When a diagnosis of Charcot disease (or amyotrophic lateral sclerosis – ALS) is received, a question arises: why me? An international team tackled this riddle by looking for the answer directly in the genes. Using genetic data on an unprecedented scale, researchers screened the DNA of thousands of patients. Their conclusions begin to reshuffle the cards.
A record genetic study on amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition where the nerves responsible for movement lose their functionality. This leads to progressive paralysis, with death usually occurring within two years of diagnosis. Approximately 10% of patients have a family history of this disease.
Published in the journal Nature Geneticsthe study coordinated by the consortium Project MinE is based on exome sequencing of 22 cohorts: 17,919 people with ALS and 200,703 witnesses. The authors show that an identifiable genetic abnormality is present in approximately one in four patients, compared to one in five in previous studies. And this, whether or not there are cases in the family. Key information for patients and their loved ones.
Amyotrophic lateral sclerosis, also called Charcot disease, destroys the neurons that control muscles and leads to progressive paralysis with death approximately two years after diagnosis. About 10% of patients have multiple cases in the family, but the majority have no known history. To explore these so-called sporadic forms, the researchers compared the exomes of 13,138 cases and 69,775 controls, then verified their results in a second cohort.
A genetic cause identified for more than a quarter of patients
This mass of data made it possible to identify rare variants or ultrarare associated with the risk of disease, sometimes carried by very few individuals. The team shows that an explanatory genetic change is present in 25% of patients. By adding gene expansion C9orf72nearly 27% of cases now have an identified genetic cause.
Rare variants, new genes and more aggressive forms of ALS
The analyzes confirm large genes already involved such as
SOD1, NEK1,
KIF5A, TBK1 Or
TARDBPand bring out new players. A gene variant YKT6for example, moderately increases risk and appears in both cohorts. Other genes, such as HTR3C, GBGT1 Or
KNTC1carry very rare but very high effect mutations.
The study also reinforces the role of hitherto little-documented genes, such as ARPP21, DNAJC7
And CFAP410. Some variants ofARPP21 are associated with earlier onset of disease and shortened survival of approximately 19 months, with effects comparable to those of very aggressive mutations in the gene
SOD1. The authors finally note that accumulating several risk variants increases the probability of developing ALS, which is in line with a model where several genes add their effects.
Towards broader genetic testing and future targeted therapies
For clinicians, these data reinforce the interest of
genetic test. “This study considerably adds to our knowledge of the causes of ALS, demonstrating the existence of a significant genetic component in approximately a quarter of affected people, regardless of family history. Therefore, genetic testing should be offered to anyone with symptoms, and this increased knowledge increases the chances of developing effective treatment.“, explains Professor Ammar Al-Chalabi, professor of neurology and genetics of complex diseases at King’s College London.