Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): A Case Report With a Complex Biochemical Profile

Area of Science:

• Biochemistry
• Genetics
• Neurology
• Metabolic Disorders

Background:

• Multiple acyl-CoA dehydrogenase deficiency (MADD) presents with diverse clinical phenotypes, including severe neonatal and later-onset forms.
• The later-onset MADD typically involves muscle symptoms like exercise intolerance and weakness, often with altered acylcarnitine profiles.
• Atypical presentations of MADD can challenge diagnosis through conventional biochemical screening.

Purpose of the Study:

• To report a unique case of adult-onset MADD presenting initially with severe psychiatric manifestations and malnutrition.
• To highlight the diagnostic utility of whole exome sequencing (WES) when biochemical tests are inconclusive for MADD.
• To demonstrate the efficacy of vitamin B2 supplementation in treating MADD diagnosed via genetic analysis.

Main Methods:

• Detailed clinical case presentation of a 33-year-old woman with progressive muscle weakness, fatigue, ptosis, and rhabdomyolysis.
• Comprehensive biochemical investigations including acylcarnitine profile, urinary organic acid analysis, and in vitro beta-oxidation assays.
• Whole exome sequencing (WES) to identify the genetic basis of the suspected metabolic disorder.

Main Results:

• Standard biochemical tests were inconclusive for MADD, despite the patient's severe clinical presentation.
• WES identified two novel pathogenic variants in the ETFDH gene, confirming a diagnosis of MADD.
• Vitamin B2 supplementation resulted in rapid clinical improvement of muscle weakness and other symptoms.

Conclusions:

• Genetic diagnosis, particularly WES, is crucial for identifying MADD when biochemical markers are atypical or absent.
• ETFDH gene variants can lead to late-onset MADD with unusual initial psychiatric and severe muscle symptoms.
• Early genetic diagnosis enables timely initiation of cofactor supplementation, significantly improving patient outcomes in MADD.