X-linked cardioskeletal myopathy and neutropenia (Barth syndrome) (MIM 302060).

X-linked cardioskeletal myopathy, neutropenia and abnormal mitochondria (MIM 302060) (synonyms: Barth syndrome, 3-methylglutaconic acid-uria type II, endocardial fibroelastosis type 2) has been reported in patients and families from Europe, North America and Australia. Previous studies characterized the main components of the disease: dilated cardiomyopathy, skeletal myopathy, neutropenia, 3-methylglutaconic aciduria and diminished statural growth. Respiratory chain impairments have been found in several studies, without pinpointing a single enzyme complex. 3-Methylglutaconic aciduria is shared with several other disorders that affect the respiratory chain. Previous studies excluded a block in the major pathway of leucine catabolism. We performed leucine loading, accompanied by fasting, in patients and observed a significant rise of 3-methylglutaconic acid and 3-methylglutaric acid. Taken together with the absence of an enzymatic block in the major leucine catabolic route, the possibility remains that the increased basal excretion of 3-methylglutaconic acid and other products of branched-chain amino acids is the result of overload of this pathway or--more likely--mitochondrial leakage. Linkage studies have localized the gene to the Xq28 region. The associated tafazzin gene (TAZ), has been fully characterized recently, and mutations located in conserved regions have been reported. Carrier detection and prenatal diagnosis have now become possible through mutation analysis. Sequence homology of the TAZ gene to a highly conserved superclass of acyltransferases (Neuwald's hypothesis) predicts a glycerophospholipid as the missing end product. This points to the (lipid) structure of the inner mitochondrial membrane as a promising new area of research.