In Ancient Egypt a person’s essence or soul was passed to their descendants, symbolized by Ka.
Amyotrophic lateral sclerosis (ALS) has too many potential causal factors to make the diagnosis and treatment of the disease obvious. Dogma says that all ALS is genetic. Genes are inherited patterns of nucleotides (DNA) and nucleotides are the universal code providing organisms limitless combinations of products that direct life. The products are RNA or protein; RNA can be directly functional, or it can be the template and code for a protein.
The phenotype, or the composite of an individual’s gene expression, is inherited from the parent to the offspring. The phenotype is an expression of the genotype (DNA sequences) but environmental and developmental factors determine what phenotype is expressed. Biological systems are influenced by many different genes and gene-environment interactions.
Errors occur during gene expression and produce mutations that are passed to offspring. Mutations are a part of evolution. If these mutations are a biological advantage to the individual, they become variants in the population. Detrimental mutations are eliminated quickly. Good and bad mutations are the process of natural selection. Sometimes there is a phenotype that isn’t terribly detrimental and perhaps slightly useful; these account for genetic drift in a population. A powerful example is the FOXP2 gene. A mutation in the FOXP2 gene was noted in 2001 and produces a syndrome whose sufferers have normal-range cognitive capabilities but cannot use complex language.
The FOXP2 has remained identical in evolution for more than a hundred million years! Two proteins coded by FOXP2 began changing in humans just after branching from chimpanzees on the evolutionary tree, 50,000 years ago. A third mutation is found in all of us today, but it is not found in Neanderthal DNA. The third mutation affects when and in what cells the FOXP2 is expressed. Is it this mutation that allowed modern humans more complex language and communication and facilitated them replacing Neanderthals after co-existing for thousands of years? There is evidence that Neanderthals were cognitively sophisticated. They made stone age tools, they cared for their sick and elderly, they appreciated symbolism. Complex language is a biological advantage that may have propelled modern humans to dominate the planet and led to the elimination of Neanderthals.
Genes have regulatory sections and coding sections, and they are not always close together. Also, the coding regions can be interspaced with bits of non-coding sequence. Some viruses can insert their DNA/RNA into the host genome! Some gene products are functional, non-coding RNAs.
The take home message is that a gene is a section of heritable, genomic sequence that alters the organisms traits (phenotype) by expressing a functional product or by regulating another gene’s expression.
ALS is a rare genetic disease. A small sub-set of ALS cases (10-15%) are caused by genes that follow Mendelian genetics, these are familial cases of ALS, fALS. More than 25 genes are associated with fALS.
ALS is recognized in families and multiple members of a family are at risk to get the disease. Some causes of ALS in families are unknown, the genes haven’t been identified. The most studied mutation codes for a protein, SOD1, that is important in cell oxidation reactions. The importance isn’t that a mutation exists, it is where that mutation is in the coding sequence. Gene mutations can result in a change in the protein that won’t affect its function. The mutation could result in protein that mildly affects the function of the protein. And yet another mutation could code for a protein that is profoundly affected and has harmful actions. Amazingly, the ALS-associated SOD1 gene shows a direct relationship in life expectancy and the location of the mutation in the protein. The pathogenicity of the gene is related to the phenotype of the final protein and how its function was changed.
There is a relationship between expansion of regions in the C9orf72 gene (dipeptide repeats) and neurological diseases. First recognized in Huntington’s disease, expansion repeats are now recognized as the most common cause of familial ALS. Most people, as they age, show expansion in the C9orf72 gene and they are of no consequence. Generally, many additional base pairs (hundreds to thousands) are repeated in the C9orf72 gene, and some researchers argue that small repeats can be associated with disease. When the C9orf72 gene is expanded by multiple repeats the resulting mutated proteins (called RAN proteins) can gain a function or lose a function. These RAN proteins can serve as a regulatory function. The “downstream” effects of either functional changes, up or down, can be catastrophic. Most commonly, the expansion is inconsequential.
The majority of ALS cases are sporadic, sALS. That means an individual with sALS has a gene mutation that is unrecognized as having an association with ALS. An offspring from a sALS parent has six times the chance of developing ALS. The analysis of a DNA sample from a patient newly diagnosed with ALS is generally for a gene panel comprising 20 genes, sometimes C9ofrf72 is included in the panel. Sporadic cases of ALS will not be detected with the fALS gene panel. If the fALS panel is negative it is appropriate to use whole genome sequencing (WGS) with a sALS diagnosis.
Everyone has mutations identified in their genome that are not necessarily related to a risk factors for a disease. In principle, a mutation would need to be identified in enough people that got related signs and symptoms of ALS to think a mutation was causal for the disease. It is impossible to know the validity of a gene variant in a single case, a hundred cases would begin to indicate causality. Surprisingly, there are only 9 cases of fSOD1 with the mutation that is expressed in the model used by most to study ALS.
New investigations supported by NDR Inc will interrogate DNA from ALS cases and their families. These families have an unidentified, apparently inherited ALS that may be scientifically interesting. This population-based, retrospective cohort may link factors to ALS onset in adulthood. The difference in this study form single patient WGS analysis is the cumulative family history and DNA samples.
There have been numerous studies that examine WGS in ALS patients and have failed to identify sALS risk genes. Because there are no ALS disease clusters, meaningful implications about mechanisms and pathologic pathways will come from natures experiments, sALS patients and their families.