Amyotrophic Lateral Sclerosis (ALS) (Ist. Auxologico)
ALS is a neurodegenerative pathology involving the upper (1st) and lower (2nd) motor neurons, leading to the progressive loss of muscle mass (trophism) and strength (sthenia) across all skeletal muscles. This results in respiratory difficulties and impairments in swallowing (dysphagia) and speech (phonation), along with related nutritional challenges.
The disease is partly genetic (with over 30 identified genes) and partly sporadic. It is also characterized by cognitive and behavioral involvement in 50% of patients. Today, targeted treatments are available when associated with SOD1 (and FUS) gene mutations. In sporadic forms, treatment requires Riluzole, an anti-glutamatergic drug, available in various formulations. Numerous clinical trials are currently available.
The IRCCS Istituto Auxologico Italiano collaborated on the development of the latest European Guidelines for the pathology (Van Damme et al., 2024).
The etiology of ALS is multifactorial, involving a combination of genetic and environmental factors. The primary pathological hallmark is the accumulation of the TDP-43 protein in both motor neurons and the motor cortex, leading to subsequent neuronal loss.
The mechanisms responsible for the cytoplasmic translocation of TDP-43 and the resulting formation of aggregates are multifaceted and include:
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Excitotoxicity
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Oxidative stress
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Neuroinflammation
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Mitochondrial dysfunction
Notably, hereditary clinical forms linked to SOD1 gene mutations appear pathogenetically distinct, as they are characterized by the absence of TDP-43 protein aggregates.
ALS manifests with the onset of a strength deficit in a limb or difficulty articulating speech/difficulty swallowing, accompanied by muscle contractions (cramps, fasciculations) indicative of motor neuron distress. This is joined by spasticity due to upper motor neuron (1st MN) involvement, resulting in increased reflexes. Symptoms tend to spread, leading to a progressive impairment of motility and increasing difficulty in walking, grasping objects, articulating speech, and consuming food. While the course of the disease is variable, it ultimately leads to a final stage of motor disability characterized by respiratory and nutritional challenges.
The diagnosis of ALS is achieved through clinical and anamnestic assessment, followed by:
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Neuropsychological evaluation
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MRI of the brain (and the entire spinal cord)
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Electromyography (EMG)
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Motor Evoked Potentials (MEP)
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Genetic testing, if the medical history suggests a familial pattern
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Biomarker acquisition: Light-chain Neurofilaments (NfL) in cerebrospinal fluid (CSF) and serum
Available therapies
The available therapies are continuously enriched by controlled clinical trials actively conducted at the Clinical Trial Center of the Istituto Auxologico. Recognized therapies include:
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Riluzole
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Tofersen for patients with the SOD1 gene mutation
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Experimental tSMS (the first trial conducted with a positive outcome)
Research in progress
The ALS Center at Auxologico is internationally recognized and coordinates the Virtual Institute for Motor Neuron Diseases within the IRCCS Network of Neuroscience and Neurorehabilitation and the European Reference Network (ERN) for Neuromuscular Diseases, with a broad impact on both clinical and basic research.
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Genetic study of familial and sporadic forms, with a particular focus on the C9orf72 gene.
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Definition of disease biomarkers (NfL and others) in cerebrospinal fluid (CSF) and blood.
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Study of in vitro motor neuron models derived from patient iPSCs (induced pluripotent stem cells), using two-dimensional and three-dimensional (organoid) models, with a specific focus on the pathogenetic role of microglia.
Reference laboratory
Contacts and informations
Referents / Key Contacts: Vincenzo Silani, Nicola Ticozzi, Claudia Morelli, Barbara Poletti, Alberto Doretti, Luca Maderna, Antonia Ratti
Email / Ph: vincenzo@silani.com/ 02 61911 2937
Link: auxologico.it (Motor Neuron Diseases, ALS Center)