Heredity of ALS

An estimated 10% of individuals with ALS have a family history of the disease. This form is known as familial ALS (fALS). For those patients, it is immediately clear that the disease is hereditary and that the risk exists other close family members might have inherited the disease as well.

Most ALS patients (approximately 90%) have a sporadic or non-familial form of ALS (sALS). Other family members haven’t been affected by ALS.

Heredity of fALS

FALS is caused by an abnormality in the genetic code (the gene), called a mutation. A faulty ALS gene can, in theory, be inherited in different ways. In reality, however, it is nearly always autosomal dominant. This means that every child of an individual with such a mutation has a one in two chance to inherit the mutated gene and to become a carrier of the mutation. Those who carry the fALS-causing mutation will almost definitely develop the disease. The age of onset, however, varies. On average the first symptoms occur between the ages of 50 and 60. Some, however, experience them before their thirties, while others won’t experience them until after the age of 80.

In recent years, knowledge about the heredity of ALS has increased significantly. Several disease-causing genes have been identified. Currently, the causative gene mutation in fALS patients has been identified in approximately 80% of their families. The most common causes are mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TARDBP or TDP-43), RNA-binding protein FUS (Fused In Sarcoma) and chromosome 9 open reading frame 72 (C9orf72).

Mutations in the SOD1 gene account for approximately 20% of families with fALS, mutations in the C9orf72 gene account for approximately 50%, mutations in the TARDBP gene account for 6%, and FUS mutations account for approximately 3%. All these mutations are autosomal dominant. Mutations in the SOD1, TARDBP and FUS genes are point mutations, where a single base modification of the genetic code causes a single amino acid change in the protein that was created based on this code. How these slightly altered proteins (or mutant protein) cause the selective deterioration of motor neurons, especially in adults, is being researched extensively. The most common hypothesis is that mutant protein acquire new toxic qualities and have a tendency to form clumps and remain trapped inside the motor neurons. FUS and TDP-43 are also vital to the cell nucleus and by clotting they can no longer adequately perform their tasks.

C9orf72 is a different kind of mutation, called a repeat expansion. At certain places, the hereditary material contains a sequence of repeats of a short string of letters. In the case of C9orf72, it concerns the repetition of GGGGCC at the beginning of the C9orf72 gene, a segment that has not been copied to the protein. Healthy individuals have a certain number of these repeats. A higher number of repeats can cause ALS. It can also cause frontotemporal dementia, a neurodegenerative condition related to ALS. The function of C9orf72 is at present still unknown. How the increase of GGGGCC repeats causes ALS is unknown as well. The mutation can, on the one hand, disrupt the formation of normal C9orf72 protein. The repeat in the mRNA, on the other hand, can cause the formation of RNA foci and can even be translated into abnormal protein consisting of a repeat of 2 amino acids.

In recent years, other ALS genes have been identified. These only account for a small percentage of patients. Examples are: OPTN, TBK1, UBQLN2, VCP, SETX, VAPB, ANG, CHMP2B, alsin, PFN1, SPG11, TUBA4A.

In families that have had the causative gene identified, we can determine if a non-affected individual is a carrier of the mutated gene. This is called preclinical detection, and only occurs under careful guidance of those who are willing to be tested. When the presence of the mutation is confirmed, personalised advice is possible (genetic counselling) in order to prevent passing on the mutation to the next generation.

The disease caused by mutations of the SOD1, C9orf72, TARDBP and FUS genes have many variables: the age of onset, the degree of deterioration, and the severity or aggressiveness of the disease (duration) differs not only among families with different mutations, but among family members with the same mutation as well. This implies there are other, most likely hereditary, factors that modify the manner in which the neuron degeneration manifests. Identifying these factors is extremely important. After all, research on patients with SOD1 mutations in Scandinavia shows that such modifying factors can completely suppress the disease.

In approximately 20% of families with fALS, the causative gene has been unidentified, and pre-clinical testing cannot take place. A negative result for SOD1, C9orf72, TARDBP and FUS mutations cannot rule out fALS, since affected patients also have negative results, but still carry a non-identified ALS gene. Those families will have to make do with the general risk prediction of one in two.

Heredity of sALS

Unexpectedly, a small number of sALS patients turn out to have fALS. This became known when SOD1, C9orf72, ARDBP or FUS mutations were found in a fraction of assumed sALS patients. Especially C9orf72 mutations can be found occasionally with ALS patients without a family history of ALS. Possible cause are: a parent who passed on the mutation but who passed away before the onset of the disease, a biological father who is not the legal father, early onset of the disease in the child before one of the parents experiences any symptoms or a new mutation occurring in one of the children that was not present in their parents. All these reasons provide justification for genetic testing of ALS patients without a family history.

Hereditary factors also seem to play a part in sALS, but not in the same ways as in fALS. In the case of sALS, it is believed that several hereditary factors combined contribute to someone developing the disease, possibly in combination with one or more external factors. Such hereditary factors are called risk genes. The risk of developing ALS during one’s lifetime is an estimated one out of 400. Risk genes can increase this risk of developing ALS, but do not automatically cause the disease. It implies a genetic predisposition, and is known as complex heredity.

The development of better tests to study the genetic code (GWAS, exome sequencing, whole genome sequencing) make it possible to identify such risk genes. Several have already been discovered in recent years, such as UNC13A, ATXN2, SQSTM1, NEK1, and C21orf2.

Conclusion

We can therefore conclude that the heredity of ALS can be both simple (familial ALS, the disease is passed on) and complex (sporadic ALS, with a genetic predisposition). More research is needed to fully understand this process.

In short, heredity of fALS is mainly autosomal dominant, whereas the risk for children of sALS patients is the same as it is for everyone else.

 

Translation: Katia Ombelets

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