Approach to the Patient With a Suspected Inherited Disorder of Metabolism

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 Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more [GSD]) or inefficient energy or protein use (eg, in organic acidemias or urea cycle defects Urea Cycle Disorders Urea cycle disorders are characterized by hyperammonemia under catabolic or protein-loading conditions. There are many types of urea cycle and related disorders (see the table) as well as many... read more ).

Developmental delay may reflect chronic energy deficit in the brain (eg, oxidative phosphorylation defects Mitochondrial Oxidative Phosphorylation Disorders Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the central nervous system, retina, and muscle. See also Approach to the Patient... read more ), 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 Galactosemia Galactosemia is a carbohydrate metabolism disorder caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive... read more ), or chronic amino acid deficit in the brain (eg, tyrosine deficiency in phenylketonuria Phenylketonuria (PKU) Phenylketonuria is a disorder of amino acid metabolism that causes a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine... read more ).

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 Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more , strokes in mitochondrial oxidative phosphorylation defects Mitochondrial Oxidative Phosphorylation Disorders Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the central nervous system, retina, and muscle. See also Approach to the Patient... read more ) 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 Urea Cycle Disorders Urea cycle disorders are characterized by hyperammonemia under catabolic or protein-loading conditions. There are many types of urea cycle and related disorders (see the table) as well as many... read more ) 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 Pyruvate dehydrogenase deficiency Inability to metabolize pyruvate causes lactic acidosis and a variety of central nervous system abnormalities. Pyruvate is an important substrate in carbohydrate metabolism. Pyruvate metabolism... read more ) 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 Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more or hereditary fructose intolerance Fructose Metabolism Disorders Deficiency of enzymes that metabolize fructose may be asymptomatic or cause hypoglycemia. Fructose is a monosaccharide that is present in high concentrations in fruit and honey and is a constituent... read more ) or from metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3⁻), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more (eg, vomiting and Kussmaul respirations in organic acidemias). Some conditions cause both (ie, in propionic acidemia Propionic acidemia Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more , 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 Tyrosinemia type I Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved... read more ).

Unusual odors in body fluids reflect accumulation of specific compounds (eg, sweaty feet odor in isovaleric acidemia Isovaleric acidemia Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more , smoky-sweet odor in maple syrup urine disease Maple syrup urine disease Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more , mousy or musty odor in phenylketonuria, boiled cabbage odor in tyrosinemia).

Change in urine color on exposure to air occurs in some disorders (eg, darkish brown in alkaptonuria Alkaptonuria Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved... read more , purplish brown in porphyria Overview of Porphyrias Porphyrias are rare disorders in which there are defects in the pathway of heme synthesis due to genetic or acquired deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies... read more ).

Organomegaly may reflect a failure in substrate degradation resulting in substrate accumulation within the organ cells (eg, hepatomegaly in hepatic forms of GSD Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more and many lysosomal storage diseases Overview of Lysosomal Storage Disorders Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects... read more , cardiomegaly in GSD type II Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more ).

Eye changes include cataracts in galactokinase deficiency Galactokinase deficiency Galactosemia is a carbohydrate metabolism disorder caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive... read more 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 Screening Tests for Newborns Screening recommendations for newborns vary by clinical context and state requirements. Blood typing is indicated when the mother has type O or Rh-negative blood or when minor blood antigens... read more 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 Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more ).

Electrolyte measurement detects metabolic acidosis Tyrosinemia type I Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved... read more and presence or absence of an anion gap Calculation of the anion gap Acid-base disorders are pathologic changes in carbon dioxide partial pressure (Pco2) or serum bicarbonate (HCO3⁻) that typically produce abnormal arterial pH values. Acidemia is serum... read more ; 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 Galactosemia Galactosemia is a carbohydrate metabolism disorder caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive... read more , tyrosinemia type I Tyrosinemia type I Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved... read more ). Anion gap acidosis occurs in inherited disorders of metabolism in which accumulation of titratable acids is typical, such as methylmalonic acidemia Methylmalonic acidemia Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more and propionic acidemia Propionic acidemia Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more ; it can also be caused by lactic acidosis Lactic Acidosis Lactic acidosis is a high anion gap metabolic acidosis due to elevated blood lactate. Lactic acidosis results from overproduction of lactate, decreased metabolism of lactate, or both. (See also... read more (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 used include biopsy (eg, liver biopsy to distinguish hepatic forms of GSDs Glycogen Storage Diseases Glycogen storage diseases are carbohydrate metabolism disorders. There are many numbered and named types, all of which are caused by deficiencies of enzymes involved in glycogen synthesis or... read more 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 Overview of Lysosomal Storage Disorders Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. Inherited defects... read more ).

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.