Barth syndrome (BTHS; OMIM #302060) is a rare, life-threatening genetic disorder primarily affecting males around the world. It is caused by a mutation in the TAFAZZIN gene, resulting in an inborn error of phospholipid metabolism.

Though not always present, cardinal characteristics of this multi-system disorder often include combinations and varying degrees of:

• Cardiomyopathy (usually dilated with variable myocardial hypertrophy, sometimes with left ventricular noncompaction and/or endocardial fibroelastosis)
• Neutropenia (can be chronic, intermittent, cyclic, or not present)
• Low muscle mass and muscle weakness
• Growth delay (short stature in the early years, followed by accelerated growth in mid- to late puberty)
• Exercise intolerance due to early fatigue
• Feeding problems (e.g., difficulty sucking, swallowing, or chewing; aversion to some food textures; selective or picky eating; frequent vomiting)
• Cardiolipin abnormalities
• 3-methylglutaconic aciduria (variable but typically a 5- to 20-fold increase)

Additional Clinical Problems May or May Not Include (in varying severity)

• Congestive heart failure
• Life-threatening bacterial infection
• Gross motor delay
• Risk of fatal arrhythmia
• Extreme fatigue
• Diarrhea and/or constipation
• Recurrent mouth ulcers
• Risk of thrombosis
• Hypoglycemia, including fasting hypoglycemia (most often in the newborn period)
• Chronic headache, abdominal pain, and/or body aches (especially during puberty)
• Osteoporosis
• Mild learning disabilities

It is critical always to remember that Barth syndrome (BTHS) is a complex inborn error of metabolism. Because the disorder affects many systems of the body, treating a patient with BTHS often requires involvement of experts from a wide range of medical specialties.

Phases of Barth Syndrome

These general phases are often, but not always, seen in BTHS:

• Children with BTHS often are seriously ill before the age of five years.
• The ages from five to eleven years can be a “honeymoon phase,” when symptoms can appear to be few.
• This does not mean that the syndrome has been “outgrown,” as adolescence often begins another difficult period. Regardless of the phase of Barth syndrome, the following serious risks ALWAYS exist:

Risks of Cardiac Dysfunction

• The natural history of BTHS cardiac disease has been described as “undulating.” Both the character and severity of heart dysfunction can change significantly. The cardiomyopathy can evolve from dilated to hypertrophic or vice versa and may or may not involve left ventricular noncompaction (LVNC) and sometimes hypertrabeculation. Furthermore, sometimes a patient sick enough to be awaiting a heart transplant can improve so dramatically as to be taken off the list, especially if the underlying metabolic abnormalities have been treated and improved. Unfortunately, the reverse also can happen, and heart function can deteriorate significantly, suddenly, and unexpectedly, even during otherwise simple viral or bacterial infections. Vigilant cardiac monitoring is essential.
• Life-threatening arrhythmias can occur, even when heart function is in the normal range.

Risks of Infection

• When well, a BTHS individual can have an absolute neutrophil count (ANC) approaching zero, but this can rise to normal or above during an acute infection. Thus, there are times when a normal ANC can be a sign of a serious infection.
• Many with BTHS have a normal body temperature that is substantially below 98.6°F (37°C), so even a mild fever may signify a problem.
• Taking a rectal temperature is contra-indicated due to risk of serious infection resulting from the possible introduction of fecal organisms into the bloodstream.

Risks of Nutritional and Metabolic Issues

• Because muscle is an important nutritional reserve during fasting, the intrinsically reduced muscle mass of BTHS individuals significantly limits their ability to fast. Even overnight fasting drains muscle reserves, causing relative hypoglycemia and, over time, further muscle atrophy. Eating cornstarch (e.g., added to yogurt) or Extend Bars™ before bedtime can alleviate these problems.
• BTHS individuals often tolerate illnesses poorly, especially those that include diarrhea or vomiting, given their reduced muscle mass resulting in diminished body stores of electrolytes and protein. Therefore, fluid and electrolyte (particularly potassium and phosphate) balance must be monitored closely and frequently during illnesses and caution exercised to prevent hyperkalemia when giving potassium-containing IV fluids. Underlying cardiac issues also must be considered in all of this.
• Caloric requirements in someone with BTHS often are reduced because of substantially underdeveloped muscle mass. Trying to achieve standard caloric intake for age and weight often leads to vomiting and diarrhea.
• Because rare but serious hypoglycemic crises have occurred in BTHS, any symptoms of low blood sugar (weakness, pallor or sweating) must be taken seriously.
• The metabolic strategies used by BTHS cells to maintain normal energy production can cause sufficiently severe depletion of certain amino acids, most notably arginine, that cardiac and skeletal muscle protein synthesis is impaired. As a result, the use of extra dietary protein and supplements of arginine and other amino acids may be considered to raise amino acid levels to their mid-normal ranges and thereby reverse serious deterioration in cardiac function caused by cardiac muscle wasting.
• Anesthesia for BTHS patients requires special consideration because of increased risks from the cardiac, muscular and metabolic issues involved in the disorder. Dilated cardiomyopathy is frequently present, the risk of ventricular arrhythmias is increased, and lactic acid may accumulate rapidly. The much-reduced muscle mass of BTHS can lead to rapid electrolyte shifts and predispose Barth syndrome patients to hypoglycemia. Thus, care should be taken to minimize pre- and post-operative fasting and to avoid use of lactated intravenous fluids. A BTHS-specific anesthesia protocol can be found in the FACT Sheet Library of the Barth Syndrome Foundation website.

ICD-10 Code for Barth syndrome E78.71

Visit the Barth Syndrome Foundation website for more information.