What is the evaluation and management approach for a patient with suspected multiple acyl-CoA dehydrogenase (MADD) deficiency?

Evaluation and Management of Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

The diagnosis of Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) requires a comprehensive laboratory evaluation including plasma acylcarnitine profile, urine organic acids, plasma carnitine levels, and in some cases muscle biopsy, followed by genetic testing to confirm the diagnosis. 1

Diagnostic Evaluation

Initial Laboratory Testing

• Plasma acylcarnitine profile - the key diagnostic test showing characteristic patterns of multiple acylcarnitine species 1
• Urine organic acid analysis - typically shows increased dicarboxylic acids and other metabolites 1
• Plasma carnitine levels (free and total) - often decreased or showing abnormal ratios 1
• Serum creatine kinase (CK) and lactate dehydrogenase (LDH) - typically elevated in late-onset forms 2

Sample Collection Considerations

• Preferred sample type for symptomatic patients is plasma or serum 1
• Dried blood spots may increase sensitivity for detecting disorders of long-chain fatty acid oxidation 1
• All samples except dried filter paper specimens should be frozen immediately and shipped on dry ice 1
• Typical testing volume for plasma/serum is 20μL 1

Additional Testing

• Electromyography (EMG) - may show myogenic or neurogenic patterns or be normal 2
• Nerve conduction studies - may reveal sensory neuropathy in some patients 2
• Muscle biopsy - shows vacuolar myopathy with increased lipid content 2
• Nerve biopsy - may show axonal degeneration with loss of myelinated fibers in patients with neuropathic symptoms 2

Genetic Testing

• Sequencing of ETFDH gene - accounts for approximately 93% of late-onset MADD cases 3
• Testing of ETFA and ETFB genes - account for approximately 5% and 2% of cases, respectively 3
• Next-generation sequencing panels may be necessary if targeted gene sequencing is negative 2
• Recently, mutations in FLAD1 gene have been identified in some MADD patients 4

Management Approach

Pharmacological Treatment

• Riboflavin (vitamin B2) supplementation - first-line therapy with nearly 98% of late-onset MADD patients showing response 3
  • Typical dosage: 400 mg/day 2
  • Results in rapid improvement in muscle strength and normalization of laboratory values 2, 4
• L-carnitine supplementation - helps clear toxic acyl-CoA compounds by forming acylcarnitine, which is excreted 5, 6
  • Promotes excretion of excess organic or fatty acids 5

Monitoring Response to Treatment

• Regular assessment of clinical symptoms, particularly muscle strength 2
• Monitoring of laboratory parameters including CK, LDH, and acylcarnitine profile 2, 4
• Repeat muscle biopsy may show improvement in lipid storage 2, 6

Special Considerations

• Neuropathic symptoms may not improve with riboflavin therapy 2
• Some patients may have medication-induced MADD (particularly with sertraline use) that responds to riboflavin but may require discontinuation of the offending medication 7
• Acute metabolic decompensations may occur in approximately 33% of patients and require prompt intervention 3

Clinical Presentation Patterns

• Chronic muscular symptoms (85% of patients) - exercise intolerance, muscle weakness, fatigue 2, 3
• Acute metabolic decompensations (33% of patients) - hypoglycemia, acidosis, encephalopathy, hepatopathy 3
• Combined presentation (20% of patients) - both acute and chronic symptoms 3
• Additional symptoms may include:
  • Difficulties in chewing and dysphagia 2
  • Dropped head syndrome 2
  • Ataxia with numbness and dysesthesia (less common) 2

Diagnostic Pitfalls and Caveats

• Diagnostic delay is common - average 3.9 years from symptom onset to diagnosis 3
• Some patients may not display typical biochemical patterns during periods of wellbeing 3
• Late-onset MADD is likely underdiagnosed and should be considered in all patients with unexplained muscle weakness or metabolic decompensation 3
• Some cases may be acquired rather than genetic, particularly in patients taking sertraline 7
• Genetic testing may be negative despite clinical and biochemical evidence of MADD 7

Early diagnosis and prompt initiation of riboflavin therapy are critical to prevent metabolic decompensations and improve long-term outcomes in patients with MADD.