Juvenile Amyotrophic Lateral Sclerosis (JALS), in which symptoms begin to appear before the age of 25, affects fewer than 1,000 people in the U.S.1 The overall prevalence of JALS worldwide is unknown.2 Perhaps the most famous case of the disease was physicist Stephen Hawking. He was diagnosed with juvenile ALS when he was 21 years old and lived with the disease for 55 years before passing away at age 76 (a very rare outcome).
The U.S. National ALS Registry indicates that the average age of disease onset is roughly 54 years, with only around 13% of patients developing symptoms before the age of 40 (only 59 cases of juvenile ALS were recorded in the database as of 2018).3
The rarity of JALS, however, hasn’t stopped researchers from investigating novel therapies to slow the progression of the disease. While JALS is more likely to be linked to a genetic mutation than adult-onset ALS, most cases still occur in young people with no family history of ALS. This makes research more complex as therapies may only be helpful to a handful of patients.
What is the Biology Behind Juvenile ALS?
Juvenile ALS targets the upper and lower motor neurons of the brain and spinal cord. As these neurons slowly degenerate, they cause a patient to lose voluntary control over specific muscles. These muscles may be the ones that control actions such as speaking, walking, facial movements, bladder function, and more.
In some cases, juvenile ALS patients can experience paralysis while still in childhood. The rate of disease progression can be hard to predict, and some patients may take decades to develop paralysis.4 Typically, JALS progresses more slowly than those diagnosed with adult-onset ALS, and in many cases, survival rates are better, with patients living for decades.5
Juvenile ALS is sometimes mistaken for another motor neuron disease called primary lateral sclerosis (PLS). PLS is a recessive genetic disease and therefore has to be inherited from both parents (even though the parents may not have the disease themselves). When PLS occurs in children, it progresses slowly and is not fatal. More research is needed, but the two diseases may be related.6
What are the Symptoms of Juvenile ALS?
Symptoms of juvenile ALS vary depending on the gene mutation, so various subtypes of the disease exist. For example, gene mutations in the Fused in Sarcoma (FUS) gene may present as muscle wasting, weakness, spasticity, and over-responsible reflexes (hyperreflexia), with patients experiencing rapid deterioration of the muscles within 1 to 2 years of onset.7
On the other hand, a mutation in the Senataxin (SETX) gene is associated with an autosomal dominant form of JALS named ALS4. Meaning a single copy of mutant SETX inherited from one parent is enough to cause the disease. This form of ALS has an average age of onset of 16 years, causes symptoms more often in males than females, and progresses slowly. Generally, taking years to progress to weakness in the muscles in the upper and lower extremities.8
There are many more forms of juvenile ALS with different causes and prognoses.
Other common symptoms of juvenile ALS include:9
- Muscle atrophy in the legs and hands.
- Difficulty swallowing (Dysphagia).
- Facial spasticity.
- Speech disorders due to muscle weakness (Dysarthria).
- Lower limb spasticity leads to gait abnormalities.
- Involuntary muscle contractions lead to abnormal postures (Dystonia).
Symptoms can less commonly include:
- Uncontrolled laughter and weeping.
- Bladder dysfunction.
- Sensory disturbances.
Those diagnosed with juvenile ALS are more likely to have symptoms affecting neural pathways as well as motor pathways.10
Diagnosing juvenile ALS is not always straightforward since no single test can confirm the disease. If symptoms progress slowly, it can take a year or more to achieve a diagnosis while excluding other potential diseases.
What Genes are Associated with Juvenile ALS?
There are several subtypes of juvenile ALS, and multiple genes have been associated with symptoms of the disease. While JALS generally progresses slowly, the rate of this progression varies based on the affected gene and on the specific mutation within the gene.11
Juvenile ALS symptoms have been associated with the following genes:
While the exact connection between JALS and some of these genes is unknown, mutations in ALS2, SETX, or SPG11 are reliably affiliated with inherited forms of juvenile ALS. Inheritance may be autosomal recessive or autosomal dominant, depending on the gene. Interestingly, a mutation in the C9orf72 gene (which is the most common inherited gene in adult-onset ALS) has not been linked to juvenile ALS.12
How is Juvenile ALS Being Researched?
Currently, there is no treatment or cure for juvenile ALS. Genetic testing is one of the most important considerations for diagnosing and understanding the prognosis for JALS, even though the exact pathogenic mechanisms are still unknown.
Because juvenile ALS is so rare, it can be challenging to find enough data to make predictions about the course of the disease or test new treatments. To aid in the understanding and treatment of this diverse disease, Target ALS has created an innovation ecosystem that houses research, biospecimens, genomic datasets, and proteomics data. These serve as invaluable resources for researchers looking for new insights into juvenile ALS. Target ALS has made this data readily available to the academic and industry research communities since 2013, facilitating the publication of over 100 studies, some of which have led to clinical trials.
Importance of Juvenile ALS Research
Studies on juvenile ALS hold great promise for understanding and possibly treating all ALS in the future since juvenile patients tend to have a longer lifespan than those diagnosed in their 50s through 70s. JALS research has the potential to drastically change lives, despite it being a very rare disease.
1. Juvenile amyotrophic lateral sclerosis – About the Disease. Genetic and Rare Diseases Information Center. (2021, Nov 8). Retrieved September 25, 2022, from https://rarediseases.info.nih.gov/diseases/11901/juvenile-amyotrophic-lateral-sclerosis
2. Juvenile amyotrophic lateral sclerosis. Orphanet: The portal for rare diseases and orphan drugs. (2014, February). Retrieved September 25, 2022, from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=300605
3. Cook SF, et al. (2021, Nov 8) A Descriptive Review of Global Real World Evidence Efforts to Advance Drug Discovery and Clinical Development in Amyotrophic Lateral Sclerosis. Frontiers in Neurology. https://www.frontiersin.org/articles/10.3389/fneur.2021.770001/full
4. Andersen, P., Al-Chalabi, A. (2011, Oct 11). Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nature Reviews Neurology. https://www.nature.com/articles/nrneurol.2011.150
5. Kuo, C. (2019, Mar 9) How Stephen Hawking Defied Amyotrophic Lateral Sclerosis for Five Decades. Clinical Medicine and Therapeutics. https://scitemed.com/article/2792/scitemed-cmt-2019-00105
6. Primary lateral sclerosis (PLS) – Symptoms and causes. Mayo Clinic. Retrieved September 25, 2022, from www.mayoclinic.org/diseases-conditions/primary-lateral-sclerosis/symptoms-causes/syc-20353968
7. Sharma, A. et al. (2016, Feb 4) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nature Communications. https://pubmed.ncbi.nlm.nih.gov/26842965/
8. Bennett, C. et al. (2018, May 3) Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients. Acta Neuropathologica. https://pubmed.ncbi.nlm.nih.gov/29725819/
9. Juvenile amyotrophic lateral sclerosis – About the Disease. Genetic and Rare Diseases Information Center. (2021, Nov 8). Retrieved September 25, 2022, from https://rarediseases.info.nih.gov/diseases/11901/juvenile-amyotrophic-lateral-sclerosis
10. Lehky, T. and Grunseichm, C. (2012, Dec 12). Juvenile Amyotrophic Lateral Sclerosis: A Review. Genes. https://www.mdpi.com/2073-4425/12/12/1935
11. Johnson JO, et al. (2021, Aug. 30) Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis. JAMA Neurology. https://jamanetwork.com/journals/jamaneurology/fullarticle/2783665
12. Lehky, T. and Grunseichm, C. (2012, Dec 12). Juvenile Amyotrophic Lateral Sclerosis: A Review. Genes. https://www.mdpi.com/2073-4425/12/12/1935