Purpose:
The aim of this study was to investigate the effects of upper extremity dynamic exercise on respiratory function and quality of life in children with Duchenne Muscular Dystrophy (DMD).
...Methods:
In this study, children who diagnosed DMD scored as Level 1 or 2 according to the Brooke Upper Extremity Functional Classification (BUEFC) were divided into study and control groups with coin toss method randomly. Demographic datas were recorded. Timed performance tests (standing from supine, T-Shirt wearing/removing), electronic respiratory muscle strength device and Pediatric Quality of Life-3.0 (PedsQL-3.0) Neuromuscular Module child/parent questionnaire were used for evaluation of upper extremity performances, peak expiratory flow (PEF) and health-related quality of life, respectively. Study group had trained in arm ergometer, 8 weeks, 3 days per week, mean 40 minutes. Control group was applied normal range of motion upper extremity exercises as home programme. Assessments were repeated after 8 weeks.
Results:
24 DMD children, 12 control and 12 study subjects, respectively with mean age 9.33±1.37 and 9.50±1.38 were evaluated. Statistically significant differences were found in favor of study group in standing from supine position and T-shirt wearing time after exercise program (p<0.05). Significant increase was found in PEF liter value in study group (p<0.01). There were positive, moderate correlation between PedsQL-child scores and PEF (r=0.590; p<0.05); negative, strong correlation between PEF and T-Shirt wearing time (r=-0.629; p<0.05).
Discussion:
It was found that upper extremity dynamic exercise with arm ergometer increased respiratory function and showed positive effect on quality of life of children with DMD.
Significance Essential tremor is one of the most frequent movement disorders of humans, but its causes remain largely unknown. In a six-generation family with both essential tremor and Parkinson ...disease, we identified a rare missense mutation of HTRA2 as the causative allele. Family members homozygous for this allele were more severely affected than those heterozygous for this allele. The same mutation had been associated with Parkinson characteristics in mouse mutants and with Parkinson disease in some, but not all, epidemiologic studies. Our results suggest that HTRA2 may be responsible for essential tremor in some families and that homozygosity for damaging alleles of HTRA2 may be responsible for Parkinson disease.
Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor ( P < 0.0001), more severe postural tremor ( P < 0.0001), and more severe kinetic tremor ( P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration ( mnd2 ) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive ...genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (
ganglioside-induced differentiation protein 1
—
GDAP1
,
SH3 domain and tetratricopeptide repeats-containing protein 2
—
SH3TC2
,
histidine-triad nucleotide binding protein 1
—
HINT1
) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in
GDAP1
, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the
SH3TC2
gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
ABSTRACT
Analyzing the type and frequency of patient‐specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial ...planning, and improved clinical care. Locus‐specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT‐NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid‐intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read‐through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
Analysing the type and frequency of patient specific mutations giving rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. We describe the development and analysis of the TREAT‐NMD DMD Global database (http://umd.be/TREAT_DMD/). We analysed and reported genetic data for 7149 DMD mutations held within the database. Additionally, we identified mutations within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read‐through therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Guillain–Barré syndrome (GBS) is an acute polyradiculoneuropathy. Symptoms may vary greatly in presentation and severity. Besides weakness and sensory disturbances, patients may have cranial nerve ...involvement, respiratory insufficiency, autonomic dysfunction and pain. To develop an evidence‐based guideline for the diagnosis and treatment of GBS, using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology a Task Force (TF) of the European Academy of Neurology (EAN) and the Peripheral Nerve Society (PNS) constructed 14 Population/Intervention/Comparison/Outcome questions (PICOs) covering diagnosis, treatment and prognosis of GBS, which guided the literature search. Data were extracted and summarised in GRADE Summaries of Findings (for treatment PICOs) or Evidence Tables (for diagnostic and prognostic PICOs). Statements were prepared according to GRADE Evidence‐to‐Decision (EtD) frameworks. For the six intervention PICOs, evidence‐based recommendations are made. For other PICOs, good practice points (GPPs) are formulated. For diagnosis, the principal GPPs are: GBS is more likely if there is a history of recent diarrhoea or respiratory infection; CSF examination is valuable, particularly when the diagnosis is less certain; electrodiagnostic testing is advised to support the diagnosis; testing for anti‐ganglioside antibodies is of limited clinical value in most patients with typical motor‐sensory GBS, but anti‐GQ1b antibody testing should be considered when Miller Fisher syndrome (MFS) is suspected; nodal–paranodal antibodies should be tested when autoimmune nodopathy is suspected; MRI or ultrasound imaging should be considered in atypical cases; and changing the diagnosis to acute‐onset chronic inflammatory demyelinating polyradiculoneuropathy (A‐CIDP) should be considered if progression continues after 8 weeks from onset, which occurs in around 5% of patients initially diagnosed with GBS. For treatment, the TF recommends intravenous immunoglobulin (IVIg) 0.4 g/kg for 5 days, in patients within 2 weeks (GPP also within 2–4 weeks) after onset of weakness if unable to walk unaided, or a course of plasma exchange (PE) 12–15 L in four to five exchanges over 1–2 weeks, in patients within 4 weeks after onset of weakness if unable to walk unaided. The TF recommends against a second IVIg course in GBS patients with a poor prognosis; recommends against using oral corticosteroids, and weakly recommends against using IV corticosteroids; does not recommend PE followed immediately by IVIg; weakly recommends gabapentinoids, tricyclic antidepressants or carbamazepine for treatment of pain; does not recommend a specific treatment for fatigue. To estimate the prognosis of individual patients, the TF advises using the modified Erasmus GBS outcome score (mEGOS) to assess outcome, and the modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) to assess the risk of requiring artificial ventilation. Based on the PICOs, available literature and additional discussions, we provide flow charts to assist making clinical decisions on diagnosis, treatment and the need for intensive care unit admission.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Spinal muscular atrophy (SMA) is a neurodegenerative disease of the motor neurons that results in progressive muscle weakness. It is also the leading hereditary cause of infant ...mortality. Homozygous loss of the survival motor neuron (
SMN1
) gene causes SMA, and the number of copies of the
SMN2
gene modulates the severity of the disease. Increasing the expression of the
SMN2
gene by pharmacological agents is one of the therapeutic approaches currently being implemented.
Methods
In this preliminary study, we investigated the effect of phenylbutyrate, a histone deacetylase (HDAC) inhibitor, on
SMN2
expression in two SMA type III Epstein—Barr virus (EBV)-transformed lymphoblastoid cell lines to understand the suitability of lymphoblastoid cell lines in drug screening. These cell lines are regarded as a good source as they can easily be established from the peripheral leucocytes of patients. Quantitative analysis of
SMN2
mRNA was performed on established cell lines treated with various concentrations of phenylbutyrate and for a range of incubation periods using real-time polymerase chain reaction. Western blot analysis was used to determine SMN protein levels.
Results
Real-time polymerase chain reaction and Western blot analysis demonstrated that the levels of
SMN2
full-length (fl-
SMN2
) transcripts and protein were not increased in phenylbutyrate-treated cell lines compared to non-treated controls.
Conclusion
These results suggest that EBV-transformed lymphoblastoid cell lines are not suitable for studying the effect of certain HDAC inhibitors on
SMN2
gene expression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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