Sleep-related breathing disorder in Duchenne muscular dystrophy: Disease spectrum in the paediatric population

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease with death usually occurring because of respiratory failure. Signs of early respiratory insufficiency are usually first detectable in sleep. Objective: To study the presentation of sleep-related breathing disorder (SRBD) in patients with DMD. Method:> A retrospective review of patients with DMD attending a tertiary paediatric sleep disorder clinic over a 5-year period. Symptoms, lung function and polysomnographic indices were reviewed. Results: A total of 34 patients with DMD were referred for respiratory assessment (1-15 years). Twenty-two (64%) reported sleep-related symptomatology. Forced vital capacity (FVC) was between 12 and 107% predicted (n = 29). Thirty-two progressed to have polysomnography of which 15 were normal studies (median age: 10 years) and 10 (31%) were diagnostic of obstructive sleep apnoea (OSA) (median age: 8 years). A total of 11 patients (32%) showed hypoventilation (median age: 13 years) during the 5-year period and non-invasive ventilation (NIV) was offered to them. The median FVC of this group was 27% predicted. There was a significant improvement in the apnoea/hypopnoea index (AHI) (mean difference = 11.31, 95% CI = 5.91-16.70, P = 0.001) following the institution of NIV. Conclusions: The prevalence of SRBD in DMD is significant. There is a bimodal presentation of SRBD, with OSA found in the first decade and hypoventilation more commonly seen at the beginning of the second decade. Polysomnography is recommended in children with symptoms of OSA, or at the stage of becoming wheelchair-bound. In patients with the early stages of respiratory failure, assessment with polysomnography-identified sleep hypoventilation and assisted in initiating NIV.

Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13

Distal spinal muscular atrophy is a heterogeneous group of neuromuscular disorders caused by progressive anterior born cell degeneration and characterized by progressive motor weakness and muscular atrophy, predominantly in the distal parts of the limbs. Here we report on chronic autosomal recessive distal spinal muscular atrophy in a large, inbred family with onset at various ages. Because this condition had some of the same clinical features as spinal muscular atrophy with respiratory distress, we tested the disease gene for linkage to chromosome 11q and mapped the disease locus to chromosome 11q13 in the genetic interval that included the spinal muscular atrophy with respiratory distress gene (D11S1889-D11S1321, Z(max) = 4.59 at theta = 0 at locus D11S4136). The sequencing of IGHMBP2, the human homologue of the mouse neuromuscular degeneration gene (nmd) that accounts for spinal muscular atrophy with respiratory distress, failed to detect any mutation in our chronic distal spinal muscular atrophy patients, suggesting that spinal muscular atrophy with respiratory distress and chronic distal spinal muscular atrophy are caused by distinct genes located in the so-me chromosomal region. In addition, the high intrafamilial variability in age at onset raises the question of whether nonallelic modifying genes could be involved in chronic distal spinal muscular atrophy.

Constraints on muscular performance: trade-offs between power output and fatigue resistance

An important functional and evolutionary constraint on the physical performance of vertebrates is believed to be the trade-off between speed and endurance capacity. However, despite the pervasiveness of physiological arguments, most studies have found no evidence of the trade-off when tested at the whole-animal level. We investigated the existence of this trade-off at the whole-muscle level, the presumed site of this physiological conflict, by examining inter-individual variation in both maximum power output and fatigue resistance for mouse extensor digitorum longus (EDL) muscle using the work-loop technique. We found negative correlations between several measures of in vitro maximum power output and force production with fatigue resistance for individual mouse EDL muscles, indicating functional trade-offs between these performance parameters. We suggest that this trade-off detected at the whole-muscle level has imposed an important constraint on the evolution of vertebrate physical performance.

Alterations in dihydropyridine receptors in dystrophin-deficient cardiac muscle

The deficiency of dystrophin, a critical membrane stabilizing protein, in the mdx mouse causes an elevation in intracellular calcium in myocytes. One mechanism that could elicit increases in intracellular calcium is enhanced influx via the L-type calcium channels. This study investigated the effects of the dihydropyridines BAY K 8644 and nifedipine and alterations in dihydropyridine receptors in dystrophin-deficient mdx hearts. A lower force of contraction and a reduced potency of extracellular calcium (P < 0.05) were evident in mdx left atria. The dihydropyridine agonist BAY K 8644 and antagonist nifedipine had 2.7- and 1.9-fold lower potencies in contracting left atria (P < 0.05). This corresponded with a 2.0-fold reduction in dihydropyridine receptor affinity evident from radioligand binding studies of mdx ventricular homogenates (P < 0.05). Increased ventricular dihydropyridine receptor protein was evident from both radioligand binding studies and Western blot analysis and was accompanied by increased mRNA levels (P < 0.05). Patch-clamp studies in isolated ventricular myocytes showed no change in L-type calcium current density but revealed delayed channel inactivation (P < 0.05). This study indicates that a deficiency of dystrophin leads to changes in dihydropyridine receptors and L-type calcium channel properties that may contribute to enhanced calcium influx. Increased influx is a potential mechanism for the calcium overload observed in dystrophin-deficient cardiac muscle.