**1. Introduction**

80 Neuromuscular Disorders

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skipping and functional restoration in dystrophin-deficient mdx mice.

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(March 2009). Efficacy of systemic morpholino exon-skipping in duchenne

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> Duchenne muscular dystrophy (DMD, OMIM #310200) is the most common form of muscular dystrophy in childhood, with an incidence of approximately 1 per 3,500 live-born males [Emery, 1991]. It is caused by mutations of the *DMD* gene located on Xp21 which codes for dystrophin, a 427-kDa protein that is expressed at the sarcolemma of skeletal muscle. The *dystrophin* gene contains 79 exons, which includes an actin-binding domain at the N-terminus, 24 spectrin-like repeat units, a cysteine-rich dystroglycan binding site, and a C-terminal domain [Hoffman et al, 1987; Koenig et al, 1988]. The large size of the *dystrophin* gene results in a complex mutational spectrum (>4,700 different mutations) as well as a high spontaneous mutation rate [Aartsma-Rus et al, 2006]. Large deletions account for approximately 65% of DMD mutations while duplications occur in up to 10% of males with DMD. The remaining 25% include small deletions, insertions, point mutations, or splicing mutations. About two-thirds of DMD cases are inherited from mothers carrying the mutations, with the remaining one-third occurring as spontaneous mutations [Laing, 1993]. According to Monaco et al, DMD-causing mutations are typically associated with an out-offrame mutation leading to a loss of functional gene product, whereas in-frame mutations that allow synthesis of an internally truncated but functional protein result in a milder Becker muscular dystrophy (BMD) phenotype [Monaco et al, 1988].

> Dystrophin is an integral component of the dystrophin glycoprotein complex. It stabilizes the muscle membrane by bridging the basal lamina of the extracelluar matrix to the inner cytoskeleton of the contractile elements [Rybakova et al, 2000]. It also serve as a transmembrane signalling complex which is essential for cell survival [Chen et al, 2000]. Loss of dystrophin results in excessive membrane fragility, unregulated influx of calcium ions into the sarcoplasm, mitochondrial dysfunction, and increased oxidative stress, leading to progressive muscle degeneration, fibrosis, and fatty replacement [Wallace & McNally, 2009]. Early presenting features in DMD include developmental delay, proximal muscle weakness as evident by Gowers' sign and waddling gait, as well as varying degree of

<sup>\*</sup> Corresponding Author

Psychosocial Support Needs of Families of Boys with Duchenne Muscular Dystrophy 83

A number of recent publications have provided comprehensive reviews on the diagnosis and multidisciplinary management of DMD, including the use of prednisone or deflazacort to preserve muscle strength [Bushby et al, 2004; Moxley et al, 2005], optimizing growth and development, surveillance for spinal deformities [Muntoni et al, 2006], managing respiratory complications [Finder et al, 2004; Birnkrant et al, 2010], and treating cardiomyopathy [American Academy of Pediatrics, 2005; Baxter, 2006]. As well, bone health, nutrition, learning disability, behaviour problems, access to wheelchair and other adaptive technology should be included as part of the comprehensive treatment plan [Bushby et al, 2010a; Bushby et al, 2010b]. As standard of care guidelines typically focus on medical management and there are no systematic strategies to meet the psychosocial needs of boys with DMD and their families, the remaining of this paper will present some of our results on pediatric HRQOL, parental experience, and family-centered care approach to DMD that may help to identify the needs and incorporate psychosocial support strategies into clinical practice. We propose the use of a modified Family Needs Survey for DMD (DMD-FNS) to help clinicians to address needs and tailor services for each family across the different stages

Chronic neurological disorders such as DMD have a significant impact on pediatric health-related quality of life (HRQOL) and functional ability. Both medical services and community-based programs are often required to address their physical, emotional, social, and educational needs. A large prospective study led by Dr. Craig McDonald and his colleagues will provide valuable longitudinal data on the natural history of DMD, associated HRQOL, and health services utilization; this 5-year study includes more than three hundred boys with a confirmed diagnosis of DMD from 20 participating CINRG centers in the United States and other international sites (personal communication). Given the lack of information on the processes of care and health outcomes of children with chronic neurological disabilities in Canada, a brief 3-month cross-sectional pilot survey was performed at the Alberta Children's Hospital, a tertiary pediatric neurosciences center in Calgary, Alberta to explore the use of health services and HRQOL among DMD and other pediatric neurosciences patients. Specifically, parents of 278 children (165 male, mean age = 11 4.5 years) were asked to describe their child's functional ability, healthrelated quality of life (HRQOL), and use of health services including access to medical professionals, rehabilitation programs, education, and social support in their communities. The children were followed because of chronic neurological diseases including brain tumour (n=33), traumatic brain injury (n=23), hydrocephalus (n=46), myelomeningocele (n=29), refractory epilepsy (n=89), or neuromuscular disease (n=58), including 14 boys with DMD. As part of the study procedure, the parents completed questionnaires regarding their socio-demographic status, their experience with rehabilitative and supportive services, their child's functional ability using the Functional Independence Measure (FIMTM/WeeFIM®)*,* and their child's HRQOL using the PedsQLTM

The FIM and WeeFIM are designed to measure functional abilities and limitations in activities of daily living. The FIM is used for persons seven years of age or older, while the WeeFIM is designed for children between six months to seven years in age. Both versions

of the disease.

(version 4.0) generic core.

**3. DMD and health-related quality of life** 

cognitive impairment and learning disability [Fitzpatrick et al, 1986; Leibowitz & Dubowitz, 1981]. Serum creatine kinase is usually markedly elevated due to on-going muscle damage and regenerative failure. Progressive muscle weakness leads to loss of independent ambulation by early teens, scoliosis, quadriplegia, respiratory insufficiency, cardiomyopathy, and death around the third decade of life.

Detection of *DMD* mutations include multiplex polymerase chain reaction (PCR) that examines the most commonly deleted regions of the gene, or other molecular genetic assays that interrogate all 79 exons, such as multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization (CGH) microarray. If the presence of a disease-causing deletion or duplication is not identified by a state-of-the-art DNA diagnostic technique, complete gene sequencing is needed to define the precise mutational event [Baskin et al, 2009; Takeshima et al, 2010]. A muscle biopsy can also be obtained for confirmation of dystrophin deficiency by immunostaining plus extraction of cDNA and RNA for further genetic testing [Mah et al, 2011].

Recent scientific advances have led to potentially new disease modifying treatments for many neuromuscular diseases including DMD [Wagner, 2008; Fairclough et al, 2011]. The main therapeutic strategies include: a) muscle membrane stabilization and up-regulation of compensatory cytoskeleton proteins such as biglycan and utrophin [Amenta et al, 2011; Tinsley et al, 2011]; b) enhancement of muscle regeneration via up-regulation of insulin growth factor (IGF-1) and modulation of members of transforming growth factor-beta such as myostatin [Schertzer et al, 2008; Morine et al, 2010]; c) reduction of the inflammatory cascade by selective nuclear factor-kappa B (NF-κB) inhibition [Tang et al, 2010]; and d) gene therapy including the use of adeno-associated virus microdystrophin [Trollet et al, 2009], nonsense suppression therapy [Welch et al, 2007; Malik et al, 2010], and exon-skipping to restore partial dystrophin protein production [Muntoni et al, 2005; van Deutekom et al, 2007]. Effective treatment of DMD will likely require multiple interventions targeting different disease processes, and updated information about DMD clinical trials is available at http://www.clinicaltrials.gov. The success of new and emerging therapeutic strategies depends on early diagnosis and precise mutational analysis for boys with DMD, the creation of a national or global disease-specific patient registries, plus on-going advocacy and interdisciplinary collaboration.
