**6. References**

Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y. & Oda, T. (2006). TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. *Biochem Biophys Res Commun*, 351, 3, 602-611

one genetic defect might act as high penetrant susceptibility factor in sporadic patients and as disease-causing factor with reduced penetrance in ALS-FTLD families, carrying also other disease modifying factors. In this respect it is interesting to note that in our studied belgian family DR14 all patients carry in addition to the disease haplotype at chromosome 9p21 also a haplotype in a novel locus at chromosome 14q32, possibly harboring a disease modifying gene (Gijselinck et al., 2010) and of which the sequences are present in the whole genome sequencing data of the family. Combining the family-based and the population-based approach to ultimately find the gene with one or more genetic defects would be of great value. For example, prioritizing the associated LD block in the whole genome sequence analysis of the family could be useful. Further, since in the associated LD block only three genes are located (*IFNK*, *C9orf72*, *MOBKL2B*) (figure 1), we could focus on these genes with respect to expression and dosage studies (eg. single exon deletions or duplications) in the family. Also, the region in and around the associated LD block can be saturated with STR markers for sharing studies with the DR14 family to detect a small founder haplotype. Combining all these comprehensive data will bring us closer to the identification of the chromosome 9 gene. As long as the genetic defect underlying linkage and association is not known, the full epidemiological impact of the chromosome 9p gene in familial and nonfamilial forms of ALS, ALS-FTLD and FTLD cannot be determined. However, the combined evidence emerging from all molecular genetic studies in chromosome 9p21-linked families and in chromosome 9p21 associated ALS/FTLD populations, suggests it is the most important genetic factor contributing to disease in the center of the disease spectrum linking ALS and FTLD (table 1). Moreover, next to the chr9p21 conclusively linked ALS-FTLD families, several other (smaller) families were also reported without conclusive linkage but with several indications pointing towards the presence of a segregating haplotype in the ALSFTD2 locus (Krueger et al., 2009; Le Ber et al., 2009; Momeni et al., 2006; Pearson et al., 2011; Valdmanis et al., 2007; Yan et al., 2008) (table 1). Identification of this major gene will undoubtedly be a steppingstone for subsequent cell biological studies aiming at better understanding of the pathobiology of neurodegenerative processes leading to ALS and

We are grateful to the patients for their cooperation. We further acknowledge the contribution of personnel of the VIB Genetic Service Facility (www.vibgeneticservicefacility.be). This research of the authors was in part funded by the Special Research Fund of the University of Antwerp, the Research Foundation Flanders (FWO-F), the Institute for Science and Technology - Flanders (IWT-F), the Methusalem excellence grant of the Flemish Government, the Interuniversity Attraction Poles program (IUAP) P6/43 of the Belgian Science Policy Office, the Stichting Alzheimer Onderzoek

Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya,

K., Yoshida, M., Hashizume, Y. & Oda, T. (2006). TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. *Biochem Biophys Res Commun*, 351, 3, 602-611

(SAO-FRMA). I.G. is holding a postdoctoral fellowship of FWO-F.

FTLD.

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**24** 

*Australia* 

**Multidisciplinary Rehabilitation in** 

Amyotrophic Lateral Sclerosis (ALS) is the most common chronic neurodegenerative disorder of the motor system in adults. It is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year worldwide and a gender ratio of 3:2 men: women. Amyotrophic Lateral Sclerosis is characterized by the loss of motor neurons in the cortex, brain stem, and spinal cord, manifested by upper and lower motor neuron signs and symptoms affecting bulbar, limb, and respiratory muscles. Death usually results from respiratory failure and follows on average two to four years after onset, but

Amyotrophic Lateral Sclerosis is a devastating condition with unknown aetiology and no current cure. The symptoms in ALS are diverse and challenging and include weakness, spasticity, limitations in mobility and activities of daily living, communication deficits and dysphagia, and in those with bulbar involvement, respiratory compromise, fatigue and sleep disorders, pain and psychosocial distress. The International Classification of Functioning, Disability and Health (ICF) (World Health Organization, 2001), defines a common language for describing the impact of disease at different levels: impairment (body structure and function), limitation in activity and participation (see Figure 1). Within this framework ALS related impairments (weakness, spasticity), can limit ''activity" or function (decreased mobility, self-care, pain) and ''participation" (driving, employment, family, social reintegration). ''Contextual factors'', such as environmental (extrinsic) and personal factors (intrinsic) interact with all the other constructs to shape the impact of ALS on patients and their families. The impact of ALS upon patients, their caregivers (often family members) and on society is substantial, often beginning long before the actual diagnosis is made, and increasing with increasing disability and the need for medical equipment and

Given the broad spectrum of needs, current management spans from diagnosis (acute neurological needs) through to symptomatic and supportive rehabilitation and palliative care. The interface between neurology, rehabilitation and palliative care is of utmost importance to ensure co-ordinated care for persons with ALS rather than duplicating services (Royal College of Physicians National Council for Palliative Care and British Society of Rehabilitation Medicine, 2008). It should be noted however that the focus of this chapter is on the rehabilitation phases, hence discussion of acute neurological and palliative care

**1. Introduction** 

some may survive for a decade or more.

assisted care (Klein and Forshew, 1996).

aspects are limited.

**Amyotrophic Lateral Sclerosis** 

*Royal Melbourne Hospital and University of Melbourne* 

Louisa Ng and Fary Khan
