Principal Clinical Diagnostic Criteria

Growth Delay

Growth delays are often observed early in infancy; however, the mean length of infants with Barth syndrome at birth is normal, whereas weight for length often is mildly decreased, most likely due to muscle hypoplasia. Typically, the growth velocity of Barth children in the first two years gradually decreases until the Z-score for length is between -2 and -4 [Kelley et al (1991) References]. Thereafter, growth velocity is normal and the length or height remains parallel but below the third percentile until puberty. At puberty, a prolonged growth spurt begins, often lasting until late teenage years until, usually, normal final adult height is attained. Because of muscle hypoplasia, Z-scores for weight can be up to 2 SD below the Z-score for height. Such abnormal weight-for-height ratios in Barth syndrome are rarely caused by nutritional failure-to-thrive, but are a “normal” characteristic of Barth syndrome.


Cardiomyopathy may present within the first months of life, but sometimes not until later in life [Barth et al (1983) References; Kelley et al (1991) References; Christodoulou et al (1994) References; Barth et al (1999) References]. Cardiomyopathy may initially present as hypertrophic type or dilated.


Neutropenia is one of the more variable features of Barth syndrome and can be chronic, cyclic, or absent. When cyclic, the duration of the cycle for most patients falls between 21 and 28 days. There is usually a moderate monocytosis associated with periods of neutropenia, which may explain why most children with Barth syndrome have relatively few bacterial infections compared to other disorders with equally severe neutropenia. Histology of the bone marrow in Barth syndrome shows normal cell lineages apart from the myeloid series, which often appears to be arrested at the myelocyte stage [Barth et al (1983) References]. The incomplete nature of the block in myelopoiesis is clear from the observations that, once a systemic bacterial infection develops, children with Barth syndrome often develop a marked neutrophilia and that they respond quite well to granulocyte colony-stimulating factor (G-CSF). [Kelley, RI; Cox G (unpublished)].

3-Methylglutaconic Aciduria Type II

Although a number of patients with Barth syndrome have been said to have normal levels of 3-methylglutaconic acid, in almost all cases the organic acid analysis was done non-quantitatively or without adequate normal control data to recognize diagnostically increased levels of 3-methylglutaconic acid. Quantification of 3-methylglutaconic acid in blood samples by isotope-dilution gas chromatography-mass spectrometry also is available [Kelley, RI (1993) References]. An increased level of 3-methylglutaconic acid is a common finding in many primary disorders of mitochondrial metabolism and other presumed metabolic diseases of unknown cause [Gibson, KM et al (1993) References]. However, whereas the level of 3-methylglutaconic acid (urine or blood) in mitochondrial diseases typically is increased only two- or three-fold, the increase in Barth syndrome typically is 5 to 20-fold. In addition, many patients with Barth syndrome have a distinctive pattern of increased urinary organic acid levels (in addition to 3-methylglutaconic acid) consisting of 2-ethylhydracrylic acid, aconitate, fumarate, and 2-ketoglutarate [Kelley et al (1991) References]. Especially in the newborn period or with fasting during an acute illness, a dicarboxylic aciduria suggesting a long-chain fatty acid oxidation defect may be present. Although these organic acid patterns are not unique to Barth syndrome, finding them in a child with cardiomyopathy should prompt the consideration of the diagnosis of Barth syndrome. Some patients will also be found to have a lactic aciduria and lactic acidemia, usually at times of a cardiac crisis. However, it is not always clear whether the increased lactate level is a metabolic abnormality per se or the result of poor circulation caused by congestive heart failure.

Due to this discrepancy in standards of organic acid screening, a diagnosis of Barth syndrome should not be ruled out in absence of this symptom. Many patients with Barth syndrome have a distinctive pattern of increased levels of urinary organic acids in addition to 3MGC. Commonly increased levels include those of 2-ethylhydracrylic acid, aconitate, fumarate, and 2-ketoglutarate. Especially in the newborn period or with fasting during an acute illness, a dicarboxylic aciduria suggesting a long-chain fatty acid oxidation defect may be found. In most cases, the timing of collection of a urine sample for diagnostic purposes is not important, apart from the usual recommendation to collect the urine sample after overnight fasting or during the daytime just before the next meal (ideally with at least 4 hours fasting between meals or feedings). Urine samples collected during a clinical “crisis” can be informative, but often are more difficult to interpret. As with 3MGC analysis, urinary organic acid analysis should be done quantitatively; which is not routine practice in all organic acid laboratories. Furthermore, not all laboratories report levels of citric acid cycle intermediates, most of which are considered normal urinary constituents.

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