Barth Syndrome and Severe Chronic Neutropenia.

Abstract 3787

Barth syndrome is an X-linked recessive genetic condition characterized by neutropenia, cardiomyopathy, growth delay, muscle weakness, and 3-methylglutaconic aciduria (an increase in organic acid caused by abnormal mitochondria). Its clinical manifestations are variable and can include fatigue, hypotonia, and dilated cardiomyopathy. Symptoms usually appear at birth or within the first few months of life. Mutations in the tafazzin (TAZ) gene cause Barth syndrome.

The Severe Chronic Neutropenia International Registry (SCNIR) is building a base of information about the natural history and response to granulocyte colony stimulating factor (G-CSF) treatment for patients with Barth syndrome and other causes of chronic neutropenia. Through the SCNIR, we follow the clinical course and treatment of seven male subjects (median age 17 years, range: 6–28 years) with Barth syndrome observed for up to 11 years (median 9, range 3–11). Six of these seven subjects were neutropenic prior to G-CSF treatment, the median absolute neutrophil count (ANC) was 0.293 × 10⁹/L (range 0 – 1.260). The seventh subject was not consistently neutropenic, median ANC 2.107 × 10⁹/L (range 0.779 – 3.520).

Sixteen bone marrow evaluations were performed on four of the seven subjects. Four of 16 bone marrows were prior to G-CSF exposure (3 subjects). Two of three subjects manifest eosinophilia in the marrow but not in the blood. Marrow exams for two of the three subjects' evaluations were read as normocellular marrow, and one of the three was read as hypocellular with a decrease in cells of the myeloid series. Twelve of the 16 bone marrow evaluations were performed in two subjects who were receiving G-CSF. One of the four subjects had bone marrow evaluations both before and after G-CSF exposure. His pre G-CSF evaluations displayed hypocellular bone marrow, and his post G-CSF evaluations showed normocellular bone marrow and eosinophilia. None of the marrow evaluations before or on G-CSF suggested myelodysplasia or showed evidence of acute myeloid leukemia.

The six neutropenic subjects have all received G-CSF for a median of 96 months (range 28 – 137) at a median dose of 1.57 mcg/kg/day (range 0.43 to 2.18). The total G-CSF exposure for all six subjects is 507 months. The median ANC of the six subjects prior to G-CSF treatment was 0.293 × 10⁹/L (range 0–1.260). The median ANC on G-CSF was 2.056 × 10⁹/L (range 1.640–3.403).

Prior to receiving G-CSF, three of the seven subjects reported mouth ulcers. Two of seven subjects reported skin infections, including one subject who reported infections around the G-tube used to maintain his nutritional status. One of seven subjects reported an episode of bacteremia. Of the six subjects who received G-CSF, three reported a reduced number of mouth ulcers and two of six reported reduced skin infections (G-tube, port-a-cath). None of the subjects experienced unusual side effects or clinically significant complications associated with G-CSF therapy.

These data indicate that patients with Barth syndrome and neutropenia have ulcers and patterns of infections similar to other patients with chronic neutropenia. They are responsive to G-CSF treatment and it appears to be safe and effective to reduce their predisposition to bacterial infections.