With the exception of mitochondrial disorders, most IEM are associated with one functional type of cardiomyopathy by echocardiography, which can help narrow down the differential diagnosis (). Most IEM present during infancy or early childhood. Diseases associated with the storage of glycogen, fat, or lysosomal substrates generally cause hypertrophic cardiomyopathy. Dilated cardiomyopathy is often caused by diseases associated with excess acidic metabolites as in the organic acidemias, amino acidopathies, and systemic carnitine deficiency. In the latter, the lack of carnitine leads to the accumulation of circulating acyl-CoA species and a decrease in free CoA, which is required for intermediary metabolism.
Cardiomyopathy may be the presenting or dominant clinical feature, but careful searching often reveals other signs of a multisystemic disease as well as abnormal metabolites in blood and urine. Clinical features may include a distinctive physical appearance (e.g., coarse facial features, cloudy corneas, slow growth, and hepatosplenomegaly), neurologic findings (acute or chronic encephalopathy, developmental delay, and seizures), myopathy (hypotonia and weakness), skeletal findings (dysostosis multiplex), or liver dysfunction. In IEM that impair energy production or produce toxic metabolites, congestive heart failure often occurs in the setting of an acute metabolic decompensation triggered by energy stressors, e.g., illness, surgery, infection, fasting, or physical exertion. These inciting events may confound the initial presentation and suggest an alternative diagnosis for the cardiomyopathy, e.g., viral myocarditis. As further described below, it is important to include laboratory testing of blood and urine as part of the initial evaluation. The detection of certain basic laboratory abnormalities, e.g., metabolic acidosis with an increased anion gap, hypoglycemia, hyperammonemia, ketosis or lack thereof, or elevated liver function tests will often point the clinician in the right direction to uncovering the underlying diagnosis.
Previously, we identified several key entry points to clinical diagnostic algorithms based on clinical features and laboratory findings.(1
) The algorithms most relevant to IEM include encephalopathy (), hypoglycemia (), metabolic acidosis (), and neuromuscular symptoms (). Acute encephalopathy is typically accompanied by metabolic abnormalities in the blood, e.g.
, metabolic acidosis, hyperammonemia, and hypoglycemia, which are characteristic of small molecule diseases, whereas chronic encephalopathy is often associated with mitochondrial or lysosomal storage disorders. In the former, an event such as an intercurrent illness will often create a state of energy imbalance that leads to ineffectual production of energy and an excess of toxic metabolites.
Diagnostic Algorithm: Encephalopathy
Diagnostic Algorithm: Hypoglycemia
Diagnostic Algorithm: Metabolic Acidosis with an Increased Anion Gap
Diagnostic Algorithm: Neuromuscular Symptoms
Hypoglycemia is often the result of ineffective fat metabolism, either from the inability to break down triglycerides, fatty acids, or ketones. Thus, the presence or absence of ketones is a useful starting point for evaluation. Patients with inappropriately low ketones in the setting of low blood sugar (hypoketotic hypoglycemia) have an inability to break down triglycerides into fatty acids and glycerol or to break down fatty acids into ketones through fatty acid oxidation. The latter are associated with low insulin and high free fatty acid levels in blood, dicarboxylic aciduria (from ω-oxidation of fatty acids in peroxisomes), and low carnitine levels in blood. A specific diagnosis is often suggested by the acylcarnitine profile in blood. The absence of dicarboxylic acids points towards the inability of fatty acids to cross the plasma membrane (systemic carnitine deficiency) or into mitochondria (Carnitine-palmitoyl transferase II deficiency). Extremely low carnitine levels (< 10 μmol/L) are seen in systemic carnitine deficiency.
The major diagnostic branch points for the evaluation of hypoglycemia involve the measurement of ketones, insulin, free fatty acids, urine organic acids (including dicarboxylic acids), and carnitine (total and free). These assist in the determination of whether the hypoglycemia is associated with a defect in mobilizing triglycerides (overgrowth syndromes and infant of a diabetic mother), the inability to convert fatty acids into ketones (fatty acid oxidation defects or carnitine-transport defects), organic acidemias, or GSD III. Specific diagnoses are often suggested by specific species identified on the blood acylcarnitine profile.
The major branch points for metabolic acidosis with an increased anion gap (> 15 mEq/L) focus on determining the identity of the offending anion, which can be lactic acid, ketoacids, more complex organic acids (propionic acid), or fatty acids. The different acids are distinguished by direct measurement in blood by routine clinical testing (lactic, ketoacids, free fatty acids) or by tandem-mass spectrometry as acylcarnitine derivatives. When the lactate level is increased, the lactate:pyruvate ratio (L:P) can help to distinguish pyruvate dehydrogenase deficiency (L:P < 15) and oxidative phosphorylation defects (L:P > 25).
The neuromuscular symptoms that point towards an IEM are weakness/hypotonia beginning in infancy and ataxia (). Pompe disease is a major cause of “floppy baby syndrome” and the hypotonia can be so severe that it can mimic spinal muscular atrophy. The diagnosis of Barth syndrome is suggested in a male by the presence of neutropenia, a low cholesterol level, and 3-methylglutaconic aciduria. Other metabolic diagnoses presenting with weakness/hypotonia may be guided by laboratory testing and/or skeletal muscle biopsy. Ataxia is a common feature in mitochondrial disorders and Refsum disease. The former is often associated with chronic encephalopathy, cardiac conduction defects, and arrhythmias, whereas Refsum disease is associated with deafness, atypical retinitis pigmentosa, and elevated plasma phytanic acid levels.