Comparisons of characteristics and outcome between abusive head trauma and non-abusive head trauma in a pediatric intensive care unit.

BACKGROUND: Abusive head trauma (AHT) is the leading cause of death in infants with traumatic brain injury (TBI). Early recognition of AHT is important for improving outcomes, but it can be challenging due to its similar presentations with non-abusive head trauma (nAHT). This study aims to compare clinical presentations and outcomes between infants with AHT and nAHT, and to identify the risk factors for poor outcomes of AHT. METHODS: We retrospectively analyzed infants of TBI in our pediatric intensive care unit from January 2014 to December 2020. Clinical manifestations and outcomes were compared between patients with AHT and nAHT. Risk factors for poor outcomes in AHT patients were also analyzed. RESULTS: 60 patients were enrolled for this analysis, including 18 of AHT (30%) and 42 of nAHT (70%). Compared with those with nAHT, patients with AHT were more likely to have conscious change, seizures, limb weakness, and respiratory failure, but with a fewer incidence of skull fractures. Additionally, clinical outcomes of AHT patients were worse, with more cases undergoing neurosurgery, higher Pediatric Overall Performance Category score at discharge, and more anti-epileptic drug (AED) use after discharge. For AHT patients, conscious change is an independent risk factor for a composite poor outcome of mortality, ventilator dependence, or AED use (OR = 21.9, P = 0.04) CONCLUSION: AHT has a worse outcome than nAHT. Conscious change, seizures and limb weaknesses but not skull fractures are more common in AHT. Conscious change is both an early reminder of AHT and a risk factor for its poor outcomes.

TRAPPC11-related muscular dystrophy with hypoglycosylation of alpha-dystroglycan in skeletal muscle and brain.

AIMS: TRAPPC11, a subunit of the transport protein particle (TRAPP) complex, is important for complex integrity and anterograde membrane transport from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment. Several individuals with TRAPPC11 mutations have been reported with muscle weakness and other features including brain, liver, skeletal and eye involvement. A detailed analysis of brain and muscle pathology will further our understanding of the presentation and aetiology of TRAPPC11 disease. METHODS: We describe five cases of early-onset TRAPPC11-related muscular dystrophy with a systematic review of muscle pathology in all five individuals, post-mortem brain pathology findings in one and membrane trafficking assays in another. RESULTS: All affected individuals presented in infancy with muscle weakness, motor delay and elevated serum creatine kinase (CK). Additional features included cataracts, liver disease, intellectual disability, cardiomyopathy, movement disorder and structural brain abnormalities. Muscle pathology in all five revealed dystrophic changes, universal hypoglycosylation of alpha-dystroglycan and variably reduced dystrophin-associated complex proteins. Membrane trafficking assays showed defective Golgi trafficking in one individual. Neuropathological examination of one individual revealed cerebellar atrophy, granule cell hypoplasia, Purkinje cell (PC) loss, degeneration and dendrite dystrophy, reduced alpha-dystroglycan (IIH6) expression in PC and dentate neurones and absence of neuronal migration defects. CONCLUSIONS: This report suggests that recessive mutations in TRAPPC11 are linked to muscular dystrophies with hypoglycosylation of alpha-dystroglycan. The structural cerebellar involvement that we document for the first time resembles the neuropathology reported in N-linked congenital disorders of glycosylation (CDG) such as PMM2-CDG, suggesting defects in multiple glycosylation pathways in this condition.

Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood. CASE PRESENTATION: A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder. CONCLUSIONS: The increase of ß-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.

Severe Ocular Complications After Blepharoptosis Correction in the Oculopharyngeal Muscular Dystrophy Patient: Literature Review and Case Presentation.

BACKGROUND: Blepharoptosis correction in oculopharyngeal muscular dystrophy (OPMD) patients may result in severe ocular complications owing to lagophthalmos and ophthalmoplegia. Managing the acute episode to prevent further aggravation of the keratopathy or blindness is of paramount importance. METHODS: A review of the literature for severe chemosis, keratopathy, and corneal ulceration in the patient population was performed using the PubMed database, with key words including ptosis surgery, ptosis correction, ptosis repair, and oculopharyngeal muscular dystrophy. A retrospective review of all patients with blepharoptosis from a single surgeon from September 2009 and May 2017 was performed, selecting those with OPMD who underwent blepharoptosis correction. RESULTS: Our literature review revealed a total of 15 articles after excluding repeated articles and selecting those meeting our inclusion criteria. A total of 232 OPMD patients underwent blepharoptosis correction. Severe ocular complications were noted in 7 patients, with treatment unspecified. For 9 years, 2 OPMD patients at our institute underwent blepharoptosis correction, with one developing severe acute keratitis, chemosis, and corneal ulceration due to lagophthalmos and ophthalmoplegia. Use of the temporary drawstring tarsorrhaphy and topical eye drop treatment for 2 weeks led to resolution of corneal ulcerations without necessitating further intervention. CONCLUSIONS: Severe ocular complications may occur after blepharoptosis correction in OPMD patients, potentially owing to lagophthalmos and ophthalmoplegia. Temporary drawstring tarsorrhaphy is an effective option to treat these adverse outcomes.

Pediatric necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies.

OBJECTIVE: Antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have recently been associated with immune-mediated necrotizing myopathy, especially in patients with statin exposure. As the data are very limited concerning phenotypes and treatment in paediatric patients, we aimed to identify the paediatric patients positive for anti-HMGCR antibodies and clarify their features and therapeutic strategies. METHODS: We screened 62 paediatric patients who were clinically and/or pathologically suspected to have inflammatory myopathy for anti-HMGCR antibodies. We further re-assessed the clinical and histological findings and the treatment of the patients positive for anti-HMGCR antibodies. RESULTS: We identified nine paediatric patients with anti-HMGCR antibodies (15%). This was more frequent than anti-signal recognition particle antibodies (four patients, 6%) in our cohort. The onset age ranged from infancy to 13 years. Five patients were initially diagnosed with muscular dystrophy, including congenital muscular dystrophy. Most patients responded to high-dose corticosteroid therapy first but often needed adjuvant immunosuppressants to become stably controlled. CONCLUSION: Paediatric necrotizing myopathy associated with anti-HMGCR antibodies may not be very rare. Phenotypes are similar to those of adult patients, but a chronic slowly progressive course may be more frequent. Some patients share the clinicopathological features of muscular dystrophy indicating that recognizing inflammatory aetiology would be challenging without autoantibody information. On the other hand, most patients responded to treatment, especially those who were diagnosed early. Our results suggest the importance of early autoantibody testing in paediatric patients who have manifestations apparently compatible with muscular dystrophy in addition to those who have typical features of inflammatory myopathy.

Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors.

INTRODUCTION: c.250G>A (p.Ala84Thr) in ETFDH is the most common mutation that causes later-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) in the southern Chinese population. No functional study has targeted this mutation. METHODS: Using cells expressing ETFDH-wild-type (WT) or ETFDH-mutant (p.Ala84Thr), reactive oxygen species (ROS) production and neurite length were analyzed, followed by pathomechanism exploration and drug screening. RESULTS: Increased ROS production and marked neurite shortening were observed in the cells expressing the ETFDH-mutant, compared with WT. Further studies demonstrated that suberic acid, an accumulated intermediate metabolite in MADD, could significantly impair neurite outgrowth of NSC34 cells, but neurite shortening could be restored by supplementation with carnitine, riboflavin, or Coenzyme Q10. CONCLUSIONS: Neurite shortening caused by the c.250G>A mutation in ETFDH suggests that neural defects could be underdiagnosed in human patients with MADD. This impairment might be treatable with mitochondrial cofactor supplementation. Muscle Nerve 56: 479-485, 2017.

Creatine and L-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish.

Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this study, we delve into the investigations of five distinct LMNA mutations, including three novel variants and two pathogenic variants identified in patients with muscular laminopathy. Our approach employs zebrafish models to comprehensively study these variants. Transgenic zebrafish expressing wild-type LMNA and each mutation undergo extensive morphological profiling, swimming behavior assessments, muscle endurance evaluations, heartbeat measurement, and histopathological analysis of skeletal muscles. Additionally, these models serve as platform for focused drug screening. We explore the transcriptomic landscape through qPCR and RNAseq to unveil altered gene expression profiles in muscle tissues. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish exhibit reduced swim speed compared to LMNA(WT) measured by DanioVision. All LMNA transgenic adult fish exhibit reduced swim speed compared to LMNA(WT) in T-maze. Moreover, all LMNA transgenic adult fish, except LMNA(E358K), display weaker muscle endurance than LMNA(WT) measured by swimming tunnel. Histochemical staining reveals decreased fiber size in all LMNA mutations transgenic fish, excluding LMNA(WT) fish. Interestingly, LMNA(A539V) and LMNA(E358K) exhibited elevated heartbeats. We recognize potential limitations with transgene overexpression and conducted association calculations to explore its effects on zebrafish phenotypes. Our results suggest lamin A/C overexpression may not directly impact mutant phenotypes, such as impaired swim speed, increased heart rates, or decreased muscle fiber diameter. Utilizing LMNA zebrafish models for drug screening, we identify L-carnitine treatment rescuing muscle endurance in LMNA(L35P) and creatine treatment reversing muscle endurance in LMNA(R453W) zebrafish models. Creatine activates AMPK and mTOR pathways, improving muscle endurance and swim speed in LMNA(R453W) fish. Transcriptomic profiling reveals upstream regulators and affected genes contributing to motor dysfunction, cardiac anomalies, and ion flux dysregulation in LMNA mutant transgenic fish. These findings faithfully mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Furthermore, our drug screening results suggest L-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models. Our study offers valuable insights into the future development of potential treatments for LMNA-related muscular laminopathy.

Pediatric immune-mediated necrotizing myopathy.

Immune-mediated necrotizing myopathy (IMNM) is a type of inflammatory myopathy. Most patients with IMNM produce anti-3-hydroxy-3-methylglutaryl coenzyme A reductase or anti-signal-recognition particle autoantibodies. IMNM is much rarer in children than in adults. We conducted this mini review focusing on pediatric IMNM to present current evidence regarding its epidemiology, clinical characteristics, diagnosis, and treatment. Our findings indicate that pediatric IMNM often causes severe muscle weakness and is refractory to corticosteroids alone. Furthermore, delayed diagnosis is common because of the clinicopathological similarity between IMNM and inherited myopathy. Raising awareness regarding pediatric IMNM may facilitate early diagnosis and effective treatment.

TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy.

OBJECTIVE: Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous muscular disease that presents with muscular dystrophy, joint contractures, and cardiomyopathy with conduction defects. Mutations in several nuclear envelope protein genes have been associated with EDMD in less than half of patients, implying the existence of other causative and modifier genes. We therefore analyzed TMEM43, which encodes LUMA, a newly identified nuclear membrane protein and also a binding partner of emerin and lamins, to investigate whether LUMA may contribute to the pathomechanism of EDMD-related myopathy. METHODS: Forty-one patients with EDMD-related myopathy were enrolled. In vitro and in vivo transfection analyses were performed to assay the binding partners and oligomerization of mutant LUMA. RESULTS: We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients. Reduced nuclear staining of LUMA was observed in the muscle from the patient with p.Glu85Lys mutation. By in vitro transfection analysis, p.Glu85Lys mutant LUMA resulted to failure in oligomerization, a process that may be important for protein complex formation on nuclear membrane. Furthermore, we demonstrated for the first time that LUMA can interact with another nuclear membrane protein, SUN2, in addition to emerin. Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei. In vivo expression of mutant LUMA by electroporation in mouse tibialis anterior muscles likewise demonstrated the decreased staining of emerin and SUN2 on myonuclei. INTERPRETATION: Our results suggest that mutant LUMAs may be associated with EDMD-related myopathy.

Lipid storage myopathy.

Lipid storage myopathy (LSM) is pathologically characterized by prominent lipid accumulation in muscle fibers due to lipid dysmetabolism. Although extensive molecular studies have been performed, there are only four types of genetically diagnosable LSMs: primary carnitine deficiency (PCD), multiple acyl-coenzyme A dehydrogenase deficiency (MADD), neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. Making an accurate diagnosis, by specific laboratory tests including genetic analyses, is important for LSM as some of the patients are treatable: individuals with PCD show dramatic improvement with high-dose oral L-carnitine supplementation and increasing evidence indicates that MADD due to ETFDH mutations is riboflavin responsive.

Intravenous Tranexamic Acid Reduces Blood Loss and Transfusion Volume in Scoliosis Surgery for Spinal Muscular Atrophy: Results of a 20-Year Retrospective Analysis.

Intravenous tranexamic acid (TXA) has been administered to reduce intraoperative blood loss in scoliosis surgery. However, the therapeutic effect of TXA on spinal muscular atrophy (SMA) scoliosis surgery is not well demonstrated. Therefore, this study aimed to assess the efficacy of intravenous TXA in SMA scoliosis surgery. From December 1993 to August 2020, 30 SMA patients who underwent scoliosis surgery (posterior fusion with fusion level of thoracic second or third to pelvis) were retrospectively enrolled and divided into the TXA group and non-TXA (control) group, with 15 patients in each group. Survey parameters were the amount of blood loss, blood transfusion, crystalloid transfusion volume, intubation time, and associated pulmonary complications (including pneumonia, pulmonary edema, and pulmonary atelectasis). The TXA group had significantly lesser blood loss than the control group (p = 0.011). Compared with the control group, the TXA group had significantly lower blood transfusion (p < 0.001), crystalloid volume (p = 0.041), and total transfusion volume (p = 0.005). In addition, the TXA group had fewer postoperative pulmonary complications, and patients with pulmonary complications were associated with a higher relative crystalloid volume and relative total transfusion volume (p = 0.003 and 0.022, respectively). In conclusion, TXA can be effective in reducing intraoperative blood loss and crystalloid fluid transfusions during scoliosis surgery in SMA patients, which may aid in reducing postoperative pulmonary complications.

Predictors for Deformity Progression in a Spinal Muscular Atrophy Cohort After Scoliosis Correction Surgery.

STUDY DESIGN: This was a single-center, retrospective study. OBJECTIVE: The objective of this study was to assess the risk factors for deformity progression after scoliosis correction surgery in spinal muscular atrophy (SMA) patients. SUMMARY OF BACKGROUND DATA: Moderate residual postoperative scoliosis curve is common in SMA populations; however, the acceptable postoperative scoliosis curve for preventing deformity progression remains uncertain. MATERIALS AND METHODS: Twenty-nine SMA patients undergoing scoliosis correction surgery were included. Scoliosis progression was defined as an increase of 10 degrees in the major curve of Cobb angle (MCCA); pelvic obliquity (PO) or concave-side hip progression was arbitrarily defined as an increase of ≥1 grade after surgery. Risk factors for deformity progression were examined using Cox proportional hazard models. The cumulative incidence rate of deformity progression was performed by the Kaplan-Meier survival analysis RESULTS:: The mean age at surgery was 13.3 years (range: 8-25 y) and the mean follow-up time was 7 years (range: 2-22.9 y). The mean MCCA was corrected from 69 to 34.6 degrees at initial follow-up and 42.2 degrees at the final follow-up. Postoperative MCCA (P=0.002) and PO (P=0.004) at initial follow-up were the risk factors for scoliosis progression. Postoperative MCCA at initial follow-up (P=0.007) and age at the time of surgery (P=0.017) were the risk factors for PO progression. Different cutoff points of postoperative MCCA at initial follow-up were compared for predicting deformity progression. We found the patient with postoperative MCCA of <30 degrees at initial follow-up had a significantly less cumulative incidence rate of progression than their counterparts for scoliosis (P=0.005), PO (P=0.023), and concave-side hip progressions (P=0.008). CONCLUSIONS: We recommended that MCCA should be corrected to <30 degrees to prevent postoperative scoliosis, PO, and concave-side femoral head coverage percentage progressions. Patients receiving surgery earlier had less postoperative MCCA at initial follow-up but with no increase in the risk of postoperative scoliosis progression.

Clinical, pathological, imaging, and genetic characterization in a Taiwanese cohort with limb-girdle muscular dystrophy.

BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs). RESULTS: We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10 years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2 N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G > T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A > G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged > 18 years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types. CONCLUSION: Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.

Treatment experience of Taiwanese patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy.

Immune-mediated necrotizing myopathy (IMNM) has emerged as a new subgroup of idiopathic inflammatory myopathy in the past decade, associated with the presence of two autoantibodies against signal recognition particle and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We aim to analyze the clinical, pathological, and imaging phenotypes of the patients with anti-HMGCR myopathy in our cohort. Five patients with anti-HMGCR myopathy have been enrolled who were all female; three were pediatric and two were adult patients. The muscle pathology of patients met the diagnostic criteria of IMNM. On muscle magnetic resonance imaging, adductors were earliest affected while lower legs were relatively preserved with highest degree of involvement in medial head of gastrocnemius. In upper extremities, biceps brachii was the most severely involved, followed by triceps. All patients were refractory to steroid mono-therapy. For pediatric patients, all three patients eventually became responsive to steroid with either intravenous immunoglobulin or rituximab despite variable motor function recovered at present due to different intervention timing. For adult patients, one with statin exposure responded well to steroid and azathioprine use and the motor function returned to the baseline. The other adult patient finally got stabilized and slowly improved with steroid and methotrexate 13 years after the start of therapy. The creatine kinase (CK) levels of all patients were decreased along with clinical severity. In conclusion, muscle imaging might be of help for the diagnosis. Treatment with immuno-suppressants could be considered together with steroid from the beginning.

Deficiency of emerin contributes differently to the pathogenesis of skeletal and cardiac muscles in LmnaH222P/H222P mutant mice.

Laminopathies are tissue-selective diseases that affect differently in organ systems. Mutations in nuclear envelopes, emerin (Emd) and lamin A/C (Lmna) genes, cause clinically indistinguishable myopathy called Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy. Several murine models for EDMD have been generated; however, emerin-null (Emd) mice do not show obvious skeletal and cardiac muscle phenotypes, and Lmna H222P/H222P mutant (H222P) mice show only a mild phenotype in skeletal muscle when they already have severe cardiomyopathy. Thus, the underlying molecular mechanism of muscle involvement due to nuclear abnormalities is still unclarified. We generated double mutant (Emd-/-/LmnaH222P/H222P; EH) mice to characterize dystrophic changes and to elucidate interactions between emerin and lamin A/C in skeletal and cardiac muscles. As H222P mice, EH mice grow normally and have breeding productivity. EH mice showed severer muscle involvement compared with that of H222P mice which was an independent of cardiac abnormality at 12 weeks of age. Nuclear abnormalities, reduced muscle fiber size and increased fibrosis were prominent in EH mice. Roles of emerin and lamin A/C in satellite cells function and regeneration of muscle fiber were also evaluated by cardiotoxin-induced muscle injury. Delayed increases in myog and myh3 expression were seen in both H222P and EH mice; however, the expression levels of those genes were similar with control and regenerated muscle fiber size was not different at day 7 after injury. These results indicate that EH mouse is a suitable model for studying skeletal muscle involvement, independent of cardiac function, in laminopathies and an interaction between emerin and lamin A/C in different tissues.

Combined noninvasive ventilation and mechanical insufflator-exsufflator for acute respiratory failure in patients with neuromuscular disease: effectiveness and outcome predictors.

BACKGROUND: To determine the effectiveness of combined noninvasive ventilation (NIV) and mechanical insufflator-exsufflator (MI-E) for acute respiratory failure (ARF) in patients with neuromuscular disease (NMD), and outcome predictors. METHODS: A prospectively observational study of patients with ARF was conducted in a pediatric intensive care unit (PICU). All received combined NIV/MI-E during PICU stays between 2007 and 2017. Pertinent clinical variables of heart rate (HR), respiratory rate (RR), pH, PaCO2, and PaO2/FiO2 ratio were collected at baseline and at 2 h, 4-8 h, and 12-24 h after initiating use of NIV/MI-E. Treatment success was defined as avoiding intubation. RESULTS: A total of 62 ARF episodes in 56 patients with NMD (median age, 13 years) were enrolled. The most frequent underlying NMD was spinal muscular atrophy (32/62, 52%). ARF was primarily due to pneumonia (65%). The treatment success rate was 86%. PICU stay and hospitalization were shorter in the success group (9.4 ± 6.1 vs. 21.9 ± 13.9 days and 16.3 ± 7.8 vs. 33.6 ± 17.9 days, respectively; both p < 0.05). HR, RR, pH, and PaCO2 showed a progressive improvement, particularly after 4 h following successful NIV/MI-E treatment. RR decrease at 4 h, and pH increase and PaCO2 decrease at 4-8 h might predict success of NIV/MI-E treatment. The multivariate analysis identified PaCO2 at 4-8 h of 58.0 mmHg as an outcome predictor of NIV/MI-E treatment. CONCLUSIONS: Applying combined NIV/MI-E in the acute care setting is an efficient means of averting intubation in NMD patients with ARF. Clinical features within 8 h of the institution may predict treatment outcome. The reviews of this paper are available via the supplemental material section.

The effect of hydroxyurea in spinal muscular atrophy cells and patients.

BACKGROUND: Spinal muscular atrophy (SMA) is a degenerative motor neuron disease caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene. Effective treatment for SMA is unavailable at present. The aim of this study was to investigate the effect of hydroxyurea (HU) in SMA cells and patients. MATERIALS AND METHODS: Fifteen SMA lymphoid and three fibroblast cell lines, 2 from SMA patients and 1 control, were treated with HU at different concentrations, and 33 patients (types II, III) randomized into three groups on different HU dosage, 20, 30, 40 mg/kg/day, were treated for 8 weeks and followed up for another drug-free 8 weeks. The effect of HU on SMN2 gene expression and clinical manifestations was evaluated. RESULTS: After treatment, in vitro, full-length mRNA level and gems number increased significantly, and hnRNP A1 protein decreased. In vivo, there were slight increases in muscle strength scores at 4 weeks and full-length SMN mRNA at 8 weeks in 30 mg/kg/day subgroup. CONCLUSIONS: Treating with HU enhanced SMN2 gene expression in SMA cells and showed slight trend towards improvement in some clinical outcome measures in SMA patients which suggests HU may be safe to use in SMA patients but larger randomized, placebo-controlled, double-blind trials are needed to further investigate its efficacy.

Clinical and genetic features in a MELAS child with a 3271T>C mutation.

A mitochondrial DNA 3271T>C point mutation was reported to be the second most common mutation (following the mutation 3243A>G) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in Japan. This mutation has rarely been reported in other countries. We present an 11-year-old Taiwanese girl with MELAS, who harbored the 3271T>C mutation and had manifested short stature, epilepsia partialis continua, and recurrent basal ganglia infarctions since age 6 years, and rapid intellectual regression, dysarthria, and unsteady gait since age 10 years. The proportion of 3271T>C mutant genomes in various tissues, including urinary sediments, hair follicles, blood leukocytes, and buccal mucosa cells from the patient and her mother, was analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis and quantitative real-time polymerase chain reaction. The proportion of mutant load in the patient's muscles was near 100%. Except for muscle, the highest mutation load was detected in urinary sediments of the patient by both methods. This is the first report involving mutant load analysis with quantitative real-time polymerase chain reaction in the 3271T>C mutation. The results suggest that urinary sediments may be an alternative tissue of choice which can be obtained noninvasively in the diagnosis of mitochondrial DNA 3271T>C mutations.

The natural history of the patients with Duchenne muscular dystrophy in Taiwan: A medical center experience.

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common hereditary muscular dystrophy and caused by DMD gene mutation. In addition to progressive proximal muscle weakness, respiratory, orthopedic, and gastrointestinal complications are often observed in DMD. The natural history of patients with DMD in Taiwan has not been reported thus far. METHODS: Medical records of 39 patients who received a diagnosis of DMD between 1999 and 2016 at Kaohsiung Medical University Hospital were reviewed. The diagnosis of DMD was confirmed through muscle biopsy or DMD genetic analysis. RESULTS: The mean onset age and mean follow-up period were 2.75 years and 6.76 years, respectively. Seventeen patients (43.5%) had a family history of DMD. The mean full intelligence quotient of the patients was 71.08, and the mean age of walking ability loss was 9.7 years (25 patients). The mean onset age of respiratory insufficiency was 10.64 years with a decline rate of 5.18% per year (25 patients). The mean onset age of cardiomyopathy was 14.69 years (seven patients). The mean onset age of scoliosis was 13.29 years with a progression rate of 11.48° per year (14 patients). Eleven (28.2%) and eight (20.5%) patients had deletions and duplications of DMD, respectively. Fourteen patients (35.9%) had point mutations or small deletions or insertions. Five patients received only multiplex ligation-dependent probe amplification (MLPA) analysis and exhibited neither deletion nor duplication. No mutation was identified in one patient through both MLPA and exon sequencing. CONCLUSION: The clinical phenotypes and disease course in our cohort were consistent with that reported in previous studies. However, the proportion of point mutations or small deletions or insertions in our study was considerably higher than that in reports from other populations. Cardiac ejection fraction was found not a reliable biomarker for identifying cardiac problems, discovering a better parameter is necessary.