A 2-day old term male infant was found to be hypotonic and minimally reactive during routine nursing care in the newborn nursery. At 40 hours of life, he was hypoglycemic and had intermittent desaturations to 70%. His mother had an unremarkable pregnancy and spontaneous vaginal delivery. The mother’s prenatal serology results were negative for infectious risk factors. Apgar scores were 9 at 1 and 5 minutes of life. On day 1 of life, he fed, stooled, and voided well. Our expert panel discusses the differential diagnosis of hypotonia in a neonate, offers diagnostic and management recommendations, and discusses the final diagnosis.

A 2-day old male infant born at 38 weeks and 4 days was found to be limp and minimally reactive during routine care in the newborn nursery. Just 5 hours before, he had an appropriate neurologic status when evaluated by the same nurse. He had breastfed once in the interim.

His mother received routine prenatal care in the United States without complications. Prenatal ultrasounds and maternal prenatal serologies were unremarkable. His mother had a history of a positive purified protein derivative tuberculin test and was treated for latent tuberculosis 3 years before. She had no other medical history. The parents immigrated from El Salvador 1 year before and had not traveled out of the country since that time. The couple’s first child was a girl who died in her sleep in El Salvador on the second day of life of unknown cause. The parents denied consanguinity.

The patient was born via spontaneous vaginal delivery to a now gravida 2, para 2 mother with Apgar scores of 9 and 9 at 1 and 5 minutes of life. His birth weight was 3.4 kg (56th percentile), length was 52 cm (87th percentile), and head circumference was 33 cm (12th percentile). His physical examination at birth was normal for gestational age, with appropriate neurologic, cardiac, and respiratory components. The infant uneventfully roomed with his mother during the first 2 days of life. He breastfed well every 2 to 3 hours, with good latching during lactation assessments. He appropriately stooled and voided. Routine physical assessments were performed every 8 hours per protocol, which revealed a consistently normal physical examination including neurologic status. The new finding on day of life 2 that he was limp and minimally reactive represented a significant change from his previous clinical status.

The pediatric resident on call presented to evaluate the patient. The infant was found ill appearing with a temperature of 35.4°C, pulse of 110 beats per minute, respiratory rate of 55 beats per minute, and blood pressure of 92/50 mm Hg. Oxygen saturation was 94% on room air with intermittent brief self-resolving desaturations to 70%. He was sleepy with a weak cry. He was normocephalic with no distinctive features. On pulmonary examination, he had mild supraclavicular and subcostal retractions with good air entry bilaterally. He was diffusely hypotonic with a prominent head lag. The Moro reflex was absent. He had a good suck reflex. Palmar grasp and plantar grasp were present but weak. Muscle bulk was normal. He had normal cardiac, abdominal, dermatologic, and genitourinary examinations. He had strong radial and femoral pulses and was well perfused throughout.

The constellation of symptoms, including hypotonia, hypothermia, and desaturations, is alarming for a serious process in this 2-day-old infant. Although a broad differential should be considered, the acuity and timing of the presentation can narrow the differential to a smaller set of more likely diagnoses. For example, had the patient developed symptoms immediately after birth, hypoxic ischemic encephalopathy (HIE) would be high on the differential. However, it would be unlikely for HIE to manifest acutely after 48 hours of otherwise normal activity. On the basis of pathophysiology and epidemiology, hypoglycemia or sepsis would be high on my differential.

Severe hypoglycemia itself can lead to a presentation similar to this infant’s, with altered mental status, poor tone, and an inability to maintain body temperature. Desaturations in this setting could be explained by hypoglycemic seizures. In term infants, common risk factors for hypoglycemia include being small for gestational age, large for gestational age, being an infant of a mother with diabetes, or having a maternal history of β-blocker usage.1,2 This patient did not have these risk factors. Although the absence of such risk factors is less common, it does not exclude the possibility that hypoglycemia was the instigating factor that led to the presentation.

Neonatal sepsis can also present similarly. Indications of neonatal sepsis are often nonspecific and include poor feeding, lethargy, temperature instability (including hypothermia), and respiratory symptoms. Furthermore, sepsis can lead to hypoglycemia through poor feeding and increased metabolic demands. Although this patient does not have risk factors associated with early neonatal sepsis, namely positive maternal group B streptococcus (GBS) status, prolonged rupture of membranes, or elevated maternal intrapartum temperature, sepsis should still be high on the differential.3 Neonatal sepsis occurs in 1 in 1000 births and causes 15% of all neonatal deaths.4,6 Furthermore, although GBS infections remain the leading cause of early-onset neonatal sepsis (∼36%),7 ∼80% of GBS infections occur in patients whose mothers had negative perinatal test results.8 Thus, this patient warrants complete workup for sepsis and empirical treatment.

In the general population, other diagnoses beyond these are significantly rarer. Such diagnoses could include in utero insults, neuromuscular disorders, metabolic and/or genetic disorders, endocrinological issues, and congenital heart disease.9 However, such diagnoses should remain higher on the differential in patients such as this who have a positive family history of infant death.

Initial management should be focused on stabilizing the infant and evaluating the most likely causes of illness. I would start with evaluation for hypoglycemia and sepsis and provide respiratory support. I would obtain a point-of-care glucose, complete metabolic panel, complete blood count (CBC) with differential, blood cultures, and a lumbar puncture with cerebrospinal fluid (CSF) studies and culture. Urine culture in this setting is of low utility because isolated urinary tract infections are exceptionally uncommon in infants <1 week old.10 I would empirically start broad-spectrum antibiotics. Regarding the patient’s desaturations and increased work of breathing, I would obtain a chest radiograph and venous blood gas. I would tailor respiratory support to the degree of respiratory distress.

The infant was transferred to the NICU for further management. Laboratory studies, including a full sepsis workup with lumbar puncture, were obtained (Table 1). Point-of-care glucose was 32 mg/dL. The CBC was reassuring, with a normal white blood cell count for age (16.8 × 103 cells/μL) and normal immature-to-total granulocyte ratio (1%). The CSF cell count was consistent with a mildly traumatic tap without significant pleocytosis. CSF chemistries revealed a low glucose of 26 mg/dL, consistent with systemic hypoglycemia and a mildly elevated protein of 165 mg/dL. Serum chemistry was normal except for an isolated elevation in aspartate aminotransferase (AST) (432 U/L) with a high-to-normal alanine aminotransferase (ALT) (58 U/L). Venous blood gas from the infant was unremarkable. His chest radiograph was normal.

TABLE 1

Initial Laboratory Evaluation (Day of Life 2)

Laboratory StudyNormal Values11 Test Result
CBC   
 WBC count, 103 cells per μL 9.4–34 16.8 
 Polymorphonuclear cells, % — 78 
 Lymphocytes, % — 15 
 Monocytes, % — 
 Immature granulocytes,a— 0.8 
 Immature-to-total granulocyte ratio, % <30 
 Hematocrit, % 56 53.5 
 Platelet count, 103 cells per μL 192 271 
CSF   
 RBC count, cells per μL — 1350 
 WBC count, cells per μL 0–12 
 Protein, mg/dL 56–102 165 
 Glucose, mg/dL 34–119 26 
 HSV PCR — Negative 
Blood gas   
 pH 7.29–7.45 7.41 
 Pco2, mm Hg 27–40 33.3 
 Base excess, mM −3.8 to +4.2 −3 
Chemistry   
 Sodium, mM 130–145 143 
 Potassium, mM 3.7–5.9 5.2 
 Chloride, mM 97–108 107 
 Bicarbonate, mM 17–24 18 
 Albumin, g/dL 3–3.9 3.3 
 Bilirubin, total, mg/dL <11.5 5.9 
 AST, U/L 47–150 432 
 ALT, U/L 13–45 58 
 Alkaline phosphatase, U/L 150–420 131 
Laboratory StudyNormal Values11 Test Result
CBC   
 WBC count, 103 cells per μL 9.4–34 16.8 
 Polymorphonuclear cells, % — 78 
 Lymphocytes, % — 15 
 Monocytes, % — 
 Immature granulocytes,a— 0.8 
 Immature-to-total granulocyte ratio, % <30 
 Hematocrit, % 56 53.5 
 Platelet count, 103 cells per μL 192 271 
CSF   
 RBC count, cells per μL — 1350 
 WBC count, cells per μL 0–12 
 Protein, mg/dL 56–102 165 
 Glucose, mg/dL 34–119 26 
 HSV PCR — Negative 
Blood gas   
 pH 7.29–7.45 7.41 
 Pco2, mm Hg 27–40 33.3 
 Base excess, mM −3.8 to +4.2 −3 
Chemistry   
 Sodium, mM 130–145 143 
 Potassium, mM 3.7–5.9 5.2 
 Chloride, mM 97–108 107 
 Bicarbonate, mM 17–24 18 
 Albumin, g/dL 3–3.9 3.3 
 Bilirubin, total, mg/dL <11.5 5.9 
 AST, U/L 47–150 432 
 ALT, U/L 13–45 58 
 Alkaline phosphatase, U/L 150–420 131 

HSV, herpes simplex virus; PCR, polymerase chain reaction; RBC, red blood cell; WBC, white blood cell; —, not applicable.

a

Immature granulocytes represents either metamyelocytes, myelocytes, and/or promyelocytes.

Given concern for a possible infectious etiology, empirical ampicillin, gentamicin, and acyclovir were started. Dextrose containing intravenous fluids was provided with the goal to maintain serum glucose >65 mg/dL. Within 6 hours, the infant’s clinical status significantly improved, though did not completely normalize. His lethargy, hypothermia, and hypoglycemia completely resolved. He had no additional hypoxic episodes and the increased work of breathing resolved. The diffuse hypotonia observed on previous examinations was improved, although he still had a slightly increased head lag, incomplete Moro reflex, slightly increased deep tendon reflexes (DTRs), and mildly weak palmar grasp. There was no evidence of muscle fasciculations.

The infant’s rapid clinical improvement with the normalization of his serum glucose strongly suggested hypoglycemia contributed to, at least in part, his initial decompensation. The rapid timeline for improvement was also thought to be less consistent with sepsis for an underlying etiology, especially in the setting of a normal CBC. However, an infectious etiology could not be ruled out; thus, the patient remained on empirical antibiotics. Importantly, the infant’s persistent, albeit mild, abnormalities on neurologic examination in the setting of euglycemia prompted consideration of additional underlying causes that led to his acute decompensation, such as neurologic and metabolic etiologies.

The differential diagnosis for a newborn with hypotonia is broad. The localization can be anywhere along the neural axis: the brain, spinal cord, nerve, neuromuscular junction, or muscle.12 However, identifying central versus peripheral hypotonia can help narrow the differential. To do this, it is important to determine if the infant has hypotonia and/or weakness.13 Hypotonia refers to decreased resistance to stretch, whereas weakness refers to decreased muscle strength. Central hypotonia is accompanied by increased DTRs and often altered mental status. Weakness with central hypotonia is less apparent at this age because the newborn’s movements are less controlled by the cortex. Examples of central etiologies include structural abnormalities such as cerebral malformation, HIE, and stroke. In contrast, peripheral hypotonia is associated with noticeable weakness, which may present as a weak cry, a weak grasp, a reduced Moro response, or decreased antigravity movements. These infants are often more alert. Examples for peripheral hypotonia include spinal muscular atrophy, congenital muscular dystrophies, and congenital or metabolic myopathies. Overall, central hypotonia is significantly more common than peripheral hypotonia in neonates.

After resolution of his hypoglycemia, this patient had persistent neurologic findings consistent with both central (increased DTRs) and peripheral hypotonia (mild weakness and normal mental status). In this setting, one should consider mixed muscle-brain etiologies, such as congenital muscular dystrophies or metabolic disorders.

Timing of when the infant developed hypotonia also provides important information. The acute change in his tone makes cerebral dysgenesis, syndromic causes such as Down syndrome or Prader-Willi syndrome, or spinal muscular atrophy less likely. The most common causes of sudden onset hypotonia in a newborn are toxic, metabolic, or infectious. Muscular conditions tend to have an insidious onset.

Syndromic causes of hypotonia are important to explore. Prader-Willi syndrome can present as hypotonia and poor feeding in a newborn without overt physical signs of a genetic syndrome,14 although I agree that the patient’s acute decompensation may make such syndromes less likely. Metabolic disorders can certainly cause hypotonia and hypoglycemia in a neonate. Thinking about metabolic causes, I like the approach outlined by Saudubray et al,15 which identifies 3 broad categories: disorders of intoxication, disorders of energy metabolism, and disorders of complex molecules.

Disorders of intoxication are due to problems with the use of basic nutrients and include amino acid and urea cycle disorders, organic acidemias, and disorders of metal intoxication. The toxic metabolites resulting from these disorders can lead to a worsening clinical picture over time. Disorders of energy metabolism are due to problems with energy production and use; examples include mitochondrial disorders, disorders of gluconeogenesis and glycogen storage, pyruvate metabolism disorders, and disorders of fatty acid oxidation. Finally, disorders of complex molecules include entities such as lysosomal and peroxisomal disorders; these tend to be rarer overall.

In the short-term, laboratories that would help explore the broad differential under inborn errors of metabolism are urinalysis for assessment of urine ketones, creatine kinase (CK), ammonia, and lactate. Blood amino acids, acylcarnitines, urine organic acids, and acylglycines would be helpful, but results would not be available immediately.

State newborn screenings are also extremely useful in these circumstances. Such tests have high sensitivity and are excellent screening studies for many inherited metabolic diseases. In many states, expedited testing can be requested for infants suspected of having metabolic disorders.

Given concerns for possible neurologic or metabolic etiologies, further imaging and blood studies were pursued. A head ultrasound was unremarkable. Metabolic laboratories were drawn in the context of resolving hypoglycemia (Tables 2 and 3). These studies were notable for a significant elevation in CK to >38 000 U/L (upper limit of normal for age is ∼800 U/L). Urinalysis showed trace ketones. Ammonia, lactate, and thyroid studies were normal. An expedited New England Newborn Screen was sent. Plasma and urine amino acids, urine organic acids, plasma acylcarnitines, and urine acylglycines were sent and were anticipated to take several days before the results would be known.

TABLE 2

Metabolic Laboratory Evaluation

Laboratory StudyNormal Values11 Test Result
Serum metabolic studies   
 Glucose, mg/dL 50–90 80 
 Lactate, mM 1.1–3.5 2.1 
 Ammonia, μM 56–92 49 
 CK, U/L 145–1578 >38 000 
 Thyroid stimulating hormone, μIU/mL 2.43–24.3 3.27 
 T4, ng/dL 0.94–4.39 1.16 
Urinalysis (bag specimen)   
 Protein Negative 2+ 
 Ketone Negative Trace 
 Blood Negative 3+ 
 Leukocyte esterase Negative Negative 
 Bacteria Negative Positive 
 RBC count, cells per HPF 0–3 0–3 
 WBC count, cells per HPF 0–5 6–10 
Laboratory StudyNormal Values11 Test Result
Serum metabolic studies   
 Glucose, mg/dL 50–90 80 
 Lactate, mM 1.1–3.5 2.1 
 Ammonia, μM 56–92 49 
 CK, U/L 145–1578 >38 000 
 Thyroid stimulating hormone, μIU/mL 2.43–24.3 3.27 
 T4, ng/dL 0.94–4.39 1.16 
Urinalysis (bag specimen)   
 Protein Negative 2+ 
 Ketone Negative Trace 
 Blood Negative 3+ 
 Leukocyte esterase Negative Negative 
 Bacteria Negative Positive 
 RBC count, cells per HPF 0–3 0–3 
 WBC count, cells per HPF 0–5 6–10 

HPF, high-power field; RBC, red blood cell; T4, thyroxine; WBC, white blood cell.

TABLE 3

Evaluation of Rhabdomyolysis

Laboratory StudyNormal Values11 Test Result
CK, U/L 145–1578 45 197 
 CK–muscle-brain, ng/mL — 235 
 Cardiac index, % 2.5 0.5 
Troponin I, ng/mL <4.8 0.027 
Urea nitrogen, mg/dL 2–19 16 
Creatinine, mg/dL 0.3–1.0 0.6 
Laboratory StudyNormal Values11 Test Result
CK, U/L 145–1578 45 197 
 CK–muscle-brain, ng/mL — 235 
 Cardiac index, % 2.5 0.5 
Troponin I, ng/mL <4.8 0.027 
Urea nitrogen, mg/dL 2–19 16 
Creatinine, mg/dL 0.3–1.0 0.6 

—, not applicable.

In addition to the significantly elevated CK, recall that the infant had an isolated elevation in AST without a similar increase in ALT (Table 1). Bagged urinalysis revealed 3+ blood on dipstick without an increase in red blood cells on microscopic examination (Table 2). Together, these studies were highly suggestive of significant rhabdomyolysis. Further assessment of cardiac involvement revealed a mild increase in the CK–muscle-brain isoform; however, this was thought to be most likely cross-reactivity in the setting of significantly elevated total CK levels (cardiac index 0.5%) (Table 3). Reassuringly, there was no associated increase in troponin I, and an echocardiogram was normal. Renal function did not appear significantly impaired because the infant’s creatinine was not elevated beyond what would be expected 48 hours after birth.

Given the degree of CK elevation, a congenital muscular dystrophy comes to the top of the neurologic differential. These can have related central nervous system malformations and can be consistent with this patient’s mixed peripheral/central hypotonia. Pure central nervous system diagnoses are much less likely at this point. Inborn errors of metabolism, however, are also on the differential.

With regard to the inborn errors of metabolism, the patient appears relatively hypoketotic. It is important to note that urine ketones can be challenging to interpret in the newborn period because many infants poorly produce ketones. However, this patient’s low ketones in the setting of hypoglycemia and significant rhabdomyolysis moves metabolic disorders such as fatty acid oxidation disorders much higher on the differential. However, this degree of rhabdomyolysis in the early newborn period would be an atypical presentation. Severe rhabdomyolysis typically is a dominant feature of fatty acid oxidation disorders that present in adolescence rather than in infancy. Although metabolic causes are now high on the differential, additional testing is necessary to make the final diagnosis.

When an inborn error of metabolism is suspected, caution with feeding is necessary. One must be mindful that in disorders of intoxication, toxic metabolites upstream of the blocked metabolic pathway can impair organ function. Thus, it is critical to remove the nutrient suspected to be precipitating the illness. In the case of suspected fatty acid oxidation disorders, it is imperative to remove fats from the diet and provide the patient with glucose as an immediate source of energy. Ongoing hydration for renal protection in this patient with significant rhabdomyolysis is also critical.

Given concern for a fatty acid oxidation disorder, breast milk and formula were restricted to eliminate fat from the diet, pending results of the metabolic workup. The patient was maintained on dextrose containing intravenous fluids. The CK substantially downtrended with these measures (Fig 1), which suggested that an underlying metabolic disorder (in which muscle damage was abrogated by limiting feeds) may be more likely than a muscular dystrophy. Throughout this time, the infant continued to be well appearing, with only mildly persistent hypotonia and slightly increased DTRs. There were no additional episodes of lethargy, profound hypotonia, hypothermia, or hypoglycemia.

FIGURE 1

Infant’s serum CK levels over time after enteral feeds were restricted to eliminate fat from diet on day of life 3.

FIGURE 1

Infant’s serum CK levels over time after enteral feeds were restricted to eliminate fat from diet on day of life 3.

Close modal

On day of life 4, the New England Newborn Screen resulted with an increase in very long-chain acylcarnitine species concerning for very long-chain acyl coenzyme A dehydrogenase deficiency (VLCADD), a fatty acid oxidation disorder as suspected above. Confirmation plasma acylcarnitine profile (Fig 2) revealed marked elevation in long and very long-chain acylcarnitine species (C12-C18), including tetradecenoylcarnitine (C14:1), the most characteristic metabolic marker of VLCADD. Ultimately, genetic sequencing confirmed the VLCADD diagnosis by identifying mutations in both alleles of the ACADVL gene.

FIGURE 2

Infant’s serum acylcarnitine profile on day of life 3. Serum concentrations were divided by the upper limit of normal to show fold increase above the normal range. Cx:y, x carbons in the fatty acid chain with y number of unsaturation sites; DC, dicarboxylic acid; OH, hydroxylation.

FIGURE 2

Infant’s serum acylcarnitine profile on day of life 3. Serum concentrations were divided by the upper limit of normal to show fold increase above the normal range. Cx:y, x carbons in the fatty acid chain with y number of unsaturation sites; DC, dicarboxylic acid; OH, hydroxylation.

Close modal

VLCADD is a rare autosomal recessive condition caused by mutations in the ACADVL gene, resulting in a deficiency in the rate-limiting step of fatty acid β-oxidation for long-chain fatty acids.16 The prevalence is reported to be 1 in 30 000 to 100 000 people.17 Skeletal muscle and cardiac muscle rely on fatty acid β-oxidation for energy. During a fasting state when glycogen stores are depleted, patients with VLCADD cannot mobilize energy from fat stores, leading to hypoketotic hypoglycemia, lethargy, and muscle damage. Buildup of toxic long-chain fatty acid precursors leads to multiorgan damage affecting the liver, heart, and skeletal muscle.

There are 3 typical phenotypes described in patients with VLCADD.18 The most severe form presents in early infancy and is characterized by hypoglycemia, hypotonia, cardiomyopathy, arrhythmias, and hepatomegaly. Patients with this severe early-onset presentation are at risk for multiorgan failure and fatal arrhythmias. The second form is characterized by hypoketotic hypoglycemia and hepatomegaly, without cardiac involvement, and typically presents in early childhood. The third form is characterized by exercise intolerance and rhabdomyolysis without hypoglycemia and can present in later childhood or even adulthood.

Long-term prognosis is closely tied to the severity of the initial presentation and subsequent metabolic decompensations. Patients with the severe early-onset form of VLCADD have the poorest prognosis because of the risk for fatal cardiac manifestations.

Patients with all forms of VLCADD are counseled to adhere to a diet low in long-chain triglycerides (LCTs), avoid prolonged fasting, and avoid dehydration to prevent complications such as symptomatic hypoglycemia, metabolic acidosis, and rhabdomyolysis.19 Even mild childhood viral illnesses that lead to diminished enteral intake can trigger catabolism in VLCADD patients. If this is suspected, serum glucose, chemistries, liver function tests, CK, and an electrocardiogram should be obtained. Concern for a catabolic state should also prompt hydration with high-dextrose fluids (eg, dextrose 10% water with normal saline at 1.5 times maintenance) and formula feeds with a high percentage of medium-chain triglycerides (MCTs). Use of a nasogastric tube or gastrostomy tube can be considered to assist with the management of minor illnesses. All care should be provided in consultation with a metabolism specialist.

The patient featured in this case is unique in that he had a severe and early clinical presentation with significant rhabdomyolysis yet did not exhibit any cardiac involvement. His initial presentation of hypotonia, hypoglycemia, and intermittent desaturations appropriately raised concern for sepsis or symptomatic hypoglycemia. The family history of infant death and persistent neurologic abnormalities were important pieces of the history and physical examination that triggered prompt workup for inherited explanations of hypotonia. Although an uncommon presentation in neonates, the identification of rhabdomyolysis ultimately allowed the differential diagnosis to be narrowed, enabling the team to reach the final diagnosis of VLCADD and provide appropriate management. It is interesting to note, however, that VLCADD is not commonly associated with increased DTRs, which added to the complexity of this case. It is possible that built-up toxic metabolites contributed to both the rhabdomyolysis and central deficits in this patient.

The patient from this case remained in the NICU until day of life 10. After diagnosis of his underlying metabolic disorder, appropriate enteral feeds (low in LCT and high in MCT) were restarted to provide complete nutrition required for growth and development. He was ultimately advanced to a regimen of 50% breast milk and 50% formula rich in MCT. His CK levels continued to downtrend. The infant had a transient, mild increase in his serum troponin T which self-resolved. Serial echocardiograms revealed no cardiac dysfunction throughout his hospitalization. His hypotonia fully resolved. He was discharged from the hospital with a strict feeding regimen (low in LCT and high in MCT), explicit instructions for when to seek medical care, and scheduled metabolism follow-up.

The patient was subsequently admitted to the hospital 4 times in his first 8 months of life for viral illnesses resulting in diminished oral intake and elevated CK levels. He has otherwise been growing well and meeting developmental milestones. He continues to be managed closely by a cardiologist and a metabolism/genetics specialist. He has not developed signs of cardiomyopathy. The family received genetic counseling; because VLCADD has an autosomal recessive inheritance pattern, the parents were advised that future offspring would have a 25% chance of being affected with VLCADD and a 50% chance of being asymptomatic carriers.

Evaluating an infant with hypoglycemia or hypotonia is not uncommon in the newborn nursery. For a vast majority of these cases, inherited metabolic disorders are not the underlying cause. Other etiologies such as transient hyperinsulinism, sepsis, or HIE are significantly more likely. However, as illustrated in this case, metabolic disorders should remain on the differential, especially in infants with a family history of infant death or in term infants with severe, persistent, or otherwise unexplained hypoglycemia.

Metabolic disorders can first present at any age, indicative of the large diversity of pathophysiology and severity that exists. Most infants who decline after an initial period of health often present with unexplained hypoglycemia, acid-base disorders, neurologic deterioration, cardiomyopathy and/or arrhythmias, or acute parenchymal liver disease.20 Presence of these findings should prompt additional workup.

Beyond the initial diagnostic evaluation, critical first steps are required for the management of infants with a suspected metabolic disorder. In general, this consists of minimizing catabolism and removing the toxic nutrients from the diet. These measures can be started before a precise diagnosis is made because clinical outcomes are linked with how fast treatment is initiated.

Workup and management of infants suspected of metabolic disorders should be performed in collaboration with metabolic specialists. Multiple online resources also exist that can assist clinicians in the diagnosis and treatment of such patients. These include the New England Consortium of Metabolic Programs,21 GeneReviews,22 Inborn Errors of Metabolism Knowledgebase,23 and the American College of Medical Genetics and Genomics ACTion Sheets and Confirmatory Algorithms.24 

Drs Long, Fiore, and Gillani conceptualized, drafted, and edited the manuscript; Drs Douglass, Fujii, and Hoffman edited the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CBC

complete blood count

CK

creatine kinase

CSF

cerebrospinal fluid

DTR

deep tendon reflex

GBS

group B streptococcus

HIE

hypoxic ischemic encephalopathy

LCT

long-chain triglyceride

MCT

medium-chain triglyceride

VLCADD

very long-chain acyl coenzyme A dehydrogenase deficiency

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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