HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease
ABSTRACT Mitochondrial HMG‐CoA synthase‐2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. We describe two patients with HMGCS2 deficiency....
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Wiley
2025-07-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.70028 |
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| author | Hathaipat Vaseenon Thipwimol Tim‐Aroon Vitchayaporn Emarach Saengow Areeporn Sangcakul Parith Wongkittichote Arthaporn Khongkraparn Duangrurdee Wattanasirichaigoon |
| author_facet | Hathaipat Vaseenon Thipwimol Tim‐Aroon Vitchayaporn Emarach Saengow Areeporn Sangcakul Parith Wongkittichote Arthaporn Khongkraparn Duangrurdee Wattanasirichaigoon |
| author_sort | Hathaipat Vaseenon |
| collection | DOAJ |
| description | ABSTRACT Mitochondrial HMG‐CoA synthase‐2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. We describe two patients with HMGCS2 deficiency. Patient 1 presented on day of life 7 with a sepsis‐like condition, coma, metabolic acidosis, and marked elevation of ammonium level at 1081 μmol/L. Metabolic screening demonstrated elevated valine and leucine/isoleucine concentrations, resembling maple syrup urine disease (MSUD). The patient received a blood exchange transfusion, which lowered the ammonium level to 92 μmol/L. Urine organic acid analysis did not confirm MSUD. At 1 year and 4 months, the patient experienced acute decompensation again. Exome sequencing revealed a homozygous HMGCS2 variant, c.1502G>C (p.Arg501Pro). Patient 2, an older sibling of Patient 1, was healthy but diagnosed through genetic testing. Both patients exhibited abnormal biochemical profiles, including dicarboxylic aciduria and increased urinary excretion of 4‐hydroxy‐6‐methyl‐2‐pyrone (4‐HMP) after 8 h of fasting, suggesting that a clinically asymptomatic patient, like Patient 2, may eventually develop acute decompensation. Therefore, preemptive treatment with fasting avoidance with or without l‐carnitine during intercurrent illness should be advised. The present cases were the second and third patients of p.Arg501Pro homozygosity. The elevated branched‐chain amino acids in the metabolic screening (without including alloisoleucine) and the described organic acid profile can be found during the catabolic state, resembling MSUD, and severe hyperammonemia is an uncommon phenotype and an exception to neonatal decompensation in HMGCS2 deficiency. Our findings demonstrated intrafamilial variability and expanded the clinical and biochemical spectrum of HMGCS2 deficiency. |
| format | Article |
| id | doaj-art-7e3377e7551c4050aae45daa3a438657 |
| institution | DOAJ |
| issn | 2192-8312 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
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| series | JIMD Reports |
| spelling | doaj-art-7e3377e7551c4050aae45daa3a4386572025-08-20T03:08:40ZengWileyJIMD Reports2192-83122025-07-01664n/an/a10.1002/jmd2.70028HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine DiseaseHathaipat Vaseenon0Thipwimol Tim‐Aroon1Vitchayaporn Emarach Saengow2Areeporn Sangcakul3Parith Wongkittichote4Arthaporn Khongkraparn5Duangrurdee Wattanasirichaigoon6Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok ThailandDivision of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok ThailandDepartment of Pediatrics Maharat Nakhon Ratchasima Hospital Nakhon Ratchasima ThailandDepartment of Pathology, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok ThailandDivision of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok ThailandDivision of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok ThailandDivision of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok ThailandABSTRACT Mitochondrial HMG‐CoA synthase‐2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. We describe two patients with HMGCS2 deficiency. Patient 1 presented on day of life 7 with a sepsis‐like condition, coma, metabolic acidosis, and marked elevation of ammonium level at 1081 μmol/L. Metabolic screening demonstrated elevated valine and leucine/isoleucine concentrations, resembling maple syrup urine disease (MSUD). The patient received a blood exchange transfusion, which lowered the ammonium level to 92 μmol/L. Urine organic acid analysis did not confirm MSUD. At 1 year and 4 months, the patient experienced acute decompensation again. Exome sequencing revealed a homozygous HMGCS2 variant, c.1502G>C (p.Arg501Pro). Patient 2, an older sibling of Patient 1, was healthy but diagnosed through genetic testing. Both patients exhibited abnormal biochemical profiles, including dicarboxylic aciduria and increased urinary excretion of 4‐hydroxy‐6‐methyl‐2‐pyrone (4‐HMP) after 8 h of fasting, suggesting that a clinically asymptomatic patient, like Patient 2, may eventually develop acute decompensation. Therefore, preemptive treatment with fasting avoidance with or without l‐carnitine during intercurrent illness should be advised. The present cases were the second and third patients of p.Arg501Pro homozygosity. The elevated branched‐chain amino acids in the metabolic screening (without including alloisoleucine) and the described organic acid profile can be found during the catabolic state, resembling MSUD, and severe hyperammonemia is an uncommon phenotype and an exception to neonatal decompensation in HMGCS2 deficiency. Our findings demonstrated intrafamilial variability and expanded the clinical and biochemical spectrum of HMGCS2 deficiency.https://doi.org/10.1002/jmd2.70028HMGCS2hyperammonemiahypoglycemiametabolic acidosis |
| spellingShingle | Hathaipat Vaseenon Thipwimol Tim‐Aroon Vitchayaporn Emarach Saengow Areeporn Sangcakul Parith Wongkittichote Arthaporn Khongkraparn Duangrurdee Wattanasirichaigoon HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease JIMD Reports HMGCS2 hyperammonemia hypoglycemia metabolic acidosis |
| title | HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease |
| title_full | HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease |
| title_fullStr | HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease |
| title_full_unstemmed | HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease |
| title_short | HMG‐CoA Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease |
| title_sort | hmg coa synthase 2 deficiency neonatal hyperammonemic coma and abnormal metabolic screening resembling maple syrup urine disease |
| topic | HMGCS2 hyperammonemia hypoglycemia metabolic acidosis |
| url | https://doi.org/10.1002/jmd2.70028 |
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