Amyotrophic lateral sclerosis (ALS - Charcot disease)

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Motor neuron degeneration still incurable

Amyotrophic lateral sclerosis is a serious, incapacitating degenerative disease which results in death within 3 to 5 years of diagnosis. The research efforts in this field in recent years have shed light on the genetics and biology of this disease. Although no curative treatment is yet available, the medium-term prospects are promising.

  • Progressive paralysis with a fatal outcome
  • Symptoms that most often appear between the ages of 50 and 70
  • A familial disease in 10% of cases
  • Reading time

    15-20 min

  • Difficulty

    4 sur 5

Report drawn up in collaboration with Séverine Boillée, Inserm Unit 1127/Université Pierre et Marie Curie, Brain and Spinal Cord Institute, Paris

Loupe comprendre Understanding amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Charcot disease, is a serious neurodegenerative disease evidenced by gradual paralysis of the muscles involved in voluntary motor function. It also affects phonation and swallowing.

This disease has a bleak prognosis, with a fatal outcome after 3 to 5 years of progression on average. Involvement of the respiratory muscles usually results in patient death.

Motor neurons are nerve cells in the spinal cord which cause muscles to contract. The image shows a fluorescent rat motor neuron in culture. The cell body is clearly distinguished, thirty microns in diameter, together with the axon and collateral fibers. © Inserm, C. Henderson

ALS is caused by the gradual death of motor neurons, nerve cells which manage and control voluntary muscles. It affects both types of effector motor neurons involved in motor function: central, located in the brain, and peripheral, located in the brainstem and spinal cord. The latter act as an intermediary between the central motor neurons and the muscles.

Genetic component still poorly defined

The cause of ALS is complex to determine: onset of the disease is said to be multifactorial, subject to both genetic and environmental influences.

No environmental trigger factors have been clearly evidenced. Tobacco, high-level sports, pesticides, heavy metals and cyanotoxin BMAA, found in certain algae, are suspected. However, no data formally implicating them are currently available.

In practice, familial ALS is observed in 10% of patients. In this case, the genetic origin is likely, even though this is not always easy to demonstrate. For a long period of time, only a single mutation responsible for the disease was known. Affecting the SOD1 gene, it gave rise to the first animal model of ALS. Since then, approximately twenty other genes have been identified to play a role: C9ORF72, mutation of which is observed in over 40% of familial forms, TARDBP, FUS/TLS, etc. When no known causal mutations are observed, this familial disease probably results from the alteration of one or more genes not as yet identified.

When the disease affects individuals without a familial genetic risk (90% of cases), it is said to be sporadic. These cases are more than likely related to the random (rather than transmitted) mutation of a causal gene or of one or more susceptibility genes (which are said to increase the risk of onset of the disease).

Sclérose Latérale Amyotrophique (SLA) – animation pédagogique – 1 min 28 – vidéo de l’association ARSLA (2012)

A gradually incapacitating disease

ALS often develops between the ages of 50 and 70 years, although it generally occurs sooner for familial forms.

According to the nature of the impairment, it takes on different forms:

  • In approximately 30% of cases, it starts in the brainstem. A bulbar-onset form is described, the first symptoms of which are difficulties speaking or swallowing.
  • In other cases, ALS first impairs peripheral motor neurons: in this spinal-onset form, the disease first becomes evident due to weakness and discomfort in an arm, leg or hand.

The disease then gradually intensifies: spasms, stiffness in the muscles and joints develop locally. This impairment spreads to other muscles. Muscle wastage and coordination disorders finally interfere with walking and the ability to grasp objects. Swallowing or speech difficulties worsen. Impairment of the respiratory muscles often occurs in the advanced stages of the disease. This hastens exacerbation and the risk of death.

More in-depth knowledge of the disease has now enabled forms of ALS to be identified which also include pain, Parkinson's type symptoms or behavioral disorders (frontotemporal dementia).

Varied and physiopathological mechanisms which are still unclear 

It is still very difficult to precisely define the mechanisms which initiate and maintain neuronal degeneration associated with ALS. However, several phenomena have been described, notably owing to the analysis of genetic mutations associated with the disease, and their impact on nerve cell function. These include folding defects, affecting mutated proteins which aggregate with other proteins in the cells: these aggregates can block vital neuronal functions, leading, for example, to dysfunctional mitochondria (which produce the cells' energy) or to disrupted neuronal transport function. Certain mutations (affecting the TDP43, FUS, C9ORF72 genes) can also lead to defective maturation of messenger RNA, molecules involved in protein synthesis essential to proper cell function. In neurons with TDP43 gene mutations, the production of messenger RNA itself would be disrupted.

Another hypothesis: excitotoxicity of glutamate (a neurotransmitter) on nerve cells. This phenomenon is said to be related to continuous and abnormal neuronal stimulation due to excessive glutamate production or inadequate elimination. Oxidative stress and damage to glial cells (neuron supporting cells) or immune cells may also be implicated. Animal models of ALS have evidenced a local chronic inflammatory state in which microglial cells, astrocytes and surrounding macrophages play a harmful role with regard to neurons. These mechanisms could therefore represent a potential therapeutic target. Lastly, certain patients present hypermetabolism which may cause significant weight loss and exacerbate the prognosis. Certain studies aim to clarify the correlation between these two phenomena. It is now essential to understand the way in which all of these mechanisms are interlinked and/or coexist.

Diagnosis by elimination

Motor neurons and axons (red), cell nuclei (blue) in the spinal cord. Image taken during the photography competition organized for the 50th anniversary of Inserm, category 1: Scientific image (result of research). Rhônes-Alpes selection. © Inserm, S. Cavagna

ALS is often diagnosed by elimination, after ruling out other neurodegenerative diseases and motor neuron disorders with a similar presentation.

This diagnosis is based on neurological and clinical examinations. The neurologist responsible for this evaluation investigates for the presence of signs of muscle neurodegeneration, signs of bulbar impairment, and concomitant symptoms or diseases. The neurological examination in combination with a laboratory work-up, electromyogram and MRI confirm the diagnosis in the presence of symptoms which have been persisting for several months.

Worsening of symptoms is one of the signs able to distinguish ALS from other motor neuron diseases, although specific examinations may be prescribed on a case-by-case basis in order to confirm the diagnosis.

ALS requires multidisciplinary management

There is no curative treatment for ALS. Management of the disease targets the symptoms: technical assistance, physiotherapy and antispastic medications to counter motor disorders, muscle relaxants and analgesics for pain, management of undernutrition, speech therapy for phonation and swallowing disorders, and psychological support, etc.

Although the prognosis for the disease remains severe, genuine progress has been made in the past twenty years:

Non-invasive ventilation (NIV), which compensates for respiratory function when this starts to decline,

and the prescription of riluzole, the only medicinal product having demonstrated its ability to slow the progression of symptoms, give rise to a modest improvement in life expectancy among ALS patients.

Since the 1990s, individuals suffering from ALS have received optimized, specialist and multidisciplinary care via a network of reference centers: approximately twenty centers currently exist, spread throughout France.

Pictogramme microscope Challenges facing research

Distinguish between the different forms of ALS for more effective treatment

In recent years, ALS has started to be perceived as a syndrome, and no longer as a disease: age at onset of the first symptoms, the initial bulbar or spinal presentation, the speed of progression, and even the concomitant disorders suggest that different motor neuron diseases could be grouped together under the generic term ALS. This heterogeneity could explain the failure of numerous clinical trials conducted on new treatments.

One of the objectives among researchers is therefore to divide all patients into more homogeneous groups; the recent discovery of different genetic mutations could help bring together patients with the same cause of the disease. Clinical symptoms may also help make a distinction between patients, even though they are not fully specific. The identification of new biomarkers will open up new prospects.

Sclérose latérale amyotrophique – Interview – 6 min – vidéo de l’Institut du cerveau et de la moelle épinière (2014)

The search for relevant biomarkers

The identification of biological or radiological biomarkers could not only facilitate this diagnosis, but also help to predict the progression of ALS and response to treatments.

Several avenues are currently being explored:

  • Neurofilaments. These protein structures form the neuronal cytoskeleton and may become aggregated in motor neurons in the event of ALS. Initial data suggest a correlation between the concentration of neurofilament protein subunits in the blood or cerebrospinal fluid and disease progression;
  • Proteins and RNA derived from certain lymphocyte sub-types, the quantities of which increase in individuals suffering from ALS. Monitoring their blood concentrations could be a marker for the rate of disease progression;
  • Functional imaging. By allowing the dynamics of brain activity to be studied, this could ultimately be useful in predicting disease progression. Experimental data show that MRI would be able to measure parameters relating to spinal cord atrophy, whereas PET scans could utilize the progression of inflammation as a predictive marker.

These studies still fall within the scope of research, and no validated markers currently exist that would enable use in a clinical context to be envisaged.

Towards new treatment prospects

Motor neurons - Characterization by immunolabeling of motor neurons derived from human embryonic stem cells. Neurons are detected in green using the TuJI marker, whereas motor neurons are visualized in red by the expression of the vesicular acetylcholine transporter. The nuclei are visualized in blue using DAPI. I-Stem, Génopole d'Evry. © Inserm, C. Martinat

Until now, numerous candidate drugs have failed to demonstrate their efficacy. However, a new wave of innovations has recently emerged from the identification of genes responsible for ALS and clarification of the biological cascades at play in the onset of the disease. Hence, each of the pathogenic mechanisms described constitutes a potential therapeutic target.

Several therapeutic agents are being studied to counter the toxicity of the mutant SOD1 protein. Phase I clinical trials have notably been successfully conducted on antisense oligonucleotides which prevent production of the protein. Likewise, antisense oligonucleotides are being studied to counter the mutant C9ORF72 protein.

The neuronal microenvironment is also the subject of interventional studies: an experimental molecule, NP001, was the subject of initial clinical studies to counter the harmful activity of surrounding macrophages.

Promoting neuronal regeneration would, furthermore, compensate for the cell death mechanism in ALS. Initial clinical studies are currently in progress with an anti-NOGO agent, targeting the NOGO protein, which inhibits axon regeneration.

Cell therapy and stem cells

Cell therapy involves restoring the function of a tissue or organ by introducing healthy cells into the diseased organ. Two options are being envisaged with a view to applying this innovative approach to the ALS issue: the first involves replacing the defective cells in the motor neuron environment so that these can provide the trophic factors conducive to their survival. For the time being, researchers are using different types of cells derived from bone marrow or stem cells taken from nerve tissue, which are injected into the spinal cord. Several clinical studies have already been conducted in Spain, Israel and in the United States. 

In the longer term, a second option could involve using induced pluripotent stem cells (iPSC), specialized into motor neurons or supporting cells before being administered. These therapeutic cells would replace the defective motor neurons or cells in their environment. We still have a long way to go before we can achieve this goal. However, regardless of the option, the difficulty in implementing cell therapy lies in introducing the replacement cells in situ. This requires complex surgery which could limit the clinical application of these approaches.