A narrative review: research progress on the genetic background of neonatal hyperkalemia

Introduction

Background

Potassium ions (K⁺) are predominantly distributed within the intracellular space of the body, with an intracellular concentration approximately 30 times higher than that in the extracellular fluid. The maintenance of potassium homeostasis plays a crucial role in regulating heart rhythm, blood pressure, water-electrolyte balance, and neurological and muscular functions (1-3). Under normal physiological conditions, potassium is mainly obtained from food. When food enters the gastrointestinal tract, insulin secretion is stimulated, promoting the influx of a large amount of potassium into liver and skeletal muscle cells for storage, thereby preventing a rapid increase in serum potassium levels (4). Conversely, when serum potassium levels decrease, potassium stored in liver and skeletal muscle cells is released into the blood to maintain potassium levels within the normal range (5). The kidneys are the primary organs responsible for potassium excretion. Renal tubular cells are rich in ion channels and pumps, which regulate sodium reabsorption and potassium excretion (6). Additionally, other organs such as sweat glands, salivary glands, intestines, bile ducts, and lungs also contribute to a small extent in potassium excretion (7). The maintenance of potassium homeostasis relies on the renin-angiotensin-aldosterone system (RAAS) and the hypothalamic-pituitary-adrenal (HPA) feedback loop. Hormones secreted by these systems are important regulators of potassium balance (8,9). Disruptions in the regulatory mechanisms of potassium homeostasis can lead to decreased potassium excretion and the development of hyperkalemia. Similarly, when cells that store K⁺ rupture or experience cation leakage, hyperkalemia can also occur. Apart from the above pathophysiological mechanism, some surgeries or severe traumas can also lead to the occurrence of acute hyperkalemia. For example, the enhancement of sodium-potassium pump function after parathyroid surgery can ultimately lead to hyperkalemia (10).

Rationale and knowledge gap

Some cases of neonatal hyperkalemia are directly or indirectly caused by genetic disorders that affect potassium metabolism. However, there is currently a lack of comprehensive understanding of these genetic diseases, which hinders clinical recognition and management of this condition.

Objectives

This article aims to describe the characteristics of neonatal hyperkalemia from a genetic perspective to provide clinical insights. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-23-60/rc).

Methods

The studies were retrieved from PubMed, Ovid-Medline, Web of Science, China National Knowledge Infrastructure and Wanfang using the title/abstract terms “Hyperkalemia”, “Potassium”, and “Neonatal Hyperkalemia”. The gene information was retrieved from OMIM using the terms “Hyperkalemia” and “Potassium”. During the literature selection process, non-newborn related hyperkalemia, hypokalemia, and non-genetic related hyperkalemia-related diseases were excluded. The entire retrieval process was conducted independently by the author. As of April 1, 2024, a total of 85 relevant literature articles that meet the requirements have been selected (Table 1). These articles have been organized to ensure clear logical flow and provide clinical doctors with some ideas and insights.

Decreased potassium excretion

The sodium-potassium pump (Na-K-ATPase) is an important protein involved in the regulation of potassium metabolism and is widely present on the cell membranes. The basolateral Na-K-ATPase in tubular epithelial cells transports potassium from the blood into the cytoplasm of the epithelial cells and transports sodium ions (Na⁺) from the cytoplasm into the blood. When this pump is dysfunctional or influenced by other ion channels, the transport of potassium is impaired. Common ion channels involved in this process include the epithelial sodium channel (ENaC), renal outer medullary K⁺ channel (ROMK), and the thiazide-sensitive sodium-chloride cotransporter (NCC). Additionally, the RAAS is an important pathway involved in potassium metabolism. Aldosterone acts on mineralocorticoid receptors (MRs) in the cytoplasm, inducing the synthesis of ENaC proteins and Na-K-ATPase through nuclear gene regulation (11). Therefore, disruptions in aldosterone synthesis (adrenal cortex, aldosterone synthase, and RAAS hormones) or its action (MR) can lead to hyperkalemia. Furthermore, other genetic disorders that cause renal insufficiency can directly result in reduced potassium excretion.

ENaC

ENaC is mainly found in epithelial cells lining the distal renal tubules, distal colon, pancreas, salivary glands, sweat glands, and lungs. It is regulated by aldosterone and works in synergy with basolateral Na-K-ATPase to reabsorb sodium from the lumen into the blood and excrete potassium into the lumen (7,12) (Figure 1). Variants in ENaC can lead to disturbances in sodium and potassium metabolism in multiple organs throughout the body. ENaC mutations can lead to pseudohypoaldosteronism 1 (PHA1, Omim#177735), which is an autosomal recessive genetic disorder caused by mutations in the SCNN1A gene on chromosome 12p13.31, SCNN1B or SCNN1G gene on chromosome 16p12.2 (13). The main manifestations include severe systemic salt loss and dehydration, which are particularly severe in newborns. Affected infants may experience vomiting, weakness, poor feeding, and slow growth, among other nonspecific symptoms (13). In some cases, complications such as meconium ileus due to thickened colonic fluid, exocrine pancreatic insufficiency, bile duct stenosis leading to liver cirrhosis and portal hypertension, rash due to elevated sweat sodium chloride, bronchiectasis and cystic changes in the lungs leading to increased susceptibility to bacterial infections, can also occur (14). Elevated levels of sodium and chloride can be detected in sweat, saliva, urine, and feces of affected patients (15), along with increased levels of renin and aldosterone in the blood (16). This condition is a lifelong systemic disease, and as the affected individuals age, the salt-wasting state becomes difficult to manage, leading to life-threatening salt crises, severe hyperkalemia, dehydration, and recurrent respiratory tract infections. Medical management of this condition is crucial yet challenging, requiring long-term and high-dose salt supplementation, and in some cases, the use of sodium bicarbonate and potassium-lowering agents such as ion exchange resins (15).

Figure 1 Mechanism of ENaC in epithelial cells (adapted from Landau D). Upon binding with MRs in the cytoplasm, aldosterone activates nuclear gene regulation, leading to an increase in the synthesis of ENaC and Na-K-ATPase, which promotes potassium excretion (11,12). When there are variants in ENaC, the transport of Na⁺ into the blood is decreased, resulting in severe systemic salt loss (including various glandular organs such as distal renal tubules, distal colon, pancreas, salivary glands, sweat glands, and lungs (7). This leads to an increased reactive secretion of aldosterone and reduced potassium excretion into the lumen, resulting in hyperkalemia. ATP, adenosine triphosphate; MR, mineralocorticoid receptor; ENaC, epithelial sodium channel.

ROMK channel

Under normal physiological conditions, the Na-K-2Cl cotransporter located in the distal tubules of the kidneys reabsorbs potassium from the lumen into the bloodstream. Conversely, ROMK facilitates the excretion of potassium into the lumen and works in conjunction with Na-K-ATPase to maintain potassium balance (17,18). When there are variants in the ROMK channel, the ability to recycle potassium from the cell back into the lumen is compromised, resulting in a low luminal potassium concentration. This subsequently leads to decreased activity of the Na-K-2Cl cotransporter that works in synergy with ROMK, resulting in reduced potassium transport into the bloodstream and manifesting as hypokalemia (Figure 2). However, in newborns, the function of Na-K-ATPase is not fully matured, leading to a temporary hyperkalemia due to reduced potassium transport into the lumen. As the function gradually matures, hypokalemia becomes evident (11).

Figure 2 Mechanism of ROMK in the distal tubules of the kidney (adapted from Landau D). Under normal physiological conditions, the Na-K-2Cl cotransporter reabsorbs Na⁺ and K⁺ from the lumen into the cell. Through the action of Na-K-ATPase and K⁺ channels, Na⁺ and K⁺ undergo ion exchange with the bloodstream, while ROMK facilitates the excretion of K⁺ into the lumen (18). When there are variants in ROMK, the excretion of K⁺ into the lumen is reduced (①), resulting in a low luminal potassium concentration. This subsequently leads to decreased activity of the Na-K-2Cl cotransporter (②), reducing the transport of K⁺ into the bloodstream (③) and manifesting as hypokalemia. However, in newborns, the function of Na-K-ATPase is immature (▲), resulting in reduced transport of K⁺ into the lumen and temporary hyperkalemia (11). As the function matures, hypokalemia persists. ROMK, renal outer medullary K⁺ channel; ATP, adenosine triphosphate.

After variants in the ROMK channel, individuals can develop Bartter syndrome type II (BS II, Omim#241200), which is an autosomal recessive genetic disorder caused by mutations in the KCNJ1 gene located on chromosome 11q24–25. The prevalence of this condition is approximately 1 in 1,000,000 (19). Affected children typically present with polyhydramnios and prematurity in the mother, and after birth, they may exhibit symptoms such as polyuria, weight loss, and growth retardation. In newborns, transient hyperkalemia is often observed, followed by the development of hypokalemic alkalosis and hypotension as the Na-K-ATPase function gradually matures (20). The main treatment focus for BS II is correcting hypokalemic alkalosis [through potassium chloride supplementation (21)] and providing supportive care such as nutritional support (22). With proper and timely treatment, the prognosis for newborns with BS is generally good (23). However, some individuals may experience long-term complications such as renal calcium deposition, renal insufficiency, and neurodevelopmental disorders resulting from prematurity (24). Severe consequences, including dehydration, acidosis, and renal failure leading to death, have also been reported in newborns with BS (25).

CUL3-KLHL3-E3-WNK-OSR2/SPAK-NCC pathway

Under the ubiquitination mediated by CUL3-KLHL3-E3, WNK kinases bind to downstream OSR2/SPAK proteins, leading to the activation of the Na-Cl cotransporter (NCC) located in the distal convoluted tubules. This activation promotes the reabsorption of Na⁺ and Cl⁻. When there are mutations in CUL3 or WNK, the activity of WNK kinases is enhanced. This results in increased opening of NCC, leading to excessive reabsorption of Na⁺ and Cl⁻ in the distal convoluted tubules. Additionally, the opening of water channel proteins (AQP) is increased. On the other hand, the reabsorption of Na⁺ by ENaC in the collecting duct epithelial cells is reduced. The transport of K⁺ by ROMK, which works in synergy with ENaC, is also decreased. As a result, there is a decrease in Na-K-ATPase-mediated transport of Na⁺ and K⁺, leading to hyperkalemia and even metabolic acidosis (26) (Figure 3).

Figure 3 Mechanism of the CUL3-KLHL3-E3-WNK-OSR2/SPAK-NCC pathway. Under normal physiological conditions, the CUL3-KLHL3-E3 complex ubiquitinates WNK kinases, which then bind to downstream OSR2/SPAK proteins. After phosphorylating three amino acid residues, this complex activates the NCC located in the distal convoluted tubules, promoting the reabsorption of Na⁺ and Cl⁻ (26). When there are mutations in CUL3 or WNK, the activity of WNK kinases is enhanced. This leads to excessive activation and opening of NCC, resulting in increased reabsorption of Na⁺ and Cl⁻ in the distal convoluted tubules (leading to hyperchloremia). Additionally, there is an increased opening of AQP (contributing to hypertension) (26) (①). In contrast, the reabsorption of Na⁺ by ENaC in the collecting duct epithelial cells is reduced (②). This leads to a corresponding decrease in Na-K-ATPase-mediated transport of Na⁺ and K⁺, as well as a decrease in the excretion of K⁺ by ROMK (③), resulting in hyperkalemia. ATP, adenosine triphosphate; AQP, water channel protein; NCC, sodium-chloride cotransporter.

Variants in the CUL3 protein or WNK kinases can lead to pseudohypoaldosteronism type 2 (PHA2, Omim#145260), which is an autosomal dominant genetic disorder. The mutated genes involved in PHA2 are the WNK4 gene on chromosome 17q21, the WNK1 gene on chromosome 12p13.3, and the KLHL3 gene (27). The exact prevalence of PHA2 is not yet clear. In addition to hyperkalemia, the main characteristics of PHA2 are hyperchloremia and hypertension. Electrolyte disturbances associated with PHA2 can be detected in infancy, and hypertension often persists for several decades. Since the NCC is sensitive to thiazide diuretics, continuous low-salt diet and thiazide diuretics can effectively treat PHA2 (28).

Aldosterone synthesis

Aldosterone is a type of mineralocorticoid hormone secreted by the adrenal cortex. It acts on MRs in the cytoplasm, forming a hormone-receptor complex that traverses the nuclear membrane and enters the nucleus. Through gene regulation, it induces the synthesis of ENaC proteins and Na-K-ATPase, while also promoting mitochondrial ATP synthesis. This plays a role in sodium retention and potassium excretion (11). Additionally, aldosterone synthesis relies on the action of aldosterone synthase. Therefore, when there is adrenal cortical insufficiency or insufficient aldosterone synthase, it can lead to hyperkalemia.

Primary adrenal insufficiency (PAI)

PAI, also known as Addison’s disease (29), is a comprehensive manifestation of a group of diseases. In newborns, the causes are often related to genetic factors (30). PAI is characterized by high potassium, low sodium, low aldosterone, high levels of corticotropin-releasing hormone (CRH), adrenocorticotrophic hormone (ACTH), and renin (Figure 4). Affected individuals often experience symptoms such as hypoglycemia, anorexia, nausea, vomiting, salt craving, hyperpigmentation, myalgia, and abdominal pain, among other nonspecific manifestations (9,31). In severe cases, adrenal crisis may occur. The reported incidence of adrenal crisis is approximately 6-8 per 100 person-years, with a mortality rate of 0.5 per 100 person-years (32). The main treatment for PAI involves replacement therapy with glucocorticoids and mineralocorticoids. Hydrocortisone is the preferred choice, with an initial dose of 8 mg/m² divided into three doses for children.

Figure 4 Mechanism of primary adrenal insufficiency. Under normal physiological conditions, the adrenal cortex secretes aldosterone, which promotes potassium excretion. When there is adrenal cortical insufficiency (①), the secretion of aldosterone decreases (②), leading to hyperkalemia and hyponatremia. In severe cases, adrenal crisis may occur, characterized by symptoms such as hypotension (③). The HPA axis has a negative feedback mechanism (9), which results in enhanced function of the hypothalamus and pituitary gland, leading to increased secretion of CRH and ACTH (③). Blue arrows refer to the negative feedback mechanism. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotrophic hormone; HPA, hypothalamic-pituitary-adrenal.

PAI mainly includes X-linked adrenal hypoplasia congenita (X-AHC, Omim#300200) and adrenoleukodystrophy (ALD, OMIM#300100). X-AHC is associated with mutations in the nuclear receptor transcription factor DAX-1, encoded by the NR0B1 gene on the Xp21 chromosome. DAX-1 is expressed in the gonads, adrenal cortex, hypothalamus, and pituitary gland (30). Mutations in DAX-1 directly lead to adrenal cortical insufficiency and also affect gonadal function. The prevalence of X-AHC is approximately 1:140,000 to 1:1,200,000 (33). In newborns, the main manifestations of X-AHC are as described for PAI, some even characterized by extreme hyponatremia (34); while in young individuals, there may be additional sequelae such as short stature, hypogonadotropic hypogonadism, azoospermia, and impaired fertility (35). ALD is caused by the inability to metabolize very long-chain fatty acids, resulting in their accumulation in the brain, spinal cord, and adrenal cortex, leading to cellular toxicity, apoptosis, and organ atrophy (36). It follows an X-linked recessive inheritance pattern and is caused by mutations in the ABCD1 gene on the Xq28 chromosome. The prevalence of ALD is approximately 1:20,000, with higher rates in Latino and African populations (37). The onset of symptoms is typically during adolescence, but newborn screening may provide important clues for early detection and treatment of the disease (38). Patients with ALD can develop spinal cord disease and cerebral ALD, leading to neurological impairments and even disability or death (39). Early hematopoietic stem cell transplantation is currently the only treatment option for cerebral ALD, but it does not alter the course of PAI (40). However, research suggests that hematopoietic stem cell gene therapy may be another important treatment approach (41).

Aldosterone synthase

The synthesis of aldosterone relies on the activity of various enzymes involved in aldosterone synthase. When there is impaired enzyme generation, it leads to decreased aldosterone synthesis. The HPA feedback loop responds by increasing the production of CRH and ACTH (42), promoting adrenal hyperplasia and resulting in congenital adrenal hyperplasia (CAH, Omim#201910). CAH is an autosomal recessive genetic disorder, and the most common type is caused by a deficiency in 21-hydroxylase (CYP21A, Omim#613815), which is due to mutations in the CYP21A2 gene located on chromosome 6p21. According to incomplete statistics, the incidence of CAH in the Chinese population is approximately 1:6,084 (43). Additionally, the enhanced function of the hypothalamic-pituitary-gonadal axis promotes the synthesis of sex hormones such as testosterone, 17-hydroxyprogesterone, and androstenedione, as well as progesterone. Therefore, affected individuals may exhibit signs of masculinization in females (44). The salt-wasting presentation in newborns with this type of CAH is often severe, and adrenal crisis can occur within two to three weeks after birth (45). Therefore, for infants with ambiguous external genitalia, non-palpable bilateral gonads, or positive results on newborn screening, salt-wasting CAH should be considered, and prompt treatment with glucocorticoids (hydrocortisone is the preferred choice for children (46), with an infant dose of 8–12 mg/m² and a child dose of 10–15 mg/m²; divided into 3-4 doses per day) as well as mineralocorticoids and sex steroid replacement therapy should be initiated (47).

RAAS

The RAAS is an important pathway that regulates potassium metabolism. Mutations in any of the components of the RAAS, including renin (REN gene, 1q32), angiotensinogen (AGT gene, 1q42), angiotensin-converting enzyme (ACE gene, 17q23), and angiotensin II receptor type 1 (AGTR1 gene, 3q24), can lead to decreased secretion of angiotensin II and aldosterone downstream (48), resulting in hyperkalemia (Figure 5). Gene mutations along this pathway can also lead to abnormal development of the proximal tubules in the kidneys, resulting in renal tubular dysgenesis (RTD, Omim#267430). RTD is a rare autosomal recessive inherited disorder and is considered a lethal disease in newborns, often seen in premature infants. The affected individuals have reduced levels of angiotensin II and aldosterone in their serum, and renal pathology reveals a severe reduction or absence of proximal tubules (49). During pregnancy, the fetus produces very little urine, leading to persistent oligohydramnios, decreased fetal movements, but apparent abnormalities in fetal kidney ultrasound are difficult to detect. In newborns, the characteristic features include the Potter sequence (pulmonary hypoplasia, abnormal facies, and limb abnormalities) and delayed cranial ossification (such as a large fontanelle and delayed closure of sutures), with severe cases presenting with respiratory failure, refractory hypotension, and death (48,50). Acute management of RTD primarily involves supportive care. It is worth noting that standard fluid replacement and catecholamines may be ineffective in treating hypotension, while vasopressin and hydrocortisone may be more effective (51). The survival rate of newborns with RTD is very low, and those who survive often develop chronic renal failure later in life, ultimately requiring kidney transplantation (52).

Figure 5 Mechanism of the RAAS. When there are gene mutations in any component of the RAAS, including renin, angiotensinogen, ACE, and AGTR1 (①), it can lead to decreased secretion of angiotensin II and aldosterone (②), resulting in hyperkalemia (③). Blue arrows refer to the negative feedback mechanism. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotrophic hormone; ACE, angiotensin-converting enzyme; RAAS, renin-angiotensin-aldosterone system; AGTR1, angiotensin II receptor type 1.

MR

The MR is mainly expressed in the distal renal tubules and distal colon, serving as the target site for aldosterone (Figure 1). It is encoded by the NR3C2 gene located on chromosome 4q31.1 (53). When there are gene mutations in the receptor, the renal tubules become resistant to the effects of aldosterone, leading to an imbalance in potassium metabolism in the kidneys and the development of renal PHA1 (Omim#177735), also known as autosomal dominant PHA1. Compared to autosomal recessive PHA1, patients with this type of PHA1 often only exhibit mild symptoms of renal salt loss and do not present severe systemic salt wasting. The treatment response is good, and oral supplementation of sodium chloride in early infancy can alleviate the symptoms without the need for lifelong treatment (54).

Others

Genetic disorders related to renal dysfunction can directly lead to potassium excretion disorders in the kidneys. For example, nephronophthisis (NPHP) is a ciliopathy that affects multiple organs in the body, with manifestations of chronic tubulointerstitial nephropathy in the kidneys. It initially presents as renal cysts that progress to end-stage kidney disease (55), eventually leading to severe hyperkalemia. NPHP is inherited in an autosomal recessive manner, and the NPHP2 gene (inversin, Omim#602088) on 9q31 is the only gene associated with the infantile form (56). This type is extremely rare (57), and there have been no reported cases in newborns. Infants with this condition can experience severe renal failure and acidosis early on, with a poor prognosis.

Birk-Landau-Perez syndrome (BILAPES, Omim#617595) is an autosomal recessive syndromic developmental disorder caused by mutations in the SLC30A9 gene on chromosome 30p9 (58). It is more common among the Bedouin population. Infants or young children present with significant developmental delay, including renal dysfunction, hypotonia, ataxia, growth impairment, and abnormal eye movements (59,60).

Isolated hyperchlorhidrosis (Omim#143860), also known as isolated high chloride sweat, is characterized by severe infantile hyponatremic dehydration and hyperkalemia due to reduced activity of carbonic anhydrase XII (CA XII) in sweat glands, leading to excessive salt loss in sweat. It is inherited in an autosomal recessive manner and is caused by mutations in the CA XII gene on chromosome 12q15.22 (61). It is primarily observed in individuals of Israeli descent, with the youngest reported case being a 1-month-old infant (62). Only one case report of a 3-month-old child from China has been documented (61). Laboratory tests show hyponatremia, hyperkalemia, increased aldosterone and renin levels, and elevated chloride concentrations in sweat. Salt deposits can be seen on the skin surface (63). The condition is characterized by growth retardation and may even lead to pulmonary cystic fibrosis (64). Infants with isolated hyperchlorhidrosis respond well to sodium chloride supplementation, with rapid improvement of symptoms and a good prognosis (61).

K⁺ distribution abnormalities can occur when there is an increase in cell permeability or rupture, causing K⁺ to be released from the intracellular fluid into the bloodstream, leading to a significant increase in blood potassium levels. Genetic factors that are associated with this include the rupture or leakage of skeletal muscle cells and red blood cells.

Abnormal K⁺ distribution

K⁺ is mainly distributed in the intracellular fluid. When cell permeability increases or even ruptures, K⁺ can be released from the intracellular compartment into the bloodstream, leading to a significant increase in blood potassium levels. Genetic factors related to this primarily include the rupture or leakage of skeletal muscle cells and red blood cells.

Rupture of skeletal muscle cells

When a large number of skeletal muscle cell membranes are damaged, the cells rupture, leading to a rapid influx of K⁺ into the bloodstream. This process is accompanied by the release of components such as creatine kinase and myoglobin. It can result in severe complications such as acute renal failure, hyperkalemia with cardiac arrest, disseminated intravascular coagulation (DIC), or compartment syndrome. This condition is known as rhabdomyolysis (65). The classic triad of rhabdomyolysis includes muscle pain, weakness, and dark urine. Conditions characterized by increased metabolism or metabolic disorders such as malignant hyperthermia (MH), lipid metabolism disorders, and mitochondrial energy synthesis disorders can lead to ATP depletion or insufficient synthesis, causing disruption of skeletal muscle cell membrane integrity and subsequent cell rupture (66).

MH

MH (Omim#145600) is a genetic disorder of skeletal muscle metabolism that manifests as a hypermetabolic response to potent volatile anesthetics such as halothane, sevoflurane, desflurane, and succinylcholine. It is inherited in an autosomal dominant pattern and is associated with mutations in the ryanodine receptor gene (RYR1) on chromosome 19 (67). The incidence of MH is estimated to be between 1:3,000 and 1:8,500 (68), with limited reports in newborns. MH patients typically exhibit significantly elevated levels of creatine kinase in their serum, along with hyperkalemic acidosis. Typical clinical manifestations include high fever, tachycardia, rapid breathing, increased oxygen consumption, and muscle rigidity and spasms (68). If left untreated, ongoing muscle cell death can lead to life-threatening hyperkalemia, and myoglobinuria may result in acute renal failure. Therefore, in cases of unexplained hypermetabolic symptoms following anesthesia, MH should be suspected. The treatment principles for MH include removing triggering agents, intravenous administration of dantrolene, active cooling, and symptomatic treatment of severe conditions such as hyperkalemia, acidosis, arrhythmias, and DIC (69).

Muscular dystrophy

Muscular dystrophy is a group of genetic disorders characterized by abnormalities in the structural proteins that maintain the integrity and function of muscle cell membranes (70). The two main types of muscular dystrophy are Duchenne muscular dystrophy (DMD, Omim#310200) and Becker muscular dystrophy (BMD, Omim#300376). Both are inherited in an X-linked pattern and are caused by mutations in the dystrophin gene (DMD) on the Xp21 chromosome. Approximately 1 in every 3,000–3,600 male newborns is affected by these conditions (71). Patients with muscular dystrophy typically experience muscle wasting and weakness. When exposed to the anesthetic succinylcholine, they may develop rhabdomyolysis, and in severe cases, hyperkalemia with cardiac arrest can occur (72). Therefore, perioperative management is crucial for patients with muscular dystrophy.

Other metabolic disorders

Other metabolic disorders include fatty acid and carbohydrate metabolism disorders. Fatty acid degradation primarily occurs through the mitochondrial fatty acid β-oxidation (mFAO) pathway, which is an important physiological process for maintaining energy homeostasis in the body. Defects in mFAO-related enzymes, such as carnitine palmitoyltransferase II deficiency (CPT2 gene, 1p32, Omim#600650) and phosphatidic acid phosphatase (LPIN1 gene, 2p25.1, Omim#605518), can disrupt fatty acid metabolism and impact the function of multiple organs, including the skeletal muscle system (73). Almost all enzymes and transport proteins associated with mFAO can have genetic defects, and they are typically inherited in an autosomal recessive manner. The prevalence of these disorders varies greatly among different countries and regions, with an estimated incidence of 1:10,000–15,000 (74). In addition to the manifestations related to rupture of skeletal muscle cells, patients may exhibit low blood ketones and hypoglycemia. TANGO2 deficiency (transport and Golgi organization protein 2, Omim#616830) is a rare mitochondrial metabolism disorder that has been discovered in recent years. It is inherited in an autosomal recessive pattern and presents clinically similar to mFAO disorders (75,76).

Ion leakage in skeletal muscle cells

Skeletal muscle cell membranes contain Na⁺ channels that regulate ion exchange. When there are mutations in the Na⁺ channel protein subunits, the transport of Na⁺ into the cells is reduced. This leads to a decrease in Na-K-ATPase activity on the skeletal muscle cell membrane, resulting in the extrusion of Na⁺ and a reduction in the transport of K⁺ into the cells. This phenomenon is known as “ion leakage” and is seen in hyperkalemic periodic paralysis (HyperPP, Omim#170500). HyperPP is a neuromuscular disorder characterized by episodes of muscle paralysis. It is inherited in an autosomal dominant pattern and is caused by mutations in the SCN4A gene on chromosome 17q23 (77). The estimated incidence is approximately 1 in 200,000 (78). Symptoms can appear within the first year of life and include recurrent episodes of slow-onset muscle weakness and temporary paralysis, which can last from minutes to days. These episodes are often triggered by a high-potassium diet and are associated with changes in serum potassium levels. Fatigue and weakness are commonly observed during these episodes (79). Therefore, individuals with HyperPP should avoid consuming potassium-rich foods or using potassium-sparing diuretics. Acute attacks can be treated with carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide), beta-adrenergic agonists, and thiazide diuretics (78). Over time, the frequency and severity of flaccid muscle weakness attacks increase until around the age of 50, after which the frequency significantly decreases. Some patients may experience permanent muscle weakness and chronic progressive myopathy (80).

Ion leakage in red blood cells

Abnormal-shaped red blood cells can cause chronic hemolytic anemia, but generally do not lead to significant hyperkalemia. However, in special cases where there is an increased permeability of cation channels in the red blood cell membrane due to ion channel mutations, “ion leakage” can occur, resulting in hyperkalemia. Hereditary stomatocytoses (HST, Omim#609153) is a group of heterogeneous hemolytic anemias that are associated with mutations in genes encoding ion transport proteins or channels (81). Under normal physiological temperature, K⁺ leakage is generally not significant, but it increases markedly at low temperatures (82). HST includes familial pseudohyperkalemia (FP, ABCB6 gene), dehydrated hereditary stomatocytosis (DHS, PIEZO1 gene), cryohydrocytosis (CHC, SLC4A1 gene), and overhydrated hereditary stomatocytosis (OHS). Except for OHS, FP, DHS, and CHC can exhibit increased cation permeability and increased K⁺ efflux under laboratory low-temperature conditions, leading to pseudohyperkalemia (83). This phenomenon does not occur at normal body temperature. Therefore, in clinical practice, it is important to differentiate whether hyperkalemia is a laboratory artifact caused by experimental conditions, to avoid excessive correction of electrolyte imbalances.

Conclusions

Neonatal hyperkalemia is a common and severe electrolyte imbalance. And the risk factors of severe hyperkalemia include renal failure, hyperglycaemia, or inappropriate use of potassium supplements and other drugs that affect potassium homeostasis (84). Neonates with severe hyperkalemia may show electrocardiogram changes and hemodynamic instability, such as peaked T waves, QRS widening, broadened ST-T segments and diminished P waves (84). The common therapies of severe hyperkalemia include intravenous calcium salts to reverse membrane polarization abnormalities bicarbonate, insulin, or beta-2 agonists to shift potassium from the extracellular to the intracellular compartment; and resins or dialysis to remove potassium from the extracellular compartment (85).

Overall, in addition to non-genetic causes, there are genetic disorders that can lead to hyperkalemia in newborns, which may not be the sole manifestation of these disorders. When encountering neonatal hyperkalemia in clinical practice, after ruling out non-genetic causes, consideration should be given to the possibility of these genetic disorders based on other clinical manifestations, and appropriate diagnosis and treatment should be provided. This article mainly summarizes the genetic background of neonatal hyperkalemia from the aspects of decreased potassium excretion and increased potassium generation (Table 2), aiming to provide some diagnostic and therapeutic insights for clinicians. When the neonatal hyperkalemia observed in clinical practice cannot be solely explained by non-genetic factors such as improper feeding and parenteral nutrition, acute renal failure, surgery, trauma, etc., the clinical characteristics, triggers, examination and treatments summarized in this article for each type of gene-related disease will provide a certain reference for clinical diagnosis. This can help clinicians make a diagnosis more quickly, clarify whether further genetic testing is needed, and consequently provide accurate diagnosis and treatment plans to reduce adverse outcomes. It is beneficial for physicians to anticipate the prognosis of affected children early on, and provide parents with a more accurate explanation in a timely manner.

In this paper, there are certain limitations. For example, some of the literature reviewed includes cases that do not strictly occur during the neonatal period, or some literature lacks comprehensive understanding of these diseases, which limits the completeness and expansiveness of this paper. In the future, it is necessary to continue tracking newly published relevant articles for further improvements and supplements, making this paper more comprehensive.

This narrative review summarizes the genetic background of neonatal hyperkalemia and related diseases, which overall meets the professional needs of current clinicians and provides certain guidance in clinical practice. However, due to the limited number of published literature, the expansiveness of this article is still lacking. Further tracking and supplementation of the literature is necessary in the future. Overall, this article has a certain clinical relevance and provides guidance in the field.

Acknowledgments

Thanks for the contributions made by ChatGPT in the translation of writing the manuscript.

Funding: None.

Footnote

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