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Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis.
JIMD Rep. 2020 Sep; 55(1):26-31.JR

Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG Co-A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20-month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4-hydroxy-6-methyl-2-pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3-hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the HMGCS2 gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge.

Authors+Show Affiliations

National Centre for Inherited Metabolic Disorders Children's Health Ireland at Temple Street Dublin Ireland. School of Medicine University College Dublin Dublin Ireland.Department of Paediatric Laboratory Medicine Children's Health Ireland at Temple Street Dublin Ireland.Department of Paediatric Laboratory Medicine Children's Health Ireland at Temple Street Dublin Ireland.Department of Paediatric Intensive Care Children's Health Ireland at Temple Street Dublin Ireland.School of Medicine University College Dublin Dublin Ireland. Department of General Paediatrics Children's Health Ireland at Temple Street Dublin Ireland.National Centre for Inherited Metabolic Disorders Children's Health Ireland at Temple Street Dublin Ireland. School of Medicine University College Dublin Dublin Ireland.National Centre for Inherited Metabolic Disorders Children's Health Ireland at Temple Street Dublin Ireland. School of Medicine University College Dublin Dublin Ireland.

Pub Type(s)

Case Reports

Language

eng

PubMed ID

32905056

Citation

Conlon, Tracey A., et al. "Hypoglycemia Is Not a Defining Feature of Metabolic Crisis in Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency: Further Evidence of Specific Biochemical Markers Which May Aid Diagnosis." JIMD Reports, vol. 55, no. 1, 2020, pp. 26-31.
Conlon TA, Fitzsimons PE, Borovickova I, et al. Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis. JIMD Rep. 2020;55(1):26-31.
Conlon, T. A., Fitzsimons, P. E., Borovickova, I., Kirby, F., Murphy, S., Knerr, I., & Crushell, E. (2020). Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis. JIMD Reports, 55(1), 26-31. https://doi.org/10.1002/jmd2.12146
Conlon TA, et al. Hypoglycemia Is Not a Defining Feature of Metabolic Crisis in Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency: Further Evidence of Specific Biochemical Markers Which May Aid Diagnosis. JIMD Rep. 2020;55(1):26-31. PubMed PMID: 32905056.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis. AU - Conlon,Tracey A, AU - Fitzsimons,Patricia E, AU - Borovickova,Ingrid, AU - Kirby,Fidelma, AU - Murphy,Sinéad, AU - Knerr,Ina, AU - Crushell,Ellen, Y1 - 2020/06/30/ PY - 2019/12/17/received PY - 2020/05/25/revised PY - 2020/05/27/accepted PY - 2020/9/9/entrez PY - 2020/9/10/pubmed PY - 2020/9/10/medline KW - 3‐hydroxyglutarate (3HG) KW - 4‐hydroxy‐6‐methyl‐2‐pyrone (4HMP) KW - HMG‐CoA synthase deficiency KW - hypertriglyceridemia KW - hypoglycemia KW - ketogenesis SP - 26 EP - 31 JF - JIMD reports JO - JIMD Rep VL - 55 IS - 1 N2 - Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG Co-A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20-month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4-hydroxy-6-methyl-2-pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3-hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the HMGCS2 gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge. SN - 2192-8304 UR - https://www.unboundmedicine.com/medline/citation/32905056/Hypoglycemia_is_not_a_defining_feature_of_metabolic_crisis_in_mitochondrial_3-hydroxy-3-methylglutaryl-CoA_synthase_deficiency:_Further_evidence_of_specific_biochemical_markers_which_may_aid_diagnosis. L2 - https://dx.doi.org/10.1002/jmd2.12146 DB - PRIME DP - Unbound Medicine ER -
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