Chest infections are serious complications in neuromuscular disorders. The predictive values of lung and respiratory muscle function including peak cough flow still remain unclear.
We performed ...retrospective analysis of 46 children and adolescents (12.7±3.7 years) in whom lung function, respiratory muscle function and peak cough flows had been obtained. Data were related to: (1). number of chest infections and days of antibiotic treatment the year prior to the study and (2). history of severe chest infection requiring hospital admission.
The number of chest infections and the number of days treated with antibiotics correlated with Inspiratory Vital Capacity IVC, peak cough flow PCF and Peak Expiratory Pressure PEP. Twenty-two patients were hospitalized at least once due to severe chest infection. IVC (0.65 vs. 1.44
l;
P<0.0001) and PCF (116 vs. 211
l/min;
P<0.0005) in these patients were significantly lower than in the non-hospitalized group. IVC<1.1
l and PCF<160
l/min were specific and sensitive thresholds to discriminate between patients who had already suffered severe chest infections and those who had not. Therefore, spirometry and peak cough flow are reliable tests to identify patients at high risk for severe chest infections.
Patients with IVC below 1.1
l and/or PCF below 160
l/min should be well monitored and introduced to assisted coughing techniques.
Infantile Pompe disease (IPD) is a fatal, autosomal recessive muscle-wasting disorder. Due to a deficiency of the lysosomal enzyme acid alpha-glucosidase patients develop a generalized myopathy, ...diaphragmatic weakness, and cardiomyopathy leading to death usually within the first year of life. So far there is no therapy available. We report on the safety and efficacy of transgenically derived recombinant human precursor acid alpha-glucosidase (rhGAA) in a 10-month follow-up study in two children with IPD who previously completed a 48-week course of enzyme replacement therapy (ERT) with the same medication at the same dose in a phase II clinical trial. Under this therapy cardiac status and muscle strength had improved, leading to survival beyond the age of one year. These results, together with data from two other phase II clinical trials encouraged further evaluation of the long-term safety and efficacy of enzyme replacement therapy in patients with infantile-onset Pompe disease. During the 10-month follow-up period, ERT was well-tolerated and neither patient experienced a single infusion-associated reaction. The initial improvements in cardiac size and function, as measured by left ventricular mass index and the fractional shortening, were maintained in both patients, and a continued improvement of motor function, as measured by the Alberta infant motor scale, was observed.
In this study, noninvasive ventilation (NIV) was prospectively applied to eight patients (35.8 +/- 11.4 years) with late-onset Pompe disease and respiratory failure apparent from severe restrictive ...lung disease, nocturnal hypoxemia (83 +/- 8%), and daytime hypercapnia (66.7 +/- 17.9 mm Hg). The impact of NIV on respiratory function was followed for 34 +/- 17 months. Despite further decrease of vital capacity and inspiratory muscle strength, NIV normalized oxygen saturation during sleep (96 +/- 1%), daytime carbon dioxide tensions (44.1 +/- 3.6 mm Hg), and symptoms.
Mutations in protein O-mannosyltransferases (POMTs) cause a heterogeneous group of muscular dystrophies with abnormal glycosylation of alpha-dystroglycan (dystroglycanopathies). The wide spectrum of ...clinical severities ranges from Walker-Warburg syndrome (WWS), associated with brain and eye abnormalities, to mild forms of limb girdle muscular dystrophy (LGMD).
The aim of this study was to elucidate the impact of mutations in POMT1 on the clinical phenotype.
We examined 2 patients with POMT1-associated alpha-dystroglycanopathy, 1 displaying a LGMD2K and 1 with a WWS phenotype. Using dermal fibroblasts, we analyzed the influence of the POMT1 mutations on the glycosylation status of alpha-dystroglycan, protein O-mannosyltransferase activity, and the stability of the mutant POMT1 protein.
We report on novel compound heterozygous mutations in POMT1 (p.L171A and p.A589VfsX38) that result in LGMD2K. We further demonstrate that a homozygous splice site mutation of a recently identified WWS patient results in POMT1 p.del77-93. Using dermal fibroblasts, we show that mannosyltransferase activity is reduced in the patients and that stability of POMT1 mutant proteins p.A589VfsX38 and p.del77-93 is significantly decreased.
Our results suggest that dermal fibroblasts can be applied to facilitate the diagnostic analysis of dystroglycanopathy patients as well as to study the pathogenic mechanism of POMT mutations. Characterization of the POMT1 substrate protein alpha-dystroglycan and POMT in vitro mannosyltransferase activity shows that the severity of the clinical phenotype of the patients analyzed is inversely correlated with POMT activity.
Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. Due to virtual absence of acid alpha-glucosidase, patients ...with classical infantile Pompe disease develop progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy. We report on the results of a phase II clinical trial including two patients with classical infantile Pompe disease receiving enzyme replacement therapy over a period of 48 weeks by weekly infusions. Recombinant acid alpha-glucosidase was derived from the milk of transgenic rabbits. Safety was evaluated by recording adverse events while clinical efficacy was evaluated by ventilator-free survival, left ventricular mass index, motor development as well as histologic and biochemical analysis of muscle biopsies. This therapy was in general well-tolerated. There was an overall improvement in left ventricular mass, cardiac function, skeletal muscle function and histological appearance of skeletal muscle.
Abstract The aim of this prospective longitudinal multi centric study was to evaluate the correlation between the Hammersmith Functional Motor Scale and the 20 item version of the Motor Function ...Measure in non ambulant SMA children and adults at baseline and over a 12 month period. Seventy-four non-ambulant patients performed both measures at baseline and 49 also had an assessment 12 month later. At baseline the scores ranged between 0 and 40 on the Hammersmith Motor function Scale and between 3 and 45 on the Motor Function Measure 20. The correlation between the two scales was 0.733. The 12 month changes ranged between −11 and 4 for the Hammersmith and between −11 and 7 for the Motor Function Measure 20. The correlation between changes was 0.48. Our results suggest that both scales provide useful information although they appeared to work differently at the two extremes of the spectrum of abilities. The Hammersmith Motor Function Scale appeared to be more suitable in strong non ambulant patients, while the Motor Function Measures appeared to be more sensitive to capture activities and possible changes in the very weak patients, including more items capturing axial and upper limb activities. The choice of these measures in clinical trials should therefore depend on inclusion criteria and magnitude of expected changes.
12 Clinical features of MDC1C are onset in the first weeks of life, inability to walk, muscle hypertrophy, and highly elevated serum creatine kinase (CK) levels. 12, 13 Mutations in the same gene ...also underlie a milder form of muscular dystrophy (limb girdle muscular dystrophy 2I or LGMD2I), characterised by childhood or adult onset and a relatively benign course, although dilated cardiomyopathy is a common feature OMIM 607115. 24, 25 Normal dystroglycan expression and the proper glycosylation of its α subunit are required for binding to a number of extracellular ligands, including laminin, neurexin, and agrin. 6, 7, 18, 23 Disruption of these interactions results in defects of basement membranes in both skeletal muscle and brain. 6, 7 The integrity of the pial basement membrane, which covers the surface of the brain, is necessary for the organisation of a subpopulation of glial cells, the radial glial cells, which guide the migration of neurones on their inside out journey from the proliferative periventricular regions to the surface of the brain. 7, 26, 27 Defects in the pial basement membrane result in the migration of neurones and glial cells beyond the interrupted pial membrane, giving rise to the cobblestone appearance of the brain. 18, 28, 29 Cobblestone lissencephaly is a consistent feature of FCMD, MEB, WWS, the Largemyd mouse, and MDC1D, but has never been previously described in patients with MDC1C or LGMD2I.
The aim of the current study was to investigate the long-term impact of nocturnal noninvasive (positive-pressure) ventilation (NIV) on sleep, sleep-disordered breathing (SDB) and respiratory function ...in children and adolescents with progressive neuromuscular disorders (NMD). Thirty patients (12.3 +/- 4.1 yrs) with various inherited NMD were treated with NIV for ventilatory insufficiency (n=14) or symptomatic SDB (n=16). Patients were prospectively followed with sleep studies, spirometry and peak inspiratory muscle pressure. Ten patients were studied before and after 3 nights withdrawal from NIV. NIV normalised nocturnal gas exchange in all patients and diurnal gas exchange in patients with ventilatory insufficiency. The effects persisted over 25.3 +/- 12.7 months. Nocturnal transcutaneous partial pressure of carbon dioxide improved from (baseline versus latest control) 7.1 +/- 1.3 to 5.5 +/- 0.6 kPa (53.7 +/- 9.9 to 41.6 +/- 4.8 mmHg), diurnal carbon dioxide arterial tension from 6.3 +/- 1.6 to 5.4 +/- 0.5 kPa (47.5 +/- 11.9 to 40.6 +/- 3.6 mmHg). NIV improved respiratory disturbance index, arousals from sleep, nocturnal heart rate and sleep architecture. Vital capacity decreased in five adolescents with Duchenne muscular dystrophy -183 +/- 111 mL x yr(-1) but remained stable in 25 children with other conditions (8 +/- 78 mL x yr(-1)). Three nights withdrawal of NIV in 10 previously stable patients resulted in prompt deterioration of SDB and gas exchange back to baseline but could be instantly normalised by resumption of NIV. Noninvasive (positive-pressure) ventilation has favourable long-term impact on nocturnal and diurnal gas exchange and sleep and in patients with non-Duchenne neuromuscular disorders on vital capacity as well. It is indicated in children and adolescents with symptomatic sleep-disordered breathing or ventilatory insufficiency due to neuromuscular disorders.
PDF
