pediatrics
Approach to the Patient With a Suspected Inherited Disorder of Metabolism
Evaluation
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 Lethargy Poor feeding Vomiting Seizures Disorders that manifest later tend to affect growth and development, but vomiting, seizures, and weakness may also appear. suggests decreased anabolism or increased catabolism and may be due to decreased availability of energy-generating substrates (eg, in Glycogen Storage Diseases [GSD]) or inefficient energy or protein use (eg, in organic acidemias or may reflect chronic energy deficit in the brain (eg, Mitochondrial Oxidative Phosphorylation Disorders ), decreased supply of needed carbohydrates that are non-energy substrates for the brain (eg, lack of uridine-5 such as seizures, muscle weakness, hypotonia, myoclonus, muscle pain, strokes, or coma, may suggest acute energy deficit in the brain (eg, hypoglycemic seizures in Glycogen Storage Diseases , strokes in 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. can result from hypoglycemia caused by increased glucose consumption or decreased glucose production (eg, vomiting, diaphoresis, pallor, and tachycardia in Glycogen Storage Diseases or 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 ). reflect accumulation of specific compounds (eg, sweaty feet odor in Isovaleric acidemia , smoky-sweet odor in on exposure to air occurs in some disorders (eg, darkish brown in Alkaptonuria , purplish brown in may reflect a failure in substrate degradation resulting in substrate accumulation within the organ cells (eg, hepatomegaly in hepatic forms of Glycogen Storage Diseases and many 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 Screening Tests for Newborns results and ordering of basic metabolic screening tests, which typically include the following: Glucose Electrolytes with calculation of anion gap Complete blood count and peripheral smear Liver tests Ammonia levels Serum amino acid levels Urinalysis Urine organic acids Glucose measurement detects hypoglycemia or hyperglycemia; measurement may have to be timed relative to meals (eg, fasting hypoglycemia in Glycogen Storage Diseases ). Electrolyte measurement detects Tyrosinemia type I and presence or absence of an 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 inureacycle 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 testsmay 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. typically begins with gene sequencing to detect one of the hundreds of known mutations. Other confirmatory tests less often used include biopsy (eg, liver biopsy to distinguish hepatic forms of Glycogen Storage Diseases 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 Challenge testingis 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,glucagonchallenge 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. 