A MADD Case of Hypoglycaemia — ASN Events
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A MADD Case of Hypoglycaemia (#439)

Rosalyn Ly 1 2 , Michelle So 1 3 4 , Thuy Vu 1 2 3
  1. Endocrinology, Northern Health, Epping, Victoria, Australia
  2. Endocrinology, Austin Health, Heidelberg, Victoria, Australia
  3. University of Melbourne, Austin Health, Melbourne, Victoria, Australia
  4. Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia

A woman in her 30s presented with loss of consciousness and a capillary blood glucose level (BGL) of 3.0 mmol/L which resolved with oral glucose and apple juice. She had a one-year history of recurrent weakness, dizziness, hunger and a distinctive “acetone” taste relieved with carbohydrate ingestion, alongside a 6-kilogram weight gain. Family history included a grandfather with diabetes mellitus and a mother with unexplained hypoglycaemic episodes in her 30s. Medical history included migraines and anxiety treated with sertraline 100 mg daily.

A 72-hour fast demonstrated a BGL of 3.0 mmol/L with appropriately suppressed C-peptide of 97 pmol/L and elevated β-hydroxybutyrate. Sulphonylurea and diabetes antibody screen were negative. Investigations for glycogen storage disorders, including urate, lactate, creatine kinase, liver function test and lipid studies were unremarkable. Serial acylcarnitine profiling showed persistently raised C8 and C10 with an elevated C8/C10 ratio. Amino acid profile, urine organic acids, free fatty acids, carnitine fractions and vitamin B2 were largely normal.

Multiple acyl-CoA dehydrogenase deficiency (MADD) was thought to explain her recurrent hypoglycaemia and genetic testing is currently pending. Sertraline cessation was recommended but declined by the patient. Current management consists of high-dose riboflavin supplementation (100-200 mg/day), dietary modification and avoidance of prolong fasting.

MADD is a rare autosomal recessive disorder of fatty acid and amino acid oxidation caused by dysfunction of electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase1, with an incidence of 1:250,0002. Dysfunction results in accumulation of toxic metabolic intermediates, depletion of acetyl-CoA and reduced ATP production, leading to hypoglycaemia, metabolic acidosis, myopathy, cardiomyopathy, neuropathy and hepatic dysfunction1. Presentation varies in Type III (Late-onset) MADD, typically featuring muscle weakness, exercise intolerance and episodic rhabdomyolysis3,4,5 with no formal diagnostic criteria1.

This case highlights an atypical MADD presentation and emphasises the importance of considering inherited fatty acid oxidation disorders in adults with unexplained hypoglycaemia

  1. Prasun P. Multiple Acyl-CoA Dehydrogenase Deficiency. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; June 18, 2020.
  2. Schulze A, Lindner M, Kohlmüller D, Olgemöller K, Mayatepek E, Hoffmann GF. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics. 2003;111(6 Pt 1):1399-1406. doi:10.1542/peds.111.6.1399
  3. Meier C, Burns K, Manolikos C, Hodge S, Bell DA. Multiple acyl-Coa dehydrogenase deficiency: an underdiagnosed disorder in adults. Intern Med J. 2024;54(9):1567-1571. doi:10.1111/imj.16473
  4. Lupica A, Oteri R, Volta S, et al. Diagnostic Challenges in Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency: Clinical, Morphological, and Genetic Aspects. Front Neurol. 2022;13:815523. Published 2022 Mar 3. doi:10.3389/fneur.2022.815523
  5. Zhang H, Ma J, Su M, et al. The difference of variation types between late-onset multiple acyl-CoA dehydrogenase deficiency patients carrying biallelic and single heterozygous variations in ETFDH: a systematic review and meta-analysis. Orphanet J Rare Dis. 2025;20(1):310. Published 2025 Jun 18. doi:10.1186/s13023-025-03845-7