Timely intervention in HMG-CoA Lyase deficiency: The role of newborn screening, metabolic management, and genomic sequencing

Résumé fourni par la source

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is a rare autosomal recessive metabolic disease caused by variants in the HMGCL gene leading to an impairment in leucine catabolism and ketone synthesis. In the United States, HMG-CoA lyase deficiency is listed on the recommended uniform screening panel as a core condition for newborn screening. A positive newborn screen will typically show an elevation of C5-hydroxylated species on the acylcarnitine profile using a dried-blood spot collected between 24 and 48 h of life. Initial follow-up testing generally includes a plasma acylcarnitine profile and a urine organic acid profile. Clinically, this metabolic alteration can lead to severe metabolic decompensation, presenting as hypoketotic hypoglycemia and, when left untreated, potential long-term neurological impairments. This report highlights the case of a 38-day-old male with an initial abnormal newborn screen. Follow-up testing showed moderate elevations of C5-hydroxylated and C6-dicarboxylated species on the plasma acylcarnitine profile and marked elevations of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric and 3-hydroxyisovaleric acid detected by urine organic acid analysis. These findings were consistent with a biochemical diagnosis of HMG-CoA lyase deficiency. Confirmatory molecular testing included targeted HMGCL sequencing including deletion/duplication analysis; the results of which were negative. Genome sequencing was then requested which identified a deep intronic complex variant of unknown significance within intron 1 of HGMCL . RNA sequencing studies were sent as follow-up which revealed that the level of expression of the HMGCL gene was negligible in comparison with tissue-matched controls, thus confirming the biochemical diagnosis of HMG-CoA lyase deficiency.

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