What Are Some Common Presentations for Inborn Errors of Metabolism?

Patient Presentation
A 14-year-old male was admitted for increasing seizures and a febrile illness. He had recently moved to a new care facility but had lived in one for several years because of ornithine transcarbamalyse deficiency (OTC deficiency), severe mental retardation and seizures, and he needed 24 hour nursing care and supervision. He had a temperature of 102° F off and on for 2 days. He was non-verbal but appeared to be having a sore throat to the staff. His seizures had increased from 2-3 tonic-clonic seizures/day to 6-7/day especially when anti-pyretics wore off. He also hadn’t been drinking as well. The staff at the new facility was very concerned and felt that they could not properly care for him, so he was transferred. The past medical history showed that he was diagnosed with OTC deficiency after multiple episodes of emesis. An allopurinol challenge test showed increased orotic acid. He also had a history of 2 episodes of cystitis but the evaluation of his genitourinary systems were negative. The review of systems showed minor cough, no rhinorrhea, rashes, or changes in bowel habits, but he did have some decreased urination.

The pertinent physical exam showed a non-verbal male with a temperature of 101.5° F and his respiratory rate was 30. His weight was 50%. HEENT revealed thick secretions in his mouth and purulent material on the tonsils. He became somewhat agitated when examining his mouth. Bilateral tympanic membranes were thickened and had decreased movement but had no erythema. There were shoddy anterior cervical nodes. Heart was normal but his lungs had coarse breath sounds and slightly diminished sounds on the right. Abdomen was normal. Neurologically he would look at the examiner, and would help with movement in the bed. His capillary refill was about 2 seconds. The laboratory evaluation showed a complete blood count with a hemoglobin of 11.5 mg/dl, white blood cell count of 16.4 x 1000/mm2 with a 20% left shift. Urinalysis, glucose and electrolytes were normal. A rapid strep test was positive. His portable chest x-ray showed some consolidation at the right lung base. The diagnosis of group A, beta-hemolytic streptococcal pharyngitis and possible lobar pneumonia was made. Because he was somewhat dehydrated he was given intravenous fluids with glucose and one dose of ceftriaxone. Genetics was consulted to assist with his OTC treatment. His glucose and electrolytes were always normal and he then began to eat his normal diet after 24 hours. Neurology was also consulted and they did not want to change his medication as he had been well controlled previously. He became afebrile and was discharged to his care on day 2 on oral antibiotics to finish a 10 day course. He had had 3 seizures in the prior 24 hours, and slightly diminished breath sounds on the right at discharge.

Each inborn errors of metabolism (IEM) by itself is often rare but taken as a whole, IEM are common. IEM often present in the newborn or infancy periods but can present at any time including adulthood. The genetic defect often causes a problem in the catabolism or synthesis of carbohydrates, fats, or proteins. The defect causes a blockage in the metabolic pathway with intermediate molecules accumulating (often toxic accumulations) before the blockage and metabolites after the blockage being scarce (inadequate energy production/utilization). Diet and stresses including surgery, trauma, and illness often can trigger intermittent decompensation.

Common IEM include:

  • Carbohydrate metabolism – carbohydrate intolerance, geoneogenic and glycogenolytic disorders, glycogenic storage defects
  • Fat metabolism – fatty acid oxidation
  • Protein metabolism – amino acidopathy, organic acidopathy, urea cycle defects
  • Oxidation defects – mitochondrial disorders, peroxisomal disorders
  • Storage disorder – lysosomal storage disorders

Learning Point
Some presentations of IEM include:

  • Acute encephalopathy
    • Usually due to toxic accumulations in organic acidemia, urea cycle defects and some amino acidemia
    • Presentation may include lethargy, poor feeding, vomiting, abnormal muscle tone, tachypnea and decreased arousal progressing to coma
    • Acute encephalopathy caused by IEM often have:
      • Hyperammonemia
        • Usually due to urea cycle defects and organic acidemia, or transient hyperammonemia of the newborn
        • Ammonia is usually in the 1700 mcg/dL but can be lower. Ammonia > 100 mcg/dL in the neonate or >80 mcg/dL in an infant are considered elevated
      • Metabolic acidosis with an increased anion gap
        • Usually due to organic acidemias such as methylmalonic acidemia, propionic acidemia and isovaleric acidemia
        • A normal anion gap is usually due to diarrhea or renal tubular acidosis
        • Pyruvate and lactate are often abnormal
  • Hypoglycemia
    • Usually due to glycogen storage diseases and fatty acid oxidation
    • Presentation may include organomegaly (tongue, liver, heart), symptoms consistent with congestive heart failure, arrhythmia, tachypnea, hypotonia, mental status changes
    • Hyperammonemia, elevated liver enzymes, metabolic acidosis
  • Jaundice and Liver Dysfunction
    • Usually due to erythrocyte metabolism or liver dysfunction
    • Presentation may also include vomiting, diarrhea, poor weight gain
    • Hypoglycemia may also be a presenting feature
  • Abnormal Odor
    • Often due to isovaleric acidemia (sweaty feet smell), glutaric acidemia (sweaty feet smell) or maple syrup urine disease (maple syrup or burnt sugar smell)
  • Dysmorphic features
    • Associated with Zellweger syndrome, neonatal adrenal leukodystrophy, and other problems
    • Dysmorphic features may be isolated
  • Storage Diseases
    • Usually present in later infancy or childhood
    • Presentation may include organomegaly, coarse facial features, skeletal abnormalities

Initial laboratory tests to investigate for possible IEM generally includes:

  • Complete blood count for neutropenia, thrombocytopenia and anemia, and possible sepsis
  • Blood gas, electrolytes, bicarbonate – for electrolyte imbalance and evaluation for metabolic acidosis
  • Blood urea nitrogen and creatinine – evaluate renal function
  • Bilirubin (direct and indirect) – direct hyperbilirubinemia is more likely to be associated with an IEM
  • Transaminases – evaluate hepatic function, hepatocyte destruction
  • Coagulation profile – evaluate hepatic synthetic function, and possible sepsis
  • Ammonia level, lactate and pyruvate – evaluate various IEMs
  • Glucose

Questions for Further Discussion
1. Where is the nearest center that can assist in managing a patient with an IEM?
2. What protocols are in place at my local hospital for evaluating an infant who presents with sudden death?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Streptococcal Infections and Throat Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Burton, BK. Inborn Errors of Metabolism in Infancy: A Guide to Diagnosis. Pediatrics. 1998;102;e69.

Weiner DL. Inborn Errors of Metabolism. eMedicine. Available from the Internet at http://emedicine.medscape.com/article/804757-overview (rev.3/30/09, cited 8/24/09).

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Systems Based Practice
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.
    26. Partnering with health care managers and health care providers to assess, coordinate, and improve health care and how these activities can affect system performance are known.

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital