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
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
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.