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Approach to the Patient With a Suspected Inherited Disorder of Metabolism

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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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.

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.

History and physical examination

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.

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.

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 ).

Initial testing

When an inherited disorder of metabolism is suspected, evaluation begins with a review of neonatal screening test Screening Tests for Newborns Hand washing is critical for all personnel to prevent transmission of infection. Active participation in the birth by the mother and her partner helps them adapt to parenting. Immediately at... read more 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

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 pH 7... 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.

Specific and confirmatory testing

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 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.

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