Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing neurodegenerative disorder that targets the nerve cells, or motor neurons, in the brain and spinal cord. These specialized cells control voluntary muscle movement, and their progressive death results in the inability to initiate and control movement, speech, swallowing, and eventually breathing. This debilitating condition, often known as Lou Gehrig’s disease, raises questions about hereditary risk. The question of whether ALS is inherited from the mother or the father depends entirely on the specific category of the disease a person has.
Sporadic Versus Familial ALS
The vast majority of ALS cases, approximately 90% to 95%, are classified as Sporadic ALS (SALS), meaning they occur in individuals with no known family history of the disease. The cause of SALS is thought to be a complex interaction of various genetic and environmental factors. While SALS is not passed down in a traditional hereditary sense, about 10% of these sporadic cases do show a mutation in a gene that has been associated with ALS.
In contrast, Familial ALS (FALS) accounts for the remaining 5% to 10% of cases and involves a clear hereditary link within a family. FALS is caused by pathogenic mutations passed from one generation to the next. The question of inheritance—and the risk to children—is only directly applicable to this smaller FALS population.
Genetic Transmission Patterns
For the majority of FALS cases, the pattern of inheritance that determines risk is known as Autosomal Dominant inheritance. The term “autosomal” means that the gene responsible for the condition is located on one of the 22 non-sex chromosomes, which are inherited equally from both parents. The sex of the parent carrying the mutation—mother or father—does not influence the probability of transmission.
The “dominant” nature of the pattern signifies that a child only needs to inherit one copy of the altered gene from either parent. In this scenario, if one parent carries the mutation, each of their children faces a 50% chance of inheriting the gene change. This 50/50 risk results from the random passing of only one member of the parent’s gene pair during reproduction, regardless of which parent it is.
Less frequently, ALS can be inherited through an autosomal recessive pattern, where a child must inherit a mutated gene copy from both parents to be affected. There are also rare instances of X-linked inheritance, which involves a gene located on the X sex chromosome, but the autosomal dominant pattern remains the most common mechanism.
Major Genes Linked to Inheritance
While the transmission pattern addresses the risk percentage, the specific genes involved explain the underlying molecular mechanism of FALS. Mutations in just a few genes account for the majority of FALS cases, with the two most common being \(C9orf72\) and \(SOD1\).
The \(C9orf72\) gene is the most frequent genetic cause, accounting for approximately 40% of familial ALS cases. The mutation is characterized by an abnormal expansion of a six-letter DNA sequence, a hexanucleotide repeat, within the gene. This expansion is believed to cause toxicity through the accumulation of abnormal RNA and proteins, disrupting normal cellular function. This gene mutation is also strongly associated with Frontotemporal Dementia (FTD), highlighting a shared disease spectrum.
The second most common gene is \(SOD1\), which accounts for about 10% to 20% of familial cases. \(SOD1\) provides instructions for the superoxide dismutase 1 enzyme, which normally helps manage toxic oxygen molecules within cells. A mutation in this gene results in a defective protein that becomes toxic and forms damaging aggregates inside the motor neurons, leading to their death.
Other genes, such as \(TARDBP\) and \(FUS\), also contribute to FALS by affecting the processing and regulation of RNA, a critical process for creating functional proteins. For families with a history of ALS, genetic testing and counseling are important tools to identify a specific mutation. Identifying the specific gene allows for targeted risk management and a better understanding of the disease’s potential progression.