Diagnosis of familial ALS
Familial ALS (FALS) share many common clinical characteristics with sporadic ALS (SALS), which makes it difficult to distinguish between the two forms.
Diagnosing FALS involves the analysis of family history and disease symptoms — their progression rate can help in diagnosis. Clinical tests can also help to rule out other conditions.
Genetic testing is usually only performed in individuals with a family history of ALS. Diagnosis of FALS by genetic testing, done using a blood or saliva sample, is challenging because many different genes have been linked to FALS, and new disease-causing mutations are continually being discovered.
There are currently no gene-specific treatment options available, but knowing the disease-causing mutation may make a patient eligible for clinical trials involving gene therapy.
Causes and inheritance of FALS
FALS has a strong genetic component, as genetic mutations can increase the susceptibility to the disease but they are not the only cause. On the other hand, an individual who has a family history of the disease and carries a genetic mutation that can cause ALS may be asymptomatic and never develop the condition.
Mutations in the C9orf72 gene is the most common genetic defect, occurring in 40 percent of FALS cases, and may also cause another neurodegenerative condition called frontotemporal dementia (FTD). People with a mutation in this gene may have symptoms of both ALS and FTD.
Mutations in the SOD1 gene account for 12–20 percent of FALS cases. This gene provides instructions to build the so-called superoxide dismutase enzyme, which neutralizes oxygen radicals. How mutations in the SOD1 gene cause ALS is not well understood, but two possibilities exist: The first is through an increase of harmful oxygen radicals, and the second is through the accumulation of misfolded superoxide dismutase enzymes.
Four percent of FALS cases are found to have mutations in the TARDBP gene, which provides instructions to build the so-called TDP-43 protein. This protein is involved in the production of other proteins. Mutations in this gene cause the TDP-43 to form aggregates in nerve cells that harm and eventually kill them.
The FUS gene is mutated in about five percent of FALS cases. This gene encodes for a protein whose function is similar to that of the TDP-43 protein. FUS protein aggregates are found in the motor neurons of ALS patients and are thought to be involved in the disease.
Most genetic mutations that cause FALS are inherited in an autosomal dominant manner meaning that inheriting one faulty copy of the gene from one parent is sufficient for the disease to develop.
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