The scientific corpus of medicine has been gradually developed by classifying diseases according to clinical signs, in order to differentiate the treatments. The interpretation of clinical signs is itself relatively subjective. This way of proceeding, differentiating treatments according to clinical signs has been particularly fruitful since the discovery of the concept of pathogen. The causative agent of the disease being capable of being detected by a technological process, of a greater reliability than the interpretation of clinical signs. However, at the end of the 1970s it was noted that progress on non-communicable diseases was slower. As past advances were linked to the introduction of technology into the diagnostic process, there was great hope at the end of the 20th century that genetic technologies could take over. Unfortunately, it is clear that at the start of the 20th century that the announced revolution did not take place.
A striking example concerns ALS (Charcot or Lou Gehrig's disease). The diagnosis of ALS is very slow and the etiology remains absolutely unknown.
ALS is not a homogeneous disease despite a very characteristic phenotype. First, many other diseases have a similar phenotype, some of which are contagious. Some of those that are non-contagious may resemble less acute forms of ALS, for example SCA36.
Among the non-contagious forms, there are those that can be obtained by poisoning, such as BMAA poisoning.
In addition, there are also forms of ALS linked to the patient's genetics (C9orf72, SOD1). These forms have things in common with other diseases such as FTD. We are talking now about spectrum of diseases rather than of different diseases. So the methodology of differentiating treatments according to clinical signs, is no more applicable.
But even obviously different diseases have something in common with ALS, for example a third of Alzheimer's forms show aggregates of the TDP-43 protein, like 95% of cases of ALS.
We therefore have a very murky picture of the clinical signs of ALS, but also of their etiology. For some patients the disease could be of viral or microbial origin, for others it could result from poisoning for still others there could be a genetic origin. Finally aging seems to have an important part in the etiology.
However, researchers have rarely worked on metabolism in the case of ALS. Yet it is known that half of the cases of ALS have an increased metabolism and that also half of the cases of ALS have developed insulin insensitivity. It is estimated that the daily energy deficit of ALS patients is around 400 to 500 kcal. So it could also be possible for neurologists to differentiate ALS patients depending on metabolic dysfunctions, even if this is not done today. A realistic strategy would be to identify treatments and nutritional interventions to improve the survival of ALS patients based on metabolism characteristics.
Many studies have shown a decrease in fat storage and an acceleration of lipolysis in ALS. At the asymptomatic stage, the effect of body fat on the delay in neurodegeneration could be interpreted as a protective effect on the risk of ALS in the population. Compelling observational studies have provided evidence of the time relationship between lifetime body mass index (BMI) and ALS and have suggested that a higher BMI is associated with a lower risk of ALS. Longitudinal cohort studies and case-control studies have consistently indicated that a higher premorbid BMI contributes to a decreased risk of ALS decades later, suggesting that early adiposity, such as birth weight (MI) and childhood BMI can be a factor delaying the onset of ALS in the long term.
But alas a higher consumption of premorbid fat contributes to an increased risk of ALS. This could be explained as follows: A high fat intake leads to dyslipidemia, subsequently increasing the risk of ALS. Studies have shown that higher low density lipoprotein increases the risk of ALS.
However, these observational studies are influenced by the possibility of confounding factors wrongly attributing adiposity to a causal role.
A new study has confirmed the protective nature of early adiposity: Life Course Adiposity and Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study. Zhang, Tang, Huang and Fan of Peking University.
A widely used genetic epidemiological method, called Mendelian randomization, has been proposed by the authors to assess the causal relationship between exposures and outcomes, in particular by exploiting significant genetic variants associated with high exposure as instrumental variables. This approach is less likely to lead to biased results resulting from the confusion or reverse causation that exist in observational studies. In addition, the availability of gigantic databases makes this type of study very easy to carry out.
Mononucleotide polymorphisms significantly associated with adiposity during life were used as instrumental variables to estimate the causal effects on ALS. The scientists used summary data from a cohort of 20,806 cases and 59,804 controls for this Mendelian randomization study.
The genetically predicted increase in body fat percentage was associated with a lower risk of ALS. A genetically higher BMI in children was genetically associated with a lower risk of ALS. The weighted median method indicated a suggestive association between BMI and ALS. Neither a genetically predicted increase in birth weight, nor the BMI and the waist / hip ratio adjusted for BMI were associated with ALS.
There are several strengths in this study, including the assessment of lifelong adiposity in relation to ALS, the use of data from large GWAS of adiposity, and the Mendelian randomization design. This design technique minimizes the confusion of known and unknown factors and avoids reverse causation.
Hopefully with the wealth of studies in this field, neurologists and doctors will now explore metabolism dysfunctions in ALS, in order to better diagnose patients and adjust treatments.
