What is the management approach for Barth syndrome?

Management Approach for Barth Syndrome

The management of Barth syndrome requires a multidisciplinary approach targeting the multiple organ systems affected by this rare X-linked disorder, including cardiac monitoring and treatment, neutropenia management, and supportive care for skeletal myopathy and growth delays. 1

Disease Overview

Barth syndrome (BTHS) is a rare X-linked recessive mitochondrial myopathy characterized by:

• Cardiomyopathy (most commonly presenting feature, affecting >70% of patients within the first year of life) 1
• Neutropenia (present in more than two-thirds of cases) 1
• Skeletal myopathy affecting proximal muscles 1
• Prepubertal growth restriction 1
• Cognitive impairments, particularly in mathematics, visual-spatial skills, and speech development 1
• Characteristic facial features (round face, full cheeks, prominent pointed chin, large ears, deep-set eyes) 1
• 3-methylglutaconic aciduria 2

BTHS is caused by mutations in the TAZ gene on chromosome Xq28, which encodes the tafazzin protein involved in cardiolipin remodeling, essential for proper mitochondrial function. 1, 2

Cardiac Management

Monitoring and Assessment

• Regular cardiac evaluations starting at diagnosis due to high prevalence of cardiac involvement 1
• Echocardiography to assess for:
  • Dilated cardiomyopathy 1
  • Left ventricular noncompaction (LVNC) 1
  • Hypertrophic cardiomyopathy 1
  • Mixed phenotypes (often evolving over time) 1
• ECG monitoring for:
  • Repolarization abnormalities (ST flattening, T-wave inversions) 1
  • Prolonged QTc interval 1
  • Ventricular arrhythmias 1

Treatment

• Standard heart failure management for cardiomyopathy 2
• Consider cardiac transplantation in cases of end-stage myocardial dysfunction (required in approximately 14% of patients) 2
• Arrhythmia management, particularly in adolescents and young adults with mild left ventricular dysfunction 1
• Close monitoring during adolescence and young adulthood due to risk of sudden cardiac death, especially in those with syncope or orthostatic symptoms 1

Neutropenia Management

• Regular complete blood count monitoring 1, 2
• Antibiotic prophylaxis for those with severe or recurrent neutropenia 2
• Granulocyte colony-stimulating factor (G-CSF) therapy for severe neutropenia 2
• Prompt evaluation and treatment of infections, as patients are at risk for:
  • Mouth ulcers (60%) 1
  • Pneumonia (28%) 1
  • Bacteremia/sepsis (10%) 1

Skeletal Muscle and Growth Management

• Physical therapy to address proximal muscle weakness 3
• Nutritional support for growth delays and feeding problems 3, 2
• Monitoring of growth parameters and pubertal development 1
• Educational support for learning disabilities 1, 3

Metabolic Management

• Monitoring for hypoglycemia 2
• Management of lactic acidosis when present 2
• Nutritional support for failure to thrive 2
• Management of episodic diarrhea 2

Emerging Therapeutic Approaches

• Bezafibrate has been investigated as a potential treatment to modify the cellular ratio of monolysocardiolipin to tetralinoleoyl-cardiolipin 4
• Other investigational approaches include:
  • Lipid replacement therapy 5
  • Peroxisome proliferator-activated receptor agonists 5
  • Tafazzin gene replacement therapy 5
  • Induced pluripotent stem cells 5
  • Mitochondria-targeted antioxidants and peptides 5
  • Resveratrol 5, 4

Multidisciplinary Care Coordination

• Establish a comprehensive care team including: 3
  • Cardiologists for cardiac monitoring and management 3, 2
  • Hematologists for neutropenia management 3, 2
  • Neurologists for myopathy management 3
  • Endocrinologists for growth monitoring 3
  • Nutritionists for feeding support 3
  • Psychologists for cognitive and behavioral support 3
  • Educational specialists 3
  • Genetic counselors for family planning 2

Genetic Counseling and Testing

• TAZ gene sequencing for:
  • Definitive diagnosis 2
  • Female carrier detection 2
  • Antenatal screening 2
• Cardiolipin testing to detect abnormal ratios of different cardiolipin species 2

Prognosis and Follow-up

• Regular follow-up with the multidisciplinary team 3, 2
• Monitor for the undulating phenotype of cardiomyopathy, which may evolve from hypertrophy to dilation during early childhood, followed by improvement during toddler years and possible late decline 1
• With appropriate management, more individuals with BTHS are now living into adulthood 2

Key Pitfalls to Avoid

• Failing to recognize the variable presentation of BTHS (some patients may never exhibit neutropenia, while others may lack increased 3-MGCA) 2
• Missing cardiac monitoring in seemingly stable patients (risk of sudden cardiac death even with only mildly decreased LVEF) 1
• Overlooking the need for regular neutrophil count monitoring due to the cyclical nature of neutropenia in some patients 2
• Focusing only on cardiac manifestations while neglecting other systemic features 2