Neutropenia in Barth syndrome: characteristics, risks, and management.

PURPOSE OF REVIEW: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 µg/kg/day (mean 1.16 µg/kg/day, median 1.16 µg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ±â€Šprophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. SUMMARY: BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ±â€Šantibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.

Clinical Characteristics and Outcomes of Cardiomyopathy in Barth Syndrome: The UK Experience.

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiomyopathy, neutropenia, skeletal myopathy and growth delay. This study describes the UK national clinical experience and outcome of cardiomyopathy in BTHS. The clinical course and echocardiographic changes of all patients with BTHS in the UK were reviewed from 2004 to 2014. In addition, strain analysis using 2D speckle tracking echocardiography was performed to further assess left ventricular function in the most recent follow-up. At last follow-up, 22 of 27 patients were alive with a median age of 12.6 (2.0-23.8) years; seven underwent cardiac transplantation at a median age of 2 (0.33-3.6) years, and five died (18.5%) at a median age of 1.8 (0.02-4.22) years. All deaths were related to cardiomyopathy or its management. Left ventricular diastolic dimension and systolic function measured by fractional shortening tended to normalise and stabilise after the first 3 years of life in the majority of patients. However, patients with BTHS (n = 16) had statistically significant reduction in global longitudinal and circumferential strain compared to controls (n = 18), (p < 0.001), despite apparent normal conventional measures of function. There was also reduced or reversed apical rotation and reduced left ventricular twist. Sustained ventricular arrhythmia was not seen at follow-up. Cardiac phenotype in BTHS is variable; however, longer-term outcome in our cohort suggests good prognosis after the first 5 years of life. Most patients appeared to have recovered near normal cardiac function by conventional echocardiographic measures, but strain analysis showed abnormal myocardial deformation and rotational mechanics.

Natural history of Barth syndrome: a national cohort study of 22 patients.

BACKGROUND: This study describes the natural history of Barth syndrome (BTHS). METHODS: The medical records of all patients with BTHS living in France were identified in multiple sources and reviewed. RESULTS: We identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2-2.3). The median age at presentation was 3.1 weeks (range, 0-1.4 years), and the median age at last follow-up was 4.75 years (range, 3-15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000. CONCLUSIONS: This survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.

The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study.

Barth syndrome (BTHS); MIM accession # 302060) is a rare X-linked recessive cardioskeletal mitochondrial myopathy with features of cardiomyopathy, neutropenia, and growth abnormalities. The objectives of this study were to further elucidate the natural history, clinical disease presentation, and course, and describe growth characteristics for males with BTHS. Patients with a confirmed genetic diagnosis of BTHS are referred to the BTHS Registry through the Barth Syndrome Foundation, self-referral, or physician referral. This study is based on data obtained from 73 subjects alive at the time of enrollment that provided self-reported and/or medical record abstracted data. The mean age at diagnosis of BTHS was 4.04 ± 5.45 years. While the vast majority of subjects reported a history of cardiac dysfunction, nearly 6% denied any history of cardiomyopathy. Although most subjects had only mildly abnormal cardiac function by echocardiography reports, 70% were recognized as having cardiomyopathy in the first year of life and 12% have required cardiac transplantation. Of the 73 enrolled subjects, there have been five deaths. Growth curves were generated demonstrating a shift down for weight, length, and height versus the normative population with late catch up in height for a significant percentage of cases. This data also confirms a significant number of patients with low birth weight, complications in the newborn period, failure to thrive, neutropenia, developmental delay of motor milestones, and mild learning difficulties. However, it is apparent that the disease manifestations are variable, both over time for an individual patient and across the BTHS population.