Heredity of ALS
In about 10% of people with ALS, the disease runs in the family. This is referred to as familial ALS (fALS). In such patients, it is clear from the outset that the disease is hereditary and that there is a risk for close relatives to also have inherited the disease.
Most people with ALS (90% approximately) have the sporadic or non-familial form (called sALS). Other members of their family do not have ALS.
Heredity of fALS
fALS is caused by a defect in an inherited factor (the gene), which we call a mutation. Such a fault in an ALS gene can theoretically be inherited in several ways, but in practice it usually involves ‘dominant’ inheritance. This means that every child of an affected person has a one-in-two chance of inheriting the mutated gene and thus becoming a ‘carrier’ of the mutation. Those who are ‘carriers’ of an fALS mutation are almost certain to get the disease. However, the age at which the disease breaks out varies greatly. On average, it is between the ages of 50 and 60, but in some it starts before the age of 30, in others only after the age of 80.
In recent years, knowledge of the heredity of ALS has improved enormously. Several disease-causing genes have been discovered. Currently, the causative gene defect in patients with fALS is found in about 80% of families. The most frequent causes are mutations in superoxide dismutase 1 (SOD1), ‘TAR DNA binding protein 43’ (TARDBP or TDP-43), ‘RNA binding protein ‘Fused in sarcoma’ (FUS) and ‘Chromosome 9 open reading frame 72’ (C9orf72).
Mutations in the SOD1 gene account for about 20% of families with fALS; mutations in C9orf72 for about 50%; mutations in TARDBP for 6% and mutations in FUS for about 3%. All these mutations are inherited in a dominant manner. The mutations in SOD1, TARDBP and FUS are point mutations, in which change of one base in the genetic code gives rise to the change of one amino acid in the protein formed from this code. Exactly how these slightly altered proteins (they are called mutant proteins) give rise to the selective death of motor neurons, and then even in adulthood, is an area of intense research. The most common hypothesis is that the mutant proteins acquire new toxic properties and tend to clump together and precipitate in the motor neuron. FUS and TDP-43 also play a very important role in the cell nucleus and clumping means they can no longer perform their functions correctly.
C9orf72 involves a different type of mutation, namely a ‘repeat expansion’. The hereditary material contains in some places a series of repeats of a short ‘string’ of letter code. In the case of C9orf72, this involves a repeat of GGGGCC at the beginning of the C9orf72 gene, a piece that does not transfer to the protein. Healthy individuals have a few repeats of this ‘repeat’. When the length of this repeat increases, it gives rise to ALS. Moreover, it can also give rise to frontotemporal dementia, a neurodegenerative disorder related to ALS. The function of the C9orf72 gene is as yet unknown. How the increase in GGGGCC repeat length gives rise to ALS is also unknown. On the one hand, the mutation may disrupt the formation of the normal C9orf72 protein; on the other hand, the repeat in the messenger RNA may give rise to the formation of RNA foci and even be translated into abnormal proteins consisting of a repeat of two amino acids.
Several other ALS genes have been discovered in recent years. In each case, these occur only in a small percentage of patients. Examples are: OPTN, TBK1, UBQLN2, VCP, SETX, VAPB, ANG, CHMP2B, alsin, PFN1, SPG11, TUBA4A.
In families where causative mutations were identified in affected individuals, we can look for possible carrier status in non-affected individuals. This is called preclinical detection, which is done only under close supervision of the individuals who want to be tested. If carrier status is confirmed, adapted advice is possible (this is called genetic advice) to prevent carrier status being passed on to the next generation.
The disease caused by mutations in SOD1, C9orf72, TARDBP or FUS is highly variable: the age of onset, the type of impairment and the severity or aggressiveness of the disease (disease duration) is highly variable between families with different mutations, but also between family members with all the same mutation. This therefore means that there are other, most likely, also hereditary factors that ‘modify’ the way motor neurone degeneration occurs. Identifying these is very important. Studies in patients with SOD1 mutations in Scandinavia show that such modifying factors can completely suppress the onset of the disease.
So in about 20% of families with fALS, we do not know the causative gene and no preclinical testing can be done. After all, a negative test for SOD1, C9orf72, TARDBP and FUS then means nothing, because affected patients then also test negative, but are still carriers of an unidentified ALS gene. In those families, we just have to make do with the one-in-two risk calculation.
Heredity of sALS
Unexpectedly, a small minority of sALS patients turn out to have fALS after all. We know this because some of the so-called sALS patients were nevertheless found to have mutations in SOD1, C9orf72, TARDBP or FUS. In particular, mutations in the C9orf72 gene are occasionally found in ALS patients without a family history of ALS. Possible reasons for this are: the parent who passed on the gene defect died before the disease could break out in him or her, the biological father is not the legal father, the disease started in the children at a young age even before one of the parents developed symptoms, or a new mutation occurred in one of the children that was not present in the parents. All these reasons make it defensible to perform a gene test even in ALS patients without a family history.
Hereditary factors also seem to play a role in sALS, but not in the same way as in fALS. For sALS, it is suspected that a number of hereditary factors come together to make it possible for a person to develop the disease, possibly in conjunction with environmental factor(s). Such hereditary factors are called risk genes. The risk of getting ALS during the course of life is estimated to be 1/400. Risk genes can increase the chance of getting ALS, but do not automatically lead to the actual development of the disease. It is therefore about the inheritance of a predisposition. This is referred to as complex heredity.
With the development of better tests to examine hereditary material (GWAS, exome sequencing, whole genome sequencing), it is possible to identify such risk genes. Several such genes have already been discovered in recent years: UNC13A, ATXN2, SQSTM1, NEK1, C21orf2.
Decision
We can thus summarise that the heredity of ALS can be both simple (for the familial cases, one inherits ‘the disease’) and complex (for sporadic cases with ‘pre-disposition’). A lot of research is still needed to clear things up.
The bottom line is that inheritance of fALS is almost always ‘dominant’, while the risk to the children of a patient with sALS is no greater than that of anyone else.
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