[Is an oral disintegrating tablets a formulation that is easy to ingest for patients experiencing difficulty with eating and swallowing?].

Oral disintegrating tablets (hereafter, ODT) can be ingested without water. We conducted a videoscopic examination to determine whether they are also useful as internal agents for patients experiencing difficulty with eating and swallowing. Normal tablets and dummy preparations of ODT were orally administered to six patients with neurological diseases who were either diagnosed with or aware of difficulty in eating and swallowing, and observations were conducted using a videoscope. Two subjects were able to ingest both the normal tablet and the dummy preparation without any problem; two subjects were able to ingest the normal tablet without any problem but the dummy preparation remained in their pharynx; and two subjects had both the normal tablet and the dummy preparation remained in the pharynx. There was no feeling of residue in the four cases in which the dummy preparation remained in the pharynx. ODT is not necessarily easy to ingest for patients with neurological diseases who have difficulty eating and swallowing, and it was believed that repeated swallowing or alternate swallowing of a thick liquid is required for ingestion.

[Prolonged apnea/hypopnea during water swallowing in patients with amyotrophic lateral sclerosis].

PURPOSE: Swallowing difficulty is increased along with progression of respiratory disturbance in patients with Amyotrophic Lateral Scalerosis (ALS). To analyze the respiratory patterns during swallowing is important for the management of this disease. In this study, we evaluated apnea/hypopnea during water swallowing and the respiratory cycle at rest and after water swallowing. METHOD: We evaluated respiratory patterns in swallowing in 10 ALS patients (66.0 +/- 7.1 years old), in 10 Myotonic dystrophy (MD) patients (46.5 +/- 12.2 years old), and in 10 healthy volunteers as control subjects (61.7 +/- 10.0 years old). The ALS and MD patients had consulted the Department of Neurology of Toneyama National Hospital or Tokushima National Hospital between April 2002 and July 2006. Respiratory patterns were evaluated by simultaneous recording of cervical swallowing sound in water swallow. A hypersensitive microphone measured cervical sound. A thermister was used for pneumography. The means of four continuous respiratory cycles at rest and after swallow of 3 ml water were used for analysis. Respiration with amplitude of 1/2 or smaller than that of the pneumography at rest was defined as hypopnea, and the apnea/hypopnea duration was evaluated as the respiratory suppression time. STATISTICAL ANALYSIS: All analyses were performed using SPSS 11.0J (SPSS Inc., Chicago, IL). RESULTS: In the ALS group, the respiratory cycle was 3.15 +/- 0.76 sec (2.31-4.39 sec) at rest, while after swallowing, it was 2.78 +/- 0.83 sec (1.77-4.80 sec) (p = 0.1). In the MD group, the respiratory cycle was 2.56 +/- 0.46 sec (1.91-3.67 sec) at rest, while after swallowing, it was 2.94 +/- 0.60 sec (2.03-4.29 sec). In the control group, it was 3.46 +/- 0.57 sec (3.18-4.34 sec) at rest and 3.24 +/- 0.50 sec (2.64-4.04 sec) after swallowing. The apnea/hypopnea duration during water swallow was 14.33 +/- 8.89 sec (2.50-30.68 sec) in the ALS group, 3.66 +/- 1.58 sec (1.78-6.42 sec) in the MD group, and 3.64 +/- 1.00 sec (2.34-5.56 sec) in the control group. The apnea/hypopnea duration in the ALS group was significantly longer than that in MD and control groups (p = 0.005, p = 0.004 by the t-test). The ALS patients with severe respiratory failure or with aspiration in videofuoroscopy showed extended apnea/hypopnea duration. CONCLUSION: Prolonged apnea/hypopnea was observed during water swallowing in ALS patients. We speculate that this prolongation is caused by severe swallowing disturbance and respiratory failure, which increases the risk of aspiration. The respiration of ALS patients should be closely monitored during eating.

Female dystrophinopathy: Review of current literature.

Skeletal muscle or cardiac symptoms are known to appear in a certain proportion of female patients carrying the dystrophin gene mutation. There is limited high-quality evidence to guide the treatment of female carriers of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD). The available evidence is mainly based on expert opinions and clinical experience. To improve this situation, we reviewed 1002 reports published from 1967 to 2017 to assess the following themes: epidemiology, clinical symptoms, cardiomyopathy, burdens on parents or caregivers, pregnancy or delivery, and prognosis. We aimed to provide guidance for the provision of support, care, and education for patients, caregivers, and health care professionals. There were 271 reports before 1987, and 731 reports after 1987 when dystrophin was first recognized. In this review, we mainly selected 37 papers that were reported after 1987. In seven large research papers, the incidence of skeletal muscle damage among female carriers, including asymptomatic carriers, was reported as 2.5%-19%, and the incidence of dilated cardiomyopathy was 7.3%-16.7% for DMD and 0%-13.3% for BMD. We integrated and summarized the genetically definite manifesting carriers with skeletal muscle symptoms from 10 case series. In combined data, among 93 manifesting carriers, 16 (17.2%) presented with cardiac abnormalities. The frequency of manifesting carriers complicated by cardiomyopathy increased with age. Reports on cardiac magnetic resonance in female carriers and the burden on caregivers are increasing, whereas literatures concerning pregnancy, delivery, and prognosis in female carriers are limited. This represents a future direction for research.

Medical Attitudes Survey for Female Dystrophinopathy Carriers in Japan.

Objective This study attempted to clarify the current status of female dystrophinopathy carriers, including the numbers of patients, the status of genetic screening, the status of counseling, physicians' understanding, and barriers to registration. Methods We sent out questionnaires to 402 physicians registered in the Remudy dystrophinopathy registry. The total number of responses received was 130 (response rate: 32%). Result In total, 1,212 cases of Duchenne muscular dystrophy, 365 cases of Becker muscular dystrophy, and 132 cases of female dystrophinopathy with a confirmed genetic mutation were encountered, and genetic testing was performed in the mother in 137, 23, and 12 cases, respectively. With respect to the risk of the onset of health problems, 25% of physicians always explained, 29% usually explained, 29% sometimes explained, and 13% never explained the risk to the mothers and female siblings of dystrophinopathy patients. The most common reason for not explaining the risk was a lack of knowledge/information. Thirty-five percent were familiar with the guidelines for testing the heart function of carriers. Conclusion Fewer mothers of dystrophinopathy patients have undergone genetic testing in Japan than in other countries. A significant portion of doctors did not explain the risks of health problems due to a lack of knowledge. We hope this survey will lead to an increased discussion of female dystrophinopathy patients.

Detection and management of cardiomyopathy in female dystrophinopathy carriers.

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

[Videofluorographic assessment of swallowing function in patients with Duchenne muscular dystrophy].

OBJECTIVE: To identify the characteristics of swallowing function in patients with Duchenne muscular dystrophy (DMD). METHODS: Swallowing function was evaluated using videofluorography (VF) in a cross-sectional observational study of 102 DMD patients (mean age 21.5 years) who had dysphagia or in whom dysphagia was suspected based on clinical signs. Reduced tongue movement, impaired bolus transport to the pharynx, decreased pharyngeal contraction, bolus delivery into the airway, and bolus residue at the epiglottic vallecula and at the piriform recess were qualitatively evaluated for test swallows of jelly and juice. During VF, the length of time of both the oral and pharyngeal phases of swallowing was measured in 59 patients. RESULTS: Patients started to show oral phase abnormalities in their mid-teens and pharyngeal phase abnormalities such as pharyngeal residue around age 20. Oral phase abnormalities was higher with juice than with jelly. Total oral/pharyngeal transit duration was longer with age, and total duration of hyoid maximum elevation was shorter with age. CONCLUSION: The weak positive correlation of total oral/pharyngeal transit duration and age was presumably due to gradual onset of functional abnormalities associated with deteriorated swallowing muscles starting in the teenage years. Reduced tongue movement and impaired bolus transport to the pharynx was more common in teenage DMD patients because they have limited tongue movements associated with structural abnormalities such as macroglossia and open bite. VF showed that the swallowing difficulties were more severe during the oral phase than in the pharyngeal phase in the teenage patients. The pharyngeal phase disorders such as pharyngeal residue and decreased pharyngeal contraction were seen more often in the patients in their 20s, presumably due to deterioration of swallowing muscles that becomes more apparent in the older age group.

Survey on genetic counseling and health management for symptomatic and asymptomatic female dystrophinopathy carriers in Japan today.

To clarify the current status of genetic counseling and health monitoring for symptomatic and asymptomatic female carriers of dystrophinopathy (Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)), we sent out questionnaires to 104 member institutions of The Japan's National Liaison Council for Clinical Sections of Medical Genetics, and responses were received from 51 institutions. Between April 2013 and March 2014, 57 carriers at 21 institutions received genetic counseling, and 37 carriers at 15 institutions underwent genetic screening for DMD/BMD mutations. At the 23 institutions that gave genetic counseling, 20 (87%) informed carriers of possible health problems, 14 (61%) informed carriers of cardiomyopathy and heart failure, and 14 (61%) advised carriers about regular medical checkups. Evidence based on accurate and up-to-date epidemiological studies of female carriers is needed and should be widely shared with the families, medical providers, and society.

Proteolysis of beta-dystroglycan in muscular diseases.

Alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), while beta-dystroglycan is a type I integral membrane protein which anchors alpha-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of alpha-and beta-dystroglycan is called the dystroglycan complex. We reported previously a matrix metalloproteinase (MMP) activity that disrupts the dystroglycan complex by cleaving the extracellular domain of beta-dystroglycan. This MMP creates a characteristic 30 kDa fragment of beta-dystroglycan that is detected by the monoclonal antibody 43DAG/8D5 directed against the C-terminus of beta-dystroglycan. We also reported that the 30 kDa fragment of beta-dystroglycan was increased in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animals of sarcoglycanopathy, and that this resulted in the disruption of the link between the ECM and cell membrane via the dystroglycan complex. In this study, we investigated the proteolysis of beta-dystroglycan in the biopsied skeletal muscles of various human muscular diseases, including sarcoglycanopathy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy, Miyoshi myopathy, LGMD2A, facioscapulohumeral muscular dystrophy, myotonic dystrophy and dermatomyositis/polymyositis. We show that the 30 kDa fragment of beta-dystroglycan is increased significantly in sarcoglycanopathy and DMD, but not in the other diseases. We propose that the proteolysis of beta-dystroglycan may contribute to skeletal muscle degeneration by disrupting the link between the ECM and cell membrane in sarcoglycanopathy and DMD.

[A clinicopathological investigation of two autopsy cases of calpainopathy (LGMD2A)].

In this study, we compared the clinicopathological findings of two autopsy cases of patients with calpainopathy (LGMD2A) from different families. The patient in case 1 was a 72-year-old man with a history of type 2 diabetes mellitus. He exhibited recent memory impairments from the age of 70. ECG revealed an incomplete right bundle branch block. A homozygous frameshift mutation c.1796dupA was found in the CAPN3 gene. Cause of death was respiratory insufficiency and heart failure. The patient in case 2 was a 70-year-old man with a history of hypertension. ECG revealed an incomplete right bundle branch block. A homozygous missense mutation c.1080G>C (p.Trp360Cys) in CAPN3 gene was identified. Cause of death was ischemic cardiomyopathy and systemic circulatory failure. In both cases, muscle pathology revealed severe dystrophic changes. In case 2, cardiac hypertrophy and old myocardial infarcts with stenosis of coronary arteries were observed. Histological examination of the sinoatrial node showed fatty infiltration with ischemic changes in case 2. In both cases, the patients' brains showed cerebral atrophy and well preserved neurons. Calpain 3 abnormality was correlated with skeletal muscle involvement. It should be considered that LGMD2A might be complicated by dysfunction of the cardiac conduction system.

Diagnostic utility of cardiac magnetic resonance for detection of cardiac involvement in female carriers of Duchenne muscular dystrophy.

BACKGROUND: Cardiac involvement is a recognised complication in female carriers of Duchenne muscular dystrophy (DMD). Since segmental or global left ventricle (LV) wall motion abnormalities in DMD carriers can arise even without apparent muscle weakness, it is difficult to differentiate cardiac involvement of a DMD carrier from other heart diseases in a non-invasive manner. Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) enables assessment of regional wall motion abnormality and myocardial damage with high spatial resolution. OBJECTIVE: To assess the utility of CMR for detection of myocardial damage in female carriers of DMD. METHODS AND RESULTS: Gadolinium-enhanced CMR was performed in seven female DMD carriers. Physical examination, electrocardiography, chest radiograph, measurements of total creatinine kinase and brain natriuretic peptide levels, and two-dimensional echocardiography were also performed. Four (57%) of the seven carriers had LGE, and LGE was frequently observed at the subepicardial layer in the inferolateral segment. Two carriers had a focal LGE at the LV inferolateral wall without LV dilation or wall motion abnormalities. CONCLUSION: CMR findings of DMD carriers were characterised by subepicardial LGE, which was localised at inferolateral segments. CMR may be a useful modality for detecting cardiac involvement in DMD carriers.