Inborn Errors of Metabolism Clinical Presentation

The history varies with age at presentation and is a function of the age at which various inborn errors of metabolism (IEMs) manifest clinically.

• The patient’s history may include the following:

  • Symptoms that range from abrupt in onset and episodic to chronic and progressive
  • Poor feeding, vomiting, failure to thrive, lethargy
  • Developmental delay, sometimes with loss of milestones
  • Onset of symptoms with change in diet and unusual dietary preferences, particularly protein or carbohydrate aversion
  • Decompensation out of proportion to what would be expected from intercurrent infection
  • Similar findings of unexplained neonatal or sudden infant deaths in siblings or maternal male relatives (A negative family history does not rule out IEM.)
  • Possible parental consanguinity (increases the likelihood of autosomal recessive IEM)
• Neonate

  • Consider an inborn error of metabolism (IEM) in any critically ill neonate.
  • Frequently, the most important clue is a history of deterioration, often life-threatening, after an initial period of apparent good health ranging from hours to weeks, usually following an uncomplicated pregnancy and delivery in a term infant.
  • In term infants without risk for sepsis who develop the symptoms of sepsis, metabolic disease may be nearly as common as sepsis. A negative newborn screen result does not exclude diagnosis of metabolic disease.
  • Nearly all states and many countries test newborns for a core set of 29 diseases, and many test for more than 50 diseases, most of which are IEMs using tandem mass spectrometry. Tests screened for by each state are provided by the National Newborn Screening and Genetics Resource Center (see National Newborn Screening Status Report).^[2] It usually takes a few days and sometimes weeks until results are available. False-negative findings can result from screening too early, from medications, from transfusions, and from sample collection and handling. For every true positive newborn screen result, 12-60 false-positive results occur depending on the inborn error of metabolism (IEM).^[3] Cut-off values have been deliberately set to yield a low rate of false-negative results.
• Infants and young children (1 mo to 5 y)

  • Onset of symptoms may coincide with what are normally developmentally appropriate changes in diet that result in increased intake of protein and carbohydrates or with increased duration of fasting as infants begin sleeping through the night.
  • A history of recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, or fulminant (Reye syndrome–like) hepatoencephalopathy.
  • Infants may appear and act normal between episodes or have a history of poor feeding, failure to thrive, fussiness, decreased activity and/or developmental delay, sometimes with loss of milestones.
  • With routine illnesses, infants with an inborn error of metabolism (IEM) may become more severely symptomatic, develop symptoms more rapidly, or require longer to recover than unaffected children.
• Older children (>5 y), adolescents

  • Undiagnosed metabolic disease should be considered in older children (>5 y), adolescents, or even adults with subtle neurologic or psychiatric abnormalities.
  • Many individuals previously diagnosed as having birth injury or atypical forms of psychiatric disorders or medical diseases, such as multiple sclerosis, migraines, or stroke, actually have an undiagnosed inborn error of metabolism.

The physical examination findings are nonspecific in most patients with inborn errors of metabolism (IEM), and examination findings may be normal. When present, physical findings provide important clues to the presence of an inborn error of metabolism, the category, and, occasionally, the specific metabolic disease (see Table 1 in Workup).

Examination finding usually relate to major organ dysfunction or failure, most commonly hepatic and/or neurologic, and less commonly, cardiac or pulmonary.

Abnormalities include failure to thrive; dysmorphic features; abnormalities of hair, skin, skeleton, or all three; abnormal odor; organomegaly; and abnormal muscle tone.

Finding may be indistinguishable from those of sepsis, respiratory illness, cardiac disease, GI obstruction, renal disease, and CNS problems. Presence of these conditions does not rule out the possibility of an inborn error of metabolism.

• Neonate

  • Symptoms for inborn errors of metabolism of substrate and intermediary metabolism develop once a significant amount of toxic metabolites accumulate following the initiation of feeding and may include the following: poor feeding, vomiting, diarrhea, and/or dehydration; temperature instability; tachypnea; apnea; bradycardia; poor perfusion; irritability; involuntary movement; posturing; abnormal tone; seizures; and altered level of consciousness.
  • Certain inborn errors of metabolism (including galactosemia during the newborn period) and certain organic acidopathies may be associated with an increased risk of sepsis.
  • For neonates with inborn errors of substrate and intermediary metabolism, the physical examination findings are usually unremarkable.
  • For inborn errors of metabolism (IEMs) of energy deficiency, symptoms usually develop within 24 hours of birth and are often present at birth. Neonates with inborn errors that result in defects in energy production and use often have dysmorphic features, skeletal malformations, cardiopulmonary compromise, organomegaly, and severe generalized hypotonia.
  • Inborn errors of metabolism most likely to cause acute decompensation in the neonate include certain forms of the tyrosinemia, organic acidemias, urea cycle defects, fatty acid oxidation defects, and galactosemia.
• Infants and young children

  • Recurrent episodes of vomiting, ataxia, seizures, lethargy, coma, fulminant hepatoencephalopathy, or a combination
  • Dysmorphic or coarse features, skeletal abnormalities, and abnormalities of the hair or skin
  • Poor feeding, failure to thrive
  • Dilated or hypertrophic cardiomyopathy, hepatomegaly, jaundice, and liver dysfunction
  • Developmental delay, occasionally with loss of milestones
  • Ataxia, hypotonia or hypertonia, and visual and auditory disturbances
• Older children, adolescents, and adults

  • Common findings include mild to profound mental retardation, autism, learning disorders, behavioral disturbances, hallucinations, delirium, aggressiveness, agitation, anxiety, panic attacks, seizures, dizziness, ataxia, exercise intolerance, muscle weakness, and paraparesis.
  • Some manifestations may be intermittent, precipitated by the stress of illness, changes in diet, exercise and/or hormones, or progressive, with worsening over time.
  • While most inborn errors of metabolism (IEMs) diagnosed in this age group are not immediately life threatening, partial ornithine transcarbamylase (OTC) deficiency, a urea cycle defect, can manifest at this time as a life-threatening metabolic catastrophe. This is observed particularly in adolescent females with a history of protein aversion, abdominal pain, and migrainelike headaches.

Diet or stress (ie, from intercurrent illness, trauma, surgery, or immunization) may precipitate episodic decompensation.