Motor neuron disease




The motor neurone disease is a group of progressive neurological disorders that destroy motor neurones, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. These five conditions are amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy and pseudobulbar palsy. They are neurodegenerative in nature and cause increasing disability and eventually, death.


Symptoms usually present themselves between the ages of 50-70, and include progressive weakness, muscle wasting, and muscle fasciculations, spasticity or stiffness in the arms and legs, and overactive tendon reflexes. Patients may present with symptoms as diverse as a dragging foot, unilateral muscle wasting in the hands, or slurred speech. Neurological examination presents specific signs associated with upper and lower motor neurone degeneration. Signs of upper motor neurone damage include spasticity, brisk reflexes and the Babinski sign. Signs of lower motor neurone damage include weakness and muscle atrophy. Note that every muscle group in the body requires both upper and lower motor neurones to function. The signs described above can occur in any muscle group, including the arms, legs, torso, and bulbar region. The symptoms described above may resemble a number of other rare diseases, known as "MND Mimic Disorders". These include, but are not limited to multifocal motor neuropathy, Kennedy's disease, hereditary spastic paraplegia, spinal muscular atrophy and monomelic amyotrophy. A small subset of familial MND cases occur in children, such as "juvenile ALS", Madras syndrome, and individuals who have inherited the ALS2 gene. However, these are not typically referred to as MND, but by their specific names.


About 90% of cases of MND are "sporadic", meaning that the patient has no family history of ALS and the case appears to have occurred with no known cause. Genetic factors are suspected to be important in determining an individual's susceptibility to disease, and there is some weak evidence to suggest that onset can be "triggered" by as yet unknown environmental factors (see 'Epidemiology' below). Approximately 10% of cases are "familial MND", defined either by a family history of MND or by testing positive for a known genetic mutation associated with the disease. The following genes are known to be linked to ALS: Cu/Zn superoxide dismutase SOD1, ALS2, NEFH (a small number of cases), senataxin (SETX) and vesicle associated protein B (VAPB). Of these, SOD1 mutations account for some 20% of familial MND cases. The SOD1 gene codes for the enzyme superoxide dismutase, a free radical scavenger that reduces the oxidative stress of cells throughout the body. So far over 100 different mutations in the SOD1 gene have been found, all of which cause some form of ALS(ALSOD database). In North America, the most commonly occurring mutation is known as A4V and occurs in up to 50% of SOD1 cases. In people of Scandinavian extraction there is a relatively benign mutation called D90A which is associated with a slow progression. In Japan, the H46R mutation is most common. G93A, the mutation used to generate the first animal model (and by far the most widely studied), is present only in a few families worldwide. Future research is concentrating on identifying new genetic mutations and the clinical syndrome associated with them. Familial MND may also confer a higher risk of developing cognitive changes such as frontotemporal dementia or executive dysfunction (see 'extra-motor change in MND' below). It is thought that SOD1 mutations confer a toxic gain, rather than a loss, of function to the enzyme. SOD1 mutations may increase the propensity for the enzyme to form protein aggregates which are toxic to nerve cells.


The diagnosis of MND is a clinical one, established by a neurologist on the basis of history and neurological examination. There is no diagnostic test for MND. Investigations such as blood tests, electromyography (EMG), magnetic resonance imaging (MRI), and sometimes genetic testing are useful to rule out other disorders that may mimic MND. However, the diagnosis of MND remains a clinical one. Having excluded other diseases, a relatively rapid progression of symptoms is a strong diagnostic factor. Although an individual's progression may sometimes "plateau", it will not improve. A set of diagnostic criteria called the El Escorial criteria have been defined by the World Federation of Neurologists for use in research, particularly as inclusion/exclusion criteria for clinical trials. Owing to a lack of clinical diagnostic criteria, some neurologists use the El Escorial criteria during the diagnostic process, although strictly speaking this is functionality creep, and some have questioned the appropriateness of the criteria in a clinical setting.



