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X-linked cardioskeletal myopathy with neutropenia (Barth syndrome) is an X chromosome–linked recessive metabolic disease expressed in the heart (dilated cardiomyopathy) and peripheral blood (neutropenia) and muscular systems (moderate muscle weakness, increased fatigue, and wasting, mainly affecting the extremity musculature). This rare disease is caused by a mutation of the tafazzin gene (TAZ) that encodes an enzyme involved in the remodeling of cardiolipin by the substitution of its 4 acyl groups. Mitochondria rely on cardiolipin for normal performance. A constituent of the inner mitochondrial membrane, cardiolipin is necessary for optimal functioning of the respiratory chain. X-linked cardioskeletal myopathy with neutropenia represents the first and, so far, only documented human disorder with a defect in cardiolipin metabolism. This causes deficient production of mature cardiolipin (L4CL) species and accumulation of excessive amounts of immature monolysocardiolipins (MLCL), leading to a highly skewed MLCL:L4CL ratio. Presentation may be by any of the three main symptoms, including delay in motor milestones due to muscle weakness. Although no causal therapy is available, early and correct diagnosis may prevent life-threatening complications. Developments include the published experiences from three large clinical centers with a dedicated service for patients with Barth syndrome and the first research data on cardiomyocytes in vitro from induced pluripotential stem cells from Barth syndrome patients.
• X-linked cardioskeletal myopathy and neutropenia, commonly known as Barth syndrome (BTHS), is a rare disorder reported in many countries.
• The clinical manifestations range from prenatal death and stillbirth with hydrops to adult cardiomyopathy and mild proximal muscle weakness with moderate disease impact and neutropenia.
• Neutropenia, which is most commonly intermittent and highly unpredictable, can cause moderate or severe bacterial disease.
• Increased excretion of 3-methylglutaconic acid is found in the majority of patients with Barth syndrome, but is not a reliable marker. Diagnosis of Barth syndrome is best achieved via cardiolipin ratio testing or, if this is not available, TAZ gene sequencing.
• The affected TAZ gene encodes tafazzin, an enzyme protein necessary for the last step in the biosynthesis of mature cardiolipin, a vital component of the inner mitochondrial membrane necessary for proper functioning of the respiratory chain.
• The prognosis has improved considerably due to new insights and treatments, but lethality is still high.
In 1983, Barth and colleagues described an extended pedigree with dilated cardiomyopathy, skeletal myopathy, growth retardation, and neutropenia (05). The disorder segregated as an apparent X-linked recessive trait and had a high rate of mortality during infancy and early childhood from either congestive cardiomyopathy or overwhelming bacterial infections. Histologic examination of the heart in patients showed swollen fibers, partial loss of cross striations, central granular material, and bizarre mitochondria with stacked or whorled layers of cristae.
Skeletal muscle had a number of nonspecific histological changes, such as mildly increased fat vacuolization of type 1 fibers; bone marrow aspirates demonstrate maturational arrest of the neutrophil line at the myelocyte level. By enzymatic assay, multiple respiratory chain complexes had moderately diminished activities, but a specific mitochondrial lesion could not be identified. Lactic acidosis with exercise was common, and some children had mildly to moderately decreased plasma levels of carnitine. The neutropenia was severe and variable but not truly cyclical.
Dilated cardiomyopathy was originally known as endocardial fibroelastosis, but the two terms now have separate connotations. The term “endocardial fibroelastosis” describes the pearl-white aspect of the endocardium due to fibrosis as it presents to the pathologist at autopsy. Importantly, endocardial fibroelastosis itself is not a disease, but is instead a secondary reaction to stress placed on the heart. It is not known whether this reaction further impedes cardiac function or constitutes a protective mechanism against further dilation (48). There are several reports of families affected by X-linked endocardial fibroelastosis, which may have been early descriptions of families affected by Barth syndrome, although this cannot be determined as other differential diagnoses exist (47; 35). Neustein and colleagues gave detailed descriptions of both altered mitochondrial morphology and dilated cardiomyopathy with X-linked inheritance (56). Following the report by Barth and colleagues (05), additional cases with the clinical triad (cardioskeletal myopathy, neutropenia, and growth retardation) have been described (30; 44; 04; 18). In 1991, a biochemical marker (3-methylglutaconic aciduria) was described (44). Patients have increased levels of 3-methylglutaconic acid at any age, but the level is especially high (from 20 to 200 times normal) between the ages of six months and three years. However, the severity of the 3-methylglutaconic aciduria appears to be independent of the severity of other features of the disorder, and levels can fluctuate markedly within a single day (16).
There is no common opinion on the origin of the 3-methylglutaconic excretion. However, no enzymatic block has been found in the leucine pathway (30). Another organic acid, 2-ethylhydracrylic acid (a derivative from l-isoleucine or l-allylisoleucine), is also elevated in Barth syndrome (44). Therefore, two metabolites of two different branched chain amino acids are elevated. Although the finding of 3-methylglutaconic aciduria is an important diagnostic, some reports mention its absence in otherwise unequivocal Barth syndrome (18; 10; 74; 85). Wortmann and colleagues compared the results of leucine loading tests on 3-MGA excretion in different inborn errors including Barth syndrome and observed significant increase only in deficiency of 3-methylglutaconyl-CoA hydratase deficiency (97). Leucine loading, therefore, has no added value in patients in whom Barth syndrome is suspected.
In 1996, Bione and colleagues were able to localize and identify the associated gene. This gene, named G4.5 (later renamed by consensus as TAZ gene), had a high level of mRNA expression in cardiac and skeletal muscle (08). Different mRNAs were produced by alternative splicing of the primary transcript. The TAZ protein products were called tafazzins. By 2005, it became clear that the full-length transcript and the transcript lacking exon 5 are the only functional mRNAs (31). Mutation analysis has shown a variety of mutations causing frameshift deletions, nonsense-, missense-, and splice-site mutations (21; 41). No genotype-phenotype correlation has been identified in Barth syndrome (28). This observation is further reinforced by the marked phenotypic variability that occurs between multiple affected members of a single family (67). By combining the search in families variously labeled in the past as X-linked endocardial fibrosis, severe X-linked cardiomyopathy, and Barth syndrome, it was shown that these entities share the defective gene.
The biochemical function of the tafazzins was enigmatic until Neuwald discovered the structure homology of the tafazzins to a superfamily of acyltransferases from prokaryotes and eukaryotes that are active in phospholipid biosynthesis and have acyltransferase activity (57). It was suggested by this author that the various mitochondrial abnormalities encountered in Barth syndrome could be related to an abnormal mitochondrial membrane phospholipid.
Following this lead, Vreken and colleagues discovered an abnormal remodeling of phosphatidylglycerol and cardiolipin using electron spray tandem mass spectroscopy on patient fibroblasts (92). Both lipids were deficient in linoleic acid incorporation. Cardiolipin synthesis was normal, whereas cardiolipin pool size in fibroblasts was diminished. The basic abnormality in Barth syndrome, therefore, is a deficient remodeling of the acyl groups of cardiolipin, leading to a specific deficiency of tetralinoleoyl-cardiolipin in fibroblasts (92). Using a different approach, Schlame and colleagues tested cardiolipin levels in muscle samples from various muscle disorders to study its presence in various disorders, and they found the compound severely deficient in samples from patients with Barth syndrome (73).
Cardiolipin is almost exclusively present in mitochondrial inner membranes. It is tightly associated with various respiratory chain complexes. It serves as a signaling platform, performing vital functions within mitochondria. This is especially valuable in the heart, given its attendant demand for high energy (26; 76). This finding well explains the multiple respiratory chain dysfunctions in Barth syndrome, and offered the first specific in vitro test apart from the mutation analysis of the TAZ gene. Findings indicate an additional role for cardiolipin interacting with the protein import at the outer mitochondrial membrane (29). Barth syndrome is the first known mitochondrial disorder with an abnormality in cardiolipin metabolism.
Families with Barth syndrome from all over the world have formed an association known as the Barth Syndrome Foundation, with the object of organizing family meetings and stimulating clinical research in Barth syndrome. Much of the surge in knowledge is due to this initiative.
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