Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 deficiency with severe hyperglycemia in a child: A rare case report

Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) deficiency is an exceptionally rare autosomal recessive metabolic disorder that impairs ketogenesis. It is typically characterized by hypoketotic hypoglycemia during periods of fasting or metabolic stress. Notably, severe hyperglycemia as an initial presenting symptom has not been previously reported. We report the case of a 6-month-old girl who suddenly developed coma after 1 day of fasting due to repeated vomiting during pneumonia. At presentation, she had hyperglycemia (25.8 mmol/L), ketonuria (1+), glucosuria (3+), metabolic acidosis (pH 6.90), elevated serum alanine transaminase and aspartate aminotransferase levels, increased blood ammonia levels, and liver enlargement on ultrasound. However, fasting insulin, glucagon, and glycated hemoglobin levels were all within the normal range. Whole-exome sequencing identified compound heterozygous mutations in the HMGCS2 gene—c.1175C>T (p.S392L) inherited from the father and c.719A>T (p.A240V) inherited from the mother—thereby confirming the diagnosis of HMGCS2 deficiency. This case highlights severe hyperglycemia as an atypical clinical feature of HMGCS2 deficiency. Increased awareness of such rare manifestations may assist in improving early diagnosis and treatment of this condition.

Introduction

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) deficiency is an exceptionally rare autosomal recessive metabolic disorder that impairs the production of ketone bodies during periods of fasting or metabolic stress. ¹ HMGCS2, encoded by the HMGCS2 gene, is a critical enzyme in the ketogenic pathway, catalyzing the condensation of acetyl-coenzyme A and acetoacetyl-coenzyme A to form 3-hydroxy-3-methylglutaryl-coenzyme A. ² This reaction represents the first step in ketogenesis, providing an essential alternative energy source for the brain and other tissues when glucose availability is limited.

Clinically, HMGCS2 deficiency typically presents in early infancy with episodes of hypoketotic hypoglycemia, metabolic acidosis, and coma. ³ These episodes arise due to an inability to generate adequate ketone bodies, forcing the body to rely heavily on glucose, which can be rapidly depleted, particularly in infants with limited glycogen stores. ³ Although hypoketotic hypoglycemia remains the canonical metabolic hallmark of HMGCS2 deficiency, scattered case reports over the past 2 years have challenged this paradigm by documenting normoglycemia or even frank hyperglycemia during acute decompensation. For instance, Li et al. ⁴ reported the case of an infant whose plasma glucose level plateaued at 15.8 mmol/L—the then highest value recorded in the literature—despite classic laboratory evidence of impaired ketogenesis. Here, we describe a unique case of HMGCS2 deficiency in an infant who presented with severe hyperglycemia as the initial symptom. By highlighting this atypical presentation, we aim to enhance clinical awareness and diagnostic vigilance, underscoring the need to consider HMGCS2 deficiency when encountering metabolic disturbances during a hyperglycemic crisis.

Case description

Presentation and initial examination

A 6-month-old girl was admitted to The Affiliated Suqian Hospital of Xuzhou Medical University (Suqian, China) in February 2024 in a comatose state. Prior to the onset of coma, she was diagnosed with pneumonia, presenting with cough and fever, and was receiving amoxicillin antibiotic therapy. In addition, she experienced multiple episodes of vomiting on the day before admission. Initially, the vomitus consisted of yellow fluid, which progressively changed to a coffee-ground appearance. Following vomiting episodes, the child did not consume food or fluids.

Upon admission, the patient presented with a body temperature of 37.1°C, blood pressure of 85/51 mmHg, and Kussmaul respirations. Auscultation revealed bilateral lung crackles, but the cardiac examination was unremarkable. The liver was palpable 3 cm below the costal margin. The neck was supple, and Kernig and Brudzinski signs were absent.

Past and family history

This was the first comatose episode reported in this patient. She was born at full term via a spontaneous vaginal delivery, which was her mother’s first pregnancy and delivery. No abnormalities were observed in the amniotic fluid, placenta, or umbilical cord, and the birth was free of trauma or asphyxia. The Apgar scores were 9 at 1 min and 10 at 5 min, and her birth weight was 3200 g. The parents are nonconsanguineous and in good health, and prenatal examinations during the mother’s pregnancy revealed no abnormalities.

Laboratory findings

Arterial blood gas analysis revealed a pH of 6.90 (normal value: 7.35–7.45), arterial partial pressure of carbon dioxide (PaCO₂) of 10.4 mmHg (normal value: 35–45 mmHg), lactate level of 0.8 mmol/L (0.5–2.5 mmol/L), ${\text{HCO}}_3^{-}$ level of 3.0 mmol/L (normal value: 22–26 mmol/L), anion gap of 31.1 mmol/L (normal value: 12–20 mmol/L), and base excess of −25.0 mmol/L (normal value: −3 to 3 mmol/L). Urinalysis revealed ketonuria (1+) and glucosuria (3+). Additional laboratory results from peripheral blood included a white blood cell count of 15.56 × 10⁹/L (normal value 4–10 × 10⁹/L), hemoglobin level of 91 g/L (normal value: 110–160 g/L), alanine transaminase level of 98.5 U/L (normal value: 7–40 U/L), aspartate aminotransferase level of 141.6 U/L (normal value: 13–45 U/L), sodium level of 128.93 mmol/L (normal value: 135–145 mmol/L), potassium level of 3.65 mmol/L (normal value: 3.5–5.5 mmol/L), calcium level of 1.71 mmol/L (normal value: 2.10–2.80 mmol/L), blood glucose level of 25.8 mmol/L (normal value: 3.9–6.1 mmol/L), blood ammonia level of 230.1 μmol/L (normal value: 18–72 μmol/L), and fibrinogen level of 0.91 g/L (normal value: 2.0–4.0 g/L). Endocrine and metabolic indices were within normal limits: fasting insulin level, 20.92 mU/L (normal value: 5–25 mU/L); glucagon level, 122.26 pg/mL (normal value: 0–200 pg/mL); glycated hemoglobin level, 5.1% (normal value: 4%–6%); total cholesterol level, 4.43 mmol/L (normal value: 3–5.7 mmol/L); and triglyceride level, 1.65 mmol/L (normal value: 0.1–1.7 mmol/L). Tandem mass spectrometry revealed decreased levels of several amino acids in the blood, whereas gas chromatography–mass spectrometry detected no abnormalities in urinary organic acids.

Imaging

Chest radiography revealed bronchopneumonia in both lungs, and abdominal ultrasonography revealed a mildly enlarged liver with increased echogenicity.

Treatment and clinical course

For treatment, insulin was immediately administered via continuous infusion at a rate of 0.1 U/kg/h to reduce the blood glucose level. Additionally, cefotaxime was initiated as anti-infective therapy. The blood glucose level was closely monitored, and fluid and electrolyte balances were maintained. Within 1 day, the acidosis resolved, the blood glucose level normalized, and the patient regained consciousness with stable vital signs, allowing suspension of insulin therapy.

Genetic testing

With informed consent from the parents and approval from the Ethics Committee of The Affiliated Suqian Hospital of Xuzhou Medical University (Suqian, China; approval number XMSQ-2024-081, dated 26 March 2024), whole-exome sequencing was performed, and the findings were validated in the parents using Sanger sequencing. Compound heterozygous mutations were identified in HMGCS2: c.1175C>T, leading to the amino acid substitution p.S392L (inherited from the father, Figure 1(a)) and c.719A>T, leading to the amino acid substitution p.A240V (inherited from the mother, Figure 1(b)).

Figure 1.

Sanger validation of HMGCS2 gene variants in the proband and her parents. (a) The HMGCS2 mutation c.1175C>T in the proband was inherited from her father and (b) The HMGCS2 mutation c.719A>T in the proband was inherited from her mother.

Follow-up

The final diagnoses were bronchopneumonia and HMGCS2 deficiency. The patient was followed up for 1 year after discharge, during which no similar episodes recurred. Notably, during this period, she had no dietary restrictions or pharmacological treatment, and serial measurements of blood glucose, alanine aminotransferase, aspartate aminotransferase, and plasma ammonia remained within the normal range. At the 12-month visit, growth parameters were appropriate for age (weight, 72nd percentile; length, 64th percentile).

Written informed consent for treatment and publication of the clinical details and genetic findings was obtained from the patient’s parents. The reporting of this study conforms to the Case Report (CARE) guidelines. ⁵

Discussion

HMGCS2 deficiency is an exceptionally rare autosomal recessive disorder of ketogenesis, with fewer than 100 cases reported worldwide. Historically, hypoketotic hypoglycemia has been widely regarded as a typical clinical feature of HMGCS2 deficiency. ³ An increasing number of case reports have shown that some children with this disorder do not present with hypoglycemia, ⁶ with one case even exhibiting hyperglycemia, ⁴ which was also observed in this patient. Our patient had severe hyperglycemia, with a blood glucose level reaching 25.8 mmol/L, far exceeding the previously reported maximum of 15.8 mmol/L in cases of HMGCS2 deficiency. ⁴ This atypical presentation closely mimics diabetic ketoacidosis (DKA), a condition commonly seen in pediatric diabetes mellitus, in which 30%–50% of children present with DKA as the initial manifestation. ⁷ However, several discordant findings—mild ketonuria despite marked acidosis, normal insulin concentrations, pronounced hyperammonemia, hepatomegaly, and markedly elevated transaminases—suggested an underlying metabolic disorder beyond classic DKA. Severe metabolic acidosis accompanied by a low lactate level suggests the absence of significant tissue hypoxia. In addition, tandem mass spectrometry revealed decreased levels of several amino acids, while gas chromatography–mass spectrometry detected no abnormalities in urinary organic acids, thereby excluding common organic acidemias. Subsequent whole-exome sequencing identified compound heterozygous mutations in HMGCS2, confirming the diagnosis. Taken together, these findings indicate that a normal urinary organic acid profile does not exclude HMGCS2 deficiency and that the diagnosis should be considered in the appropriate clinical context.

Unlike DKA, where hyperglycemia arises from insulin deficiency, leading to unchecked gluconeogenesis and glycogenolysis, the primary mechanism of HMGCS2 deficiency involves impaired ketogenesis. ² The exact mechanism underlying severe hyperglycemia remains unclear; however, we hypothesize that it may be related to excessive gluconeogenesis. During infection, vomiting, or other metabolic stress states, the body releases significant amounts of stress hormones such as cortisol, adrenaline, and growth hormone. ⁸ These hormones markedly promote the conversion of amino acids to carbohydrates, leading to an elevated blood glucose level. ⁸ In this case, ketonuria (1+) and an elevated blood ammonia level may have served as indirect evidence. In addition to stress hormone–mediated gluconeogenesis, infection-related insulin resistance may play a contributory role. During acute infections, proinflammatory cytokines can impair insulin signaling, reducing peripheral glucose uptake and exacerbating hyperglycemia. ⁹ However, further studies are required to confirm this hypothesis.

Insulin was administered during the acute phase of HMGCS2 deficiency, as suggested by Li et al., ⁴ which resulted in significant clinical improvement. Due to impaired ketogenesis, fatty acids continue to undergo β-oxidation, leading to the production of substantial acidic metabolic byproducts and exacerbating acidosis. Insulin induces the synthesis of acetyl-coenzyme A carboxylase, fatty acid synthase, and citrate lyase and promotes the dephosphorylation of acetyl-coenzyme A carboxylase, thereby enhancing its enzymatic activity.^10,11 This stimulation facilitates fatty acid synthesis, reduces the accumulation of acidic substances, and assists in correcting acidosis. Additionally, the patient had an elevated blood ammonia level, with protein catabolism as the primary source of ammonia. This process facilitates anabolic metabolism and inhibits the breakdown of proteins to amino acids, ¹² thereby reducing the production of blood ammonia. However, insulin administration can induce hypoglycemia and hypokalemia, and patients with HMGCS2 deficiency are particularly susceptible to hypoglycemia. ¹³ Therefore, careful monitoring and maintenance of normal blood glucose and potassium levels are crucial.

Most patients with HMGCS2 deficiency have a favorable prognosis following treatment, although occasional cases may present with developmental delays secondary to brain injury. ¹⁴ The patient was followed up for 1 year, during which no recurrence or developmental delays were observed. However, given that HMGCS2 deficiency was first identified and reported in 1997, long-term clinical data remain limited. In this context, the underlying genetic variants may hold prognostic value. The c.1175C>T (p.S392L) variant identified in our patient has previously been reported as a pathogenic variant and is known to result in complete loss of enzymatic activity, as demonstrated by in vitro functional assays. ¹⁵ Conversely, the c.719C>T (p.A240V) variant is novel and has not been functionally characterized to date. The uncertain pathogenicity of this variant raises questions regarding its potential contribution to long-term outcomes, underscoring the importance of continued clinical monitoring and strict avoidance of metabolic stressors such as prolonged fasting, infections, and excessive physical exertion.

This case underscores the clinical variability of HMGCS2 deficiency and highlights the potential for an atypical presentation, such as hyperglycemia. Early recognition and genetic confirmation are essential to prevent misdiagnosis and implement appropriate metabolic management.