A New Way to Spot ALS: Understanding the Latest Diagnostic Breakthrough

If you or a loved one has faced the uncertainty of an ALS diagnosis, you know how critical early, accurate testing can be. A recent study published in Nature Medicine offers hope for a faster, more reliable way to detect ALS—even before symptoms start. Here’s what you need to know about this promising new tool and how it could change the future of ALS care.

What You’ll Learn

This article dives into a new biomarker (a biological "signal" in the body) that researchers have identified for ALS. Called cryptic HDGFL2, this marker could help doctors diagnose ALS earlier, with more certainty, and even spot the disease in people who carry genetic risks but haven’t developed symptoms yet. We’ll explain how it works, what the research found, and what it might mean for you or someone you care about.

A Quick Look at ALS (and Why Diagnosis Is Hard)

ALS (amyotrophic lateral sclerosis) is a progressive neurodegenerative disease that damages the motor neurons—cells that control muscle movement. Over time, this leads to muscle weakness, difficulty speaking, eating, or breathing, and eventually loss of mobility.

One of the biggest challenges with ALS is diagnosis. There’s no single test for ALS: doctors usually rule out other conditions (like multiple sclerosis or Parkinson’s) using a combination of exams, scans, and nerve tests. This process can take 12–18 months on average, delaying access to treatments and support. For people with genetic forms of ALS (like those with the C9orf72 mutation), waiting for symptoms to appear can be an agonizing wait.

Why Better Diagnostic Tools Are Needed

For ALS patients, time is everything. Early diagnosis means:

• Earlier access to treatments (like medications that slow disease progression).
• Better management of symptoms (e.g., physical therapy, breathing support).
• Family planning for those with genetic risks (knowing their status can help loved ones make informed decisions).

Right now, many patients go through a "diagnostic odyssey"—visiting multiple doctors, undergoing endless tests, and living with uncertainty. A more accurate, faster test could end that journey.

What’s New in Diagnosing ALS?

Researchers have been searching for biomarkers—substances in blood, cerebrospinal fluid (CSF), or urine—that signal ALS. The latest breakthrough focuses on a protein fragment called cryptic HDGFL2. Here’s the science (simplified):

What Is Cryptic HDGFL2?

HDGFL2 is a gene that makes a protein involved in cell function. Normally, a protein called TDP-43 keeps a "hidden" part of the HDGFL2 gene (called a cryptic exon) turned off. But in ALS, TDP-43 malfunctions—either clumping in cells or moving out of the nucleus (the cell’s "control center"). When this happens, the cryptic exon turns on, and the body produces a faulty version of HDGFL2: cryptic HDGFL2.

This faulty protein builds up in the brain and spinal cord. The study found it also leaks into CSF (the fluid around the brain and spine) and blood—making it a potential biomarker for ALS.

How Does the Test Work?

The researchers developed a highly sensitive ELISA test (similar to a blood test) to detect cryptic HDGFL2 in CSF and blood. ELISA tests use antibodies to "catch" specific proteins, making them accurate and relatively easy to perform.

What Did the Study Find?

The team tested the marker in:

• 157 CSF samples from people with ALS (including those with the C9orf72 mutation) and healthy controls.
• 66 plasma (blood) samples from the same groups.

Key results:

1. Presymptomatic Detection: Cryptic HDGFL2 was detectable in the CSF and blood of people with the C9orf72 mutation before they developed symptoms. This is a game-changer for genetic ALS, where early intervention could be life-changing.
2. Correlation with Disease Stage: Levels of cryptic HDGFL2 were higher in early-stage ALS and decreased as the disease progressed. This means the marker could help track how ALS is advancing.
3. Better Than Current Markers: Unlike neurofilaments (the most common ALS biomarkers), cryptic HDGFL2 is specific to TDP-43 malfunction—a core feature of ALS. Neurofilaments are released when neurons die, but they can also be elevated in other diseases (like MS or stroke). Cryptic HDGFL2 is more likely to signal ALS alone.
4. Blood vs. CSF: The marker was detectable in both CSF (the "gold standard" for ALS testing) and blood. Blood tests are less invasive than CSF (which requires a spinal tap), making them easier for patients.

What Could This Mean for Patients?

If this test is validated in larger studies, it could:

• Shorten the diagnostic odyssey: Instead of waiting months for a diagnosis, patients could get answers faster.
• Improve clinical trials: Researchers could use cryptic HDGFL2 to identify people with early-stage ALS for trials, which often struggle to recruit participants.
• Enable personalized care: For people with genetic ALS, the test could spot the disease before symptoms start, allowing for preventive treatments (if they become available).

Important Note: When Will This Test Be Available?

This is still early-stage research. The study was small (most cohorts had fewer than 100 participants), and the test needs to be validated in larger, more diverse groups. It could be several years before it’s widely available in clinics.

Limitations and Next Steps

No test is perfect, and this one has limitations:

• Small Sample Sizes: The study included mostly white participants with the C9orf72 mutation. More research is needed to confirm it works for all ALS types (sporadic and genetic) and diverse populations.
• Variable Levels: Cryptic HDGFL2 levels decreased in later-stage ALS, which means it might not be as useful for tracking advanced disease.
• Cost and Access: ELISA tests are relatively cheap, but widespread adoption would require approval from agencies like the FDA (in the U.S.) or EMA (in Europe).

The researchers plan to:

• Test the marker in larger, more diverse cohorts.
• Combine it with other biomarkers (like neurofilaments) to improve accuracy.
• Explore whether it can predict how fast ALS will progress.

Key Points to Remember

• Cryptic HDGFL2 is a new biomarker for ALS that detects faulty protein buildup from TDP-43 malfunction.
• It can be found in CSF and blood—making it less invasive than current tests.
• It’s detectable before symptoms start in people with genetic ALS (C9orf72 mutation).
• It’s more specific to ALS than current markers (like neurofilaments).

Talk to Your Doctor

If you or a loved one is living with ALS or at risk (e.g., family history of C9orf72), ask your doctor about:

• Current diagnostic options (e.g., EMG, MRI, neurofilament tests).
• Research studies using cryptic HDGFL2 (you might be eligible to participate).
• Genetic testing (if you’re concerned about inherited ALS).

Remember: This test isn’t yet available for routine use, but staying informed about the latest research can help you advocate for the best care.

For more information about ALS and diagnostic research, visit organizations like the ALS Association or MDA (Muscular Dystrophy Association). Early detection could be the key to better outcomes— and this study is a big step in the right direction.