Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: phase III study results.

BACKGROUND AND OBJECTIVE: To evaluate the efficacy and tolerability of budesonide/formoterol as maintenance and reliever therapy versus budesonide/formoterol maintenance plus terbutaline in adults with persistent asthma not adequately controlled with inhaled corticosteroid (ICS) therapy alone. METHODS: In this 12-month, randomized, double-blind, parallel-group, phase III study (NCT00839800), patients (age ≥ 16 years; receiving maintenance ICS; ≥ 1 severe exacerbation in the 12 months prior to study entry) were randomized to either budesonide/formoterol 160/4.5 µg 1 inhalation twice daily plus budesonide/formoterol 160/4.5 µg as-needed or budesonide/formoterol 160/4.5 µg 1 inhalation twice daily plus terbutaline 0.4 mg as-needed for 12 months. PRIMARY OUTCOME: time to first severe asthma exacerbation; secondary outcomes included: lung function, asthma symptom variables and tolerability. RESULTS: Two thousand and ninety-one patients were randomized: 170 (16%) receiving budesonide/formoterol maintenance and reliever therapy experienced 259 severe exacerbations versus 229 patients (22%) receiving budesonide/formoterol plus terbutaline who experienced 363 severe exacerbations. Budesonide/formoterol maintenance and reliever therapy prolonged the time to first severe exacerbation versus budesonide/formoterol plus terbutaline (P = 0.0007) and reduced the instantaneous risk of an exacerbation by 30% (hazard ratio 0.70, 95% confidence interval 0.57-0.85, P = 0.0003). Times to first oral steroid use, first hospitalization and first emergency room treatment were all significantly prolonged in the budesonide/formoterol maintenance and reliever group versus budesonide/formoterol plus terbutaline. Both treatment groups were well tolerated. CONCLUSIONS: Budesonide/formoterol maintenance and reliever therapy provided more effective asthma control, including a prolonged time to first severe asthma exacerbation, than budesonide/formoterol plus terbutaline and was well tolerated. Budesonide/formoterol maintenance and reliever therapy also improved lung function and asthma symptoms.

Reduction rate of body mass index predicts prognosis for survival in amyotrophic lateral sclerosis: a multicenter study in Japan.

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

[An experience of administration of modafinil for excessive daytime sleepiness in a patient with myotonic dystorophy].

We report the beneficial and adverse effects of modafinil for daytime sleepiness in a 62-year-old female patient with myotonic dystrophy. Although it was effective for excessive daytime sleepiness, orolingual dyskinesia appeared the day following administration of modafinil (100 mg/day), and dyskinesia disturbed her daily life including dental treatment. When modafinil was stopped, dyskinesia was improved. However, excessive daytime sleepiness deteriorated gradually; re-treatment with smaller dosage (50 mg every other day) resulted in partial improvement but aggravation of both dyskinesia and diabetes mellitus. Modafinil should be administered carefully when the patient is older or has complications such as glucose intolerance.

[Establishment of an evaluation method for muscular dystrophy and a patient registration system for clinical trials].

About 20 years have passed since the discovery of the causative protein of Duchenne muscular dystrophy, in 1987, and treatments targeting causative factors such as exon skipping, read-through of stop codons, and the upregulation of utrophin are approaching practical levels. In Japan, also, clinical trials are planned as the final stage of treatment development. In this field, an appropriate outcome measure has not been established due to the lack of experience in clinical trials. Treatments for muscular dystrophy are deemed effective only when increases in the muscle mass and muscle strength and improvements in the ADL and QOL as well as biological marker levels at target points have been demonstrated. The Muscular Dystrophy Clinical Study Group has addressed the development of these evaluation methods since 2002. Also, as treatments for muscular dystrophy being developed today are so-called tailor-made treatments aimed at specific mutations, a system that facilitates identification of the type and site of mutation in each individual must be prepared. The Gene Analysis Center was only just established in the National Center of Neurology and Psychiatry in 2009. Also, it is expected to be difficult to secure a sufficient number of subjects to start a clinical trial in a short period. Therefore, the Registry of Muscular Dystrophy (REMUDY), a system for the registration of patients with muscular dystrophy including their clinical and genetic information was implemented. This system, which provides information concerning the number of patients required by the protocol to researchers and pharmaceutical companies and the latest information regarding the development of treatments to patients, is expected to serve as a prototype for the establishment of the basis of clinical trials against rare diseases.

[Nasal flaring during hypoxemia in myotonic dystrophy and duchenne muscular dystrophy].

We investigated the relationship between nasal flaring and SpO2 in 19 patients with Duchenne muscular dystrophy (DMD) and 26 patients with myotonic dystrophy (DM1). In DMD patients, nasal flaring was observed when SpO2 was lower than 96%, while it was not seen even at 82% of SpO2 in DM1. None of the DM1 patients could perform voluntary nasal flaring. Nasal flaring is a useful indicator of hypoxemia in DMD but not in DM1. It remains to be elucidated whether the lack of nasal flaring in DM1 patients is due to abnormal respiratory central mechanism or nasal muscle weakness.

[Case of suspected multiple sclerosis with transcallosal lesions involving the upper surface of the corpus callosum].

A 26-year-old woman noticed gradually progressive, right lower leg weakness over a 1.5-month period. Neurological examination revealed right hemiparesis with slightly increased deep tendon reflexes, Babinski's sign on the right side, loss of position sense in the right leg, and slight loss of superficial sensation in the right toes. MR FLAIR images showed a high intensity area measuring 5 x 2 x 3 cm in the left frontal lobe, extending to the outer surface of the body of the corpus callosum and the adjacent right cingulate gyrus. Gadolinium enhancement was seen along the cortex and the outer surface of the body of the corpus callosum. CSF findings showed no pleocytosis, a protein content of 32 mg/dl, a sugar level of 85 mg/dl, and an IgG index of 0.46. The biopsy specimen obtained from the superior frontal gyrus showed perivascular cuffing of T-lymphocytes and some B-lymphocytes, as well as multiple small foci of demyelination. Starting on the second day of admission, the patient was treated with methylprednisolone pulse therapy (1,000 mg/day for 3 days); she was then switched to oral prednisolone (20 mg/day). Thereafter, the patient had two clinical relapses: one was due to a lesion in the dorsal part of the medulla oblongata associated with a disturbance of deep sensation in both hands, and the other was due to a lesion involving the right internal capsule, the globus pallidus, and the caudate nucleus associated with left facial nerve palsy. Visual evoked potentials suggested a demyelinating lesion in the right optic nerve. We suspected a diagnosis of multiple sclerosis based on the presence of more than two clinical episodes of neurological deficits with identifiable lesions on MRI. Multiple sclerosis should be considered in the differential diagnosis of lesions located in the outer part of the corpus callosum and transcallosal bilateral hemispheres on MRI, even though inner callosal lesions are common in multiple sclerosis.

A Japanese male with a novel ANO5 mutation with minimal muscle weakness and muscle pain till his late fifties.

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with anoctamin 5 (ANO5) gene mutation, mainly reported from Northern and Central Europe. We report the case of a Japanese male patient with a novel homozygous mutation of c.2394dup, p.Arg799Thrfs in ANO5 gene, the second patient in the Asian population. He had had marked elevation of creatine kinase (CK) level for more than 10 years with minimal muscular symptoms consisting of muscle stiffness and occasional cramps, preceding the onset of proximal limb weakness. Calf hypertrophy and selective fatty replacement of the adductor magnus and gastrocnemius muscles were prominent clinical and muscle imaging features. This case suggests that LGMD2L may affect a broader population than has been previously thought, physicians should consider the possibility of ANO5 mutation even in patients showing elevated CK level with no apparent muscle weakness but muscle stiffness or cramps.

Study of Duchenne muscular dystrophy long-term survivors aged 40 years and older living in specialized institutions in Japan.

The national muscular dystrophy wards database of Japan lists 118 long-term Duchenne muscular dystrophy (DMD) patients who were at least 40 years old as of October 1, 2013. To elucidate the clinical features of DMD patients aged 40 years and older, we obtained gene analysis and muscle biopsy findings, as well as medical condition information. Ninety-four of the registered patients consented to participate, of whom 55 meeting genetic or biochemical criteria confirming DMD were analyzed. The mean age at the time of the study was 43.6 ± 3.0 years, while at the time of independent ambulation loss it was 10.6 ± 1.5 years and at mechanical ventilation introduction it was 24.1 ± 5.5 years. All were receiving continuous ventilation support, 27 with non-invasive positive pressure ventilation and 28 with tracheal intermittent positive pressure ventilation. Thirty-eight were receiving ß-blockers or a renin-angiotensin system inhibitor, while 9 were free from those agents. Forty had maintained oral nutrition. The 55 analyzed patients had survived into their 40s by receiving multidisciplinary intervention. Our findings emphasize the need of future studies to investigate disease modifiers and the mechanism of long-term survival. In addition, establishment of a worldwide care standard with focus on quality of life for adult males with DMD is important.

T cell gene expression profiling identifies distinct subgroups of Japanese multiple sclerosis patients.

To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we characterized the gene expression profile of peripheral blood CD3+ T cells isolated from MS and healthy control (CN) subjects by using a cDNA microarray. Among 1258 cDNAs on the array, 286 genes were expressed differentially between 72 untreated Japanese MS patients and 22 age- and sex-matched CN subjects. When this set was used as a discriminator for hierarchical clustering analysis, it identified four distinct subgroups of MS patients and five gene clusters differentially expressed among the subgroups. One of these gene clusters was overexpressed in MS versus CN, and particularly enhanced in the clinically most active subgroup of MS. After 46 of the MS patients were treated with interferon-beta (IFNbeta-1b) for two years, IFNbeta responders were clustered in two of the four MS subgroups. Furthermore, the IFNbeta responders differed from nonresponders in the kinetics of IFN-responsive genes at 3 and 6 months after starting IFNbeta treatment. These results suggest that T-cell gene expression profiling is valuable to identify distinct subgroups of MS associated with differential disease activity and therapeutic response to IFNbeta.

Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population.

In order to identify genetic polymorphisms and haplotype frequencies of CYP1A2 in a Japanese population, the enhancer and promoter regions, all the exons with their surrounding introns, and intron 1 were sequenced from genomic DNA from 250 Japanese subjects. Thirty-three polymorphisms were found, including 13 novel ones: 2 in the enhancer region, 5 in the exons, and 6 in the introns. The most common single nucleotide polymorphism (SNP) was -163C>A (CYP1A2*1F allele) with a 0.628 frequency. In addition to six previously reported non-synonymous SNPs, three novel ones, 125C>G (P42R, CYP1A2*15 allele, MPJ6_1A2032), 1130G>A (R377Q, *16 allele, MPJ6_1A2033), and 1367G>A (R456H, *8 allele, MPJ6_1A2019), were found with frequencies of 0.002, 0.002, and 0.004, respectively. No polymorphism was found in the known nuclear transcriptional factor-binding sites in the enhancer region. Based on linkage disequilibrium analysis, the CYP1A2 gene was analyzed as one haplotype block. Using the 33 detected polymorphisms, 14 haplotypes were unambiguously identified, and 17 haplotypes were inferred by aid of an expectation-maximization-based program. Among them, the second major haplotype CYP1A2*1L is composed of -3860G>A (*1C allele), -2467delT (*1D allele), and -163C>A (*1F allele). Network analysis suggested that relatively rare haplotypes were derived from three major haplotypes, *1A, *1M, and *1N in most cases. Our findings provide fundamental and useful information for genotyping CYP1A2 in the Japanese, and probably Asian populations.

[Perception of dyspnea due to breath-holding in myotonic dystrophy].

Patients with myotonic dystrophy (DM1) rarely complain of dyspnea despite of severe hypoxemia. We studied the perception of dyspnea caused by breath-holding in 9 DM1 patients and 8 healthy control subjects. The patients, as well as the control subjects, complained of dyspnea and showed decrease in SpO2. In none of the patients but one, however, the bottom SpO2 became lower than the minimal SpO2 recorded in 24-hour monitoring. DM1 patients were able to realize hypoxia caused by apnea, although they had not realized hypoxia that already existed. Consequently, the breath-holding test does not uncover a blunted perception of dyspnea in DM1; an afferent system contributable to air hunger sensation in breath-holding is preserved in DM1. Breath-holding test may be useful for a DM1 patient to recognize the significance of sleep apnea.

[Long-term treatment of diabetes mellitus in myotonic dystrophy with pioglitazone].

We report beneficial effects of pioglitazone on insulin resistance in diabetes mellitus accompanied with myotonic dystrophy (DM1). We studied eight DM1 patients with diabetes mellitus aged 32 to 60 (mean age 52.1 +/- 8.6 years). Three of them were under glibenclamide treatment, but their plasma glucose control was poor because of occasional hypoglycemia; others had not been treated with any hypoglycemic drugs. We administered a daily dose of 15 mg pioglitazone for 6-36 months (mean period 14.8 +/- 9.1 months). Plasma glucose control improved in all patients. In a 75 g oral glucose tolerance test, plasma glucose level at 120 min dropped from 203.3 +/- 41.7 mg/dl to 153.9 +/- 39.5 mg/dl (p = 0.04); the area under the insulin curve up to 120 min (sigma IRI) dropped from 236.9 +/- 170.2 microU x hr/ml to 169.6 +/- 81.3 microU x hr/ml (p = 0.12). Sigma IRI decreased in four patients with pretreatment sigma IRI > or = 250 microU x hr/ml; it slightly increased in other patients with pretreatment sigma IRI < or = 150 microU x hr/ml. The homeostasis model assessment-insulin resistance (HOMA-IR) improved from 2.1 +/- 1.0 to 1.1 +/- 0.4 (p = 0.04). Impairment of liver functions, cardiac failure, or hypoglycemia was not observed. Pioglitazone treatment is useful to improve insulin resistance and glucose control in DM1 patients with diabetes mellitus, especially patients with reactive hyperinsulinemia to glucose loading.

[Survey of the actual state of medical care of patients with Duchenne muscular dystrophy in Japan].

It has been suggested that many physicians feel it is difficult to manage patients with Duchenne muscular dystrophy (DMD) and that support from experts is required. Therefore, to assess the effects of Japanese practical guidelines for DMD, we distributed a survey questionnaire to certified neurologists and child neurologists in Japan. The survey revealed the actual state of medical care for patients with DMD in Japan prior to publication of guidelines. Many pediatric patients visited academic medical centers (AMCs) and general hospitals (GHs). In contrast, adult patients visited mainly National Hospital Organization (NHO) hospitals and other hospitals that can manage cardiopulmonary care and inpatient therapy. Medical insurance approval for steroid therapy was well known by subjects surveyed. Beta-blockers and angiotensin converting enzyme inhibitors were widely used as cardioprotective agents. However, the rates of obtaining written informed consent before genetic testing, regular radiological testing for scoliosis, usage of mechanical-assisted cough, disaster response plan instruction for patients receiving mechanical ventilation, and management of patients with female dystrophinopathy were below satisfactory. More than 20% of doctors surveyed practiced or recommended muscle strengthening training. Although the details of the training were not specified, this may indicate overuse of resistance training exercises. Our goal is to promote an educational campaign to better disseminate best practice care and clinical guidelines. We plan to conduct another round of surveys in several years to assess the effects of the clinical guidelines.

Arterial changes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter: examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case.

BACKGROUND AND PURPOSE: There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. METHODS: We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. RESULTS: We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. CONCLUSIONS: These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO2 levels and systemic blood pressure in CADASIL.

Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis.

The molecular mechanisms for the interferon beta (IFNbeta) treatment of multiple sclerosis (MS) remain to be characterized. Using cDNA microarray technology, we have compared the gene expression profile of T and non-T cells derived from relapsing-remitting MS before and after treatment with IFNbeta-1b. IFNbeta treatment significantly altered expression of 21 genes out of 1263 at 3 and 6 months after treatment. These genes included nine with IFN-responsive promoter elements. Whereas there was no change in Th1 or Th2 marker genes, some of the changes were unexpected but coincided with the beneficial effect of IFNbeta in MS.

D-cycloserine for the treatment of ataxia in spinocerebellar degeneration.

We studied the effects of D-cycloserine, a partial NMDA receptor allosteric agonist, on ataxia in patients with spinocerebellar degeneration. Fifteen Japanese ataxic patients enrolled in a 14-day single-blind trial of D-cycloserine (daily oral dose of 50 mg) following a 14-day single-blind placebo phase. At the end of the D-cycloserine administration, there was a significant reduction in the posture, gait and total score of the international cooperative ataxia rating scale and in the time for walking and speech tasks. D-Cycloserine was well-tolerated and no adverse effect was observed. D-Cycloserine may have therapeutic efficacy for spinocerebellar ataxia.

Five novel single nucleotide polymorphisms in the EPHX1 gene encoding microsomal epoxide hydrolase.

Five novel single nucleotide polymorphisms (SNPs) were found in the EPHX1 gene from 96 Japanese epileptic patients. The detected SNPs were as follows: 1) SNP, MPJ6_EX1009; GENE NAME, EPHX1 ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-CCTCACTTCAGTG/ACTGGGCTTTGCC-3'. 2) SNP, MPJ6_EX1013; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-TCCGCAGCCAGGG/CAGGACGACAGCA-3'. 3) SNP, MPJ6_EX1026; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-GTTCTCCCTGGAC/TGACCTGCTGACC-3'. 4) SNP, MPJ6_EX1028; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-AGGCAGGGGGACG/AGCCAGTCTTGGG-3'. 5) SNP, MPJ6_EX1030; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-TGAAAAGTGGGTG/AAGGTTCAAGTAC-3'. The frequencies were 0.016 for MPJ6_EX1028 (IVS8+54G>A) and 0.005 for the other SNPs. The SNP MPJ6_EX1013 (130G>C) results in an amino acid alteration (E44Q). The other three SNPs in the coding region, MPJ6_EX1009 (30G>A), MPJ6_EX1026 (1056C>T), and MPJ6_EX1030 (1239G>A) result in synonymous changes (V10V, D352D, and V413V, respectively).

Eleven novel single nucleotide polymorphisms in the NR1I2 (PXR) gene, four of which induce non-synonymous amino acid alterations.

Eleven novel single nucleotide polymorphisms (SNPs) were found in the NR1I2 (PXR/SXR) gene from 205 Japanese subjects. The detected SNPs were as follows: 1) SNP, MPJ6_1I2001; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TTTCTACCTCTAC/TTATTGAAAGGGC-3'. 2) SNP, MPJ6_1I2004; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-AGGCCCAAATGTG/AAGTGATGCATAG-3'. 3) SNP, MPJ6_1I2007; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TGCCAGGCCTGCC/TGCCTGCGCAAGT-3'. 4) SNP, MPJ6_1I2008; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GAGTGAGCAGTGG/CGCGCGCGGGCGG-3'. 5) SNP, MPJ6_1I2010; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-CAGAGGAGCAGCG/AGATGATGATCAG-3'. 6) SNP, MPJ6_1I2011; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-CTGGAAGTGGCCA/GGGAGGTTCAAAG-3'. 7) SNP, MPJ6_1I2013; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TCTTCCTCTCGCC/TCCCAACTTCTGG-3'. 8) SNP, MPJ6_1I2017; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-ATTGAATGCAATC/TGGCCCCAGCCTG-3'. 9) SNP, MPJ6_1I2018; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GGTGAGCACAGCA/GGGGGGTGAGGAC-3'. 10) SNP, MPJ6_1I2019; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GAGCTCCGCAGCA/GTCAATGCTCAGC-3'. 11) SNP, MPJ6_1I2021; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GGTGACACCTCCG/AAGAGGCAGCCAG-3'. The frequencies were 0.0293 for MPJ6_1I2021, 0.0073 for MPJ6_1I2011, and 0.0024 for the other 9 SNPs. All SNPs were found as heterozygous. Among these SNPs, MPJ6_1I2007, MPJ6_1I2010, MPJ6_1I2017 and MPJ6_1I2019 induce non-synonymous amino acid alterations (R98C, R148Q, R381W and I403V, respectively, in PAR1).

[Respiratory system elastance and resistance measured by proportional assist ventilation in patients with respiratory muscle weakness].

OBJECTIVE: Non-invasive ventilatory therapy has prolonged survival of myopathy patients with hypoventilation. Efficacy of non-invasive ventilation depends on both elastance and resistance of the respiratory system. Although these parameters are important in the prescription of respiratory management, conventional respiratory function test does not show the appropriate answer in patients with severe respiratory muscle weakness. In muscular dystrophy, muscle tends to be shortened due to its fibrosis, when muscle becomes atrophic and weak; fibrosis of respiratory muscle tissues presumably causes high thoracic elastance. We evaluated the total respiratory system elastance and resistance during proportional assist ventilation (PAV) in myopathy patients. METHODS: In PAV with 100% assist, using BiPAP Vision ventilator, airway pressure exceeds 20 cmH2O or tidal volume exceeds 1.5 liter (run-away phenomenon) when the volume assist or the flow assist is higher than the individual elastance or the resistance, respectively. Twenty myopathy patients with ventilatory failure and 7 healthy controls were evaluated, including 7 patients with Duchenne muscular dystrophy (DMD), 2 patients with congenital myopathy (CM), 1 patient with limb-girdle muscular dystrophy (LG), 6 patients with myotonic dystrophy (MyD) and 4 patients with acid maltase deficiency (AMD). Seventeen patients used a nasal mask and 3 patients had a tracheostomy tube. Fifteen patients used a pressure-preset ventilator, and 3 patients used a volume-preset ventilator. RESULTS: In all patients with DMD, CM and LG, respiratory system elastance was higher than 20 (cmH2O/L) and than in all patients with AMD and MyD except 1 MyD patient. Follow-up measurement after half a or one year showed increase of respiratory system elastance in 2 DMD patients and 1 CM patient, but almost no change in 3 AMD patients. The elastance measured during PAV was consistent with the clinical impression of muscle shortening. One exceptional MyD patient showed extremely high elastance (more than 58 cmH2O/L), which reflected the fixed thoracic spine and increase of abdominal visceral fat. Resistance was normal in all patients except a LG patient with pulmonary aspergillosis and a history of pulmonary tuberculosis who showed 14 (cmH2O/L/s). In a CM patient who developed emphysema, resistance increased from 5 to 12 (cmH2O/L/s) in a year, although forced expiratory volume 1.0% (FEV1.0/FVC) remained normal. Respiratory system resistance measurement was useful to detect a lung disease, because obstructive disorder is underestimated with FEV1.0/FVC when vital capacity is low. CONCLUSION: The respiratory system elastance and resistance measured during PAV are useful parameters in evaluation of mechanical features of the lung, thorax and airway. It is recommended to keep both parameters normal in patients who may require ventilatory assist due to progression of respiratory muscle weakness.