Spotlight: Niche-Disease — Barth Syndrome

Barth syndrome is a serious X-linked genetic disorder that primarily affects boys. It is caused by a mutation in the tafazzin gene (Taz) that creates an inborn error of lipid metabolism. The condition is named after Dutch pediatric neurologist Peter Barth, who published his discovery of it in 1983.

The syndrome often manifests at birth in a number of ways. Patients are born hypotonic, show signs of cardiomyopathy within the first few months of life, and despite adequate nutrition experience a deceleration in growth through their first year. On into childhood, their height and weight lag significantly behind those of other children. Physical activity is limited by diminished muscular development and muscular hypotonia. Some issues resolve themselves after puberty, during which growth accelerates, with patients reaching a normal adult height.

A boy’s myocardium is dilated in Barth syndrome cardiomyopathy, reducing the systolic pump of his heart ventricles. So most patients develop left-side myocardial hypertrophy and endocardial fibroelastosis. And although neutropenia is another deadly manifestation of the disease, Barth patients do develop fewer bacterial infections than other neutropenia patients. Although not always present, other characteristics of this multisystem disorder include underdeveloped skeletal musculature and muscle weakness, growth delays, exercise intolerance, cardiolipin abnormalities, and 3-methylglutaconic aciduria.

Epidemiology: Barth syndrome has been documented in just fewer than 200 boys so far — and just one girl. But it is believed to be severely underdiagnosed. Some experts estimate it to occur in one of ~300,000 babies. The syndrome can be associated with stillbirth, suggesting that it may well have been responsible for some such instances before the disease was identified — and before modern neonatal intensive care. (When I first began to research this condition, in fact, I couldn’t help thinking of my brother who died at birth back in the 1960s. In a small-town upstate-NY hospital, he was described merely as having “an underdeveloped heart.”)

Barth syndrome genetics are complex. The Taz gene product is believed to function as an acyltransferase in complex lipid metabolism. Barth patients have shown abnormalities in mitochondrial lipids involved with electron transport and mitochondrial membrane structure, compromising their cells’ ability to produce energy. The >10,000 bp gene encodes a predicted 33 .5-kDa protein with 292 amino acids. Although some Barth syndrome Taz mutations are spontaneous, they are usually transmitted from mother to son, with a 50% chance that a boy born to a female carrier will have it and a 50% risk of daughters being carriers themselves.

Treatment Options: Current medical treatments address the consequences rather than the underlying cause of Barth syndrome. They include physical therapy and drugs for cardiomyopathy, neutropenia, and so on. Historically, boys died of heart failure or infections before three years of age. But improved diagnoses have led to better treatment and monitoring of symptoms, with much improved survival rates and outlooks for most patients.

One potential target for treatment may be iPLA2- VIA, the 85-kDa calcium-independent phospholipase A2 enzyme involved in catalyzing the release of fatty acids from phospholipids. The encoded protein also might play a role in arachidonic acid release, leukotriene and prostaglandin synthesis, Fas-receptor–mediated apoptosis, and transmembrane ion flux in glucose- stimulated B cells.

Organizations: Dedicated to saving lives through education, treatment advances, and finding a cure, the Barth Syndrome Foundation (BSF, www .barthsyndrome .org) sponsors a competitive annual research grant program as well as international conferences every two years for affected families, attending physicians, and scientists. Since 2002 the foundation has awarded >US$3 .6 million to dozens of investigators worldwide working to better understand this rare disease. Grants cover gene-therapy research, Bezafibrate drug approval, knock-down mouse studies, clinical trials, and more. Many past and present grant awardees will be attending the next major conference in 2016.

I recently spoke with Kevin Woodward, a member of the foundation’s board of directors and father of a Barth syndrome patient. It took over a year for his son to get diagnosed after being born with cardiomyopathy in June 2010. “That began a long journey of hospital stays, doctors’ visits, and tests,” Woodward recalls. Due to Connor’s range of symptoms (including weakness and small size), a Johns Hopkins team ran a specialized genetics test in early 2012 that officially diagnosed the boy with Barth syndrome. “We were grief stricken as we began to read about it,” Woodward says, “yet at the same time, there was a strange sense of relief in finally understanding why.”

Connor’s parents registered with the BSF the same day they learned of his diagnosis, and the next day the director of family services called them. “We have been deeply involved and committed ever since. We wouldn’t be the people we are today without the support of this wonderful foundation. Dealing with such a rare and deadly disease is difficult to say the least. Knowing there is a community of knowledgeable experts and other supportive families out there is invaluable.“

Barth syndrome is probably underdiagnosed because many physicians don’t even know to test for it. “Connor is quite lucky to be born where he was geographically,” Woodward explains, “because a significant amount of Barth-related research and treatment takes place at Johns Hopkins and the Kennedy Krieger Institute in Baltimore, near where we live.”