Introduction

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare genetic disorder related to metabolism, wherein the fatty acid oxidation process occurring in the mitochondria is disrupted. It is inherited in an autosomal recessive pattern [1]. Over the past few years, many pathogenic mutations have been identified in the ACADM gene, with the c.985A>G (p.Lys329Glu) mutation being the most prevalent one [2]. The global frequency of MCADD occurrence is 1 in 14,600 live births, with a higher prevalence in European populations – up to 1 in 4,900 births in Germany [3]. The carrier frequency of the ACADM gene mutation is estimated at 1 in 40 to 1 in 100 among Northern and Western Europeans [4]. Fatty acids are the key molecules for energy production and storage in cells, particularly during fasting or increased energy demand [1, 5]. Long-chain fatty acids are transported as acyl-CoA through the outer mitochondrial membrane and subsequently from the intermembrane space into the mitochondrial matrix; this transportation process is mediated by carnitine. In the mitochondrial matrix, fatty acids undergo oxidation, known as β-oxidation, leading to the production of acetyl-CoA, which serves as a substrate for many cellular metabolic processes such as adenosine triphosphate synthesis and ketogenesis [5]. Medium-chain acyl-CoA dehydrogenase catalyzes the oxidation of fatty acids with a chain length of 6–12 carbon atoms (C6–C12). A mutation in ACADM generates an enzyme with reduced catalytic activity, leading to impaired β-oxidation of fatty acids in the cell. Due to reduced enzyme activity, during fasting or in states of increased energy demand, the amount of acetyl-CoA formed is insufficient for effective ketogenesis. As a result, patients may present with hypoketotic hypoglycemia, which is one of the characteristic symptoms of MCADD.

In Poland, since 2014, newborn screening has included tests for inherited metabolic disorders, including MCADD. A blood sample collected on a screening card is analyzed by tandem mass spectrometry. MCADD is indicated by elevated levels of acylcarnitines: C8 (octanoylcarnitine), C6 (hexanoylcarnitine), C10 (decanoylcarnitine), and C10:1 (decenoylcarnitine) [6, 7]. In patients with deficiency of C0 (free carnitine) and C2 (acetylcarnitine), acylcarnitine C6, C8, and C10 levels may be only slightly reduced or normal [8]. The next diagnostic step is genetic testing to identify mutations in the ACADM gene. This involves DNA sequencing using the Sanger method, wherein the nucleotide sequence of the ACADM gene is determined to identify the type and location of mutations [9, 10]. In European populations, the most common mutation is c.985A>G (p.Lys329Glu), although other ACADM mutations with varying frequencies have been reported worldwide [2, 11]. The differential diagnosis should include Reye’s syndrome, which can show similar presentation to MCADD (hypoglycemia, vomiting, and elevated levels of aminotransferases) as well as other inherited disorders of fatty acid metabolism [12, 13].

Patients with MCADD experiencing metabolic crisis are at risk of developing life-threatening complications, which may lead to shock or death [1]. Despite MCADD being a rare disease, we present this case to underline the importance of taking into consideration inborn errors of metabolism when working with neonatal patients.

Case presentation

A male newborn with a body birth weight of 3340 g (10–90^th percentile) was delivered by a 30-year-old primipara. Because of imminent intrauterine asphyxia, the full-term infant was delivered through cesarean section at 41 gestation weeks according to the last menstrual period. The infant’s Apgar scale score was 9 at 1 minute and 9 at 5 minutes. The pregnancy was normal. Both infant and mother were placed in the nursery unit. The infant received standard care for a healthy newborn, including newborn screening tests. At the end of the third day of life, physical examination revealed that the newborn was lethargic, did not wake up for feeding, responded weakly to touch, and showed decreased muscle tone. As part of the treatment process, an intravenous peripheral line was inserted. Blood was collected to conduct laboratory tests, including tests for bacterial infections and blood culture. Blood glucose levels at the first measurement and after giving 5 ml of 5% glucose orally were 21 and 19 mg/dl, respectively. The newborn was immediately transferred to the Intermediate Care Unit of the Neonatology Clinic and administered a 10% glucose infusion (4 mg/kg/min). Glucose levels were closely monitored, reaching 98 mg/dl one hour after the start of the infusion and later 154 mg/dl. Because of presumed infection and low viability, broad-spectrum empirical antibiotic therapy (ampicillin + gentamicin) was initiated. Laboratory tests revealed elevated serum levels of urea (244.7 mg/dl), lactate (31.5 mg/dl), and creatine kinase (CK) (887 U/l). Following consultation with a metabolic disease specialist, glucose infusion was restarted as required (6 mg/kg/min), and breastfeeding was provided at 2-h intervals, with 25 ml per feeding.

The saturation, heart rate, critical parameters – glucose, pH, pCO₂, pO₂ (measured using an ABL Automatic Blood Gas Analyser), urine output, and daily fluid balance of the newborn were monitored every 3–4 h, with regular testing for the levels of CK, lactate, NH₃, urea, transaminases, electrolytes, bilirubin, and coagulation profile (Table I). Blood was also collected on the Whatman Neonatal Screening Card for genetic testing of inherited metabolic diseases at the Institute of Mother and Child, Warsaw. Laboratory tests did not reveal any abnormalities that suggested an infection. In the following period, the infant’s condition gradually improved: his feeding became regular, and vitality increased, although hypotonia persisted. Blood CK levels continued to increase, while blood glucose levels remained stable at 79–99 mg/dl. Blood cultures for aerobic and anaerobic bacteria were negative. The newborn screening results (Table II) showed increased levels of C6 (hexanoylcarnitine): 3.15 μmol/l (normal up to 0.26 μmol/l), C8 (octanoylcarnitine): 12.06 μmol/l (normal up to 0.27 μmol/l), C10:1 (decenoylcarnitine): 0.238 μmol/l (normal up to 0.23 μmol/l), and C10 (decanoylcarnitine): 1.13 μmol/l (normal up to 0.45 μmol/l).

In the following period, the newborn’s condition further improved; the infant was in a stable, good condition, adequately nourished with breast milk, and showed normal muscle tone as well as weight gain. Laboratory parameters – CK, lactate, NH₃, urea, transaminases, electrolytes – were normalized. Glucose infusion was gradually reduced and discontinued on the 10^th day of life, as well as antibiotics (the duration of antibiotic treatment was 7 days). The newborn was discharged home on the 13^th day of life. Following another consultation with a metabolic disease specialist, the parents were advised to feed the infant every 2–2.5 h, even at night, and to add maltodextrin to the milk if the infant showed reluctance to feed. The infant was referred to a genetics clinic and a neonatal pathology clinic for further care. At discharge, genetic test results were pending. Based on the results of genetic testing, a homozygous ACADM gene mutation c.985A>G (p.Lys329Glu) confirmed the diagnosis of MCADD.

Discussion

The first symptoms of MCADD usually appear between 3 and 24 months of age; however, these symptoms can manifest any time from the neonatal period (as in the case described above) to early adulthood [12]. It is estimated that before the introduction of screening tests, up to 25% of patients with undiagnosed disease experienced sudden death during their first metabolic crisis [14]. According to the newborn case presented above, the first symptoms occurred at the end of the third day of life.

The severity of symptoms is influenced by numerous factors, including fasting, surgical procedures, intense physical exertion, alcohol consumption, or use of other substances, including medications. Infections play a particularly important role, as they lead to increased body temperature and higher energy demands while simultaneously reducing appetite and decreasing food intake [15]. In healthy individuals, these factors lead to a low insulin-to-glucagon ratio, which further promotes lipolysis and ketogenesis, using fatty acids as a primary source of energy [5]. However, in patients with MCADD these pathways are impaired due to reduced enzyme activity, leading to hypoglycemia and metabolic crisis. The newborn was lethargic at the end of the third day of life. Physical examination revealed that he did not wake up for feeding, responded weakly to touch, and showed decreased muscle tone. These symptoms were probably caused by prolonged fasting, which is frequent even in healthy newborns during their first week of life.

A characteristic symptom of MCADD is hypoketotic hypoglycemia, which initially presents as lethargy and refusal to feed – as was observed in the present case. As hypoglycemia worsens, seizures and vomiting may occur. In the absence of prompt medical treatment, dehydration, electrolyte disturbances, and hyperammonemia can lead to cardiac arrhythmias, respiratory arrest, shock, and death [16]. CK levels may be elevated in patients with MCADD; however, it is not characteristic for this disorder. High levels of CK are indicative of rhabdomyolysis. In some patients with MCADD, prolonged hypoglycemia and seizures may lead to muscle tissue damage, causing CK levels to rise.

Each episode of metabolic decompensation carries a risk of central nervous system damage and permanent neurological deficits [1, 12]. Patients with MCADD may also develop hepatomegaly [17]. The symptoms of MCADD are listed in Table III.

Treatment of metabolic crisis in MCADD is symptomatic and aims to normalize blood glucose level (> 90 mg/dl) [18], alleviate electrolyte disturbances, restore acid-base balance, and prevent severe neurological complications. It is critical to identify the contributing factors of metabolic decompensation; if an infection is present, the corresponding treatment may be initiated [12].

Regular meals and avoiding prolonged fasting are crucial for patients with MCADD. Since MCADD affects the β-oxidation of fatty acids (which are used in many metabolic pathways as the primary source of energy when glucose serum levels are low), patients should rely on complex carbohydrates (whole grain bread, starches) to maintain stable blood glucose levels. At the first signs of hypoglycemia (weakness and hand tremors), patients should consume rapidly absorbable carbohydrates (fruit juice or glucose tablets) to elevate blood glucose levels. Patients with MCADD are also advised to exercise caution during infections, particularly those causing vomiting, diarrhea, and reduced food intake. If symptoms worsen, MCADD patients should seek prompt medical attention [12, 14, 19].

Other treatment options for MCADD remain under development. Glycerol phenylbutyrate, a drug used in urea-cycle disorders, is undergoing clinical trials for treatment of MCADD. It is proposed that glycerol phenylbutyrate may be used to address secondary hyperammonemia that occurs in some patients with MCADD during metabolic crises [1, 20]. Due to major improvements in the field of genetics and molecular biology, gene therapy is considered as a novel treatment option for MCADD. In vitro studies involving adenoviral vectors showed improvement in expression of MCADD in deficient fibroblasts, inspiring further research [21].

Historically, MCADD had a high mortality rate and was associated with sudden unexplained infant deaths, with survivors having subsequent neurologic injury. Currently, earlier diagnosis and treatment have dramatically improved mortality and morbidity.