3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: case report of a child with rare HMGCL gene variants

Milena Bjelica; Aleksandra Stojadinović; Marija Knežević Pogančev; Katarina Koprivšek; Jӧrn Oliver Sass; Sarah C. Grünert; Falko Wünsche; Raina Yamamoto

doi:10.1515/jpem-2025-0156

Artikel

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: case report of a child with rare HMGCL gene variants

Milena Bjelica , Aleksandra Stojadinović , Marija Knežević Pogančev , Katarina Koprivšek , Jӧrn Oliver Sass , Sarah C. Grünert , Falko Wünsche und Raina Yamamoto

Veröffentlicht/Copyright: 13. Juni 2025

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Aus der Zeitschrift Journal of Pediatric Endocrinology and Metabolism Band 38 Heft 9

Abstract

Objectives

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessive organic aciduria. Most patients present within the first year of life with metabolic decompensation, which can cause neurological damage or death if untreated.

Case presentation

A 20-month-old previously healthy boy was admitted to the hospital after a nocturnal seizure. Upon admission, the child was unconscious and laboratory analysis revealed severe hypoglycemia and metabolic acidosis without ketonuria. Hypoglycemia was corrected with a bolus of 10 % glucose followed by continuous glucose-electrolyte infusion. Status epilepticus was treated with midazolam and phenobarbital. Magnetic resonance imaging (MRI) performed on the second hospital day, revealed bilateral and symmetric T2 hyperintense lesions in the cortex, supratentorial white matter, basal ganglia and central pons, along with slight white matter volume reduction. Urinary organic acids indicated HMGCLD. HMG-CoA lyase activity in immortalized lymphocytes was significantly decreased. Sanger sequencing of the HMGCL gene identified a heterozygous sequence variant, c.796T>C, p.(Cys266Arg). MLPA analysis showed a reduced gene dosage for exons 3 and 4 of HMGCL, consistent with a heterozygous deletion. Upon diagnosis, a low-protein diet was recommended, as well as oral l-carnitine therapy with a high-calorie supplement drink at night. Initially, the child had slightly impaired psychomotor development, which normalized by age 3.5. He was without metabolic crises or seizures since diagnosis.

Conclusions

In any child presenting with hypoketotic hypoglycemia and metabolic acidosis of unknown etiology, HMGCLD should be considered. Given the rarity of HMGCLD and its sporadic cases across Europe, management should involve a well-experienced multidisciplinary team.

Keywords: inborn errors metabolism; HMG-CoA lyase; hypoglycemia; seizure; child

Corresponding author: Milena Bjelica, Institute for Child and Youth Health Care of Vojvodina, Novi Sad, Serbia; University of Novi Sad, Faculty of Medicine, Branka Bajića 38, 21000 Novi Sad, Serbia, E-mail: milena.bjelica@mf.uns.ac.rs

Marija Knežević Pogančev: Deceased author.

Funding source: MVZ Dr. Eberhard & Partner Dortmund

Acknowledgments

Research of J.O.S. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project numbers 514177501, 528562393-FIP26, and 538669957.

Research ethics: Ethics approval was obtained from institutional Ethics Committee (EC letter dated 2 October 2024; document ID 4742-4).
Informed consent: Informed consent was obtained from the legal guardian of the patient included in this study.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: MVZ Dr. Eberhard & Partner Dortmund: testing of the parental samples.
Data availability: Not applicable.

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Received: 2025-03-18

Accepted: 2025-06-01

Published Online: 2025-06-13

Published in Print: 2025-09-25

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https://doi.org/10.1515/jpem-2025-0156

Schlagwörter für diesen Artikel

inborn errors metabolism; HMG-CoA lyase; hypoglycemia; seizure; child