Barth syndrome

Barth syndrome is a metabolic and neuromuscular disorder, occurring almost exclusively in males, that primarily affects the heart, immune system, muscles, and growth. It typically becomes apparent during infancy or early childhood, but the age of onset, associated symptoms and findings, and disease course varies considerably among affected individuals. The main characteristics of the condition include abnormalities of heart and skeletal muscle (cardiomyopathy and skeletal myopathy); low levels of certain white blood cells called neutrophils that help to fight bacterial infections (neutropenia); and growth retardation, potentially leading to short stature. Other signs and symptoms may include increased levels of certain organic acids in the urine and blood (such as 3-methylglutaconic acid), and increased thickness of the left ventricle of the heart due to endocardial fibroelastosis, which can cause potential heart failure. Barth syndrome is caused by mutations in the TAZ gene and is inherited in an X-linked recessive manner.^[1][2] Treatment is directed toward the specific symptoms that are apparent in each individual.^[1]

Symptoms associated with Barth syndrome may be evident at birth, infancy, or early childhood. Rarely, the disorder may not be diagnosed until adulthood. Most individuals with Barth syndrome present with weakened heart muscle (cardiomyopathy) that leads to the enlargement of the heart's lower chambers (ventricles). Known as dilated cardiomyopathy, signs of this condition are often present at birth, or may appear during the first months of life. Dilated endocardial myopathy typically weakens the heart's pumping action, reducing the volume of blood circulating to the lungs and the rest of the body (heart failure). Symptoms of heart failure may depend on the child's age and other factors. In young children, for example, heart failure may be manifest as fatigue and shortness of breath with exertion.^[1]

Barth syndrome is also associated with abnormally diminished muscle tone (hypotonia), and muscle weakness (skeletal myopathy), that often leads to delays in development of gross motor skills. Gross motor skills include such activities as crawling, walking, running, jumping, and maintaining balance. Weakness of the facial muscles may lead to unusual facial expressions. In addition, affected infants and children may fail to thrive, and fail to gain weight at the expected rate. Some affected children have mild learning disabilities (although they are usually of normal intelligence), and in many cases, may be prone to recurrent bacterial infections due to low levels of circulating neutrophils in the blood (neutropenia).^[1]

In addition to the signs and symptoms previously mentioned, individuals with Barth syndrome have abnormally increased levels of a substance called 3-methylglutaconic acid in their urine and blood. However, there does not appear to be an association between the increased acid levels and the severity of other symptoms and signs associated with Barth syndrome.^[1]

Barth syndrome is caused by mutations in the TAZ gene, which is located on the X chromosome. The TAZ gene provides "instructions" for a group of proteins called tafazzins that serve at least two functions. First, these proteins play a role in the maintenance of the inner membranes of structures inside cells called mitochondria. Cells depend on mitochondria to produce the energy they need. Tafazzins are supposed to make sure that the concentration of a specific fat (cardio-lipin) is sufficient to maintain energy production inside the mitochondria. Tafazzins also promote the development of bone cells. Mutations in the TAZ gene that cause Barth syndrome disrupt the protein's ability to function correctly, thereby causing the signs and symptoms of Barth syndrome.^[1]

The malfunctioning gene that causes Barth syndrome is located on the X chromosome, and Barth syndrome is inherited in an X-linked recessive manner. Chromosomes, inside the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes - 23 inherited from each parent. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes.^[1]

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are considered carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off", and they have another X chromosome with a working copy of the gene. A male has only one X chromosome. Therefore, if he inherits an X chromosome that contains a non-working gene, he will develop the disease that is associated with that gene.^[1] This is why Barth syndrome occurs exclusively in males.

Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons, because males always pass their Y chromosome instead of their X chromosome to male offspring (which is what makes the offspring male).^[1] A female carrier of an X-linked disorder has two X chromosomes and will always pass one of them onto her offspring (whether it is male or female). Female carriers of and X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son. In some instances, the mother of an affected male may not be a carrier for Barth syndrome and there is no apparent family history of the disease. In such cases, the disorder appears to result from a new mutation of the gene on the X chromosome of the affected individual that occurred randomly for unknown reasons (sporadically).^[1]

Genetic testing is available for Barth syndrome. GeneTests lists laboratories that are offering clinical genetic testing for this condition. To view the contact information for these laboratories, click here. Please note that most of the laboratories listed through GeneTests do not accept direct contact from patients and their families; therefore, if you are interested in learning more, you will need to work with a health care provider or a genetics professional.

Barth syndrome may be diagnosed during infancy or early childhood (or, in some cases, at a later age), based upon a thorough clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and a variety of specialized tests. Experts indicate that a diagnosis of Barth syndrome should be considered for any male infant or child with dilated cardiomyopathy of unknown cause (idiopathic); low levels of circulating neutrophils (neutropenia); elevated urinary levels of 3-methylglutaconic acid (aciduria); abnormal mitochondria within heart muscle; and/or muscle abnormalities (myopathy) of unknown cause that occur in association with growth retardation. For infants and children with signs of cardiomyopathy, metabolic screening tests should be conducted, including studies to measure levels of 3-methylglutaconic acid and other organic acids in the urine and blood. An elevated urinary level of 3-methylglutaconic acid (3-methylglutaconic aciduria) has been recognized as a diagnostic sign of Barth syndrome. Persistent low levels of neutrophils in the blood help to confirm the diagnosis in combination with these other signs. Diagnosis may also be confirmed via genetic testing.^[1]

The treatment of Barth syndrome is generally directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of medical professionals which includes a pediatrician, pediatric cardiologist,  hematologist, specialist in the treatment of bacterial infections, physical therapist, occupational therapist, and/or other health care professionals. Many infants and children with Barth syndrome require therapy with diuretic and digitalis medications to treat heart failure. Some affected children are gradually removed from such cardiac therapy during later childhood due to improvement of heart functioning. For affected individuals with confirmed neutropenia, complications due to bacterial infection are often preventable by ongoing monitoring and early therapy of suspected infections with antibiotics. For example, antibiotics may be provided as a preventive (prophylactic) therapy during neutropenia to prevent the onset of infection. Other treatment for this disorder is typically symptomatic and supportive.^[1]