Rhabdomyolysis and Respiratory Insufficiency in Late-Onset MADD

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Rhabdomyolysis and Respiratory Insufficiency in Late-Onset MADD: Two Cases Linked to the Common ETFDH c.250G>A Mutation

Imagine having muscle weakness that gets worse with exercise—then being given a standard treatment that makes it life-threatening. That’s what happened to two men in China, whose rare metabolic disease was misdiagnosed as an autoimmune condition. Their story, published by neurologists at Fujian Medical University’s First Affiliated Hospital, highlights the dangers of mismanaging rare disorders and the power of targeted treatments like riboflavin (vitamin B2).

What Is MADD?

Multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM 231680) is a rare genetic disorder that disrupts how the body uses fats, amino acids, and choline for energy. It’s inherited in an autosomal recessive pattern—meaning you need two faulty genes (one from each parent) to develop it. Most people with the late-onset form (type III) have mild symptoms: muscle weakness in the hips/thighs/shoulders (proximal myopathy), exercise intolerance (getting tired quickly), digestive issues (nausea, vomiting), and liver problems. The good news? Up to 90% of late-onset cases are riboflavin-responsive (RR-MADD), meaning high-dose vitamin B2 fixes the enzyme problem.

The root cause? Mutations in the ETFDH gene, which makes an enzyme called electron transfer flavoprotein dehydrogenase. This enzyme is critical for converting fats into energy. In China, the most common ETFDH mutation is c.250G>A—found in over half of RR-MADD patients.

The Patients’ Journeys: Misdiagnosis to Crisis

The two men—46 and 60 years old—had similar stories:

Patient 1 (46-year-old man)

He started with muscle weakness, fatigue, and digestive issues after a cold. He couldn’t stand up from a squat, climb stairs, or chew food. Doctors suspected polymyositis (an autoimmune muscle disease) and gave him high-dose steroids (methylprednisolone, 60 mg/day). His condition worsened: he couldn’t lift his head, swallow, or breathe on his own. Tests showed:

  • Sky-high muscle enzymes (creatine kinase, CK: 23,500 IU/L—normal is 38–174 IU/L), indicating rhabdomyolysis (muscle breakdown).
  • Respiratory failure (low oxygen, high carbon dioxide in blood).
  • Liver damage (elevated ALT/AST enzymes) and fatty liver.

Patient 2 (60-year-old man)

He had shortness of breath, chest pain, and muscle weakness for 8 months. Doctors first diagnosed hypertension and heart failure. When his symptoms worsened—he couldn’t hold his head up, walk, or eat—he was given steroids. Within a week:

  • CK spiked to 16,444 IU/L.
  • Severe rhabdomyolysis (urinary myoglobin: 635 mg/L—normal is undetectable).
  • Life-threatening hyperkalemia (high potassium) and acidosis (blood pH: 7.263).

The Correct Diagnosis: MADD

Both men were finally tested for metabolic disorders. Key clues:

  1. Blood acyl-carnitine profiling: Abnormally high levels of short- and medium-chain acyl-carnitines (C4, C6, C8, C10)—a hallmark of MADD, which prevents the body from breaking down fats.
  2. Muscle biopsy: Vacuoles (tiny sacs) filled with lipid droplets (fat) in muscle fibers—classic for lipid storage myopathies like MADD.
  3. Genetic testing:
    • Patient 1 had a homozygous ETFDH c.250G>A mutation (inherited the same faulty gene from both parents).
    • Patient 2 had a compound heterozygous mutation: c.250G>A + a new variant (c.959C>T).

Muscle MRI confirmed the damage: fatty infiltration (fat replacing muscle) and edema (swelling) in the gluteus maximus and thigh muscles—signs of chronic muscle stress and acute rhabdomyolysis.

The Turnaround: Riboflavin Saves Lives

When doctors stopped the steroids and switched to riboflavin (150 mg/day) + L-carnitine (90 mg/day) + coenzyme Q (60 mg/day), the results were dramatic:

  • Patient 1: Off a ventilator and feeding tube in 1 week. Back to normal strength and daily activities in 3 weeks.
  • Patient 2: Symptom-free and walking independently within 1 month.

Follow-ups showed their muscle enzymes (CK, LDH), liver function, and acyl-carnitine levels returned to normal. Both now take low-dose riboflavin (30 mg/day) and coenzyme Q to prevent relapses.

Why Steroids Made It Worse

Steroids are often used for autoimmune muscle diseases like polymyositis, but they’re dangerous for MADD. Here’s why:

  • Steroids increase oxidative stress (damage from free radicals) when the body is already stressed (from infection, starvation, or fatigue).
  • They push the body into a metabolic crisis: MADD patients rely on carbs for energy—steroids raise blood sugar, but when carbs are low (from poor eating), the body can’t use fats (due to MADD) and breaks down muscle instead (rhabdomyolysis).

Key Takeaways from the Study

This research, published in the Chinese Medical Journal (2019), is the first to link the common ETFDH c.250G>A mutation to life-threatening rhabdomyolysis and respiratory failure in late-onset MADD. Normally, late-onset MADD is mild—but these cases show it can be severe if misdiagnosed.

The biggest lessons:

  1. Think metabolic first: If someone has muscle weakness + exercise intolerance + digestive issues, test for MADD before using steroids.
  2. Riboflavin is a lifesaver: RR-MADD responds quickly to high-dose riboflavin—no need for steroids.
  3. MRI matters: Muscle MRI can show fatty infiltration and edema, helping confirm MADD when biopsies are inconclusive.

The Original Study Details

Hai-Zhu Chen, Ming Jin, Nai-Qing Cai, et al. “Rhabdomyolysis and respiratory insufficiency due to the common ETFDH mutation of c.250G>A in two patients with late-onset multiple acyl-CoA dehydrogenase deficiency.” Chinese Medical Journal 2019;132(13):1615–1618. doi:10.1097/CM9.0000000000000288

For more information on MADD, visit OMIM (Online Mendelian Inheritance in Man) or the National Organization for Rare Disorders (NORD).

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