Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Barth syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of TAZ is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected, particularly in females. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
• A cardiomyopathy multigene panel that includes TAZ and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 2).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by cardiomyopathy and/or hypotonia, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Affected Males

To date, more than 200 individuals with Barth syndrome have been identified [Miller et al 2020]. The vast majority of affected individuals are male (see Female Heterozygotes). The following description of the phenotypic features associated with this condition is based on these reports.

Most affected individuals with Barth syndrome are male and present in infancy with cardiac issues, specifically dilated cardiomyopathy. In a French study of 22 males with Barth syndrome from 16 families, the median age at which medical care was first sought was 3.1 weeks (range: 0-1.4 years) [Rigaud et al 2013].

In another study of 73 males enrolled in the Barth Syndrome Registry, the age of onset was 0.76±1.6 years and the mean age at diagnosis was 4.04±5.45 years [Roberts et al 2012]. Therefore, there is on average a three-year delay between presentation and diagnosis of Barth syndrome. Cardiomyopathy was the presenting manifestation in 73% and infection was the presenting manifestation in 18%.

Cardiomyopathy in Barth syndrome is usually dilated but can also have features of combined dilated and hypertrophic cardiomyopathy, or isolated hypertrophic cardiomyopathy. Left ventricular noncompaction is also seen in many affected males.

The cardiomyopathy characteristically follows an undulating course in which the cardiac tissue can undergo remodeling, including a transition between hypertrophic and dilated appearances.

Cardiomyopathy almost always presents before age five years [Clarke et al 2013]. In many affected individuals the cardiomyopathy improves and in some it stabilizes after the toddler years. In the study by Rigaud et al [2013], left ventricular size and mass increased during the first six months of life, then decreased until age two years, and then appeared to stabilize. However, data in this study were insufficient to characterize these parameters in older children.

In a study by Kang et al [2016] of 27 individuals with Barth syndrome followed in the United Kingdom, those with normal left ventricular size and function had abnormalities of longitudinal and circumferential strain and reduced apical rotation. This finding led to the suggestion that cardiac medications be continued as long as functional or mechanical abnormalities persist.

Heart failure is a significant cause of morbidity and mortality; however, overall cardiac function varies greatly in individuals with Barth syndrome. Roberts et al [2012] noted that there may be a trend toward decline in cardiac function over time, as data from the Barth Syndrome Registry showed that for each five-year increase in age, ejection fraction z-score decreases on average by 0.6.

In the study by Rigaud et al [2013], out of 54 total hospitalizations for heart failure, 11 were due to worsening of heart failure attributed to infections. In this cohort, nine died from heart failure and two from sepsis. Median age of death was 5.1 months (range: 1.2-30.7 months). In the study by Kang et al [2016] of 27 people with Barth syndrome followed in the United Kingdom, seven underwent cardiac transplantation at a median age of two years, and five died at a median age of 1.8 years. All deaths were reported to be due to cardiomyopathy or the side effects of its management.

The response to medical therapy for cardiac failure is generally good. Spencer et al [2006] observed that with standard cardiac medications for dilated cardiomyopathy more than 16/30 affected males had normal ejection fraction and left ventricular diastolic volume. However, some responded to therapy initially but deteriorated after a period of stability, requiring cardiac transplantation [Adwani et al 1997, Mangat et al 2007].

Arrhythmia. The risk for arrhythmia (including supraventricular and ventricular tachycardia) and sudden death is increased. While arrhythmia has been most often reported in adolescents and young adults, it can occur in children of all ages. ECG abnormalities can include repolarization abnormalities and prolonged QTc intervals.

All 20 affected males with ECGs in the French cohort had a normal sinus rhythm. Repolarization abnormalities (including ST flattening and T-wave inversion) were seen in 17. Five had QTc values within the normal range (QTc <420 ms), and five had QTc greater than 460 ms. The median QTc was 440 ms (range: 360-530 ms). In the study by Kang et al [2016], nine of 21 affected individuals had prolonged QTc of greater than 460 ms and three had borderline QTc prolongation between 450 and 460 ms.

In five instances of ventricular arrhythmia leading to cardiac arrest or placement of an internal defibrillator [Spencer et al 2005]:

• All five individuals had normal QTc intervals;
• All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability;
• Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest;
• Three showed inducible ventricular arrhythmias on electrophysiologic testing;
• Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia;
• One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates;
• One had both ventricular and supraventricular tachycardia.

In the study by Kang et al [2016], 42 Holter recordings were performed in 16 affected individuals, and none had sustained tachyarrhythmia. Two had loop recorder implantation and brief atrial tachycardia was identified in one. One affected individual was noted to have broad complex tachycardia lasting five beats during an echocardiogram, correlating with symptoms.

Neutropenia and infections. In the Barth Syndrome Registry study, self-reported data revealed that neutropenia * was present in 69.1% at some point, a number similar to that from the French study, in which 16 of 22 males had a median absolute neutrophil count (ANC) of fewer than 500 cells/µL at least once.

• In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [Dale et al 2013].
• These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [Rigaud et al 2013]. In both studies, the ANC fluctuated, but without detectable periodicity.
• In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [Steward et al 2019].

* Defined as follows:

• Mild neutropenia: ANC between 1,000 and 1,500 cells/µL
• Moderate neutropenia: ANC between 500 and 1,000 cells/µL
• Severe neutropenia: ANC below 500 cells/µL

In the original description of the syndrome by Barth et al [1983] three of seven males with a known cause of death died from infection; however, such high mortality from infection was not observed in subsequent publications. In fact, the effects of neutropenia are more often limited to mild involvement, such as persistent oral infections [Barth et al 1999]. However, significant complications can occur. A recent review of the UK NHS Barth Syndrome Service documented infections in 35 affected individuals prior to the introduction of G-CSF therapy: two had complications of acute tubular necrosis secondary to streptococcal septicemia; one developed renal failure requiring transplant due to haemophilus septicemia; two had osteomyelitis; one had septic arthritis; three had soft tissue abscesses; five had cellulitis; two had balanitis; four had lobar consolidation/pneumonia; two had gingivitis; and one had a urinary tract infection [Steward et al 2019]. In the more recent Barth Syndrome Registry study, 60.2% of affected males had mouth ulcers, 28% had pneumonia, and 10% had blood infections.

This relatively low incidence of bacterial infections despite an ANC persistently below 1,000 cells/µL could be due to the development of a chronic, substantial monocytosis [Kelley 2002], which has been reported in two studies:

• In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL)
• Vernon et al [2014] reported an average AMC of 894±449 cells/µL (range: 500-2,400 cells/µL), with five of 17 affected males having monocyte counts at or above 1,000 cells/µL.
• In a report of 88 individuals with Barth syndrome [Steward et al 2019], monocyte counts greater than 1,000 cells/µL were observed at least once in 75%.

Of note, hematologic parameters neither worsen nor improve with age [Dale et al 2013]. Patterns of neutropenia seen in people with Barth syndrome can vary between intermittent and unpredictable, chronic and severe, or cyclical with a predictable pattern [Steward et al 2019].

Skeletal myopathy, which predominantly affects the proximal muscles, is non-progressive during childhood [Clarke et al 2013]. Frequently, affected children are diagnosed with hypotonia.

• In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives.
• In the French study the median age for walking was 19 months (range: 12-24 months).

Some males with Barth syndrome were born with talipes equinovarus, indicating a possible prenatal onset of hypotonia [Adès et al 1993, Gedeon et al 1995].

Of note, the exercise intolerance seen in males with Barth syndrome is due to both cardiac impairment and decreased skeletal muscle oxygen utilization [Spencer et al 2011].

In a study of individuals with Barth syndrome, six-minute walk test (6MWT) distance was abnormal in 33/34 individuals compared to controls [Thompson et al 2016]. In a study of functional exercise capacity and strength in 31 individuals with Barth syndrome [Hornby et al 2019], participants with Barth syndrome demonstrated abnormal 6MWT, increased five times sit-to-stand time (5XSST), and decreased knee extensor strength compared to controls.

Growth delay. Between ages six and 36 months the 50th percentile for length for boys with Barth syndrome is roughly equivalent to the third percentile in the standard curve; between ages 27 and 36 months, the 50th percentile for weight is roughly equal to the third percentile in the standard curve [Roberts et al 2012].

• Roberts et al [2012] published specific growth curves for boys with Barth syndrome [Roberts et al 2012; see Figure 1a-d].
• Spencer et al [2006] found that males with Barth syndrome show a delayed post-pubertal growth spurt with remarkable "catch-up" growth.

In males younger than age 18 years:

• Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile.
• Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%.

In males older than age 18 years, mean weight was in the 13th percentile (range: <1-63) and mean height in the 50th percentile (range: 8-90).

Dysmorphology. Younger males with Barth syndrome have a characteristic facial gestalt that is most evident during infancy, characterized by a tall and broad forehead, round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes. This appearance persists through childhood, becoming less obvious following puberty. The ears tend to remain prominent and the eyes deep-set.

At this point and after the late pubertal period of "catch-up" growth the most striking feature is that of gynoid fat distribution [Hastings et al 2009].

Intellectual development. Cognition in boys with Barth syndrome is characterized by age-appropriate vocabulary and basic reading skills, but a below-average performance in mathematics and selective difficulties in visuospatial skills that are not due to impaired motor functioning from myopathy [Mazzocco et al 2007]. Math difficulties are not evident in preschool but appear to emerge in kindergarten [Raches & Mazzocco 2012].

In the Barth Syndrome Registry study, 30 of 60 males older than age three years reported delay either in first words or in putting words together; 31 of 67 participated in speech therapy. Twenty-two of 46 males older than age seven years reported some form of "learning disability."

Sensory issues related to feeding and eating are common, and many affected males have a strong preference for salty, cheesy, and spicy foods while having an overall restricted repertoire of foods. Some issues such as a strong gag reflex manifest early in development [Reynolds et al 2012].

Psychosocial functioning. Boys with Barth syndrome experience lower quality of life than both healthy controls and boys with cardiac disease alone [Storch et al 2009]. Nine of 34 children were being monitored by a school psychologist, and eight of 34 children had close contact with a school counselor.

Acute decompensation. An acute metabolic presentation with metabolic acidosis, elevated plasma lactate, elevated transaminases, hypoglycemia, and hyperammonemia has been reported [Donati et al 2006]. Of note, this presentation has been described even in the setting of largely preserved cardiac function [Yen et al 2008, Steward et al 2010]. All four males reported to date with this metabolic presentation had onset of symptoms during the neonatal period (between days 1 and 13). Their subsequent course is not known to differ from that of other males with Barth syndrome.

Other. Based on data collected by the Barth Syndrome Registry study, other observed findings were:

• Delayed bone age (in 58%);
• Scoliosis (in 20%);
• Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals).

Perinatal. In 19 families with Barth syndrome, Steward et al [2010] found that six had serious perinatal issues including male fetal loss, nine stillbirths, and severe neonatal illness or death. The authors noted that Barth syndrome may be an under-recognized cause of male fetal loss. Others have described characteristic cardiac pathology of Barth syndrome (endocardial fibroelastosis and subendocardial vacuolization of myocytes) as early as 18 weeks' gestation [Brady et al 2006].

In the Barth Syndrome Registry study, preterm birth from 29 to 36 weeks occurred in nine of 65 males; birth weight was below 2.5 kg in nine of 48 males.

In the French study, median birth weight was 2.77 kg (range: 2.18-3.73 kg) and seven of 22 males had severe intrauterine growth restriction with birth weight below the third percentile.

Prognosis. The two factors that correlate with survival are severe neutropenia at the time of diagnosis and birth year (before 2000 or in/after 2000) [Rigaud et al 2013].

• Males with an ANC <500 cells/µL at the time of diagnosis have a one-year survival rate of 25% compared to 68% for those with an ANC >500 cells/µL.
• Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years.

In the French study, the five-year survival rate was 51%, with no deaths reported in males age three years or older; thus, the risk for early mortality appears to peak in the first few years of life.

Ronvelia et al [2012] report a man age 51 years with Barth syndrome, while Mazar et al [2019] reported seven individuals ages 37.2 to 58.6 years (the latter the oldest living individual with a confirmed diagnosis). Two affected males in their 60s are known [Author, personal observation].

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) [Vernon et al 2014] (see Table 1). In contrast, only eight of 16 individuals in the French cohort had elevated 3-MGC levels [Rigaud et al 2013].

Monolysocardiolipin:cardiolipin ratio. Using high-performance liquid chromatography-mass spectrometry (HPLC-MS), van Werkhoven et al [2006] 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 [2008] found that all males with Barth syndrome had an MLCL:CL ratio greater than 0.40 and all controls had a ratio of 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 for atypical phenotypes if only tetralinoleoyl cardiolipin is measured. [Bowron et al 2015]. 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.

• A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [Houtkooper et al 2009].
• In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [Rigaud et al 2013].
• 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).
• Plasma amino acids
  • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [Rigaud et al 2013].
  • 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 2014]. These 28 males also showed significantly higher proline levels (291 μmol/L) than controls (165 μmol/L).
• Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 patients tested [Spencer et al 2006]. In another study, only two of 28 were found to be hypocholesterolemic, with a mean cholesterol level of 137±26 mg/dL [Vernon et al 2014].
• Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [Kelley et al 1991, Christodoulou et al 1994] and in at least one case was the presenting complaint [Rigaud et al 2013].
• Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [Spencer et al 2006].
• Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [Spencer et al 2006]. In a separate study 13 of 18 affected males showed decreased prealbumin levels with a mean of 16.9±4.0 mg/dL [Vernon et al 2014].

Respiratory chain studies reveal decreased activity of complex III and IV in skeletal muscle [Barth et al 1983] and fibroblasts [Barth et al 1996].

Pathology

• Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [Barth et al 1983, Ino et al 1988, Kelley et al 1991]. In at least one case the initial presentation was a lipid storage myopathy [Takeda et al 2011].
• Liver. Lipid storage in the liver has also been described [Ino et al 1988, Kelley et al 1991, Donati et al 2006].
• Bone marrow
  • A maturation arrest at the myelocyte stage was noted in the original description of the disease [Barth et al 1983].
  • 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 [Rigaud et al 2013].

Female Heterozygotes

Heterozygous females typically do not manifest the disease. Biochemical abnormalities have not been found in eight heterozygous females [Vernon et al 2014].

It is proposed that heterozygous females are asymptomatic due to selection against cells with the mutated TAZ allele on the active X chromosome, based on a study of the X-chromosome inactivation pattern in 16 obligate heterozygotes [Orstavik et al 1998]. In this study, six of the 16 had an extremely skewed pattern of X-chromosome inactivation (≥95:5) and five had a skewed pattern (80:20≤95:5) that was not observed in 148 female controls.

Two females with Barth syndrome have been reported:

• One had biallelic pathogenic variants in TAZ as a result of (1) a complete deletion of the paternal allele (associated with a ring X chromosome with a large deletion that included TAZ) and (2) a deletion of exons 1-5 in the maternal TAZ allele [Cosson et al 2012]. Analysis of lymphocyte and fibroblast cultures showed monosomy X with mosaicism for the ring X chromosome; thus, at least in lymphocytes, she lacked a normal TAZ allele.
• A second affected female with pathogenic TAZ variant c.253insC (p.Arg85ProfsTer54) in exon 3 had left ventricular noncompaction and hypotonia. Skewed X inactivation (presumably where the X chromosome with the nonmutated TAZ was preferentially inactivated) was identified in her blood [Avdjieva-Tzavella et al 2016].