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.
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.
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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. 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:
(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.].)
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FROM THE INTERNET
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