2025 – PAGE 353 – INBORN ERRORS OF METABOLISM & MISCELLANEOUS METABOLIC DISORDERS

ORNITHINE TRANSCARBAMYLASE DEFICIENCY

In ornithine transcarbamylase deficiency, the serum is completely void of citrulline and arginine because OTC is not catalyzing the reaction needed to make citrulline! This is the most common defect, and it’s X-linked. It is much more symptomatic in boys than in the girl carriers, who only get symptoms when they are sick. Look for a HIGH urine Orotic Acid (all of the built-up carbamoyl phosphate gets turned into this).

MNEMONICS: ORnithine transcarbamylase deficiency results in elevated ORotic acid in BOYS who watch “ORotic” movies. Girls can also be symptomatic from this disorder, and from “ORotica,” but it’s more sympto­matic in boys.

CITRULLINEMIA

Look for a very high citrulline level to indicate citrullinemia because it is not being broken down into Argininosuccinic Acid (ASA) and then Arginine, due to a defect in Argininosuccinic Synthetase (ASS).

ARGININOSUCCINIC ACIDURIA

In argininosuccinic aciduria, the defect is at Argininosuccinate Lyase. Look for a moderately elevated citrulline and an elevated Argininosuccinic Acid level, of course.

UREA CYCLE LAB SUMMARY (TABLE)

MITOCHONDRIAL DISORDERS

These are disorders of ENERGY metabolism; therefore, anaerobic metabolism kicks in, and there will be elevated LACTIC ACID and PYRUVATE levels. Uric acid levels are also increased because of increased protein catabolism. The clinical picture can be quite varied between different defects and even among people with the same defect. Muscle disease is usually a feature. Multisystem disease is common. Skeletal and visceral muscle, heart, brain, liver, eyes, hearing system, and other organs can all be affected. Patients can also have strokes in mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS). Confirmatory diagnosis requires gene analysis for a mitochondrial disorder.

PEARL: Associate the word “mitochondrial” with energy since it is the powerhouse of the cell.

PEARL: Don’t think about mitochondrial inheritance. Most of these disorders are autosomal recessive, while a few rare ones do have mitochondrial inheritance.

FATTY ACID OXIDATION DISORDERS

The fatty acid metabolism disorders include deficiencies in MCAD (medium chain acyl-coA dehydrogenase), LCAD (long chain acyl-coA dehydrogenase), and VLCAD (very long chain acyl-coA dehydrogenase). The problem here is that the mitochondria is not able to break down fatty acids. Patients present when there is a stressor, or meals are spread out and carbohydrate reserves become depleted, resulting in an inability to metabolize fatty acids. Look for hypoglycemia (because that’s the trigger), metabolic acidosis (lactic acid ± uric acid from protein breakdown), and hyperammonemia (from excessive protein breakdown) but NO KETOACIDOSIS because the fatty acids cannot be broken down into ketones! Urine will be negative for reducing substances (since this is not a carbohydrate issue), negative for ketones, and the serum will have normal organic acids. There may be a transaminitis and possible hepatomegaly (but no splenomegaly). Diagnosis requires a carnitine and acylcarnitine levels. These only present when there is hypoglycemia, so they do not present in the first week of life.

PEARL: If given an answer choice with a disease that has “Acyl-Co-A dehydrogenase” in the name of it, that IS a fatty acid oxidation disorder.

MNEMONIC: Ever heard of a FATTY LIVER? Imagine the inability of fatty acid breakdown being so bad that all of the fat deposits in the liver cause it to be a palpable FATTY ACID LIVER.