Barth Syndrome and Neutropenia

Barth syndrome is an X-linked, hereditary cause for neutropenia, cardiomyopathy, muscle weakness and growth retardation. It is attributable to mutations of TAZ, a gene encoding a highly conserved acyltransferase necessary for the maintenance of the phospholipids of the inner layers of mitochrondrial membranes. There is a wide diversity in the TAZ mutations but as yet no recognized genotype-phenotype correlations.

We collected and analyzed data for 83 patients (all males, Severe Chronic Neutropenia International Registry, Barth Syndrome Foundation and NHS Barth Syndrome Service in the UK). Fifty-four are currently less than 18 years old (median age 13.6 years, range 0.2-31.6 years). Absolute neutrophil counts (ANC) varied remarkably (median 1.1 x 10⁹/L, range 0.14-5.4 x 10⁹/L). A few patients have cyclic variations in the ANCs, but most have not had a sufficient series to determine if the variations show periodicity. Mouth ulcers, bleeding gums, skin infections, and upper respiratory infections were the most common complications, but pneumonia, sepsis, and more severe infections occurred sporadically. Comparisons of reported events for the population suggest that patients with baseline neutrophil counts< 0.5 x 10⁹/L have more infections than patients with higher counts.

Data were available for 42 patients with neutropenia sufficiently severe to be treated with G-CSF by their physicians. On average, G-CSF was begun at 5.8 years (median age 4.3, range 0.05-21.5 years), with the median dose of 1.67 mcg/kg/d, mean 2.78 +/- 0.78 (SEM) mcg/kg/d (range 0.45-12.8 mcg/kg/d), with an average exposure of 7.3 years.

With longitudinal follow-up, 15 patients have had cardiac transplants and no patients have developed AML or received bone marrow transplantation and treatment responses to G-CSF are maintained long term. Bone marrow examinations were generally not performed, either before or on G-CSF treatment. Longitudinal observation suggests that the hematological profiles of individual patients are largely unchanged from childhood into adulthood, without evidence of worsening or amelioration. Additional clinical and laboratory data are need to define the genetic determinants and hematological features of Barth syndrome.