Clinical and biochemical footprints of inherited metabolic disorders: XIX. Hypoglycemias

Abstract

Hypoglycemia is one of the most common metabolic emergencies in childhood. If not promptly recognized and treated, it can cause irreversible neurological injury. In newborns, infants, and children, inherited metabolic diseases (IMDs) account for a large proportion of persistent or recurrent hypoglycemia, though other genetic and endocrine disorders can also be underlying causes. Timely etiological diagnosis is critical, as many causes are treatable and require specific management to prevent recurrence. We systematically reviewed and updated the list of inherited causes of hypoglycemia and identified 340 disorders, displaying characteristic clinical and biochemical “footprints” that can guide the diagnostic process. Despite the high burden and potential for targeted therapy, underdiagnosis and delayed management remain common. This article represents the nineteenth in a series aimed at creating and maintaining a comprehensive catalogue of clinical and biochemical differential diagnoses for IMDs according to system or symptom involvement.

1. Introduction

This is the 19th in a series of articles that intends to provide a comprehensive list of inherited metabolic diseases (IMDs) associated with specific signs and symptoms. The first 18 issues were dedicated to IMDs associated with movement disorders [1, 2], metabolic liver diseases [3], those with psychiatric presentations [4], metabolic cardiovascular diseases [5], those with cerebral palsy phenotypes [6], metabolic dermatoses [7], ocular phenotypes [8], neoplasms [9], metabolic ear diseases [10], metabolic myopathies [11], gastrointestinal symptoms [12], immunological defects [13], respiratory symptoms [14], metabolic kidney diseases [15], epilepsy [16], hematological abnormalities [17], dysmorphisms [18] and endocrine abnormalities (in revision). The list follows the classification of IMDs as included in the knowledge base of IMDs (IEMbase) [19] and in the Nosology of inborn errors of metabolism [20]. This issue is dedicated to inherited causes of hypoglycemia, including IMDs.

A continuous supply of glucose is crucial for brain function and development. In case of insufficient supply, at the molecular level hypoglycemia can ultimately lead to brain cell death through multiple mechanisms (e.g., activation of neuronal glutamate receptors, oxidative stress, neuronal zinc release and activation of poly-ADP-ribose polymerase-1) [21]. Consequently, hypoglycemia can cause serious clinical symptoms (such as encephalopathy, coma, convulsions, and developmental delay) and can even be life-threatening, especially in childhood [22]. Hypoglycemia is amongst the most common metabolic emergencies [23]. Between 8–19.4% of the children presenting to the emergency department with hypoglycemia have a serious underlying disease, requiring specialist treatment and follow-up [24 ].

Hypoglycemia is an alarm symptom rather than a stand-alone diagnosis. Knowledge on the pathophysiology of glucose homeostasis and the clinical and biochemical symptoms of individuals presenting with acute hypoglycemia is essential to timely reach the correct etiological diagnosis and to initiate proper management. Therefore, the objectives of this article are twofold: (1) to present an overview of all inherited causes of hypoglycemia, including IMDs, and (2) to provide key tools to assist pattern recognition when approaching these patients.

2. Materials and Methods

Sources of the information were IEMbase (http://www.iembase.org) [25], Online Mendelian Inheritance in Man (OMIM) and The Human Phenotype Ontology (HPO). As of April 18th, 2025, IEMbase tabulated 1,993 IMDs and 4,107 corresponding clinical and biochemical signs and symptoms grouped in 22 organ systems and conditions, OMIM tabulated 7,610 phenotype descriptions for which molecular basis is known and the HPO contained over 18,000 terms. The three databases were independently checked for “hypoglycemia” and related terms (details on the search algorithm are presented in supplemental figure 1). In total 725 disorders were retrieved, reaching 340 after screening each database for duplicates and removing non-inherited disorders and *MIM genes (Figure 1 and supplemental table S1). The clinical signs and symptoms associated with hypoglycemia were extracted from all the groups.

Figure 1.

Distribution of inherited conditions associated with hypoglycemia (n= 340) across three major databases, IEMBase (pink), OMIM (blue) and HPO (green). For each group and intersection, the number of conditions is displayed.

3. Glucose homeostasis: biochemistry and physiology

Basic knowledge of the biochemistry and physiology of energy homeostasis at different phases after a meal is important while clinically approaching individuals with hypoglycemia (Figure 2).

Figure 2.

Normal physiology of fasting and glucose homeostasis.

A) Filled area shows percentage of each macronutrient substrate contributing to the total energy Expenditure; B) regulatory hormones of glucose homeostasis; C) the metabolic processes providing energy substrates under fed and fasted states and D) in-depth display of used energy substrates by fasting time. Published before by Jager, E. (2023). Disorders of mitochondrial fatty acid oxidation: towards preventive, predictive, personalized and participatory medicine. [Thesis fully internal (DIV), University of Groningen]. University of Groningen. https://doi.org/10.33612/diss.788364762.

Living organisms constantly generate energy and direct it into biological processes such as biosynthesis of complex molecules and maintenance of concentration/electric gradients, that are essential for their survival. Intermediary metabolism enables energy production by making use of chemical fuel. The fuel supplying these pathways can derive either from dietary macronutrients (i.e., carbohydrates, protein and lipids) during the fed state or from energy storage compounds (e.g., glycogen, triglycerides) upon fasting. During the postprandial state, excess glucose is stored as glycogen primarily in the liver and skeletal muscle through the coordinated action of glycogen synthase and branching enzymes. Hepatic glycogen serves as a critical buffer for blood glucose concentrations during short-term fasting, as glycogenolysis can rapidly release glucose into the circulation via the action of glycogen phosphorylase and glucose-6-phosphatase [26]. In contrast, muscle glycogen is used locally to support energy demands during contraction and does not directly contribute to circulating glucose levels. Additionally, during fasting fatty acids released from adipose tissue undergo mitochondrial β-oxidation (FAO) to generate acetyl-CoA, which provides energy for hepatic gluconeogenesis and serves as a substrate for ketone body synthesis. Ketone bodies, including acetoacetate and β-hydroxybutyrate (BHB), become an important alternative fuel for the brain when glucose availability is limited [27]. Glucose is the circulating fuel compound which can be more rapidly and more efficiently employed by all cells in the body to produce energy. Glucose oxidation is responsible for ~95% of the energy production in the brain, with lactate and ketone bodies employed as alternative, less efficient energy substrates. Given the brain’s limited capacity to store energy, a continuous supply of glucose is crucial for the function and development of the central nervous system. The liver plays a pivotal role in glucose homeostasis by balancing the uptake and storage of glucose via glycogenesis and the joint contributions of glycogenolysis and gluconeogenesis (GNG) for endogenous glucose production (EGP). The kidney also contributes significantly to glucose homeostasis. In the post-absorptive state, renal gluconeogenesis may account for up to 20–25% of EGP. In addition, nearly all filtered glucose is reabsorbed in the proximal tubule through sodium-glucose cotransporters, preventing urinary glucose loss under physiological conditions [28].

Multiple biochemical pathways and physiological processes coordinate the maintenance of stable glucose concentrations in the bloodstream (i.e., glucose homeostasis). These biological processes can be numerically expressed as follows:

1. There is a small pool of glucose molecules available in the blood compartment (i.e., approximately four grams in adults) [29].

2. In the blood compartment, glucose concentrations are kept within a narrow bandwidth [fasting reference values 3.9–5.6 mmol/L (70–100 mg/dL)] to avoid any unwanted decrease and only allowing a 2- to 3-fold increase in fed conditions.

3. The joint activity of several hormones [i.e., glucagon, adrenalin, cortisol and growth hormone (counter-regulatory hormones)] avoids hypoglycemia, whereas insulin is the only hormone with a glucose-lowering action in response to (postprandial) hyperglycemia. When circulating glucose concentrations decline, a coordinated counter-regulatory response is triggered to restore normoglycemia. In healthy individuals, suppression of endogenous insulin secretion typically occurs when plasma glucose falls to approximately 4.3 mmol/L (≈75 mg/dL). Secretion of glucagon and epinephrine is stimulated at circulating glucose concentrations of approximately 3.6 mmol/L (≈65 mg/dL), while activation of growth hormone and cortisol occurs at slightly lower thresholds [30, 31]

4. The high EGP rate (2.7–8.2 mg/kg/min depending on individual’s age) ensures that fasting adults can replace the total pool of blood glucose molecules in less than 30 minutes [32]. This EGP corresponds to approximately 41 sugar cubes per day in adults [33].

At a biochemical level, the following processes collaborate in a tissue-specific manner:

• The existence of a facilitated diffusion mechanism allows rapid transmembrane transfer of glucose molecules. This continuous glucose flux is mediated by distinct facilitative glucose transporters (GLUT) with tissue-specific expressions. GLUT1 (ubiquitously expressed) and GLUT3 (neuronal, high affinity) provide basal glucose uptake in tissues with high metabolic demand, including the brain. In contrast, GLUT2 is expressed in hepatocytes, pancreatic β-cells, renal tubular cells, and enterocytes and functions as a low-affinity, high-capacity transporter that facilitates bidirectional glucose flux and plays a key role in glucose sensing. GLUT4, an insulin-responsive transporter expressed primarily in skeletal muscle and adipose tissue, mediates insulin-stimulated glucose uptake following carbohydrate ingestion [34].

• Multiple metabolic pathways use glucose as a substrate whereas hepatic glycogenolysis and GNG from non-carbohydrate substrates contribute to EGP. These pathways are critical to ensure energy homeostasis that is required for cell functioning (Figure 2). Seven reversible GNG steps are catalyzed by the same enzymes used in glycolysis. Three irreversible GNG steps (corresponding to 4 reactions) that are mostly restricted to the liver, kidney, and intestine are catalyzed by pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PCK), fructose 1,6-bisphosphatase (FBP), and glucose 6-phosphatase (G6PC). These enzymes ensure EGP in the fasted state. The liver is responsible for approximately 80% of EGP, with the remainder largely accounted for by the kidneys and to a lesser extent, the intestine [35]. While glycogenolysis relies on liver glycogen storage, GNG enables EGP from non-hexose precursors, namely glucogenic amino acids, glycerol, lactate and pyruvate [36].

As already mentioned, glucose homeostasis is strongly regulated at a hormonal level. In addition, the portosystemic vasculature guarantees an anatomic-functional organization structure to ensure that these biochemical and physiological processes collaborate in a coordinated manner in different phases of glucose homeostasis. Hence, porto-systemic shunts may display a characteristic combination of postabsorptive hyperinsulinemic hypoglycemia and fasting hypoglycemia [37].

Disruption in one or more of the (metabolic, endocrine or anatomic) functions of glucose homeostasis results in fasting intolerance. Hypoglycemia is the key biochemical sign of fasting intolerance, which forces organisms to use other, less efficient energy metabolites, such as lactate and ketone bodies. In contrast to glucose, the metabolism of these compounds is less well regulated, with their circulating levels increasing more than 10-fold in case of lactate and over 100-fold for ketones during pathologic circumstances [38–40] (Figure 2D).

Although the metabolic and hormonal responses to fasting are common to all humans, they occur with an accelerated, age-dependent rate in children [41]. Experimental stable isotope studies have demonstrated that children have a higher EGP compared to adults [42]. This is likely caused by combinations of increased energy expenditure, higher brain/body weight ratio and lesser liver glycogen storage and muscle protein mass. Such factors explain why children are at an increased risk of developing hypoglycemia compared to adults. Newborns are especially vulnerable to hypoglycemia during the perinatal transition, as they need to switch from the passive in utero continuous transplacental glucose supply to the active self-regulation of glucose concentrations. Shortly before birth, multiple metabolic pathways are activated in the fetus, including glycogenolysis, GNG, proteolysis (leading to the production of lactate and other substrates for GNG), lipolysis and mitochondrial fatty acid oxidation (leading to the production of ketone bodies). Lactate and ketone bodies as such produced can be used as glucose-sparing metabolites and prepare the fetus for the postnatal adaptation to intermittent (exogenous or endogenous) energy supply [43]. After birth, glucose concentrations around 2.5 mmol/L (45 mg/dL) are commonly observed in healthy newborns. These values progressively decline reaching a nadir between 1 and 2 hours after birth, as low as 1.5 mmol/l (27 mg/dl) in at term newborn or even lower in preterm newborns [44]. Likely, this decrease is necessary to stimulate vital processes such as hunger and integration of endocrine and metabolic responses to fasting. A successful integration is reflected by the observation that around 3 hours after birth glucose concentrations increase back to 2.5–3 mmol/L(45–55 mg/dL). In the early post-natal phase glucose homeostasis is mainly sustained by the liver glycogenolysis. As liver glycogen storage is limited and exogenous sources (i.e. feeding) are not sufficient to ensure the energy demand, GNG is also required to maintain euglycemia in the first days of life.

4. Definitions of hypoglycemia

There is no consensus on the plasma glucose concentration at which a person is considered to have hypoglycemia. In addition to the above-mentioned considerations that specifically apply to the perinatal transition of glucose homeostasis, variable definitions of hypoglycemia have been proposed, such as glucose concentration < 2.5 mmol/L (45 mg/dL) at all ages, < 3.3 mmol/L (60 mg/dL) in older infants and children, < 2.2 mmol/L (40 mg/dL) on the first day of life, < 2.5 mmol/L (45 mg/dL) after 24 hours of age, or < 1.4 mmol/L (25 mg/dL) in preterm infants [45, 46].

Despite controversies on the definitions of hypoglycemia, the glucose concentrations and the related management thresholds [45, 47], hypoglycemia can be considered as any plasma glucose concentration that is low enough to cause clinically relevant symptoms. In adolescents and adults, the so-called “Whipple triad” has been used to describe the combination of (i) symptoms of hypoglycemia, (ii) confirmed low blood glucose concentration and (iii) an immediate relief of these symptoms after glucose intake. The Whipple triad appears unsatisfactory in newborns and infants, who often display subtle/nonspecific symptoms and are unable to communicate them [45]. It is challenging to identify a standardized glucose threshold for symptom appearance. As a matter of fact, symptom development results from a combination of factors, including age, the ability to use alternative substrates (e.g., lactate, ketone bodies) for energy production, which can mask symptoms of neuroglycopenia. Also, the recurrence and duration of “low glucose” episodes may give rise to metabolic adaptation resulting in blunted symptoms [47].

5. Pathophysiology and differential diagnosis

Mechanistically, decreasing plasma glucose concentrations can result from either increased clearance and/or decreased supply of glucose molecules in the bloodstream [48]. At least in theory any defect in enzyme, transporter and/or hormone synthesis/secretion involved in the above-mentioned metabolic pathways may result in hypoglycemia. To date more than 100 specific IMDs are associated with hypoglycemia (Figure 3 and Supplemental Table S1). Different classifications have been proposed for IMDs presenting with hypoglycemia, including:

Figure 3.

Occurrence (in percent) of most common symptoms associated with the categories of IMDs presenting with hypoglycemia. The percentages for each symptom were calculated using the denominator of the total number of IMDs in each category presenting with hypoglycemia. The heat scale ranges from red (0%; diseases with no particular symptom reported) to violet (100%; diseases with particular symptoms reported) within the disorders group. For further information about the 9 categories of disorders affecting respiratory system, see Supplemental Tables 1.

1. Pathophysiology

The traditional clinical classification in three major groups of IMDs can also be applied to those presenting with hypoglycemia [49]:

• group 1: disorders of (intra-/extra-mitochondrial) energy production. The symptoms result from disrupted energy production in organs with relatively high energy requirements, such as the liver, heart, muscle and brain. This group includes glycogen storage diseases (GSDs), disorders of GNG and fatty acid oxidation disorders (FAOD), among others.

• group 2: intoxication disorders. These disorders are characterized by acute or progressive intoxication because of the accumulation of a toxic metabolite. Typically, they present after a symptom-free interval with either acute (e.g., vomiting, lethargy, liver failure,) or chronic (e.g., developmental delay, intellectual disability, movement disorders) symptoms. This group includes organic acidemias (OAs), galactosemia and hereditary fructose intolerance, among others.

• group 3: complex molecules disorders. The symptoms are progressive, permanent, often multisystemic and independent from food intake. This group includes congenital disorders of glycosylation (CDG) and peroxisomal disorders, among others.

2. Biochemical profile of the critical sample

During hypoglycemia, the blood critical sample analysis of ketones (hypoketotic versus hyperketotic) and lactate (normal or increased concentrations) profile shows the characteristics of specific IMDs (Figure 3). The kinetics of glucose, lactate and ketone bodies in critical samples during acute decompensation are swiftly influenced by rescue feeds and there is lack of reference values under these circumstances. Often critical sampling is not performed thus preventing the generation of a comprehensive metabolic pattern.

3. Clinical

Clinically, disorders presenting with hypoglycemia can be classified according to whether hepatomegaly is present or absent. Hypoglycemia with hepatomegaly, such as observed in GSDs, hereditary fructose intolerance, and certain defects in GNG, typically involve intrahepatic accumulation of glycogen, fat, or toxic metabolites, also leading to elevated transaminases, and risk of liver damage. Conversely, hypoglycemia without hepatomegaly, as usually observed in isolated defects of insulin regulation or disorders of counter-regulatory hormone action, often points toward extrahepatic energy production defects. Recognizing hepatomegaly in the context of hypoglycemia can therefore direct clinicians toward specific metabolic/hormonal pathways and guide targeted investigations, such as liver ultrasound, and genetic testing.

Nevertheless, each of these classifications appears an artificial simplification of reality. In some IMDs metabolic disruption may give rise to an endocrine imbalance (e.g., hyperinsulinism in CDG, GLUD1 deficiency or SCHAD deficiency, adrenal insufficiency in peroxisomal disorders) causing hypoglycemia.

The clinical phenotype in hypoglycemic patients may largely overlap between IMDs and other inherited causes. Hence, it is essential to be aware of non-metabolic causes of hypoglycemia, which should always be part of the initial differential diagnosis (Table 1). As already mentioned, endocrinopathies can co-occur in certain monogenic disorders causing an IMD (e.g., hypothyroidism in GSD Ib, GH deficiency in methylmalonic acidemia and liver GSDs, adrenal insufficiency in peroxisomal disorders, or the previously mentioned IMDs associated with hyperinsulinism). The relative contribution of different etiologies of hypoglycemia varies substantially with age. In the neonatal period and early infancy, hypoglycemia most commonly results from disorders of insulin regulation, including congenital hyperinsulinism, which represents the most frequent cause of persistent hypoglycemia in this age group. Endocrine disorders such as hypopituitarism or adrenal insufficiency may also present during infancy but are less common. In contrast, IMDs account for an increasing proportion of hypoglycemia presenting beyond the neonatal period, particularly during infancy and early childhood when fasting tolerance remains limited [1]. Evidence from a tertiary cohort of children with hypoglycemia shows approximately: 29% ketotic hypoglycemia, 41% congenital/transient hyperinsulinism, 9% IMDs, 5% hormone deficiencies, 16% other [51]. There is no-one-size-fits-all method to describe the relationship between decreasing plasma glucose concentrations and the development of clinically relevant symptoms. Nevertheless, it is helpful to distinguish between symptoms resulting from the release of catecholamines from the adrenal glands and cerebral glucose deficiency (neuroglycopenia). Adrenal-related or neurogenic symptoms due to the activation of the autonomic nervous system (adrenergic counter-regulation leading to adrenaline release) appear first [circulating glucose 2.2–3.9 mmol/L (40–70 mg/dL)] and may include sweating, pallor, tachycardia, hunger, weakness, tremulousness, nausea, paresthesias. Neuroglycopenic symptoms are secondary to decreased cerebral glucose availability and appear as blood glucose concentrations further decreases [circulating glucose < 2.8 mmol/L (50 mg/dL)]: headache, confusion, lethargy, visual disturbances, altered behavior, dizziness, incoordination. Seizures, encephalopathy and coma can eventually develop if hypoglycemia is not promptly treated. Gataullina et al. reported that 53% of patients referred for hypoglycemia caused by an IMD experienced at least one hypoglycemic seizure [52]. The symptoms in newborns may be nonspecific or subtler including hypothermia, hypotonia, poor feeding, cyanosis, apnea and seizures. In addition, the symptoms of hypoglycemia may be influenced by concomitant medications (Table 2), or metabolic counter regulation.

Table 1.

Major non IMD-related causes of hypoglycemia.

1. Congenital hyperinsulinism *

Isolated

Channel defects

Transcription factors defect

Overgrowth syndromes

Beckwith-Wiedemann syndrome

Weaver syndrome

Sotos syndrome

Simpson-Golabi-Behmel syndrome

Perlman syndrome

Syndromes with growth failure

Kabuki syndrome

Coffin-Siris syndrome

Rubinstein-Taybi syndrome

CHARGE

MEHMO syndrome

Costello syndrome

Schaaf-Yang syndrome

Chromosome abnormalities

Turner syndrome

Trisomy 21

Trisomy 13

16p11.2 microdeletion

Contiguous gene deletion

Usher-CHI syndrome (deletion including ABCC8)

9p deletion syndrome

Other

Insulin receptor disorders

Congenital central hypoventilation syndrome

Timothy syndrome

PASNA

Long-QT syndrome (KCNQ1, KCNH2)

2. Adrenal insufficiency (AI)

Primairy AI

Secondary AI

3. Growth hormone deficiency

4. Congenital hypopituitarism

Including causes listed by M. Zenker et al [50].

PASNA: Primary aldosteronism with seizures and neurologic abnormalities

The complete list of inherited disorders associated with hypoglycemia retrieved from the database screening is provided in supplemental table 1.

^*In addition to causes herein listed, congenital hyperinsulinism may also present in the context of specific inherited metabolic disorders, including congenital disorders of glycosylation (CDG), glutamate dehydrogenase deficiency, hexokinase deficiency, glucokinase superactivity, Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and aminoacyl-tRNA synthetases (CARS1, YARS1). Congenital porto-systemic shunts may also result in hypoglycemia [31].

Table 2.

Key history, clinical and laboratory data in the management of hypoglycemia.

History	Medications	Physical Examination	Labs
Timing of hypoglycemia	Insulin and analogs	Liver and spleen	Glucose
Age of onset	Insulin seretagogues	Growth and development	BHB
Associated conditions	Quinolones	Dysmorphic features	Lactate
Relation to/Avoidance of food	Pentamidine	Eye/ear examination	Blood gases
Fasting tolerance	B-blockers	Heart/muscle	FFA
High glucose requirements*	ACE-inhibitors	Skin	Insulin/C-peptide
Family history	Salicylates		Amino acid/Acylcarnitines
Development milestones	Alcohol		Ammonia
Epilepsy			Urine organic acids, tetrasaccharide
			Cortisol/GH
			AST, ALT
			Cholesterol, Triglycerides
			Uric acid

^*high glucose infusion rate suggests congenital hyperinsulinism

A diagnostic evaluation is generally warranted in individuals with documented plasma glucose concentrations consistent with hypoglycemia, particularly when episodes are recurrent, severe, or associated with neuroglycopenic symptoms. Approaching a person presenting with hypoglycemia requires the integration of clinical, dietary and biochemical information. First it should be ascertained whether any measured/confirmed low glucose concentration is available. Furthermore, the timing in relation to the last meal, nutritional history, physical examination (growth, hepatomegaly, skin abnormalities, dysmorphic features), critical blood sample (combined metabolic and hormonal profile of glucose, ketones, lactate, blood gas analysis, free fatty acids, insulin, C-peptide and crisis urine) are key elements to reach a (working) diagnosis. Maintaining a structured record of blood glucose (along with any additional metabolite) measurements that document the timing and clinical characteristics of hypoglycemic episodes can be valuable for both patients and their families.

History taking is crucial to collect key information on the presence of symptoms related to hypoglycaemia such as fasting tolerance (e.g., need for night snack, nighttime crying with a demand for food, lethargy) and presence of early morning ketosis (strong breath smell in the early morning, vomiting). It should include:

• Age of onset (newborn, infant, child, adult)

• Associated conditions (e.g., intercurrent disease, recurrent acidosis, muscle pain/exercise intolerance, small for gestational age, maternal diabetes)

• Relation to the last meal (fasting hypoglycaemia, post-prandial hypoglycaemia, random)

• Relation to/Avoidance of food (e.g., protein, fruit, fruit juice, (ga)lactose, sweet food)

• (Overnight) fasting tolerance (e.g., feeding frequency, night snack, morning ketosis)

• Glucose requirements (e.g., > 10 mg/kg/min)

Specific questions should be asked to investigate symptoms of adrenergic counterregulation that normally occur before symptoms of neuroglycopenia. Notably, these symptoms are also dependent on the underlying pathophysiology. Adrenergic symptoms may be suppressed in patients taking beta blockers. In patients with a defect in GNG, symptoms of neuroglycopenia may be masked, probably by the increased lactate concentrations.

The timing of hypoglycaemia is of critical importance and can help focusing on specific groups of disorders (e.g., hypoglycaemia after short fasting suggests hepatic GSDs; disorders of GNG and FAOD typically present with hypoglycaemia after medium to long fasting (Figure 2). The interpretation of the nutritional history can be strongly influenced by cultural differences between the requesting healthcare providers and different responding family members. To further objectify the nutritional history dietary intake can be assessed through either a 3-day food record, 24h recall or food frequency diary to check overall food intake and any restricted/exceeded nutrient.

Information on personal history should also be carefully detailed, including:

• Perinatal history: birth weight, gestational age, gestational diabetes, and any other form of perinatal distress and perinatal glucose requirements. In newborns risk factors for hypoglycemia include maternal diabetes and macrosomia (pointing toward hyperinsulinism), prematurity (resulting in decreased EGP), sepsis, hypoxic-ischemic encephalopathy, intracranial hemorrhage, seizures (resulting in increased glucose utilization) and maternal medication (e.g., labetalol use resulting in masking of adrenergic hypoglycemia symptoms). Iatrogenic hypoglycemia may also occur following abrupt discontinuation of i.v. glucose (secondary to reactive hyperinsulinemia)

• Growth and developmental milestones (e.g., failure to thrive, intellectual disability, movement disorders, epilepsy)

• Family history: relatives with (symptoms suggestive of) fasting intolerance or hyperglycemia or IMD, previous miscarriages or sudden unexpected deaths, consanguinity, medications (Table 2), and social history.

Physical examination should be performed thoroughly as it can reveal signs pointing to IMDs and/or endocrine dysfunction and/or genetic syndromes. Clinical and ultrasound evaluation of liver and spleen size and structure is key as hepato(spleno)megaly is found in several IMDs. However, several IMDs associated with hypoglycemia do not display hepatomegaly (Figure 3). As the liver and spleen size become larger with age, patient age and height should be considered for adequate interpretation. Similarly, signs of liver disease (e.g., jaundice, itching, bruising, spider angiomas) are also suggestive of an IMD. Additional clinical features can be found pointing to a specific diagnosis including: short stature in glycogen storage diseases, hypopituitarism or isolated growth hormone deficiency, cataract in galactosemia, arrhythmias and/or cardiomyopathy in FAOD, multisystem involvement (e.g., variable combination of dysmorphic features, bleeding tendency, developmental delay, hypotonia, abnormal subcutaneous fat distribution, hearing/visual impairment, epilepsy) in congenital disorders of glycosylation (CDG), mitochondrial disorders and peroxisomal disorders, micropenis, cryptorchidism and midline anomalies in hypopituitarism, skin hyperpigmentation in primary adrenal insufficiency (Addison’s disease), and signs of hyperandrogenism in adrenal insufficiency due to congenital adrenal hyperplasia, dysmorphic features and macrosomia/lateralized overgrowth in overgrowth syndromes.

Awareness of the signs and symptoms occurring in IMDs associated with hypoglycemia is crucial to establish a proper treatment plan and prevent long-term sequelae (Figure 3).

Biochemical investigations can provide pivotal information by measuring metabolites and hormones involved in energy homeostasis. Various diagnostic algorithms have been proposed [45,47,49, 53]. Samples are ideally collected during hypoglycaemia (“critical sample”), otherwise it may be non-informative. Important blood investigations include: glucose, lactate, blood gases, ketones [mainly 3-hydroxybutyrate (BHB), free fatty acids (FFA), acylcarnitines, amino acids, ammonia, insulin, C-peptide, cortisol, GH, as well as urine organic acids (assessed either on urine collected during hypoglycemia or first urine void after hypoglycemia) [1] (Table 2). In a pragmatic approach, one spare tube could also be collected for any additional investigations to be performed afterwards. The combination of measuring point-of-care (POC) glucose and BHB has the potential to be applied as a screening test for hypoglycemia. When checking glucose and BHB in both the critical sample and after an overnight fast, specific combinations can point into the direction of a pathological cause of hypoglycemia (see panel). It should be emphasized that a single-point measurement may not be sufficient to appreciate the swift fluctuations in the blood concentration of several metabolites (e.g. ketones, lactate). The concurrent observation of post-prandial hyperglycemia can provide helpful information to point towards specific disorders (e.g., GSD0a, Fanconi-Bickel syndrome or the non-inherited dumping syndrome).

Two specific combinations of results are highly suspicious for an underlying pathological cause:

1. glucose < 2.8 mmol/L (50 mg/dL) + BHB < 1.8 mmol/L may point into the direction of hyperinsulinism [1], GSD type I or a defect in mitochondrial fatty acid oxidation or ketogenesis or GH deficiency

2. BHB > 1 mmol/L after an overnight fast can be a sign of premature, compensatory fatty acid oxidation and ketogenesis (like in the ketotic liver GSD subtypes), decreased ketolysis or MCT1 deficiency [54]

Additional tests can be considered based on available information and/or clinical suspicion including: blood count, C-reactive protein, electrolytes, liver/renal function tests, CK, uric acid, cholesterol, triglycerides, and ammonia. Urine reducing substances test can be helpful to assess the presence of reducing sugars (e.g., fructose, galactose). Specific biochemical patterns can point to specific defects, such as low ketones at the time of hypoglycemia may immediately suggest a diagnosis of congenital hyperinsulinism (with low FFA) or FAOD (with high FFA). FFA/Ketone bodies ratio can help distinguish between FAOD/ketogenesis defect (FFA/KB > 2.5) and ketolysis defects (FFA/KB < 2.5) [55].

Evaluation of metabolic changes in dynamic conditions (e.g., fasting, metabolite loading) has been historically used to assess individual response to a “metabolic challenge”. This procedure can lead to the accumulation of toxic metabolites and sometimes fatal complications. Therefore, it is essential to first rule out IMDs with a recognizable metabolic profile, such as liver GSD subtypes, FAODs and disorders of ketogenesis, prior to a controlled fasting challenge. Hence, these tests have been largely superseded by enzyme or genome analysis and are nowadays only performed in selected cases and in specialized metabolic units. Yet, controlled fasting challenge remains employed in the management of congenital hyperinsulinism [56]. Additionally, in vivo continuous glucose monitoring (CGM) is an increasingly recognized tool to manage the (dietary) treatment once the (working) diagnosis has been established. CGM systems were originally developed for diabetes management. Although CGM reliability has improved over the past years, observations in individuals with GSD Ia and congenital hyperinsulinism revealed suboptimal CGM accuracy in the low glucose range [57, 58], thus requiring fingerstick confirmation. CGM readings may also be affected by additional variables, including sensor-related artifacts such as “compression lows” (which can produce falsely low values when external pressure is applied to the sensor site) and distribution of the subcutaneous fat. Despite these limitations, CGM can provide relevant insight on the extent, timing and duration of fluctuations of blood glucose compared to traditional capillary glucose monitoring. As such, CGM is experiencing a growing adoption in inherited disorders associated with hypoglycemia, including liver glycogen storage diseases and congenital hyperinsulinism [59,60]. Yet, formally adopted recommendations on CGM use in these disorders are lacking [61]. More recently, tracer metabolomics has emerged as a monitoring technique to clarify the clinical relevance of genetic findings [62]. Furthermore, a subgroup of conditions (e.g. FAOD, OAs, CAH) associated with hypoglycemia are included in many population newborn screening programs worldwide. However, large differences still exist among countries and sometimes even within the same country/state with regard to the number of screened conditions as well as methodology used in each screening panel [63; https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp]. Approximately only 1% of the IMDs is included in national screening panels. Unfortunately, some newborns have severe presentations of FAODs and OA before the NBS result become available [64]; alternative phenotypes can be associated with false negative NBS test, emphasizing the importance of clinical awareness [65,67].

Imaging tests can provide additional information. For example, abdominal ultrasound and Magnetic Resonance Imaging/Computed tomography scan can define the structure and size of liver (e.g., liver steatosis, focal lesions), spleen, kidneys sizes and rule out porto-systemic shunts. Fibroscan can provide information on the degree of fibrosis/cirrhosis. Hand and wrist X-ray to assess skeletal maturation can be helpful in patients with growth retardation due to growth hormone deficiency. Additional tests can be required based on specific clinical features (e.g., brain MRI, PET scan, heart ultrasound, dynamic endocrine function tests).

The (combination of) results from the above-mentioned investigations can clarify whether all components of the hormonal and metabolic regulation are functioning adequately to prevent hypoglycemia [68]. However, alternative causes of abnormal test results should always be considered (e.g., lactate elevation secondary to laborious exercise or postprandial blood collection in some GSD patients or increased pCO2 secondary to apnea during blood collection, hypoglycemia secondary to exogenous drug administration).

Eventually the working diagnosis can be confirmed through molecular testing, possibly coupled with enzyme testing. Enzymatic diagnosis is generally performed in blood cells or skin fibroblasts (e.g., debranching enzyme or very-long chain acetyl-CoA dehydrogenase activity). However, some enzymes (like for example glucose 6-phosphatase) are not expressed in these mediums and require a liver biopsy. As liver biopsy and skin biopsy are invasive, and DNA-testing becomes faster and cheaper, biopsies have been largely replaced by DNA-testing. Timely molecular testing is paramount in the management of inherited disorders associated with hypoglycemia and can unveil any genotype-phenotype correlation. Various molecular biology techniques are available to detect pathogenic and likely pathogenic variants in genes associated with hypoglycemia. Currently, exome sequencing (ES) using gene panels (e.g.,‘hypoglycemia panel’ or ‘metabolic disorders panel’) or HPO-terms for analyses are predominantly used [69]. Genome sequencing (GS), in which gene panel analysis is also incorporated and often only the exome is fully analyzed, is becoming increasingly available and affordable. These sequencing techniques should include sequencing-based detection of copy number variations (e.g., deletions, duplications), if not then additional techniques such as Single Nucleotide Polymorphism (SNP)-array or Multiplex ligation-dependent Probe Amplificaton (MLPA) should be added. Depending on the differential diagnoses other targeted techniques can be added or used as a first test (e.g., methylation testing, testing of mitochondrial DNA, testing for mosaicism, target testing of few genes after abnormal enzymatic testing). With the increased use of ES and GS, it is becoming increasingly important to provide data on family history (especially when using child-parents trio-analyses), results of metabolic testing, results of endocrinological testing and clinical features to DNA-laboratories to facilitate accurate interpretation of genetic variants. With the growing use of molecular biology techniques, the list of disorders associated with hypoglycemia is expected to expand as compared to currently available databases, as recently exemplified by CARS1 deficiency [70]. Unpublished personal observations by the authors include hypoglycemia in several patients with MYL2 deficiency.

It should be noted that database-driven screening strategies based on phenotype terms such as “hypoglycemia” may not capture all inherited conditions in which hypoglycemia occurs secondary to endocrine dysfunction, particularly adrenal insufficiency. In several disorders—especially peroxisomal disorders (e.g., X-linked adrenoleukodystrophy/adrenomyeloneuropathy, Zellweger spectrum disorders, and peroxisomal acyl-CoA oxidase deficiency) and selected defects of steroidogenesis or multisystem syndromes (e.g., CYP17A1 deficiency, CYP11B1 deficiency, CYP27A1 deficiency, NGLY1-related disorder, and RBM28-related alopecia–neurologic defects–endocrinopathy syndrome)—adrenal insufficiency represents a clinically relevant manifestation that may present with hypoglycemia, even though “hypoglycemia” itself is not always explicitly annotated in database clinical summaries. These conditions were therefore not captured by the primary search strategy but remain important considerations in the differential diagnosis of inherited causes of hypoglycemia and should be interpreted within the broader framework of endocrine-mediated glucose dysregulation.

Idiopathic Ketotic hypoglycaemia (IKH) is the most common cause of childhood hypoglycaemia. These individuals usually present between 18 months and 5 years and symptoms resolve spontaneously by the age of 9 years. IKH includes a group of conditions presenting with hypoglycaemia together with high amounts of ketones in which the exact genetic cause is unknown (impaired gluconeogenesis secondary to decreased alanine availability has been postulated). In otherwise healthy children, accelerated ketone production during fasting provides an alternative energy substrate for the brain and is generally considered an appropriate metabolic response. However, recurrent or severe episodes of ketotic hypoglycemia, particularly when occurring after relatively short fasting intervals or accompanied by additional clinical features such as hepatomegaly, growth abnormalities, or metabolic acidosis, should prompt evaluation for underlying disorders. Distinguishing physiologic fasting ketosis from pathologic causes therefore requires careful assessment of fasting tolerance, biochemical parameters obtained during hypoglycemia, and the broader clinical context. Typically, the child improves dramatically on dextrose infusion (conversely glucagon injection elicits little or no increase in glucose concentrations) and is usually restored to normal health within hours. There are no specific diagnostic tests for IKH. Therefore, all possible causes of hypoglycaemia must be ruled out (diagnosis of exclusion). Several patients previously diagnosed with ketotic hypoglycaemia are being diagnosed with specific IMDs with the increasing availability of innovative diagnostic techniques (e.g. next generation sequencing) [71].

5. Management

In any individual presenting with hypoglycemia, particularly in infancy or childhood, immediate correction of low plasma glucose is crucial to prevent irreversible neurological damage. Clinical management must be initiated without waiting for a definitive diagnosis.

Key principles in the acute setting include:

• Prompt administration of glucose to restore plasma glucose concentration to a safe range

• Oral or enteral glucose (e.g., glucose gel or sugar solution, 10–20 grams) should be given if the patient is alert and can safely swallow or if IV access is delayed or difficult. It should be followed by a snack of complex carbohydrates or milk in infants. In individuals with hypoglycemia of unknown origin, oral glucose should always be prioritized over sucrose. There exist some IMDs [e.g., hereditary fructose intolerance or defects in GNG such as Fructose 1,6 bisphosphatase (FBPase) deficiency] in which the administration of sugary drinks containing sucrose could worsen the metabolic decompensation.

• When the individual is unconscious/unable to swallow, iv glucose should be administered, starting with a bolus of 200–500 mg/kg (2–5 ml/kg of 10% glucose/dextrose solution) followed by an infusion with 10% glucose adjusted to maintain euglycemia based on the estimated endogenous glucose production (EGP) (Table 3)

• Frequent glucose monitoring (every 15–30 minutes) should be instituted initially.

• Collect a critical sample during spontaneous or provoked hypoglycemia before glucose correction if possible (see Section 4 for details).

Table 3.

Glucose requirements per age.

Age (year)	<1	1–3	4–6	7–12	>12	Adult (>16)
Glucose (mg/kg/min)	8–10*	7–8	6–7	5–6	4–5	3–4

^*Glucose requirement may be higher in congenital hyperinsulinism

Glucagon is effective in congenital hyperinsulinism. However, it should be administered carefully as it could be ineffective in case of long-lasting hypoglycemia or fasting, when liver glycogen stores may have already been depleted or give rise to rebound hypoglycemia. Furthermore, it is ineffective in some IMDs (e.g., GSD I); with the risk of worsening hypoglycemia. In patients with a confirmed diagnosis excessive glucose administration should also be avoided to prevent rebound hypoglycemia and complications from rapid shifts in glucose concentrations.

In clinical situations, the expected calculated EGP based on experimental studies is extrapolated to estimate patients’ glucose requirements when establishing a management plan (Table 3). EGP must always be estimated to tailor therapy and prevent hypoglycemia relapse. These values should guide intravenous peripheral dextrose infusion. Central venous access may be needed if higher glucose concentrations and/or lipid sources are required.

Some causes of hypoglycemia are life-threatening but treatable with targeted therapies. Hence, it is imperative not to overlook these early, even before a definitive diagnosis is reached. For instance:

• Congenital hyperinsulinism may require diazoxide or octreotide. Additional therapeutic strategies may be required when diazoxide is ineffective or contraindicated, including continuous enteral dextrose administration and long-acting somatostatin analogues (e.g., lanreotide).

• Adrenal insufficiency warrants immediate stress-dose iv steroids pending confirmation results.

• Fatty acid oxidation disorders (FAODs) require avoidance of both fasting and intravenous lipids. Riboflavin supplementation may be considered.

• Glycogen storage diseases (GSDs) warrant avoidance of fasting and specific dietary management which may include cornstarch supplementation/gastric drip feeding.

• Organic acidemias and urea cycle defects may require ammonia scavengers, protein discontinuation and/or dialysis in case of hyperammonemia.

• Galactosemia or hereditary fructose intolerance: remove offending sugar and administer glucose.

Once acute hypoglycemia has been addressed, the cornerstone of long-term management is the prevention of hypoglycemia recurrence and the mitigation of neurological and systemic sequelae. Disease-specific management strategies should be established after the diagnosis is confirmed, ideally in collaboration with a multidisciplinary team (metabolic physician, endocrinologist, dietitian, and genetic counselor). To this aim, affected individuals should be referred to a specialized center where periodic evaluations are performed, including:

• Monitoring for growth, development, and neurocognitive outcomes

• Monitoring of organ functions and blood glucose, often via continuous glucose monitoring (CGM).

• Dietary (re)assessment, ensuring adequate caloric and carbohydrate intake, particularly during periods of fasting (e.g., overnight). This may include corn starch supplementation and/or gastric drip feeding

• Evaluation of treatment side effects

• Emergency letter, including a sick-day regimen with increased carbohydrate intake or early IV glucose initiation during stress or infection [72]

• Patient and caregiver education on signs of hypoglycemia and emergency management.

In selected cases, surgical therapies may be indicated. These include (partial/near-total) pancreatectomy in focal congenital hyperinsulinism, liver transplantation in individual cases of GSD, organic acidemias, or urea cycle defects and the surgical correction of portosystemic shunts.

Several experimental treatments are also being investigated with the aim of targeting the underlying disease cause instead of its symptoms. These include gene replacement therapy (e.g., GSDIa) [73], mRNA therapy (e.g., GSDIa, OAs), gene editing (GSDIa, UCDs), substrate replacement therapy (e.g., triheptanoin in long-chain FAOD) [74], substrate detoxification (e.g., drug repurposing of SGLT2 inhibitors in GSDIb and FBS) [75,76].

6. Discussion

Hypoglycemia represents a medical emergency with potential for serious neurological sequelae. Management must be approached in two parallel tracks: immediate stabilization of the patient to prevent hypoglycemic brain injury, and initiation of a targeted diagnostic evaluation to uncover the underlying etiology. In the acute phase, clinicians must estimate the patient’s glucose needs (EGP), ensure continuous glucose delivery, and avoid triggers (e.g., catabolism, specific intoxicating macronutrients) that may precipitate metabolic crises. Once a diagnosis is made, multidisciplinary long-term care focuses on prevention of recurrence, optimizing neurodevelopmental outcomes, and tailoring treatment to the specific disorder—including dietary management, pharmacotherapy, or in selected cases, surgical or experimental interventions.

Several key issues require further attention and research. First, there remains a gap in clinical awareness and training related to rare diseases causing hypoglycemia, leading to underdiagnosis, misdiagnosis, or diagnostic delay. Educational strategies, practical diagnostic algorithms and the use of artificial intelligence could prevent diagnostic delay. Second, standardized practical protocols for the evaluation and management of hypoglycemia, particularly in low-resource settings, are lacking. Third, emerging therapies, such as gene therapy and mRNA-based treatments, hold promise for disease modification, but they are currently experimental. Fourth, more work is needed to establish long-term neurocognitive outcomes associated with different etiologies and management strategies, as this will guide prognosis and therapeutic targets. Fifth, exome sequencing (ES) and genome sequencing (GS) have emerged as key tools, especially in neonates or children with unexplained hypoglycemia. However, its diagnostic yield is highly dependent on the optimization of filtering strategies. Many IMDs are caused by variants in genes with poorly annotated transcript isoforms, non-canonical exons, or complex inheritance patterns. Moreover, standard pipelines often filter out potentially causative variants due to assumptions about zygosity, population frequency thresholds, or lack of phenotype-driven prioritization. Additional limitations include a relatively high proportion of variants of uncertain significance (VUS) and challenges in detecting non-coding or regulatory variants, which may contribute to missed diagnoses. Careful interpretation in the context of symptoms and signs, biochemical findings and (in vivo and in vitro) functional tests remains essential. Therefore, applying a phenotype-informed and gene-aware filtering strategy is critical. Collaboration between clinicians, geneticists, and bioinformaticians is essential to ensure that diagnostic variants are not missed due to overly stringent or poorly contextualized filters.

7. Conclusions

Hypoglycemia is a diagnostic and therapeutic emergency that can be caused by an increasing group of at least 340 inherited disorders. A structured approach is warranted for evaluation, prompt acute management, and multidisciplinary long-term care to reach optimal outcomes. As diagnostic and treatment tools are evolving, the clinical landscape is expected to change rapidly in the upcoming years. The challenge remains to implement these advances in a timely, equitable, and clinically meaningful way for people affected by these often rare but treatable inherited disorders.

Supplementary Material

1

Supplemental Figure 1. PRISMA-style flow diagram illustrating identification and curation of disorders associated with hypoglycemia from IEMBase, OMIM, and HPO. The search strategy was designed to capture inherited disorders associated with hypoglycemia. The following terms were queried individually and in combination: “hypoglycemia”, “hypoglycemic coma”, “hypoglycemic seizures”, “hypoglycemic encephalopathy”, “recurrent hypoglycemia”, and “hypoketotic hypoglycemia”. IMDs: inherited metabolic diseases.