Rare mosaic variant of GJA1 in a patient with a neurodevelopmental disorder.

GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs.

[Treatment of Juvenile Myasthenia Gravis].

The pathogenesis of juvenile myasthenia gravis is similar to that of adult-onset cases, but does differ significantly in that it is predominantly ocular type, has a low antibody-positive rate, a low thymoma complication rate, and a high remission rate. The evidence for the adult treatment strategy of low-dose steroids and fast-acting treatment is insufficient in children, and the safety of immunosuppressive drugs has not been established. Steroid use in children in particular requires caution due to the risk of growth retardation, and while lower doses are desirable, the efficacy of lower doses has not been as fully investigated as in adults. Conversely, experience has shown that the use of adequate doses of steroids results in high remission rates, and there is currently no rationale for recommending lower doses.

The Clinical Course and Treatment of a Case of Refractory Systemic Juvenile Myasthenia Gravis Successfully Treated with Thymectomy.

Juvenile myasthenia gravis (JMG) exhibits a more favorable response to glucocorticoids and has a better prognosis than adult myasthenia gravis. However, no established treatment exists for refractory JMG. Although thymectomy has been performed in several patients with refractory systemic JMG, there are few detailed clinical descriptions of patients who underwent thymectomy. Here, we present the case of a 10-year-old boy with refractory systemic JMG who was successfully treated with thymectomy. The patient developed symptoms, including dysphagia, malaise, diurnal ptosis, and weakness in the trunk muscles, and he was diagnosed with generalized JMG. Despite undergoing various treatments, including steroids, tacrolimus, steroid pulse therapy, intravenous immunoglobulin, azathioprine (AZT), and rituximab, his symptoms did not improve. Therefore, he underwent a thoracoscopic thymectomy 24 months after disease onset. Thymectomy led to remission, as demonstrated by a significant reduction in the quantitative myasthenia gravis score and anti-acetylcholine receptor antibody levels, which persisted for 43 months after surgery. Our case demonstrates the effectiveness of thymectomy in systemic JMG patients with positive anti-acetylcholine receptor antibodies, despite therapeutic failure with AZT and rituximab, within 2 years of disease onset.

In utero transplantation of myoblasts and adipose-derived mesenchymal stem cells to murine models of Duchenne muscular dystrophy does not lead to engraftment and frequently results in fetal death.

Introduction: Duchenne muscular dystrophy (DMD) is a progressive disease that leads to damage of muscle and myocardium due to genetic abnormalities in the dystrophin gene. In utero cell transplantation that might facilitate allogenic transplantation is worth considering to treat this disease. Methods: We performed allogeneic in utero transplantation of GFP-positive myoblasts and adipose-derived mesenchymal stem cells into murine DMD model animals. The transplantation route in this study was fetal intraperitoneal transplantation and transplacental transplantation. Transplanted animals were examined at 4-weeks old by immunofluorescence staining and RT-qPCR. Results: No GFP-positive cells were found by immunofluorescence staining of skeletal muscle and no GFP mRNA was detected by RT-qPCR in any animal, transplantation method and cell type. Compared with previous reports, myoblast transplantation exhibited an equivalent mortality rate, but adipose-derived stem cell (ASC) transplantation produced a higher mortality rate. Conclusions: In utero transplantation of myoblasts or ASCs to murine models of DMD does not lead to engraftment and, in ASC transplantation primarily, frequently results in fetal death.

Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Efficacy of steroid therapy for Fukuyama congenital muscular dystrophy.

Although there is only symptomatic treatment for Fukuyama congenital muscular dystrophy (FCMD), several reports have suggested that steroid therapy could be effective for FCMD; however, no independent intervention studies have been conducted. This study aimed to evaluate the efficacy of steroid therapy for restoring motor functions in FCMD patients. This study involved 3-to-10-year-old FCMD patients who exhibited a decline in motor functions, requested steroid therapy. Patients with consent started oral administration of 0.5-mg/kg prednisolone every alternate day, which was increased to 1.0 mg/kg if the response was inadequate. We used the Gross Motor Function Measure (GMFM) to evaluate and compare the motor functions of all patients. Wilcoxon signed-rank test (significance level, P ≤ 0.05) was used for statistical analysis. At the onset of steroid therapy, 8.10 years (SD, 2.14 years) was the mean age of FCMD patients. The mean GMFM difference between before and after the steroid therapy was + 1.23 (SD, 1.10), and a P value of 0.015 represented significant improvement in GMFM. Our results indicate that steroid therapy may contribute to the maintenance and improvement of the motor functions of advanced-stage FCMD patients.Clinical Trial Registration Registration Number: UMIN000020715, Registration Date: Feb 1st, 2016 (01/02/2016).

Urinary titin as a biomarker in Fukuyama congenital muscular dystrophy.

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.

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).

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 ).

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

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.

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

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.

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

OBJECTIVE: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D2 (PGD2 ) 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.

Renal dysfunction is rare in Fukuyama congenital muscular dystrophy.

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 ±â€¯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 ß2-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.

National registry of patients with Fukuyama congenital muscular dystrophy in 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 ±â€¯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.

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

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.

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

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.

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

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.

Respiratory management of patients with Fukuyama congenital muscular dystrophy.

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.

Congenital fiber type disproportion myopathy caused by LMNA mutations.

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.