**1. Introduction**

200 Neuromuscular Disorders

Wells, L., Vosseller, K. & Hart, G. W. (2001). Glycosylation of nucleocytoplasmic proteins:

Wirtz, P. W., Titulaer, M. J., Gerven, J. M. & Verschuuren, J. J. (2010). 3,4-diaminopyridine

Wu, H., Xiong, W. C. & Mei, L. (2010). To build a synapse: signaling pathways in

Yasaki, E., Prioleau, C., Barbier, J., Richard, P., Andreux, F., Leroy, J. P., Dartevelle, P.,

Yeung, W. L., Lam, C. W., Fung, L. W., Hon, K. L. & Ng, P. C. (2009). Severe congenital

Zenker, M., Aigner, T., Wendler, O., Tralau, T., Muntefering, H., Fenski, R., Pitz, S.,

*Human Molecular Genetics*, Vol. 13, No. 21, pp. 2625-2632, ISSN 0964-6906 Zhang, B., Luo, S., Wang, Q., Suzuki, T., Xiong, W. C. & Mei, L. (2008). LRP4 serves as a coreceptor of agrin. *Neuron*, Vol. 60, No. 2, pp. 285-297, ISSN 0896-6273

ISSN 0022-1295

Vol. 6, No. 6, pp. 867-874, ISSN 1744-666X

1, pp. 24-32, ISSN 0960-8966

0036-8075

0950-1991

ISSN 1661-7800

myasthenic syndrome. *Journal of General Physiology*, Vol. 116, No. 3, pp. 449-462,

signal transduction and O-GlcNAc. *Science*, Vol. 291, No. 5512, pp. 2376-2378, ISSN

for the treatment of Lambert-Eaton myasthenic syndrome. *Expert Rev Clin Immunol*,

neuromuscular junction assembly. *Development*, Vol. 137, No. 7, pp. 1017-1033, ISSN

Koenig, J., Molgo, J., Fardeau, M., Eymard, B. & Hantai, D. (2004). Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation. *Neuromuscular Disorders*, Vol. 14, No.

myasthenia gravis of the presynaptic type with choline acetyltransferase mutation in a Chinese infant with respiratory failure. *Neonatology*, Vol. 95, No. 2, pp. 183-186,

Schumacher, V., Royer-Pokora, B., Wuhl, E., Cochat, P., Bouvier, R., Kraus, C., Mark, K., Madlon, H., Dotsch, J., Rascher, W., Maruniak-Chudek, I., Lennert, T., Neumann, L. M. & Reis, A. (2004). Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Neurologists in the 19th century recognized that muscle weakness could be due to primary disorders of muscle or secondary to loss of neuromuscular integrity, as happens when peripheral nerves are cut or when motor neurons degenerate. Furthermore, it was observed that there are forms of motor neuron degeneration which selectively affect upper motor neurons or lower motor neurons. A combination of upper and lower motor neuron dysfunction was named amyotrophic lateral sclerosis (ALS) by Charcot and Joffroy (Ringel, et al 1993). Jean-Martin Charcot first characterized the disease in 1874, naming the illness Amyotrophic lateral sclerosis (ALS) (Swash, 2001). In USA, ALS or Lou Gehrig's disease are terms used to describe all forms of the disease, whatever the combination of upper and lower motor neuron involvement (Ringel, et al 1993). ALS is now a term which classifies the most common form of the illness and is often used synonymously with MND (Swash, 2001). In the UK the umbrella term motor neuron disease (MND) is more common. MND is a disease of middle to late life with a mean age of onset of 58 years, (Ringel, et al 1993).

Actually, motor neuron diseases (MND) are a group of degenerative disorders that selectively affect motor neurons in the brain and spinal cord. Two groups of motor neurons are involved, lower motor neurons located in ventral horns of the spinal cord and brainstem motor nuclei, and upper motor neurons located in the cerebral cortex together with pyramidal tracts in spinal cord. The term MND is a broad spectrum term including amyotrophic lateral sclerosis.

### **2. Definitions and terminology of motor neuron disease (MND)**

MND is a group of incurable progressive neurodegenerative disorders in which degeneration involves upper and lower motor neurons in different body regions, resulting in progressive weakness of bulbar, limbs and respiratory musculature, in different combination.

MND is an adult onset neurodegenerative disease which leads inexorably via weakness of limb, bulbar and respiratory muscles to death from respiratory failure three to five years later. (Allum and Shaw 2010).

#### **3. Epidemiology of motor neuron disease**

The prevalence of MND is 4-6 per 100,000 in most parts of the world, except the Western Pacific foci, (Leigh, 1991). However, its annual incidence is between 1.5 and 2/100,000 and

Motor Neuron Disease 203

Excitotoxicity, (3) Oxidative stress, (4) Mitochondrial dysfunction, (5) Impaired axonal transport, (6) Neurofilament aggregation, (7) Protein aggregation, (8) Inflammatory dysfunction and contribution of non-neuronal cells, (9) Deficits of neurotrophic factors and dysfunction of signaling pathways, and (10) Apoptosis, (Wijesekera and Leigh.2009 and

Up to 90% of all ALS cases, occurs without family history, (sporadic ALS) and about 10% of cases are familial ALS (FALS). SALS is clinically indistinguishable from FALS, but the average age of onset in FALS is somewhat earlier, (Celveland and Rothstein (2001). Enteroviral infections and mutations of superoxide dismutase 1gene (SOD1) have been implicated in the pathogenesis of MND (oluwale et al 2001). About 25% of ALS cases, (Celveland and Rothstein (2001)**,** and 2% of the sporadic cases, are linked to mutations in the gene encoding copper/zinc superoxide dismutase (SOD1). It is Known that there may be as many as six gene loci that code for the ALS phenotype, but only three have been identified. Several other mutations have also been documented to possibly take part in the pathogenesis of ALS, (Wijesekera and Leigh, 2009)**.** Since the link between SOD1 and FALS was first established, >90 FALS-linked SOD1 mutations have been discovered, (Celveland and Rothstein (2001). Most of these mutations are point missense mutations, (Anderson, et al. 2003). Most of the genetics are transmitted via the autosomal dominant route, though some are autosomal recessive and others may be sex-linked, (Wijesekera

Excitotoxicity is a term used to signify the damage that occurs to neuronal cells that are characterized by overstimulated glutamate receptors, as glutamate is the major excitatory neurotransmitter in the human central nervous system (Riluzol monograph. 2011). As SOD1 codes for the major reuptake protein of glutamate, a mutation limits the concentration levels of that reuptake protein, allowing an excessive amount of glutamate to be present in the neuronal synapse. It is also postulated that glutamatergic toxicity plays a direct role in the

Oxidative stress is of particular interest to researchers due to the fact that the SOD1 gene mutation that is known to cause ALS, normally codes for an anti-oxidant protein. (Riluzol

There are many new data which supports the theory that mitochondrial dysfunction plays an important role in the pathogenesis of ALS. Multiple cases of dysfunctional mitochondria have been noted in post-mortem analyses of ALS patients. (Wijesekera and Leigh.2009) Dysfunctional mitochondria have also been linked to the SOD1 gene mutation in mice

destruction of neuronal cells in patients with ALS.( Shaw. 2005).

Shaw. 2005).

**4.2 Genetics** 

and Leigh.2009).

**4.3 Excitotoxicity** 

**4.4 Oxidative stress** 

**4.5 Mitochondrial dysfunction** 

momgraph. 2011)

models. (Shaw. 2005)

males are more commonly affected than females (1.4:1). The incidence increases with age with a mean age of onset of 63 years, (Ringel, et al 1993). It ranks as the third most common neurological degenerative disorder after Alzheimer's and Parkinson's disease (Talbot 2002).

In Guam, the incidence of MND has fallen from 87/100,000 in 1962 to 5/100,000 in 1985, (Rodgers-Johanson, et al. 1986).

Within the Caucasian population of Europe and North America, where most of the studies have been conducted, the lowest reported incidence of MND was 0.6 per 100.000 person – years in Italy,(De Domenice, et al. 1988) and the highest reported was 2.4 per 100.000 personyears in Finland(Murros and Fogelholm.1983). However, a lower incidence rate of 0.3/100,000 person-years was reported among Asian population, in China, (Fong, et al. 1996).

In the only well-conducted study of MND incidence among black African population, the incidence of MND was noted to be 0.9 per 100,000 person-years in Libya, (Radhakrishnan, et al. 1986).

The incidence of MND is said to be increasing, but this is probably the result of improved diagnosis, better awareness of the disease and an aging population, (Leigh and Ray-Chaudhuri.1994). The incidence increases after the age of 40 years, peaks in the late 60s and early 70s, and declines rapidly after that, (Logroscino, et al. 2008).
