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.
Corrigendum: This article has been corrected as per the corrigendum published with (Doi: 10.1055/a-2678-0792).
