Barth Syndrome

Genetic disorder with dilated cardiomyopathy, neutropenia, and skeletal myopathy with muscle weakness.

Fatal Infantile X-Linked Cardiomyopathy; Cardioskeletal Myopathy with Neutropenia and Abnormal Mitochondria; Cardioskeletal Myopathy-Neutropenia; 3-Beta Methylglutaconic Aciduria, Type II.

Rare, but families from various parts of the world have been described.

Barth syndrome (BTHS) is ascribed to mutations in the G4.5 gene (tafazzin, TAZ), which is encoded on chromosome Xq28. The syndrome is transmitted in an X-linked recessive mode, and heterozygous females are healthy carriers because of skewed X-chromosome inactivation.

Electron microscopic examination reveals abnormal mitochondria in skeletal muscle, myocardium, liver, kidney, and myelocytes. Diminished cytochrome concentrations have been demonstrated in isolated mitochondria, presumably associated with defects in the respiratory chain reaction. Neutropenia results from arrested granulopoiesis at the myelocyte stage.

Clinical picture, family history, muscle biopsy, and genetic analysis. In addition, mildly elevated levels of 3-methylglutaconate, 3-methylglutarate, and 2-ethylhydracrylate in the urine are common. Low l-carnitine levels have been described occasionally.

The hallmark of BTHS is a combination of dilated cardiomyopathy with endocardial fibroelastosis, neutropenia with severe infections, and skeletal myopathy with muscle weakness, sparing the extraocular and bulbar muscles. Onset of cardiomyopathy may be precipitous and the response to standard congestive heart failure treatment variable. The degree of myeloic dysfunction ranges from chronic severe neutropenia to sporadic episodes of neutropenia. Phenotypic expression of BTHS is variable. Forms with late onset and milder courses have been described, as have severe forms with lethal noncompaction of the left ventricular myocardium. Fasting ketone production is normal, but mild lactacidosis and hypoglycemia have been observed in some patients. One case report described rapid deterioration with l-carnitine; the patient subsequently showed dramatic improvement of cardiac function, growth, and neutrophil count with large doses of pantothenic acid. Before the advent of transplantation medicine, affected males died of cardiac failure or septic complications in infancy or early childhood. Now, survival for more than 7 years following heart transplantation has been reported.

Cardiac dysfunction should be assessed and treatment optimized preoperatively. Personal history should include previous anesthesias, palpitations, syncopes, and current medication. Electrolytes must be within the normal range. For elective surgery, the patient should be free of current infections. If muscle weakness is clinically relevant, pulmonary function testing including measurement of maximum inspiratory pressures identifies those who might be at risk for prolonged mechanical ventilation after anesthesia.

Fluid administration and systemic vasoconstriction must be carefully titrated to optimize cardiac output and maintain blood pressure stability. Maintaining a high heart rate decreases left ventricular filling during diastole, thereby decreasing end-diastolic pressure and myocardial oxygen demand. Note that in advanced stages, myocardial sensitivity to catecholamines often is increased. Adequate glucose administration should be provided and glucose and lactate levels monitored. A strictly aseptic technique is mandatory to prevent infections in patients with neutropenia, which may already be present at birth.

Volatile anesthetics are safe in lower concentrations, but may cause myocardial depression at higher concentrations. Benzodiazepines usually are well tolerated, but may cause hypotension if cardiac performance is marginal or if the patient is relatively volume depleted from chronic diuretic therapy. In contrast, barbiturates are better avoided for myocardial depression, and ketamine is generally regarded as disadvantageous because of its sympathomimetic effects and consequent increase in afterload. Succinylcholine is best avoided because of the potential risk of hyperkalemia in the presence of generalized myopathy. Although nondepolarizing muscle relaxants are not contraindicated, because of the generalized muscle weakness they should be used, if at all, in reduced doses and with a peripheral nerve stimulator only.

X-linked endocardial fibroelastosis and X-linked cardiomyopathy are regarded as different phenotypic expressions of the same disorder.