Rare Rheumatology News

Disease Profile

Barth syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Childhood

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ICD-10

E71.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

BTHS; 3-methylglutaconic aciduria type II; MGA type II;

Categories

Congenital and Genetic Diseases; Eye diseases; Heart Diseases;

Summary

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

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]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Dilated cardiomyopathy
Stretched and thinned heart muscle
0001644
30%-79% of people have these symptoms
Abnormal mitochondrial morphology
0008322
Abnormality of neutrophils
0001874
Endocardial fibroelastosis
0001706
5%-29% of people have these symptoms
Neutropenia
Low blood neutrophil count
Low neutrophil count

[ more ]

0001875
Organic aciduria
0001992
Talipes equinovarus
Club feet
Club foot
Clubfeet
Clubfoot

[ more ]

0001762
Percent of people who have these symptoms is not available through HPO
3-Methylglutaconic aciduria
0003535
Arrhythmia
Abnormal heart rate
Heart rhythm disorders
Irregular heart beat
Irregular heartbeat

[ more ]

0011675
Broad forehead
Increased width of the forehead
Wide forehead

[ more ]

0000337
Congestive heart failure
Cardiac failure
Cardiac failures
Heart failure

[ more ]

0001635
Deeply set eye
Deep set eye
Deep-set eyes
Sunken eye

[ more ]

0000490
Exercise intolerance
Decreased ability to exercise
Inability to exercise

[ more ]

0003546
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Fatigue
Tired
Tiredness

[ more ]

0012378
Full cheeks
Apple cheeks
Big cheeks
Increased size of cheeks
Large cheeks

[ more ]

0000293
Gait disturbance
Abnormal gait
Abnormal walk
Impaired gait

[ more ]

0001288
Granulocytopenia
0001913
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Hypertrophic cardiomyopathy
Enlarged and thickened heart muscle
0001639
Intermittent lactic acidemia
0004913
Macrotia
Large ears
0000400
Mandibular prognathia
Big lower jaw
Increased projection of lower jaw
Increased size of lower jaw
Large lower jaw
Prominent chin
Prominent lower jaw

[ more ]

0000303
Motor delay
0001270
Myopathic facies
0002058
Recurrent infections in infancy and early childhood
0005437
Round face
Circular face
Round facial appearance
Round facial shape

[ more ]

0000311
Skeletal myopathy
0003756
X-linked recessive inheritance
0001419

Cause

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]

Diagnosis

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]

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.

Newborn Screening

  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
  • Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
  • National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

    Treatment

    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]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

          In-Depth Information

          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Barth syndrome. Click on the link to view a sample search on this topic.

            References

            1. Barth Syndrome. NORD. 2007; https://rarediseases.org/rare-diseases/barth-syndrome/.
            2. Barth syndrome. Genetics Home Reference. July 2014; https://ghr.nlm.nih.gov/condition/barth-syndrome.

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