Motor neuron disease (MND), or amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease of motor neurons. MND is not identical to ALS, because MND also comprises other disorders of lower motor neurons, such as progressive spinal muscular atrophy (PSMA), segmental spinal muscular atrophies and progressive bulbar palsy. Primary lateral sclerosis is a disorder only of the upper motor neurons and reflects the other end of the spectrum. The terms MND and ALS are, however, often used to denominate the same rapidly progressive disorder which is characterized by hypertonia, impairment of skilled movements and hyperreflexia due to involvement of upper motor neurons, and by fasciculations, muscle cramps, weakness and muscle atrophy as manifestations of involvement of lower motor neurons.

M.M. van der Graaff, M.D.
L.H. van den Berg, M.D., Ph.D.
J.H. Veldink, M.D.

In most studies the mean age of onset is between 55 and 60 years. When the initial symptoms arise from lower motor neuron dysfunction, the disease is heralded by weakness that is asymmetric. In such instances, the initial symptom, usually only recognized retrospectively, is volitional cramping that is most pronounced early in the morning. Muscle twitching from fasciculations may be another early manifestation. The most common site of onset is in the distal lower extremities. There may initially be foot-drop, first recognized when an individual trips over a low object such as a curbstone. If the disease first affects the hands, there is a subtle and progressive difficulty manipulating fine objects, such as keys or coins, or problems with buttons or pulling a wallet from a pocket. Lower motor neurons innervating bulbar muscles may be involved initially, in which case the presenting problems are flaccid dysarthria or difficulty chewing. Very rarely, the first manifestation of lower motor neuron pathology may be isolated diaphragmatic weakness.

When upper or corticospinal neurons are involved at the outset, the presenting complaint is usually weakness with stiffness, due to spasticity. With early involvement of corticospinal neurons, the complaint may be stiffness and slowness on walking, perhaps with falling from decreased ability to execute subtle, rapid postural adjustments. In the upper extremities, there is diminished ease of movements of the fingers and hands. If the corticobulbar system is first affected, patients will present with spastic dysarthria and may also show evidence of heightened emotional responses ("pseudobulbar affect") characterized by a tendency to excessive crying or laughing. Even in advanced disease, systems mediating sensation, cognition, coordination, and bowel and bladder function are  (mostly) spared. Oculomotor function is also preserved in most cases.

Although disease progression may vary between patients, the 50% survival probability after the first symptoms of ALS is three to five years. The prognosis of patients whose first complaints are of bulbar origin is worse than of patients who have limb-onset disease. Prognosis depends mainly upon the degree of respiratory insufficiency, which is also the main cause of death.

In 1993, a major breakthrough in ALS research was achieved by the discovery of mutations in the copper/zinc superoxide dismutase 1 (SOD1) gene on chromosome 21 in approximately 20% of all familial cases.¹ Currently, eight additional loci have been identified in familial ALS (see Genetics/ genetica). The majority of autosomal dominant familial ALS remains thus unexplained.

Currently, more than 100 mutations in superoxide dismutase 1 (SOD1) have been described (see www.alsod.org). Some attempts have been made to correlate the genotype with the phenotype of the patients with SOD1 gene mutations and the available evidence suggests that only a few mutations could be linked to a consistent age at onset or pattern of survival.^2,3 The same SOD1 mutation within one family may result in highly variable phenotypes.^4,5 Furthermore, “atypical” variants of familial ALS have been described, including a markedly delayed disease duration of over 10 years, variants with features such as pain, paraesthesia or urgency micturition, pure lower motor neuron involvement and familial ALS with a SOD1 mutation showing multidegenerative features, including oculomotor or cerebellar involvement.⁶ Several modifier genes most probably account for part of this phenotypic variability. The CNTF gene is one of these potential modifier genes in SOD1 mediated familial ALS that may influence duration of disease.⁴

Since the discovery of mutations in SOD1 in familial ALS and the production of transgenic in vitro and in vivo models with mutant SOD1, most studies on the pathogenesis of ALS have focussed on SOD1-mediated motor neuron death. However, many downstream pathologic processes in SOD1-mediated cell death most probably also have a role in sporadic ALS. Currently, several - not mutually exclusive - pathologic processes may contribute to motor neuron death in sporadic and familial ALS in a so-called “convergence model.⁷ These include oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity, and defects in neurotrophins biology.

In summary, a toxic gain of function of mutant SOD1 probably arises from aberrant, copper-mediated chemistry leading to oxidative stress^8,9 and/or misfolding of mutant SOD1 leading to aggregates of mutant SOD1.^10,11 Mutant SOD1 has been shown to exist in the intermembrane space of mitochondria, which could lead to oxidative damage to mitochondria.¹⁰ In addition, aggregates including mutant SOD1, could damage the outer mitochondrial membrane.¹⁰ Both mechanisms would lead to expansion of the intermembrane space with mitochondrial vacuolisation as a consequence, and mitochondrial release into the cytosol of cytochrome C and other toxic substances ¹² Mitochondrial dysfunction, defective ATP synthesis¹³ and apoptosis due to the activation of caspases result.¹² Also, the resulting aggregates in the cytoplasm would subsequently choke the proteasome, which is normally responsible for degrading redundant intracellular proteins, and which shows an age-dependent decrease in activity,¹⁴ possibly explaining the adult onset of the disease. Observed astrocyte dysfunction with reduced levels of glutamate transporters (EAAT2) resulting in increased extracellular glutamate levels, may lead to glutamate excitotoxicity:¹⁵ an increased influx of calcium in motor neurons, combined with the minimal calcium buffering capacities of motor neurons,¹⁶ and combined with the absence of one of the subunits of the glutamate receptor, GluR₂, that renders a motor neuron more susceptible to calcium-mediated toxicity following glutamate receptor activation,¹⁷ leads to further oxidative stress and mitochondrial dysfunction. Furthermore, reactive microglia and reactive astrocytes are abundant in affected areas of human ALS,^18-20 and in the SOD1 mouse model.²¹ These processes may participate through the release of pro-inflammatory molecules including an upregulation of the enzyme cyclooxygenase-2 (cox-2).^22,23 Inflammation might contribute further to oxidative stress, glutamate excitotoxicity and mitochondrial dysfunction. In addition, neurofilaments seem to contribute to the pathogenesis in ALS. In several studies, in about 1% of mainly sporadic ALS patients, mutations have been found in the repetitive tail domain of the large neurofilament subunit NF-H, but not in controls^24-26 (see also http://www.alsod.org/). Also, manipulations of NF-L and NF-H both have considerable influence on the progression of disease in the SOD1-mutant mouse.^27,28 It has been suggested that these NF changes act through a further buffer against increased calcium levels²⁸ or through disorganization of neurofilament leading to axonal strangulation and slowing of axonal transport, one of the earliest cellular abnormalities in motor neurons in SOD1-mutant mice.²⁹

There is a growing body of evidence that susceptibility genes and modifier genes also have a role in sporadic ALS/ MND. Although many association studies have been performed examining specific candidate genes, only two candidate genes are currently plausible candidates in sporadic ALS/ MND: vascular endothelial growth factor (VEGF) ³⁰ and survival motor neuron gene.³¹ Unfortunately, many epidemiological association studies using specific candidate genes are not yet reproduced or cannot be reproduced, and therefore the reliability of these kinds of studies has been questioned.³²

Numerous studies have investigated environmental factors in relation to the risk for ALS/ MND, including exposure to pesticides, physical activity and trauma/fractures. In a recent evidence-based review, only smoking emerged as a probable (more likely than not) risk factor for ALS.³³ Conflicting results in environmental risk studies most probably originate from relatively small effects studied in relatively small samples, variable phenotype-definitions and therefore heterogeneous patients samples and missed interactions.³⁴

The diagnosis of ALS should be relatively straightforward, although it has been shown that false positive and false negative diagnosis occur frequently. Table 1 lists conditions that must be differentiated from classical ALS or variants thereof, including progressive spinal muscular atrophy (PSMA), segmental spinal muscular atrophies, progressive bulbar palsy, and primary lateral sclerosis.

Table 1. Differential diagnosis of ALS/MND (see Belsh and Schiffman: Amyotrophic Lateral Sclerosis; diagnosis and management for the clinician; Futura Publishing Company, Inc. 1996)

For the diagnosis of ALS, abnormalities of both lower and upper motor neurons (LMN and UMN) are required combined with the progressive spread of symptoms and signs within a body region or to other regions (Revised El Escorial criteria, see http://www.wfnals.org/oldsite/Articles/elescorial1998criteria.htm). Their presence can be established in the consulting room. In clinically unaffected muscles, electromyography can help to uncover denervation activity as a sign of subclinical involvement of lower motor neurons. For the clinical (revised) El Escorial criteria for ALS the human body is subdivided into four regions: head, arms, thorax and trunk and legs (table 2).

Table 2. The revised El Escorial criteria

Both sporadic and familial forms of the disease exist, with familial ALS (FALS) accounting for 5-10% of cases. Familial ALS shows a mostly autosomal dominant pattern of inheritance. In 20% of familial cases, a mutation in the SOD1 gene is present. Testing for such a mutation is possible in Amsterdam (AMC) or Rotterdam (EMC).

A few additional loci have been found, however the genes involved have not yet been determined (table 3). Genetic testing, therefore, is not yet available for SOD1 negative familial cases.

Table 3. Loci/genes identified in familial ALS/MND

World Federation of Neurology: Amyotrophic Lateral Sclerosis
ALS Association
Motor Neuron Disease Association
VSN over spierziekte Amyotrofische Lateraal Sclerose (Dutch)
VSN Myonet Amyotrofische Laterlaal Sclerose (pdf) (Dutch)
VSN Samenwerkingsmodel ALS, Multidisciplinaire samenwerking in de zorgverlening aan patiënten met Amyotrofische Lateraal Sclerose (pdf) (Dutch)
ALS-centrum Nederland (Dutch)

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