Final Diagnosis -- Lipid Storage Myopathy (LSM)


Lipid Storage Myopathy (LSM)

Genetically, there are four types of LSMs: primary carnitine deficiency (PCD), multiple acyl-coenzyme A dehydrogenase deficiency (MADD), neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. The finding of elevated glutaric and ethylmalonic acids in his urine and the elevated plasma carnitines would strongly suggest MADD which results from mutations in Electron Transport Flavoprotein (ETF)-A, ETF-B, or ETF-dehydrogenase (ETFDH) genes. Genetic testing revealed compound heterozygous variants of c.1286G>A (p.G429E) and c.1506delC (p.C502*) in ETFDH. Both are novel variants. The G429E mutations was from his mother, and the C502* from his father (Figure 2)


Multiple acyl-CoA dehydrogenase deficiency (MADD), late onset: with novel mutations of ETFDH.


Multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM No. 231680) or glutaric aciduria type II is a very rare autosomal recessive lipid storage myopathy caused by a defect in one of the electron transfer flavoproteins (ETF or ETFDH), encoded by ETFA, ETFB, and ETFDH. MADD has been classified into 3 subtypes. The early onset form (type I or II) presents with severe metabolic acidosis and cardiomyopathy from birth, and subsequent early death (4). By contrast, late onset (type III) MADD shows a highly variable age of onset and clinical course, from early infancy to late adulthood, and from acute metabolic crisis to chronic deterioration or intermittent decompensated events (2), which makes early diagnosis of late onset MADD very challenging. In this case, the patient developed normally until the age of 3 months, and generalized hypotonia and progressive weakness followed from 3 months of age without any other clinical features or suspicious symptoms of metabolic disease. Although his symptoms and laboratory findings were concordant with late onset MADD at his age (4), his initial clinical features were also not discordant with more common early onset neuromuscular disorders such as congenital muscular dystrophy or spinal muscular atrophy. That led us to suspect SMA type I at first, but basic investigations including a genetic test were all within normal limits. We decided to perform a muscle biopsy and additional metabolic screening at a very early stage, which offered us a chance for early diagnosis and to start appropriate treatment.

Muscle biopsy has been changed to a second-line diagnostic tool, especially in infancy, in response to advances in genetic technology, such as target gene panels or whole exome sequencing (3). However, in this case, early muscle biopsy provided a key clue for diagnosis, which helped us to avoid diagnostic delay. The patient was able to be treated from 5 months of age with riboflavin, which is a well-proven treatment option (1, 2), and he showed catch-up growth and a dramatic improvement in muscle power, all underscoring the crucial role of early diagnosis and treatment.

In conclusion, we present a rare case of late onset MADD with novel mutations of ETFDH that could be properly treated due to early diagnosis by muscle biopsy.


We thank the patient's family for allowing us to report this case.


  1. Gregersen N, Wintzensen H, Christensen SK, Christensen MF, Brandt NJ, Rasmussen K (1982) C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects. Pediatric research.16(10):861-8.
  2. Grunert SC (2014) Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet journal of rare diseases.9:117.
  3. O'Grady GL, Lek M, Lamande SR, Waddell L, Oates EC, Punetha J, Ghaoui R, Sandaradura SA, Best H, Kaur S, Davis M, Laing NG, Muntoni F, Hoffman E, MacArthur DG, Clarke NF, Cooper S, North K (2016) Diagnosis and aetiology of congenital muscular dystrophy: we are halfway there. Annals of neurology.
  4. Scriver CR, Beauder AL, Sly WS, Valle D (2001) The metabolic and molecular vases of inherited disease. 8 Edition, McGraw-Hill: New York.

Contributed by Soo Yeon Kim, Jung Min Ko, Sun Ah Choi, Anna Cho, Jin Sook Lee, Byung Chan Lim, Ki Joong Kim, Jong-Hee Chae

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