Barth Syndrome: Causes, Symptoms, Treatment, Prognosis, Pathophysiology

Barth syndrome (BTHS) is a rare X-linked genetic disorder. It was discovered for the first time in 1979 by Dr. Peter Barth in Netherlands and hence, named after him.

What is Barth Syndrome?

What is Barth Syndrome?

Barth syndrome is an X-linked serious genetic disorder, which is inherited in a recessive manner. It is seen only in case of males and not in case of females. Barth syndrome is characterized by a triad of symptoms such as cardiomyopathy, skeletal myopathy and neutropenia. Barth syndrome was reported to be a cause of male fetal death due to miscarriage and stillbirth.

In Barth syndrome, there is a problem with lipid metabolism, especially the cardiolipin metabolism. Cardiolipin is a phospholipid found mainly in mitochondria. The male children who are born alive show a number of body defects from fetal to adult stage.

In addition, there are a number of biochemical defects observed as reduced levels of pre-albumin and LDL cholesterol, elevated levels of enzyme creatine kinase and transaminase. There is lactic acidosis, hypoglycemia and mild hyperammonemia. These lead to metabolic decompensation and death in neonates.

Symptoms of Barth Syndrome

Barth syndrome shows symptoms such as:

  • Problems with lipid metabolism, which leads to cardiolipin deficiency.
  • Neonates or infants have cardiomyopathy. They have dilated or hypertrophic heart. The heart muscles are usually weak and associated with enlargement of heart.
  • Skeletal myopathy can also be a symptom of Barth syndrome.
  • Neutropenia or reduction in number of neutrophils.
  • Serious bacterial infections.
  • Growth delay is observed. In spite of proper nutrition during growing days, the affected Barth syndrome children are below the normal height and weight.
  • Muscle weakness which leads to exercise intolerance and exhibit fatigue.
  • 3-Methylglutaconic aciduria (3-MGCA) – An increase in organic acid content in urine due to abnormal metabolism in mitochondrion function.
  • Other problems associated with Barth syndrome include:
    • Feeding problems.
    • Mild learning disabilities.
    • Frequent diarrhea.

Epidemiology of Barth Syndrome

Barth syndrome is a rare disorder, which occurs only in case of males; however, this disorder may be underestimated. Today, due to increased awareness, more number of cases is being reported. It has an incidence of 1 in 300,000 to 1 in 400,000 live births. Barth syndrome occurs in all races and ethnic populations.

Prognosis of Barth Syndrome

Most male fetuses die during neonatal stage or infancy due to heart problems or an increased infection. Hence, early diagnosis is important. Once detected, they can be given improved supportive care system, which will increase the life span of infants with Barth syndrome. One of the study reported that patient with Barth syndrome was alive at age 53 years.

Causes of Barth Syndrome

Barth syndrome is a genetic disorder. It is inherited by the male fetus from the carrier mother; while the female fetuses are carriers. When an adult male has Barth syndrome, none of the sons are affected.

Pathophysiology of Barth Syndrome

There is a genetic defect or mutation of gene Tafazzin (TAZ) present on the X-chromosome at location Xq28. This gene contains 10 exons and encodes an enzyme acyltransferase, which is required in cardiolipin formation. Cardiolipin is a special type of phospholipid found in the membranes of mitochondrion associated with number of mitochondrial proteins and mitochondrial apoptosis. It is an important lipid component of the Electron Transport Chain (ETC) and helps in energy formation.

TAZ gene undergoes a number of mutations such as nonsense, missense, frameshift, deletion and splicing, which gives rise to a defective acyltransferase enzyme. Defective enzyme cannot make appropriate type of cardiolipin lipid. This gives rise to varying degrees of structural and functional abnormalities in the mitochondria. For example, the defective mitochondria found in heart and skeletal muscles are very large in size and cannot function appropriately, which give rise to serious cardiac and skeletal defects.

Barth syndrome is seen only in case of males and not females since males carry only one X-chromosome while females carry two X-chromosomes. Although, a defective TAZ gene is carried on one X-chromosome, the presence of normal gene on other chromosome dominates over the recessive mutation and thus, does not exhibit the syndrome.

Diagnosis of Barth Syndrome

  • Urinary 3-MGCA Test for Diagnosis of Barth Syndrome: Most Barth syndrome cases show 5-20 fold increase in Urinary 3-MGCA levels.

Since it is a nonspecific test, hence further diagnosis is done using Cardiolipin and genetic testing which includes:

  • Urinary Biochemical Testing of Monolysocardiolipin/Cardiolipin (MLCL:L4-CL) to Diagnose Barth Syndrome: Cardiolipin analysis involves measurement of ratio of MLCL: L4-CL in muscles and platelets. This can be applied to a variety of cells and tissues including stored dried blood spot cards. The test has shown 100% diagnostic sensitivity and specificity for Barth syndrome.
  • Genetic Test for Barth Syndrome: TAZ gene sequencing is done for mutation screening of TAZ mutations.
  • Pedigree Analysis: Once the causative mutation is known, then pedigree analysis is performed to know about the carriers in the family.
  • DNA Analysis for Barth Syndrome: In the family with Barth syndrome, one can perform molecular genetic analysis using DNA from chorionic villus sampling and amniocentesis to know about the affected male child.
  • Complete and differential blood count is done.
  • Echocardiogram is also advised to diagnose heart conditions.

Treatment of Barth Syndrome

Till date, there is no specific cure for Barth syndrome. All Barth syndrome patients do not exhibit all the symptoms at a time. The common ones such as heart problems, infections and nutrition problems are treated.

  • Treating Heart Problems in Barth Syndrome: For treatment of the heart problems in Barth syndrome patients, the standard heart failure management is done by prescribing the following–
    • Angiotensin converting enzyme inhibitors.
    • Beta blockers.
    • Digoxin.
    • Diuretics.
    • Few patients require heart transplant.
  • Treating Nutritional Deficiency in Barth Syndrome: For nutritional problems in Barth syndrome patients, cornstarch supplements are given at the bedtime as an alternative source of glucose production.
  • For neutropenia, a combination of subcutaneous G-CSF and antibiotics is used. This therapy helps in increasing the neutrophil count.
  • Barth syndrome patients with complications can be managed with the help of a multidisciplinary team of physiotherapist, occupational therapist, psychologist and support workers.

Prevention of Barth Syndrome

Overall, Barth syndrome cannot be prevented since it is genetic in origin. However, if it is diagnosed early, then the symptoms can be managed by administration of certain drugs and by food supplements which will lead to improved life span. Moreover, if the history of the syndrome in the family is already known, then diagnostic tests or genetic tests must be when daughters of the family is pregnant to rule out the chances of the disorder in the fetus.


Barth syndrome is a rare X-linked genetic disorder. Today due to improved diagnostics one can identify this disorder in the idiopathic cases too, which exhibit unexplained heart problems and sudden death. Early identification allows proper family screening and patient counseling, which helps in proper disease management and reduce early mortality.

Pramod Kerkar, M.D., FFARCSI, DA
Pramod Kerkar, M.D., FFARCSI, DA
Written, Edited or Reviewed By: Pramod Kerkar, M.D., FFARCSI, DA Pain Assist Inc. This article does not provide medical advice. See disclaimer
Last Modified On:July 18, 2017

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