3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency in an adolescent male: a case report and narrative review of Chinese patients

Abstract

Objectives

This study aimed to examine the clinical characteristics of Chinese patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGLD) and identify the prevalent mutations in the HMGCL gene among these patients.

Methods

The clinical features, biochemical parameters, imaging findings, and genetic variations in 16 previously documented Chinese patients with HMGLD, along with one newly reported case in this study, were comprehensively analyzed.

Results

Within the cohort of Chinese patients with HMGLD, 76.5% were diagnosed during infancy, while 35.3% were identified through newborn screening protocols. Acute metabolic disturbances were reported in 88.2% of patients, with neurological manifestations—particularly coma and unconsciousness—presenting as the initial symptoms in 58.9% of cases, and vomiting occurring in 52.9%. Imaging revealed white matter abnormalities in 47.1% of patients and basal ganglia alterations in 17.6%. The homozygous c.122G > A mutation emerged as the predominant genetic variant among Chinese patients with HMGLD, followed by the c.252 + 1G > A mutation.

Conclusions

HMGLD is a rare metabolic disorder with significant mortality rates, highlighting the necessity for early diagnosis to prevent metabolic crises. This study is the first to report a case of adolescent-onset HMGLD and characterize the clinical presentation of Chinese patients with the disorder. The study additionally identified a novel homozygous c.133 C > T/p.Gln45Ter mutation in the HMGCL gene.

Introduction

The deficiency of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMG-CoA lyase (HL) deficiency, HMGLD; OMIM 246450) is a rare autosomal recessive inborn error of leucine catabolism or ketone body synthesis, characterized by acute episodes of hypoglycemia, hypoketosis, metabolic acidosis, hyperhomocysteinemia, hyperammonemia, and seizures. These episodes are frequently triggered by inadequate feeding, fasting, or infection, and can potentially lead to coma or death [1–9]. The condition affects fewer than one in 100,000 live births [10]. Although HMGLD is more prevalent in Saudi Arabia, the precise incidence rates remain to be determined [10]. Approximately 200 cases have been documented to date, following the first case reported by Faull in 1976 [3]. Although clinical onset typically occurs in infancy or early childhood, four cases of adult diagnosis have been reported, at ages of 23, 29, 36, and 54 years [11–14], and no cases of onset during puberty have been documented to date.

This study is the first to document a case of an adolescent male with HMGLD presenting with leukoencephalopathy and hyperammonemia, which are previously unreported manifestations.

Given the rarity of HMGLD, documented cases in China remain limited and geographically dispersed. The present study examined the characteristics of Chinese patients with HMGLD through a comprehensive review of the clinical symptoms, biochemical findings, genetic mutations, and disease progression, and the results are described hereafter.

Methods

The present study describes a new case of HMGLD and provides a comprehensive review of data for 16 Chinese patients with HMGLD reported in previous studies. The clinical data for all the patients are presented in Table 1, with Patient 17 representing the new case described in this study.

Table 1.

Chinese patients with HMG-CoA lyase deficiency in the literature and this study

ID	Year	Sex	HMGCL variant (c.)	Protein change (p.)	Age at onset	Age at diagnosis	Leukoencephalopathy	clinical symptom/clinical features	Outcome	Follow-up findings
P1 [1]	2023	M	c.122G > A Hom	R41Q	5 y	7 y	+	Hypoglycemia, Lactic acidosis, Metabolic acidosis, Hyperammonemia, Impaired liver function, seizures, delayed development	S	Delayed development
P2 [1]	2023	M	c.122G > A Hom	R41Q	10 d	3 m	+	Hypoglycemia, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting	S	Normal development
P3 [1]	2023	F	c.1452 A > G /c.590G > A	NR/ C197Y	1 m	1 m	-	Hypoglycemia, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting, lethargy	D	/
P4 [1]	2023	F	c.697 C > T Hom	H233Y	AS	NBS	-	-	S	Normal development
P5 [1]	2023	M	NR	/	2 y	NBS	-	Hypoglycemia, Lactic acidosis, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting, seizures,	S	Normal development
P6 [1]	2023	F	NR	/	8 m	NBS	-	Hypoglycemia, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting, seizures, lethargy, hypothyroidism	D	/
P7 [2]	2021	M	c.122G > A Hom	R41Q	4 m	4 m	NR	Hypoglycemia, Metabolic acidosis, Hyperammonemia, dystonia, hyperuricemia	NR	NR
P8 [3]	2020	F	c.494G > A/ c.122G > A	R165Q /R41Q	AS	NBS	NR	-	S	Normal development
P9 [4]	2014	M	c.122G > A Hom	R41Q	2 m	NBS	+	Hyperammonemia	S	Normal development
P10 [5]	2017	F	c.252 + 1G> AHom	/	4 m	4 m	NR	Hypoglycemia, Lactic acidosis, Metabolic acidosis, Hyperammonemia, vomiting, seizures, myocardial injury	D	/
P11 [6]	2016	M	c.509G > A/ c.348 + 1G > C	N	1 y	1 y	+	Hypoglycemia, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting, diarrhea, coma, nephritis, electrolyte disorders	S	Delayed development
P12 [7]	2011	M	NR	/	7 y	7 y	+	Impaired liver function, headache, vomiting, electrolyte disorders, leukopenia	S	Dysarthria
P13 [8]	2009	M	c.494G > A/ c.562-1G > A	R165Q/	3 d	3 m	-	Hypoglycemia, hypoglycemia, metabolic acidosis, coma	S	Normal development
P14 [8]	2009	F	c.252 + 1G> AHom	/	4 m	NBS	-	Hypoglycemia, Metabolic acidosis, Hyperammonemia, Impaired liver function, seizures, mental disability	S	Delayed development
P15 [9]	2024	F	c.722 C > T Hom	A241V	9 m	9 m	+	Hypoglycemia, Lactic acidosis, Metabolic acidosis, Impaired liver function, seizures, dystonia	NR	NR
P16 [9]	2024	M	c.121 C > T Hom	R41*	4 m	4 m	+	Hypoglycemia, Lactic acidosis, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting, seizures, dystonia, myocardial injury, delayed myelination	NR	NR
P17 Thiswork	/	M	c.133 C > T Hom	Q45X	14 y	14 y	+	Lactic acidosis, Metabolic acidosis, Hyperammonemia, Impaired liver function, vomiting, diarrhea, coma, leukopenia, electrolyte disorders, myocardial injury, hyperuricosuria, hyperhomocysteinemia	S	Normal development

F Female, M Male, S Survival, D Death, NR Not reported, AS Asymptomatic, NBS Newborn screening, y Year(s), m Month(s), d day(s), + Positive, - Negative

New case presentation

A 14-year-old male patient was admitted to our hospital in a comatose state after experiencing vomiting, diarrhea, and abdominal pain for one day following breakfast. He was the firstborn child, delivered at 40 weeks of gestation following an uncomplicated pregnancy and delivery. His parents were non-consanguineous. He weighed 3,800 g at birth and measured 50 cm in length. Starting at the age of 12 years, he experienced two episodes of hypoglycemia and frequently reported malaise and dizziness, which improved with rest. Upon hospital admission, physical examination revealed no significant abnormalities.

The abnormal laboratory values included: WBC count 30.67 × 10⁹/L (4 ~ 10 × 10⁹/L), pH 7.42 (7.35 ~ 7.45), PaCO₂ 16 mmHg (35 ~ 45 mmHg), PaO₂ 125 mmHg (80 ~ 100 mmHg), BE -11.5 mmol/L ( -3 ~ + 3 mmol/L), HCO₃₋ 10.4 mmol/L (22 ~ 26 mmol/L), serum glucose 3.4 mmol/L (3.9 ~ 7.8 mmol/L), blood lactate 11.3 mmol/L (0.5 ~ 2.2 mmol/L), blood ammonia 647.7 µmol/L (18 ~ 72 µmol/L), AST 214 U/L (5 ~ 40 U/L), ALT 97.8U/L (5 ~ 40 U/L), CK 5062 U/L (25 ~ 200 U/L), CKMB 107.2 U/L (0 ~ 24 U/L), LDH 452 U/L (110 ~ 295 U/L), and blood homocysteine 72.2 µmol/L (5.0 ~ 15.0 µmol/L).

Analysis of the blood acylcarnitine profile revealed elevated levels of 3-hydroxyisovaleryl carnitine (C5-OH) and hydroxybutyryl carnitine (C4-OH), which measured 2.96 µmol/L (references 0.2 ~ 0.5 µmol/L) and 0.427 µmol/L (references 0 ~ 0.22 µmol/L), respectively, substantially exceeding the reference values of 0.5 and 0.22, respectively. The levels of glutamine and glutamate were elevated, and the concentrations of methionine, proline, tyrosine, threonine, and valine were significantly increased. Analysis of the urinary organic acid profile indicated that the excretion of 3-hydroxyisovaleric acid, 2-ketoglutaric acid, and lactic acid was elevated in the patient. More details were shown on Table 2.

Table 2.

Abnormal metabolic findings from patient 17

	Index	Test result	Reference range	Unit
blood	3-Hydroxyisovaleryl Carnitine(C5-OH)	2.96	0.2–0.5	µmol/L
	Hydroxybutyryl Carnitine(C4-OH)	0.427	0-0.22	µmol/L
	Isovaleryl Carnitine(C5)	1.682	0-0.85	µmol/L
	Butyryl Carnitine(C4)	0.373	0-0.31	µmol/L
	Glutamic (Glu)	164.64	23–120	µmol/L
	Methionine (Met)	61.72	3.4–25.6	µmol/L
	Proline (Pro)	4873.35	195–1269	µmol/L
	Tyrosine (Tyr)	137.88	9-81.4	µmol/L
	Threonine (Thr)	128.24,	22-51.5	µmol/L
	Valine (Val)	315.68	80–243	µmol/L
urine	3-hydroxy isovaleric acid	478.40	0-6.10	µmol/L
	Creatine	1.055	0.004–0.676	mmol/mmol Crn
	2-ketoglutaric acid	73.2	0-52.5	µmol/L
	Lactic acid	5.75	0-2.23	µmol/L
	Uric acid	0.76	0.04–0.72	mmol/mmol Crn

Magnetic resonance imaging (MRI) revealed leukoencephalopathy. T2/FLAIR sequences showed abnormal patchy and linear signals in the white matter, basal ganglia and pons on both sides, with diffuse signal enhancement in the periventricular white matter. Restricted diffusion was revealed by DWI and ADC sequences. The corpus callosum appeared thin, and additional details are provided in Fig. 1. Magnetic resonance spectroscopy (MRS) revealed abnormal peaks. Holter ECG showed premature atrial contractions, and cardiac ultrasound revealed decreased left ventricular systolic function. Computed tomography (CT) scans revealed decreased liver parenchymal density.

Fig. 1.

Brain MRI in Patient 17 during metabolic crisis and at 4-month follow-up. FLAIR (A, E) and axial T2-weighted (B, F) images demonstrate elevated signal intensity in patchy and linear patterns within the white matter. Diffusion-weighted (C, G) and apparent diffusion coefficient (D, H) images revealed restricted diffusion in the bilateral basal ganglia. Panels A, B, C, and D represent MRI scans obtained during the acute phase, while panels E, F, G, and H were acquired four months later during the asymptomatic period

Blood sample was collected after informed consent from the patient and his parents, and subjected to whole-genome sequencing. Analysis revealed a homozygous nonsense mutation in exon 2 of the HMGCL gene (NM-000191.3:c.133 C > T-p.Gln45Ter), a variant that had not been described previously. This loss-of-function mutation is a low-frequency variant in population databases and is predicted to be pathogenic (PVS1+PM2_Supporting+PM3_Supporting+PP4), according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines [15]. This variant is included in the ClinVar mutation database (ID:1459880). It was validated by Sanger sequencing, which revealed that both parents carry the same mutation in the HMGCL gene, c.133 C > T-p.Gln45Ter.

The diagnosis of HMGLD was established based on clinical manifestations, laboratory abnormalities, MRI findings, and the identification of mutations in the HMGCL gene.

During hospitalization, treatment was initiated with plasma exchange, L-carnitine, folic acid, betaine, phosphocreatine, and coenzyme Q10. The patient regained consciousness on the seventh day, and his blood ammonia levels returned to normal. Following implementation of a low-fat, low-protein diet, his myocardial zymogram, hyperhomocysteinemia, and transaminase levels normalized by the ninth day. A follow-up MRI performed two weeks later revealed a reduction in abnormal brain signals, although the FLAIR signal had intensified, with persistent areas of restricted diffusion. Follow-up examinations conducted over the four months following treatment initiation showed no significant changes in imaging patterns. Additional details are presented in Fig. 1. The patient remained asymptomatic at one-year follow-up, without neurological or systemic abnormalities.

Literature review

A total of nine articles describing 16 Chinese patients with HMGLD were identified through literature review. The clinical characteristics, biochemical data, MRI findings, treatment approaches, and prognosis were analyzed for all 16 patients, as well as the current case, totaling 17 verified cases (Table 1; Fig. 2).

Fig. 2.

Abnormalities in Chinese patients with HMGCLD

Results

Age of onset, clinical features, biochemical findings, and changes in cranial MRI patterns

Among the 17 Chinese patients, 10 were male. Two (11.8%) were asymptomatic and 15 (88.2%) symptomatic. The median age at onset was 4 months (2, 24), the age groups were neonatal (n = 2, 11.8%), infant (n = 8, 47.1%), toddler (n = 2, 11.8%), preschool (n = 1, 5.9%), school-age (n = 1, 5.9%), and adolescent (n = 1, 5.9%). The diagnosis: newborn screening (n = 6, 35.3%); onset (n = 8, 47.1%); and post-onset (n = 3, 17.6%) (Patient 1: aged 7, onset age five; Patient 2: aged 3 months, onset 10 days; Patient 13: age three months, onset age three days).

Initially, fifteen (88.2%) patients presented with acute metabolic decompensation, while ten (58.9%) displayed neurological symptoms, and nine (52.9%) experienced vomiting. Additionally, fourteen (82.4%) patients developed hepatic dysfunction, thirteen (76.5%) patients presented with metabolic acidosis, twelve (70.6%) showed hypoglycemia, nine (53.0%) manifested hyperammonemia, eight (47.1%) demonstrated leukoencephalopathy, and six (35.3%) exhibited hyperlactatemia. Electrolyte disturbances (hyponatraemia, hypokalaemia and hypochlorhydria) were found in 17.6% of patients. More details were shown in Fig. 2.

Among the ten patients who underwent brain MRI, nine (90%) showed abnormalities, and eight (80%) patients developed white matter abnormalities during the acute attack phase, while three patients exhibited abnormalities in the basal ganglia. Three patients displayed nonspecific hyperintense signal changes in the periventricular and deep white matter, two patients exhibited abnormal signals in the brainstem, while one patient showed abnormalities in the dentate nucleus.

Family background

Four of the 17 patients had an unusual family background. Patient 1 was born to consanguineous parents, while Patients 2, 8, and 14 had a family history of unexplained deaths among close family members, along with associated birth defects. The remaining cases were sporadic.

Diagnosis and genetic analyses

Among the 17 Chinese patients with HMGLD included in this study, fourteen (82.4%) underwent whole-genome sequencing. The analysis revealed that ten patients harbored homozygous mutations, while four patients harbored compound heterozygous mutations. Twelve distinct allelic variants were identified among the 17 patients, including c.122G > A, c.252 + 1G > A, c.1452 A > G, c.590G > A, c.697 C > T, c.509G > T, c.348 + 1G > C, c.494G > A, VS6-1G > A, c.722 C > T, c.121 C > T, and c.133 C > T. The most prevalent mutation was c.122G > A (35.8%, 5/14), followed by c.252 + 1G > A (14.3%, 2/14). A novel homozygous mutation, c.133 C > T, was recently identified. The remaining 17.6% (3/17) were diagnosed based on MRI and biochemical findings.

Treatment and outcomes

All patients were treated with intravenous infusions of glucose, L-carnitine (100–200 mg/kg), and sodium bicarbonate during the acute phase. In the remission phase, the patients followed a high-carbohydrate, low-protein, and low-fat diet, along with oral L-carnitine supplementation (100–200 mg/kg/d) to maintain caloric requirements and prevent metabolic stress triggered by hunger, overexertion, or infection.

At the most recent follow-up, three patients had died during infancy, while ten showed normal development, three exhibited delayed development, and one patient was lost to follow-up. The mortality rate of HMGLD in China is 17.6%.

Discussion

This study presents the case of an adolescent patient diagnosed with HMGLD, providing a detailed account of the clinical features and radiographic abnormalities. This study is also the first to provide a comprehensive literature review of HMGLD in China.

HL is a mitochondrial enzyme that catalyzes the cleavage of HMG-CoA into acetyl-CoA and acetoacetic acid, playing a critical role in leucine metabolism and fatty acid oxidation [1]. Ketone bodies, including acetoacetic acid, β-hydroxybutyric acid, and acetone, serve as an essential energy source for extrahepatic organs, particularly the brain, during periods of energy deficiency [1–3, 10]. The serum levels of ketone bodies are typically low, ranging from 0.03 to 0.50 mmol/L. Ketone bodies are generated during periods of starvation and glucose deprivation [1]. HL exhibits peak activity in the liver under low-glucose concentrations, catalyzing the production of ketone bodies as an alternative energy source [1–3]. Additionally, ketone bodies serve as substrates for lipid synthesis in the brain [2]. HL, like other enzymes in its family, has a homodimeric TIM barrel structure with a divalent cation-binding site in its catalytic core [10]. Defects in this enzyme impair leucine degradation and prevent the generation of ketone bodies from the intermediate HMG-CoA, leading to the accumulation of toxic metabolites such as 3-hydroxymethylglutaric acid. This accumulation leads to hypoketogenic hypoglycemia and causes damage to multiple organs, including the brain, heart, and liver, potentially resulting in death [10].

The clinical manifestations of HMGLD are variable and may present in neonates, infants, or adults, and can be asymptomatic in certain cases. HMGLD may be triggered by acute metabolic abnormalities following infection or prolonged starvation. Patients typically present with nonspecific symptoms such as recurrent vomiting, seizures, and coma. Common laboratory findings include hypoglycemia, metabolic acidosis, hyperammonemia, and elevated blood transaminase levels. The majority of patients with HMGLD develop symptoms within the first year of life [16]. Research indicates that 90.3% of patients with HMGLD in Saudi Arabia experienced disease onset during the first year of life [17]. The present study revealed that 58.9% of patients with HMGLD in China experienced disease onset in infancy, which contrasts with the higher incidence observed among patients in Saudi Arabia. Patients with HMGLD in Australia typically present with acute acidosis and encephalopathy [18], while 79.03% of patients in Saudi Arabia were found to have developed metabolic acidosis [17]. In this study, 88.2% of patients with HMGLD in China experienced acute metabolic decompensation, with 76.5% experiencing acute metabolic acidosis, consistent with the findings from previous reports.

Neurological symptoms represent the most frequent complication in patients with HMGLD. Among the 17 Chinese patients with HMGLD, neurological symptoms were the initial presentation in 58.9% of cases, with 35.3% experiencing disturbances of consciousness, and 35.3% developing seizures. Furthermore, 11.8% of patients exhibited developmental delay. Research suggests that HMG induces oxidative stress and disrupts bioenergetics, dynamics, endoplasmic reticulum-mitochondria communication, and signaling pathways in the brain [19]. The neurological deficits are likely the result of hypoglycemia and ketone body deficiency [13].

Hyperammonemia was observed in 52.9% of the patients in this study, representing a significantly higher prevalence than that previously documented in other countries. The mechanism underlying the occurrence of hyperammonemia remains uncertain. However, research suggests that CoA derivatives, which accumulate due to the inhibition of the leucine degradation pathway, suppress the activity of enzymes in the urea cycle, including N-acetylglutamate synthase (NAGS) and carbamoyl phosphate synthetase 1 (CPS1). Furthermore, a reduction in the levels of acetyl-CoA and glutamate, which serve as substrates for NAGS, inhibits the urea cycle at the step of carbamoyl phosphate synthesis [16].

Lesions in the white matter and basal ganglia constitute characteristic neuroimaging findings in HMGLD. Although several studies have reported abnormal cerebral CT images [20], brain MRI offers superior diagnostic capabilities. In a study of 62 patients in Saudi Arabia, brain MRI revealed white matter signal hyperintensities in 16 patients and cerebral atrophy in one patient [17]. In a previous study, neuropathological examination of brain lesions in patients with HMGLD revealed spongy degeneration of white matter, astrocytic gliosis, and glycogen accumulation [21], which were potentially associated with chronic recurrent hyperammonemia, accumulation of organic acids, and hypoketotic hypoglycemia [21]. In our cohort, 6 out of the 8 patients (75%) exhibited leukoencephalopathy accompanied by hyperammonemia. We reviewed the literature on documented cases of HMGCLD worldwide and identified an additional 32 patients with matter abnormalities on MRI scans [17]. Of these 32 patients, 20 had diffuse lesions, 10 had patchy signal changes, and 15 showed abnormal signals in the basal ganglia. More details are provided in Fig. 3. In our Chinese cohort, three patients with hypoglycemia exhibited abnormal findings in the basal ganglia on imaging. It has been reported that HMG increases the activity of catalase while reducing the activity of glucose-6-phosphate dehydrogenase [22]. MRS provides valuable diagnostic insights, as confirmed by characteristic spectroscopic patterns, including abnormal peaks at 1.33 and 2.42 ppm in patients with HMGLD [21].

Fig. 3.

Abnormal signals in the cerebral MRI scans of 32 patients

HMGLD affects multiple organ systems apart from the brain, including the liver, kidneys, heart, and endocrine system. A previous study documented that liver enzymes were elevated in 14.51% of patients with HMGLD in Saudi Arabia [17]. Notably, patients with HMGLD in China exhibited a higher prevalence of liver dysfunction, with 82.4% showing impaired liver function and two patients demonstrating compromised coagulation function. The increased prevalence of HMGLD may be related to the predominant activity of HMG-CoA lyase in the liver and its reliance on ketones for energy production during periods of hypoglycemia. Additionally, several patients presented with elevated cardiac enzymes and interstitial nephritis, while one patient presented with hypothyroidism.

The patient reported in this study exhibited premature atrial contractions on Holter monitoring and decreased left ventricular systolic function on ultrasound. A previous case report from 2009 described a 23-year-old patient with cardiac enlargement and reduced ejection fraction [11]. Ketones derived from the beta-oxidation of free fatty acids provide 60–90% of myocardial energy requirements, with glucose providing the remainder. Consequently, the insufficient availability of energy substrates may contribute to myocardial dysfunction in cases of reduced HMG-CoA lyase activity [11].

The early and accurate diagnosis of HMGLD presents challenges due to the rarity of the condition and clinical variability. The diagnosis of HMGLD traditionally involves newborn screening using tandem mass spectrometry to measure the levels of C5-OH, which is typically elevated in this disorder, followed by assessment of the levels of organic acids, including 3-methylglutaric, 3-hydroxy-3-methylglutaric, and 3-hydroxyisovaleric acids, which are characteristically elevated in patients with HMGLD [17]. The urinary levels of 3-methyl-crotonylglycine may also be elevated in this condition [17]. The combination of clinical symptoms, blood biochemical and metabolic abnormalities, and reduced enzyme activity (detected in lymphocytes, fibroblasts, and immortalised lymphoblastoid cells) offers diagnostic utility [1]. Abnormalities in brain MRI findings were also supportive [1]. A definitive molecular diagnosis requires the identification of homozygous or compound heterozygous pathogenic mutations in HMGCL [1].

The HMGCL gene consists of 9 exons, spanning 23,582 bp [8–10]. The exons range from 64 to 527 bp in length, while the introns span 600 to 3400 bp [11]. The c.122G > A/p.Arg41Gln missense mutation and the c.109G > T/p.Glu37Ter nonsense mutation have been frequently documented in patients with HMGLD in Saudi Arabia and the Iberian Peninsula, with frequencies of 87% and 94%, respectively [17]. The c.835G > A/p.Glu279Lys mutation is relatively common in Japan [23]. This study identified the c.122G > A/p.Arg41Gln homozygous mutation as the predominant variant among Chinese patients with HMGLD. However, establishing clear genotype-phenotype correlations in HMGLD remains challenging. Evidence suggests that mutations resulting in complete loss of enzyme activity typically lead to earlier disease onset, while those preserving residual activity of the enzyme are associated with later clinical presentation [23]. Patient 17 was found to have a homozygous mutation in the HMGCL gene, resulting in a late onset during adolescence, which was attributable to preserved residual enzyme activity. As the patient had a favorable prognosis and his family refused further tests, we were unable to obtain his enzyme activity test results. This is a limitation of the study.

The disease exhibits a mortality rate of 20% and frequently presents with non-ketotic hypoglycemia during periods of metabolic stress, including fasting, intense physical activity, and febrile states [6]. The timely implementation of standardized treatment protocols can enhance patient outcomes. During acute episodes, treatment primarily focuses on the management of hypoglycemia, metabolic acidosis, hyperammonemia, and hepatic dysfunction. Long-term management includes dietary modifications such as protein restriction—specifically leucine—and fat limitation, prevention of metabolic stress conditions like infections or nutritional deficiency, and carnitine supplementation to facilitate the elimination of toxic metabolites. Previous research demonstrates that L-carnitine can effectively prevent DNA damage caused by 3-hydroxy-3-methylglutaric acid and 3-methylglutaric acid [24].

Conclusions

This study is the first reported adolescent case in China with HMGLD, harboring a novel homozygous c.133 C > T/p.Gln45Ter mutation in the HMGCL gene. A comprehensive analysis of all documented HMGLD cases in China revealed a higher prevalence of hepatic impairment and hyperammonemia among these patients. The mortality rate for HMGLD in China stands at 17.6%, with the homozygous c.122G > A/p.Arg41Gln mutation representing the most common variant (35.8%).

Authors’ contributions

KY contributed to conceptualization, formal analysis, methodology, data curation, writing of the original draft, reviewing and editing. LLZ prepared figure1. YDZ, YL, YJL, WHW, PZ, ZZ, LT, and JXL contributed to investigation, and reviewing and editing. All authors reviewed and approved the final manuscript.

Funding

This work was founded by Baoding City Science and Technology and Intellectual Property Bureau(2441ZF126).

Data availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol and related procedures were approved by the local institutional research ethics committees at Baoding Hospital of Beijing Children’s Hospital affiliated to Capital Medical University, Baoding, Hebei province, China.

Competing interests

The authors declare no competing interests.