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At a glance

A genetic mitochondrial disorder with cardiomyopathy, neutropenia, skeletal myopathy with muscle weakness, 3-methylglutaconic aciduria, growth retardation, and respiratory chain dysfunction.

Synonyms

Fatal Infantile X-Linked Cardiomyopathy; X-linked Cardioskeletal Myopathy, Neutropenia Syndrome; Cardioskeletal Myopathy with Neutropenia and Abnormal Mitochondria; Cardioskeletal Myopathy-Neutropenia Syndrome; 3-Beta Methylglutaconic Aciduria, Type II.

History

First described by the Dutch physician Peter G. Barth and colleagues in 1983.

Incidence

BTHS affects approximately 1 in 140,000 (UK) to 400,000 (USA) individuals worldwide. Approximately 500 cases have been described in the scientific literature. Families from various parts of the world have been described. Due to its phenotypic heterogeneity BTHS may be under-diagnosed. Some experts advise that all boys with unexplained dilated cardiomyopathy should be investigated for BTHS, particularly those presenting already within the first year of life.

Genetic inheritance

The syndrome is transmitted in an X-linked recessive mode, and heterozygous females are usually healthy carriers because of skewed X-chromosome inactivation. In less than 20% of affected boys the mutation cannot be identified in maternal somatic DNA and are hence considered de novo mutations. BTHS is caused by mutations in the TAZ gene (also known as G4.5) on chromosome Xq28 that encodes for Tafazzin, an ubiquitous mitochondrial acyltransferase involved in the biogenesis of cardiolipin. Cardiolipin is a diglycerol phospholipid that is almost exclusively found in mitochondrial membranes (and peroxisomes), particularly in the inner membrane, where it is involved in numerous mitochondrial processes including mitochondrial electron transport chain, energy conversion, cellular signaling, and apoptotic pathways. Dysfunctions related to cardiolipin have been linked to several cardiac disorders.

Pathophysiology

Electron microscopic examination reveals abnormal mitochondria in the myocardium, skeletal muscles, liver, kidneys, and myelocytes. Diminished cytochrome concentrations have been demonstrated in isolated mitochondria, presumably associated with defects in the respiratory chain reaction. The respiratory chain provides 90% of the cardiac energy and the dysfunction in BTHS mainly affects mitochondrial complexes I, III, and IV. Under normal conditions, fatty acids are the main carbon source for cardiomyocytes. A loss of succinate dehydrogenase in cardiomyocytes, an enzyme linking the respiratory chain with the tricarboxylic acid cycle, was recently described in BTHS. Neutropenia results from arrested granulopoiesis at the myelocyte stage (as seen on bone marrow aspiration).

Diagnosis

Based on the clinical picture, family history, muscle biopsy, and genetic analysis. Elevated urinary levels of 3-methylglutaconate (5- to 20-fold increase), 3-methylglutarate, and 2-ethylhydracrylate confirm the clinical diagnosis. In addition, the elevated monolysocardiolipin/cardiolipin ratio and tafazzin gene sequencing can also be used. Decreased plasma arginine levels have been described in some patients and it was hypothesized that arginine depletion might be associated with growth retardation. Hence, arginine supplementation could be beneficial in the treatment of growth retardation and low muscle mass in BTHS, particularly given the fact that ...

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