5 (-43.3 to 70.2) m in the TAS-205 low-dose group and 9.5 (-33.3 to 52.4) m in the TAS-205 high-dose group. No obvious differences were observed in the incidences of adverse events between treatment groups. No adverse drug reactions specific to TAS-205 treatment were observed.

Interpretation: The HPGDS inhibitor TAS-205 showed a favorable safety profile in DMD patients. Further research is required to examine the effectiveness of TAS-205 in a larger trial.
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http://dx.doi.org/10.1002/acn3.50978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034509PMC
February 2020

[Study of care practices for patients with myotonic dystrophy in Japan-Nationwide patient survey].

Rinsho Shinkeigaku 2020 Feb 18;60(2):130-136. Epub 2020 Jan 18.

Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center.

We conducted a comprehensive anonymous questionnaire survey on medical care and treatment for patients with myotonic dystrophy, who registered in the Japanese national registry (Remudy) or were undergoing care in seven hospitals specializing neuromuscular diseases. The questionnaire consisted of 49 questions were distributed to 813 patients, and 342 valid responses were collected. Most prevalent symptoms or complaints were dysfunction of fingers and fatigue. One-third of the adult patients left the job, half of which was due to the disease. Twelve percent of the patients did not visit the specialist regularly, the main reason being distance. The most common reason that the patients did not follow the advice of using a ventilator by medical professionals was lack of feeling the need. One-fourth of the adult female patients had infertility treatment, 80% of which was before a diagnosis of this disorder. This first-time nationwide survey revealed the actual condition of Japanese patients with myotonic dystrophy and raised various care-related issues.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001349DOI Listing
February 2020

[Study of medical practices for patients with myotonic dystrophy in Japan-Nationwide specialist survey].

Rinsho Shinkeigaku 2020 Feb 18;60(2):120-129. Epub 2020 Jan 18.

Division of Health Science, Osaka University Graduate School of Medicine.

To reveal current status of medical practice, we made a nationwide self-questionnaire survey to Japanese certified Neurologists and Child Neurologists. Most specialists seeing patients with myotonic dystrophy (DM) were aware that genetic analysis is approved in health insurance. The ratio of pre-explanation about genetic analysis was also high however written informed consent was not always obtained. Over 60% of specialists regarded motor dysfunction, conduction block/arrhythmia, heart failure, dysphagia, hypoventilation as important complications, while no more than 35% of specialists regarded hypoxia/apnea, multi-organ complications, which are feature of myotonic dystrophy, as important. Over half specialists did not check Holter electrocardiogram, sleep respiratory examination, or swallowing function regularly. This fact implied that cumbersome examinations tended to be refrained from regular assessment. Child neurologists were more aggressive in respiratory care and consultation of cardiovascular specialists. A few neurologists hesitated to introduce mechanical ventilation and tube feeding.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001347DOI Listing
February 2020

Study of uterine kinetics in nonpregnant women using cine-mode magnetic resonance imaging.

Reprod Med Biol 2019 Oct 8;18(4):370-377. Epub 2019 Aug 8.

Soranomori Clinic Yaese Japan.

Purpose: To evaluate the uterine kinetics in each phase of the menstrual cycle when observed in detail using cine-mode magnetic resonance imaging (MRI) of sagittal and transverse plane images.

Methods: Seven volunteers with a history of multiple natural pregnancies and deliveries were enrolled from January 2017 to May 2017. The kinetic parameters (depth, frequency, and direction) of uterine muscle contractions were evaluated in cine-mode MRI.

Results: Strong contractions from the uterine cornua to cervix were detected during menstruation. In the late follicular phase, the frequency of opposing contractions from the cervix and uterine cornua increased. Immediately before ovulation, contractions from the cervix reached the uterine fundus. After ovulation, opposing contractions returned. These contractions gradually decreased in the mid-luteal phase, while fine contractions from the cervix to the middle of the uterine body were frequently observed until 7 days after ovulation. Few contractions were observed in the implantation phase.

Conclusions: Our data suggest that the uterine kinetics change in each phase of the menstrual cycle in accordance with the purpose of the uterus in each phase. Further, cine-mode MRI studies of each phase are needed to assess the relationships between uterine kinetics and infertility.
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http://dx.doi.org/10.1002/rmb2.12295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780040PMC
October 2019

Assessment of muscle involvement in patients with Duchenne muscular dystrophy via segmental multifrequency bioelectrical analysis.

Neuromuscul Disord 2019 09 21;29(9):671-677. Epub 2019 Aug 21.

Department of Neurology, Yokohama Rosai Hospital, Yokohama, Japan.

We investigated the usefulness of segmental multifrequency bioelectrical impedance analyses (MBIA) for assessing muscle involvement in Duchenne muscular dystrophy (DMD) patients. Bioelectrical impedance data of the upper arm, thigh, and lower leg were obtained from 29 boys with DMD (ages 2-17 years old; mean 10.8 ± 3.9 years) at three institutions along with 41 healthy controls (ages 3-16; mean 9.8 ± 3.5 years). Then the muscle density index (MDI: 1- Z/Z) was calculated using segmental MBIA and compared between groups. The MDI was lower in boys with DMD, relative to controls, with older DMD patients exhibiting a significant decrease in MDI. The MDI of patient thighs was significantly correlated with the percent muscle volume index (%MVI), as measured using computed tomography (r = 0.79). MDI values for the upper arm, thigh, and lower leg were all significantly correlated with the Brooke and the Vignos scales, respectively, with correlation coefficients of 0.56-0.77. Finally, MDI was significantly greater in the glucocorticoid-treated group, relative to the untreated group in all regions. Taken together, these data show that segmental MBIA is feasible for evaluating muscle involvement and might serve as an outcome measure in DMD.
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http://dx.doi.org/10.1016/j.nmd.2019.08.006DOI Listing
September 2019

National registry of patients with Fukuyama congenital muscular dystrophy in Japan.

Neuromuscul Disord 2018 10 10;28(10):885-893. Epub 2018 Aug 10.

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan; The Japan Muscular Dystrophy Association, Tokyo, Japan.

Fukuyama congenital muscular dystrophy (FCMD) is the second most common form of muscular dystrophy in the Japanese population and is caused by mutations in the fukutin (FKTN) gene. In 2011, the Japan Muscular Dystrophy Association (JMDA) developed a nationwide registry of genetically confirmed patients with FCMD. We retrospectively reviewed the registry dataset of patients with FCMD to obtain data, including age, sex, developmental milestones, intellectual level, complications, and primary treatments. In total, 207 patients with FCMD (104 boys and 103 girls) were registered by the end of September 2013. Mean patient age at first registration was 8.1 ± 7.8 years (median, 6 years; range, 0-42 years). A homozygous 3-kb founder insertion mutation in the FKTN gene was present in 80% of registrants, whereas 20% had a compound heterozygous mutation. Sixty-nine patients (33%) had febrile seizures and/or epilepsy. Myopia was the most frequently detected abnormality (8.7%), followed by strabismus (5.9%). Overall, 16% of patients required respiratory support and this percentage increased with age. Cardiac dysfunction was detected in 16%, and dysphagia was observed in 22% of patients with FCMD. The FCMD patient registry is useful for clarifying the natural history of FCMD and recruiting patients for clinical trials.
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http://dx.doi.org/10.1016/j.nmd.2018.08.001DOI Listing
October 2018

Characteristic findings of skeletal muscle MRI in caveolinopathies.

Neuromuscul Disord 2018 10 31;28(10):857-862. Epub 2018 Jul 31.

Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan. Electronic address:

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.
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http://dx.doi.org/10.1016/j.nmd.2018.07.010DOI Listing
October 2018

Renal dysfunction is rare in Fukuyama congenital muscular dystrophy.

Brain Dev 2019 Jan 1;41(1):43-49. Epub 2018 Aug 1.

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.

Background: The leading cause of death in patients with Fukuyama congenital muscular dystrophy (FCMD) is congestive heart failure or respiratory dysfunction, which is same as that in Duchenne muscular dystrophy (DMD). Recent studies reported that renal dysfunction is a common complication and an increasing cause of death in advanced DMD. It can be attributable to circulatory instability or inappropriate use of drugs for treating cardiac dysfunction.

Methods: We retrospectively evaluated renal function in 38 genetically diagnosed patients with FCMD (range, 1.3-32.9 years; mean age, 13.7 ± 6.9 years) using cystatin C. We examined possible relationships of cystatin C with blood natriuretic peptide and creatinine levels along with cardiac echocardiography findings.

Results: Twenty-five patients were treated for cardiac dysfunction. Elevated cystatin C level was detected only in two, who also showed proteinuria, glycosuria, hematuria, and extremely high β2-microglobulin levels on urine tests, and were thus diagnosed with renal tubular cell damage. Because both patients were treated for intractable epilepsy with various antiepileptic drugs, including valproic acid (VPA), and had low serum carnitine levels, renal tubular cell damage was considered as an adverse effect of VPA. Unlike patients with DMD, no patient with FCMD had renal dysfunction. Such a rare occurrence of renal dysfunction can be attributable to mild cardiac dysfunction, short disease duration, and careful and early fluid management.

Conclusion: Renal dysfunction is rare in patients with FCMD; however, renal tubular cell damage should be ascertained, particularly in those undergoing VPA treatment for epilepsy.
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http://dx.doi.org/10.1016/j.braindev.2018.07.012DOI Listing
January 2019

[The pitfalls of using diagnosis and treatment guidelines for patients with juvenile myasthenia gravis].

Authors:
Keiko Ishigaki

No To Hattatsu 2017 03;49(2):87-93

Even though evidence-based clinical guidelines are useful for the management of common diseases, there are several problems in applying such guidelines to patients with rare diseases. First, there are few references providing high-level evidence pertaining to such diseases, and randomized control as well as large cohort studies are lacking. Most grades of recommendation are “suggest” rather than “recommend” or, often, are based on “expert opinion”. Juvenile myasthenia gravis (MG) is a rare disease and has mainly been reported in East Asia. In 2014, evidence-based clinical guidelines for MG diagnosis and treatment were published in Japan. Since references were scarce, these guidelines were also based on expert opinions such as those of a few institutes or specialists who had gathered most of the patients in Japan. The guidelines might be of limited usefulness for general pediatricians or pediatric neurologists with no MG experience, and we should be aware of strengths and pitfalls when applying such guidelines. For example, while knowing when to start steroid administration or the appropriate steroid dose is feasible, the optimal timing of switching from an anti-cholinesterase drug to a steroid or adding an anti-inflammatory drug and how to decrease or stop steroid administration cannot be ascertained from the guidelines. The lack of references with high-level evidence makes the guidelines difficult to apply, since this would be the information most desired by clinicians. Another problem is that a recommendation may easily be reversed if opposing results are obtained in a single study of a rare disease. Thymectomy was recognized as not being beneficial for MG without thymoma but one recent study reversed this recommendation in the guidelines. Herein, we discuss pitfalls in applying diagnostic and treatment guidelines in patients with juvenile MG.
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March 2017

The gross motor function measure is valid for Fukuyama congenital muscular dystrophy.

Neuromuscul Disord 2017 Jan 20;27(1):45-49. Epub 2016 Sep 20.

Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address:

Fukuyama congenital muscular dystrophy (FCMD) is the second most common muscular dystrophy in Japan. FCMD is an autosomal recessive disorder caused by mutations in the fukutin gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities, and mental retardation associated with cortical migration defects, and most patients are never able to walk. To date, the development of a quantitative motor scale for FMCD has been difficult due to the moderate-to-severe intellectual impairment that accompanies FCMD. Gross motor function measure (GMFM), originally developed as a quantitative motor scale for cerebral palsy, can precisely and quantitatively assess motor function without complicated instructions, and was recently reported to be useful in the assessment of Down syndrome and spinal muscular atrophy. To confirm the validity of GMFM for the assessment of FCMD, 41 FCMD patients (age range: 0.6-24.4 years) were recruited for this study. The GMFM scores correlated significantly with those of two previously used motor scales, and the time-dependent change in GMFM scores was consistent with the natural course of FCMD. The inter-rater reliability, based on determinations made by four physiotherapists blinded to each other's assessment results, was excellent. We concluded GMFM to be a useful and valid measure of motor function in FCMD patients.
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http://dx.doi.org/10.1016/j.nmd.2016.09.014DOI Listing
January 2017

[Central Nervous Involvement in Patients with Fukuyama Congenital Muscular Dystrophy].

Authors:
Keiko Ishigaki

Brain Nerve 2016 Feb;68(2):119-27

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine.

Fukuyama congenital muscular dystrophy (FCMD), the second most common muscular dystrophy in the Japanese population, is an autosomal recessive disorder caused by mutations in the fukutin (FKTN) gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities and central nervous system involvement with mental retardation and seizures associated with cortical migration defects. The FKTN gene product is thought to be necessary for maintaining migrating neurons in an immature state during migration, and for supporting migration via α-dystroglycan in the central nervous system. Typical magnetic resonance imaging findings in FCMD patients are cobblestone lissencephaly and cerebellar cystic lesions. White matter abnormalities with hyperintensity on T(2)-weighted images are seen especially in younger patients and those with severe phenotypes. Most FCMD patients are mentally retarded and the level is moderate to severe, with IQs ranging from 30 to 50. In our recent study, 62% of patients developed seizures. Among them, 71% had only febrile seizures, 6% had afebrile seizures from the onset, and 22% developed afebrile seizures following febrile seizures. Most patients had seizures that were controllable with just 1 type of antiepileptic drug, but 18% had intractable seizures that must be treated with 3 medications.
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http://dx.doi.org/10.11477/mf.1416200361DOI Listing
February 2016

[Clinical characteristics and managements of juvenile myasthenia gravis].

Authors:
Keiko Ishigaki

Nihon Rinsho 2015 Sep;73 Suppl 7:533-8

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September 2015

Respiratory management of patients with Fukuyama congenital muscular dystrophy.

Brain Dev 2016 Mar 9;38(3):324-30. Epub 2015 Sep 9.

Tokyo Women's Medical University, School of Medicine, Tokyo, Japan. Electronic address:

Background: Fukuyama congenital muscular dystrophy (FCMD), characterized by intellectual impairment associated with cortical migration defects, is an autosomal recessive disorder caused by mutation in the fukutin gene. It is the second most common type of muscular dystrophy in Japan. Respiratory dysfunction, along with cardiomyopathy, can be life-threatening in patients with advanced-stage FCMD. However, few reports have focused on this issue.

Methods: We retrospectively studied respiratory dysfunction and therapeutic management in 48 genetically diagnosed FCMD patients (mean age 11.0 years; range 3.6-31.9 years).

Results: Mechanical ventilation was initiated at a median age of 12.1 years in 16 patients, 14 of whom received non-invasive positive pressure ventilation (NPPV) while the other 2 underwent tracheostomy with invasive ventilation (TIV). The two TIV cases had unexpectedly required the initiation of ventilatory support at the ages of 15.7 and 18.0 years, respectively, because of unsuccessful extubation followed by serious respiratory infections, despite rather good respiratory function before these episodes. Patients carrying a compound heterozygous founder mutation or with a severe phenotype tended to need ventilatory support 2-3 years earlier than homozygous patients and those with the typical or mild phenotype. Mechanical insufflation-exsufflation (MI-E) interventions were also employed in six patients with serious dysphagia and were well-tolerated in all cases.

Conclusion: For respiratory management, it is important to regularly evaluate respiratory function in FCMD patients over 10 years of age, since intellectual impairment and insomnia often mask the signs of respiratory dysfunction. Most patients, despite poor cooperation due to intellectual impairment, can tolerate NPPV and MI-E provided that a carefully worked-out plan is adopted.
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http://dx.doi.org/10.1016/j.braindev.2015.08.010DOI Listing
March 2016

Congenital myasthenic syndrome in Japan: ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits.

Neuromuscul Disord 2015 Jan 10;25(1):60-9. Epub 2014 Sep 10.

Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Congenital myasthenic syndromes (CMS) are caused by mutations in genes expressed at the neuromuscular junction. Most CMS patients have been reported in Western and Middle Eastern countries, and only four patients with COLQ mutations have been reported in Japan. We here report six mutations in acetylcholine receptor (AChR) subunit genes in five Japanese patients. Five mutations are novel, and one mutation is shared with a European American patient but with a different haplotype. Among the observed mutations, p.Thr284Pro (p.Thr264Pro according to the legacy annotation) in the epsilon subunit causes a slow-channel CMS. Five other mutations in the delta and epsilon subunits are splice site, frameshift, null, or missense mutations causing endplate AChR deficiency. We also found a heteroallelic p.Met465Thr in the beta subunit in another patient. p.Met465Thr, however, was likely to be polymorphism, because single channel recordings showed mild shortening of channel openings without affecting cell surface expression of AChR, and the minor allelic frequency of p.Met465Thr was 5.1% in the Japanese population. Lack of shared mutant alleles between the Japanese and the other patients suggests that most mutations described here are ethnically unique or de novo in each family.
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http://dx.doi.org/10.1016/j.nmd.2014.09.002DOI Listing
January 2015

Congenital fiber type disproportion myopathy caused by LMNA mutations.

J Neurol Sci 2014 May 5;340(1-2):94-8. Epub 2014 Mar 5.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan. Electronic address:

A boy, who had shown muscle weakness and hypotonia from early childhood and fiber type disproportion (FTD) with no dystrophic changes on muscle biopsy, was initially diagnosed as having congenital fiber type disproportion (CFTD). Subsequently, he developed cardiac conduction blocks. We reconsidered the diagnosis as possible LMNA-myopathy and found a heterozygous mutation in the LMNA gene. This encouraged us to search for LMNA mutations on 80 patients who met the diagnostic criteria of CFTD with unknown cause. Two patients including the above index case had heterozygous in-frame deletion mutations of c.367_369delAAG and c.99_101delGGA in LMNA, respectively. Four of 23 muscular dystrophy patients with LMNA mutation also showed fiber type disproportion (FTD). Importantly, all FTD associated with LMNA-myopathy were caused by hypertrophy of type 2 fibers as compared with age-matched controls, whereas CFTD with mutations in ACTA1 or TPM3 showed selective type 1 fiber atrophy but no type 2 fiber hypertrophy. Although FTD is not a constant pathological feature of LMNA-myopathy, we should consider the possibility of LMNA-myopathy whenever a diagnosis of CFTD is made and take steps to prevent cardiac insufficiency.
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http://dx.doi.org/10.1016/j.jns.2014.02.036DOI Listing
May 2014

Pneumothorax in patients with severe combined immunodeficiency.

Pediatr Int 2014 Aug 30;56(4):510-4. Epub 2014 May 30.

Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Background: Most infants with pneumothorax have underlying conditions. Pneumocystis jirovecii pneumonia (PCP) frequently occurs in patients with severe combined immunodeficiency (SCID). The aim of this study was to determine clinical features of PCP-associated pneumothorax in SCID patients.

Methods: The medical records of four SCID patients with pneumothorax were retrospectively reviewed.

Results: All four patients were diagnosed as having SCID at the time of contracting PCP. All patients received mechanical ventilation because of severe respiratory failure. Only one patient was successfully extubated and was alive following hematopoietic stem cell transplantation (HSCT); of the remaining patients, however, two died of respiratory failure, and one patient died of early HSCT-related complications.

Conclusions: Pneumothorax associated with PCP can occur in SCID patients, and they may have a poor prognosis. If pneumothorax occurs in infants, both respiratory management and prompt investigation of the underlying conditions are needed, considering the possibility of PCP associated with SCID.
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http://dx.doi.org/10.1111/ped.12325DOI Listing
August 2014

Microdeletions of 3p21.31 characterized by developmental delay, distinctive features, elevated serum creatine kinase levels, and white matter involvement.

Am J Med Genet A 2013 Dec 16;161A(12):3049-56. Epub 2013 Aug 16.

Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.

Interstitial deletions of chromosome 3 are rare, and only one patient with a microdeletion of 3p21.31 has been reported to date. We identified two additional cases of patients with microdeletions of 3p21.31. The characteristic clinical features of developmental delay and distinctive facial features (including arched eyebrows, hypertelorism, epicanthus, and micrognathia) were seen both in the previously reported patient and in the two newly identified patients. In these two new cases, additional features, including elevated serum creatine kinase levels and characteristic neuroradiological features with white matter involvement, were seen. These features had not been described in the previous case in which the patient was examined during infancy, suggesting an age-dependent mechanism. The shortest region of overlap among the three deletions narrowed down the candidate genes that may be responsible for the common neurological features to the bassoon (presynaptic cytomatrix protein) gene (BSN), which has an important function in neuronal synapses. In this study, we confirmed common phenotypic features in the patients with microdeletions of 3p21.31 and identified additional features that have not been reported previously. Because the constellation of such characteristic features is quite unique, clinical manifestations of the patients with microdeletions of 3p21.31 would be clinically recognizable as a contiguous gene deletion syndrome.
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http://dx.doi.org/10.1002/ajmg.a.36156DOI Listing
December 2013

[Pre-evening meal administration of tacrolimus improved refractory ocular symptoms in two young children with latent general myasthenia gravis].

No To Hattatsu 2013 Jul;45(4):318-22

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Tokyo.

We report two patients with latent general myasthenia gravis (MG) with refractory ocular symptoms who were successfully treated with pre-evening meal administration of tacrolimus. Patient 1 was a 4-year-old girl with persistent ocular symptoms despite high-dose steroid therapy and thymectomy. Oral tacrolimus was initiated at the age of 3 years, which was resulted in complete resolution of symptoms. After one year, hemilateral ptosis recurred. The plasma consentration of tacrolimus was very low, probably due to sudden weight gain. Increasing the dose and a change from post- to pre-evening meal administration of tacrolimus enabled maintenance of its concentration and complete control of ocular symptoms. Patient 2 was a 2-year-old boy whose symptoms were refractory to steroid therapy after his first relapse. Since post-meal administration of tacrolimus provided partial benefit, the closing schedule was changed to pre-evening meal administration, with good results. Neither patient had adverse effects of tacrolimus. It is difficult to maintain an effective tacrolimus concentration in children due to marked growth and rapid metabolic rates. Pre-evening meal administration of tacrolimus is an easy, safe and useful method of treatment in MG young children.
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July 2013

[Clinical features and care of patients with congenital and childhood-onset myotonic dystrophy].

Rinsho Shinkeigaku 2012 ;52(11):1264-6

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder with variable expression. DM1 results from a trinucleotide expansion in the 3' untranslated region or the gene for myotonic dystrophy protein kinase (DMPK). Severity tends to increase and it shows a younger onset age with vertical transmission, a phenomenon known as anticipation. Congenital myotonic dystrophy (CDM) is classified as the most severe form of DM1, and its phenotype, with severe hypotonia, neonatal respiratory distress and feeding difficulties, is completely different from that of adult-onset type. Involvement of respiratory muscles may be the major cause of mortality in affected infants. Facial weakness with a tented upper lip is often recognized. If infants survive the neonatal period, muscle involvement symptoms gradually improve and most children do not require respiratory support or tube feeding. As CDM patients grow older, mental retardation or a developmental disorder becomes prominent. Furthermore, the main problems in childhood-onset DM, with an onset age under 10 years, are developmental disorders or learning disabilities, rather than muscle symptoms. Early meticulous support and cooperation with teachers are necessary. Medications such as methylphenidate may be helpful in DM1 children with attention deficit/hyperactivity disorder.
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http://dx.doi.org/10.5692/clinicalneurol.52.1264DOI Listing
April 2014

[A case of spinal muscular atrophy type 0 in Japan].

No To Hattatsu 2012 Sep;44(5):387-91

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Tokyo.

The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature.
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September 2012

Severe muscle damage following viral infection in patients with Fukuyama congenital muscular dystrophy.

Brain Dev 2012 Apr 2;34(4):293-7. Epub 2011 Jul 2.

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Japan.

Fukuyama congenital muscular dystrophy (FCMD), which is characterized by cortical migration defect and eye abnormalities, is the most common subtype of CMD in Japan. Fukutin (FKTN), the responsible gene for FCMD, encodes a protein involved in the glycosylation of alpha-dystroglycan. We have experienced some patients with FCMD who showed sudden exacerbation of muscle weakness with marked elevation of serum creatine kinase (CK) and urinary myoglobin levels a few days after a febrile episode of viral infection, occasionally leading to death. To describe this peculiar phenomenon, we focused on 12 patients who developed a sudden exacerbation of muscle weakness among 96 genetically defined FCMD patients and hospitalized because of a febrile illness at Tokyo Women's Medical University between 1997 and 2008. All the 12 patients were homozygous for a 3-kb insertion mutation of FKTN. The patients developed exacerbation of muscle weakness ranging from paralysis to loss of head control. The onset was concentrated in summer, and coxsackieviruses and enteroviruses were most often detected, especially in infantile patients. Eight of the 12 patients were treated with corticosteroids and recovered within 2 weeks. Four patients were treated without steroid, and needed 18.5 days on mean for improvement. None developed renal failure. The reason for muscle damage induced by viral infection remains unknown; however, physicians should consider its risk, sometimes leading to death, and draw it to parents' attention, especially in the defervescent stage.
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http://dx.doi.org/10.1016/j.braindev.2011.06.002DOI Listing
April 2012

High-density CT of muscle and liver may allow early diagnosis of childhood-onset Pompe disease.

Brain Dev 2012 Feb 24;34(2):103-6. Epub 2011 Jun 24.

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Shinjuku-ku, Tokyo, Japan.

Pompe disease is classified into infantile-, childhood- and adult-onset forms based on onset age and the degree of organ involvement. Differing from the infantile-onset form which is characterized by marked organ involvement, the childhood-onset form usually presents with muscle weakness and elevation of serum creatine kinase (CK), mimicking those of progressive muscular dystrophy. We report our successful early diagnosis and initiation of enzyme replacement therapy (ERT) in a young girl with childhood-onset Pompe disease before the development of skeletal muscle symptoms. She was referred to our hospital at the age of 2 years 4 months because of hyperCKemia detected incidentally. She was active and lacked developmental delay and muscle weakness; however, hepatomegaly was noted. The combination of high-density changes in the liver and skeletal muscle on computed tomography (CT) images was suggestive of glycogen storage disorder, especially childhood-onset Pompe disease. Low alpha-glucosidase (GAA) activity on dried blood spots facilitated the diagnostic process, and genetic analysis of GAA allowed a definitive diagnosis, without performing muscle biopsy. We promptly started ERT at the age of 2 years 6 months. After 1 year, she still had not developed any skeletal muscle symptoms, and serum CK level was almost normal. Since the efficacy of ERT is thought to depend on the extent of muscle damage at its commencement, we expect that ERT may have prevented the manifestation of skeletal muscle involvement in this patient.
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http://dx.doi.org/10.1016/j.braindev.2011.05.013DOI Listing
February 2012

Close monitoring of initial enzyme replacement therapy in a patient with childhood-onset Pompe disease.

Brain Dev 2012 Feb 14;34(2):98-102. Epub 2011 Jun 14.

Department of Pediatrics, Heart Institute of Japan, Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.

Pompe disease is classified into infantile and late-onset (childhood and adult) forms based on onset age and degree of organ involvement. While benefits of enzyme replacement therapy (ERT) for the infantile form have been confirmed, efficacy for late-onset forms reportedly varies. We report close monitoring of initial ERT, focusing especially on the first year, in a 12-year-old boy with childhood-onset Pompe disease. At age 10, he started ERT at 20 mg/kg every other week. Respiratory and motor functions were evaluated at each infusion, and by skeletal muscle computed tomography (CT) and cardiac echography every 4 months. He gained the ability to climb stairs without a rail and % vital capacity improved just 1.5 months after starting ERT. Grip power, manual muscle testing (MMT) and the timed and 6-min walking distance tests (6MWT) improved promptly, paralleling improvements in clinical symptoms. However, this steady improvement stopped around 8 months, with deterioration to the initial level by about 24 months. Antibody against recombinant human alpha-glucosidase was very low at 15 months; therefore, the lack of treatment response did not completely correspond to antibody production. On the other hand, cardiac wall thickening worsened after 4 months, then improved to better than baseline after 8 months, and this improvement was well maintained. Among our set parameters, the timed test results corresponded better to his changing clinical course than did grip power, MMT or 6-min walking test results.
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http://dx.doi.org/10.1016/j.braindev.2011.05.004DOI Listing
February 2012

High-density areas on muscle CT in childhood-onset Pompe disease are caused by excess calcium accumulation.

Acta Neuropathol 2010 Oct 3;120(4):537-43. Epub 2010 Aug 3.

Department of Pediatrics, Tokyo Women's Medical University, School of Medicine, Shinjuku-ku, Tokyo 162-8666, Japan.

We report two patients with childhood-onset Pompe disease showing striking changes with high-density areas on skeletal muscle CT, not seen in adult- or infantile-onset forms of this disease. While the anterior compartment of the thigh muscles was less affected in the adult-onset form, the rectus femoris and tibial muscles were preferentially involved from the early stage in the childhood-onset form of Pompe disease. The high-density areas became increasingly diffuse with disease progression, producing a marbled pattern and ultimately resulting in homogeneous high density and muscle atrophy. Muscle biopsy specimens from the high-density areas showed striking vacuolar changes with many dense globular bodies in lysosomes. High calcium signals were identified by X-ray microanalysis using energy-dispersive X-ray spectroscopy in these areas. Excess calcium accumulation in the vacuoles was also confirmed with the glyoxal-bis(2-hydroxyanil) (GBHA) staining. The high density on CT was slightly reduced together with clinical improvement after enzyme replacement therapy in patient 2. Our data demonstrate that in childhood-onset Pompe disease, high-density areas on skeletal muscle CT images are due to the accumulation of calcium in dense globular bodies formed by a chronic degenerative process affecting autophagic vacuoles.
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http://dx.doi.org/10.1007/s00401-010-0732-8DOI Listing
October 2010

Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: from our experience of 4 cases including an autopsy case.

Mol Genet Metab 2010 May 4;100(1):14-9. Epub 2010 Feb 4.

Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato-ku, Tokyo, Japan.

We report 4 cases of late onset glycogen storage disease type II (GSD II) or Pompe disease (OMIM #232300), under enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rh-GAA, OMIM *606800). In these 4 cases, we focused on the case of a 28-years-old man, whose condition at the ERT starting was the worst and resulted in poor prognosis. The autopsy was done under his family's permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragm or iliopsoas, and pulmonary veno-occlusive disease (PVOD) which resulted in severe pulmonary hypertension (PH). This is the first report of PVOD as the cause of PH in Pompe disease. We studied this case comparing to another 3 cases of late onset Pompe disease under the same course of ERT in our hospital, and the average data of the group of late onset Pompe disease with severe pulmonary insufficiency receiving ERT, supposed that low score of the body mass index (BMI) on the baseline, the presence of specific genotype (p.R600C), and signs of pulmonary dysfunction suggesting PH (tachypnea, ultrasound cardiography data) were factors that influenced the prognosis. For a better prognosis in the late onset Pompe disease, an early diagnosis for the early start of ERT before the onset of respiratory failure should be important, and the deliberate management and care should be needed even after the ERT start, especially for severe cases including pulmonary dysfunction.
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http://dx.doi.org/10.1016/j.ymgme.2010.01.015DOI Listing
May 2010