Clinical and muscle magnetic resonance image findings in patients with late-onset multiple acyl-CoA dehydrogenase deficiency

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Clinical and muscle magnetic resonance image findings in patients with late-onset multiple acyl-CoA dehydrogenase deficiency

For people with late-onset multiple acyl-CoA dehydrogenase deficiency (MADD), everyday tasks like climbing stairs or carrying groceries can feel impossible. This rare genetic disorder disrupts fat metabolism, leading to muscle weakness, exercise intolerance, and other health issues. But until 2019, doctors lacked clear guidelines for using muscle MRI—the gold standard for many muscle diseases—to diagnose or monitor MADD in the lower limbs. A landmark study from Chinese neurologists changed that, revealing distinct MRI patterns that could transform how we care for people with this condition.

What Is Late-Onset MADD?

MADD is an inherited metabolic disorder (you get it from both parents) caused by mutations in the ETFDH gene. This gene makes a protein called electron transfer flavoprotein dehydrogenase, which is critical for breaking down fats into energy. When the protein doesn’t work, fats build up in cells—especially muscles—leading to damage.

Late-onset MADD (starting after age 10) often causes:

  • Muscle symptoms: Weakness (usually in the hips, thighs, or shoulders), trouble exercising without fatigue, and muscle pain.
  • Extramuscular symptoms: Digestive problems, fatty liver, high homocysteine (a blood chemical linked to heart and brain issues), or sensory neuropathy (numbness/tingling in the hands/feet).

The good news? Many patients respond dramatically to riboflavin (vitamin B2), which helps the faulty protein function better.

The Study: Who, What, How?

Led by Dr. Dao-Jun Hong (Peking University People’s Hospital) and Dr. Min Zhu (The First Affiliated Hospital of Nanchang University), the study analyzed 25 patients with confirmed late-onset MADD. To ensure accuracy, the team used:

  • Clinical data: Symptoms, blood tests (like creatine kinase, a marker of muscle damage), and electromyography (to check muscle/nerve function).
  • Muscle biopsies: Small muscle samples to look for fat buildup (a hallmark of MADD).
  • Genetic testing: To confirm ETFDH mutations (and rule out other causes).
  • MRI scans: Of the thighs and legs before treatment, with follow-up scans for 8 patients after riboflavin therapy. They used two key MRI sequences:
    • T1-weighted (T1WI): Shows fat buildup (white spots on scans).
    • STIR: Shows edema (swelling from inflammation or cell damage—bright spots).

The team scored fat buildup and edema using standardized scales (like the modified Mercuri scale for fat) to make comparisons easier.

Key Findings: Distinct MRI Patterns

The biggest breakthrough was selective muscle involvement—some muscles were damaged while others next to them were completely fine. Here’s what the team found:

1. The “SO+/GA–” Sign (Legs)

The soleus (a deep calf muscle that helps you stand on tiptoe) showed both edema (bright STIR spots) and fat buildup (white T1 spots). But the gastrocnemius (the larger, more visible calf muscle) was almost always normal. This pattern—soleus involved, gastrocnemius untouched—was called the “SO+/GA–” sign.

2. The “BFL+/ST–” Sign (Thighs)

In the thigh, the biceps femoris longus (a back thigh muscle that bends the knee) had edema and fat buildup. The semitendinosus (another back thigh muscle) was untouched. This was the “BFL+/ST–” sign.

How Useful Are These Signs?

When combined—either SO+/GA– or BFL+/ST–—these patterns correctly diagnosed MADD in 80% of patients (sensitivity) and ruled it out in 83.5% of people with other muscle diseases (specificity). For context, a test with 80% sensitivity catches most cases, and 83.5% specificity means few false positives—making this a strong tool for doctors.

Treatment Response: What MRI Tells Us

One of the most hopeful findings was how MRI tracked treatment success. All 8 patients who had follow-up scans took riboflavin, and:

  • Edema (STIR signal): The bright spots in the soleus and biceps femoris longus faded within 1 month. This matched patients’ reports of feeling stronger and less tired.
  • Fat buildup (T1 signal): The white spots from fat took longer to disappear—usually 1 year or more.

This means the STIR signal (edema) could be a biomarker for treatment response. Doctors can use MRI to see if riboflavin is working within weeks, instead of waiting months for symptoms to improve.

Expanding the MADD Picture

The study also added new details to our understanding of late-onset MADD:

  • Neuropathy: Four patients had sensory neuropathy (numbness/tingling in the feet/hands)—a symptom not always linked to MADD before.
  • High homocysteine: 15 patients had extremely high homocysteine levels (up to 126 mmol/L, vs. the normal 0–15 mmol/L). Riboflavin lowered these levels, likely because it helps an enzyme break down homocysteine.
  • Genetic discoveries: The team found 8 new ETFDH mutations (e.g., c.34G>C, c.35-2A>C), including some that caused severe protein changes. These were confirmed using the American College of Medical Genetics and Genomics (ACMG) criteria—ensuring they were linked to MADD.

Why This Matters for Patients and Doctors

This study is a game-changer for MADD care:

For Patients

  • Faster relief: The fact that edema (a key cause of muscle weakness) improves in 1 month means symptoms like fatigue or difficulty walking could get better quickly with riboflavin.
  • Clearer monitoring: MRI can show if treatment is working—no more guessing.

For Doctors

  • Faster diagnosis: If a patient has muscle weakness and an MRI shows SO+/GA– or BFL+/ST–, doctors can prioritize ETFDH testing (instead of waiting for biopsies).
  • Better differential diagnosis: The patterns help distinguish MADD from other muscle diseases (e.g., mitochondrial myopathy, which often affects both the soleus and gastrocnemius).

Limitations and Next Steps

Like all studies, this one has limitations:

  • Small sample: Only 25 patients were included—larger studies are needed to confirm results.
  • Retrospective design: The team looked back at past data, so some long-term follow-up information was missing.
  • Heterogeneous controls: The 200 non-MADD patients included different muscle diseases (dystrophinopathy, limb-girdle muscular dystrophy), which might affect how we interpret sensitivity/specificity.

But the findings are strong. Next steps include:

  • Prospective studies: Following patients from diagnosis to long-term treatment to confirm MRI patterns.
  • Larger cohorts: Including more patients from diverse backgrounds to see if the patterns hold.
  • Mechanistic research: Figuring out why MADD targets specific muscles (like the soleus)—could it be related to how those muscles use fat for energy?

Conclusion

This 2019 study expands our understanding of late-onset MADD in three key ways:

  1. It reveals distinct MRI patterns (SO+/GA–, BFL+/ST–) that improve diagnosis.
  2. It shows edema (STIR signal) improves quickly with riboflavin—a potential biomarker for treatment response.
  3. It adds new clinical and genetic insights (neuropathy, high homocysteine, novel ETFDH mutations).

For people with MADD, this research means better, faster care. For doctors, it provides a roadmap for using MRI to diagnose and monitor the condition. While MADD is rare, this study proves that even small, focused research can have a big impact on patient lives.

Clinical and muscle magnetic resonance image findings in patients with late-onset multiple acyl-CoA dehydrogenase deficiency. Dao-Jun Hong, Min Zhu, Zi-Juan Zhu, Lu Cong, Shan-Shan Zhong, Ling Liu, Jun Zhang. Chinese Medical Journal. 2019;132(3):275–284. doi.org/10.1097/CM9.0000000000000032

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