The synergy of different methods for the final diagnosis of MCADD in Slovenian patient
2Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Slovenia
Background
Medium-chain acyl-coenzyme dehydrogenase deficiency (MCADD) is the most common congenital disorder of fatty acid metabolism (OMIM #201450) and is inherited in an autosomal recessive manner. MCADD is caused by homozygous or compound heterozygous changes in the ACADM gene, which encodes the medium-chain acyl-CoA dehydrogenase (MCAD). Hypoketotic hypoglycemia, vomiting, seizures, and coma provoked by fasting, catabolic stress, or common illness are clinical symptoms of MCADD.
We present the case of a 2-year-old female patient with MCADD and the path to a final diagnosis.
Case report
The female patient was admitted to the hospital due to persistent vomiting, dehydration, and lethargy caused by viral infections. Analysis of organic acids in urine using gas chromatography/mass spectrometry (GC/MS) showed the presence of hexanoylglycine and suberylglycine, laboratory markers of MCADD. In addition, analysis of the acylcarnitine profile using tandem mass spectrometry (MS/MS) revealed a characteristic pattern with elevated levels of octanoylcarnitine (C8), decanoylcarnitine (C10), and decenoylcarnitine (C10:1).
However, next-generation sequencing detected only a single pathologic heterozygous variant in exon 5 of the ACADM gene (a novel variant, c.353G>T, p.Gly118Val).
The activity of MCAD in the patient`s lymphocytes was measured and was below the limit of quantification. This confirmed the diagnosis of MCADD, however, without a known genetic cause.
The next step was to identify possible major changes in the second allele of the ACADM gene, which were not determined by sequencing.
Copy number variation analysis using a consensus of multiple calling tools (gatk, cnvkit, exomecopy, manta) showed a heterozygous deletion of exons 1 and 2 of the ACADM gene. The deletion was confirmed using multiplex ligation-dependent probe amplification (MLPA) analysis and revealed deletion of at least 3.9 kb in the chromosomal region 1p31.
Conclusion
We present a case of an MCADD patient caused by a novel variant in the ACADM gene combined with a rare deletion of exons 1–2, and the use of a multidisciplinary approach using a combination of several different methods to conclusively determine the final diagnosis.
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