Barth syndrome

Colin Steward PhD (Dr. Steward of University of Bristol Medical School has no relevant financial relationships to disclose.)
Katie B Gregory (Ms. Gregory of University of Bristol Medical School has no relevant financial relationships to disclose.)
Gary D Clark MD, editor. (Dr. Clark has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated October 6, 2016; expires October 6, 2019

This article includes discussion of Barth syndrome, X-linked cardioskeletal myopathy and neutropenia, and 3-methylglutaconic aciduria type 2. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 relatively 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. Cardiolipin is a constituent of the inner mitochondrial membrane, 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 3 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. Recent developments include the published experiences from 3 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.

Key points

 

• 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.

Historical note and terminology

In 1983, Barth and colleagues described an extended pedigree with dilated cardiomyopathy, skeletal myopathy, growth retardation, and neutropenia (Barth et al 1983). 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.

Image: Congestive thyroid-related orbitopathy (CT)
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 2 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 (Lurie 2010). 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 (Lindenbaum et al 1973; Hodgson et al 1987). Neustein and colleagues gave detailed descriptions of both altered mitochondrial morphology and dilated cardiomyopathy with X-linked inheritance (Neustein et al 1979). Following the report by Barth and colleagues (Barth et al 1983), additional cases with the clinical triad (cardioskeletal myopathy, neutropenia, and growth retardation) have been described (Gibson et al 1991; Kelley et al 1991; Ades et al 1993; Christodoulou et al 1994). In 1991, a biochemical marker (3-methylglutaconic aciduria) was described (Kelley et al 1991). 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 6 months and 3 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 (Cantlay et al 1999).

There is no common opinion on the origin of the 3-methylglutaconic excretion. However, no enzymatic block has been found in the leucine pathway (Gibson et al 1991). Another organic acid, 2-ethylhydracrylic acid (a derivative from l-isoleucine or l-allylisoleucine), is also elevated in Barth syndrome (Kelley et al 1991). Therefore, 2 metabolites of 2 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 (Christodoulou et al 1994; Bleyl et al 1997; Schmidt et al 2004; Takeda et al 2011). 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 (Wortmann et al 2014). 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 (Bione et al 1996). 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 (Gonzalez 2005). Mutation analysis has shown a variety of mutations causing frameshift deletions, nonsense-, missense-, and splice-site mutations (D'Adamo et al 1997; Johnston et al 1997). No genotype-phenotype correlation has been identified in Barth syndrome (Gaspard and McMaster 2015). This observation is further reinforced by the marked phenotypic variability that occurs between multiple affected members of a single family (Ronvelia et al 2012). 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 (Neuwald 1997). 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 (Vreken et al 2000). 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 tetralinoleyl-cardiolipin in fibroblasts (Vreken et al 2000). 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 (Schlame et al 2002).

Cardiolipin is almost exclusively present in mitochondrial inner membranes. It is tightly associated with various respiratory chain complexes. 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 (Gebert et al 2009). 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 recent surge in knowledge is due to this initiative.

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