Genetics of PLS (and ALS)

Adult-onset PLS is overwhelmingly sporadic — the large majority of people diagnosed have no family history of PLS or related motor neuron disease, and no causative genetic mutation is identified. Juvenile PLS is a different entity: it is caused by mutations in the ALS2 gene (which encodes the protein alsin) and follows an autosomal recessive inheritance pattern. There is also a genetic boundary with hereditary spastic paraplegia (HSP), which can produce an identical clinical picture and has numerous identifiable genetic causes of its own.

PLS genetics: what is known

Most adult PLS patients have sporadic disease. The genetic basis in these cases is largely undetermined. Whole-genome sequencing (WGS) studies are beginning to change this: a 2025 WGS analysis of PLS patients (Manini et al., UNIMI) identified variants potentially relevant to upper motor neuron degeneration that had not previously been associated with PLS. This work is early — the variants identified are candidates, not confirmed causes — but it establishes the infrastructure for future genetic discoveries in PLS.

Some adult PLS patients carry ALS-associated variants, including C9orf72 repeat expansions and SOD1 variants. This overlap supports the view that PLS and ALS may share genetic architecture in a subset of cases, even when their clinical presentation is quite different.

Juvenile PLS (JPLS) — with onset in childhood or adolescence — is caused by mutations in the ALS2 gene. ALS2 encodes alsin, a protein involved in endosomal trafficking in motor neurons. JPLS follows an autosomal recessive pattern: both copies of ALS2 carry a mutation, and parents are typically carriers without symptoms. Genetic testing for ALS2 confirms the diagnosis in juvenile-onset cases.

Genetic testing in adult PLS is useful to: (1) rule out or identify ALS-associated variants that may have treatment or trial implications; (2) distinguish PLS from hereditary spastic paraplegia, which has numerous identifiable genetic causes (SPG genes) and a different prognosis; and (3) inform family members if a relevant variant is found. Genetic counseling before and after testing is recommended.

ALS genetics — for context

ALS has a substantially different genetic landscape from PLS. Understanding ALS genetics is relevant to PLS patients because they are often managed through ALS clinics, because some genetic variants overlap, and because ALS research increasingly produces treatments that may eventually extend to PLS. The sections below describe the major ALS genes.

Familial Versus Sporadic ALS

Approximately 90–95% of ALS cases are sporadic — they arise without a clear family history, and the cause in any individual case is not known. The remaining 5–10% are familial, meaning there is a genetic mutation that can be identified and may be inherited by biological relatives.

However, this distinction is less clear-cut than it seems. About 10% of people with apparently sporadic ALS carry a genetic mutation that contributes to their disease — meaning they had a gene change without knowing it or without family members having been diagnosed. Genetic testing identifies these mutations, which has implications for their own treatment (tofersen for SOD1 mutations) and for their relatives.

The Major ALS Genes

C9orf72

C9orf72 is the most common genetic cause of both familial ALS and familial frontotemporal dementia (FTD) worldwide. The mutation is a hexanucleotide repeat expansion — an abnormally large repetition of a six-letter DNA sequence in the C9orf72 gene. Normal individuals have fewer than 30 repeats; people with ALS or FTD caused by this mutation often have hundreds to thousands of repeats.

C9orf72 mutations account for approximately 40% of familial ALS and about 5–10% of sporadic ALS. They are more common in European populations than in other ethnic groups. People with C9orf72 ALS are at higher risk for cognitive and behavioral changes (ALS-FTD).

SOD1

SOD1 (superoxide dismutase 1) was the first ALS gene discovered, identified in 1993. It encodes a protein that protects cells from oxidative damage. Mutations in SOD1 cause a toxic gain of function — the mutant protein misfolds and aggregates, damaging motor neurons.

SOD1 mutations account for approximately 20% of familial ALS and 2% of sporadic ALS cases. They are the target of tofersen, the first gene-targeted ALS therapy. If you have an ALS diagnosis, knowing your SOD1 status is important for treatment eligibility.

TDP-43 (TARDBP)

TDP-43 is an RNA-binding protein that normally resides in the nucleus but mislocalizes and forms aggregates in the cytoplasm in ALS and most cases of FTD. While mutations in the TARDBP gene that encodes TDP-43 are relatively rare as a genetic cause of ALS (about 3% of familial ALS), the pathological protein aggregates are found in approximately 97% of all ALS cases — making TDP-43 pathology the most common hallmark of the disease, even in people without TDP-43 gene mutations.

FUS

FUS (Fused in Sarcoma) is another RNA-binding protein. FUS mutations cause about 4% of familial ALS and tend to be associated with earlier disease onset — sometimes in patients in their 20s or 30s. FUS-ALS is one of the targets of gene therapy approaches currently in early clinical development.

Other genes

More than 40 genes have been associated with ALS risk or causation. Among the more clinically important are: UBQLN2, OPTN, VCP, NEK1, TBK1, ANG, SETX, and ATXN2 (an ALS modifier rather than direct cause). Each has different frequencies, inheritance patterns, and clinical implications.

ALS and Frontotemporal Dementia — The Genetic Link

The overlap between ALS and FTD is not merely clinical — it is genetic and pathological. The C9orf72 repeat expansion can cause either ALS, FTD, or a combined ALS-FTD syndrome within the same family. This shared genetic basis has led to the concept of an ALS-FTD disease spectrum, unified by C9orf72 and TDP-43 pathology.

Understanding this link is important because: (1) family members of someone with C9orf72 ALS may be at risk for either ALS or FTD; and (2) cognitive screening in ALS patients, particularly those with C9orf72, is essential.

Genetic Testing — Who Should Consider It

Genetic testing is now recommended for all newly diagnosed ALS patients, regardless of family history. Reasons include:

Tofersen is available only for SOD1-ALS — testing identifies eligible patients
Clinical trial eligibility often depends on genetic profile
The ATLAS trial for pre-symptomatic SOD1-ALS requires identification of SOD1 carriers before symptom onset
Family members may benefit from knowing their genetic status
Understanding the genetic cause helps contextualize cognitive and behavioral symptoms

Genetic testing for ALS should be accompanied by genetic counseling — both before testing (to understand what results may mean) and after (to interpret results and discuss implications for family members). This is particularly important for familial cases or when a causative mutation is found.

The major ALS research centers and the ALS Association can facilitate access to genetic testing and counseling. Many ALS-specific genetic tests are now covered by insurance when ordered with an ALS diagnosis.

Biomarkers — What They Measure and Why They Matter

Beyond genetic testing, neurofilament light chain (NfL) has emerged as the most clinically important ALS biomarker. NfL is a structural protein released into blood and cerebrospinal fluid when neurons are damaged. In ALS, NfL levels are elevated and correlate with disease severity and progression rate.

NfL is used clinically to:

Support ALS diagnosis, particularly in ambiguous cases
Track disease activity over time
Monitor response to tofersen (NfL levels fall significantly with tofersen treatment, which was the basis for the FDA's accelerated approval)
Identify pre-symptomatic disease progression in genetic ALS (as in the ATLAS trial)

NfL testing is increasingly available in clinical practice, though it is not yet universally standardized. Ask your neurologist whether it is relevant to your care.

What the Future Holds

Genetic medicine for ALS is advancing faster than at any previous point in the disease's history. The success of tofersen for SOD1-ALS has opened the door for a wave of gene-targeted approaches addressing C9orf72, FUS, and other genetic causes. The broader goal — developing treatments that address TDP-43 pathology regardless of genetic status — would benefit the majority of ALS patients who have no identified genetic mutation.