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Barth syndrome causes and risk factors including inheritance

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Barth syndrome is a rare, inherited condition that mainly affects boys and often shows up early in life with heart weakness, low infection-fighting white blood cells, and muscle fatigue. What makes it distinctive is that the problem begins inside the cell’s “power plants,” the mitochondria, where a key membrane fat called cardiolipin is not remodeled correctly. That small molecular error can ripple outward—weakening heart muscle contraction, lowering exercise tolerance, and making infections more dangerous when neutrophil counts drop. Families often describe a confusing pattern: a baby who struggles to feed and gain weight, a toddler who tires quickly, or a child who cycles between doing well and suddenly becoming sick. Although Barth syndrome is serious, early recognition and coordinated care can improve stability, support growth and development, and reduce preventable complications.

Table of Contents

What Barth syndrome is and how it affects the body

Barth syndrome is an X-linked genetic condition in which changes in a single gene disrupt how mitochondria maintain the inner membrane that drives energy production. The best way to picture it is to imagine mitochondria as a power station with carefully arranged wiring. In Barth syndrome, the “insulation” in that wiring is altered: a mitochondrial phospholipid called cardiolipin is present in the wrong mix of shapes and chain lengths. Because cardiolipin helps organize the protein complexes that make cellular energy (ATP), the heart and skeletal muscles—tissues with high energy demand—tend to suffer first and most.

In the heart, Barth syndrome can cause several forms of cardiomyopathy. Many infants present with a dilated, weakened pumping chamber, but some develop thickened heart muscle or a pattern called left ventricular noncompaction, where the heart muscle looks more “spongy” than usual. These patterns can change over time, so the same child may have different echo findings at different ages. When the heart struggles, the body compensates by increasing stress hormones and heart rate, which can worsen fatigue and feeding difficulty.

Outside the heart, skeletal muscle weakness is common and often shows up as low stamina rather than obvious paralysis. Children may walk later than peers, struggle with stairs, or need frequent breaks during play. Growth delay before puberty is also typical and is usually influenced by a mix of heart function, muscle energy, frequent illness, and nutrition challenges.

Barth syndrome also affects the immune system—most notably neutrophils, the white blood cells that rapidly respond to bacterial infection. Neutropenia (low neutrophil count) may be persistent or intermittent, which is why some families see a “good week, bad week” pattern. Finally, many patients have a metabolic signature detectable in blood: an altered ratio of cardiolipin-related molecules, which helps confirm the diagnosis.

A helpful clinical takeaway is that Barth syndrome is rarely a single-symptom condition. The heart, muscle, immune system, and growth patterns interact, so the best care plan anticipates how one system’s flare (for example, an infection) can quickly stress the others (such as heart function and appetite).

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What causes Barth syndrome and who is at risk

Barth syndrome is caused by pathogenic variants in the TAFAZZIN (TAZ) gene. TAZ provides instructions for an enzyme (tafazzin) involved in remodeling cardiolipin—essentially refining cardiolipin into a mature form that mitochondria can use to maintain stable structure and efficient energy transfer. When tafazzin does not function correctly, mitochondria produce an abnormal cardiolipin profile and a higher proportion of related “intermediate” lipids. Over time, this affects the energy balance and stress response of cells, especially in heart and muscle tissue.

Because the condition is X-linked, risk is shaped by sex and family genetics:

  • Boys (who have one X chromosome) are most often affected when they inherit an X chromosome carrying a disease-causing TAZ variant.
  • Girls (who have two X chromosomes) are usually carriers and often have no symptoms, because the second X chromosome may provide enough functional tafazzin. However, biology is not always binary—some carriers can have mild features depending on X-inactivation patterns, and they still need informed genetic counseling.
  • A family history of early cardiomyopathy in male infants, unexplained heart failure, or recurrent severe infections in boys can be an important clue.
  • In some families, a child is the first known case due to a new (de novo) variant or because prior male pregnancies were lost before a diagnosis was made.

It is important to understand what “risk factors” mean in a genetic condition. Lifestyle factors do not cause Barth syndrome. Instead, the most meaningful risk factors are genetic and reproductive:

  • Being the biological child of a carrier mother increases the chance that a male child will be affected.
  • Having an affected male relative on the maternal side (maternal uncles, male cousins) can suggest an inherited pattern.
  • Families with a known variant can consider options such as carrier testing for relatives, prenatal testing, or preimplantation genetic testing, depending on values and local availability.

Clinically, risk is also influenced by timing. Many children present in infancy or early childhood, but milder cases can be diagnosed later, especially if early heart symptoms improved or were attributed to another cause. Some individuals are identified during evaluation of left ventricular noncompaction, unexplained cardiomyopathy, chronic fatigue, or recurrent infections.

One practical insight is to treat uncertainty as actionable. If Barth syndrome is suspected, clinicians often accelerate evaluation because early diagnosis changes monitoring intensity, infection planning, and family counseling—even before every symptom becomes obvious.

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Early symptoms and potential complications

Symptoms of Barth syndrome vary, but many families recognize a cluster: heart-related signs, unusual fatigue, and vulnerability to infections. In infants, the first red flags can be subtle—poor feeding, sweating with feeds, fast breathing, slow weight gain, or an unusually sleepy baby who cannot sustain activity. In older children, the story may shift to exercise intolerance, muscle weakness, and frequent illness that seems “too intense” for routine exposures.

Common early symptoms include:

  • Signs of heart strain: rapid breathing, poor feeding endurance, sweating, irritability, swollen belly, or slow growth
  • Low stamina and muscle fatigue: delayed motor milestones, difficulty climbing stairs, frequent rest breaks, leg pain after exertion
  • Recurrent infections: skin infections, mouth ulcers, pneumonia, or severe infections that start quickly
  • Growth delay: smaller size before puberty, poor weight gain, or a need for calorie-dense nutrition plans
  • Low blood counts: neutropenia may be persistent or intermittent, and some children have a history of “normal labs” between low-count episodes

Complications usually fall into two categories: heart-related events and infection-related events.

Heart-related complications may include:

  • Progressive heart failure symptoms, especially during infancy and toddler years
  • Arrhythmias, which can present as palpitations, fainting, or unexplained fatigue
  • Blood clots in the setting of severe heart dysfunction or structural changes, requiring careful specialist decisions about anticoagulation
  • Need for advanced support, such as mechanical circulatory support or heart transplantation in severe cases

Infection-related complications may include:

  • Febrile neutropenia (fever plus very low neutrophil counts), which can become life-threatening if not treated promptly
  • Severe bacterial infections that escalate rapidly, sometimes with fewer early warning signs
  • Hospitalizations that trigger a cascade: infection reduces appetite and hydration, which stresses the heart and worsens weakness

There are also “hidden” burdens that matter day to day: fatigue that limits school participation, anxiety around illness exposure, and nutritional challenges that feel constant. Families often benefit from naming these as legitimate medical impacts, not personal shortcomings.

Because symptoms can wax and wane, a child may look well in clinic even while the condition remains high risk. The safest approach is to take patterns seriously—especially repeated infections, exercise intolerance, or any new breathing difficulty—because these can be early signals that the heart or immune system needs reassessment.

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How Barth syndrome is diagnosed

Diagnosis typically begins when a clinician evaluates cardiomyopathy in a boy, especially in infancy, and notices additional clues such as growth delay, muscle weakness, or neutropenia. Because the condition is rare, it is often found through a combination of targeted testing and broader genetic workups.

A typical diagnostic pathway includes:

  • Cardiac evaluation
  • Echocardiogram to characterize cardiomyopathy (dilated features, hypertrophy, or left ventricular noncompaction) and measure function over time
  • Electrocardiogram (ECG) and rhythm monitoring when arrhythmia risk is a concern
  • Cardiac biomarkers and clinical heart failure assessment to guide urgency
  • Laboratory evaluation
  • Complete blood count with differential, repeated over time, because neutrophil counts may fluctuate
  • Metabolic screening in selected cases (often prompted by genetics or specialty clinics), which may show supportive patterns
  • Disease-specific biochemical testing
    One of the most distinctive confirmatory tests measures cardiolipin-related molecules in blood, focusing on the ratio between monolysocardiolipin and cardiolipin. An abnormal ratio strongly supports Barth syndrome and can be especially useful when symptoms are suggestive.
  • Genetic confirmation
    A definitive diagnosis is made by identifying a pathogenic variant in the TAZ gene. Many children are diagnosed using cardiomyopathy gene panels, mitochondrial disorder panels, or whole exome/genome sequencing. Genetic confirmation matters because it enables family testing, clarifies recurrence risk, and can streamline access to specialized monitoring and clinical trials.

Several conditions can look similar early on, so clinicians often consider differentials such as other inherited cardiomyopathies, metabolic disorders, viral myocarditis, and primary immune disorders. What pushes Barth syndrome higher on the list is the combination of heart disease plus muscle fatigue plus neutropenia, especially in a male child.

After diagnosis, many teams recommend baseline assessments that help with long-term planning:

  • Serial echocardiograms to track changes, not just a single snapshot
  • Rhythm surveillance if palpitations, fainting, or concerning ECG findings occur
  • Infection history review and an emergency plan for fever
  • Nutrition and growth assessment, including feeding endurance and caloric needs
  • Developmental and functional assessment, focusing on stamina and school participation

A practical point for families is that diagnosis is not the finish line—it is the start of predictability. Once the condition is named, clinicians can coordinate care around known risks: preventing avoidable infections, stabilizing heart function, and supporting muscle energy and growth.

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Treatment options and what to expect

Treatment for Barth syndrome is usually personalized and multidisciplinary, because no single therapy addresses every feature equally. Most care focuses on three priorities: protecting heart function, preventing and treating infections safely, and supporting nutrition and physical function.

Heart-focused care often resembles modern pediatric heart failure management, adjusted for the child’s size, symptoms, and heart structure. Common strategies may include:

  • Medications to reduce cardiac workload and improve pumping efficiency (chosen by a cardiologist and adjusted carefully as the child grows)
  • Diuretics when fluid overload is present
  • Monitoring for arrhythmias and treating them when needed
  • Advanced interventions in severe cases, which may include mechanical circulatory support or heart transplantation

Infection and neutropenia management is equally central. Because neutrophil counts can be low or fluctuate, the plan typically emphasizes:

  • A clear “fever protocol,” so families know when to seek urgent evaluation
  • Prompt assessment for bacterial infection when fever occurs, often with early antibiotics if neutropenia is present or suspected
  • Consideration of granulocyte colony-stimulating factor (G-CSF) in selected patients with recurrent severe infections or persistently low counts, balancing benefits with side effects and monitoring needs

Nutrition and muscle support can be transformative for quality of life. Many children benefit from:

  • High-calorie, nutrient-dense feeding plans when growth is faltering
  • Support for feeding endurance in infants (for example, strategies to reduce fatigue during feeds)
  • Physical therapy that builds strength without triggering prolonged exhaustion, often using short sessions with rest breaks and gradual progression
  • School accommodations that recognize fatigue as a physiologic limitation, not a motivation issue

Some therapies aim to address the mitochondrial and cardiolipin biology more directly. These approaches have been explored in clinical trials and may be discussed in specialist centers, but availability and suitability vary by region and individual circumstances. If a clinician offers a disease-targeted therapy pathway, families should ask practical questions:

  1. What outcome is the therapy expected to improve (exercise tolerance, fatigue, heart function, biomarkers)?
  2. How will benefits be measured and over what timeframe?
  3. What side effects or burdens (for example, injections or frequent visits) should we anticipate?
  4. What is the plan if the child becomes ill or has a heart failure flare during treatment?

What to expect over time depends on severity and early stability. Some children improve significantly with optimized heart failure care and strong infection planning, while others remain medically fragile and require intensive monitoring. Progress often happens in stages: first preventing crises, then improving endurance, then supporting growth and developmental participation. Even when symptoms are controlled, ongoing surveillance matters because heart structure and function can evolve across childhood and adolescence.

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Management, prevention and when to seek care

Day-to-day management in Barth syndrome is about reducing risk without shrinking life. The most effective plans are specific, written down, and shared across caregivers, schools, and medical teams.

Key management pillars include:

  • A coordinated care team
    Many families do best with a primary clinician plus cardiology, hematology/immunology, genetics/metabolic specialists, nutrition, and physical therapy. Coordination prevents conflicting advice, such as a heart-friendly fluid plan that unintentionally worsens constipation or fatigue.
  • Infection prevention that stays practical
  • Keep routine vaccines up to date, and ask clinicians which additional protections are appropriate for your child
  • Teach hand hygiene as a household habit rather than a fear-based rule
  • Have a clear plan for sick contacts and travel
  • Maintain quick access to medical evaluation if fever occurs, especially if neutropenia is known or suspected
  • A home “red flag” checklist
    Families often track a few high-signal signs: breathing rate, feeding endurance, energy level, urine output, and fever. A small change across several of these can matter more than a single symptom.
  • Heart-protective routines
  • Avoid dehydration, which can stress the heart and worsen fatigue
  • Use activity pacing: short bursts with planned recovery rather than one long session
  • Reassess exercise plans after illness, because recovery can temporarily reduce tolerance
  • Growth and nutrition consistency
    Many children need proactive calorie planning, not just “eat when hungry.” Helpful tactics include calorie-dense snacks, protein-rich options, and scheduled meals that match fatigue patterns. For some families, feeding support tools reduce conflict and improve weight gain.
  • School and psychosocial support
    Fatigue can be invisible but disabling. School plans may include rest breaks, modified physical education, elevator access, and flexibility after illness. Emotional support matters too; children may fear infections or feel different from peers, and parents may carry constant vigilance. Naming that burden and getting support can improve resilience.

When to seek urgent care is especially important in Barth syndrome. Seek prompt medical evaluation for:

  • Fever, especially if your child has a history of neutropenia or severe infections
  • Fast breathing, trouble breathing, blue lips, or worsening feeding fatigue
  • New swelling, sudden weight gain, or signs of fluid overload
  • Fainting, chest pain, severe palpitations, or unexplained collapse
  • Lethargy that is out of character, confusion, or poor urine output

Prevention in a genetic condition means preventing complications—not preventing the gene itself. The goal is to prevent delayed treatment of infection, prevent dehydration and overexertion that stress the heart, and prevent nutritional decline that compounds weakness. With careful planning, many families find a steady rhythm: fewer emergencies, clearer expectations, and more room for normal childhood experiences.

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References

Disclaimer

This article is for educational purposes and does not provide medical advice, diagnosis, or treatment. Barth syndrome can involve serious complications such as heart failure, arrhythmias, and severe bacterial infections, especially when neutrophil counts are low. If you or your child has fever, breathing difficulty, fainting, chest pain, severe weakness, or any sudden worsening of symptoms, seek urgent medical care. Treatment choices and monitoring schedules must be individualized by qualified clinicians who understand your medical history and current condition.

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