Barth Syndrome

Clinical characteristics: Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.

Diagnosis/testing: The diagnosis of Barth syndrome is established in a male proband with either an increased monolysocardiolipin:cardiolipin ratio (if available) or a hemizygous pathogenic variant in TAZ identified by molecular genetic testing. The diagnosis of Barth syndrome is usually established in a female proband with suggestive clinical findings and a TAZ pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: Standard treatment of heart failure including careful fluid and volume management and avoidance of over-diuresis and dehydration, standard heart failure medications to improve symptoms, and cardiac transplantation when heart failure is severe and intractable; consideration of antiarrhythmic medications or implantable cardiac defibrillator for cardiac arrhythmia; granulocyte colony-stimulating factor for neutropenia; physical therapy for skeletal muscle weakness; standard treatment for talipes equinovarus and/or scoliosis; feeding therapy and consideration of gastrostomy tube for persistent feeding issues; uncooked cornstarch prior to bedtime for hypoglycemia; standard treatment for developmental delay / intellectual disability. Prevention of secondary complications: Aspirin therapy for prevention of clot formation in those with severe cardiac dysfunction and/or marked left ventricular noncompaction; antibiotic prophylaxis to prevent recurrent infections; limiting fasting or providing intravenous glucose infusion prior to planned procedures; regular monitoring of potassium levels during administration of IV fluids that contain potassium and during episodes of diarrhea; consultation with a nutritionist and/or gastroenterologist to determine optimal caloric delivery. Surveillance: At least annual electrocardiography with Holter monitor and echocardiography; electrophysiologic study to assess for potentially serious arrhythmia as needed; complete blood count with differential with all febrile episodes and at least semiannually; measurement of height and weight, clinical assessment of strength and for scoliosis, and assessment of developmental progress and educational needs at each visit; formal developmental assessments every three to five years during childhood. Agents/circumstances to avoid: Prolonged fasting, use of rectal thermometers in those with neutropenia, and use of succinylcholine. Growth hormone is typically discouraged unless growth hormone deficiency is conclusively established, as the majority of affected males will attain normal stature by adulthood. The muscular involvement in Barth syndrome may increase the risk for malignant hyperthermia compared to the general population. Evaluations of relatives at risk: It is appropriate to evaluate the older and younger brothers of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Pregnancy management: Pregnancies of male fetuses known to have Barth syndrome should be managed by a high-risk maternal fetal obstetrician; there are no specific recommendations regarding mode, timing, or location of delivery.

Genetic counseling: Barth syndrome is inherited in an X-linked manner. If a mother has a TAZ pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the TAZ pathogenic variant will be affected; females who inherit the TAZ pathogenic variant are typically not affected. Affected males pass the TAZ pathogenic variant to all of their daughters and none of their sons. Testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the TAZ pathogenic variant has been identified in an affected family member.