Neonatal Rhabdomyolysis: A Case Report and Review of the Literature

Abstract

Rhabdomyolysis is a potentially life-threatening condition in pediatric patients, often triggered by various factors, such as infections, trauma, hereditary metabolic disorders, and certain medications. Elevated creatine kinase levels are commonly observed in newborns and are often attributed to factors such as hypoxia, labor dystocia, and birth trauma. However, rhabdomyolysis in this population is rare and typically associated with hereditary metabolic disorders, medications, or infections. In this report, we describe the case of a neonate diagnosed with very long-chain acyl-CoA dehydrogenase deficiency after markedly elevated creatine kinase levels and rhabdomyolysis were identified during the neonatal period. Additionally, we suggested a guideline for the evaluation of creatine kinase elevation and rhabdomyolysis in neonates.

Keywords

very long-chain acyl-CoA dehydrogenase deficiency - rhabdomyolysis - newborn

Introduction

Rhabdomyolysis is a critical condition characterized by the breakdown of skeletal muscle tissue due to various triggers, leading to the release of cellular components into the bloodstream. These components include electrolytes (e.g., potassium and phosphorus), enzymes (e.g., lactate dehydrogenase, aldolase, and aspartate aminotransferase), creatine kinase (CK), myoglobin, and purines.[1] Although there are no universally established criteria for diagnosing rhabdomyolysis in the pediatric population, in adult patients, a CK level exceeding five times the upper limit of normal or greater than 1,000 U/L is commonly used. Similar criteria are often applied to children for identifying rhabdomyolysis.[2] [3]

In the pediatric population, the primary causes of rhabdomyolysis include infections, particularly viral infections, followed by hereditary conditions, trauma, and exercise. Although infections and hereditary disorders are more common during the first decade of life, trauma, exercise, and drug-related factors are more prevalent in the second decade. Additional contributing factors include inflammatory myopathies (e.g., sarcoidosis, dermatomyositis), illicit substances (e.g., heroin, cocaine), toxins (e.g., ethanol, carbon monoxide, snakebites), and certain food items (e.g., mushrooms, licorice).[3]

Among hereditary causes, Carnitine Palmitoyl Transferase 2 (CPT2) deficiency is the most common genetic etiology, characterized by autosomal recessive inheritance. Other significant hereditary causes include fatty acid oxidation disorders, glycogen storage disease type V (McArdle disease), glycogen storage disease type VII (Tarui disease), and mitochondrial disorders.[4]

Although elevated CK levels are frequently observed in the neonatal period, rhabdomyolysis is rare in this age group. This article presents a case of neonatal rhabdomyolysis and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) in a patient diagnosed due to significantly elevated CK levels on the first postnatal day. Additionally, we propose a guideline for evaluating elevated CK levels during the neonatal period.

Case Report

Our patient was admitted to the neonatal intensive care unit (NICU) for monitoring on the first postnatal day due to observations of weak crying, hypotonia, and reduced feeding during bedside assessment with the mother. The female patient, born weighing 3,080 g to a mother with gravida 3, parity 2, alive 1, and curettage 1, had a sibling who died of sudden cardiac arrest on the second postnatal day. There was no history of consanguinity between the mother and father. On physical examination, the patient exhibited hypotonia and bradykinesia, along with a 2/6 systolic murmur detected at the mitral focus. No pathological findings were observed in evaluations of other body systems. Laboratory tests revealed an alanine aminotransferase (ALT) level of 141 U/L and an aspartate aminotransferase (AST) level of 662 U/L. The CK level was markedly elevated at 60,516 U/L. Blood gas analysis showed no evidence of metabolic acidosis or elevated lactate levels. Tandem mass spectrometry suggested a fatty acid oxidation disorder, with the following levels measured: Sebacyl (C10DC): 0.3 µmol/L (reference range: 0–0.25); Dodecanoyl (C12): 1.17 µmol/L (reference range: 0–0.4); Myristoyl (C14): 8.03 µmol/L (reference range: 0–0.36); Tetradecenoyl (C14:1): 10.16 µmol/L (reference range: 0–0.33); Tetradecadienoyl (C14:2): 0.9 µmol/L (reference range: 0–0.41); Palmitoyl (C16): 15.77 µmol/L (reference range: 0–1.51); Palmitoleyl (C16:1): 2.12 µmol/L (reference range: 0–0.27); Stearoyl (C18): 3.26 µmol/L (reference range: 0–0.61); Oleyl (C18:1): 2.15 µmol/L (reference range: 0–1.51). Urine organic acid analysis was normal.

Ophthalmologic examination, brain magnetic resonance imaging (MRI), and abdominal ultrasonography revealed no pathological findings. However, an atrial septal defect was detected during the echocardiographic examination. Based on the clinical and laboratory findings, the possibility of a fatty acid oxidation disorder, particularly mitochondrial trifunctional protein deficiency, was considered in the patient. Consequently, during the 15-day follow-up in the neonatal intensive care unit, treatment with riboflavin (100 mg) and coenzyme Q10 (30 mg) was initiated. The patient's diet was adjusted to contain 15% fat, utilizing enteral products devoid of long-chain fats and enriched with medium-chain triglycerides (MCTs), along with breast milk. Genetic analysis revealed a compound heterozygous mutation in the ACADVL gene, specifically c.1377del (p.Ile460SerfsTer32) and c.1269 + 1G > A (IVS12 + G > A), confirming the diagnosis of VLCADD.

During outpatient follow-up, the patient was hospitalized twice in the intensive care unit due to metabolic crises. The first hospitalization occurred at 3 months of age with complaints of vomiting, which led to an elevation in CK levels to 7,865 U/L and the subsequent development of hypertrophic cardiomyopathy and hepatomegaly during monitoring. During this period, it was determined that the mother did not fully adhere to the prescribed dietary treatment. The diet was subsequently revised to be appropriate for her age and weight. Dietary adjustments, including a diet with 20% fat (25% as MCT of total fat) and 15% protein, resulted in significant improvement in cardiomyopathy and hepatomegaly. The second hospitalization occurred at 8 months of age due to constipation and decreased oral intake, which triggered a metabolic crisis, manifesting as a subfebrile fever following admission. During this episode, CK levels rose to >149,668 U/L. Currently, at 14 months of age, the patient shows no evidence of hepatomegaly on physical examination and continues to develop appropriately for age. The patient's diet is maintained with 20% fat content (25% as MCT) and 15% protein, along with complementary nutrition and triheptanoin.

Discussion

Rhabdomyolysis in children can be attributed to various etiological factors, with approximately two-thirds of cases resulting from infections and trauma. Other causes include genetic and metabolic disorders, medications, toxins, and excessive exercise. In healthy newborns, CK levels are higher than those in adults and peak 24 to 48 hours after birth. Mild elevations in CK levels during the neonatal period (two to four times the upper limit of normal) are common and are generally associated with birth trauma.

There is a lack of clear and sufficient data in the literature regarding the definition and etiological classification of rhabdomyolysis in the neonatal period, with most available information coming from case reports. No definitive criteria have been established to determine when secondary CK elevation due to hypoxia can be classified as rhabdomyolysis.

There are a few reported cases of neonatal rhabdomyolysis in the literature. Among these, metabolic disorders were identified as the underlying cause in most cases. Medications, hypoxia, infections, and congenital muscular dystrophy have been reported less frequently as causes of neonatal rhabdomyolysis.

In the literature, 15 cases of neonatal rhabdomyolysis due to metabolic causes have been documented. Among these, five patients were diagnosed with VLCADD,[5] [6] two patients had mitochondrial trifunctional protein (MTP) complex deficiency (one of whom had long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency [LCHADD]),[7] one patient had long-chain 3-ketoacyl-CoA thiolase (LCKAT) deficiency,[8] one patient had cytochrome-C oxidase (COX) deficiency,[9] three patients had methylmalonic acidemia (MMA),[10] one patient had phosphopantothenoylcysteine synthetase (PPCS) deficiency,[11] one patient had multiple acyl-CoA dehydrogenase deficiency (MADD),[12] and one patient had propionic acidemia (PA).[10] In total, 8 out of 15 cases (53.3%) of metabolic causes were attributed to fatty acid oxidation disorders.

Among five patients diagnosed with VLCADD, three were reported deceased, while two were alive. The highest CK level in VLCADD cases was 25,660 U/L, observed in one of the two surviving patients. This patient presented on postnatal day 3 with feeding difficulties, fever, dehydration, and elevated CK levels. There was no reported history of consanguinity or sibling death in the family. The patient, confirmed to carry pathogenic variants c.848T > C (p.Val243Ala) and c.751A > G (p.Ser251Gly) in the ACADVL gene, was discharged on postnatal day 19.[5]

Our case presented with weak crying, reduced movements, and decreased feeding on the first postnatal day. A CK level of 60,516 U/L was detected. Although there was no consanguinity, a history of sibling death prompted consideration of inherited metabolic disorders, ultimately leading to the confirmation of VLCADD through metabolic and genetic investigations. The significant elevation of CK levels due to rhabdomyolysis in a newborn on the first postnatal day is a surprising finding. To date, there have been no reports in the literature of a VLCADD case with a higher CK level. We suggest that VLCADD should be considered in neonates presenting with such markedly elevated CK levels.

The medications implicated in cases of rhabdomyolysis secondary to drug use include valproic acid,[13] propofol,[14] and pyridoxine.[15] In the case of pyridoxine toxicity, complications were associated with an underlying deficiency of cystathionine β-synthase (homocystinuria).

In conclusion, elevated CK levels are frequently encountered in newborns; however, complications such as renal dysfunction, cardiac arrhythmias, and death are extremely rare in neonatal rhabdomyolysis. The number of reported cases of rhabdomyolysis in the neonatal period is very low, which may be attributed to the lack of clear criteria for diagnosing rhabdomyolysis in newborns based on CK levels. The most common cause of neonatal rhabdomyolysis is reported to be congenital metabolic disorders, followed by medications. Among congenital metabolic disorders in the neonatal period, fatty acid oxidation defects, particularly VLCADD, are the most frequently observed. In these patients, CK levels can vary widely. While reviewing cases of CK elevation and rhabdomyolysis in the neonatal period from the literature, we propose a diagnostic algorithm for CK elevation ([Fig. 1]).

Fig. 1 The algorithm for elevated creatine kinase (CK) levels in the neonatal period.

Conflict of Interest

None declared.

Acknowledgments

The authors would like to thank metabolic dietitian Eşgi M. for her excellent care of our patients and Çavuşoğlu A. M. for algorithmic graphic support. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Publikationsverlauf

Eingereicht: 17. September 2024

Angenommen: 13. Dezember 2024

Accepted Manuscript online:
19. Dezember 2024

Artikel online veröffentlicht:
09. Januar 2025