Most inherited disorders of metabolism (inborn errors of metabolism) are rare, and therefore their diagnosis requires a high index of suspicion. Timely diagnosis leads to early treatment and may help avoid acute and chronic complications, developmental compromise, and even death.
Symptoms and signs tend to be nonspecific and are more often caused by something other than an inherited disorder of metabolism (eg, infection); these more likely causes should also be investigated.
Disorders manifesting in the neonatal period tend to be more serious; manifestations of many of the disorders typically include
Disorders that manifest later tend to affect growth and development, but vomiting, seizures, and weakness may also appear.
Growth delay suggests decreased anabolism or increased catabolism and may be due to decreased availability of energy-generating substrates (eg, in glycogen storage disease [GSD]) or inefficient energy or protein use (eg, in organic acidemias or urea cycle defects).
Developmental delay may reflect chronic energy deficit in the brain (eg, oxidative phosphorylation defects), decreased supply of needed carbohydrates that are non-energy substrates for the brain (eg, lack of uridine-5′-diphosphate-galactose [UDP-galactose] in untreated galactosemia), or chronic amino acid deficit in the brain (eg, tyrosine deficiency in phenylketonuria).
Neuromuscular symptoms, such as seizures, muscle weakness, hypotonia, myoclonus, muscle pain, strokes, or coma, may suggest acute energy deficit in the brain (eg, hypoglycemic seizures in GSD type I, strokes in mitochondrial oxidative phosphorylation defects) or muscle (eg, muscle weakness in muscle forms of GSD). Neuromuscular symptoms may also reflect accumulation of toxic compounds in the brain (eg, hyperammonemic coma in urea cycle defects) or tissue breakdown (eg, rhabdomyolysis and myoglobinuria in patients with long-chain hydroxyacyl dehydrogenase deficiency or muscle forms of GSD).
Congenital brain malformation may reflect decreased availability of energy (eg, decreased ATP output in pyruvate dehydrogenase deficiency) or critical precursors (eg, decreased cholesterol in 7-dehydrocholestrol reductase deficiency or Smith-Lemli-Opitz syndrome) during fetal development.
Autonomic symptoms can result from hypoglycemia caused by increased glucose consumption or decreased glucose production (eg, vomiting, diaphoresis, pallor, and tachycardia in GSD or hereditary fructose intolerance) or from metabolic acidosis (eg, vomiting and Kussmaul respirations in organic acidemias). Some conditions cause both (ie, in propionic acidemia, accumulation of acyl-CoAs causes metabolic acidosis and inhibits gluconeogenesis, thus causing hypoglycemia).
Nonphysiologic jaundice after the neonatal period usually reflects intrinsic hepatic disease, especially when accompanied by elevation of liver enzymes but may be due to inherited disorders of metabolism (eg, untreated galactosemia, hereditary fructose intolerance, tyrosinemia type I).
Unusual odors in body fluids reflect accumulation of specific compounds (eg, sweaty feet odor in isovaleric acidemia, smoky-sweet odor in maple syrup urine disease, mousy or musty odor in phenylketonuria, boiled cabbage odor in tyrosinemia).
Organomegaly may reflect a failure in substrate degradation resulting in substrate accumulation within the organ cells (eg, hepatomegaly in hepatic forms of GSD and many lysosomal storage diseases, cardiomegaly in GSD type II).
Eye changes include cataracts in galactokinase deficiency or classic galactosemia, and ophthalmoplegia and retinal degeneration in oxidative phosphorylation defects.
When an inherited disorder of metabolism is suspected, evaluation begins with a review of neonatal screening test results and ordering of basic metabolic screening tests, which typically include the following:
Glucose measurement detects hypoglycemia or hyperglycemia; measurement may have to be timed relative to meals (eg, fasting hypoglycemia in GSD).
Electrolyte measurement detects metabolic acidosis and presence or absence of an anion gap; metabolic acidosis may need to be corroborated by arterial blood gas measurement. Non-anion gap acidosis occurs in inherited disorders of metabolism that cause renal tubular damage (eg, galactosemia, tyrosinemia type I). Anion gap acidosis occurs in inherited disorders of metabolism in which accumulation of titratable acids is typical, such as methylmalonic acidemia and propionic acidemia; it can also be caused by lactic acidosis (eg, in pyruvate decarboxylase deficiency or mitochondrial oxidative phosphorylation defects). When the anion gap is elevated, lactate and pyruvate levels should be obtained. An increase in the lactate:pyruvate ratio distinguishes oxidative phosphorylation defects from disorders of pyruvate metabolism, in which the lactate:pyruvate ratio remains normal.
Complete blood count and peripheral smear detect hemolysis caused by red blood cell energy deficits or white blood cell defects (eg, in some pentose phosphate pathway disorders and GSD type Ib) and cytopenia caused by metabolite accumulation (eg, neutropenia in propionic acidemia due to propionyl CoA accumulation).
Liver tests detect hepatocellular damage, dysfunction, or both (eg, in untreated galactosemia, hereditary fructose intolerance, or tyrosinemia type I).
Ammonia levels are elevated in urea cycle defects, organic acidemias, and fatty acid oxidation defects.
Urinalysis detects ketonuria (present in some GSDs and many organic acidemias); absence of ketones in the presence of hypoglycemia with or without acidosis suggests a fatty acid oxidation defect or hyperinsulinism.
More specific tests may be indicated when ≥ 1 of the previously described simple screening tests support an inherited disorder of metabolism. Carbohydrate metabolites, mucopolysaccharides, and amino and organic acids can be measured directly by chromatography and mass spectrometry. Quantitative plasma amino acid tests should include a plasma acylcarnitine profile. Urine organic acid tests should include a urine acylglycine profile.
After screening and initial tests suggest a disorder or group of disorders, confirmatory testing typically begins with gene sequencing to detect one of the hundreds of known mutations. Other confirmatory tests less often currently needed include biopsy (eg, liver biopsy to distinguish hepatic forms of GSDs from other disorders associated with hepatomegaly, muscle biopsy to detect ragged red fibers in mitochondrial myopathy) and enzyme studies (eg, using blood and skin cells to diagnose lysosomal storage diseases).
Challenge testing is used judiciously to detect symptoms, signs, or measurable biochemical abnormalities not detectable in the normal state. The need for challenge testing has diminished with the availability of highly sensitive metabolite detection methods, but it is still occasionally used. Examples include fasting tests (eg, to provoke hypoglycemia in hepatic forms of GSD); provocative tests (eg, fructose challenge to trigger symptoms in hereditary fructose intolerance, glucagon challenge in hepatic forms of GSD [failure to observe hyperglycemia suggests disease]); and physiologic challenge (eg, exercise stress testing to elicit lactic acid production and other deformities in muscle forms of GSD). Challenge tests are often associated with an element of risk so they must be done under well-controlled conditions with a clear plan for reversing symptoms and signs.