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Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease involving the upper and lower motor neurons, located respectively in the motor cortex and the brainstem motor nuclei of the cranial nerves and the anterior horns of the spinal cord. This results in a progressive loss of muscle strength and trophy of the skeletal muscles of the limbs, as well as the bulbar and respiratory districts. It is the most common form of motor neuron disease in adults, typically affecting individuals with a peak onset between the fifth and sixth decades of life. It has an incidence of 2-3 cases per 100,000 inhabitants/year and a prevalence of 4-6 cases per 100,000 inhabitants, with a median survival of approximately 3-5 years from diagnosis.

Currently, there are no treatments capable of halting the progressive motor neuron degeneration, although numerous clinical trials are underway. Riluzole (an anti-glutamatergic drug) is the only medication approved for all forms of ALS and is capable of increasing survival by 6 to 19 months.

This pathology is studied at two institutes affiliated with the “Centro Dino Ferrari”:
- IRCSS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit (Prof. Comi) and Neuromuscular and Rare Diseases Unit (Prof. Corti): This center has contributed significantly to research on the genetic and myopathological aspects of the disease. The Policlinico is an integral part of the Virtual Institute for Motor Neuron Diseases and the Virtual Institute for Rare Neurological Diseases, as well as a member of the ERN (European Reference Network) for neuromuscular diseases.
- IRCCS Istituto Auxologico Italiano (Prof. Ticozzi): This center collaborated on the development of the latest European Guidelines for the pathology (Van Damme et al., 2024). The ALS Center at Auxologico is internationally recognized and coordinates the Virtual Institute for Motor Neuron Diseases (Prof. Silani) 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.

The etiology of Amyotrophic Lateral Sclerosis (ALS) is multifactorial, involving a combination of genetic and environmental factors. Approximately 90% of cases are sporadic, while the remaining 10% exhibit familial transmission, predominantly in an autosomal dominant pattern.

To date, more than 30 genes involved in the pathogenesis of ALS have been identified, some of which contribute significantly (high penetrance) to the onset of the disease. Among these:

C9orf72 expansion: The most frequent genetic cause of ALS, accounting for up to 40% of familial cases and up to 10% of sporadic forms.
SOD1: The second most common genetic form. Notably, a compassionate-use therapy is currently available in Italy for this specific mutation.
TARDBP and FUS: Other highly relevant genes in the disease’s landscape.

There are also other genes whose mutations can increase susceptibility to ALS and other motor neuron diseases.

Pathogenetic Mechanisms

The underlying mechanisms are diverse and include:

Proteostasis dysfunction
Alterations in RNA metabolism
Oxidative stress
Mitochondrial damage
Glutamate excitotoxicity

ALS symptoms typically have an insidious onset and vary depending on the initial site of involvement:

Spinal Onset (nearly 70% of cases): Characterized by progressive weakness and atrophy, generally focal and distal, affecting a limb (hand or foot). This is often associated with cramps and fasciculations. There are also symmetric proximal forms (flail arm variant) and symmetric distal forms (flail leg variant).
Bulbar Onset (nearly 30% of cases): Characterized by dysarthria (difficulty articulating speech), followed by dysphagia (impaired swallowing) and sialorrhea (excessive salivation).
Respiratory Onset (less than 5% of cases): Characterized primarily by orthopnea and dyspnea due to early respiratory failure.

Neurological Examination

During a clinical examination, signs of both upper and lower motor neuron involvement can be identified:

Upper Motor Neuron (1st MN) signs: Spasticity, hyperreflexia, pyramidal signs, and loss of dexterity.
Lower Motor Neuron (2nd MN) signs: Weakness, muscle atrophy, fasciculations, and hyporeflexia.

Disease Progression

Symptoms tend to spread, leading to a progressive impairment of mobility. Patients face increasing difficulty walking, grasping objects, articulating speech, and consuming food. While the course of the disease varies, it ultimately leads to a state of motor disability with respiratory and nutritional challenges.

In up to 50% of patients, cognitive and behavioral symptoms may emerge, with 15-25% of cases meeting the criteria for Frontotemporal Dementia (FTD).

The diagnosis of ALS requires a specialist clinical assessment and the performance of instrumental tests to support the diagnosis and exclude other pathologies. There is no single diagnostic test capable of confirming or ruling out the disease. These include:
- Clinical Evaluation: Anamnesis, neurological physical examination aimed at identifying signs of 1st and 2nd motor neuron involvement within the same muscular district, and the use of functional scales (ALSFRS-R, MRC).
- Electromyography (EMG): Evidence of acute denervation and chronic neurogenic damage, presence of fibrillation potentials, and fasciculation potentials.
- Nerve Conduction Study (NCS/ENG): To exclude peripheral neuropathies.
- Motor Evoked Potentials (MEP): Study of conduction along the corticospinal tract.
- Magnetic Resonance Imaging (MRI): Used primarily to exclude structural lesions (diagnosis of exclusion); it may show hyperintensity of the corticospinal tracts or paramagnetic deposits in the motor cortex.
- Genetic Testing: Analysis of NGS (Next-Generation Sequencing) panels in cases with a family history or to search for specific mutations such as SOD1, which are eligible for targeted therapy.
- Biomarkers: Plasma/serum and cerebrospinal fluid (CSF) neurofilament light chains (NfL).

Available therapies

Pharmacological therapies include:

Riluzole: 50 mg twice daily (totaling 100 mg/day) orally, approved for all forms of ALS.
Tofersen: An antisense oligonucleotide administered intrathecally for patients with the SOD1 gene mutation. Both the Istituto Auxologico and the Policlinico di Milano are authorized prescribing centers.
Clinical Trials: Currently, several clinical trials for ALS are underway. Some are conducted at the clinical trial center of the Istituto Auxologico Italiano, such as the experimental tSMS (the first trial conducted with a positive outcome).

Symptomatic Therapies

There are also symptomatic therapies available to manage specific aspects of the disease:

Spasticity: Baclofen, Tizanidine, and intrathecal Baclofen.
Sialorrhea: Amitriptyline, Glycopyrrolate, and Botulinum toxin.
Emotional Lability: Dextromethorphan-quinidine and SSRIs.

Multidisciplinary Support Therapies

Finally, multidisciplinary support is essential for patient care:

Respiratory Management: Non-invasive ventilation (BiPAP), CoughAssist, and invasive ventilation.
Nutritional Support: Dietary modifications and PEG (Percutaneous Endoscopic Gastrostomy).
Rehabilitation: Physiotherapy, occupational therapy, and speech therapy.
Palliative Care and psychosocial support.

Research in progress

Development of targeted gene therapies (antisense oligonucleotides, AAV vectors) in cellular models.
Identification of diagnostic and progression biomarkers, including serum and cerebrospinal fluid (CSF) neurofilaments, microRNAs, and Optical Coherence Tomography (OCT).
Patient-specific innovative disease models (brain organoids, induced pluripotent stem cells – iPSCs).
Genetic study of familial and sporadic forms, with a particular focus on the C9orf72 gene (through the Virtual Institute for Motor Neuron Diseases, coordinated by the Auxologico center).
Study of pathogenetic mechanisms and identification of new biomarkers through patient muscle biopsies.
Neuroimaging sequence studies in atypical forms of motor neuron diseases.
International trials in collaboration with the TRICALS and ENCALS networks.