Barth syndrome is a genetic ultra-rare, infantile-onset, X-linked recessive metabolic mitochondrial disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present and mainly affects males. It is caused by mutations in the TAZ gene, which is known to encode the protein Magazin. Tafazzin plays an important role in the remodeling of cardiolipin, a component of the mitochondrial membrane necessary for maintaining mitochondrial structure as well as for mitochondrial apoptosis and the functioning of the electron transport chain.[rx,rx]
Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Some of the symptoms of the condition include an enlarged heart, low blood cell count, weakness of muscles, and fatigue. Additionally, there can be increased levels of chemicals like 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood. Barth syndrome is caused by changes (mutations) in the TAZ gene and has an X-linked inheritance pattern.
Barth syndrome is an X-linked inborn error of metabolism, which almost exclusively affects males. The main phenotypic manifestations are cardiomyopathy, mitochondrial myopathy, growth delay, intermittent neutropenia, and 3-MGA-uria. The underlying cause has been traced to variants in the TAZ gene on chromosome Xq28.[rx] TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl-chain remodeling.[rx] Absence of tafazzin results in heterogeneity of cardiolipin molecular species, increased levels of monolysocardiolipin, and low cardiolipin abundance. Dysfunction of cardiolipin perturbs the inner mitochondrial membrane, and impairs respiratory chain functions and thus aerobic respiration.[rx] Decreased electron flow from fuel metabolism via complex-I activity leads to accumulation of NADH and product inhibition of key tricarboxylic acid (TCA) cycle enzymes.;[rx] Reduction of TCA cycle activity results in the diversion of pyruvate, generated by glycolysis, to lactic acid.[rx] As a consequence, lactic acid (Cori) cycle activity increases to supply muscle with glucose for continued ATP production.[rx] Acetyl-coenzyme A, which is unable to enter the TCA cycle, is diverted to organic acid waste products that are excreted in the urine.[rx] Diagnosis of the condition is confirmed by mutational analysis of the TAZ gene and documentation of an increased ratio of monolysocardiolipin to tetralinoleoyl-cardiolipin.[rx]
Symptoms
Barth syndrome is mainly found in early infancy or childhood. However, in some patients, symptoms appear in adulthood. Symptoms can present differently and can vary from one person to another.
Males with Barth syndrome could have various heart problems like dilated cardiomyopathy, hypertrophic cardiomyopathy, endocardial fibroelastosis, and left ventricular non-compaction. Dilated cardiomyopathy is when the left ventricle muscle becomes enlarged and weak which decreases the heart’s ability to pump blood. In some people with Barth syndrome, the heart muscles become very thick making it difficult to pump blood (hypertrophic cardiomyopathy). Sometimes, this thickening may be due to the build-up of connective tissues and elastin fibers (endocardial fibroelastosis). In other patients, the left ventricles do not develop properly (left ventricular noncompaction) so instead of the muscle being smooth, it becomes thick and spongy making it difficult to pump blood. These heart findings are almost always present before the age of 5. Sometimes the heart problems can be seen on an ultrasound exam in the last trimester of pregnancy. In addition to structural differences in the heart, in some adolescents and young adults, there could be an irregular heartbeat identified (arrhythmia). The heart problems might lead to a decrease in blood circulation in the body and the lungs (heart failure). Symptoms of heart failure may include shortness of breath, tiredness, and nausea, but the symptoms depend on the child and other factors.
People with Barth syndrome have a low level of white blood cells (neutropenia). The white blood cells in our body help us fight infections. Due to neutropenia, people have mouth ulcers, pneumonia, or blood infections. Males with Barth syndrome have weak muscles (hypotonia), especially in the hands and feet. Due to the hypotonia, children take longer to develop gross motor skills like crawling, sitting, or walking. Due to heart issues and weak muscles, these boys do not tolerate exercise well. Males with the condition have growth delay during childhood, but there is a significant growth spurt in puberty. Other symptoms include curvature of the spine (scoliosis) and delayed bone age.
Males with Barth syndrome have distinct facial features. They have a round face with a prominent chin and full cheeks. The ears are large, and they have deep-set eyes. The facial features become less noticeable with age. The striking feature in adolescence and adulthood is the fat distribution in the hips, thighs, and chest.
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At least one of the following cardiac findings:
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Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium
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Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity
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Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness
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Skeletal myopathy or hypotonia
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Prepubertal growth delay
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Typical dysmorphic findings in infants and toddlers include a round face, full cheeks, prominently pointed chin, large ears, and deep-set eyes
People diagnosed with the condition have some form of learning disability. They have age-appropriate reading skills and vocabulary. However, they may need extra help with mathematics. Their first words or forming sentences can be delayed in comparison to other people. They have delays in developing skills like reading a map, recognizing shapes, and finding objects in a picture. The boys have feeding difficulties. The Barth syndrome registry data suggest that a third of males with this condition would need a tube put through the nose or directly to the stomach for feeding. Boys with this condition are picky eaters. Salty, cheesy, and spicy food are some of the foods they prefer.
In addition to the cardiomyopathy, neutropenia, and growth delay, people with this condition have increased levels of biochemical markers. Increased levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood is the common marker used to reach a diagnosis. However, no symptoms have been associated with the increased levels of these chemicals.
The phenotype of Barth syndrome is highly variable but most frequently patients present with hypertrophic/dilated/non-compaction cardiomyopathy, fibroelastosis, arrhythmias, neutropenia, mitochondrial myopathy, and growth retardation, dysmorphism, cognitive impairment, and other, rarer features. Lactic acid and creatine kinase, and blood and urine organic acids, particularly 3-methylglutaconic acid and monolysocardiolipin, are often elevated. Biochemical investigations may show the decreased activity of various respiratory chain complexes.
Causes
Barth syndrome is caused by mutations in the TAZ gene. The TAZ gene produces a protein called Magazin. Tafazzin helps in altering a fat called cardiolipin. Cardiolipin is present in the inner membrane of structures called mitochondria. Mitochondria are structures in the cell that help in making energy. Loss of tafazzin protein mainly affects energy-requiring organs like the heart and skeletal muscles. However, more research is required to understand how the loss of tafazzin leads to cardiomyopathy and neutropenia.
Barth syndrome is inherited in an X-linked manner. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. No females who are carriers of Barth syndrome have reported any symptoms.
Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all his 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.
Diagnosis
Barth syndrome is usually diagnosed during infancy or early childhood but has been diagnosed later in some patients. Diagnosis is based upon clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and a variety of specialized tests.
Consider Barth syndrome if someone has:
- Heart findings like dilated cardiomyopathy, hypertrophic cardiomyopathy, and noncompaction of left ventricle
- Increased levels of 3-methylglutaconic acid in the blood and/or urine
- Neutropenia
- Hypotonia
- Growth delay
- Characteristic facial features.
Multiple pregnancy losses involving a male fetus have been observed in some families with Barth syndrome.
Laboratory findings
Laboratory findings that may be associated with Barth syndrome include the following.
Plasma 3 methylglutaconic acid (3-MGC). In a single study, 28 of 28 affected individuals ranging in age from ten months to 30 years had elevated plasma 3-MGC levels, with an average of 1,088 nmol/L ± 435 (range: 393-2,326 nmol/L) [rx]. In contrast, only eight of 16 individuals in the French cohort had elevated 3-MGC levels [rx].
Monolysocardiolipin:cardiolipin ratio. Using high-performance liquid chromatography-mass spectrometry (HPLC-MS), van Werkhoven et al [rx] measured monolysocardiolipin (MLCL) and cardiolipin (CL) levels from cultured fibroblasts of males with Barth syndrome and controls. They found that the range of MLCL: CL ratios was 5.41–13.83 in Barth syndrome and 0.03–0.12 in controls.
Using a screening method in bloodspots, Kulik et al [rx] found that all males with Barth syndrome had an MLCL: CL ratio greater than 0.40 and all controls had a ratio lower than 0.23. Using a cutoff of 0.30, they reported a sensitivity and specificity of 100%. Males with classic Barth syndrome tend to have ratios greater than 1 but those with an intermediate form or atypical phenotype (mild cardiac involvement, good exercise tolerance, mild/no neutropenia) can have ratios lower than this but greater than 0.4. It is important that the MLCL: CL ratio is used for diagnosis, rather than CL content alone, as false-negative results can result in atypical phenotypes if only tetralinoleoyl cardiolipin is measured. [rx]. It is also advised to confirm the results from MLCL: CL either through molecular genetic testing or with a repeat sample, ideally in a different medium.
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A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [rx].
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In the French study, all 16 affected males had an elevated MLCL: CL ratio: in fibroblasts (14 individuals); lymphoblasts (1 individual); and platelets (1 individual) [rx].
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Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L).
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Plasma amino acids
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In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [rx].
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This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [Vernon et al 2014rx]. These 28 males also showed significantly higher proline levels (291 μmol/L) than controls (165 μmol/L).
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Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [rx].
Respiratory chain studies reveal the decreased activity of complex III and IV in skeletal muscle [rx] and fibroblasts [rx].
Pathology
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Liver. Lipid storage in the liver has also been described [rx].
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Bone marrow
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A maturation arrest at the myelocyte stage was noted in the original description of the disease [rx].
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More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [rx].
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Clinical testing and workup
- As a part of routine follow-up, the growth and height of the children are monitored regularly. Annual cardiac follow-up using ECG, echocardiogram, and Holter monitor is considered.
- Molecular genetic testing for mutations in the TAZ gene confirms the diagnosis of Barth syndrome. The TAZ gene testing can be done individually or as a part of a multigene panel.
Treatment
There is no curative therapy for Barth syndrome available. However, several symptomatic measures can be offered.
The treatment of Barth syndrome is for specific symptoms. Such treatments may need the 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 threats to a patient with Barth syndrome. This is one of the main reasons for a reduced life expectancy. Standard heart failure medications like beta-blockers, ACE inhibitors, and digoxin are used. This helps in improving heart function and reduces symptoms of heart failure. Aspirin is used for reducing clot formation. A heart transplant is considered when there is severe heart failure. Heart functioning tends to improve after infancy, so heart transplants should be carefully considered.
For affected people with confirmed neutropenia, complications due to bacterial infection can be prevented by monitoring and starting 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. Giving uncooked cornstarch before bedtime is recommended to prevent muscle loss. An early intervention like physical therapy is recommended for increasing muscle tone and helps children to attain various developmental milestones
Cardiac
Patients developing heart failure require appropriate treatment with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, or diuretics. In cases of severe heart failure or atrial fibrillation and a CHADSVASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke/transient ischemic attack, vascular disease, and sex) score >1, oral anticoagulation should be considered. The response to this standard therapy is usually favorable. In a study of 30 patients with dilated cardiomyopathy, 16 recovered to normal systolic function.[rx] In several patients, however, heart failure therapy may be ineffective, and these patients require other approaches, including heart transplantation.[rx, Rx–rx] The interval until heart transplantation becomes feasible may be bridged by mechanical circulatory support.[rx] In the case of right ventricular failure, the administration of prostaglandin E1 may be beneficial.[rx]
Neutropenia
Neutropenia can be treated by regular administration of granulocyte–colony-stimulating factor (G-CSF).11 To prevent infections, prophylactic administration of antibiotics may be necessary. All prophylactic measures available should be taken to avoid recurrent infections. Despite administration of G-CSF and normalization of the granulocyte count, however, patients may develop severe infections.[rx]
Myopathy
In cases of muscle weakness, patients may benefit from foot or ankle orthoses, walkers, or wheelchairs.[rx] In a study on nine patients, progressive exercise resistance training (ERT) for 12 weeks was demonstrated to improve muscle strength.[rx] Endurance training has also been shown to be beneficial, at least in four adult patients with Barth syndrome.[rx] If respiratory muscles become affected, invasive or non-invasive ventilatory support may be necessary. It has been demonstrated that exercise training in a mouse model of Barth syndrome ameliorated complex III deficiency in these animals.[rx]
Other
Supplemental feeding via a gastrostomy tube or nasogastric tube may be necessary for one-third of patients.[rx] Since patients with Barth syndrome experience reduced quality of life,[rx] they may benefit from monitoring by a school psychologist or contact with a school counselor.[rx] Prophylactic use of antibiotics may be useful during conditions with a high risk of infection.[rx] Because of the propensity to hypoglycemia, prolonged fasting should be avoided.[rx] As patients with Barth syndrome carry an increased risk of abnormal serum potassium levels, this parameter should be carefully monitored.[rx] Patients with Barth syndrome also carry an increased risk of developing malignant hyperthermia-like conditions, and therefore elective general anesthesia should be designed, as in patients with malignant hyperthermia susceptibility. There is no evidence of any benefit from the application of coenzyme Q, pantothenic acid, L-carnitine, or L-arginine.
Experimental findings
In TAZ knockdown mice, bezafibrate attenuated cardiac dysfunction and improved exercise intolerance.[rx,rx] Expression of monolysocardiolipin acyltransferase-1 in lymphoblasts from Barth syndrome patients improved mitochondrial respiratory functions.[rx] In a yeast model of Barth syndrome, overexpression of the mitochondrial azodicarboxylate carrier (ODC1) preserved oxidative phosphorylation.[rx] Exogenous application of cardiolipin in myeloid progenitor cells prevented apoptosis of these cells induced by TAZ knockdown.[rx] In a mouse model of Barth syndrome, replacement of the TAZ gene by an AAV9 vector improved the expression profile of cardiac proteins.[rx] In a similar study with the same experimental setting, gene therapy restored mitochondrial and cytoskeletal functions.[rx]
Administration of exogenous cardiolipin in nanodisk delivery particles failed to show a beneficial effect in TAZ knockdown mice.[rx] Whether resolution of mitochondrial oxidative stress may be sufficient to prevent cardiomyopathy and myopathy in Barth syndrome remains speculative. In a crossing of mice that overexpressed catalase in mitochondria and mice that were TAZ deficient (TAZKD mice), resolution of oxidative stress was not sufficient to suppress the development of cardioskeletal myopathy, despite decreased mitochondrial H2O2 emission and decreased lipid peroxidation in these animals.[rx] Of interest for future gene therapy studies is a study of 42 Barth syndrome patients showing that there are genotypes with a less severe metabolic and clinical profile.[rx]
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
- Pantothenic acid. The original report of successful treatment of Barth syndrome with pantothenic acid [rx] was not substantiated by later reports [rx].
- Coenzyme Q10. The rationale behind the use of coenzyme Q10 is based on the fact that both coenzyme Q10 and 3-methylglutaconic acid (3-MGC) can be produced from dimethylallyl pyrophosphate (DMAPP), an intermediate in the synthesis of cholesterol. Thus, if coenzyme Q10 production is impaired, more DMAPP could potentially be shunted toward the production of 3-MGC [rx]. However, no formal study has been undertaken to prove the efficacy of coenzyme Q10 therapy in males with Barth syndrome. In a study of 15 males with Barth syndrome, three took coenzyme Q10 [rx].
- Carnitine. Although early reports claimed significant benefits from carnitine supplementation in males with Barth syndrome [rx], subsequent reports identified rapid deterioration in cardiac function in some cases with carnitine supplementation [rx]. Thus, unless plasma carnitine levels are low, its supplementation has no role in the treatment of Barth syndrome.
- Arginine. Because lower plasma arginine levels detected in males with Barth syndrome [rx] could contribute to growth delay and cardiac abnormalities by impairing protein synthesis, it has been proposed that oral arginine supplementation be used. Improvements in ventricular function have also been noted concurrently with normalization of the amino acid profile [R Kelley, personal communication]. However, to date, no formal assessments of the efficacy of this treatment have been published.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay/learning disability in the United States; standard recommendations may vary from country to country.
- Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services and special educators. In the US, early intervention is a federally funded program available in all states that provide in-home services to target individual therapy needs.
- Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, or social delay. The early intervention program typically assists with this transition. Developmental preschool is center-based; for children too medically unstable to attend, home-based services are provided.
- All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of the appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
Individualized education plan (IEP) services
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
- PT, OT, and speech services will be provided in the IEP to the extent that he he need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
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A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
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Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated adaptive disabilities.
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Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Gross Motor Dysfunction
- Physical therapy is recommended to maximize strength.
Social Behavioral Concerns
- Consultation with a developmental pediatrician may help guide parents through appropriate behavior management strategies or provide prescription medications, when necessary.
- Genetic counseling is recommended for affected individuals and their families. Another treatment for this disorder is symptomatic and supportive.
| Aljishi and Ali[rx] Case report | A 6-year-old male with Barth syndrome | Medical: digoxin, furosemide, and captopril Dietary: oral carnitine supplementation |
Acquisition of developmental milestones, normalization of liver size, improvement of ejection fraction on echocardiogram Poor tolerance of carnitine |
| Afrikan and Khuchua[rx] Literature review | Barth syndrome | Medical: Granulocyte Colony-Stimulating Factor (G-CSF) | Increased levels of circulating neutrophils result in reduced frequency of infection |
| Avery[rx] Fact sheet | Barth syndrome | Dietary: cornstarch gave before bedtime | Prevention of hypoglycemia and minimization of muscle protein loss overnight |
| Bachou et al[rx] Case report | 5.5-month-old with Barth syndrome | Medical: G-CSF Medical: digoxin, diuretics, and angiotensin-converting enzyme (ACE inhibitors) |
Neutrophil count sustained near-normal levels, fewer infections Cardiac function deteriorated leading to heart failure and death at 28 months |
| Barth Syndrome Foundation[rx] Fact sheet | Barth syndrome | Medical: ACE inhibitors, diuretics, vasodilators, β-blockers, cardiac glycosides (eg, digoxin), inotropes, anticoagulants, angiotensin II receptor blockers, calcium channel blockers Medical: antiarrhythmic medications, pacemaker, or implantable cardioverter-defibrillator (ICD) Medical: G-CSF, antibiotics Dietary: daily vitamin-mineral supplement, mitochondrial cocktail (eg, mitochondrial cofactors), vitamin C (eg, ascorbic acid), potassium, L-carnitine |
Medicines are often given in combination to prevent symptoms of heart failure. Side effects are common Medicines for arrhythmias alter electrical conduction in the heart or block impulses that can lead to abnormal heart rhythms. If drug therapy does not work, implanted devices are an alternative option G-CSF stimulates the formation and maturation of neutrophils in bone marrow, decreasing infection. Side effects include headaches and bone pain. Antibiotics can be used to stop the spread of infection No significant benefit has been found with the use of the supplement carnitine. Prescription of potassium should be based on blood levels and closely monitored |
| Barth Syndrome Foundation[rx] Fact sheet | Barth syndrome | Dietary: intravenous (IV) fluids containing potassium Dietary: a daily multivitamin with minerals Feeding aids: Nasogastric (NG) tube, gastrostomy button, IV fluid bag, bolus feedings Feeding aids: preemie nipple, supplemental nutrition system, syringe, Habermann feeder, consultation with a lactation specialist Feeding strategies: giving choices to a child, do not force feed, small portions, slowly introduce new foods |
Potassium in IV fluids can cause hyperkalemia, which must be done with caution Multivitamins can be used to prevent vitamin and other minor nutrient deficiencies Feeding tubes can provide appropriate nutrition and caloric intake to help maintain/gain weight Adaptive feeding strategies may increase feeding capabilities for children with low muscle tone, oral fatigue, or poor coordination of suck |
| Bowen et al[rx] Fact sheet | Barth syndrome | Medical: topical or oral corticosteroids, mouth rinses | Used for treatment and pain relief of mouth ulcers secondary to neutropenia |
| Clarke et al7 Literature review | Barth syndrome | Medical: cardiac medications (ACE inhibitors, β-blockers, digoxin, and diuretics), cardiac transplant, ICD, G-CSF, prophylactic antibiotics Rehabilitative: mobility aids Educational: special education Dietary: L-carnitine, pantothenic acid supplements, dietary supplementation with arginine, and cornstarch supplements may be used at bedtime Feeding aid: NG or gastrostomy tube |
Most Barth patients need to be maintained on standard cardiac medications throughout childhood; no published studies had analyzed the efficacy of these ICD may minimize sudden death due to ventricular arrhythmia G-CSF is widely used for the treatment of neutropenia Mobility aids used to conserve energy No evidence for use of carnitine or pantothenic acid supplements No drug or food supplement has so far been shown to be conclusively beneficial |
| Dedieu et al[rx] Case report | 3-year-old with Barth syndrome | Medical-prolonged ventricular assistance with the Berlin Heart EXCOR | Successful bridge to heart transplant |
| Finsterer and Frank[rx] Literature review | Barth syndrome | Rehabilitative: physiotherapy Dietary: carnitine supplementation Medical: application of lactate-lowering agents, biweekly injection of G-CSF Medical: ventricular assist device as a bridge to a heart transplant, placement of an in-line oxygenator to maintain end-organ function |
May improve muscle weakness Normalized levels of carnitine Reduction of lactic acidosis and increase in neutrophil count Successful cardiac transplantation |
| Folse et al[rx] Case report | Male with Barth syndrome (birth to 2 years) | Medical: G-CSF, furosemide intravenously, captopril, spironolactone, carvedilol, enalapril, aldactazide medications | Discharge from the hospital in stable cardiac condition with the maintenance of function post-discharge |
| Hanke et al[rx] Case report | Male with Barth syndrome (3 days old) | Medical: mechanical circulatory support, in-line oxygenator (Quadrox iD), Berlin EXCOR biventricular device (Bi-VAD), cardiac transplant, G-CSF | Successful cardiac transplantation 24 days after Bi-VAD placement |
| Huang et al[rx] Case report | 11-month-old male with Barth syndrome | Medical: mitral valvuloplasty, furosemide, captopril, and aspirin | Mitral annuloplasty could be used as an alternative to heart transplant for infants with severe heart failure and mitral regurgitation |
| Huhta et al[rx] Case report | 18-year-old male with Barth syndrome | Medical: G-CSF, carvedilol, methadone, atrial intracardiac defibrillator (AICD) implantation Feeding aid: gastrostomy and PEG tube |
Carvedilol improved heart function, while G-CSF was used to address neutropenia |
| Jefferies[rx] Literature review | Barth syndrome | Medical: G-CSF possibly combined with appropriate prophylactic antibiotics Medical: Growth hormone (GH) supplementation Dietary: arginine supplementation Medical: ACE inhibitors, angiotensin receptor blockers, β-blockers, potassium-sparing diuretics, IV agents such as vasodilators and inotropes Medical: mechanical circulatory support (Berlin EXCOR device), cardiac transplantation Medical: ICDs |
Treatment of neutropenia GH supplementation is not routinely used to address growth delays since levels seem to normalize in the late teens and early 20s. Arginine supplementation may be used as a possible treatment to improve the growth rate Cardiac medications can be used to alleviate symptoms of heart failure and prolong the life Successful transplants and bridges to transplant have been reported Limited data regarding the effectiveness of ICDs for the management of arrhythmias in Barth syndrome |
| Kelley[rx] Fact sheet | Barth syndrome | Dietary: IV fluids containing potassium, parenteral amino acid nutrition, or IV supplemental amino acids | Management of diarrheal illness |
| Malhotra et al[rx] Literature review | Barth syndrome | Medical: β-blockers (eg, carvedilol, metoprolol, bisoprolol), cardiac glycosides (eg, digoxin), diuretics (eg, furosemide, ethacrynic acid), cytokines (eg, G-CSF) | The use of multiple drugs simultaneously (polypharmacy) may lead to inadvertent life-threatening consequences in some children with Barth syndrome |
| Mangat et al[rx] Case reports | Four males with Barth syndrome: ages 2 years, 3.5 years, 1.5 years, and 10 months | Medical: cardiac transplant | To date, all children have normal coronary angiography No clear benefit to using either carnitine or pantothenic acid |
| Marziliano et al[rx[ Case report |
A 12-year-old male with Barth syndrome | Medical: inotropic agents, ACE inhibitors, and diuretics | Progressive improvement of left ventricle function |
| Rigaud et al[rx] Cohort study | 22 males with Barth syndrome | Medical: inotropic support, invasive ventilation, ventricular assist device, cardiac transplant, echocardiograms Medical: ACE inhibitors, β-blockers, digoxin, diuretics, anticoagulants, aspirin Medical: G-CSF, antibiotic prophylaxis Feeding aid: long-term enteral nutritional support Dietary: arginine supplementation |
Systematic use of β-blockers and modern inotropic drugs such as milrinone has decreased the incidence of heart failure Neutropenia seemed to respond well to G-CSF, though two episodes of severe infection occurred while patients were on G-CSF therapy Arginine may improve the growth rate of patients with Barth syndrome |
| Sabater-Molina et al[rx] Case report | A 30-year-old male with Barth syndrome | Medical: β-blockers, losartan | Good tolerance of medications: symptom benefit related to fatigue and muscular claudication |
| Singh et al[rx] Case report | 7-month-old male with Barth syndrome | Medical: mechanical support via a Berlin left ventricular assistive device implantation followed bextracorporealal membrane oxygenation (ECMO), orthotropic cardiac transplantation at the age of 2 years Rehabilitative: physical therapy |
Muscle tone improved with physical therapy |
| Storch et al[rx] Descriptive comparison | Boys with Barth syndrome (n=34) and healthy controls (n=22); ages 2–25 years | Educational: accommodations including classroom seating changes, rest periods, schedule adjustments, note-takers, extra books for home use, alternative assignments, medication administration at school, extra tutorials, use of tape recorders, peer mentors Psychological: monitored by school psychologist or guidance counselor Dietary: special diet at school |
Supports were in place to improve school functioning in boys with Barth syndrome |
| Sweeney et al[rx] Case report | Male with Barth syndrome (birth to 20 months) | Medical: treatment with digoxin, captopril, Lasix; sent home from the hospital on the monitor and supplemental oxygen | The patient died at 20 months of age Digoxin therapy appeared to have been effective in improving heart function as evidenced by the patient’s decompensation upon its withdrawal |
| Tajima et al[rx] Case report | 18-year-old male with Barth syndrome | Dietary: magnesium supplementation | Slight improvement in muscle strength, normalization of serum magnesium levels |
| Takeda, et al[rx] Literature review | Barth syndrome | Medical: ACE inhibitors, β-blockers, diuretics, cardiac transplantation Medical: G-CSF, parenteral antibiotics Medical: ICD placement |
Heart failure is most responsive to standard medication therapy; successful heart transplantation has also been reported in patients with severe heart failure Neutropenia can usually be managed with parenteral antibiotics and GCS-F therapy Prevention of sudden death has been documented with the placement of ICD No treatment is needed for hypotonia because it usually improves spontaneously |
| Yen et al[rx] Case report | 11-month-old male with Barth syndrome | Medical-emergent mitral valve replacement | Improved symptoms related to mitral insufficiency; patient waitlisted for cardiac transplantation |
References
Osteopetrosis
