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Barth Syndrome

Synonyms of Barth Syndrome

  • 3-Methylglutaconic Aciduria, Type II (MGA, Type II)
  • Cardioskeletal Myopathy, Barth Type
  • Cardioskeletal Myopathy With Neutropenia and Abnormal Mitochondria
  • Endocardial Fibroelastosis, Type 2 (EFE2)
  • X-Linked Cardioskeletal Myopathy and Neutropenia

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Barth syndrome is a rare, metabolic, and neuromuscular, genetic disorder that occurs exclusively in males, since it is passed from mother to son through the X chromosome. Although Barth syndrome typically becomes apparent during infancy or early childhood, the age of onset, associated symptoms and findings, and disease course varies considerably, even among affected members of the same family (kindred). Primary characteristics of the disorder include abnormalities of heart and skeletal muscle (cardioskeletal myopathy), low levels of certain white blood cells (neutrophils, neutropenia) that help to fight bacterial infections, and growth retardation, potentially leading to short stature. The disorder is also associated with increased levels of certain organic acids in the urine and blood, such as 3-methylglutaconic aciduria/acidemia.

The left ventricle of the heart may show increased thickness as a result of unusually high concentrations of elastic, collagenous fibers (endocardial fibroelastosis). The thickening reduces the ability of the left ventricle to push blood though to the lungs and thus is the prime source of potential heart failure.

Barth syndrome is transmitted as an X-linked recessive trait. A gene responsible for the disorder has been located on the long arm (q) of chromosome X at Xq28.


Symptoms associated with Barth syndrome may be evident at birth (congenital), or infancy, or early childhood. Yet, on rare occasions the disorder may not be diagnosed until adulthood.

Most individuals with Barth syndrome present with weakened heart muscle (cardiomyopathy) that leads to the enlargement (dilation) of the heart's lower chambers (ventricles). Known as dilated cardiomyopathy, signs of this condition are often present at birth (congenital), or may appear during the first months of life. Dilated endocardial myopathy (see above), 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 (dyspnea) with exertion.

Barth syndrome is also associated with abnormally diminished muscle tone (hypotonia), and muscle weakness (skeletal myopathy), that often leads to delays in the acquisition of gross motor skills. Gross motor skills include such activities as crawling, walking, running, jumping, and maintaining balance. These are the skills that require the use and coordination of large muscle groups. 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. They may 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. Without prompt detection and appropriate treatment, heart failure and bacterial infections can be life-threatening complications.

In addition to abnormalities of heart and skeletal muscle, neutropenia, and growth retardation, patients with Barth syndrome have a specific biochemical marker that has been recognized for many years as a primary indicator of Barth syndrome. A biochemical marker is any substance, such as an enzyme or small molecule, that is detected in urine or other body fluids and serves as a diagnostic sign of a particular disorder. Researchers have shown that individuals with Barth syndrome have abnormally increased levels of 3-methylglutaconic acid in the urine and in the liquid portion of the blood. According to clinicians, children with Barth syndrome may have elevated blood levels of 3-methylglutaconic acid from mid-infancy up to about age three. There does not appear to be an association, however, between the increased acid levels and the severity of other symptoms and signs associated with Barth syndrome.

Viewed by the microscope, the heart muscle cells of patients with Barth syndrome have abnormally shaped mitochondria. Other metabolic signs that are not diagnostic themselves but serve to support a diagnosis based on other criteria are, high blood and urine levels of lactic acid (a by-product of intense muscular activity) and low carnitine levels. Carnitine plays a role in the movement of chemicals, especially fatty acids, across the cell membrane.


Barth syndrome is transmitted as an X-linked recessive trait. The malfunctioning gene has been traced to a site on the X chromosome at gene map locus Xq28.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. 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. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq28" refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

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 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". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. 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. Female carriers of an 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 that occurred randomly for unknown reasons (sporadically).

The gene located at chromosome X28 is known as the TAZ gene. The TAZ gene codes for a group of proteins called taffazins, that serve at least two functions. First, these proteins play a role in the maintenance of the inner, much-folded, membranes of the mitochondria in cells. The mitochondria are the energy-producing factories upon which the cell depends. The taffazins serve to assure that the concentration of a specific fat (cardio-lipin) is sufficient to maintain energy production in the mitochondria. Taffazins also promotes the development of bone cells from the precursor cells of bone (osteoblasts).

Mutations in the TAZ gene are also responsible for the appearance of 3-methylglutaconic acid in the Barth patient's blood and urine.

Affected Populations

Barth syndrome appears to affect all ethnic groups. Epidemiologists at Johns Hopkins University Medical Center estimate the incidence of this syndrome to be somewhere between 1 in 200,000 to 400,000 births. They caution, however, that these figures may be underestimated since they believe that many cases of Barth syndrome go unrecognized and unreported.

Related Disorders

Symptoms of the following disorders may be similar to those of Barth syndrome. Comparisons may be useful for a differential diagnosis:

Researchers have described a large multigenerational family in which several male infants developed severe cardiac disease (i.e., dilated cardiomyopathy) in the absence of other features characteristically associated with Barth syndrome (e.g., skeletal myopathy, neutropenia, growth retardation). Originally known as "dilated cardiomyopathy, type 3A," investigators have since determined that affected family members have a mutation of the gene responsible for Barth syndrome (BTHS gene) transmitted as an X-linked recessive trait. (For more information, see "Causes" above.) Therefore, this condition is now considered a variant form or "allelic variant" of Barth syndrome. (An allele refers to one of two or more alternative forms of a particular gene.) Researchers indicate that the severe cardiac manifestations in those with this disease variant may be related to the severity of the unique BTHS gene mutation in affected family members.

A family has also been described in which several male infants have had severe abnormalities of the heart muscle (myocardium) of the left ventricle (cardiomyopathy) also resulting from a mutation of the BTHS gene. In family members with the disorder, termed "isolated noncompaction of the left ventricular myocardium" (INVM), other findings typically associated with Barth syndrome were inconsistently present. Because this X-linked recessive disorder has been shown to result from a previously unreported BTHS gene mutation, it is also now considered an allelic variant of Barth syndrome. In affected family members, myocardial abnormalities have included multiple, prominent, irregular bands and bundles of muscle (trabeculations) projecting from the interior of the walls of the left ventricle. In addition, in some cases, such myocardial defects have been present within the right ventricle and the fibrous partition separating both ventricles (septum). This disease variant may also be associated with widespread (diffuse) thickening of the internal lining (endocardium) of the left ventricle with overgrowth of fibrous and elastic tissues (endocardial fibroelastosis).

Endocardial fibroelastosis may also occur as a primary condition that appears to be transmitted as an X-linked recessive trait. Investigators have reported several families (kindreds) in which affected members, primarily infants and children, have developed diffuse, patchy thickening of the endocardium, primarily of the left ventricle, due to overgrowth (proliferation) of elastic and fibrous tissues. Associated findings may include symptoms of heart failure in the first months or years of life. Some researchers question whether X-linked endocardial fibroelastosis is a distinct disease entity, indicating that it may in fact represent a variant of Barth syndrome. However, very few families with apparently isolated, X-linked endocardial fibroelastosis have been tested for mutations in the Barth gene.

Familial dilated cardiomyopathy has also been described in adolescent and adult members of several kindreds in which the condition appears to be transmitted as an X-linked recessive trait. Reports suggest that signs of dilated cardiomyopathy may tend to develop in affected males during adolescence or early adulthood. In addition, in some instances, females who carry a copy of a mutated gene for the condition may develop symptoms. In such cases, symptoms tend to become apparent later during adulthood. In those with such X-linked dilated cardiomyopathies, cardiac disease has occurred in the absence of low levels of circulating neutrophils (neutropenia) or biochemical abnormalities associated with Barth syndrome (e.g., 3-methylglutaconic aciduria). In some affected families, the condition has been shown to result from mutations of a gene (known as "dystrophin") on chromosome X (Xp21.2) that is thought to play a role in maintaining the structure of cardiac and skeletal muscle units. (Note: Various mutations of the dystrophin gene have also been identified in males with Duchenne or Becker muscular dystrophy. For further information on these disorders, please use "Duchenne" or "Becker" as your search term in the Rare Disease Database.) In other families with X-linked dilated cardiomyopathy, the responsible gene on chromosome X has not been determined. (Several forms of familial dilated cardiomyopathy have also been reported that have been shown to result from mutations of various genes transmitted as autosomal dominant or autosomal recessive traits.)

Acute viral cardiomyopathy is a heart condition characterized by sudden (acute) inflammation of heart muscle (myocarditis) due to viral infections. Initial symptoms may include a sudden onset of fever and flu-like symptoms. In addition, myocardial inflammation causes weakening of the heart muscle, leading to enlargement of the heart's lower chambers (dilated cardiomyopathy) and reduced efficiency of the heart's pumping action (heart failure). Associated findings may include fatigue, shortness of breath, irregular heart rhythms (arrhythmias), and other findings, leading to potentially life-threatening complications without appropriate treatment. Viral cardiomyopathy has often been the diagnosis given to children with Barth syndrome before recognition of other abnormalities, such as neutropenia or 3-methylglutaconic aciduria, led to the correct diagnosis.

There are additional disorders of mitochondrial metabolism that may be associated with certain symptoms and findings similar to those seen in Barth syndrome, such as cardiomyopathy, neuromuscular abnormalities, growth retardation, and/or elevated urinary levels of 3-methylglutaconic acid (aciduria). However, evidence suggests that such disorders may not be associated with other findings characteristic of Barth syndrome (e.g., neutropenia)--and/or may have other, distinctive features, such as additional biochemical findings, severe neurological symptoms, and/or other abnormalities. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Standard Therapies

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. As mentioned above, an elevated urinary level of 3-methylglutaconic acid (3-methylglutaconic aciduria) has been recognized as a biochemical marker that may function as a diagnostic sign of Barth syndrome. It is important to measure the concentration of neutrophils in the blood. Persistent low levels of neutrophils help confirm the diagnosis in combination with these other signs. Prenatal and postnatal testing for the presence of the TAZ gene is available at a few genetic laboratories.

The treatment of Barth syndrome is directed toward the specific symptoms that are apparent in each individual. Such supportive treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who specialize in childhood heart disease (pediatric cardiologists); specialists in the study of the blood and blood-forming tissues (hematologists); specialists in the treatment of bacterial infections, physical therapists; occupational therapists; and/or other health care professionals.

Heart failure and/or bacterial infections are the more grave threats to a patient with Barth syndrome. Many infants and children with Barth syndrome require therapy with diuretic and digitalis medications to treat heart failure. Evidence suggests that many affected children may be 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. For some individuals with neutropenia, such as those with repeated bacterial infections and neutrophil levels that are persistently below 500, physicians may recommend the use of agents that stimulate the bone marrow's production of white blood cells.

Genetic counseling will also benefit affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010

For information about clinical trials sponsored by private sources, contact:

Barth Syndrome Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., dilated cardiomyopathy, heart failure, neutropenia, etc.].)

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at

Other Organizations:


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Dimauro S. Mitochondrial myopathies. Curr Opin Rheumatol. 2006;18:636-41.

Acehan D, Xu Y, Stokes DL, Schlame M. Comparison of lymphoblast mitochondria from normal subjects and patients with Barth syndrome using electron microscopic tomography. Lab Invest. Oct 16; [Epub ahead of print]

Schlame M, Ren M. Barth syndrome, a human disorder of cardiolipin metabolism. FEBS Lett. 2006;580:5450-55.

Van Werkhoven MA, Thorburn DR, Gedeon AK, Pitt JJ. Monolysocardiolipin in cultured fibroblasts is a sensitive and specific marker for Barth syndrome. J Lipid Res. 2006;47:2346-51.

Spencer CT, Bryant RM, Day J, Gonzalez IL, et al. Cardiac and clinical phenotype in Barth syndrome. Pediatrics. 2006;118:e337-46. Epub 2006 Jul 17.

Huhta JC, Pomerance HH, Barness EG. Clinicopathological conference: Barth syndrome. Fetal Pediatr Pathol. 2005;24:239-54.

McKusick VA, Ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Barth Syndrome; BTHS. Entry Number; 302060: Last Edit Date; 10/11/2006.

NINDS Barth Syndrome Information Page. NINDS, NIH. Last updated January 23, 2006. 2pp.
Accessed 11/6/2006

TAZ. Genetics Home Reference. National Library of Medicine. Published: October 27, 2006. 4pp.
Accessed 11/6/1006

3-methylglutaconic aciduria. Genetics Home Reference. National Library of Medicine. Published: October 27, 2006. 5pp.
Accessed 11/6/1006

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Report last updated: 2007/09/17 00:00:00 GMT+0

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