A 3‐Month‐Old Boy With Progressive Weakness

Clinical History

A 3‐month‐old boy was referred to our hospital because of slowly progressing weakness, which commenced a month earlier. He was delivered normally from an uneventful pregnancy from nonconsanguineous parents. A neonatal screening test had revealed mildly increased serum carnitine, which was normal in a repeated test. He showed generalized hypotonia with an absence of deep tendon reflexes and a lagged head on neurological examination. During the admission, respiratory muscle weakness progressed and he became dependent on mechanical ventilation with tracheal fenestration. Laboratory tests were unremarkable except for increased aspartate aminotransferase (154 IU/L), alanine aminotransferase (68 IU/L), and creatinine kinase (478 U/L) levels. Multiplex ligation‐dependent probe amplifications for SMN1/SMN2, the causative gene for spinal muscular atrophy (SMA) type I, revealed no deletion or duplication. He had additional tests, including metabolic screening, brain MRI, and muscle biopsy. Brain MRI was unremarkable for his age, whereas metabolic screening revealed elevated glutaric acid and ethylmalonic acid in his urine, and elevated plasma C14, C14:1, and C16:1 carnitines.

Pathology

A muscle biopsy was performed on his left quadriceps. The fibers diameters were remarkably variable. There were many degenerating and regenerating muscle fibers without inflammatory cell infiltration. There was no evidence of fiber type predominance. Many droplet‐like structures within muscle fibers were observed on H&E staining (Figure 1A), which appeared as red spots in Oil Red O staining (Figure 1B). What kind of storage myopathy is this?

Figure 1.

Although the pathologic findings are non‐specific, when combined with the metabolic abnormalities found in the urine and plasma a more specific diagnosis should be suspected. What is the most likely diagnosis and which three genes need to be tested for mutations?

Diagnosis

This is a 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 (Fig 2)

Figure 2.

Final diagnosis

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

Discussion

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.