Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, the nerve cells controlling voluntary muscle movement. Most ALS cases (about 90%) are sporadic, occurring without a known family history. However, a smaller proportion (5-10%) is inherited, known as familial ALS (fALS). Familial ALS results from specific genetic changes passed down through generations.
The Primary Inheritance Pattern in Familial ALS
Familial ALS is most frequently inherited through an autosomal dominant pattern. This means inheriting one copy of a mutated gene from either parent is sufficient for the condition to develop. The genes are on autosomes (non-sex chromosomes), so males and females are equally likely to inherit the mutation. If one parent carries a disease-causing mutation, each child has a 50% chance of inheriting it.
This pattern often leads to ALS appearing in multiple generations, with affected individuals typically having an affected parent. However, symptom onset and disease progression can vary considerably even within the same family. Genes like C9orf72 and SOD1 are commonly associated with fALS cases following this pattern, accounting for a significant portion of identified genetic causes.
Less Common Inheritance Patterns
While autosomal dominant inheritance is most prevalent, familial ALS can follow other, less common patterns. Autosomal recessive inheritance requires a child to inherit two mutated gene copies, one from each parent, to develop the disease. Parents in this scenario typically do not have ALS but are carriers. This pattern is rarer and more frequent in populations with higher rates of consanguineous marriages. For instance, the SOD1 mutation p.Asp90Ala, and mutations in rarer genes like ALS2 and SPG11, can be inherited recessively.
Another very rare pattern is X-linked inheritance, involving a mutated gene on the X chromosome. Since females have two X chromosomes and males have one X and one Y, X-linked conditions can manifest differently. For example, UBQLN2 gene mutations on the X chromosome can cause X-linked fALS, primarily affecting males, though females can also develop the disease.
The Role of Specific Genes
Several specific genes contribute to familial ALS. The C9orf72 gene is the most common genetic cause, accounting for approximately 40% of familial cases. Mutations involve an expanded repeat sequence, leading to abnormal protein aggregates and affecting RNA processing and transport, disrupting neuronal function.
Mutations in the SOD1 gene are the second most common cause, found in about 12% of familial ALS cases. SOD1 normally produces an enzyme protecting cells from harmful molecules, but mutations can cause the protein to misfold and aggregate, leading to a toxic gain-of-function that impairs cellular processes. While most SOD1 mutations are autosomal dominant, the p.Asp90Ala mutation can be autosomal recessive.
Other genes, such as TARDBP and FUS, each account for approximately 4% of familial ALS cases. TARDBP codes for TDP-43, an RNA-binding protein involved in gene regulation and RNA metabolism. Mutations can lead to both a loss of normal function and a toxic gain-of-function, often resulting in abnormal protein inclusions within neurons. FUS codes for another RNA-binding protein; its mutations can also cause protein aggregation and disrupt RNA processing.
Understanding Genetic Risk and Penetrance
Individuals who inherit a gene mutation associated with familial ALS often wonder if they will definitely develop the disease. The answer involves incomplete penetrance, meaning not everyone who carries a disease-causing gene mutation will ultimately develop the condition. The likelihood of developing ALS, or penetrance, can vary based on the specific gene mutation and a person’s age.
For instance, the penetrance for C9orf72 mutations is estimated to be around 60% by age 60 and can increase to about 91% by age 80. Similarly, for some SOD1 mutations, such as A4V, the penetrance is estimated to be at least 90% by age 70, while other SOD1 mutations may have different penetrance rates. This variability suggests that additional genetic or environmental factors might influence whether and when the disease manifests. Genetic counseling plays a valuable role for individuals with a family history of ALS, providing personalized information about genetic risk, the implications of genetic testing, and support for making informed decisions.